Ownership of Human Tissues and Cells

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New Developments in Biotechnology: Ownership of Human Tissues and Cells

March 1987

NTIS order #PB87-207536 Recommended Citation: U.S. Congress, Office of Technology Assessment, New Developments in Biotechnology: Ownership of Human Tissues and Cells—Special Report, OTA-BA-337 (Washington, DC: U.S. Government Printing Office, March 1987).

Library of Congress Catalog Card Number 87-619804

For sale by the Superintendent of Documents U.S. Government Printing Office, Washington, DC 20402-9325 Foreword

In the 1960s, the term “biotechnology” did not exist. In the 1970s, development of techniques for: 1) splicing genetic information of one organism into that of another, and 2) fusing cells to produce large quantities of valuable proteins led to recognition that a revolution in biological technology—that is, biotechnology—was at hand. In the 1980s, biotechnology is best viewed as a growing cohort of technologies, each with its own scientific benefits and risks, and allied social, economic, legal, and ethical issues. In this special report, OTA analyzes the economic, legal, and ethical rights of the human sources of tissues and cells and also those of the physicians or researchers who obtain and develop these biological materials. The study describes the potential of three rapidly moving technologies (tissue and cell culture, cell fusion to produce monoclinal antibodies, and recombinant DNA) for manipulating human tissues and cells to yield commercially valuable products. The report includes a range of options for congressional action related to commercialization of human biological materials, regulation of research with human subjects, and disclosure of physicians’ commercial interest in patient treatment. This special report is the first in a series of OTA studies being carried out under an assessment of "New Developments in Biotechnology. ” Forthcoming reports wrill include evaluations of: U.S. investment in biotechnology; public attitudes toward biotechnology; genetic and ecological issues in the environmental release of genetically engineered organisms; and the impact of intellectual property law on biotechnology. The assessment was requested by the House Committee on Science and Technology and the House Committee on Energy and Commerce. OTA was assisted in preparing this study by an advisory panel, a workshop group, and reviewers selected for their expertise and diverse points of view on the issues covered in the report. OTA gratefully acknowledges the contribution of each of these individuals. As with all OTA reports, responsibility for the content of the special report is OTA alone. The special report does not necessarily constitute the consensus or en- dorsement of the advisory panel, the workshop group, or the Technology Assessment Board.

Director

. . Ill New Developments in Biotechnology Advisory Panel

Bernadine P. Healy, Panel Chair The Cleveland Clinic Foundation Cleveland, OH Timothy B. Atkeson Sheldon Krimsky Steptoe & Johnson Tufts University Washington, DC Medford, MA David Blumenthal Joshua Lederberg Brigham and Women’s Hospital Corp. The Rockefeller University Boston, MA New York, NY Hon. Edmund G. Brown, Jr. William E. Marshall Reavis & McGrath Pioneer Hi-Bred International, Inc. Los Angeles, CA Johnston, IA Nancy L. Buc Ronald L. Meeusen Weil, Gotshal & Manges Rohm and Haas Company Washington, DC Spring House, PA Mark F. Cantley Robert B. Nicholas Concertation Unit for Biotechnology in Europe Blum, Nash & Railsback Brussels, Belgium Washington, DC Alexander M. Capron Eric J. Stanbridge University of Southern California University of California, Irvine Los Angeles, CA Irvine, CA Jerry D. Caulder James M. Tiedje Mycogen Corporation Michigan State University San Diego, CA East Lansing, MI Lawrence I. Gilbert Kunio Toriyama The University of North Carolina ZEN-NOH Chapel Hill, NC Tokyo, Japan Conrad A. Istock Pablo D.T. Valenzuela The University of Arizona Chiron Corporation Tucson, AZ Emeryviile, CA Edward L. Korwek Thomas E. Wagner Keller and Heckman Ohio University Washington, DC Athens, OH Tsune Kosuge Luther S. Williams University of California, Davis Atlanta University Davis, CA Atlanta, GA Richard Krasnow Resources for the Future Washington, DC

NOTE: OTA appreciates and is grateful for the valuable assistance and thoughtful critiques provided by the panel members. The panel members do not, however, necessarily approve, disapprove, or endorse this report. OTA assumes full responsibility for the report and the accuracy of its contents. iv Ownership of Human Tissues and Cells—OTA Project Staff

Roger C. Herdman, OTA Assistant Director Health and Life Sciences Division

Gretchen S. Kolsrud, Biological Applications Program Manager

Gary B. Ellis, Project Director

Gladys B. White, Study Director and Analyst

Lisa J. Raines, Study Director and Legal Analyst Robyn Y. Nishimi, Analyst Kevin W. O’Connor, Legal Analyst

Support Staff Sharon Kay Oatman, Administrative Assistant Linda S. Ray ford, Secretary/Word Processing Specialist Barbara V. Ketchum, Clerical Assistant

Editor Chris Elfring, Takoma Park, MD

Outside Contributors James F. Childress, University of Virginia Iver P. Cooper, Mackler, Cooper and Marx Jeffrey N. Gibbs, Mackler, Cooper and Marx Bruce G. Goodman, Damon Corporation Warren Greenberg, George Washington University Rosemary Gibson Kern, American Enterprise Institute Patricia A. King, Georgetown University Gilah Langner, ICF, Inc. Robert J. Levine, Yale University Mark J. Minasi, Moulton & Minasi Thomas H. Murray, University of Texas Medical Branch, Galveston Fay A. Rozovsky, Halifax, Nova Scotia Emanuel Thorne, Washington, DC Allen B. Wagner, Berkeley, CA

Acknowledgment to Other OTA Staff Clyde J. Behney, Health Program, Manager R. Alta Charo, Legal Analyst Kathi E. Hanna, Analyst Jane E. Sisk, Senior Associate —

New Developments in Biotechnology Working Group on Ownership of Human Tissues and Cells

LeRoy Walters, Working Group Chair Georgetown University Washington, DC Thomas L. Beauchamp Barbara Mishkin Georgetown University Hogan & Hartson Washington, DC Washington, DC Bruce G. Goodman Thomas H. Murray Damon Corporation University of Texas Medical Branch Needham Heights, MA Galveston, TX Geoffrey M. Karny Joseph G. Perpich Finnegan, Henderson, Farabow, Garrett and Meloy Laboratories, Inc. Dunner Springfield, VA Washington, DC Patricia A. King Ivor Royston Georgetown University Law Center University of California, San Diego Washington, DC San Diego, CA Robert J. Levine Herbert F. Schwartz Yale University School of Medicine Fish & Neave New Haven, CT New York, NY Charles R. McCarthy Howard S. Schwartz National Institutes of Heal th Jewish General Hospital Bethesda, MD Montreal, Quebec

OTA is grateful for the valuable assistance and thoughtful critiques provided by the Working Group members. The views expressed in this OTA report, however, are the sole responsibility of the Office of Technology Assessment. Contents

Chapter 1. Summary, Policy Issues, and Options for Congressional Action ...... 3 2. Introduction ...... 23 3. The Technologies ...... 31 4. The Interested Parties ...... 49 5. Legal Considerations ...... 69 6. Informed Consent and Disclosure...... 93 7. Economic Considerations ...... 115 8. Ethical Considerations ...... , ...... 129

Appendix A. Code of Federal Regulations, Part 46, Subpart A ...... 147 B. Acknowledgments ...... 155 C. Glossary...... 156 Index ...... 161

vii chapter 1 Summary, Policy Issues, and Options for Congressional Action —

CONTENTS

Human Biological Materials: Questions for the Future ...... 3 Definitions ...... 3 The Problem of Uncertainty ...... 4 The Technologies ...... 5 Tissue and Cell Culture Technology ...... 5 Hybridoma Technology ...... 5 Recombinant DNA Technology ...... 5 The Interested Parties ...... 7 Commercial Interest in Human Biological Research and Inventions 7 Sources of Human Tissue...... 7 The Research Community ...... 8 Industry ...... 8 Legal Considerations ...... 9 Can Human Biological Materials Be Sold Like Property? ...... 9 Informed Consent and Disclosure ...... 10 Consent and the Prospect of Commercial Gain ...... 10 Are Changes Needed in the Consent Process?...... 11 Economic Considerations...... 11 Equity of Production and Distribution ...... 12 Added C:osts...... 12 Resolving the Payment Dilemma ...... 13 Ethical Considerations ...... 13 The Moral Status of Bodies and Their Parts ...... 13 Tomorrow’s Choices ...... 15 Policy Issues and Options for Congressional Action...... 15

Tables Table No. l. Human Biological Materials: Many Questions, Few Definitive Answers ...... 3 2. Possible Sources of Rights Relating to Human Biological Materials ...... 9

Figure Figure No. Page l. The Genetic Engineering of Human Cells ...... 6

Boxes Box No. Page A. The Hagiwara Case: An Example of a Dispute Over Human Biological Materials ...... 4 B. A Hypothetical Case Study: How the Relationship Between Doctor and Patient Might Change ...... 14 Chapter 1 Summary, Policy Issues, and Options for Congressional Action

HUMAN BIOLOGICAL MATERIALS: QUESTIONS FOR THE FUTURE

New developments in biotechnology hold great Table 1 .—Human Biological Materials: promise for advancing knowledge about various Many Questions, Few Definitive Answers life forms and improving human health. But with ● Are bodily substances “property” to be disposed of by any this promise come greater responsibilities for sci- means one chooses, including donation or sale? entists and policymakers. Human biological ma- ● Do property rights to their genetic identity adhere to in- terials—tissues and cells—can be used to develop dividuals or to the species? commercial products (e.g., hybridomas and cul- ● Who should make the basic decisions affecting the acqui- tured cell lines]), and for diagnostic and thera- sition of tissues and cells, and under what circumstances should such acquisition be permitted or denied? peutic purposes. The use of human biological ma- ● What are patients and research subjects entitled to know terials for therapy, research, and profit raises about the potential for commercial exploitation of an in- important legal, ethical, and economic issues (see vention that uses their bodily materials? And what is the table 1). probability that an individual’s tissues and cells will end up in a commercial product? Many of these issues are similar to those that ● How is it that inventions incorporating human cells are have been raised concerning human organ dona- patentable in the first place? How similar is the invention to the original biological material? tion, which is currently regulated as a result of ● What is the nature of the researcher’s contribution versus the Uniform Anatomical Gift Act (National Con- the source’s contribution to the invention? ference of Commissioners on Uniform State Laws, ● Who should profit from federally funded research using 1968) and the 1984 National Organ Transplant Act human tissue? To what extent are the issues raised by ownership of human biological materials related to com- (Public Law 98-507). But the use of human tissues mercial relationships between universities and companies? and cells in biotechnology raises questions that ● What are the implications of these issues for scientists, have not been answered in previous public pol- physicians, patients, volunteer research subjects, univer- icy deliberations concerning the acquisition of hu- sities, and the biomedical product industry? man organs, Who owns a cell line-the human SOURCE: Office of Technology Assessment, 1987 source of the original tissues and cells or the scientist who developed the cell line? Should biological materials be sold, and if so, what are Definitions the implications for equity of distribution? Should disclosure, informed consent, and reg- Human bodies contain a number of elements ulatory requirements be modified to cope with that are useful in biomedical research. Healthy the new questions raised by the increased im- people continually produce a variety of replenish- portance and value of human biological mate- able substances, including blood, skin, bone mar- rials? There are no easy answers. These issues row, hair, urine, perspiration, saliva, milk, semen, are novel and complex, and no single body of law, and tears. Human bodies also contain nonreplen- policy, or ethics applies directly. ishing parts, such as organs or oocytes. Organs may be either vital (e.g., heart) or to some extent expendable (e.g., lymph nodes or a second kid- ‘A hybridoma is a hybrid cell resulting from the fusion of a particular type of immortal tumor cell line, a myeloma, with an anti- ney). Finally, the body can also have diseased parts. body producing B lymphocyte. Cultures of such cells are capable While this report refers to all human parts- of continuous growth and specific, monoclinal antibody produc- replenishing and nonreplenishing, living and tion. A cell line is a sample of cells, having undergone the process of adaptation to artificial laboratory cultivation, that is now capable nonliving beneficial and detrimental—collec- of sustaining continuous, long-term growth in culture. tively as human biological materials, it focuses

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4 ● Owmership of Human Tissues and Cells

The Problem of Uncertainty

At present, there is great uncertainty about how courts will resolve disputes between the human sources of specimens and specimen users. This could be detrimental to both academic researchers and the nascent biotechnology industry, particularly if the rights of a human source are asserted long after the specimen was obtained. The assertion of rights by human sources would affect not only the researcher who obtained the original specimen, but other researchers as well because biological materials are routinely distributed to other researchers for experimental purposes. Thus, scientists who obtain cell lines or other specimen-derivative products (e.g., gene clones) from the original researcher might also be sued. Furthermore, because inventions containing biological materials can be patented and licensed for commercial use, companies are unlikely to invest in developing, manufacturing, or marketing a product when uncertainty about clear title exists. This uncertainty about the rights of specimen sources and specimen users could have far-reaching implications as research and development progresses. Research using human biological materials could be thwarted if universities and companies have difficulty obtaining title insurance covering ownership of cell lines or gene clones, or liability insurance. Insurers would be concerned not only with suits by individuals who can be identified as the sources of specimens, but also by the potential for class action lawsuits on behalf of all those who contributed specimens to a particular research project. Researchers generally claim that the pervasive use of human cells and tissues in biomedical research makes it impractical and inefficient to try to identify the sources of various specimens or to try to value their contributions. Regardless of the merit of these claims, however, resolving the current uncertainty may be more important to the future of biotechnology than resolving it in any particular way. Ch. l—Summary, Policy Issues, and Options for Congressional Action 5

THE TECHNOLOGIES

Three broad classes of basic biological tech- knowledge about cell biology and set the stage niques are of particular relevance to this report. for the development of hybridoma technology. They are tissue and cell culture technology, hybridoma technology, and recombinant DNA Hybridoma Technology technology. In response to foreign substances, the body Tissue and Cell Culture Technology produces a constellation of different substances. Antibodies are one component of the immune re- Cells are the basic structural unit of living organ- sponse and they have a unique ability to identify isms. A single cell is a complex collection of specific molecules. Lymphokines, sometimes called molecules with integrated functions forming a self- bioregulators, are also produced during an im- assembling, self -regulating entity. There are two mune response. broad classes of cells: prokaryotic and eukaryotic. Cell culture technology provides the tools sci- Prokaryotes, generally considered to be the simpler entists need to produce pure, highly specific an- of the two classes, include bacteria. Their genetic tibodies. By fusing two types of cells-an antibody- material is not housed in a separate structure (a producing B lymphocyte with a certain tumor cell nucleus) and the majority of prokaryotic organ- line (a myeloma)–scientists found that the result- isms are unicellular. Eukaryotes are usually mul- ing immortal hybrid cells, called hybridomas, se- ticellular organisms; they contain a nucleus and crete large amounts of homogeneous (or mono- other specialized structures to coordinate differ- clinal) antibodies, Monoclinal antibodies have led ent cell functions. Human beings are eukaryotes. to a greater understanding of the intricacies of Because eukaryotes are complex, scientists often the immune response and they have become pow- study these organisms by examining isolated cells erful and widely used laboratory tools. They also independent of the whole organism. This reduc- have been approved for use as therapeutic agents. tionist approach, called tissue and cell culture, is Although the production of human mono- an essential technique for the study of human bio- clonal antibodies has proven much more diffi- logical materials and the development of related cult than the production of rodent monoclinal biotechnologies. Establishing human cell cul- antibodies, the increasing availability of large ture directly from human tissue is a relatively supplies of monoclinal antibodies is revolu- difficult enterprise and the probability of es- tionizing research, commerce, and medicine. tablishing a cell line from a given sample Lymphokines (e.g., interferon) were previously varies, ranging from 0.01 percent for some available in minute and usually impure amounts— liver cells to nearly 100 percent for some hu- if at all. Hybridoma, cell culture, and recombinant man skin cells. DNA technologies now permit lymphokines to be Cell cultures isolated from nontumor tissue have isolated in pure form and in quantities facilitat- a finite lifespan in the laboratory and most will ing further analysis or use. The increased pro- die after a limited number of population doublings. duction and availability of these molecules has sig- These cultures will age (called senescence) unless nificant therapeutic promise in the treatment of pushed into immortality by outside interventions a spectrum of diseases because of their exquisite involving viruses or chemicals. The type of donor specificity and reduced toxicity. tissue involved and culture conditions are important variables of cell lifespan. Long-term growth Recombinant DNA Technology of human cells and tissues is difficult, often an art. Most established cell cultures have been de- Recombinant DNA technology, also referred to rived from malignant tissue samples. Tissue and as genetic engineering, involves the direct manipu- cell culture techniques have greatly increased lation of the genetic material (the DNA) of a cell. 6 ● Ownership of Human Tissues and Cells

mation. It is an important tool that accelerates the study or production of genes. All recombinant DNA methods require the following: ● a suitable vector to move DNA into the host cell, ● an appropriate host, ● a system to select and cull host cells that have received recombinant DNA, and ● a probe to detect the particular recombinant organisms of interest. Recombinant DNA techniques have done much to illuminate the regulation and control of important human processes. In addition, advances in this technology underlie many commercial ventures to isolate or manufacture large quantities of scarce biological commodities.

Figure 1 .-The Genetic Engineering of Human Cells Retrovirus Human Cell with Functional Gene

DNA Equivalent of Retroviral RNA with Major Genes Deleted DNA Segment Containing \ Functional Gene

Recombinant Retrovirus

+ Bone Marrow Cell with Defective Gene

Bone Marrow Cell Containing Functional Gene

SOURCE: Steve Olson, Biofechno/ogy: An /rrdustry Comes of Age, prepared for the Academy Industry Program of the National Academy of Sciences/National Academy of Engineering/Institute of Medicine (Washington, DC” National Academy Press, 1986) Ch. l—Summary, Policy Issues, and Options for Congressional Action “ 7

THE INTERESTED PARTIES

Although tissues and cells can be used for di- search remained unexploited. To resolve this prob- agnostic, therapeutic, research, and commercial lem, Congress passed the Patent and Trademark purposes, in fact the various uses of biological ma- Amendment Act in 1980 to prompt efforts to terials are usually intertwined, sometimes inex- develop a uniform patent policy that would en- tricably. This means that a variety of people, in- courage cooperative relationships between univer- cluding scientists in the research community sities and industry, and ultimately take govern- (universities and industry), plus physicians, ment-sponsored inventions off the shelf and into and patient and nonpatient sources, share an the marketplace. interest in the acquisition and use of human The changing legal climate has provided a fer- tissues and cells. All would likely benefit from a resolution of the uncertainty surrounding the tile medium for the growth of university biomedical research and development using novel biotech- uses of biotechnology. nologies. From 1980 through 1984, patent applications by universities and hospitals for Commercial Interest in Human inventions containing human biological in- Biological Research and Inventions creased more than 300 percent (compared to the preceding 5-year period). The extent to The government has always maintained an in- which these and forthcoming patents will be terest in the legal, ethical, and economic implica- of commercial value is difficult to assess. tions of the research it is funding, and this interest is magnified when such research might result in inventions that are patentable under Federal Sources of Human Tissue law. In addition to advances in technology, two There are three major sources of specimens: events occurred in 1980 to precipitate the in- patients, healthy research subjects, and cadavers. creasing research and commercial interest in human biological materials. First, the U.S. Su- ● Patients are a source of both normal and atyp- preme Court held for the first time that Fed- ical specimens and these individuals may or eral patent law applies to new life forms cre- may not be research subjects. Patient-derived ated by DNA recombinations-opening up the specimens may be “leftovers” obtained from possibility that products containing altered diagnostic or therapeutic procedures and human cells and genes might also be patenta- most human tissues or cells that find their ble. Second, Congress amended the patent stat- way into research protocols are of this type. ute to encourage patenting and licensing of Patient-derived samples can also be provided inventions resulting from government-spon- as part of a research protocol. sored research (Public Law 96%17). ● Healthy volunteer research subjects may donate replenishing biological if specimen Even though the government is the primary removal involves little or no risk of harm, source of funding for basic biomedical research, according to generally accepted principles of no single patent policy existed for government- human subject research. supported research until 1980. Instead, each ● Cadavers are the only permissible source of agency developed its own rules, resulting in 26 normal and atypical-vital organs (including different patent policies. Under this system, only the brain, heart, and liver, but excluding kid- about 4 percent of some 30,000 government- neys and corneas). They are also the only per- owned patents were licensed. Furthermore, the missible source of healthy benign organs (e.g., government policy of granting nonexclusive li- corneas) destined for research rather than censes discouraged private investment, since a transplantation, company lacking an exclusive license is reluctant to pay the cost of developing, producing, and mar- While these donor classifications may seem fairly keting a product. Thus, potentially valuable re- straightforward, the human relationships involved 8 ● Ownership of Human Tissues and Cells

are more dynamic than these categories suggest. sider these issues and the possible roles of the In particular, the physician-patient relationship interested parties now, in advance of their becom- may change over the course of time into a re- ing highly visible, so that public policy perspec- searcher-subject relationship. tives can be developed with wisdom and foresight. The Research Community Industry Research uses of human tissue are diverse and difficult to categorize. Generally, researchers are The biotechnology industry is a major interested studying the characteristics and functions of party in the controversy surrounding the use of healthy and diseased organs, tissues, and cells. human tissues and cells for financial gain. It is Commercial products developed from human comprised of a variety of different types of orga- specimens are usually related to medical or re- nizations including the established pharmaceuti- search uses. The use of human biological is wide- cal companies, oil and chemical companies, agri- spread; a recent survey conducted by the House cultural product manufacturers, and the new Committee on Science and Technology found that biotechnology companies. Of the nearly 350 com- 49 percent of the researchers at the medical in- mercial biotechnology firms in the United States stitutions surveyed used patients’ tissues or fluid actively engaged in biotechnology research and in their research. commercial product development, approximately 25 to 30 percent are engaged in research to de- The revolutionizing effect of biotechnology on velop a human therapeutic or diagnostic reagent. the use of human specimens is principally due to There is a strong international component to the three factors: biotechnology industry, with numerous research ● isolation of increasingly smaller amounts of and development arrangements and partnerships important naturally occurring human biologi- between American firms and firms in Japan and cal factors (also known as biopharmaceuti- Europe. cals, bioresponse modulators, or biological mediators); ● production of virtually unlimited quantities of these factors (usually found in the body in only small amounts) using recombinant DNA methods; and ● discovery of techniques to create hybridomas, making it possible to generate large, pure supplies of specific antibodies. At the most fundamental scientific level, human material is a source for studies designed to understand basic biological processes. From this basic research, commercial development may follow. However, the probability that any one person’s biological materials will be developed into a valuable product is exceedingly small. Thus, the issue of great potential commercial gain from donated materials is relevant to a small minority of sources. However, in the future— as biotechnology progresses—the importance of the issue and the number of people involved could increase. The potential for commercial gain, while Photo credit: U.S. Department of Agriculture to date mostly a speculative consideration, could Researcher withdraws a cell line sample quickly become a reality. It is appropriate to con- from a freezing device. Ch. l—Summary, Policy Issues, and Options for Congressional Action ● 9

LEGAL CONSIDERATIONS

United States law has long protected people Table 2.—Possible Sources of Rights Relating to from injury and damages. Much of this protec- Human Biological Materials tion is afforded by the common law, the body of Law of Patents judge-made law built on judicial precedents. This Law of Cadavers and Autopsies body of legal principles has evolved over centu- Property rights in corpses Emotional distress caused by wrongful acts toward cadavers ries as judges are called on to resolve disputes that Law of Organ Transplantation have not been addressed by statute. Congress and Donation of organs for transplantation State legislatures, however, have enacted numer- Sale of organs for transplantation Law of Blood and Semen Sales ous statutes to codify, modify, or overrule the com- Sale of blood and semen mon law, or to address larger societal issues that Product liability generally are inaccessible through the use of common law. Implied warranties under the Uniform Commercial Code Specific performance under the Uniform Commercial Code The common law does not provide any de- Blood as a product for tax law purposes Law of Copyright finitive answer to the questions of rights that Law of Trade Secrets arise when a patient or nonpatient source sup Law of Conversion and Trespass to Chattel plies biological materials to an academic or Property interest Possession commercial researcher. Because neither judicial Injury to plaintiff precedents nor statutes directly address this ques- Abandonment tion, the court must do what common law judges Res Nullius Law of Accession have done for centuries: reason by analogy, using Cases involving crops legal principles and precedent developed for other Specification circumstances. SOURCE: Office of Technology Assessment, 1987. Three large collections of legal principles could prove relevant to the use of human tissues and cells: property law, tort law, and contract law. These three areas include a broad va- any law prohibit the use or sale of human bodily riety of statutes and precedents that might be substances by the living person who generates relevant and thus this issue could arguably touch them or one who acquires them from such a per- almost all facets of U.S. law (see table 2). Overall, son, except under certain circumstances unrelated however, there is no discrete body of law that to biotechnology research. In the absence of deals specifically with these human biological clear legal restrictions, the sale of tissues and materials. Because common law reacts to cells is generally permissible unless the cir- damages only after they have occurred, it does cumstances surrounding the sale suggest a sig- not anticipate possible interests that have not ex- nificant threat to individual or public health, isted previously. In the area of the use of human or strong offense to public sensibility. To date, tissues and cells, technology in fact has advanced neither deleterious health effects nor public moral beyond existing law. It is not possible to predict outrage have occurred even though occasional what principles and arguments of law might ac- reports of sales of replenishing cells have been tually be used as cases of this sort come before publicized. But while the law permits the sale of the courts. such replenishing cells as blood and semen, it does not endorse such transactions and does not char- Can Human Biological Materials acterize such transactions as involving property. Be Sold Like Property? In this sense, either permitting or forbidding the sale of human specimens by patients and No area of law clearly provides ownership rights research subjects can be claimed to be consist- with respect to human tissues and cells. Nor does ent with existing law. 10 “ Ownership of Human Tissues and Cells

INFORMED CONSENT AND DISCLOSURE

Every human being of adult years and sound of human subjects, The success of these regula- mind has a right to determine what shall be done tions in achieving this balance is in no small meas- with his own body . . . ure a function of the integrity of investigators and –Scholendorff v. Society of New York Hospital, 1914 the diligence of institutional review boards, which review proposed research projects for compliance The fundamental principle underlying the need with human subject research regulations. for consent for medical or research purposes is respect for personal autonomy. Consent is a process of communication, a two-way flow of infor- Consent and the Prospect of mation between caregiver/researcher and pa- Commercial Gain tient/subject about the risks and benefits of the treatment or research. The traditional view has been that in therapeutic settings, information disclosed to patients For consent to be valid, the patient or research should be related to the risks and benefits of diag- subject must be given an adequate amount of in- nostic tests or treatment, and that it should information with which to reach a reasoned choice. clude alternative procedures. Similarly, in the re- Although there are differences from State to State, search setting the disclosure of information has the information that generally needs to be dis- focused on the nature of the study and its effects closed to obtain consent focuses on the nature on subjects. Until recently, little thought had and purpose of the treatment or research, risk- been given to disclosing information about the benefit information, and the availability of bene- prospect for commercial gain, but with the ad- ficial, alternative procedures or treatment. Con- vent of biotechnology and its potential use of sent in a research setting, like consent in a tradi- human tissues and cells in valuable products, tional treatment context, must be obtained in this issue merits consideration. circumstances free from the prospect of coercion or undue influence. Arguments can be made both for and against the idea of including information about potential There are two main sources of Federal regula- financial gain in the required disclosure of infor- tions governing human research. The Department mation to patients and research subjects. of Health and Human Services (DHHS) and the Food and Drug Administration (FDA) have promul- Arguments Favoring Disclosure of gated regulations that delineate the elements nec- Potential Commercial Gain essary for informed consent to research. DHHS regulations govern research conducted or funded If the notion of personal autonomy and the right by DHHS, including the National Institutes of to decide what will be done with one’s body is Health. FDA regulations govern clinical investi- to be given full legal recognition, then the pros- gations that support applications for research or pect of commercial gain should be disclosed be- marketing permits for products such as drugs, cause this information may help a person decide food additives, medical devices, and biological whether or not to take part in research. Indeed, products. Where these Federal regulations apply, the overall trend has been toward greater disclo- disclosure requirements go beyond the accepted sure of information-details about the probable norms and include disclosure regarding confiden- impact of a procedure on lifestyle, the financial tiality, compensation for research-related injuries, costs of one procedure over another, even the and the right to withdraw from research with- length of disability. Requiring disclosure about out incurring a penalty or loss of rights. commercial gain can be viewed as a logical extension of the consent process. These Federal regulations are a deliberate attempt to set ethical and legal constraints on hu- In fact, it can be argued that the Federal regu- man research. A balance has been struck between lations should explicitly require disclosure of po- the needs of researchers and the rights and safety tential commercial gain because they require dis- Ch. l—Summary, Policy Issues, and Options for Congressional Action ● 11 closure of “significant new findings developed in research specifically because they might profit during the course of the research that may relate financially. Some people thus might argue that to the subject’s willingness to continue participa- banning reference to the prospect of financial gain tion. ” Discovery of a commercially significant tis- is necessary to safeguard subjects from undue in- sue or cell in a subject’s body may constitute a fluence on their decisions. “significant new finding. ” Are Changes Needed in the Arguments Against Disclosure of Consent Process? Potential Commercial Gain The question of disclosing potential commer- The primary argument against disclosing the cial gain related to diagnostic tests or treatment prospect of commercial gain concerns the impact is one the courts or State legislatures will need such information might have on the subject’s abil- to address. However, the Federal Government ity to reach an informed choice free of undue in- funds substantial amounts of human research and fluence. The prospect of financial gain stemming will also need to consider its regulations in light from marketable discoveries could hamper sub- of this debate. Policymakers, institutional rejects from reaching informed decisions because view boards, and researchers face these ques- attention to this highly speculative topic could dis- tions related to disclosure: Should potential tract attention from other important aspects of commercial gain be disclosed? If so, what per- the consent process. tinent information is necessary? When is such Disclosing information about commercial gain disclosure best made? What safeguards need could sometimes jeopardize the health and safety to be developed to minimize any detrimental of subjects, as well as the validity of the research impacts resulting from disclosure of probable itself. The hope of gain, for example, might lead commercial gain? subjects to give less than candid answers to questions about medical or personal history that might The prospect of financial gain is a troublesome otherwise disqualify them from the study. It might issue in terms of voluntary consent and the use encourage them to expose themselves to risks they of human biological materials. It can be argued would otherwise consider unacceptable. In addi- that to assure truly voluntary consent, re- tion, because disclosure of potential gain is so search subjects should not be offered compen- speculative, such disclosure could generate un- sation for their time and inconvenience, let reasonable expectations or be considered misin- alone substantial financial gain. The counter formation. argument is that the sources of human tissues and cells have rights or interests in marketa- It can also be argued that Federal human re- ble substances taken or developed from their search regulations embody a philosophy that bans bodies and so have a right to know about po- participation for inappropriate reasons. DHHS reg- tential profits or to be paid outright for their ulations, for example, make it clear that parole tissues and cells. Regardless of what decision is boards should not consider participation when reached, care must be taken so research is not making prisoners’ parole decisions. DHHS might adversely affected because it becomes too com- consider it improper for subjects to participate plicated to get specimens.

ECONOMIC CONSIDERATIONS

The traditional relationships between donors mation and biological materials have been ex- and researchers, and among researchers at differ- changed freely. Today, however, the techniques ent institutions, have been informal; both infor- of biotechnology and the potential for profits and .

12 . Ownership of Human Tissues and Cells scientific recognition have introduced new con- Equity of Production and cerns, At present, there is no widespread senti- Distribution ment favoring a move toward a market system for the exchange of human tissues and cells. How- The equity of a system can be considered from ever, a few types of materials, such as plasma and both the production and distribution sides. On the some patented cell lines, are currently transferred production side, one issue to consider is whether within a market system. Future changes in the any of the participants are not receiving an equi- extent of profits generated from the biotechnol- table return for their services or products. On ogy industry could force some changes in the cur- the distribution side, the main issue is whether rent, primarily nonmarket system. there is adequate access to the goods by parties who seek them. Two key factors probably will determine whether a change occurs in the current sys- With respect to human biological materials tern of free donation of human biological ma- obtained for research, it can be argued that terials for use in biotechnology research and sources are not entitled to the value of their commerce. First, a change could arise from ju- donated materials because they do nothing to dicial decisions in present or future cases develop the materials into the valuable prod- under litigation Second, a change could be ini- uct. To a donor, replenishable tissue is often use- tiated through greater public interest as the less, and diseased tissue is actually a threat. It is commercial applications of biotechnology in- only the intervention of the researcher that gives crease and profits begin to be realized. value to these materials. Therefore, it is the researcher who should legitimately realize any eco- There are arguments both for and against pay- nomic gains from cell lines or other products de- ments for donations of human biological materi- veloped from the original biological material. als. Arguments over payments for human tissues and cells used in biotechnological research echo With respect to distribution, researchers gen- similar debates about markets in human organs. erally cooperate with each other in supplying bio- There are five principal issues in the debate: logical materials. The main incentive to this cooperation is the scientific commitment to the free ● the equity of production and distribution, flow of ideas and materials and to date the sys- ● the added costs of payments to sources and tem has operated fairly efficiently. However, as costs associated with that process, biotechnological processes and products are com- ● social goals (the merits of an altruistic sys- mercialized, this free flow of information and ma- tem of donations versus a market system), terials is facing increasing constraints. Shortages ● safety and quality (both of the source and the of human tissues and cells for basic research biological materials), and could occur if the incentives to cooperate are ● potential shortages or inefficiencies resulting insufficient to motivate researchers to go to from a nonmarket system or from changing the trouble of supplying fellow researchers. from a nonmarket system to a market system.

The factors related to social goals, safety and Added Costs quality, and shortages do not now offer compelling support either for or against paying the Two types of additional costs would be incurred sources of human tissues and cells. But two of if human sources were compensated for their tis- the issues are central to the debate, and they seem sues and cells or if they shared in royalties accru- to argue in favor of opposing approaches. Issues ing from licensing agreements concerning the of equity argue in favor of a payment system transfer of developed cell lines: the actual com- to human sources. On the other hand, the pensation to the sources and the cost of adminis- added costs of payments to sources argue tering the program (also called ‘(transaction costs”). against such a payment system. These costs could add significant burdens to the Ch. l—Summary, Policy Issues, and Options for Congressional Action ● 13 process of developing biotechnology products hesitate to share materials at all. Such negotia- from human materials. tions would further increase transaction costs.

The actual compensation to the human Resolving the Payment Dilemma sources of original tissues and cells is unlikely to have a large economic impact on the use of From the point of view of equity, a market struc- human biological materials, but transaction ture is favored because it eliminates the potential costs are likely to dwarf the costs of payments windfall realized by those who would otherwise to these individuals. Studies involving the de- receive free tissues and cells. On the other hand, velopment of cell lines can take years to complete the magnitude of the transaction costs associated and commercial application years longer, so the with payment to human sources maybe sufficient cost of keeping records of the origin of all the cell to deter any forays into a market structure. Non- lines involved might be considerable. In addition, profit organizations can play an important role most of the cell lines studied are unlikely to have in the procurement and distribution of human any commercial value so a large portion of the biological materials, just as they have played a key transaction costs would actually be unnecessary. role in marketing blood and organs. At present, Furthermore, under a payment system scientists there does not appear to be movement toward would no longer exchange materials freely; they a change-in the existing system of free dona- would have to negotiate over the transfer and tions of human biological materials for use in value of property rights for cell lines and might research and commerce in biotechnology.

ETHICAL CONSIDERATIONS

Are the human body and its parts fit objects derance of good results over bad. Those who hold for commerce, things that may properly be bought differing ethical perspectives might consider and sold? There are three broad ethical different outcomes as beneficent. grounds for objecting to or supporting commercial activities in human biological materi- A third relevant principle is justice. Would a als: respect for persons, concern for benefi- market setting be equitable to all members of so- cence, and concern for justice. ciety, including those who are financially disadvantaged? Part of the public ambivalence about a mar- First, the ethical principle of respect for per- ket in human tissues stems from a sense that such sons relates to the idea that trade in human tis- a market would foster inequities. sues and cells ought to be limited if the body is considered part of the basic dignity of human beings. To the extent that the body is indivisible from The Moral Status of Bodies and that which makes up personhood, the same re- Their Parts spect is due the body as is due persons. If the body Ethical and religious traditions do not provide is incidental to the essence of personhood, how- clear guidelines about the ways in which human ever, then trade in the body is not protected by biological materials should be developed or ex- the ethical principle of respect for persons. changed. The absence of established customs re- The second ethical principle relevant to the garding these materials is due to the relatively new acceptability of trade in human materials is be- potential for conducting and profiting from the neficence—who would benefit. The basic ques- development of human cells into cell lines. The tion could be stated this way: would commerciali- debate about whether or not it is ethical for zation of human materials be more beneficial than bodily materials to be bought and sold under- a ban on such commercialization? Marketing hu- lies all discussions about the commercializa- man tissues and cells might be justified if that tion of human biological materials. In addition, would lead to only good results or to a prepon- there are important questions about how justice [page omitted] This page was originally printed on a dark gray background. The scanned version of the page was almost entirely black and not usable. Ch. l—Summary, Policy Issues, and Options for Congressional Action 15

Two major variables are present in these West- Tomorrow’s Choices ern religious traditions that affect the use of human tissues and cells: the type of materials and Choices about how to handle transfers of tis- the mode of transfer. The significance of differ- sues and cells from patients and research subjects ent modes of transfer (or acquisition, if viewed to doctors, teachers, and researchers are impor- from the viewpoint of the user) and different ma- tant ethical decisions in two respects. First, these terials hinges on various ethical principles, such as: choices will characterize how individuals regard the human body. If certain human parts are “dig- ● respect for persons; nified,” then social traditions suggest that they may ● benefits to others; be given, but not sold. Second, like the choice of Ž not harming others; and how to obtain blood for transfusions, the system ● justice, or treating others fairly and distrib- that is chosen for obtaining human tissues and uting benefits and burdens equitably. cells will convey a sense of the symbolic weight There is a distinction between ethically accept- modern society places on the human body and able and ethically preferable policies and prac- the use of human biological materials in order to tices, Some modes of transfer and some uses may relieve suffering and enhance human health. be ethically preferred—for example, tradition The dispute between those who believe that prefers explicit gifts and donations without nec- commercialization of the human body is justi- essarily excluding sales, abandonment, and ap- fied and those who think it is not is in part an propriation in all cases. Western religious tradi- argument between people who accept a phi- tion prefers transfer methods that depend on losophical view that separates the body (a ma- voluntary, knowledgeable consent. Thus, pre- terial, physiological being) from personhood, ferred methods recognize some kind of property identity, or mind (an immaterial, rational be- right by the original possessor of the biological ing) and those who do not. materials.

POLICY ISSUES AND OPTIOlNS FOR CONGGRESSIONAL ACTION

Four policy issues related to the use of human sional oversight or direction. The order in which tissues and cells in biotechnology were identified the options are presented should not imply their during the course of this study. The first concerns priority. Furthermore, the options are not, for the actions that Congress might take to regulate the most part, mutually exclusive: adopting one does commercialization of human tissues and cells. The not necessarily disqualify others in the same cat- second involves the adequacy of existing regula- egory or within another category. A careful com- tions covering commercialization of cell lines, gene bination of options might produce the most desira- probes, and other products developed from hu- ble effects. In some cases, an option may suggest man biological materials. The third concerns the alterations in more than one aspect of using hu- adequacy of existing regulations covering research man tissues and cells in biotechnology. It is im- with human subjects. The fourth centers on portant to keep in mind that changes in one area whether present practice is adequate to ensure have repercussions in others. that health care providers disclose their potential research and commercial interests in the care ISSUE 1: Should the commercialization of hu- of a specific patient or group of patients. man tissues and cells be permitted by Associated with each policy issue are several the Federal Government? options for congressional action, ranging in each Option 1.1: Take no action. case from taking no specific steps to making major changes. Some of the options involve direct Congress may conclude that at present, the legislative action. Others are oriented to the ac- largely nonmarket basis for the transfer of hu- tions of the executive branch but involve congres- man tissues and cells is appropriate. If a commer- 16 ● Ownership of Human Tissues and Cells cial market in human biological materials should jects, or other sources from making money from arise, the lack of Federal regulation might result providing their tissues and cells. If Congress in great variability in the amounts of money paid enacted a statute modeled after the National Or- to the sources of the original tissues and cells. If gan Transplant Act in particular, there would be no action is taken, it is unlikely that human pa- a consistent line of Federal reasoning concerning tients or research subjects will be routinely com- the transfer of human organs, tissues, and cells. pensated for their tissues or cells in the near future. ISSUE 2: Should the commercialization of cell lines, gene probes, and other prod- Option I. L?: Mandate that donors of human tissues ucts developed from human tissues and cells are compensated for their and cells be modified by the Federal donations. Government? Some people argue that in the interest of eq- Option 2.1: Take no action. uity, the sources of human tissues and cells should be compensated. Congress could decide that human At present, cell lines, gene probes, and other biological materials have a monetary value, even products developed from human tissues and cells in their unimproved state, and that the sources are exchanged informally among researchers as of these materials have a right to this value. The well as by means of a market system. For the most amount and form of such compensation could part, profits are accrued in the form of royalties vary. Sources could be paid for their time and paid by those who want access to the developed trouble or paid for the actual specimen. Payment products. If Congress takes no action, the use of for service as opposed to substance is now stand- patented inventions based on human biological ard practice in the case of sperm donation. Re- materials will continue to be restricted to those searchers argue that compensation for human who engage in licensing agreements for access tissues and cells in their unimproved form is im- to the patented products. practical because the vast majority of these materials will have no ultimate value. Economists Option 2.2: Amend current patent law so parties argue that the transaction costs of such compen- other than inventors (e.g., patients, re- sation would outweigh any payment for the origi- search subjects, or the Federal Gov- nal biological material. In addition, many parties ernment) have protected interests and are concerned that any payment to the sources access to any commercial products of human tissues and cells, no matter how small, developed from their tissues and cells. would be so inefficient and inconvenient as to sti- Within the context of current patent law, the fle research efforts in general. Lastly, some ethi- inventor has exclusive rights to patented mate- cists worry that any trade or market in human rial and this effectively bars access by the sources tissues and cells unacceptably alters the meaning to their original biological material. Some argue, and value of the human body. however, that the patients or research subjects, Option 1.3: Enact a statute modeled after the Na- particularly if they suffer from a disease, should tional Organ Transplant Act that pro- have access to or some say in the use of patented hibits the buying and selling of hu- products derived from their tissues and cells. At man tissues and cells. present, licensing agreements for the use of these patented materials do not commonly stipulate any Congress may conclude that at present, the ex- protected interest for the original source. isting situation in which human tissues and cells are largely either donated or abandoned for re- Option 2.3: Enact a statute protecting the rights search purposes is satisfactory. If Congress con- of patients or research subjects to cludes that any for-profit market in human tis- share in profits accruing from licens- sues and cells should be stifled or avoided, it could ing agreements for the use of cell lines prohibit the sale of these biological materials. Such or gene probes developed from their a statute would prevent patients, research sub- original human biological material. Ch. l—Summary, Policy Issues, and Options for Congressional Action . 17

The profitable features of patented cell lines and and cells. Such action would affirm that commer- gene probes are the royalties that accrue from cialization of products developed through the use licensing agreements for access to these products. of human biological materials should be limited Congress may conclude that it is fair and equi- to the patent holder and licensees, and that pa- table for the original sources of human biological tients and research subjects have no right to the materials to share in the derived profits. Such value of their tissues and cells in their altered profit sharing could be in addition to or instead forms. While such an action might serve as an of a flat fee for the original unimproved tissues economic inducement for those who would ob- and cells. Some researchers argue, however, that tain human tissues and cells for the purposes of it is often impossible to identify the source of the developing new inventions, it is arguably contrary original material as cell lines and gene probes are to current patent and contract law (which en- developed. Many laboratory transformations over courages commercial negotiation between will- a long period of time separate the original sam- ing parties) as well as the concept of a person’s ple from the patented invention. If Congress enacts autonomy over the use of bodily materials. a statute ensuring that the sources of human tissues and cells share in the profits accruing from ISSUE 3: Are guidelines on the Protection of licensing agreements, then an extensive and costly Human Subjects (4/5 CFR Part 46) is- system of recordkeeping will be necessary to es- sued by the Department of Health and tablish the identity and whereabouts of the origi- Human Services adequate for the use nal sources. of human tissues and cells in biotech- Option 2.4: Mandate that any cell line be pre- nology? sumed to be in the public domain un- Option 3.1: Take no action. less it has been formally registered at the time the tissue was extracted or If no action is taken by the Department of Health placed into culture. and Human Services to alter the guidelines on the Protection of Human Subjects, it will remain un- The presumption that cell lines are in the pub- necessary for researchers to inform subjects about lic domain would bar anyone from claiming prop- possible uses of pathological or diagnostic speci- erty rights to these products. While this would mens. As a result, researchers can continue to use not directly compensate the donor or source of these materials as they choose without inform- the unimproved tissues and cells or the researching the patient (see option 3.2). In addition, if the er, it might relieve any sense of exploitation that guidelines are not altered, it will not be possible someone else has taken over that original prop- for subjects to specifically waive their interests erty right. The patent and similar systems could in the uses of their tissues and cells when giving still apply for further inventions made in devel- informed consent because of the existing ban on oping applications of the cell line. the use of exculpatory language (see option 3.4). Option 2.5: Enact a statute prohibiting parties other than inventors from sharing in Option 3.2: Direct the Secretary of Health and Hu- any reimbursement for, or any prof- man Services to modify or remove the its derived from, the use of products exemption regarding the collection or developed from human tissues and study of existing pathological or diag- cells. nostic specimens from the regulatory requirements (46.101(b)(5)). Under the present market system, only those who have patent law protection or enter into a Current DHHS guidelines exempt research in- contractual relationship (e.g., licensing agreement) volving the collection or study of existing data, realize commercial gain from developed tissues documents, or pathological or diagnostic speci- and cells. Congress may conclude that the sources mens if these are publicly available or if the donor should be barred from obtaining any reimburse- is otherwise unidentifiable. Researchers are there- ment for products developed from their tissues fore not obliged to disclose their research inter- 18 ● Ownership of Human Tissues and @//S ests to sources of specimens when this exemp- exculpatory language as it pertains to tion applies. commercial gain (46.116). Congress could modify or remove this section Under the current DHHS regulations, informed of the regulations so that it becomes necessary consent documents may not include exculpatory for research subjects covered by this exemption language which is used to make research subjects to be informed about and have some say in the or their representatives waive or appear to waive use of their tissues and cells. This option would any of the subject’s legal rights. The intent of this assure that additional research subjects would be provision is to safeguard subjects and to make cer- informed of the possible uses of biological speci- tain that they do not relinquish any legal rights. mens and related data and may be consistent with Some subjects may not want to reap financial ben- the general spirit of the guidelines to protect the efits as the result of or as a byproduct of their interests of the research subject. Removal of the participation in research, and some researchers exemption, however, could restrict research on and their sponsors may be deterred from con- a wide variety of currently available data, docu- ducting important research if they must share pos- ments, records, and pathological or diagnostic sible financial gain with research subjects. A specimens when a researcher cannot: 1) deter- change in the regulations could be made to mod- mine the identity of the subject, and 2) assure that ify the prohibition on the use of exculpatory lan- the subject provided an informed consent as re- guage to permit research subjects to waive any quired by the DHHS regulations. Modifying the rights to commercial gain. Such a provision would exemption by removing only pathological speci- need to be clearly worded. Research subjects mens or diagnostic specimens could likewise curb should understand exactly what rights are being research using currently available unidentified waived and that they will not be denied treatment specimens, but would continue the exclusion for to which they are otherwise entitled even if they other existing data, documents, and records. decide not to waive their rights. If the regulations are amended to permit the use of exculpatory lan- Option 3.3: Direct the Secretary of Health and Hu- guage as it relates to potential commercial gain, man Services to amend the general the Institutional Review Board will have a greater requirements for informed consent role. (46.116) to include potential commercial gain as a basic element of in- Option 3.5: Under its power to regulate interstate formed consent. commerce, Congress could enact a Under the current DHHS regulations, certain statute to permit and regulate the information must be provided to each subject dur- buying and selling of human tissues ing the informed consent process. It could be and cells. decided to add a provision requiring that in seek- The advantage of such a statute is that it would ing informed consent, a disclosure be made re- offer the possibility of financial compensation to garding the potential for commercial gain result- the sources of human tissues and cells. In addi- ing from data, documents, records, or pathological tion, such a statute would apply to the interstate or diagnostic specimens obtained during the re- transfer of these materials from all sources and search. Such a requirement could be codified as therefore go far beyond any alteration in guide- a basic element of informed consent that shall be lines for the protection of human subjects involved provided to each subject (46.l16(a)), or as an addi- in federally funded research. The disadvantage tional element of informed consent to be provided of such a statute is that it would permit commer- to each subject when appropriate (46.l16(b)). cialization of all human tissues and cells trans- Such a requirement would make clear that po- ferred interstate and extend Federal regulation tential commercial gain is an issue that would be into a previously unregulated area. reviewed by the Institutional Review Board. Option 3.4: Direct the Secretary of Health and Hu- ISSUE 4: Is present practice adequate to en- man Services to remove the ban on sure that health care providers dis- Ch. l—Summary, Policy Issues, and Options for Congressional Action 19

close their potential research and lines that require health care commercial interests in the care of a providers receiving any Federal reim- specific patient or group of patients? bursement to disclose any research or commercial interests they may Option 4.1: Take no action. have in the care of a specific patient Congress may decide that existing or altered or group of patients. DHHS guidelines concerning the protection of hu- If Congress acts to ensure that health care pro- man subjects provide sufficient safeguards to en- viders disclose their research and commercial insure that individuals are aware of the purposes terests in caring for particular patients, it will be and methods of the research in which they are necessary to discern what sort of commercial in- involved. At the present time, however, these terests in particular merit disclosure. Physicians guidelines only extend to research subjects par- in private practice obviously have commercial in- ticipating in federally funded research. There are terests in treating patients so their practice reno protections for research subjects in privately mains economically viable. It comes as a surprise funded research. to many people, however, to learn that their phy- There are no guidelines to ensure that health sician might also engage in research using a pa- care providers disclose their commercial interests tient’s tissues and cells and subsequently develop in caring for a particular patient or group of pa- a profitable product based on these donated or tients. If Congress takes no action, physician/re- abandoned materials. The relationship between searchers will not be obliged to tell a patient about physician and patient may be compromised if pa- their intention to develop commercially valuable tients suspect that their caregivers may profit in products from the patient tissues and cells. Con- unanticipated ways. The development of guide- gress may decide that the commercial interests lines concerning this type of disclosure could proof health care providers do not necessitate new mote greater trust between physicians and pa- forms of disclosure in order for patients to be ade- tients in the delivery of health care. quately informed. Option 4.2: Direct the Secretary of Health and Hu- man Services to promulgate guide- —.— ..— .—

chapter 2 Introduction

“I suspect at least the patient[s] should have some inherent right in the materials taken from them and any patents . . . at least for their lifetime and conceivably for their heirs’ lifetimes.” —John Moore Congressional testimony, Oct. 29, 1985

“I am lucky in that I am one of the so-called long-time survivors of [an acute leukemia research program]. If progress in the treatment of leukemia or anything else can be made through the use of my cells, then that is my contribution to mankind. I benefited from treatment which came about from years of scientific experiments, by many in and outside my particular place of treatment, funded by government grants as well as university, foundation, private and public funds.” “Human nature being such as it is, I would want to know of any breakthrough that came about as a result of my participation in research. But to those dedicated men and women in research belongs the glory. Without their endless quest, all would be for naught. ” —Mildrene C. Thomasson Washington Post, July 23, 1986 CONTENTS

Definitions ...... 24 Case Histories ...... 24 Case 1 ...... 25 Case 2 ...... 25 Case 3, $ ...... 26 Case ...... 26 The Problem of Uncertainty 27 Summary and Conclusions . 27 Chapter p references...... 28

Figure Figure No. Page 2.Normal Human Epidermal Cells in Culture ...... 25 Chapter 2 Introduction

Experiment V. After evaporating two quarts of urine to dryness by gentle heat, there remained a white cake, which was granulated and broke easily between the fingers. It smelled like brown sugar, neither could it from the taste be distinguished from sugar. —Matthew Dobson, 1776

Although surely not the earliest use of a human under what circumstances should such ac- biological material in research, this original ob- quisition be permitted or denied? servation concerning the urine of a diabetic pa- ● What are patients and research subjects en- tient was reported to the Medical Society of Lon- titled to know about the potential for com- don in 1776 (12). Thus, the use of human materials mercial exploitation of an invention that uses in research is not a new issue. Over the past dec- their bodily materials? And what is the prob- ade, however, technological advances have re- ability that an individual’s tissues and cells sulted in new, enhanced methods for studying and will end up in a commercial product? using human body parts—particularly tissues and ● How is it that inventions incorporating hu- cells. Using these technologies with intelligence, man cells are patentable in the first place? creativity, hard work, and a measure of seren- How similar is the invention to the original dipity, researchers have greatly increased our un- biological material? derstanding of both human health and disease, ● What is the nature of the researcher’s con- Human samples are not only an integral part of tribution versus the source’s contribution to the biomedical research process, but they are now the invention? also used as a component of (or in the production ● Who should profit from federally funded re- of) a variety of commercial products ranging from search using human tissue? To what extent drugs and vaccines to pregnancy test kits. are the issues raised by ownership of human biological materials related to the increasingly Some of the new research and commercial uses commercial relationships between universi- of human biological materials have raised legal ties and companies? and ethical questions regarding the acquisition of And, most importantly: bodily substances. These issues are novel; and little has been written about them. They are also ● What are the implications of these issues for extremely complex, and thus it is not surprising scientists, physicians, patients, volunteer re- that there is no single body of law, policy, or ethics search subjects, universities, and the biomedi- from which indisputable conclusions can be drawn. cal product industry? Questions to consider include: This report does not address the use of tissue for the direct medical benefit of patients who need ● Are bodily substances “property, ” to be dis- healthy human biological material—as is the case posed of by any means one chooses, includ- in organ transplantation, blood transfusion, or arti- ing donation or sale? ficial insemination—except to the extent that sim- ● Do property rights to genetic identity adhere ilar legal, ethical, economic, and policy issues oc- to individuals or to the species? cur. Nor does this report explore the special ● Who should make the basic decisions affect- concerns arising from research using special kinds ing the acquisition of tissues and cells, and of cells, such as fetal or germ cells.

23 -. —

24 Ž Ownership of Human Tissues and Cells

DEFINITIONS

Biotechnology, broadly defined, includes any logical materials, this report is primarily con- technique that uses living organisms (or parts of cerned with the biological materials that are most organisms) to make or modify products, to im- frequently obtained from humans and used in bio- prove plants or animals, or to develop micro- technology: tissues and cells. The terms speci- organisms for specific uses—including recently mens, samples, body parts, human tissue, developed techniques such as gene cloning and bodily substances, primary tissue, and biolog- cell fusion. ical are also used. OTA distinguishes these undeveloped human biological materials from What are human biological materials? Human the biological inventions developed from them bodies contain a number of parts that can be use- (and in some cases patented) such as cell lines, ful in biomedical research. Healthy individuals l hybridomas, and cloned genes. These inven- continually produce a number of replenishable tions, and the techniques investigators use to de- substances, including blood, skin, bone marrow, rive them, are described in chapter 3. The issue hair, urine, perspiration, saliva, milk, semen, and of patentability of most biological inventions in tears. Human bodies also contain nonreplenish- the United States is discussed in chapters 4 and 5. ing parts, such as oocytes or organs, which may either be vital (e.g., heart) or to some extent expendable (e.g., lymph nodes or a second kidney). Finally, diseased examples of these body parts also exist. *“Products of nature,” are unpatentable because they lack novelty (6). However, the biological inventions being patented today While OTA refers to all human parts-replenish- are not crude, unaltered products of nature. A claim to the entire genetic material of a single cell would probably be rejected; but one ing and nonreplenishing, living and nonliving, may properly seek a patent on an isolated gene encoding a protein healthy and diseased-collectively as human bio- of interest (see ch. 5).

CASE HISTORIES

Reports of sales of cells have generally aroused noncommercial hepatitis researchers. Slavin made more public curiosity than controversy. In 1986, news when he formed a company, Essential Bio- a Colorado company, Clonetics Corp., introduced logical, that not only marketed his own blood but the world’s first commercial product that contains that of others with rare blood characteristics. Be- live normal cloned human skin cells (see figure fore his death in 1984, his blood benefited research 2-1). The product is sold to basic researchers who on the development of a hepatitis vaccine and pre- use it to study a variety of questions. Pharmaceu- vention of liver cancer. Recently, clinical research- tical, cosmetic, and other firms also use the cloned ers who used Slavin’s blood eulogized him as a skin cells to test products. Clonetics uses samples gallant man who greatly contributed to biomedi- from elective surgery (e.g., plastic surgery) that cal research efforts (2). are purchased from both patients and doctors (3, However, disputes over the acquisition and 7,9). ownership of human cells have occurred. While In another instance, when hemophiliac Ted such cases have arisen infrequently, they have Slavin was discovered to have a high concentra- great practical significance to the parties involved tion of antibodies to the hepatitis B virus, he mar- and have been scrutinized by the research and keted his blood for up to $10 per milliliter (a mil- corporate communities for their broader impli- liliter is approximately 1/4 teaspoon, so this is the cations. Four cases involving human biological ma- equivalent of more than $6,000 per pint) to com- terials provide insight into the complex issues that mercial organizations while providing it free to can arise. Ch. 2—introduction ● 25

Figure 2.—Normal Human Epidermal Cells in Culture Case 1

In 1962, a Stanford University microbiologist working under a Federal research grant estab- (A) 2 days after the skin sam- lished the first strain of normal human cells in ples are put culture. After developing and cultivating the cell into culture, clonal growth line, designated WI-38, the scientist formed a com- can be ob- pany to market the cells for use in the produc- served; tion of viral vaccines. The National Institutes of Health claimed that the cells were Federal property and charged him with wrongfully exploiting his federally funded research. Stanford was apparently about to take disciplinary action when the researcher resigned and filed suit seeking title to (B) after 4 days the cells. The dispute was finally settled out of the colonies are develop- court in 1981, with the scientist retaining the ing rapidly; money from sales of the cells but with the question of ownership of the cell line still unresolved (11),

Case 2

In 1977, a man with leukemia agreed to allow a sample of his cells to be taken from his bone (C) at 6 days the culture is marrow for scientific research. Although the man ready to be died shortly afterwards, claims over who may shipped; profit from his cells continued. Two research hematologists at the UCLA Medi- cal Center (one of whom was also involved in case 2) succeeded in making the cells grow and divide, producing a new cell line that could be used to study leukemia. A sample of the new cell line, (D) after 8 days, named KG-1, was sent to a National Cancer Insti- the culture tute (NCI) researcher with written instructions can be divided into limiting its use. During a screening procedure, the two or more NCI scientist noticed that the cell line produced subcultures; a low concentration of interferon, a natural an- tiviral protein. The NCI researcher sent a sample of KG-1 to the Roche Institute of Molecular Biol- ogy, a wholly funded research arm of pharma- (E) 10 days after the first skin ceutical manufacturer Hoffman-LaRoche, and cells were they found that the cell line could be manipulated seeded into culture, the to optimally produce interferon. At Genentech, human skin a biotechnology firm with contracts from cells have multiplied to Hoffman-LaRoche, techniques were used to iso- cover the sur- late substantial quantities of the interferon gene face of the growth from the cell line. chamber. A dispute ensued between the University and Normal human skin cells are supplied commercially in Hoffman-LaRoche over who in fact owned the KG- culture. 1 cell line. The University, as home of the scien- Photo credits: Clonetics Corp., Boulder, CO. tists who had developed the cell line, claimed 26 ● Ownership of Human Tissues and Cells ownership and the right to royalties from the pro- Case 4 duction of interferon. Hoffman-LaRoche also claimed ownership and had even filed a patent In 1976, John Moore was diagnosed as having application covering both the interferon and the a rare form of cancer, hairy cell leukemia, a con- manufacturing process. The dispute was finally dition that affects an estimated 250 Americans settled out of court in 1983, with the drug com- each year (1). The recommended treatment for pany retaining the right to use the cells and genes Moore’s condition was removal of the spleen and in exchange for payment of an undisclosed sum surgery was performed at the University of Cali- to the University (11). fornia, Los Angeles Medical Center. As a patient, Moore had signed a standard surgical consent form (providing for the postoperative disposition Case 3 of the tissue) to remove his diseased spleen, which had enlarged to approximately 40 times its nor- In both the Stanford and UCLA cases, claims mal size. to cell line ownership were based on the intellec- After the surgery, Moore’s doctor and his tech- tual (intangible) contributions of researchers. Le- nician developed a cell line (designated “Mo”) from gal conflict over cell line ownership has also a sample of Moore’s spleen obtained from the occurred based on the tangible contribution of pathologist. These scientists found that the cell biological materials. line developed from the spleen produced high In early 1981, a researcher at the University of quantities of a variety of interesting and poten- California, San Diego, was developing human tially useful proteins. In 1979, the university ap- hybridoma cell lines that would secrete antibod- plied for a patent on the “Mo” cell line and in 1984 ies to cancer cells. Learning of the project, Dr. a patent naming the scientists as inventors was Heideaki Hagiwara suggested the use of lymph obtained and assigned to the university. In 1981, cells from his mother, who was suffering from the university, on behalf of the scientists, entered cervical cancer. The researcher agreed, and the into a 4-year collaborative research program with Hagiwara cells were fused to an immortal cell line two biotechnology and pharmaceutical companies developed and patented by the investigator. A for exclusive use of the “Mo” cell line. hybridoma that secreted an anti-tumor antibody After his splenectomy, blood samples were ob- was found. tained from Moore by the doctor over the course Without the investigator’s permission, Hagiwara of several years. In 1983, Moore initially signed took a subculture of the hybridoma cell line with a research consent form waiving any claims to him to Japan and gave it to the Hagiwara Insti- the results of the university’s research and giv- tute of Health, directed by his father. The univer- ing the university all rights to products. On a re- sity and the Hagiwaras subsequently executed an search consent form signed at a later date, how- agreement that permitted the Hagiwaras to use ever, Moore refused to waive his rights to any the cell line for scientific research but forbade products developed from his blood. their transfer to any other party for commercial purposes. In 1984, Moore filed a lawsuit claiming that his blood cells were misappropriated, and that he was Several months later, the Hagiwaras asserted entitled to share in profits derived from commer- rights to the cell line and antibody, claiming that cial uses of these cells and any other products re- they had tangible property rights in the original sulting from research on any of his biological ma- tissue and were therefore entitled to a pecuniary terials (the patent for the “Mo” cell line clearly interest in the derivative cell line. In 1983, the par- states that it was derived from splenic tissue), In ties reached an agreement under which the March 1986, the trial judge dismissed Moore’s university retained all patent rights and the complaint as failing to state a legally cognizable Hagiwaras received an exclusive license to exploit claim. As this report goes to press, this ruling is the patent in Asia (4,13). being appealed (5,8)10,14,15). Ch. 2—Introduction . 27

THE PROBLEM OF UNCERTAINTY

Uncertainty about how courts will resolve dis- likely to invest heavily in developing, manufac- putes between specimen sources and specimen turing, or marketing a product when uncertainty users could be detrimental to both academic re- about clear title exists. searchers and the infant biotechnology industry, Research using human biological materials could particularly when the rights are asserted long af- be thwarted if universities and companies have ter the specimen was obtained. The assertion of difficulty obtaining title insurance covering owner- rights by sources would affect not only the ship of cells or genes, as well as liability insur- researcher who obtained the original specimen, ance for related disputes. Insurance carriers will but perhaps other researchers as well, likely be concerned not only with suits by indi- Biological materials are routinely distributed to viduals who are identifiable as the specimen other researchers for experimental purposes, and sources, but also by the potential for class action scientists who obtain cell lines or other specimen- lawsuits on behalf of all those who contributed derived products, such as gene clones, from the specimens to a particular research project. Re- original researcher could also be sued under cer- searchers generally claim that the pervasive use tain legal theories (see ch. 5), Furthermore, the of human tissues and cells in biomedical research uncertainty could affect product developments makes it highly impractical and inefficient to iden- as well as research. Since inventions containing tify the sources of the various specimens for pur- human tissues and cells may be patented and poses of valuing individual contributions. These licensed for commercial use, companies are un- concerns are addressed in chapter 7.

SUMMARY AND CONCLUSIONS

The government has always maintained an in- ilar legal, ethical, economic, and policy issues oc- terest in the legal, ethical, and economic implica- cur. Nor does this report explore the special tions of research it is funding, and this interest concerns arising from research using special kinds is magnified when such research results in inven- of cells, such as fetal or germ cells. tions that are patentable under Federal law. This Advances in technology and increased use of report considers each of these aspects, as they human biological materials for therapy, research, apply to research and product development using and commerce has raised a number of important human biological materials—undeveloped tissues questions that likely will need to be addressed in and cells. The report also examines the scientific the immediate future. There are no easy answers. techniques that serve as the foundation of the The issues are novel and complex and no single boom in biotechnology and the parties interested body of law, public policy, or ethics directly ap- in the boom. plies. But regardless of the merit of claims by the This report does not address the use of tissues different interested parties, resolving the current for the direct medical benefit of patients who need uncertainty may be more important to the future healthy human biological material—as is the case of biotechnology than resolving it in any particu- in organ transplantation, blood transfusion, or arti- lar way. ficial insemination-except to the extent that sim- 28 ● ownership of Human Tissues and Cells

CHAPTER 2 REFERENCES

1. “Biopharmaceuticals: New Technology Unlocks the 9. Holy field, J., “Company Announces Commercial Body’s Medicine Cabinet, ” Medical World iVews Skin Cloning,” The Associated Press, Nov. 4, 1986. 25:40-56, March 1985. 10. Moore v. Regents of the University of California 2. Blumberg, B. S., Millman, I., London, W. T., et al., et al., appeal docketed, No. C513755 (CA Super. Ct,, “Ted Slavin’s Blood and the Development of HBV Los Angeles County, 1985). Vaccine)” New England Journal of Medicine 11. Nelkin, D., Science as Intellectual Propert@ (New 312(3):189, 1985. York: MacMillan, 1984). 3. Bulman, P., “Biotech Company Clones Skin for Com- 12. Sih~erman, W. A., Human Experimentation—A mercial Use, ” The Washington Post, Nov. 16, 1986. Guided Step Into the Unknown (New York: Oxford 4, Cooper, I. P., Biotechnology and the Law’ (New York: University Press, 1985). Clark Boardman Co., Ltd., 1985). 13. “Update: U. Cal. and the Hagiwaras Settle Owner- 5. Culliton, B. J., “Patient Sues UCLA Over Patent on ship Dispute, ’’l?iotechnologv Law Report 2(3-4):43, Cell Line,” Science 225:1458, 1984. 1983. 6. Diamond v. Chakrabarty, 477 U.S. 303 (1980). 14, Wagner, A., Berkeley, CA, personal communica- 7. Garner, S., Clonetics Corp., Boulder, CO, personal tions, June, October, and November, 1986. communication, November 1986. 15. Zackey, J., Gage & Mazursky, Beverly Hills, CA, 8. Golde, D., University of California, Los Angeles, Los personal communications, May, November, Decem- Angeles, CA, personal communication, August ber 1985, and October 1986. 1986. chapter 3 The Technologies

“We must, as far as we can, isolate physiological occurrences outside the organism by means of experimental procedures. This isolation allows us to see and understand better the deepest associations of the phenomenon, so that their vital role maybe followed later in the organism. ”

—CIaude Bernard 1813-1878 CONTENTS

Page Tissue and Cell Culture Technology ...... 31 Culturing Human Cells ...... 32 Human Cell Lines ...... 33 Using Cell Cultures .. <...... 4 ...... $ ...... 35 Hybridoma Technology ...... 35 Monoclinal Antibodies ...... 37 Lymphokines ...... 38 Recombinant DNA Technology ...... 41 History ...... 41 Gene Cloning ...... t,,...... 41 Summary and Conclusions ...... 44 Chapter 3 References ...... 45

Table No. 3. Comparison of Microbial and Mammalian Cells ...... 31 4. Some Nutrient and Growth Condition Requirements for Culturing Human

Cells ...... $ ...... 32 5.Some Lymphokines With Therapeutic Potential ...... 40

Figures F@reNo. Page 3. Plastic Monolayer Cell Culture Flasks . 33 4.Human Tumor Cells in Cuhure ...... 35 5.Evolution of a Cell Line...... 36 6. Structure of an Antibody Molecule . . . 37 7. Preparation of Mouse Hybridomas and Monoclinal Antibodies 39 8. The Structure of DNA ...... 41 9. The Process of Gene Expression . . . . 42 10. Recombinant DNA: The Technique of Recombining Genes From One Species With Those From Another...... ,,...... 43 Chapter 3 The Technologies

Progress in the scientific techniques of biotech- techniques and how they can be used to manipu- nology clearly has affected society on many late tissues and cells into useful products in or- levels–medical, social, economic, legal, and ethi- der to appreciate the novel legal, economic, and cal. Most of the technologies used to transform ethical issues raised in this report. undeveloped human tissues and cells mentioned The following brief review outlines the principal in this report can be categorized into three broad tenets of the three main techniques; the large-scale areas: tissue and cell culture technology, hybri- commercial applications of these technologies are doma technology, and recombinant DNA technol- discussed in another OTA report (23). While each ogy. Advances in these technologies have in- technology is reviewed individually, keep in mind creased our capability to identify and produce that it is the marriage of technologies that is the important human therapeutic agents. These fun- norm—no single technology is the central element damental scientific techniques are having pro- in the development or commercialization of hu- found, practical impacts on our society. Thus, it man biological material. is important to understand the nature of the basic

TISSUE AND CELL CULTURE TECHNOLOGY

Cells are the basic unit of all living organisms. Table 3.-Comparison of Microbial and They are the smallest components of plants and Mammalian Cells animals that are capable of carrying on all essen- Mammalian cells tial life processes, A single cell is a complex collec- Characteristic Microbial cells (in culture) tion of molecules with many different activities Size (diameter) 1 to 10 microns 10 to 100 microns all integrated to forma functional, self-assembling, Metabolic self-regulating entity. Higher organisms and plants regulation ... Internal Internal and hormonal Nutritional are multicellular, with certain cells performing spectrum Wide range of Fastidious specialized (i.e., differentiated) functions, substrates Doubling time Typically 0.4 to 2.0 hours Typically 12 to 60 hours There are two broad classes of cells: prokaryotic Environment Wide range of tolerance Narrow range of tol- and eukaryotic. The classes are basically defined erance by the manner in which the genetic material is SOURCE: Office of Technology Assessment, 1987 housed. Prokaryotes, generally considered the simpler of the two classes, include bacteria. Their (prokaryotes) from cultured mammalian cells (eu- genetic material is not housed in a separate struc- karyotes). ture (called a nucleus), and the majority of prokaryotic organisms are unicellular. Eukaryotes, Multicellular eukaryotes are complex and diffi- on the other hand, are usually multicellular organ- cult, if not impossible, to examine in vivo at the isms. They contain their genetic material within organismal level. Thus, scientists at the turn of a nucleus, and have other specialized structures the century began studying these organisms using within their cell confines to coordinate different a reductionist approach, They dissected the many cellular functions. The genetic material of eu- biological processes in vitro by examining cells karyotic organisms is a structure called a chromo- isolated and maintained independently of a whole some—a DNA and protein complex that is usually organism. This approach, called tissue and cell visible to the eve with standard light microscopy. culture, has been refined considerably over the Humans are eukaryotes. Table 3 compares some years and the following section discusses this tech- of the features that distinguish microbial cells nology as it applies to human cells. A separate sec-

31 — — —

32 . Ownership of Human Tissues and Cells

tion is devoted to a special application of cell cul- While it is significantly less difficult to cultivate ture technology-making hybridomas. human cell lines than it is to establish them, working with human materials is still much more prob- Culturing Human Cells lematic than working with simpler organisms such as bacteria or yeast. Nevertheless, scientists are The first experiments using tissue and cell cul- continuing to make progress in developing optimal ture technology were conducted in 1907 when growth conditions and cell culture equipment. a scientist successfully grew frog nerve cells in culture (7). The technology was originally consid- The food required to sustain human cells in cul- ered a “model system”—a way for scientists to ture is a liquid called growth medium. Different examine physiological events outside an intact types of human cells require different growth me- organism. The approach was initially criticized dia. Growth media are complex, and until recently as myopic and artifactual, but tissue and cell cul- animal serum-containing many unidentified, but ture are now seen as fundamental scientific tools. vital components —was a necessary ingredient of These techniques are no longer only used as model all media. However, media with the identity and systems, but are widely exploited techniques used quantities of all components defined have been in biomedical research. successful in sustaining long-term growth of human cells (8)20). As a practical matter, the distinction between tissue culture and cell culture is often blurred so In addition to the many nutrient requirements the terms are frequently used interchangeably. of human cells in culture, strict temperature con- Strictly speaking, in cell culture technology sam- ditions must be maintained. Variation in temper- ples are removed from an organism and in vitro ature exceeding 20 C from the optimum usually manipulation has destroyed the original integrity is not tolerated; higher temperatures in particu- of the sample. In time, a sample isolated and estab- lar are quickly lethal. Buffers are added to growth lished in the laboratory maybe called a cell line, media to prevent drastic shifts in acidity, and the In tissue culture, isolated pieces of tissue are main- media must be sterilized. Contamination of sam- tained with their various cell types arranged much ples during the early stages of culturing is a par- as they existed in the whole organism and their ticular concern, and rigorous care must be taken functions remain largely intact, Tissue cultures to keep the culture free of contaminants such as presumably have more of their native identity, yeast, fungi, bacteria, and viruses. Antibiotics and but are much more difficult to maintain than cell fungicides may be added to further discourage cultures. infestation. Table 4 lists some of the requirements for successful cultivation of human cells in the Although many advances have occurred laboratory. since 1907, establishing a human cell culture directly from human tissue--called a primary ceil culture--is still a relatively difficult enterprise. The probability of establishing a cell line Table 4.—Some Nutrient and Growth Condition Requirements for Culturing Human Cells from a given sample is low. Success can be un- dermined by contamination during collection and Water storage, and is also dependent on how much dam- Salts Sugars age the tissue suffered during collection of the Vitamins sample. The success rate also depends on the type Amino acids of human tissue being used. Some cells are easy Hormones Fats to culture—human skin fibroblasts and human Buffers (to maintain proper pH—i.e., prevent drastic shifts glial cells can be successfully established nearly in acidity) 100 percent of the times attempted (14,19). Others, Gases (oxygen, nitrogen, carbon dioxide) Temperature (usually 98.6° F [37° C] for optimal growth) however can be very difficult to establish. Some Sterilization human tumors can be cultured with about a 10 Antibiotics and fungicides (optional) percent success rate (13). SOURCE: Office of Technology Assessment, 1987. Ch. 3—The Technologies ● 33

Figure 3.—Plastic Monolayer Cell Culture Flasks original specimen (2,4). For some liver cells, the fraction of cells resulting in viable outgrowth for any given sample is between only 1/1,000 to 1/100)000 (0.01 to 0.10 percent) (10). Primary human cell cultures typically maintain /. the normal diploid number of human chromosomes—46. They may also exhibit the functions and properties indicative of their differentiated origin: liver cultures may produce certain liver- specific proteins or white blood cell cultures may express their own specialized characteristics. Cell cultures isolated from nontumor tissue have a finite lifespan in vitro (i.e., most cultures die after a limited number of population doubling. ) These cultures will almost always age unless pushed into immortality by outside intervention involving viruses or chemicals. This aging phenomenon, called senescence, does not occur en masse, but is a gradual deterioration and death of the cell population. The type of tissue involved and culture conditions are important variables in Photo credit: Ventrex Laboratories, Inc. determining cell lifespan. However, the age of the human tissue source is also a component, and thus primary cell cultures can be studied as models Cultured human cells grow as a suspension in of human aging. solution, or attached to specially treated glass or plastic and submerged in growth medium (figure Human Cell Lines 3). Human cells typically double in number in 18 to 36 hours, compared to approximately 20 min- Long-term adaptation and growth of human tis- utes for the bacterium Escherichia coli. Samples sues and cells in culture is difficult—often con- of human cells can be stored frozen in liquid ni- sidered an art—but it has been accomplished and trogen ( – 1960 F) for future use. Certain types many established human cell lines (cells capable of cells are more fragile than others, but with mod- of continuous and indefinite growth in culture) ern freezing techniques most samples can be exist. A primary culture that has been transformed thawed and recovered decades later—often with into an immortal cell line usually has undergone a greater than 95 percent survivor rate. a “crisis” period. Most established cell cultures have been derived from malignant tissue samples Primary cell cultures are derived directly from solid human tissue or blood. In the case of cul- (figure 4). It is important to point out, however, tures isolated from solid samples, extensive minc- that immortalization does not occur in all samples isolated from tumors. As was mentioned ing or enzyme treatment maybe necessary to dis- earlier, certain types of tumors seem more likely perse the tissue. Since the earliest days of tissue and cell culture, it has been clear that not to establish continuous cultures. Figure 5 illus- all the cells that are isolated from tissue and trates the evolution of cultured cells. put into culture will survive. Thus, as soon as It is not known precisely why a given sample a sample is cultured it may not be representa- gives rise to a continuous cell culture. It is possi- tive of the total specimen used, and the longer ble that a small number of cells in the original the sample is in culture, the less it is like the sample become the immortal cell line. On the other 34 ● Ownership of Human Tissues and Cells

hand, one or a few cells may undergo a transfor- may be a result of the nature of the tumor used mation event during the “crisis” period to give rise to establish the cell line, or they may be the re- to the immortal cell line. Evidence indicates that sult of changes the cells have undergone in order the latter explanation is more probable, but the to achieve continuous, long-term culture. After possibility that there is a subpopulation of the origi- initial immortalization, established lines are usu- nal sample with a predisposition to undergo the ally isolated and expanded from a single cell—a transformation event cannot be discounted (4). process referred to as cloning. This means that the entire population of cells has resulted after Established cell lines are usually aneuploid, continual growth starting from a single cell. which means that the number of chromosomes deviates from the normal number of 46 for hu- Cells that have adapted to continuous culture mans. The first human tumor cell line, HeLa, was can not be considered entirely representative of isolated in 1951 (5). Derived from a cervical carci- the total population of the original isolate and they noma, this widely used cell line has a chromosome may continue to change with time (4). Cloning is number that varies from about 50 to 80, depend- performed, therefore, to provide a uniform pop- ing on the particular isolate. ulation of cells so that uniformity and accuracy in experimental results can be improved. But, con- In addition to having aberrant numbers of chro- tinuous growth of cells is a dynamic process— mosomes, established cell lines may not display subpopulations of cells may suddenly accelerate differentiated functions. Both of these properties their growth rate, shut down production of or Ch. 3—The Technologies ● 35

Figure 4.— Human Tumor Cells in Culture search and commercial levels, cell cultures are used as tools to study basic biological processes. A cell line may be used as a biological factory to produce small or large quantities of a substance. Human proteins may be isolated directly from cultured cells. Cell cultures can also be the source of the genetic material needed to apply recombinant DNA technology in further studying a problem. As will be described later in this chapter, cultured human cells, both primary and established, play an important role in recombinant DNA technology. And finally, companies may use primary and established cultures to test drugs or the toxicity of compounds. The ability to maintain and manipulate many types of human cell lines in a controlled environment has expanded our knowledge of the biological sciences significantly and facilitated biomedical research. In addition to increasing our knowledge, nearly 50 years after frog nerve cells were first cultured in vitro an important offshoot of growing cells in culture was invented: a technique to fuse cells from different sources. This technique, called cell fusion, has elucidated much of what is currently known about:

● the structure and function of the human genome, ● the expression and mechanism of heritable Photo credit: Robyn Nlshimi conditions, ● the regulation of normal biological reactions, begin to overproduce compounds, or alter their and chromosome number. So in order to reproduce ● the processes of carcinogenesis and many earlier experimental results, repeated subcloning other diseases. of cultured cells may be required. Cell fusion was also central to the development Using Cell Cultures of hybridoma technology.

The applications of tissue and cell culture technology are wide and varied. At both the basic re-

HYBRIDOMA TECHNOLOGY

Refinements in cell fusion (also called cell The immune response in higher animals serves hybridization) are responsible for the explosion to protect the organism against invasion and per- in hybridoma technology. Hybridomas are spe- sistence of foreign substances. It occurs only in cial types of hybrid cells and to understand how vertebrates and is a cooperative effort among sev- they were invented and why they are important eral types of cells that results in a complex series it is helpful to understand the immune system. of events involving the production of antibodies 36 ● Ownership of Human Tissues and cc//s

Figure 5.— Evolution of a Cell Line

u d 4 5 8 10 12 14 16

Weeks in culture The vertical axis represents total cell growth on a log scale and the horizontal axis the number of weeks the hypothetical sam. ple has been in culture since it has been obtained from a donor. In this example, a continuous cell line is depicted as arising at about 12.5 weeks. Different cultures will give rise to a continuous cell line at different times. In addition, senescence may occur in a sample at any time, but for human diploid fibroblasts it usually happens between 30 and 60 population doublings (10 to 20 weeks).

SOURCE: Adapted from R.1. Freshney, Culture of Anirna/ Cc//s: A Manua/ of Basic Technique (New York: Alan R. Liss, Inc., 1983), Ch. 3—The Technologies ● 37

and a class of molecules called lymphokines. Anti- Figure 6.—Structure of an Antibody Molecule bodies bind to a foreign invader, while lymphokines are necessary for coordinating, enhancing, and amplifying an immune response. Both antibody and lymphokine production operating in concert are necessary for a complete and effica- cious response to a foreign challenge. Scientists realized that obtaining a constant and uniform source of a single type of antibody would be essential to understanding the intricacies of the immune response and that such a uniform source of antibodies could provide a powerful, general analytical tool. High concentrations of Constant reliable antibodies and lymphokines also prom- region ise rewards in diagnosing and treating human ills, The following two sections describe recently developed technologies that yield pure antibodies and higher concentrations of many lymphokines.

Monoclinal Antibodies ! SOURCE: Office of Technology Assessment, 1984 An antibody is a protein molecule with a unique structural organization that enables it to bind to a specific foreign substance, called an antigen. and blood. A particular subclass of lymphocytes, Antibody molecules have binding sites that are called B lymphocytes or B cells, recognizes anti- specific for and complementary to the structural gens as foreign substances and responds by pro- features of the antigen that stimulated their forma- ducing antibodies highly specific for a given anti- tion. Antibodies formed by a sheep, for example, gen. Any single B lymphocyte is capable of in response to injection of human hemoglobin (the recognizing and responding to only one antigen. antigen) will combine with human hemoglobin and Once a B cell has been activated by an antigen not an unrelated protein such as human growth it is committed to producing antibodies that bind hormone. to only that one specific antigen. All antibodies are comprised of four protein During an immune response to an invasion by chains—two identical light chains and two identi- a foreign substance (e.g., a virus), one of the events cal heavy chains. These subunits are always linked that occurs within an organism is that many differ- in a fixed and precise orientation, as illustrated ent B cells react and produce antibodies. Differ- in figure 6. One end of the antibody contains two ent B cells produce antibodies recognizing differ- variable regions, the sites of the molecule that ent parts (called determinants) of the virus, but recognize and bind with the specific antigen, To as mentioned above, an individual B lymphocyte accommodate the many antigens that exist, the and its progeny produce only one specific kind variable end of an antibody differs greatly from of antibody. This multiple B cell reaction produces molecule to molecule. The other end of the anti- a mixed bag of antibodies with each type of antibody is nearly identical among all structures and body represented in only limited quantities, and is known as the constant, or effecter, region. The is called a polyclonal response. Polyclonal antibod- constant region is not responsible for antibody ies can be isolated from blood serum, and, until binding specificity, but has other functions. recently, were the principle source of antibodies other important actors in the immune response used by physicians and researchers. While anti- are specialized white blood cells called lympho- bodies produced this way were and still are use- cytes that are present in the spleen, lymph nodes, ful tools to scientists and clinicians, a method to 38 . Ownership of Human Tissues and Cells

produce a constant and pure source of a single Independently isolated lines of hybridomas, each type of antibody was still sought. originating from a single B cell fusing with a single myeloma cell, produce distinctive monoclinal The discovery in 1975 of the technique to pro- antibodies. Each line is unique to the original con- duce a special hybrid cell known as a hybridoma tribution of the particular B cell parent. In the that produces a specific type of antibody was, in case of Milstein and Kohler each different hybri- the words of one of the inventors, a “lucky cir- doma cell line isolated is an immortal antibody- cumstance)” but one with profound effects for producing factory targeted toward a different part biomedical research and commerce. Cesar Milstein l of a sheep red blood cell. The method used to pro- and Georges Kohler, working at the Medical Re- duce mouse monoclinal antibodies is illustrated search Council’s Laboratory of Molecular Biology in figure 7. in Cambridge, England, used the well-established tissue culture technique of cell fusion to produce Virtually all of the monoclinal antibodies cur- a new type of hybrid cell—a hybridoma-capable rently being used in humans as therapeutic agents of indefinitely proliferating and secreting large or imaging tools are rodent antibodies because amounts of one specific antibody (11,12). the production of human hybridomas has been much more difficult than the production of rodent Hybridomas are hybrid cells resulting from the hybridomas. To avoid some of the complications fusion of a type of tumor cell called a myeloma in patients treated with rodent antibodies, refine- with a B lymphocyte freshly isolated from an ments in human monoclinal antibody technology organism (usually from the spleen or lymph nodes) will be necessary. Researchers have developed in- that had been recently injected with the foreign genious in vitro methods and successfully isolated substance of interest. Due to the recent exposure suitable immortal parental cell lines, so produc- to the antigen, many of the B cells in such an organ- tion of human hybridomas is rapidly progressing ism will be producing antibodies specifically com- (16,17). Recently, researchers have developed a plementary to the foreign substance just injected. promising new method to produce large quanti- This enrichment process is a key step in hybri- ties of human monoclinal antibodies (1). doma technology, since a human, for instance, is capable of producing up to a million different The availability of large supplies of monoclinal kinds of antibodies. antibodies is revolutionizing basic research, medicine, and commerce. Researchers have come to The hybridoma that results from the fusion of value monoclinal antibodies as important tools these two types of cells has characteristics of both for dissecting the molecular structure and mech- cells. As is often the case with tumor cells, the anisms of genes; more often than not, monoclinal myeloma parent cell has the ability to grow and antibody technology is combined with recombi- multiply continuously in culture—it contributes nant DNA technology. High-volume production this characteristic of “immortality” to the hybri- of rodent monoclinal antibodies has had a signif- doma. From the B cell, which is incapable of sus- icant impact on the diagnostic industry in particu- tained growth and cultivation in vitro, comes the lar. Monoclinal antibodies are reagents that are ability to secrete a single, specific type of antibody. easily standardized and provide reproducible re- Thus, a particular hybridoma clone is a distinct sults, These substances have been adapted to clin- cell line capable of continuously producing one ical and home test kits, such as pregnancy diag- and only one kind of antibody—hence the name nostic kits, with much success. Use of monoclinal monoclinal antibody. The culture conditions and antibodies for prophylactic or therapeutic regi- techniques used for hybridomas essentially are mens in humans is in an embryonic stage. those described for tissue and cell culture. Lymphokines

Two other specialized cell types involved in the ‘In this case, the antibody recognized a particular part of a sheep red blood cell. It is interesting to note that Milstein and Kohler did immune response are T lymphocytes and macro- not apply for a patent on this technique. phages. Like B lymphocytes, both of these cell —

Ch. 3—The Technologies 39

Figure 7.— Preparation of Mouse Hybridomas and Monoclinal Antibodies

% Mouse is immunized with a foreign substance or “antigen”

removed and minced to release antibody producing cells (B lymphocytes)

Mouse spleen cells

Myeloma cells are mixed and fused with B lymphocytes The products of this fusion are grown in a i selective medium. Only those fusion products which are both “immortal” and contain genes from the antibody-producing cells survive. These are called “hybridomas.” Hybridomas are cloned and the resulting cells are screened for antibody production. Those few cells that produce the antibodies being sought are grown in large quantities for production of monoclonal antibodies. SOURCE: Office of Technology Assessment, 1987. types can detect and respond to the presence of Lymphokines may recruit other cells to partici- foreign substances. However, rather than produc- pate in and augment an immune response. Some ing antibodies, T cells and macrophages produce lymphokines stimulate B cells to produce antibod- a variety of protein molecules that regulate the ies. Other molecules are released that suppress immune response. These molecules serve as mes- the immune reaction or ensure that the system sengers that transmit signals between cells to or- focuses on the irritant and does not run rampant chestrate a complete and efficient immune rein a nonspecific attack that would damage host sponse against a foreign invader. The term tissue. “lymphokines” was coined in 1969 to describe this group of nonantibody immune response modu- Lymphokines are present in human blood in ex- lators (3). Since that time, more than 90 lym- tremely small amounts-on the order of parts per phokine activities have been described. . billion. Interferon, for example, has been the most ———

40 ● Ownership of Human Tissues and Cells

widely examined Iymphokine to date by virtue of ucts of fusion events between immortal cancer its relatively “high” abundance. It takes approxi- cells and isolated T lymphocytes. mately 65,000 liters of blood to produce 100 mil- Even though researchers have isolated and iden- ligrams of interferon (21). A comparable task tified many types of human cells producing lym- would be the search for less than one-eighth of phokines, these cell lines are still not capable of a teaspoon of salt in a swimming pool. Thus, sci- generating sufficient quantities of these molecules entists knew that to use lymphokines to treat hu- for widespread use. The human cell lines are very man illness would require a source yielding a high- important, however, as rich deposits of source quality, high-quantity sample. material to clone lymphokine genes. Several dif- In addition to the problem of obtaining suffi- ferent genes have been cloned from human cells cient quantities of these important biological reg- that produce measurable amounts of lymphokines ulators, different lymphokines with antagonistic (16), and once a particular lymphokine gene has functions are often difficult to separate. In the been cloned, large quantities of the protein mole- past, such impure preparations of lymphokines cule can be obtained via the methods developed have hampered efforts to understand the basic for large-scale production of recombinant DNA mechanism of how the immune system responds products. to cancer or an agent of disease. Autoimmune dis- Large-scale production of pure lymphokines eases, for instance, are aberrations of the immune now enables scientists to examine many aspects system resulting in an organism attacking itself of the immune system puzzle by manipulating cells as a foreign substance. The availability of a lym- and lymphokines in vitro. The availability of com- phokine drug to suppress an individual’s immune mercial quantities of these pure immune regula- response could alleviate much suffering. Similarly, tors also affords physicians an opportunity to use other lymphokines could be used as therapeutic lymphokines for treating human disease. Human agents to boost a patient’s own immune system alpha-interferon has been approved by the Food to combat a foreign invasion. and Drug Administration (FDA) to treat certain Recent progress in obtaining pure lymphokine medical conditions and interleukin-2 is being used preparations is a result of advances in cell cul- in clinical trials to combat certain types of cancers ture, hybridoma, and recombinant DNA technol- or viral infections. Table 5 lists some of the lym- ogy. Scientists have now developed cell culture phokines that have been characterized and have conditions capable of sustaining continuous received considerable attention for their possible growth of cell lines producing elevated levels of use as human therapeutic agents. one or more lymphokines. Some of these lymphokine-producing cell lines are derived from tumor cells that have been adapted to tissue culture con- Table 5.—Some Lymphokines With ditions. Other cell lines have been isolated from Therapeutic Potential normal cells that have been manipulated in a man- Interferon ner to transform them into immortal lymphokine- Interleukin-l (also known as lymphocyte activation factor) producing cultures. lnterleukin-2 (also known as T cell growth factor) lnterleukin-3 The explosion in hybridoma technology also has lnterleukin-4 Colony stimulating factors influenced the study and development of hybrid B-cell growth factor T cell lines to produce lymphokines (6). Investiga- Microphage activity factor tors have had some success producing these hy- T-cell replacing factor Migration inhibition factor brid lymphokine factories, often referred to as SOURCE: Adapted from A. Mizrahl, “Biological From Animal Cells In Culture, ” T cell hybridomas. T cell hybridomas are the prod- Biotechnology 4:123-127, 1966. Ch. 3—The Technologies ● 41

RECOMBINANT DNA TECHNOLOGY

History Figure 8.— The Structure of DNA

In 1865, Mendel postulated that discrete biological units were responsible for maintaining characteristics in organisms from one generation to the next. The faithful transmission, or inheritance, of these units—called genes—is common to the entire spectrum of living organisms, It is a result of the remarkable capacity of a living cell to en- code, translate, and reproduce a chemical into its ultimate biological fate. The chemical responsible for inherited characteristics is deoxyribonucleic acid, or DNA. In 1965, a century after Mendel described the concept and principles of inheritance, also called genetics, the term “genetic engineering” was coined (9). The term genetic engineering is now also popularly referred to as “gene cloning” or “recombinant DNA .“ These techniques usually involve direct manipulation of the genetic material— the DNA-of a cell. Rather than rely on the appear- ance of spontaneous mutants or laborious extrac- SOURCE” Office of Technology Assessment, 1984 tion of minute quantities of a valuable substance from tissue, it is now possible to use these tech- the complete blueprint for an organism is coded niques to isolate, examine, and develop a wide within its DNA. range of biological compounds quickly. Like the use of cell culture, the use of recombinant DNA There are two broad categories of genes: struc- techniques is a reductionist approach that has shed tural and regulatory. Structural genes code for further light on the molecular details of regula- products, such as enzymes—proteins that cata- tion of many important biological processes, in- lyze biological reactions. Regulatory genes func- cluding arthritis, cancer, and development, The tion like traffic signals, directing when or how principal advantages of these techniques are speed much of a substance is produced. The process and ease of application. whereby the code of DNA is interpreted and a protein synthesized is summarized in figure 9. Gene Cloning All cells, except egg and sperm cells and some cells of the immune system, contain the total in- DNA, which takes the structural form of a dou- formation capacity of the organism. Thus, the DNA ble-stranded helix (figure 8), is the information present in one human cell is identical to all other system of living organisms. DNA in all organisms cells within the individual and has the capability is composed, in part, of four chemical subunits of directing all possible functions. In individual called bases. These four bases—guanine (G), ade- human cells, however, not all functions operate nine (A), thymine (T), and cytosine (C)—are the simultaneously. coding units of genetic information. These bases normally pair predictably—A with G, and T with The amount of DNA present in each cell of a C—to form the DNA double helix structure. It is human being is 3.3 billion base pairs (15). About the unique ordering of these bases in the helix 50,000 genes make up the complete human master that determines the function of a given gene, and plan, and the average gene contains about 1,000 42 ● Ownership of Human Tissues and Cells

Figure 9.-The Process of Gene Expression base pairs. Since this accounts for about only 50 million base pairs, it is apparent that not all of DNA the DNA within a human cell is devoted to modu- lating or specifying a particular gene product. To I date, specific functions have only been assigned to Transcription about 50 million of the 3.3 billion base pairs pres- I ent in humans. There is speculation that some of the unassigned 3.25 billion base pairs may contain . some genes, but that much of the “excess” DNA is for architectural or other unknown functions.

DNA Gene cloning refers to a process that uses a variety of procedures to produce multiple copies of a particular piece of DNA. Since the amount mRNA released and of DNA in a human cell is enormous compared transported to protein- to the amount present in an individual gene, the synthesizing machinery search for any single gene within a cell is like searching for a needle in a haystack. Therefore, a range of tools have been developed that allow investigators to both identify a gene and amplify the number of copies of the gene. As a metal de- tector allows easier detection of a needle in a haystack, and a photocopy machine reproduces doc- Translation uments, “recombinant DNA technology” is a group of methods that accelerates the investigation or production of genes. The specific details of these methods to join segments of DNA—sometimes I —vary from project to proj- from different species ect and purpose to purpose. In general, however, all recombinant DNA methods require the fol- Protein lowing: ● a suitable vector, ● an appropriate host, ● a system to select host cells that have received + recombinant DNA, and ● a probe to detect the particular recombinant organism of interest.

During gene expression, the genetic material of an organism Perhaps the hallmark discovery that allowed sci- is decoded and processed into the final gene product (usually entists to clone genes was the isolation of natu- a protein). In the first step, called transcription, the DNA double helix unwinds in the area near the gene, and a product rally occurring enzymes in bacteria that recog- called messenger ribonucleic acid (mRNA) is synthesized. nize and cut DNA at specific strings of bases. The This piece of mRNA is a single-stranded, linear sequence of string of bases recognized by the enzyme is usu- nucleotide bases chemically very similar to DNA and it is complementary to the section of the unzipped DNA. The sec- ally four to six bases in length and depends on ond step of the process is called translation. The mRNA is the particular bacteria from which the enzyme released from the DNA, becomes associated with the protein- is isolated. These enzymes, called restriction en- synthesizing machinery of the cell, and is decoded and “trans- Iated” into a protein product. donucleases, are used in gene cloning to fragment DNA into discrete, precise segments. Recent SOURCE: Office of Technology Assessment, 1987. reports have described modified restriction en- Ch. 3—The Technologies . 43

Figure 10.— Recombinant DNA: The Technique of Vectors serve as vehicles for the isolation and Recombining Genes From One Species With high copy reproduction of a particular DNA frag- Those From Another ment free from its normal environs. Vectors can be bacterial, viral, phage, or eukaryotic DNA-or they may be combinations of these DNAs. The characteristics of vectors differ from construc- New DNA tion to construction. Some are capable of stably enzvmes \ I maintaining a large piece of foreign DNA, some reproduce rapidly and in high copy number, while others, called shuttle vectors, can reproduce and function in both eukaryotic and prokaryotic cells. A critical consideration in commercial development of a cloned gene is the ability of the vector to achieve high product expression. The other principal player in a cloning system ~ produces large produces is the host organism. Once foreign, or donor, DNA amount of DNA protein has been inserted into the vector, the recombinant molecules must be introduced into an organism that provides an optimal environment for increasing the number of copies of the cloned DNA, producing large amounts of a gene product, or both. The host is often the bacterium Escherichia coli, but human cells, yeasts, and other cells can be suitable hosts. Mean generation time, ease of culture, ability to stabilize and adjust to presence Restriction enzymes recognize sequences along the DNA and of the vector(s), and ability to add sugar groups can chemically cut the DNA at those sites. This makes it pos- to a gene product are some important factors to sible to remove selected genes from donor DNA molecules to form the recombinant DNA. The recombinant molecule can consider in selecting a host. then be inserted into a host organism and large amounts of the cloned gene, the protein that is coded for by the DNA, In general, recombinant DNA technology works or both, can be produced. in this sequence: first, donor DNA is cut by restriction enzymes into many fragments, one of SOURCE: Office of Technology Assessment, 1987 which contains the sequence of interest. These different fragments are joined with vector DNA zymes that are now capable of cutting DNA at to become recombinant DNA molecules. The re- a sequence of the investigator’s choice (18,22). combinant molecules are then introduced into the With the aid of restriction enzymes, a particular host; for a variety of reasons, only some host cells fragment of DNA-often the gene of interest and will take up the recombinant DNA. After this proc- some neighboring bases-can be excised away ess, the fraction of host cells that received any from large, unwieldy pieces of DNA. recombinant DNA must be identified. This initial Cloning human and other eukaryotic genes is selection is often accomplished through the use usually more difficult technically than cloning bac- of antibiotics that kill those host cells that did not terial and viral genes. Refinements in recombi- receive recombinant molecules. nant DNA methods, however, have been invented. Finally, the small number of recombinant organ- Figure 10 illustrates the basic technique for pre- isms containing the specific donor DNA fragment paring a recombinant DNA molecule. The recom- of interest must be found. This process is combinant molecule can be prepared in a number of pleted via a tool that detects the gene or gene prod- ways, but ultimately the process involves linking uct of interest. This tool is called a gene probe. the DNA sequence of interest to a second piece Examples of gene probes include a segment of of DNA known as the vector, DNA similar to the gene of interest, but from a —

44 ● Ownership of Human Tissues and Cc//s

different organism; a synthetic fragment of DNA been achieved, the host population containing the deduced from the protein sequence of a gene cloned gene can be expanded and the cloned gene product; a piece of RNA; or an antibody that binds used to identify, isolate, and scrutinize scarce bio- to the product of interest. logical compounds. Once identification and purification of the genetically engineered (recombinant) organism has

SUMMARY AND CONCLUSIONS

Technologies grouped under the umbrella term able in minute and usually impure amounts—if “biotechnology” include tissue and cell culture, at all. Lymphokines, also called bioregulators or hybridoma technology, and recombinant DNA biological response modifiers, have significant technology. Tissue and cell culture, the oldest of therapeutic promise in the treatment of a spec- the three technologies, involves converting un- trum of diseases because of their exquisite speci- developed human biological materials into cell ficity and reduced toxicity. Hybridoma, cell cul- lines capable of indefinite growth in a laboratory. ture, and recombinant DNA technologies permit Establishing human cultures is still a relatively dif- lymphokines to be isolated in pure form and in ficult enterprise, and the human cell line result- quantities facilitating further analysis or use. Hu- ing from any single sample has undergone many man alpha interferon, a lymphokine produced by changes. Continuous cultivation of cell cultures a combination of the biotechniques, was approved requires stringent control of temperature, nutri- in 1986 by the FDA for use in the treatment of ent, pH, and sterile conditions. The use of human one form of leukemia. cell lines in research has contributed much to our Genes are composed of DNA and they are re- knowledge about human genetics and the regu- sponsible for the faithful inheritance of char- lation of normal and abnormal biological proc- acteristics from one generation to the next. Re- esses. Cell lines also have been used for a broad combinant DNA technology, also called genetic range of commercial purposes. engineering, involves techniques that allow direct Hybridoma technology is a spinoff technique manipulation of the genes—the DNA-of a cell. from cell culture. Hybridomas are special hybrid cells that are produced by fusing two types of cells: an antibody-producing B lymphocyte and a tumor cell called a myeloma. A hybridoma is capable of multiplying continuously in culture (a property it receives from the myeloma) as well as secreting antibodies with a single specificity (an ability gained from the B lymphocyte). The antibodies produced by hybridomas are called monoclinal antibodies. Not only are monoclinal antibodies important laboratory tools, but some are significant commercial commodities. one specific mouse monoclinal antibody was approved by the FDA in 1986 for use in the treatment of kidney transplant rejection. Lymphokines are molecules that are secreted by specialized cells called T lymphocytes and macrophages. Many of these substances occur naturally in the human body, but were previously avail- Courtesy of: L. Gonich and M, Wheelis, The Cartoon Guide to Genetics Ch. 3—The Technologies ● 45

Gene cloning uses a variety of these recombinant The ease of application of biotechnology proc- DNA techniques to join segments of DNA, some- esses has allowed researchers to turn undeveloped times from different species, in a form that al- human tissues and cells into human biological lows multiple copies to be made. These multiple products with significant therapeutic promise and copies can then be used to examine the regula- commercial potential. Yet the ultimate value of tion of a biological process, identify and isolate these technologies may not be simply their end scarce compounds, or produce commercial quan- products; their greater value may be the insights tities of an important substance. Three commer- they provide about disease processes. cial products created through gene cloning— human growth hormone, human insulin, and human alpha interferon–have been approved for use in humans by the FDA.

CHAPTER 3 REFERENCES

1. Casali, P., Inghirami, G., Nakamura, M., et al., “Hu- 11. Kohler, G., and Milstein, C., “Continuous Cultures man Monoclonals From Antigen-Specific Selection of Fused Cells Secreting Antibody of Predefine of B Lymphocytes and Transformation by EBV, ” Specificity, ” Nature 256:495, 1975. Science 234:476-479, 1986. 12. Kohler, G., and Milstein, C., ‘(Derivation of Specific 2. Dendy, P.P. (cd.), Human Tumors in Short Term Antibody-Producing Tissue Culture and Tumor Culture: Techniques and Clinical Applications (New Lines by Cell Fusion, ” European Journal of Immu- York: Academic Press, 1976). nology 6:511, 1976. 3. Dumonde, D. C., Wolstencroft, R. A., Panayi, G. S., 13. Lasfargues, E. Y., ‘(Human Mammary Tumors,” Tis - et al., “ ‘Lymphokines’: Non-Antibody Mediators of sue Culture: Methods and Applications, P.F. Kruse, Cellular Immunity Generated by Lymphocyte Ac- Jr., and M.K. Patterson, Jr. (eds.) (New York: Aca- tivation, ” A’ature 224:38-42, 1969. demic Press, 1973). 4. Freshney, R. I., Culture of Animal Cells: A Manual 14 Martin, G. M., “Human Skin Fibroblasts, ” Tissue Cul- of Basic Technique (New York: Alan R. Liss, Inc., ture: Methods and Applications, P.F. Kruse, Jr., and 1983). M.K. Patterson, Jr. (eds.) (New York: Academic 5. (;eY, G.()., Coffman, W .D., and Kubicek, M. T., “Tis- Press, 1973). sue Culture Studies of the Proliferative Capacity 15. McKusick, V. A., The Johns Hopkins University of Cervical Carcinoma and Normal Epitheliums,” School of Medicine, Baltimore, MD, personal com- Cancer Research 12:264, 1952. munication, May 1986. 6 Ha”mmerling, G. J., Hammering, U., and Kearney, 16. Mizrahi, A., “Biological From Animal Cells in Cul- J. (eds.), Monoclinal Antibodies and T-cell Heybri- ture,” Bio/Technology 4:123-127, 1986. domas: Perspectives and Technical Advances (New 17. Pinsky, C. M., ‘(Monoclinal Antibodies: Progress Is York: Elsevier/North Holland, 1981). Slow But Sure, ” New England Journal of Medicine 7. Harrison, R. G., “Observations on the Living Devel - 315(11):704-705, 1986. oping Nerve Fiber, ” Proceedings of the So;iettiv for 18. Podhasjska, A.J., and Szybalski, W., “Conversion Experimental BiologV and Medicine 4:140-143, of the F’okI Endonuclease to a Universal Restric- 1907. tion Enzyme: Cleavage of Phage M13mp7 DNA at 8. Hayashi, I., and Sate, G., “Replacement of Serum Predetermined Sites, ” Gene 40:175-182, 1985. by Hormones Permits Growth of Cells in a Defined 19. Pont&, “Human Glial Cells, ” Tissue Culture: Meth- hledium,” Nature 259:132-134, 1976. ods and Applications, P.F. Kruse, Jr., and M .K. Pat - 9. Hotchkiss, R. D., “Portents for a Genetic Engineer- terson, Jr. (eds.) (New York: Academic Press, 1973). ing, ” Journal of Heredi{v 56:197, 1965. 20. Sate, G., “The Role of Serum in Cell Culture, ” Bio- 10. Kaighn, M. E., “Human Liver Cells,” Tissue Culture: chemical Action of Hormones, G. Witlack (cd. ) (New Methods and Applications, P,F. Kruse, Jr., and M.K. York: Academic Press, 1975). Patterson, Jr. (eds. ) (New York: Academic Press, 21. Stewart, W. E., The Interferon S&vstem (Wien, ATY: 1973). S~ringer-Verlag, 1981). 46 ● ownership of Human Tissues and cc//S

22. Szybalski.Szybalski, W., “Universal Restriction Endonucle- 23. U.S. Congress, Office of Technology Assessment, ases: Designing Novel Cleavage Specificities by Commercial Biotechnology: An International Anal- Combining Adapter Oligodeoxynucleotide and En- ysis, OTA-BA-218 (Elmsford, NY: Pergamon Press, zyme Moieties, ” Gene 40:169-173, 1985. Inc., January 1984). —— — —..— —-— . .—.—. . ————-

Chapter 4 The Interested Parties

“Biomedical research is in considerable measure so esoteric an activity that a great deal of the social control that guides it must be in the hands of the biomedical research community itself. Yet, like all other specialized and esoteric social activities, biomedical research is too important to the larger society to be left entirely to its experts. In part it needs to be effectively and continuously scrutinized and controlled by outsiders. An effective system of control, including both insiders and outsiders would better protect all the parties of interest . . .“ —Leon R. Kass Science, 174:779-788, 1971 1

CONTENTS

Page Why Commercial Interest in Human Biological Research and Inventions? ...... 49 Patentability of Recombinant and Nonrecombinant Cell Lines ...... 49 Patenting and Licensing of Government-Sponsored Inventions ...... 50 Effect of 1980 Patent Law Changes on Biocommerce ...... 50 Sources of Human Tissue ...... 51 The Research Community ...... 52 Obtaining Human Biological Materials for Research ...... 52 Uses of Tissues and Cells in Research ...... 54 The Research Process and Rarity of Human Tissue ...... 55 Industry ...... 56 The Companies ...... 56 Industrial Product Development ...... 60 University-Industry Relationships ...... 61 Fee-for-Service Research ...... 62 Summary and Conclusions ...... + ...... 63 Chapter preferences...... 63

Tables Table No. Page 6. Repositories for Human Tissues and Cells, Cell Cultures, and Cloned Genes . . 53 7. Financial Statistics for Selected Biotechnology Companies ..., ...... 58 8. Estimated U.S. Marketing Date for Some Human Therapeutic Products...... 58 9. Some Human Therapeutic Products Being Developed by the Biotechnology Industry ...... 59

Figures Figure No. Page 11. Rarity of Human Tissues and Cells Used in Biotechnology ...... 56 12. Number of Human Therapeutic Biotechnology projects by Company ...... 57 13. The Development of Angiogenin ...... 61

Box Box No. Page C. Angiogenin: A Case History From Research to Product Development...... 60 Chapter 4 The Interested Parties

Why has controversy arisen over the use of hu- ing legal climate in the United States also has been man biological materials, and who are the stake- a factor responsible for increasing interest in hu- holders in this controversy? How has it even come man biological materials. These events have led to pass that naturally occurring substances, such to an increased commercial interest in human as genes, plasmids, and even organisms, can be specimens and have affected three major groups patented? While the technological advances de- of stakeholders: the sources of human tissues and scribed in chapter 3 have increased the availabil- cells, the research community, and the biotech- ity and promise of new inventions and products nology industry. of great importance to human health, the chang-

WHY COMMERCIAL INTEREST IN HUMAN BIOLOGICAL RESEARCH AND INVENTIONS?

The controversy that has arisen over the use Later, the U.S. Court of Customs and Patent Ap- of human tissues and cells can be attributed in peals (CCPA) reversed this ruling (29), relying on part to two landmark events that occurred in 1980 a prior decision in In re Bergy that held “the fact to accelerate industry-sponsored research and in- that microorganisms are alive is a distinction with- terest in human biological materials. First, the U.S. out legal significance” (27). Bergy concerned the Supreme Court held for the first time that Fed- creation of a biologically pure culture of a natu- eral patent law applies to new life forms created rally occurring but previously undiscovered by DNA recombination, thus opening the possi- micro-organism capable of efficiently producing bility that products containing human cells and an antibiotic similar to penicillin. A patent had not genes might also be patentable. Second, Congress been sought for the naturally occurring micro- amended the patent statute to encourage patent- organism, but one was sought for the purified sam- ing and licensing of inventions resulting from gov- ple and the processes used to create the pure ernment-sponsored research. culture. A chain of related Supreme Court and CCPA Patentability of Recombinant and decisions ultimately led to a five-to-four Supreme Nonrecombinant Cell Lines Court ruling upholding the CCPA’s decision that genetically engineered microorganisms are within In the early 1970s, General Electric microbiolo- the scope of patentable subject matter defined by gist Ananda Chakrabarty used both classical section 101. The high court Diamond v. Chakra- genetic selection and recombinant DNA tech- barty decision (14) makes it clear that the ques- niques to find and develop a novel bacterial strain tion of whether or not an invention embraces capable of digesting oil slicks. Chakrabarty and living matter is irrelevant to the issue of pat- his employer sought patent protection under the entability, as long as the invention is the re- Federal patent statute (35 U.S.C. 101). While judg- sult of human intervention. ing the process for producing and maintaining the new bacterium to be patentable, the Patent and The court did not directly address the question Trademark Office examiner rejected patent claims of whether purified nonrecombinant cell samples to the bacterium itself. The Patent and Trademark are patentable since Chakrabarty dealt with a ge- Office’s Board of Appeals upheld the examiner’s netically recombined organism and the Bergy case rejection on the ground that living organisms were was not directly considered, However, the CCPA’s per se unpatentable. second Bergy decision (28) suggests that a puri-

49 50 . Ownership of Human Tissues and Cells fied strain of naturally occurring organisms is stat- production facility. Potentially valuable research utory subject matter unless precluded under the thus remained unexploited. “product of nature” doctrine (6). Congressional concern about this so-called “in- Under the product of nature doctrine, a cell or novation lag” prompted efforts to develop a uni- other substance occurring in nature is not patent- form patent policy that would encourage coop- able unless it is given a substantially new form, erative relationships between universities and quality, or property not present in the original industry, with the goal of taking government- (6,46). Purification of a naturally occurring sub- sponsored inventions off the shelf and into the stance or organism must result in a substantial marketplace. In 1980, Congress passed the Pat- change in its characteristics, functions, or activ- ent and Trademark Amendment Act (Public Law ity for the purified material or cell line to be patent- 96-517) and added additional amendments in 1984 able (6). If a patent examiner decides to reject (Public Law 98-620).’ The law allows nonprofit patentability for an invention on grounds that it institutions (including universities) to apply for is a product of nature, he must show that the patents on federally funded inventions, with the claimed product, such as a biologically pure cul- Federal agency retaining a nonexclusive world- ture, is likely to exist in nature as a result of nat- wide license. Universities are required to share ural processes and not merely that it possibly royalties with the inventor and to use their own exists in nature (6,56). share for research, development, and education. The patent policy of the National Institutes of The Patent and Trademark Office has histori- Health (NIH) served as a model for the uniform cally taken the position that, in the absence of a patent policy established by the law. Supreme Court ruling addressing the issue, higher life forms such as mammals, fish, and insects will not be considered to be patentable subject mat- Effect of 1980 Patent Law Changes ter under section 101 (56). This position finds some on Biocommerce support in a statement in Bergy that biologically The impacts of technological breakthroughs and pure cultures created and used for their chemi- the changing legal climate on human biological cal reactions are more similar to inanimate chem- product development is demonstrated by a 1985 ical compositions than they are to animals or plants survey of American medical institutions conducted (27). However, the rationale for this position is by the House Science and Technology Commit- somewhat weakened by the Court’s statement in tee’s Investigations and Oversight Subcommittee. Chakrabarty that “Congress intended statutory During the 5 years from 1980 to 1984, patent ap- subject matter to include anything under the sun plications by universities and hospitals for inven- that is made by man” (14). tions containing human biological increased more than 300 percent as compared with the preced- Patenting and Licensing of ing 5-year period and constituted 22 percent of Government-Sponsored Inventions all patent applications filed by these institutions. Forty-nine percent of all medical institutions have The Federal Government is the primary source applied for such patents (50). of funding for basic biomedical research. Yet until 1980, no single patent policy existed with re- Whether these and forthcoming patents will be spect to government-supported research. Each of commercial value is difficult to assess. The phar- agency developed its own rules, resulting in 25 maceutical industry has usually experienced a different patent policies, and under this system, higher rate of commercial value for its patents only about 4 percent of some 30,000 government- than industry in general (10). There is reason to owned patents were licensed (40). Furthermore, believe that biopharmaceuticals will have a still the government policy of granting nonexclusive higher rate since they often have the potential licenses discouraged investment, since a company lacking an exclusive license was reluctant to pay IThe U.S. Department of Commerce recently requested comment the cost of developing a product and building a on revised regulations under this statute (51 FR 22508). Ch. 4—The Interested Parties ● 51

to supplant an entire, well-established market oc- pattern will be established in the biotechnology cupied by a conventional drug (41). At this point, industry for the commercial value of patents. however, it is still too early to determine what

SOURCES OF HUMAN TISSUE

Individuals who are sources of human tissues ● Cadavers are the only permissible source of and cells are one major group of people affected normal and atypical vital organs (including by the U.S. Supreme Court and congressional ac- the brain, heart, and liver, but excluding kid- tions contributing to increased development and neys and corneas). They are also the only per- commercialization of human biological materials. missible source of healthy organs (e.g., cor- Tissues and cells can be removed from sources neas) destined for research rather than for medical purposes, research purposes, or both. transplantation. The primary medical reasons for withdrawing human biological materials are diagnosis (removal While the different classifications of human of specimens to determine the nature and extent sources—patient, volunteer research subject, or of a disease) and therapy (removal of diseased tis- cadaver—may seem to be fairly straightforward, sue, either permanently or for treatment and rein- the human relationships involved between sources troduction, as in renal dialysis or homologous bone and physician/researchers (or another interested marrow transplants). Removing human specimens party) are more dynamic than these categories can involve a variety of procedures, including: suggest. ● aspiration of bodily fluids (e.g., blood, am- For example, the distinction between an indi- niotic fluid) through a needle; vidual as a patient versus a research subject can ● examination of cells from a surface (e.g., skin sometimes change over the course of time. The or cervix cells from a Pap smear); relationship between physician and patient can ● surgical removal of nonsurface tissue (e.g., also evolve from physician-patient to researcher- lymph node biopsy, tumor material); and subject. Thus, if a patient’s specimen is removed ● noninvasive procedures to collect excretions for diagnostic or therapeutic purposes and the (e.g., urine and feces) and certain secretions physician subsequently uses the specimen in re- (e.g., semen, saliva, milk, and perspiration). search, should the patient still be considered a There are three major categories of sources of patient, or has he become a research subject and human tissues and cells: patients, healthy research has the relationship become one between research subjects, and cadavers. subject and researcher? Or, if a patient hospi- talized with a broken leg is asked to donate a blood ● Patients area source of both normal and atyp- sample, should he be considered a research sub- ical specimens and these individuals may or ject because any risk he undergoes is for altruis- may not be research subjects. Patient-derived tic rather than selfish reasons, or is he still a pa- specimens may be ‘(leftovers” from diagnos- tient because of the possibility that he may feel tic or therapeutic procedures and most hu- coerced to cooperate with the hospital staff on man tissues or cells that find their way into whom he is physically and psychologically de- research protocols are of this type. Patient- pendent? derived samples can also be provided as part of a research protocol. Determining whether a person is a patient or ● Healthy volunteer research subjects may a research subject is relevant in determining the donate replenishing biological if specimen applicability of Federal regulations governing fed- removal involves little or no risk of harm, erally funded research using human biological ma- according to generally accepted principles of terials. These issues are addressed further in chap- human subject research. ter 6. .— — .

52 ● ownership of Human Tissues and Cells

THE RESEARCH COMMUNITY

Investigators who use human tissues and cells or receive the material after pathologists have ex- in their research are a second stakeholder in the amined it (48). controversy about access, use, and profit from Nonphysician researchers or clinicians needing specimens. A recent survey conducted by the human tissues or cells that are not obtainable from House Committee on Science and Technology their own patients or patients within the hospital found that 49 percent of the researchers at medi- obtain specimens by other avenues. Informal cal institutions surveyed used human tissues or transfers are common among researchers at hos- cells in their research (50). According to one re- pitals and universities around the country. Re- cent estimate, at least 500 principal investigators searchers and companies are becoming more cau- nationwide use human cell lines (42). NIH provides tious, however, and are moving toward a much grants to about 200 individuals whose primary tighter, more formal system of transferring re- research focuses on human cell lines and to an search materials. This caution is a result of con- undetermined number of scientists whose second- cerns over patent and ownership rights and it ap- ary interest is human-related (34). The use of hu- plies to newly isolated tissue, as well as man specimens is principally due to three factors: investigator-developed cell lines and gene clones ● the newly emerging abilities to isolate increas- (41,43). ingly smaller amounts of important naturally Researchers at some large universities and re- occurring human biological factors (also search institutes also can obtain needed material known as biopharmaceuticals, bioresponse from volunteers who are asked to donate tissue modulators, or biological mediators); samples. For example, at NIH, blood is collected • the ability to produce virtually unlimited by the NIH Blood Bank specifically for research quantities of these factors, usually found in purposes. Most volunteer donors are members minute amounts in the body, through recom- of the NIH staff, although some outside donors binant DNA methods; and are also used. Payment for blood donations for ● the invention of hybridomas, making possi- research purposes is usually about $25. Volun- ble the generation of large, pure supplies of teers providing bone marrow for research pur- specific antibodies (47). poses receive around $75 for a specimen (45). Gen- erally, these types of arrangements are ad hoc, and no systematic data are available on the Obtaining Human Biological amounts and type of human materials collected Materials for Research or on payments for such material. Although tens of thousands of samples of hu- Researchers at biotechnology and pharmaceu- man tissue are probably used in research, detailed tical companies who need human biological also information on the amount and type of human have a variety of options at hand for obtaining biological materials used is difficult to obtain. No materials. They can pay individual volunteers for central records are kept on this data, and infor- occasional specimens, usually of blood, or pur- mation on the source or use of human biological chase outdated blood from the Red Cross or other by biotechnology companies is often considered blood banks. Biotechnology companies often ob- confidential business information. Moreover, the tain specimens as a result of their research rela- ways in which researchers obtain human samples tionships with universities and medical research vary with the type of scientist and the nature of centers. The biotechnology company may obtain the research. specimens either through individual affiliations with university/hospital researchers or through Physicians working at a university hospital will research arrangements with university and hos- often obtain tissue as a result of biopsies or surgery pital departments (12,25,38)41,43), done on their patients. The physician/researcher may obtain samples directly from the operating Organized repositories provide an additional room in cases when fresh, live tissue is needed, avenue for both noncommercial and commercial Ch. 4—The Interested Parties 53 investigators to obtain research material. Most of the material available from these “warehouses” are not human biological as defined in this report–i.e., primary tissues or cells–but are cell lines or gene clones (containing human DNA pieces) developed and discovered by investigators and deposited at the repositories. Organizations in this field are usually funded by NIH and operated on a nonprofit basis, providing samples of tissue and genetic material to qualified researchers for a nominal processing fee. Many universities and cancer research centers maintain their own collections as well. Table 6 lists some of these facilities and indicates some of the types of mate-

rial each stores. Photo credit: National Institutes of Health Although no systematic survey was undertaken Human cell lines at the American Type Culture for this analysis, anecdotal information suggests Collection’s Human Tumor Cell Bank are put into that most university or other nonprofit research- ampules for shipment to researchers. ers usually are able to obtain the samples they need for research, but individuals who need cer- mens. Colon and bladder carcinomas are two tis- tain types of tissue must make their own arrange- sues currently in high demand (1,13,23). ments. The process, however, of obtaining samples is sometimes characterized as a “scramble. ” To assist in this process, various organizations, Additionally, odd samples are usually less in de- networks, and interchanges, are undertaking mand than some common types of cancer or tis- more comprehensive coordinating activities. In sue. Research popularity coupled with a higher 1980, a nonprofit organization, the National Dis- incidence of a particular tumor can result in fierce ease Research Interchange (NDRI), pioneered the competition for a continued supply of new speci- world’s first retrieval/preservation/distribution mechanism for organs and tissues. NDRI makes over 100 types of tissues available to researchers studying a wide range of diseases, including dia- Table 6.— Repositories for Human Tissues and Cells, betes, retinitis pigmentosa, cardiovascular disease, Cell Cultures, and Cloned Genes cystic fibrosis, and glaucoma (55). In response to Organization Type of material collected inquiries, the National Cancer Institute (NCI) has The American Type Culture Collection issued a request for cooperative agreement ap- (ATCC)a Cell cultures, cloned genes plications to establish a cooperative network, in- b The Human Genetic Mutant Cell Repository, cluding computer communication, to improve col- Coriell Institute (formerly the Institute for Medical Research) ., Cell cultures lection and distribution of human cancer tissues The National Cancer Institute, Biological (54). The network is not a tissue bank, but will Carcinogenesis Branch Sera, tumor tissue respond to requests from investigators to help (benign and malignant) The Cell Culture Center, Massachusetts them obtain the multiple fresh tumor samples they Institute of Technology Cell cultures need to screen for tumor protein markers, genes, aThe ATCC IS one of the largest repositories of Its type mamtammg some 40000 cultures mclud- lng about 1 325 human cell Imes (48) These materials are prowded fo nonproht researchers and other characteristics (1). NIH recently for an average fee of $40 and to for-profit researchers at an average fee of $64 Many research- awarded a contract to the University of Minnesota ers send samples of their cell cultures to the ATCC I or other repositories) once they have been developed and reported 10 avoid the t[me and money required to respond to requests for samples Hospital in Minneapolis for a “Liver Tissue Pro- from o!her researchers Samples are requued to be placed m a repowtory If a patent apphca!!on has been f(led relatlng 10 the sample Access to samples for which patents are pending IS strictly curement and Distribution System. ” This program restricted once a palent IS granted [he sample IS ava(lable to anyone In 1985 ATCC distributed is designed to establish regional centers to collect between 12000 and 19000 human cell cultures 10 researchers the majority of which went to unlversltles and hosp!tal research centers (see refs 19351 livers removed from transplant patients and then bThe Human Genetic Mutant Cell Reposlfory with 3550 human Cd 1106’S In stock responded to 3472 requests In 1985 (see refs 52 53 I distribute them to researchers nationwide. Finally, SOURCE Off Ice ot Technology Assessment 1987 a project at the University of Alabama is also be- 54 ● Ownership of Human Tissues and Cells ing designed to address shortages in the availability produced; or serve as a medium to propagate of tissue for research (23). viruses or amplify cloned DNA sequences. At the most fundamental scientific level, human mate- Uses of Tissues and Cells rial is used in experiments to examine and under- in Research stand basic biological processes. This basic research can subsequently lead to other uses of The research community uses undeveloped tis- human tissue, such as product development by sues and cells provided by sources for a wide the commercial sector. range of purposes. Material obtained from an in- Commercial enterprises use specimens as raw dividual is not necessarily used strictly for re- materials for both product-oriented purposes and search purposes, however, but can be divided for nonproduct--oriented basic research. The use of medical, research, or commercial uses. In fact, human biological by companies for nonproduct diagnostic, therapeutic, research, and commer- research differs little from that just described for cial uses of biological are usually intertwined, nonindustrial research. In product-oriented re- sometimes inextricably. The present economic dy- search, a specimen could be used for a one-time namics of research coupled with the proliferation process to produce or test something, or it could of biotechnology companies have spawned a pleth- be used as part of a long-term investigation to pro- ora of university-industry relationships that have duce a product. Proteins might be extracted from made it increasingly difficult to separate the use human specimens or tissue culture cell lines de- of human samples in university (or other rived from specimens. Similarly, genes for these institution-based) basic research from basic and useful proteins might be isolated by industrial re- applied research in commercial settings. searchers directly from undeveloped material or Uses of human tissues and cells in basic research from an established cell line. These cloned genes are diverse and thus difficult to categorize, once can then be used to mass produce large quanti- human biological material is provided by an indi- ties of therapeutic or diagnostic human-derived vidual, it is examined, manipulated, and developed products. Human insulin, human growth hor- by researchers. Human tissues and cells can be mone, and human alpha-interferon are three prod- examined directly from the patient with limited ucts produced through recombinant DNA tech- handling (e.g., screened for a particular tumor niques that are licensed for therapeutic use in the marker) or they can be manipulated extensively United States. Standardized diagnostic products to obtain a useful research tool or potentially mar- (e.g., pregnancy test kits) often contain human ketable product. Generally, basic researchers use proteins. these materials to study the characteristics and Companies also sometimes use human-derived functions of healthy and diseased organs, tissues, material to study the efficacy of an item prior to and cells. marketing, to meet safety criteria, or to manu- The researcher’s choice of a source of specimen facture a biological product such as a viral vac- is based on the type of tissue being studied and cine. Specimens can be used as reagents in feder- the goals of the particular research project. The ally required, preclinical testing of pharmaceutical material could be used for a “one-shot” experi- products (44). Use of such reagents is necessary ment or used in the long-term development of to develop the potential value of the product, but something (e.g., a cell line, cloned gene, or gene is not itself the marketable item. The material used probe) that expands the base of knowledge about by the company for testing or manufacturing could a complex problem and advances the investiga- be newly isolated specimens or standard cell lines. tor’s project. Specimens can also be used by the The new technologies, such as hybridoma tech- researcher to create cell lines that generate a con- nology or recombinant DNA technology, led the tinual supply of products such as monoclinal an- Food and Drug Administration (FDA) to recently tibodies; provide insight into a patient’s heredi- amend its regulations to establish general require- tary disease; provide the basic genetic material ments for cell lines used for manufacturing any from which recombinant products can be biological product for human use (5 I FR 44451). Ch. 4—The Interested Parties ● 55

Some firms maintain that they do not use any Although the goal of a researcher is often to original human tissue in research, concentrating obtain many random samples of human tissue or their efforts on established cell lines instead. These cells, once a scientist has investigated different companies obtain and manipulate generally avail- tissue samples it may become apparent that one able cell lines, resulting in new, unique, or im- or a few specimens (or the cell line the investiga- proved cell lines. tor has developed) “overproduces” an interesting substance. Some people might naturally produce greater than normal amounts of a substance, or some might overproduce it because of an illness. The Research Process and Rarity of This overproduction could enable the researcher Human Tissue to identify a novel entity that would otherwise To what extent are human biological mate- have gone undiscovered, or the overproduction rials, provided by any single (or very few) in- could be useful in further research and experi- dividuals), potentially profit-yielding to the re- ments (21)—particularly if the investigator has search community because the material is been fortunate and able to establish a culture of the sample that continues the overproduction. both commercially useful and rare? Biomedi- Thus, once found (usually serendipitously) a novel cal research and development using human ma- tissue or cell can become a valuable research tool terial is a dynamic process that rarely culminates or be developed into a potential commercial prod- in a profit-making product. Research results are typically a series of several joint efforts with uct. It should be emphasized, however, that a sys- specimens provided by several individuals. tematic method of obtaining such unique tissues or cells does not appear to exist. Furthermore, This diversity is critical to advancing the knowl- unique human samples do not necessarily edge about an area under study and the expecta- have any actual or potential commercial value. tion of developing a commercial product at the outset of the research is often extraordinarily It is conceivable, of course, that one person or small. Thus, any product developed is a conse- only a handful of people are overproducers of a quence of many source and researcher contri- potential commercial substance. More likely, how- butions. A determination of the contribution ever, many people are overproducers but simply of any single individual in the marketable have not been identified by researchers (nor could product would be speculative. they feasibly be identified). Furthermore, while some people are overproducers, nearly all per- In general, the value to the researcher of cer- sons are capable of being high, moderate, or low tain types of tissue results more from the key is- producers of the substance (unless an individual sues of access and availability to the sample than has a deletion in the gene for the substance— from the inherent rarity or commercial potential which is a rare condition itself), and once the sub- of the tissue. Both industry and nonindustry- stance has been identified with the aid of the over- supported investigators usually are interested in producer, it usually can be detected in and iso- a specified type of tissue that occurs with a known lated from anyone’s tissue. Thus, while the original frequency in the population, but cannot be termed specimen(s) may have been useful to initially iden- truly rare—such as cells from a cystic fibrosis pa- tify an interesting product, its value for commer- tient; a particular type of tumor (e.g., breast, lung, cial exploitation is diminished because the sam- liver, or other); or a collection of samples from several generations of a family. Certain types of ple is not truly rare. specimens might be more easily obtained (e.g., In a few instances, however, a specific biologi- blood instead of bone marrow), or certain sam- cal substance is sought in a group of individuals ples might not be commonly removed during sur- to produce a specific quantity of a pharmaceuti- gery (e.g., healthy spleens). The typical goal when cal product (which may or may not be produced obtaining human specimens is acquiring any liver with the aid of biotechnology). These sources are tumor, for instance, not obtaining one from a spe- usually paid for their specimens; the amount paid cific individual that is truly rare. depending on a variety of factors, including the Figure 11 .- Rarity of Human Tissues and Cells takes the form of a pyramid (see figure 11). At Used in Biotechnology the bottom are the vast majority of materials, relatively common and easy to obtain (though by no means does this irnply an infinite supply). Much farther up the pyramid is an intermediate level,

where particular samples may exhibit uncommon characteristics (e.g., the overproducers of certain substances mentioned above) or occur in the pop-

ulation at a low frequency (e.g., a genetic disorder like Tay-Sachs). At the top of the pyramid are the few cases of true uniqueness, which are by defi-

nition difficult, if not impossible, to identify in ad-

vance of chance discovery. Assigning, a priori} a value to any one level is not possible since a commercial product can be developed from tissues and ceils obtained from any level. Fi- nally, to an increasing degree, both the “uncom- SOURCE: Office of Technology Assessment, 1987, monness” of cell tissue at the intermediate level and the “rarity” of some specimens at the top level number of people who are potential sources. An can be overtaken by technology. That is, rarity example would be the bleeding of people with of the original sample is not the only important chronic hepatitis who have the viral antigen nec- factor because as newer techniques develop, re- essary to prepare hepatitis B vaccine from human searchers are better able to detect novel sub- serum (9). In these isolated instances, a reason. stances or purify smaller amounts of known com- able attempt can be made to determine the ratio pounds. Once the peculiarities of the tissue or ceil of source material to final commodity. line have been identified and studied, biotechniques (e.g., gene cloning) provide a means to re- the issue of rarity in human bi- In summary) produce the peculiarity without further need of ological used in biotechnological research the material itself,

INDUSTRy

The biotechnology industr is a third major y The Companies stakeholder in the controversy surrounding the use of human tissues and cells for financial gain. There are nearly 350 commercial biotechnol. It is comprised of a variety of different types of ogy firms in the UI ited States activ.ely engaged organizations including the established pharma- in—biotechnology research and commercial prod- ceutical companies, oil and chemical companies, uct development and approximately 25 to 30 per- agricultural product manufacturers, and the new cent appear to be engaged in research to develop biotechnology companies, A detailed treatment a human therapeutic or diagnostic reagent (37), of commercial biotechnology activities was pub- Many companies are developing several human lished in 1984 by OTA (51); thus this section pro- therapeutic products (see figure 12). Most, but not vides only a brief description of pharmaceutical. all, of the human therapeutic products are derived related biotechnology companies to give a sense from human tissues and cells, or human cell lines of the current and projected levels of activity in or cloned genes. (Most human diagnostic reagents the industry. This section also discusses the prod- are rodent-derived.) uct development process. Ch. 4—The Interested Parties ● 57

Figure 12.—Number of Human Therapeutic Biotechnology Projects by

41)

(19)

(11) (lo)

1 (5) (4) v (3) (2) (2) (1) (1) (1)

1 23 4 5 6 7 8 9 10 11 12 13 14 15 >15

Number of products SOURCE: L 1. Miller, E?iotec/mo/ogy Industry 1986 Fact Book (New York: Paine Webber, 19S6). 58 Ownership of Human Tissues and Cells

In addition to the commercial firms operating established firms provide two significant advan- in the United States, there is a strong international tages to fledgling, startup companies. First, the component to the biotechnology industry, with experience and long-term funding capacities of numerous research and development arrange- pharmaceutical firms are believed to be needed ments and partnerships between American firms for the extensive product testing phases that must and firms in Japan and Europe. Recent financial precede any commercial marketing of a human statistics on the top 10 U.S. firms in the industry therapeutic product (57). Second, the professional are provided in table 7. sales forces of the pharmaceutical companies are seen as necessary for immediate, successful mar- Through 1985, no new biotechnology firm had keting of biotechnology products. Major multina- reported annual sales over $100 million or net tional pharmaceutical firms based in the United profits over $6 million. Revenues in the industry have come largely from contract research and research and development (R&.D) partnerships, Table 8.—Estimated U.S. Marketing Date for Some Human Therapeutic Productsa rather than product sales (7). Since 1980, the biotechnology industry has raised about $1 billion 1982 1990 in corporate and public investments, excluding Insulin Bone morphogenic protein 1983 Colony stimulating factor about $400 million in R&D limited partnerships 1984 (alpha) (5). Nevertheless, many business analysts consider 1985 Colony stimulating factor that the human biological market has come of Human growth hormone (GM) 1986 Colony stimulating factor age in the last 2 years, as witnessed by govern- Interferon (alpha) (megakaryocyte) ment approval for marketing of the industry’s first Orthoclone OKT-3 Colony stimulating factor commercial therapeutic products. Hepatitis B vaccine (granulocyte) 1987 Colony stimulating factor Table 8 is a business analysis of the human ther- Immunoagents (microphage) Human osteogenic protein apeutic products (many using human-derived ma- Immunocytotoxic agents Immunotoxins Interferon (gamma terial) most likely to be marketed in this country IMREG-1 analogue) over the next 10 years. The industry as a whole Interferon (beta) Interferon (gamma Interferon (gamma) fragment) is actively researching and developing over 100 Pro insulin Interleukin-1 (alpha) different therapeutic products with commercial Protein A Interleukin-1 beta potential, as demonstrated in table 9. Again, many, Tissue plasminogen blocker activator Lipocortin but not all, of these products use human-derived 1988 Lung surfactant protein material. Acylated plasminogen 1991 streptokinase complex Factor VIIIC The established pharmaceutical industry’s in- Alpha-1 antitrypsin 1992 volvement in biotechnology indicates that biotech- Calcitonin Angiogenin Epidermal growth factor Anti-inflammatory nology is viewed as commercially valuable. These Erythropoietin peptide Immunoradiotherapeutic- B-cell factors S Burst promoting activity Table 7.-Financial Statistics for Selected lnterleukin-2 Colony stimulating factor Biotechnology Companies (as of Dec. 31, 1985) Superoxide dismutase (G-pluripoietin) Vitamin E microemulsion Factor IX Annual sales Net profits 1989 Fertility hormones Company ($ millions) ($ millions) Atrial natriuretic factor (FSH, LH, and HCG) Genentech (CA) ...... 89.6 5.6 Herpes vaccine Fibroblast growth factor Cetus (CA) ...... 45.9 1.4 Hyaluronic acid (anti- Tissue inhibitor of Biogen (MA) ...... 31.4 – 19.1 infIammatory) metalloproteinases Centocor (PA)...... 22.4 3.5 IMREG-2 Urokinase-antibody Amgen (CA) ...... 19.8 –1.5 Lipid emulsion conjugate Genex (MD)...... 16.2 – 15.9 Protein C 1993 California Biotech (CA)...... 9.6 –0.5 Pro-urokinase 1994 Collaborative Research (MA) . . . 8.8 4.3 Tumor necrosis factor 1995 Molecular Genetics (MN) ...... 8.3 –2.5 Renin inhibitors Integrated Genetics (MA) . . . . . 7.3 –3.7 aMany, but not ail, Of these therapeutic products contain humanderived material SOURCE: Shearson Lehman Brothers, Inc. (reprinted in The Economist, Apr. 19, SOURCE L.1 Miller, EJiotectmo/ogy /ndustry 1986 Fact Book (New York: Paine 1966) Webber, 1966). Ch. 4—The Interested Parties 59

Table 9.—Some Human Therapeutic Products Being Developed by the Biotechnology Industrya . . . . Immune modifiers: AntlCellular factors Hormones: Allogeneic effect factor Cytotoxic glycoprotein Angiogenin B cell growth factors Detox Angiogenic factor Burst promoting activity Human endogenous regulatory factors Angiogenesis factor Colony stimulating factor (GM) Immunoagents Atrial natriuretic factor Colony stimulating factor (alpha) Immunocytotoxic agents Atrial natriuretic factor analogue Colony stimulating factor (granulocyte) Immunoradiotherapeutics Bone morphogenic protein Colony stimulating factor (microphage) Immunotoxins Bone growth factors Colony stimulating factor (megakaryoctye) Lectin Calcitonin Colony stimulating factor (G-pluripoietin) Lymphotoxin Calcitonin analogue Colony stimulating factor (other) Minactivin Calcitonin gene related peptide D-glutamic acid, d-lysine conjugates OH-1 Calcitonin precursor Desacetylthymosin alpha-1 Oncostatin Cartilage inducing factor (a) lgE peptides Ovamid Cartilage inducing factor (b) IMREG-1 Tumor growth inhibitor factors Connective tissue activator protein IMREG-2 Tumor necrosis factor CNS growth factor Interferon (alpha) Tumor necrosis factor KBS Enkephalines Interferon (alpha) receptor Blood proteins/enzymes: Epidermal growth factor Interferon (beta) Acylated plasminogen streptokinase Fertility hormones Interferon (gamma) complex Gonadotrophin releasing hormone Interferon (gamma analogue) PEG-Adenosine deaminase Growth associated protein Interferon (gamma fragment) Alpha-1 antitrypsin Growth hormone releasing factor Interferon (gamma) receptor Antithrombin Ill Human growth hormone Interferon analogue Apolipoprotein-E Hyaluronic acid Interferon inducer PEG-Asparaginase Inhibin Interferon-interleukin hybrid PEG-Catalase Insulin Interleukin-1 (alpha) Coagulation agents Insulin receptor Interleukin-1 (beta) Elastase Luteinizing hormone releasing hormone Interleukin-1 antagonist Elastase inhibitor Nerve growth factor (beta) Interleukin-1 receptor Enzyme 1 Neuropeptide Y lnterleukin-2 Enzyme 2 Neurotransmitter agents lnterleukin-2 analogue Erythropoietin Neurotrophic factors lnterleukin-2 in Iiposomes Factor VIIIC Oxytocin lnterleukin-2 receptor Factor IX Parathyroid hormone inhibitors lnterleukin-3 Factor Xa Platelet derived growth factor lnterleukin-4 Fibrinolytic agents Proinsulin Lipocortin Hementin Prolactin-release inhibiting factor Microphage activating factor Hemopoietin-l Relaxin Microphage migration inhibiting factor Hirudin Secretin Microphage peptides Human serum albumin Somatomedin C Monoclinal antibodies to T cells Lipoproteins Somatostatin Monoclinal antibodies to HLA antigens Lung surfactant protein Somatostatin analogue Monoclinal antibodies to lnterleukin-2 Lysozyme Somatostatin peptides receptor Protein C Tetragastrin Orthoclone OKT-3 Pro-urokinase Thyrotropin releasing hormone Protein A Renin inhibitors Transforming growth factor (alpha) Protein A analogue Renin monoclinal antibody Transforming growth factor (beta) Suppressive factor of allergy Streptokinase Vasopressin Suppressor factor L Streptokinase complex Other products: Suppressor factor S Superoxide dismutase Chimeric antibodies Suppressor factors, other Superoxide dismutase analogue Encapsulated islet cells T cell suppressor inducer factor PEG-Superoxide dismutase Monoclinal antibodies against human Tissue inhibitor of metalloproteinases Extracellular superoxide dismutase proteins XL factor Tissue plasminogen activator Vaccines for contraception XN factor Trypsin inhibitor Vaccine for Epstein-Barr virus-induced Anticancer therapy agents: Urokinase malignant Iymphoma Ampligen Urokinase antibody conjugate Vaccine for lung cancer Angiogenin PEG-U rokinase Vaccine for melanoma Anaiaoaenesis inhibitor von Willebrand factor aMany~ ~ut-not all, of these therapeutic products COfMi3in humanderived material. SOURCE: L.1. Miller, E7iotechrro/ogy /rrdushy 19S6 Factbook (New York: Paine Webb@r, 19S6). 60 ● Ownership of Human Tissues and Cc//s

States budget between $300 million and $400 mil- a detailed process of research, development, and lion annually for research and development (5). testing before the product can be marketed. Studies of the conventional pharmaceutical de- Industrial Product Development velopment process have shown that only about 12 percent of the drugs that enter the human test- The Food and Drug Administration (FDA) re- ing- process reach the marketplace, and that the quires a biopharmaceutical product to undergo testing process itself is lengthy and costly (24). The Ch. 4—The Interested Parties • 61

Figure 13.—The Development of Angiogenin been filed by a physician, rather than the corporation. ● Clinical Trials-Phase I: Patient trials to de-

PrOCeSS of angiogenesis first described termine drug safety and appropriate dosing schedules with only modest information regarding efficacy generated. ● Clinical Trials-Phase II: Broadened clinical patient trials to determine drug efficacy in one or more indications. 1930 ● Clinical Trials-Phase III: Advanced clinical patient trials to determine drug efficacy Additional report on process in one or more indications. ● Additional report on process Product License Approval Filing: Materi- als filed with the FDA to apply for marketing approval (36).

1960 While it is difficult to predict whether all pharmaceuticals produced by biotechnology will emu-

Additonal report on process late traditional pharmaceuticals, it is likely that standard government requirements for testing of Monsanto. Harvard agreement signed HT 29 cell Iine isolated pharmaceutical products will apply to all biotechnology products (51 FR 23309). Partial purification using HT 29 cell conditioned medium Molecule purified. cloned, separated

1991 Expected U S marketing of 1992 University-Industry Relationships angiogenin A critical aspect of the controversy surrounding the use of undeveloped human tissues and cells SOURCE” Off Ice of Technology Assessment, 1987 is the increasing overlap between the spheres of two of the interested parties: the research commu- cost associated with bringing a single new prod- nity and the biotechnology industry. University- uct to the marketplace is on the order of $65 mil- industry research relationships in biotechnology lion to $100 million (spread over several years or assume a variety of forms, and these relationships two to three decades) (4). In general, the biophar- are of relatively recent vintage. One estimate in- maceutical product development process includes dicates that the total amount of money industry the following steps: supplied to universities for biotechnology research ● Research: Identification and purification of in 1984 was about $120 million, accounting for the natural protein; characterization of the 16 to 24 percent of all funds for biotechnology molecule, often including genetic engineer- R&D available to institutions of higher education ing technology to produce the product. that year (11). ● Research and Development: Improvement Faculty consulting and research relationships of product yield, initial formulation, and lab- between individual professors and corporations oratory testing. can include: ● Development: Formulation of the product into a pharmaceutical; preparation and scale- ● single or occasional visits and interchanges, up of product manufacture. informal collaboration; ● Preclinical Testing: Animal testing for acute ● formal collaboration with or without consult- or long-term toxicity and activity of the product. ing arrangements; ● Clinical Testing—Physician IND: Human ● consulting arrangements with or without for- patient testing at one or more clinical centers mal collaboration (exclusive or nonexclusive); where the actual application for testing has and 62 . Ownership of Human Tissues and Cells

● ● formal exclusive relationships with under- cooperative research; stood financial commitments and patent ● privately funded research centers, with ei- rights. ther a single funder or multicorporate sponsors; Faculty may also be involved with scientific advi- ● long-term contracts, such as those between sory boards for biotechnology companies and may Monsanto and Harvard or Exxon and Massa- be offered some type of restricted stock or stock chusetts Institute of Technology; options not generally awarded to external con- ● university-controlled companies set up to de- sultants. velop commercial potential from university Relationships between universities and cor- research; and porations can include: ● private companies that secure patent rights for resale (30). ● corporate contributions, directed or un- directed or in the form of fellowships; The implications for a market in human speci- ● industrial procurement of particular services, mens involving researchers, universities, uni- for example, education and training or con- versity-industry partnerships, and industry are tract research; discussed in detail in chapter 7. ● industrial affiliates;

FEE-FOR-SERVICE RESEARCH

In addition to the commercial biotechnology charged for processing and preserving the pa- firms and basic research members of the research tient’s tumor for future use in therapy. Patient- community, a novel party that uses human tis- funded research accounted for approximately 65 sues and cells has emerged. In 1984, the first for- percent of Biotherapeutics’ total revenues. profit company offering personalized cancer treat- Biotherapeutics also uses interleukin-2, a lym- ments was established in Franklin, TN. Biother- apeutics, Inc., was founded by R.K. Oldham, phokine, to activate certain cells of the patient to former director and founder of NCI's Biological become “lymphokine-activated killer cells.” These cells can attack tumor cells in some individuals. Modifiers Program, and W.H. West, his colleague. A second branch in La Jolla, CA, is scheduled to The therapy regimens offered at Biotherapeutics open soon. It is a pioneer in what has been termed are in use as experimental treatments elsewhere, ‘(fee-for-service” research: the company offers particularly at NCI (32). Unlike other programs, services to individuals who can afford to bear the however, patients at Biotherapeutics bear the cost of their individualized research/treatments. Per- costs of the research protocol involved in the cancer treatment (32). sons contracting with Biotherapeutics waive all rights to “any cell line, reagent, product, approach, As one part of its program, Biotherapeutics or properties that may be derived from tumor makes hybridomas producing monoclinal anti- tissue, blood, or other specimens . . ,“ (8). bodies unique to an individual’s tumor. These mon- At present, Biotherapeutics is a unique combi- oclinal antibodies are used with a mixture of other nation of business, therapeutic institution, and re- monoclinal antibodies (produced in response to search venture that uses human biological mate- tumors from other individuals) to treat the pa- rials. About 200 patients have been treated at the tient’s tumor. The current cost of participating Tennessee facility, and it is difficult to evaluate in the full service, not covered by conventional whether fee-for-service research companies will insurance policies, is $35,000. A $2)750 fee is be an important interested party in the future. Ch. 4—The Interested Parties ● 63

SUMMARY AND CONCLUSIONS

In addition to scientific advances in biotechnol- The research community, including both univer- ogy, the legal and economic considerations sur- sity and industry scientists, obtains human speci- rounding research on human biological have mens for a broad spectrum of uses. These tissues changed in the past decade. Many parties now and cells may be sought for single experiments have an interest in developing human tissues and as well as for the long-term development of cell cells: the source, the physician (or physician/ lines or cloned genes. A sample might also be used researcher), the researcher, the university, and directly to extract a commercial product. Re- the biotechnology company. And, importantly, the searchers obtain human biological materials via spheres in which these parties operate are fre- many avenues, ranging from ad hoc agreements quently intertwined—making resolution of con- with local hospitals to federally supported col- flicts difficult. lections. The ability to patent novel life forms created In most cases, it is difficult to ascertain the through biotechnology has spurred interest in de- contribution of anyone individual’s sample to veloping human tissue and cells into marketable a final commercial product. Moreover, because inventions. The crucial element of patentabil- the process of research is a continuum, the ex- ity for most biological inventions in the United pectation of developing a commercial product at States, as shown in the Chakrabarty case, was the outset of research is extraordinarily small. the fact that the substance was in some way Atypical human tissues and cells are sometimes changed from the naturally occurring sub- discovered, however, and can be valuable to the stance by human intervention. This decision, R&D process of a marketable human commodity. coupled with technical advances in biotechnology, Recently, researchers and universities have has resulted in increased interest in developing sought innovative methods to fund research. The primary human biological material into market- emerging presence of the biotechnology indus- able products. try has become a logical partner in such research Patients, healthy research subjects, and cadavers funding, and consequently a number of university- are all sources of undeveloped human tissues and industry or investigator-industry arrangements cells, providing both normal and diseased speci- have developed. These arrangements range— from mens. As a general principle, sources of specimens informal col laboration to formal contracting or are not paid for the types of samples most com- funding. monly used in biotechnology research. Volunteer research subjects, however, may be reimbursed for time or out-of-pocket expenses.

CHAPTER 4 REFERENCES

1. Aamondt, R. L., Division of Cancer Biolo~v and Diag- 4. Antdbi, E., and Fishlock, D., Biotechno]ogv: Strate- nosis, National Cancer Institute, Bethesda, MD, per- @“es for Life (Cambridge, MA: The MIT Press, 1986). sonal communication, April 1986. 5. Behrens, M. K., “Biotechnology,” 1985 Aledical Con- 2. Alderman, E. M., Lobb, R. R., and Fett, J. W., “Isola- ference Review (N’ew York, NY: Robertson, Colman tion of Tumor-Secreted Products From Human Car- & Stephens, NOV. 8, 1985). cinoma Cells Maintained in Defined Protein Free 6. Biggart, W. A., PatentabilitJr, Disclosure Require- Medium, ” Proceedings of the IVa tional Academv of ments, Claiming and Infringement of Microorga - Science (USA) 82:5771-5775, 1985. nism-Related Inventions, reprinted in Genetical!t~ 3. Algire, G. H., and Chalkey, H .Vt’., “\’ascular Re- Engineered Microorganisms and Cells (Washing- actions of N’ormal and Malignant Tissues In \’i\ro, ton, DC: Patent Resources Group, Inc., 1981). I: k’ascular Reactions of ltlice to Wounds and to 7. “Biotechnology’s Hype and Hubris, ” The Economist Normal and Neoplastic Transplants, ’’Journal of the Apr. 19, 1986, Arational Cancer Institute (USA) 6:73-85, 1945. 8. Biotherapeutics, Inc., Franklin, TN, “CellularCom- 64 ● Ownership of Human Tissues and Cells

ponent Development Patient Research Contract,” 26. Ide, A, G., Baker, N. H., and Warren, S. L., ‘(Vascular- January 1986. ization of the Brown-Pearce Rabbit Epithelioma 9. Blumberg, B. S., Millman, I., London, W. T., et al., Transplant as Seen in the Transparent Ear Cham-

‘Ted SIavin’s Blood and the Development of HBV ber)” American Journal of Roentgenologv and Vaccine, ” New England Journal of Medicine Radium Therapy 42:891-899, 1939. 312(3):189, 1985. 27. In re Bergy, 563 F.2d 1031 (CCPA 1977). 10. Blumenthal, D., Harvard University, Cambridge, 28. h re Bergy, 596 F.2d 952 (CCPA 1979). MA, personal communication, April 1986. 29. In re Chakrabarty, 571 F.2d 40 (CCPA 1978). 11. Blumenthal, D., Gluck, M., Louis, K. S., and Wise, 30. Kenney, M. F., “Biotechnology: From University to D., “Industrial Support of University Research in Industry,” Ph.D. dissertation, Cornell University, Biotechnology,” Science 231:242-246, 1986. 1984. 12. Byers, B., Kleiner, Perkins, Caufield, & Byers, San 31. Kurachi, K., Davie, E. W., Strydom, D.J., et al., “Se- Francisco, CA, personal communication, April quence of the cDNA and Gene for Angiogenin: A 1986. Human Angiogenesis Factor, ” Biochemistruv 24: 13. Der, C.J., La Jolla Cancer Research Foundation, La 5494-5499, 1985. Jolla, CA, persona] communication, April 1986. 32. Lind, S. E., ‘(Sounding Board: Fee-for-Service Re- 14. Diamond v. Chakrabarty, 477 U.S. 303 (1980). search)” New England Journal of Medicine 314(5): 15. Ehrmann, R. L., and Knoth, M., “Choriocarcinoma: 312-315, 1986. Transfilter Stimulation of Vasoproliferation in the 33. Lobb, R. R., Key, M. E., Alderman, E. M., and Fett, Hamster Cheek Pouch—Studied by Light and Elec- J. W., “Partial Purification and Characterization of tron Microscopy, ” Journal of the National Cancer a Vascular Permeability Factor Secreted by a Hu- Institute (USA) 41:1329-1341, 1968. man Colon Adenocarcinoma Cell Line, ” Interna- 16. Fett, J. W., Strydom, D.J., Lobb, R. R., et al., “Isola- tional Journal of Cancer 36(4):473-478, 1985. tion and Characterization of Angiogenin and An- 34. McKay, C., Office for Protection from Research giogenic Protein From Human Carcinoma Cells,” Risks, National Institutes of Health, Bethesda, MD, Biochemistry 25:5480-5486, 1985. personal communication, April 1986. 17. Fogh, J, (cd.), Human Tumor Cells In Vitro (New 35 Macy, M., American Type Culture Collection, Rock- York: Plenum Press, 1975). vil]e, MD, personal communication, April 1986. 18. Folkman, J., and Cotran, R., “Relation of Vascular 36 Miller, L. I., Biotechnology Industry 1985Fact Book Proliferation to Tumor Growth,” International Re- (New York: Paine Webber, lgsi). view of Experimental pathology, G.W. Richter (cd.) 37. Miller, L. I., Biotechnology Industry 1986Fact Book (New York: Academic Press, 1976). (New York: Paine Webber, 1986). 19. Francomano, C., The Johns Hopkins Medical Insti- 38. Mochizuki, D. Y., Immunex Corp., Seattle, WA, per- tution, Baltimore, MD, personal communication, sonal communication, March 1986. April 1986. 39. “Monsanto To Reap First Fruits of Stake in Har- 20. Goldmann E., ‘(The Growth of Malignant Diseases vard: Sole Rights To ‘Angiogenin’, ” Biotechnology in Man and the Lower Animals With Special Refer- Newswatch 3(20):3, 1985. ence to the Vascular System,” Lancet 2:1236-1240, 40. Nelkin, D,, Science as Intellectual Property (New 1907. York: Macmillan, 1984). 21. Goldstein, H., National Institutes of Health, Be- 41. Ostrach, M., Cetus Corp., Emeryville, CA, personal thesda, MD, personal communication, April 1986. communication, April 1986. 22. Greenblatt, M., and Shubik, P., “Tumor Angiogen- 42. Patterson, M. K., The Noble Foundation, Ardmore, esis: Transfilter Diffusion Studies in the Hamster OK, personal communication, March 1986. by Transparent Chamber Technique,” Journal of 43. Perpich, J., Meloy Laboratories, Springfield, VA, the National Cancer Institute (USA) 41:111-124, personal communication, April 1986. 1968. 44. Rathman, G. B., “The Role of Patients, Researchers, 23 Grizzle, B., University of Alabama, Birmingham, AL, Universities and Private Companies in the Develop- personal communication, April 1986. ment and Marketing of Human Biological Products, ” 24 Hansen, R., “The Pharmaceutical Development in U.S. Congress, House Committee on Science and Process: Estimates of Development Costs and Times Technology, Subcommittee on Investigations and and the Effects of Proposed Regulatory Changes, ” Oversight, The Use of Human Biological Materials Issues in Pharmaceutical Economics, R.I. Chien (cd.) in the Development of Biomedical Products, hear- (Lexington, MA: Lexington Books, 1979). ings, Oct. 29, 1985, Serial No. 99-71 (Washington, 25 Henney, C., Immunex Corp., Seattle, CA, personal DC: U.S. Government Printing Office, 1986). communication, April 1986. 45 Read, E., and Lancono, B., National Institutes of Ch. 4—The Interested Parties ● 65

Health Blood Bank, Bethesda, MD, personal com- eral Laboratory and Technolog}[ Resources, 1986- munication, February 1986. 87 (Springfield, VA: National Technical Informa- 46. Rosenberg, P. D., Patent La}v Fundamentals (Ne\v tion Service, 1986). York: Clark Boardman Co., 1980). 53. U.S. Department of Health and Human Ser\~ices, 47. Spalding, B. J., “Biotech’s Ne\v-\va\re Biological, ” National Institute of General Medical Sciences, Hu- Chemical ~~’eek, Dec. 18, 1985. man Genetics Mutant Cell Repository, Comprehen - 48. Stevenson, R., American Type Cukure Collection, si~re Annual Report, Jan. 1, 1985 to Dec. 31, 1985. Rockville, MD, personal communication, April 54. U.S. Department of Health and Human Ser\rices, 1986. National Institutes of Health Guide for Grants and 49. Strydom, D. J., F’ett, J. W., Lobb, R. R., et al., “Amino Contracts, “Request for Cooperative Agreement Ap- Acid Sequence of Human Tumor Deri\red Angioge- plications: RFA 86-CA-06, National Cancer Institute nin,” Biochemistry 24:5486-5494, 1985. Cooperative Human Tissue Network, ” Feb. 28, 50. U.S. Congress, House Committee on Science and 1986. Technology, Subcommittee on Investigations and 55. U.S. Department of Health and Human Ser\rices, Oversight, The [Jse of Human Biological Materials “Research Service: National Diabetes $3esearch In- in the De\~elopment of Biomedical Products, hear- terchange, ” Research Resources Reporter Reprint ings, Oct. 29, 1985, Serial ,No. 99-71 (Washington, 9(10):1-2, 1985. DC: U.S. Government Printing Office, 1986). 56. Van Horn, C., “Remarks to Association of Biotech- 51. U.S. Congress, Office of Technolo~v Assessment, nology Companies Symposium, ” Biotechnology La ti~ Commercial Biotechnology: An International Anal- Report 5(3):86-91, 1986. .vsis, OTA-BA-218 (Elmsford, NY: Pergamon Press, 57. Webber, D., “consolidation Begins for Biotechnol - Inc., January 1984). o@ Firms,” Chemical & Engineering Neti’s, No\T. 52. U.S. Department of Commerce, Directory of Fed- 18, 1985. .

chapter 5 Legal Considerations

“If biotechnologists fail to make provision for a just sharing of profits with the person whose gifts made it possible, the public’s sense of justice will be offended and no one will be the winner.” —Thomas H. Murray Congressional testimony, Oct. 19, 1985 CONTENTS Page Injuries to Persons v. Injuries to Property ...... 69 Personal Rights ...... 69 Property Rights ...... 70 Possible Sources of Rights ...... 70 Law of Patents ...... 70 Law of Cadavers and Autopsies ...... 72 Law of Organ Transplantation ...... 75 Law of Blood and Semen Sales ...... 76 Law of Copyright ...... 78 Law of Trade Secrets ...... 78 Law of Conversion and Trespass to Chattel ...... 79 Law of Accession ...... 83 Remedies ...... +...... 84 Variation Among States ...... 85 Third-Party Liability ...... 86 Summary and Conclusions ...... 86 Chapter 5 References ...... 87

Table Table No. Page 10. Possible Sources of Rights Relating to Human Biological Materials ...... 70 Chapter 5 Legal Considerations

As the use of human tissues and cells becomes tions raised by the use of tissues and cells in re- more prevalent in biotechnology-related research search, the courts must do what common law and development, increased attention will need judges have done for centuries; reason by anal- to be focused on the legal considerations of such ogy, using principles and precedents developed use. Are tissues and cells property? If so, what for other circumstances. right does a patient or research subject have in United States law has long protected people such materials? Does the provision of tissues and from those who would harm them physically or cells constitute the sale of a product or service? who would deprive them of full enjoyment of their No area of existing law definitely sets forth the property. Generally, this protection was afforded rights held by an individual who provides tissues by the common law, the body of judge-made law and cells to an academic or commercial researcher. built on judicial precedents. Common law has No area of law clearly provides ownership rights evolved “over centuries, as judges have been called with respect to human tissue and cell materials. on to resolve disputes that have not been ad- Nor does any law prohibit the use or sale of hu- dressed by statute. Congress and State legislatures man bodily substances by the living person who have enacted a variety of statutes to codify, mod- generates them or one who acquires them from ify, and overrule the common law. Today, while such a person, except under certain circumstances. statutes specify many of our legal rights and These circumstances relate to particular cell ar- duties, common law remains the basis for our le- rangements (e.g., organs, bodies) and uses (e.g., gal principles, and common law analysis and rea- transplantation) that are not typically related to soning forms the basis for our techniques of stat- biotechnology research. Because neither judicial utory interpretation. precedents nor statutes directly address the ques-

INJURIES TO PERSONS V. INJURIES TO PROPERTY

The common law classifies many injuries for damages resulting from harmful or offensive phys- which recovery is permitted as either injuries to ical contacts. persons (which are analyzed under tort law principles) or injuries to property (which generally Invasions of physical autonomy are permitted only in those few situations where either individ- are within the domain of property law). Contracts ual or public interests (particularly health) would can be made with respect to both persons and be substantially and justifiably benefited by a mod- property, although certain types of contracts and est encroachment on individual autonomy. Exam- contractual remedies are permitted with respect ples of legally permissible invasions of physical to property but not human beings. integrity include laws compelling vaccinations; blood tests for marriage licenses; and blood and Personal Rights urine sampling of suspected criminals, military service, and penal service. The common law gives individuals various “personal” rights to exclude others from interfering Although the law clearly affords people substan- with their physical and mental integrity. Many in- tial means of protecting themselves from harm- vasions of bodily integrity are subject to criminal ful or offensive physical contacts, the extent to penalties; in addition, the common law tort of bat- which people can use their bodies is less clear. tery allows for recovery for physical and mental State law generally prohibits disfigurement, prosti-

69 70 ● Ownership of Human Tissues and Cells tution, and drug use. Federal law reflects similar while the law permits the sale of such replenish- policies and recently has added a new prohibi- ing cells as blood and semen, it neither endorses tion against organ sales (public Law 98-507). These such transactions nor does it often characterize restrictions rest on concerns about individual such transactions as involving property. In this health, public health, and public moral sensibility. sense, either permitting or forbidding the sale of human specimens by patients and research sub- Property Rights jects can be claimed to be consistent with existing law. Property is generally viewed not as a single indivisible concept but as a bundle of legally pro- The broad array of legal principles that might tected interests, including the right to possess and have implications for the use of tissues and cells use, to transfer by sale or gift, and to exclude in biotechnology (table 10) are discussed in the others from possession. Although the property following section. concept can be invoked to protect various legal interests, one’s right to use property is commonly limited to uses that do not offend public safety Table 10.—Possible Sources of Rights Relating to or sensibilities. For example, a person may own Human Biological Materials a car but not have a right to use it without first obtaining a driver’s license. Law of Patents Law of Cadavers and Autopsies Nevertheless, the term property introduces cer- Property rights in corpses tain economic and market connotations and call- Emotional distress caused by wrongful acts toward cadavers Law of Organ Transplantation ing the body property may act to make the use Donation of organs for transplantation of market incentives with respect to the body and Sale of organs for transplantation its parts more acceptable. Alternatively, if human Law of Blood and Semen Sales Sale of blood and semen tissues and cells are not characterized as prop- Product liability generally erty but as a severed part of a person, then tort Implied warranties under the Uniform Commercial Code Specific performance under the Uniform Commercial Code law principles would still provide certain rights Blood as a product for tax law purposes with respect to one’s tissues and cells (e.g., right Law of Copyright to privacy, right to adequate disclosure to give an Law of Trade Secrets Law of Conversion and Trespass to Chattel informed consent). However, a right to buy or sell Property interest would probably not be among the rights provided. Possession Injury to plaintiff In the absence of clear legal restrictions, the sale Abandonment of tissues and cells is generally permissible un- Res Nullius Law of Accession less the circumstances surrounding the sale sug- Cases involving crops gest a significant threat to individual or public Specification health, or strong offense to public sensibility. But SOURCE: Office of Technology Assessment, 1987.

POSSIBLE SOURCES OF RIGHTS

Law of Patents vey exclusive rights to their holders, they are personal property (35 U.S.C. 261). Patent law has direct application to biotechnology research and development. The Constitution Under U.S. law, inventions belong in the first gives Congress the power “[T]o promote the Prog- instance to their inventors. An employed inven- ress of Science and useful Arts” by securing to tor is ordinarily obligated to assign his invention inventors exclusive right to their inventions (Ar- to his employer under the “hired to invent” doc- ticle 1, Section 8, Clause 8). Because patents con- trine and by express provision in his employment ——

Ch. 5—Legal Considerations ● 71 agreement. Patents obtained by researchers thus The case law on what constitutes an act of in- generally are assigned to the institution funding vention has developed through interpretation of the research. various provisions of the patent law. Under a section of the patent statute relating to who of sev- A patent may be granted on any new, useful, eral claimants is the true inventor, the inventive and nonobvious composition of matter, or article process is divided into conception (an outwardly of manufacture, machine, or process (35 U.S.C. manifested mental act), reduction to practice (a 101-103). In 1980, the Supreme Court held in Dia- physical demonstration of practicability, or the mond v. Chakrabarty that the mere fact that sub- filing of a well-framed patent application) and dili- ject matter is “living” does not render it unpatent- gence (efforts to reduce a conception to practice) able (36). “Products of nature,” however, are (35 U.S.C. 102(g)). unpatentable because they lack novelty. The biological inventions being patented today are not Conception means that the person claiming to crude, unaltered products of nature. A claim to be the inventor thought of both the desired re- the entire genetic material of a single cell would sult and the means for achieving that result, that be rejected; but one may properly seek a patent means being an operative form of the invention on an isolated gene encoding a protein of interest. claimed. Conception must be manifested by ex- terior acts or declarations that disclose the con- The obviousness of a product is another bar to ception in a form enabling a person of ordinary its protection by patent. Patent law creates a three- skill in the art to practice the invention without step test to determine whether an invention meets the exercise of the inventive faculty (80). the non-obvious test for patentability (35 U.S.C. 103). This analysis consists of three factual in- In Brenner v. Manson (14), the Supreme Court quiries concerning the prior art, that fund of in- held that a patent cannot be obtained on a method formation which is available or accessible to the of producing a novel composition unless the com- public (81): 1) the scope and content of the prior position has a practical (nonresearch) utility. One art, 2) the difference between the prior art and patent law book states that, based on the context the patent claims at issue, and 3) the level of ordi- of the case, “a necessary implication of Brenner nary skill in the pertinent art. If the claims in the is that discovery of the utility is part of the act patent would have been obvious, in view of the of inventing” (29). The Patent Office apparently prior art, to a person having a level of ordinary agrees (34). skill in the pertinent art, then the patent is deemed If contemplation of a nonresearch utility is a obvious and does not meet the requisite criteria necessary part of conception, then the patient’s for patentability. For example, a patent on vita- or research subject’s assertion that tissues have min C (purified from lemon juice crystals) was de- a value in research is not a conception unless there nied because “lemon juice has been known for is recognition of a practical use for those tissues, ages as a satisfactory specific for scurvy. ” But a or their derivatives, outside research. Besides ap- patent on adrenalin crystals was held valid in view preciating the utility of the cells, the patient or of the dangerous side effects of dried gland ex- research subject must also appreciate that the cells tracts of lesser purity (71,102). are novel. In a case involving a chemical inven- While it is clear that researchers may alter tion, for example, a plaintiff who accidentally donated tissues and cells into a patentable in- produced a particular catalyst but did not recog- vention, patients and research subjects who nize that it differed in form from the prior art contribute cells to research will not be con- was held not to conceive the new catalyst (43). sidered inventors. Typically, the person provid- The rule that “there is no conception or reducing the material will not make any suggestion re- tion to practice where there has been no recogni- garding the use of the cells, or of the means for tion or appreciation of the existence of the new using them. While the patient’s cells may have form” was acknowledged in Silvestri v. Grant (86), some novel characteristic, it is unlikely that the but led to a different holding since Silvestri had characteristic was appreciated by the patient. recognized that ampicillin II was different from 72 ● Ownership of Human Tissues and Cells

ampicillin I, even though he had not recognized sess and use, to transfer by sale or gift, and to its superior stability. exclude others from possession (15), few of these rights were applied to bodies: the theft of a ca- Law of Cadavers and Autopsies daver was not larceny, the sale of a cadaver was a common law crime, the heirs had no right to Property Rights in Corpses repossess a body wrongfully taken from them, The earliest Anglo-Saxon cases to consider owner- and a cadaver could not be the subject of a lien. ship of human tissue-specifically, corpses—were Recognizing the limited applicability of property decided almost 1,000 years ago by special eccles- law to corpses, 20th century American courts iastical courts in England. Established by William retreated from the broad pronouncement of bod- the Conqueror, the church courts were completely ies as property and began referring to more lim- independent of the civil courts and were eventu- ited “quasi-property rights” vested in the next of ally given complete jurisdiction over all matters kin and arising out of their legal duty to bury the concerning burials and disposition of corpses (49). dead. These rights include the right to possession With few exceptions, control of dead bodies re- and custody of the body for burial, the right to mained within the exclusive jurisdiction of the have it remain in its final resting place, and the church courts until the 19th century, when the right to recover damages for any outrage, indig- growth of medical schools and their need for nity, or injury to the body of the deceased (1). The cadavers for dissection created a challenge to ec- family’s interest in the dead body was subject to clesiastical dominion over bodies (85). various interests of the State government, includ- In colonial America, the absence of ecclesiasti- ing concern for public sensibility, promotion of cal courts resulted in civil jurisdiction over bod- public health, identifying cases of murder, and ies and the application of common law principles. protecting the economic interests of undertakers There were no commercial rights in cadavers, no and insurers. right for a decedent to direct the manner of bur- Quasi-property analysis became the prevailing ial, and no burial rights enforceable by the next rule in both the United States and England dur- of kin. The refusal to create commercial rights ing the early 20th century and continues to be was unquestionably based on religious and moral applied to disputes over funeral arrangements (61). tradition. The absence of property rights led to the other rules, following the common law prin- Emotional Distress Caused by Wrongful ciple that courts should only be concerned with Acts Toward Cadavers commercial considerations and not with sentimen- tal concerns, In the 1930s, American jurists and legal scholars began questioning the applicability of prop- During the 1800s, it became apparent that the erty law concepts to cases involving wrongful strict common law doctrine was inequitable and conduct toward corpses. Gradually, the newly de- courts began assigning to the next of kin an en- veloping tort law framework of intentional inflic- forceable right to possession of a body for burial. tion of emotional distress (also called “outrageous To preserve the continuity of common law prin- conduct”) was viewed as a more appealing theo- ciples, the right was sometimes characterized as retical basis for a legal claim based on unautho- a “property right” (49). This right became so well rized retention of body parts and other forms of established that in 1891, a court suggested that wrongful conduct. As William Presser stated in the “fact that a person has exclusive rights over Law of Torts: a body for the purposes of burial leads necessarily to the conclusion that it is his property in the There are a great many cases involving the mis- broadest and most general sense of the term” (59). handling of dead bodies, whether by mutilation, disinterment, interference with proper burial, or Judicial references to property rights in corpses other forms of intentional disturbance. In most were misleading, however. While common law of these cases the courts have talked of a some- property rights generally include the right to pos- what dubious ‘(property right” to the body, usu- Ch. 5—Legal Considerations Ž 73

ally in the next of kin, which did not exist while party claiming such rights to demonstrate that the decedent was living, cannot be conveyed, can the biological, economic, social, and ethical differ- be used only for the one purpose of burial, and ences between dead and living specimens are not only has no pecuniary value but is a source more important than their similarities, and that of liability for funeral expenses. It seems reason- living human specimens merit protection as a re- ably obvious that such “property” is something sult of these differences. evolved out of thin air to meet the occasion, and that it is in reality the personal feelings of the sur- As mentioned earlier, there are noncommercial vivors which are being protected, under a fiction quasi-property rights in a cadaver that arise out likely to deceive no one but a lawyer (77). of the legal duty placed on survivors to bury their Today, cases concerning wrongful acts dead (1). The kin’s duty to bury the dead appears toward a dead body are generally treated as to be irrelevant to research or commercial uses tort cases rather than property disputes. The of biological materials from living sources, so any American Law Institute’s most recent Restatement rights derived from such a duty would have little of Torts, which describes the general principles relevance. of American tort law, states that one who inten- The emotional distress theory provides a use- tionally, recklessly, or negligently removes, with- ful legal framework in cases where biological holds, mutilates, or operates on the body of a dead were obtained or used wrongfully, since the ba- person, or who prevents its proper interment or sis for the tort is the wrongfulness of the con- cremation, is subject to tort liability to a member duct and its effect on the living rather than prop- of the family who is entitled to disposition of the erty law concepts. To fulfill the legal requirements body (4). The cause of action is a personal right of the tort, the physician’s conduct would prob- of the survivor rather than a right of the dece- ably have to demonstrate willful and wrongful dent or his estate, since the courts are not pri- disregard for the express or implied desires of marily concerned with the extent of the physical the patient and that the conduct resulted in se- mishandling or injury to the body per se, but vere emotional distress. In one case, for example, rather with the effect of such improper activities a woman gave birth to a premature baby who on the emotions of the surviving kin (6). died shortly thereafter. Several weeks later, through It is important to note that to be actionable, the an unusual course of events, a hospital employee emotional distress must be genuine, not theoreti- showed the mother a jar containing the infant’s cal. If the plaintiff does not learn of the offensive body. The mother suffered various physical and conduct, or learns of it but is not distressed as psychological injuries as a result and was awarded a consequence, there is no basis for suit. Also, ex- $175,000 in damages for the tort of “outrageous cept in cases where the defendant has knowledge conduct” (41,52). of the plaintiff’s peculiar susceptibility and practices despite this knowledge, the distress must be Variables Affecting Emotional of a nature that a reasonable person of “ordinary Distress Claims sensibilities” would also experience under the circumstances (7’7). A plaintiff must therefore show A plaintiff in an emotional distress case in- both subjective and objective elements of emo- volving the use of human tissues or cells in tional distress. research must prove two fundamental facts to prevail. First, the physician or researcher Applicability to Cases Involving must have acted wrongfully. Acts that could be Human Tissues and Cells considered sufficiently wrongful in their disregard for the plaintiff’s feelings include: Society’s traditional refusal to allow commercial rights in cadavers or dead body parts sug- ● using an individual’s specimens in research gests that a claim for property rights in living body without consent, parts could be judicially rejected as failing to state ● misrepresenting the purpose of diagnostic or a cause of action. The burden would be on the medical procedures when they are performed 74 . Ownership of Human Tissues and Cells . F

solely for the purpose of obtaining specimens, Similarly, the use to which a specimen is put and may affect the patient’s emotional reaction, par- ● suggesting to a patient that refusal to donate ticularly if the patient has religious or moral be- specimens for research will affect the avail- liefs that conflict with the use. For instance, some ability or quality of medical care. people consider altruistic gifts of human tissues and cells to be less offensive than profitable ex- All of these acts are related to the physician’s changes. This is illustrated by the altruistic moti- or researcher’s duty to disclose information to the vation that spurs most blood donations despite patient or research subject and to obtain consent. the legal permissibility of selling blood. For those The generally accepted standards of professional who believe that altruism is the only proper moti- medical conduct are described in chapter 6. vation for transactions involving human biologi- Second, the plaintiff must also prove that cal, it would be less objectionable to them if their substantial emotional distress-both objec- physician donated a specimen to biomedical re- tively and subjectively—was suffered as a researchers than if he sold it for a profit to those suit of the wrongful act. While these factors will same researchers. vary from case to case, a few generalizations can be made, particularly about the objective element For other individuals, sales of biological mate- that examines whether a “reasonable person” rials might be permissible for some uses but not would be emotionally disturbed by the conduct. for others: one might agree to sell one’s hair for use in a wig but not in a voodoo doll. Thus, selling Whether emotional distress can be shown is re- placentas to shampoo manufacturers for use in lated to variables such as the type of biological formulating hair care products (which several hos- material involved, the use to which the specimen pitals allegedly did in the 1960s, causing substan- is put, the method of procuring the specimen, tial public outrage) is probably more egregious and the knowledge of the attending physician than selling them to scientists for research to re- or end-user, In addition, these variables may af- duce infant mortality. Similarly, some people may fect the size of consequential damage awards, find some forms of research objectionable but not which are based on the degree of the emotional others. stress and its effect on the patient’s life, health, happiness, and pocketbook. These factors are also The degree of emotional distress may also vary relevant in determining whether the wrongful with the method of procurement. For example, conduct was so reprehensible that a court will a doctor who solicits and uses a urine sample for permit the plaintiff to seek an additional (puni- diagnostic purposes and who later uses the speci- tive damage) award, beyond actual damages, to men in research may have acted wrongfully if he punish the offender and create a strong deter- did not first obtain the patient’s consent for re- rent for future wrongdoing. search. However, any consequential emotional distress may not be actionable, unless it is shown It maybe especially upsetting to patients when that the physician acted outrageously, recklessly, certain types of biological materials are involved. wantonly, or willfully, or because a reasonable per- For instance, most patients will probably have son of ordinary sensibilities would not experience greater emotional sensitivity about research using serious emotional effects as a result. their organs, limbs, or brain cells than research using their fingernail clippings, hair, blood, urine, A deception accompanied by an invasive or pain- or sweat. The enhanced sensitivity might be due ful medical procedure is probably even more to the fact that the former types of biological ma- offensive. If the specimen obtained in the preced- terials were especially important to the patient’s ing example was not urine but bone marrow, the well-being prior to removal, or because they are resulting emotional distress would probably be generally nonrenewable, or because they were more severe. In addition, the plaintiff would be removed using more invasive and traumatic tech- entitled to collect for his physical pain and suffer- niques. ing during and as a result of the extraction pro- Ch. 5—Legal Considerations ● 75 cedure if it was proven that the physician was part of his body for purposes such as medical edu- also liable for battery due to invalidation of the cation, research, and transplantation. Donations patient’s consent to the procedure. for research purposes may only be made to hospitals, physicians, medical and dental schools, and The knowledge of those who procure the tissue banks. Post mortem donations of human specimen would also have an effect on culpabil- tissues and cells to noncommercial biomedical re- ity since the tort generally requires an outrageous searchers are therefore permitted, although trans- act and not merely a negligent one. As mentioned fers from noncommercial researchers to commer- earlier, knowledge of the peculiar emotional sus- cial researchers are not addressed by the model ceptibilities of a patient can lead to liability where law. Organs removed during surgery are not gifts, it otherwise would not exist. Early emotional dis- because the donative intent required for a legal tress cases dealing with dead bodies, for exam- gift generally is lacking (44). ple, held that unauthorized embalming of a corpse was not actionable unless the mortician knew that Gifts may be made either by will or by a gift the decedent’s religious beliefs forbade embalm- document such as a donor card. In the absence ing (7). Similarly, a patient who is distressed by of contrary instructions by a decedent, the next an incident that would not distress a person of of kin may authorize a gift. Recipients may ac- ordinary sensitivities would not be entitled to sue cept or reject the gift, and a researcher who re- unless the physician knew that the patient was moves or accepts an organ in good faith in accord- unusually squeamish and the doctor therefore ance with the terms of the UAGA is not liable for should have foreseen the deleterious consequences civil damages or subject to criminal prosecution. of his act. Thus, a pyrophobic patient whose leg It has been argued that the UAGA recognizes was amputated and cremated was not permitted rights in the human body that may be classified to recover damages for the mental anguish he as property rights (64). However, the UAGA does claimed he suffered as a result of the cremation not discuss inter vivos (during life) gifts, nor does because the hospital staff did not know of the pa- it say anything about the sale of organs or other tient phobia and had not acted unreasonably by body parts. The chairman of the committee that disposing of the limb through the usual method drafted the UAGA has written that it was intended (16). neither to encourage nor prohibit sales (87). Law of Organ Transplantation As a result of ethical concerns raised by reports of impoverished Americans offering to sell a Donation of Organs for Transplantation “spare” kidney or cornea (typically for $10,000 In the mid-20th century, scientific advances led to $50,000) (57) and physicians offering rewards to an increasing need for transplantable tissue. or finder’s fees for acceptable organs (25), a few From 1947 until 1968, 40 States enacted statutes States have passed laws expressly prohibiting permitting anatomical donations from cadavers remuneration to living or dead organ donors (35). for transplantation or scientific research (85). Var- In the majority of States, however, a donor is iations among the statutes lead to the formation apparently able to make a legal contract to sell of a special committee of the Commissioners on a part of his body, unless the biological transfer Uniform State Laws to draft a uniform donation is to take place after death and the common law statute. The result of this effort is the Uniform provisions on cadaver disposition are held to for- Anatomical Gift Act (UAGA) which, after receiv- bid such a sale (69). ing final approval from the commissioners in 1968 (94), has been adopted throughout the 50 States Sale of Organs for Transplantation and the District of Columbia (82). The UAGA su- In 1984, Congress enacted the National Organ persedes only those areas of the common law of Transplant Act (NOTA; Public Law 98-507). NOTA cadavers that are addressed by the act. prohibits the sale of a human kidney, liver, heart, The UAGA permits any competent adult to make lung, pancreas, bone marrow, cornea, eye, bone, a gift—to take effect upon death-of all or any and skin. Although the act makes it a felony to 76 . Ownership of Human Tissues and Cells purchase specified human organs for transplan- defects in those products. Four possible theories tation, reasonable payments for a living donor’s of recovery are available under the complexities expenses (e.g., travel, housing, and lost wages) are of modern product liability law: permitted. NOTA’s prohibition does not apply to ● strict liability in contract for breach of an ex- sales of human tissues and cells for research, com- press or implied warranty, mercial, or other nontransplantation purposes. ● strict liability in tort largely for physical harm The statute’s organ sale prohibition was based to persons and tangible things, primarily on congressional concern that permit- ● negligence liability in contract for breach of ting the sale of human organs might undermine an express or implied warranty that the prod- the Nation’s system of voluntary organ donation uct was designed and constructed in a (102). It was also driven by concern that the poor workman-like manner, and would sell their organs to the rich, to the detri- Ž negligence liability in tort largely for physi- ment both of poor people who might feel economi- cal harm to persons and tangible things (78). cally coerced to become organ suppliers and those Generally, negligence liability may exist with re- who need but cannot afford transplantable or- spect to both products and services, but strict lia- gans. It may also reflect congressional distaste for bility is applicable only to products. Thus, charac- sales of human body parts generally. The consider- terization of blood and semen sales as services ations that mitigate against the sale of organs for enables blood and semen banks to avoid liability transplant may or may not apply to the sale of when a specimen was defective (e.g., contaminated other human tissues and cells for research and or infected) if the bank was not negligent in its development (37). handling of the specimen (55).

Law of Blood and Semen Sales Implied Warranties Under the UCC Sale of Blood and Semen If sales of tissues and cells were to be treated as sales of goods as opposed to sales of services, No State or Federal statute prohibits the sale then UCC warranties would be applicable. The of blood, plasma, semen, or other replenishing UCC provides that commodity contracts (but not tissues if taken in nonvital amounts (69). Never- service contracts) are subject to two implied war- theless, State laws usually characterize these paid ranties: transfers as the provision of services rather than the sale of a commodity, either in the State’s ver- ● the implied warranty of merchantability sion of the UAGA or in their version of the Uni- requires goods to be of “fair average quality” form Commercial Code (UCC), which governs vari- within the description provided by the seller ous commercial transactions including contracts and fit for the ordinary purposes for which for the sale of goods (95). such goods are used (97), and ● the implied warranty of fitness requires The primary legal reason for characterizing goods to be suitable for the buyer’s particu- these transactions as involving services rather than lar purpose to the extent this purpose is goods is to avoid liability for contaminated blood known by the seller (98). products under either general product liability principles or the UCC’s implied warranty provi- The merchantability warranty only applies to sions. In addition, services are not subject to the sales by “merchants,” defined by the UCC as those UCC’s specific performance provisions. who regularly supply the product (e.g., hospitals, tissue banks) but not occasional sellers (96). The Product Liability fitness warranty applies equally to regular dealers and occasional sellers (98). Product liability is the name given to the area of law involving the liability of suppliers of goods If transactions for blood or semen were treated or products for the use of others, and their respon- as sales of commodities, these implied warranties sibility for various kinds of losses resulting from could result in substantial liability for injuries re- Ch. 5—Legal Considerations . 77 suiting from transfusion or insemination with a Specific Performance Under the UCC specimen infected with hepatitis, AIDS, or another The UCC and the common law of contracts pro- contagious disease. Insemination with sperm con- vide that if a seller breaches or repudiates a containing a genetic defect could also result in sub- tract, the buyer may recover monetary damages stantial liability. Since liability would be based on or, under appropriate circumstances, seek an in- strict liability for breach of warranty rather than junction compelling specific performance (ful- negligence principles, careful examination of speci- fillment of the contract according to its precise mens for contamination or a genetic flaw would terms) (99). Generally, specific performance may not entitle the providing entity to avoid liability be decreed if the goods are unique or in other if an injury occurred. circumstances where monetary damages are in- Alabama has added a subsection to its UCC as adequate to make the buyer whole (100). follows: If a transaction in human tissues or cells is Procuring, furnishing, donating, processing, dis- treated as the sale of goods, the UCC provides tributing, or using human whole blood, plasma, a possible remedy for the buyer, since it “seeks blood products, blood derivatives, and other hu- to further a more liberal attitude than some courts man tissues such as corneas, bones or organs for the purpose of injecting, transfusing, or trans- have shown in connection with the specific per- planting any of them in the human body is de- formance of contracts of sale” (102). However, a clared for all purposes to be the rendition of a contract to render personal services will not be service by every person participating therein and specifically enforced because it is undesirable to whether any remuneration is paid is declared not compel a continued personal association after dis- to be a sale of such whole blood, plasma, blood putes have arisen and confidence and loyalty are products, blood derivatives, or other human tis- gone. In some instances, such imposed associa- sues (8). tions may seem like involuntary servitude, which The amendment prevents recovery on a breach is unconstitutional (2,48). of warranty theory where a plaintiff contracts A 1978 case involved the forced donation of a disease such as hepatitis as a result of a blood bone marrow to a man with a plastic anemia by transfusion (88). Other State courts have reached his genetically compatible cousin (62). Initially, the the same conclusion as Alabama by judicial inter- healthy cousin agreed to undergo tests to deter- pretation (26), while other States have enacted stat- mine his suitability as a donor. Early tests showed utes specifically exempting hospitals and blood him to be a good match, but he failed to appear banks from liability for disease transmitted by for additional confirmatory tests and refused to transfused blood without amending the official donate any bone marrow. The ill cousin sought text of the UCC (9). an injunction that would have forced the healthy If exchanges involving human tissues and cells cousin to undergo the confirmatory tests and to are treated like those involving blood and semen— donate bone marrow if found to be sufficiently i.e., if such exchanges are considered to be trans- genetically compatible. The court denied the in- actions for services rather than commodities— junction, saying “(forcible extraction of living body then certain types of liability may similarly be tissues causes revulsion to the judicial mind. Such avoided by tissue and cell banks, research insti- would raise the specter of the swastika and the tutions, hospitals, and companies. While liability Inquisition, reminiscent of the horrors this por- would continue to exist for negligence (e.g., fail- tends (62). ” While the case was argued on equi- ing to use an available and appropriate test to table rather than contractual grounds, the court screen suppliers for viral infections) there would abhorrence to coerced tissue donations might ap- be no liability for imperfect specimens in the ab- ply with equal force to a repudiated contract for sence of negligence. human tissues and cells, 78 ● Ownership of Human Tissues and Cc//s

Blood as a Product for Tax Law Purposes author because the patient exercises no conscious control over the sequence of bases. Thus, to the State laws usually characterize payment for extent that copyright protection is available, it blood as for the provision of services rather than would be applied solely to recombinant DNA as the sale of a commodity. However, this charac- a composite work. terization has not been applied consistently in the tax treatment of such transactions. The Tennes- see Supreme Court has held that whole blood is Law of Trade Secrets an item of tangible personal property subject to The precise source of trade secret rights is a a State sales tax (51,72). An Alabama court has matter of dispute. Some consider trade secrets indicated that it would have preferred to make to be intangible property. Others regard trade a similar holding on the sales tax issue had it not secrets as merely information subject to restric- felt constrained by the language in the Alabama tions on disclosure and use as a result of express version of the UCC to rule otherwise (88). contract provisions, or by operation of law in view In an income tax case, a Federal appellate court of the trust and confidence reposed in the recipi- considered whether the sale of blood is a service ent by the discloser (so). Since a trade secret is or a product (104). While the case was decided rooted in secrecy, publication impairs the legal on due process grounds rather than on the basis right to control disclosure and use. Unlike a paten- of the property versus services distinction, the tee, a trade secret owner has no recourse against case suggests that “blood plasma . . . is tangible a later independent developer, or even one who property which in this case commanded a selling discerns the secret by analysis of the products price dependent on its value.” placed on the open market by the owner. Only the abuse of a confidential relationship creates liability. Law of Copyright Liability may flow from a statute or a contract (express or implied) between the parties. In mak- Copyright provides protection for “original ing theft of a trade secret unlawful, a number of works of authorship fixed in any tangible means State criminal laws include cultures and micro- of expression” (I7 U.S.C. 102). Works of authorship organisms among the types of articles which may include literary, musical, dramatic, choreographic, represent a trade secret (23,30)40,46). Recently, pictorial, graphic, sculptural, and audiovisual patent attorneys at one company published some works (17 U.S.C. 102(b)). Copyright protection, suggested confidentiality agreements for use in however, does not attach to any idea, procedure, disseminating biological materials, The most de- process, system, method of operation, concept, tailed of these agreements addressed the follow- principle, or discovery. Copyright provides an ing issues: author with exclusive rights for the specific form of expression, but not for the underlying idea. ● When the recipient is a university researcher, how should responsibilities be apportioned One writer on intellectual property law topics between the researcher and his or her uni- has suggested that DNA molecules are copyright- versity? able as express “information, ” albeit genetic in- ● What types of biological material are covered? formation. To him, bases are letters; codons are In particular, what modification of the mate- words; and genes are sentences. Switching meta- rial might take it outside the agreement? phors, he compares DNA molecules to computer ● To whom may the material be transferred? programs; both are sets of instructions (53). ● How may the material be used? Others have challenged these views as based ● Is the researcher free to publish his/her work? on false analogies (31). In any event, these argu- ● Does the recipient have an obligation to dis- ments would not, even if fully accepted, confer close his/her work to the supplier in advance copyright protection on human biological mate- of publication? rials other than DNA. Even if DNA were copyright- ● If the work is patentable, what recognition able, a patient probably could not claim to be its will be given to the supplier’s contribution? .

Ch. 5—Legal Considerations 79

● Is the transfer a sale or a license? tort has been defined as “an intentional exercise ● Is the material warranted in any way? of dominion or control over a chattel which so ● Who will bear liability for any harm arising seriously interferes with the right of another to from use of the material (54)? control it that the actor may justly be required to pay the other the full value of the chattel (3).” A sample of human tissues and cells is not itself Thus the potential recovery for a plaintiff in a con- a trade secret (73), but may be characterized as version suit (full value of the property) can be a tangible article representing an intangible trade much greater than in a claim only alleging tres- secret (65). Still, unless the patient contemplated, pass (actual damages to the property). at the time of transfer, that the excised tissues or cells had commercial value, it would be diffi- Hundreds of decisions involving the tort of con- cult to argue that the biological material repre- version have been decided over the last several sented a “trade secret” of the patient. Because a decades. Because tort law is determined primar- trade secret is information used in one’s business, ily by individual States, and not by Federal law, a patient must be in the business of selling or using significant variation in the conversion doctrine those tissues or cells in order to hold a trade secret. exists from State to State. Federal courts trying Under the more liberal Uniform Trade Secrets conversion cases usually apply the law of the rele- Act, use in business is not necessary, but reason- vant State. Because of a lack of uniformity in State able efforts by the patient to maintain the secrecy conversion laws, the outcome of suits alleging con- of the tissue still would be required to retain trade version of biological substances would depend secret status. permitting a researcher to publish partly on the specific laws of the State whose law a description of the tissue would seem antitheti- is being applied. Nevertheless, some general prin- cal to recognition of a trade secret therein. ciples can be distilled from the different State and Federal cases. One analysis of tort law suggests that the following factors should be considered Law of Conversion and Trespass by a court in determining whether conversion has to Chattel taken place:

● Personal property is protected by both crimi- the extent and duration of the actor’s exer- nal and civil law. The theft of property is a crime cise of dominion or control, ● known as larceny. Interference with another’s the actor’s intent to assert a right in fact in- property is the tort of trespass to chattel, or con- consistent with the other’s right of control, ● version, depending on the severity of the inter- the actor’s good faith, ● ference. the extent and duration of the resulting interference with the other’s right of control, The tort of “trespass to chattel” occurs when ● the harm done to the chattel, and one person intentionally interferes with someone ● the inconvenience and expense caused to the else’s personal property. However, to prevail in other (3). a trespass claim the owner must show he suffered some actual damages as a result. Establishing actual damages could be extremely difficult for an Property Interest individual whose biological materials had been removed from the body for a diagnostic or thera- The essence of the tort of conversion is inter- peutic purpose. Furthermore, damages are limited ference with the owner’s right of possession or —a plaintiff can only recover for the actual loss control. The plaintiff in a conversion suit must therefore show a right to possess the property in value of the property caused by the inter- or the suit will fail. Historically, establishing a prop- ference. erty interest in a bodily part has been quite diffi- For these reasons, a plaintiff seeking remuner- cult. As discussed earlier, the sale or disposition ation for use of biological substances would more of cadavers, cadaver tissues, or the cadaver or- likely claim that conversion has occurred. This gans has generally been restricted. 80 ● Ownership of Human Tissues and Cells

Perhaps the most direct support for a patient’s the burden of proving a clear property right in property claim in tissue comes from State crimi- excised tissue (106). In a State where a statute or nal statutes defining property. Listing the types regulation forbids possession of tissue taken dur- of articles protected against larceny, a number ing treatment except for use in scientific research, of States have specifically included cultures and a patient would probably have a difficult time in micro-organisms (23,30,40,46). A patient residing showing entitlement to immediate possession of in such a State could cite the statute as evidence the chattel. of a legislatively recognized property interest in If a right to possess tissue exists, this right could cultures made from excised patient tissues and be argued to apply to all tissue removals, not just cells. tissues that later prove to be of commercial value. If this were true, any bodily material disposed of Possession by a physician could potentially present a claim To successfully bring a claim of conversion, a for conversion. The broad scope of acts amena- plaintiff must be “entitled to immediate posses- ble to a conversion claim would have potentially large consequences because bodily tissues are rou- sion of the chattel” (l3,30). Without this clear right to possession, there is no tort of conversion. For tinely discarded by physicians. The interference with the patient’s bodily material would not ap- example, an owner who leases equipment to another cannot bring an action against a third pear to be different whether tissue is thrown away after analysis or the researchers deny that the party for conversion during the lease period because the owner has no immediate right of pos- patient/plaintiff has an ownership interest in a bioengineered product. In both situations, the pa- session (10). Similarly, a right that is contingent tient loses control over the tissue once it leaves on future events will not support a claim for conversion (70,76). The individual’s right to posses- the body. Thus it may be necessary for a patient/plaintiff to articulate criteria that would re- sion must therefore exist at the time the biologi- strict the applicability of the conversion doctrine cal material is removed, and not arise months or so that it would not apply to all human tissue that years later when the substance has been shown is tested by a researcher. to be commercially valuable. Whether a person whose biological material is One such distinction may involve the type of tissue. Some substances, such as urine, feces, incorporated into a bioengineered product could saliva, and sweat, are byproducts of life that are be able to meet the test of possession is not al- naturally exuded by the body. Because these sub- together clear. Often, the material used by a stances are routinely discarded by all humans, an researcher has been removed during some medi- individual’s claim of a property interest in such cal procedure. Neither State statutes nor the com- substances may be regarded as attenuated due mon law appear to have provided the patient with clear ownership rights in tissue removed during to abandonment (103). perhaps a patient’s claim would be strengthened if the tissue was one that diagnosis or treatment. was purposefully removed during a surgical pro- For example, a California statute requires that: cedure to which the patient had consented, and not simply as part of an ongoing, natural process . . . recognizable anatomical parts, human waste, of secretion or excretion. Some researchers have anatomical human remains, or infectious wastes argued, however, that any deliberately excised dis- following conclusion of scientific use shall be diseased tissue is within the public domain once it posed of by treatment, incineration, or any other has been examined by a surgical pathologist (103). method determined by the State [Health] Depart- ment to protect the public health and safety (22). Whether a meaningful distinction can be drawn based on the mechanism by which the tissue is While this statute does not foreclose the patient removed from the patient is not entirely clear. Nei- from having a limited property right in the ana- ther case law nor statutes provide any definite tomical parts that were amenable to use in scien- answer. Nevertheless, it does appear that the tific research, neither does it help a patient meet strength of a “lack of possession” defense in a con- Ch. 5—Legal Considerations . 81

version suit may be affected by whether the tis- from the files at night, photocopied, and returned sue used in the research is naturally and repeat- to the file undamaged before office operations re- edly discarded, or is surgically excised. sumed in the morning.” The court found that these actions had not substantially deprived the sena- Injury to Plaintiff tor of the utility of his records. Because the plaintiff was not significantly deprived of his property, In addition to demonstrating a property inter- or its value, the court found that conversion had est in the tissue, a successful suit for conversion not taken place. must show that the plaintiff has suffered some In a situation where the amount of cultured tis- injury through interference with the property. sue is limited by the physical environment, and One form of injury is a diminution in the avail- not by time, a researcher possibly could draw on ability (and hence the value) of the property to the plaintiff. But “raw” tissues and cells have lit- this photocopying case in defending against a claim tle pecuniary value in themselves, especially to of conversion (32). When an original manuscript is taken, copied by an outside agent, and replaced, the typical patient or research subject who is not there is no conversion; the same reasoning could trained to identify biological characteristics or de- apply when a portion of an original culture is taken velop cell lines or cloned gene probes. Arguably, but naturally replaced by the fecundity of the re- tumor cells and other diseased tissue have a negative value, so a patient who is “deprived” of these maining original material, Either way, the value biological may typically experience an increase of the original substance does not appear to have in his physical, psychological, and financial well- diminished, and the ability of the person who provided the original material to exercise dominion being. In addition, a researcher’s patent on a cell and control over the property probably has not line, recombinant DNA clone, or hybridoma does been substantially impaired. not reduce the source’s right to engage in research on his own (or to employ another scientist) using This line of defense, however, probably would a similar cell. Since a patent is granted only to not rebut the plaintiff claim to ownership of the that which makes an invention new and unique, original culture. That is, while the researcher’s using raw material in a patented invention does use of the subculture may not have interfered not prohibit others from using the same raw ma- with the patient’s exercise of control over prop- terial in a different way. erty, to exclude the patient from exercising con- culture Frequently, researchers will create a subculture trol over the entire could constitute conversion. from an existing cell line (i.e., take a sample of an existing culture and grow this smaller sample Researchers might attempt to draw a different separately) and will conduct tests on this subcul- analogy from the photocopying case. Frequently, ture. In the meantime, the cells in the original sam- surgery is not successful in removing from the ple may reproduce themselves so that total size patient’s body the entire tumor or all pathogenic of the original sample is unaffected. The period cells. In this situation, additional cultures could of time when the total amount of the cell popula- be obtained by removing some of the cells remain- tion is “diminished” is dependent on the rate of ing in the body. Accordingly, a researcher could cell division. The removal of a subculture of the argue that use of the initial culture did not de- cell line that is replaced by growing cells may not prive the patient of any property because the cul- be regarded by a court as being inconsistent with ture could readily be duplicated by using cells still the patient/plaintiff property rights in the origi- within the patient’s body. Items that are readily nal culture. replaceable may be the basis for only a very limited financial recovery by the plaintiff in a conversion This argument may derive support from a case suit (107). decided by a Federal appellate court, Pearson v. Dodd (74). In that case, reporters had obtained This argument, however, may not afford com- possession of photocopies of papers owned by a plete protection for the researcher. In some in- senator. The papers had been furtively “removed stances, the treatment might eradicate the sam- 82 ● Ownership of Human Tissues and Cells pie, or make it very difficult to locate additional Res Nullius cells. Moreover, a new sample of the diseased tis- Another defense that a researcher might assert sue in vivo may not be easily accessible. Often, is res nullius, which means things that are not the tumor can only be reached through invasive owned (90). The res nullius category included is- treatment of the patient. A patient probably would lands newly risen from the sea and wild animals. not be barred from claiming conversion on the Under common law, for instance, a distinction was ground that a replacement culture can be estab- drawn between domestic and wild animals. Do- lished if the patient must undergo surgery for that mestic animals could be acquired and held as prop- new culture to be developed. erty just like inanimate articles, but wild animals could only be the subject of a qualified property right. Initially, wild animals were common prop- Abandonment erty. The owner of land had the right to take wild animals found on his land, but this right was lost The courts have consistently ruled that aban- when the animals escaped from the land. The right donment of a person’s property is a complete de- was mainly of significance in disputes between fense in any suit alleging conversion. This princi- landowners and poachers (17). ple applies to all property, including organic material (28). The main way of acquiring rights in wild animals was to lawfully domesticate or confine them. In a recent Louisiana case that may be analo- Mere pursuit of a hunted animal was insufficient. gous, the plaintiff owned a 130-year-old tree whose If the wild animal escaped, moreover, it could law- limbs extended over a neighbor’s house. After a fully be seized by others unless they had perpetu- tree surgeon removed these overhanging limbs ated the escape or unless the animal had been at the neighbor’s request, the landowner sued the domesticated to the point that it probably had an tree surgeon for conversion for not having chopped intention to return. the limbs into firewood. The court ruled in favor of the tree surgeon, finding that he had given the It could be argued the patient and his tissues landowner access to the branches. Since the land- stand in a relationship similar to that between a owner had not exercised any control over the ex- landowner and wild animals on his land. If tis- cised limbs—even though she had the opportu- sues were removed without consent, the wrong- nity to do so—she could not assert a right to the ful possessor would be like a poacher of wild ani- limbs. The court further supported its conclusion mals, and would have rights inferior to those of by citing evidence that the landowner had given the patient. If, however, the tissues were removed permission to the tree surgeon to prune the limbs without the removal itself being wrongful, their without ever mentioning her desire to keep the status would be that of wild animals in a state of excised limbs (11). Although arising in an entirely nature and the possessor could attempt to exer- different factual setting, another case suggests that cise dominion over them. Not having exercised an individual who takes no affirmative steps to dominion or control over the tissues, the patient’s ensure a possessor interest in tissue removed rights therein would be like those of a landowner during treatment will encounter difficulties in sub- who had made no attempt to capture wild ani- sequently asserting any claim to that tissue (12). mals passing over his land. The argument seems strongest in the case of tumors because these are Abandonment, if proven by the defendant, pre- not normal, healthy parts of the body. A defen- cludes a claim of conversion. Whether abandon- dant/researcher could contend that it was he, not ment of biological materials has occurred, how- the patient, who isolated and cultured the abnor- ever, can only be decided by looking at the facts mal bodily constituents and thereby reduced them in each individual case. The defendant must show to “possession. ” “an intention to abandon or relinquish accompanied by some actor omission to act by which such This defense, however, is subject to the coun- an intention is manifested” (83). terargument that the physician has a fiduciary —.—

Ch. 5—Legal Considerations . 83 duty to the patient, that is, a duty to act in the skill of another), even where such addition extends patient’s best interest. This common law duty is to a change of form or materials. Under this prin- imposed because of a patient emotional vulner- ciple, the possessor of property becomes entitled ability as well as his reliance on the physician’s to it, rather than the original owner, where the specialized knowledge. Since the physician’s pri- addition made by skill and labor is of greater value mary duty is to the patient, the exploitation of than the original property, or where the change specimens without the patient knowledge or con- is so great as to render it impossible to restore sent arguably constitutes a conflict of interest. Fur- it to its original shape (92). thermore, since property entrusted to a fiduci- Accession may provide a useful analytical frame- ary remains the property of the original owner, work for property ownership disputes involving a patient could claim that any research performed hybridomas and other substantially modified bio- without the patient consent is required to be for engineered products, If the labor of the researcher the patient’s own benefit, Thus, a patient might is regarded as of paramount importance, then ti- claim that the transformation of the tumor from tle should vest with the researcher. However, if res nullius to a living substance now under con- the efforts of the researcher are considered of trol was achieved pursuant to a relationship from lesser importance, then the major contributor to which the patient should derive the principle ben- the finished product is the patient or research sub- efit. This argument probably could not be made ject. This might be particularly true if the patient by volunteer research subjects because their par- had supplied a very rare type of cell. The limited ticipation in providing cells is not for personal availability of the raw biological material might benefit. then be said to enhance the value of the patient contribution—even if involuntary—vis-a-vis the Law of Accession labors of the researcher. Although tissue is a valuable starting point, substantial modifications ordinarily must take place Cases Involving Crops before a commercially valuable product is created. A specialized subset of accession cases may have For example, the researcher might take the pa- some relevance. Under Roman law, seeds, plants, tient’s cellular material, subject it to mutation- and trees acceded to the land. Once in the soil, causing agents, and then select those mutated cells these botanic materials became the property of that show a desirable trait. The biological mate- the owner of the land, regardless of how they rial may be combined with material obtained from were planted or who did the planting (90). As long an entirely independent source. The researcher as the crops remained in the ground, ownership might, for instance, develop a patient’s cells into resided with the landowner. For crops that had an immortal cell line and then fuse this cell line been removed from the soil, ownership depended with the lymphocyte cell of another patient to yield on whether they were fructus naturales or an entirely new hybridoma cell line. fructus industrials. The former were generally When a product combines biological material perennials, such as trees, shrubs, and grasses; the obtained from more than one source, or where latter were usually annuals, such as wheat, corn, the biological material has been significantly mod- rye, and potatoes. Severed fructus industrials ified, the legal doctrine of accession maybe help- crops were owned by the gardener, while severed ful in analyzing ownership issues. The doctrine fructus naturales crops belonged to the land- of accession is derived from the civil law of con- owner. This distinction arose because of the rela- tinental Europe, not Anglo-American common law. tive amounts of human inputs: in fructus indus- It has, however, been invoked by American courts. trials) much effort was expended, while fructus naturales were much less labor-intensive (27)56). Accession is the principle by which the owner of property becomes entitled to all which it pro- This test would appear to favor the researcher duces, and to all that is united or added to it, ei- over the patient. Cells taken from the individual ther naturally or artificially (i.e., by the labor or can be analogized to a severed crop. To maintain —

84 ● Ownership of Human Tissues and Cells these cells requires considerable effort and en- Specification might provide a basis for analyz- ergy; they would not thrive if left untended. There- ing many of the factual situations that arise in bio- fore, a researcher could plausibly assert that a technology. For example, a researcher might take cell culture is a fructus industrial, not a fructus a blood sample of little commercial value and naturales. Thus, the cells (the severed crop) should through mutation and careful selection develop belong to the researcher (the cultivator). a commercially valuable new cell line. In such a situation, the researcher could assert that speci- Specification fication has taken place because the original cell cannot be recovered from the genetically modi- Another variation on the Roman doctrine of ac- fied culture (103). cession provides a conceptually helpful tool. Known as specification, this doctrine governs situations Judicial precedents will be of little help in ap- in which a second person fashions an entirely new plying the specification doctrine to modern cir- product out of materials belonging to another. If cumstances. The case law is generally quite old specification is applicable, the person who engi- and often inconsistent. While one court has held neers the transformation, not the person whose that grass that is cut and made into hay is not materials are used, owns the final product. In de- covered by specification (5), another court held termining whether specification has occurred, that specification vested ownership in the person courts look to the uses, values, and common names who had fired the bricks and not the person who of the starting material and finished product. had owned the clay (58).

REMEDIES

If the supplier of human tissues and cells pre- market value of the property at the time of con- vailed in a lawsuit concerning ownership of a version (93,105). Usually, providing the owner with biological product by virtue of cell or tissue owner- that sum should restore the owner to the finan- ship, the court would then have to devise a rem- cial position enjoyed before the conversion. edy. Unless title has passed through the doctrine It may not be entirely clear, however, when the of accession, an original owner would be entitled conversion of a biological substance actually oc- to recover the original property (or its cash value) curred. The plaintiff would probably assert that from the person who had converted the property. value should be measured at the time when the Restoration of ownership, however, does not cell line or gene probe was developed or even later. always occur when property has been disturbed. The researcher, in contrast, would assert that In a recent case, for example, the plaintiff bought value should be determined earlier, either at the a $2,000 movable home, placed it on cement block, time the tissues or cells were still within the pa- and then left the home for 2 years. In the inter- tient’s body (when the patient still had physical vening period, the defendant spent $18,000 to im- possession), or after excision but before develop- prove the house. The court refused to award the ment. Neither time would be likely to yield a sig- plaintiff the house, saying that this would result nificant damage award for the patient. The tis- in “unjust enrichment,” particularly since the plain- sues or cells would seem to have little value while tiff had virtually abandoned the building (89). This still in the patient’s body or immediately after situation could be compared to a patient who as- removal. serts ownership of a bioengineered product that Nor is it clear that the tissues or cells would have had acquired its substantial value only after sev- much value once developed. The great majority eral years of research and development efforts. of cultures and cloned genes are of no commer- More commonly, a plaintiff alleging conversion cial value-only a small fraction are ever patented will seek monetary damages. In a conversion suit, and only a fraction of patents are licensed (103). the plaintiff’s damages will ordinarily be the fair Thus, even if the moment of culturing was the Ch. 5—Legal Considerations ● 85 appropriate time point, the patient would have owner, in accordance with the maxim partus se- to rely on the latent, potential value of the cells— quitur ventrem (“the birth comes from the not the immediate utility of the culture—to recover womb”). And an owner who was wrongfully de- more than a nominal sum (108). However, there prived of livestock can recover for lost output pro- may be certain types of tissues or cells which, vided that this loss can be established with suffi- through rarity or immediately apparent special cient certainty, including eggs from converted properties, would have some ascertainable mar- chickens (39) and milk from converted heifers (63). ket value once they were cultured (51). These cases would seem to support a patient’s claim for the value of the output of a cell line re- Case law does not provide much direct author- sulting from a wrongfully taken tissue or cell. As- ity concerning the point in time that should be suming that a patient did prevail on the conver- used to compute damages. Nineteenth century sion claim (68), the recovery might therefore British cases involving the conversion of coal by include not only the value of the cells themselves, secretly removing it from a mine do tend to sup- but also the value of any cell line and product de- port choosing an earlier point. Cited with approval rived from the cell line. by the U.S. Supreme Court, these cases hold that the measure of damages is “the value of the coal Variation Among States as it was in the mine before it was distributed, and not its value when dug out and delivered at State courts vary widely in the degree to which the mouth of the mine” (38). If this is analogized they depart from the strict test of market value to a biological materials case, the appropriate point at the time of conversion. Thus the amount that is when the cells are still in the patient. If so, the a plaintiff could recover for conversion of biologi- monetary harm to the patient probably would be cal material could depend largely on which State’s trivial, In addition, not all patient tissue is unique law applies to the claim. or rare. If a bioengineered product is based on The differences among the States in comput- tissue with a relatively common trait, the market ing damage awards is illustrated by a California value of the tissue might be nil, because some bio- statute. (California is home to many biotechnol- logical materials are available at little or no cost ogy companies.) The basic rule in California is that from numerous sources. “the owner of a thing owns also all its products Nevertheless, while the general rule is that dam- and accessions” (18). Under this law, ages are determined at the time of conversion, . . . [w]hen things belonging to different owners this rule has numerous exceptions. For example, have been united so as to form a single thing, and courts have held that under certain circumstances cannot be separated without injury, the whole be- the plaintiff could recover the highest value of longs to the owner of the thing which forms the a converted crop at any time between the date principal part (19). of conversion and the date of trial (42,47). Simi- The legislature recognized the potential difficulty larly, an individual ordered to leave the land on in determining which part was “principal .“ To give which he was growing crops was awarded the guidance to the courts, the following statute was money that he would have received had the crops enacted: matured, not the value of the crops at the moment of his ejection (79). Because the plaintiff had That part is deemed to be the principal to which introduced substantial evidence of what the yield the other has been united only for the use, orna- of the crop would have been, the court rejected ment, or completion of the former, unless the lat- the defendant’s argument that damages should ter is the more valuable, and has been united with- be fixed at the moment of the conversion. out the knowledge of its owner, who may, in the latter cases, require it to be separated and re- Well-established agricultural doctrine may turned to him, though some injury shall result to the thing to which it has been united (20). strengthen the claim of the patient or subject to a larger recovery. Unless the parties agree other- Once the owner of the “principal” part has been wise, the progeny of animals belong to the mother’s ascertained, that person can claim ownership to 86 ● Ownership of Human Tissues and Cells

the entire object. However, the owner must “researchers frequently test tissues without knowing imburse the value of the residue to the other the source of the material (103). If a patient sus- owner, or surrender the whole to him” (21). This pected that his or her tissue had been used to gen- is a substantial change from the common law ap- erate a bioengineered product, the individual proach followed in most jurisdictions. would need to trace the product back to the tissue originally provided. This could be quite diffi- It is clear that computing damages might be dif- cult where material has been pooled or where ficult in many biological tissue conversion cases. full documentation of tissue source has not been The problems could be further compounded by maintained by the research facility. the need for the plaintiff to identify with specificity his or her property. It will not be enough for the patient to demonstrate that a cell culture or Third-Party Liability bioengineered product contains tissues or cells Good faith of the defendant is generally irrele- that originated with him or her. The patient also vant to the merits of the claim in a conversion must identify specifically the cells which he or suit and the person whose property has been con- she claims to own (45). For example, if cows are verted can prevail, regardless of whether the converted and then mingled with another person’s defendant acted inadvertently (91). The intent of herd, the cows’ owner must identify his particu- the defendant may, however, affect the damages. lar cows in order to receive an award of damages Some courts have held that where the acts are (60). Simply showing commingling is not enough willful, the defendant must reimburse the lawful to justify a monetary recovery. owner for the full value of the property even if This need to establish ownership of discrete arti- the defendant had enhanced the value of the prop- cles may not be difficult in some situations. Typi- erty through labor or materials (75). cally, considerable efforts are expended to main- Because good faith is not a defense, third par- tain the purity of a cell line; biological material ties who unknowingly participated in the conver- from another source is ordinarily excluded from sion may be held liable to the plaintiff (84). Thus a cell culture. Thus in many cases, it would not an auctioneer who unwittingly sold property that be difficult to trace to a single source the original had been converted by a third party has been held material used to make a cell line. When this sepa- liable to the true owner of the property (91). This rate existence is not maintained, however, the principle could have important applications for plaintiff may have the difficult task of segregat- the biotechnology industry. If good faith is not ing the tissue or cells which he or she originated a defense to possession of a bioengineered prod- from those coming from another source. uct derived from a patient’s tissue, then innocent Moreover, this need to identify specific prop- purchasers of the product are potentially liable erty may be a barrier to recovery in cases involv- to the patient; similarly, licensees using the prod- ing anonymous or unidentifiable sources. Re- uct might also be at risk of suit.

SUMMARY AND CONCLUSIONS

U.S. law has long protected people from those utes to codify, modify, and overrule the common who would harm them physically or who would law. deprive them of full enjoyment of their property. The common law classifies many injuries to per- No area of existing law definitely sets forth the sons (which are analyzed under tort law princi- rights held by an individual who provides tissues ples) or injuries to property (which generally are and cells to an academic or commercial researcher. within the domain of property law). Congress and Because neither judicial precedents nor statutes State legislatures have enacted a variety of stat- directly address the questions raised by the use Ch. 5—Legal Considerations ● 87 of tissues and cells in research, courts must han- merchantability and fitness of such products. In dle emerging legal questions by using principles addition, State sales taxes would apply. Although and precedents developed for other circumstances. State law generally characterizes such transfers In reasoning by analogy, courts can draw upon as the sale of commodities, such characterization possible sources of rights that are outlined in this has not been applied consistently. chapter. The law of copyright will not provide a legal Patent law has direct application to biotechnol- remedy for the provider of human biological ma- ogy research and development. Although patent terial unless it can be shown that the source of law does provide inventors with a personal prop- such material is an author of such material. The erty right in the invention, it does not provide in- law of trade secrets provides protection, either ventors or their sources with property rights in by contract or through statute, against the dis- the original, unimproved tissues and cells. closure of certain information. A sample of hu- The law of cadavers and autopsies provides man tissues and cells is not itself a trade secret a historical context for considering the property but may be characterized as a tangible article rep- and quasi-property rights in human tissue. Al- resenting an intangible trade secret. Still, unless though property law concepts have been useful the patient contemplated, at the time of transfer, in this area, the tort of intentional infliction of that the excised tissues or cells had commercial emotional distress has been developing as a more value, it would be difficult to argue that the bio- appealing theoretical basis for a legal claim based logical material represented a “trade secret” of on unauthorized retention of body parts and other the patient. forms of wrongful conduct. Today, cases concern- The law of conversion and trespass to chat- ing wrongful acts toward a dead body are gener- tel may provide tort protection for sources of hu- ally treated as tort cases rather than property man tissues and cells where it can be shown that disputes. there was intentional interference with personal The law of organ transplantation is relevant property. Because tort law is determined primar- because it shows congressional intent banning ily by State law, significant variation in the con- sales of certain human organs. The law of blood version doctrine exists from State to State. The and semen sales is an area where regulation has law of accession, whereby the owner of prop- been minimal. This area of law does open up the erty becomes entitled to all it produces, may be question of whether the sale of replenishing tis- helpful in analyzing issues related to ownership sues and cells constitutes the sale of services rather of tissues and cells, particularly where the analy- than the sale of a commodity. If such sales are sis hinges on the comparative value of the raw treated as the sale of commodities, then Uniform material provided by the source and the labor ex- Commercial Code warranties would apply to the pended by the recipient of the material,

CHAPTER 5 REFERENCES

1. American Jurisprudence, 2d cd., Jur. 2d, vol. 22, 8. Ala. Code ~7-2-314(4) (Supp. 1985). Dead Bodies 1$4 (Supp. 1986). 9. Ariz. Rev. Stat. $36-1151 (Supp. 1986). 2. American Law Institute, Restatement of the Law, 10. John A. Artukow”ch & Sons, Inc. v. Reliance Truck, Contracts 2d, $367, comment a (1981). 614 P.2d 327 (Az. 1980). 3, American Law Institute, Restatement of the Law, 11. l?eals v. Griswold, 468 So.2d 641 (La. App. 4 Cir. Torts 2d, $222A. 1985). 4. American Law Institute, Restatement of the Law, 12. Bell v. Red Ball Potato Co., Inc., 430 A.2d 835 (Nle. Torts 2d, $868. 1981). 5. Corpus Juris Secundum, vol. 1, Accession $5. 13. Benton v. Division of State Lands and Forestry, 6. Corpus Juris Secundum, vol. 25A, Dead Bodies 709 P.2d 362 (Utah, 1985). ‘$8 (1985). 14. Brenner v. Manson, 683 U.S. 519 (1966). 7. Corpus Juris Secundum, \Iol. 25A, Dead Bodies 15. Brown, R., The Law of Personal Propertuv, $1.5 $8(3)(b) (1985). (3d ed. 1975). 88 ● ownership of Human Tissues and Cells

16. Browning v. Norton Children’s Hospital, 504 S.W.2d 51. Jansen, “Sperm and Ova as Property)” 11 J. of Med- 713 (Ky. 1974). ical Ethics 123 (1985). 17. Cal. Civ. Code !656 (West Supp. 1986). 52. Johnson v. Women’s Hospital, 527 S.W.2d 133 18. Cal. Civ. Code $732 (West Supp. 1986). (Term. Ct. App. 1975). 19. Cal. Civ. Code !1025 (West Supp. 1986). 53. Kayton, I., “Copyright in Genetically Engineered 20. Cal. Civ. Code jj1026, 1027 (West Supp. 1986). Works,” Gee. Wash. U. L. Rev. 191 (1982). 21. Cal. Civ. Code $1028 (West Supp. 1986). 54. Kelly and Jaworski, “Agreements Covering Ex- 22. Cal. Health and Safety Code j7054.4. (West Supp. changes of Biological Materials, ” 3 Trends in Bio- 1986). technology, 22 (1985). 23. Calif. Penal Code, j499c (West Supp. 1986). 55. Kessel, R., “Transfused Blood, Serum Hepatitus, 24. Calamari, J,, and Perillo, J., Contracts $16-5 (1977). and the Cease Theorem, 17 Journal of La w and 25. Caplan, A., “Organ Transplants: The Cost of Suc- Economics 183 (october 1974). cess)” 13 Hastings Center Rep. 23 (December 56. Key v. Uder, 182 A.2d 60 (D.C. Mun. Ct. App. 1983). 1962); 26. Carter v. Interfaith Hospital of Queens, 304 N.Y.S.2d 57. “Kidneys and Eyes for Sale as Well as Parts of 97 (1969). Blood,” Evening Journal (Wilmington, Delaware), 27. Casner, A., 5 American Law of Property [1952). Apr. 14, 1975, at 10. 28. Chemical Sales Co., Inc., v. Diamond Chemical Co., 58. Lamptonh Executors v. Prestonh Executors, 24 Inc., 766 F.2d 364 (8th Cir. 1985). Ky. (J.J. Marsh) 454 (Ky. Ct. App. 1828). 29. Chisum, D., Patents $10.01 [6] (1978). 59. Larson v. Chase, 50 N.W. 238 (Minn. 1891). 30. Col. Rev. Stat. $18-4-408 (Supp. 1983). 60. Lettinga v. Agristor Credit Corp., 686 F.2d 442 31. Cooper, I., Biotechnology and the Law, jll.02 (6th Cir. 1982). (1985). 61. Matthews, “Whose Body? People as Property, ” 32. Cooper, I., Biotechnolo~ and the Law, $11.03 Current Legal Problems 193 (1983). (1985) 62. McFa]Z v. Shimp, No. 78-17711 in Equity (C.P. Al- 33. Cruickshank & Co., Ltd. v. Sorros, 765 F.2d 20 legheny County, PA, July 26, 1978). (2d Cir. 1985) 63. McGrath v. Wilder, 60 A. 801 (Vt. 1905). 34, D’Amimco v. Brown, 155 USPQ (BNA) 534 (Pat. 64. Moore v. Regents of the University of California Off. Bd. Pat. Interf. 1967). (Docket No. C 513755, Super. Ct. Calif, 1985), Brief 35, Del. Code Ann., tit. 24, $7051 (West 1970). for Plaintiff in Opposition to Defendant’s at 12, 36. Diamond v. Chakrabarty, 477 U.S. 303 (1980). Demurrer to Plaintiff’s Third Amendment Com- 37. Dukeminier, J., “Supplying Organs for Transplan- plaint. tation,” 68 Mich. L. Rev. 811 (1970). 65. N.M. Stat. Ann. $$30-16-24 (Supp. 1983). 38. E.E. Belles Wooden-ware Co. v. United States, 106 66. N.Y. Pub. Health Law $580[4] (McKinney Supp. U.S. 432 (1883). 1985). 39. Eizen v. Hilbert, 131 N.W. 449 (Mich. 1911). 67. N.Y. Pub. Health Law ~3200(1) (McKinney Supp. 40. Fla. Stat. Ann. ~812-081 (Supp. 1986). 1985). 41. Glantz, L., “Property Rights and Excised Tissue, ” 68. AVKA Corp. v. City of Kansas City, 582 F. Supp. H?B 5 (october 1979). 343 (W.D. Mo, 1983). 42. Graham v. Frazier, 66 S.E.2d 77 (Ga. App. 1951). 69. Note, “The Sale of Human Body Parts,” 72 Mich. 43. Heard v. Burton, 333 F.2d 239 (CCPA 1964). L. Rev 1182 (1974). 44. Holder and Levine, “Informed Consent for Re- 70. Pacific Gamble Robinson Co. v. Chef-Reddy Foods search on Specimens Obtained at Autopsy or Sur- Corp., 710 P.2d 804 (Wash. App. 1985). gery: A Case Study in the Overprotection of Hu- 71. Parke-Davis & Co. v. J.D, Mulford Co., 189 Fed. man Subject,” 24 Clinical Research 68 (1976). 95 (S. D.N.Y. 1911). 45. Hughes B]anton, Inc. v. Shannon, 581 S.W.2d 538 72. Parkridge Hospital, inc. v. Woods, 561 S.W.2d 754 (Tex. App. 1979). (Term. 1978). 46.111. Rev. Stat. ch. 38, \15-1 (Supp. 1986). 73. Parks v. International Harvester Co., 218 USPQQ 47. Industrial Welding Supplies, Inc. v. Atlas Vend- 189 (N.D. Ill.). ing Co,, Inc., 277 S.E.2d 885 (S.C. 1981). 74, Pearson v. Dodd, 410 F.2d 701 (D.C. Cir. 1969), 48. Jackson v. Muhlenberg Hospital, 232 A.2d 879 cert. denied, 395 U.S. 947 (1969). (N.J. Super. 1969). 75. Pine River Log@-ng Co, v. United States, 186 U.S. 49. Jackson, P., The Law of Cadavers (1936). 279 (1902). 50. Jager, M., Trade Secrets Law j4.01 (1985). 76, Potts Run Coal Co. v. Benjamin Coal Co., 426 A,2d Ch. 5—Legal Considerations ● 89

1175 (Pa. Super. 1981); 93. Tyrone Pacific Int’1, Inc. v. MVEurychili, 658 F.2d 77. Presser, W., and Keeton, W., The Law of Torts, 664 (%h Cir. 1981). j12 (5th cd., 1984). 94. Uniform Anatomical Gift Act, 8A U.L.A. 15 (1985) 78. Presser, W., and Keeton, W., The Law of Torts, (Proposed official Draft 1968). ch. 17 (5th Ed. 1984). 95. Uniform Commercial Code, The American Law 79. Richardson v. Scroggham, 307 N.E.2d 80 (Ind. Institute and National Conference of Commis- App. 1974). sioners on Uniform State Laws (Official Text— 80. Rivise, C., and Caesar, A., Interference Law and 1978). Practice (1948). 96. UCC ~2-104(1). 81. Rosenberg, P., Fundamentals of Patent Law, $7.01 97. UCC $2-314. (1980). 98. UCC ~2-315. 82. Rozovsky, F., Consent to Treatment: A Practical 99. UCC ~2-711. Guide (1984). 100. UCC $2-716. 83. Sanchez v. Fortuy’s Texaco Service, Inc., 499 A.2d 101. UCC $2-716, Official Comment 1. 436 (Corm. App. 1985). 102. U.S. Congress, H.R. 98-769, accompanying H.R. 84. Shaw’s D.B. and L., Inc. v. Fletcher, 580 S.W.2d 5580 (Committee on Energy and Commerce, 91 (Tex. App. 1979). 1984). 85. Sideman, R., and Rosenfeld, E., “Legal Aspects of 103. U.S. Congress, Office of Technology Assessment, Tissue Donations From Cadavers,” 21 Syracuse Working Group on Patient Rights in Human Bio- Law Review 825 (1970). logical Materials: Legal and Ethical Issues, Wash- 86. Sih~estri v. Grant, 496 F.2d 593 (CCPA 1974). ington, DC, Jan. 17, 1986. 87. Stason, E. B., “The Uniform Anatomical Gift Act, ” 104. U.S. v. Garber, 589 F.2d 843 (5th Cir. 1979), reh’g 23 Bus. Law. 919 (1968). granted, 607 F.2d 92 (5th Cir. 1979) (rev’d and 88. State v. Community Blood and Plasma Service, remanded). Inc., 267 So.2d 176 (Ala. Civ. App. 1972). 105. United States v. TugwelZ, 779 F.2d 5 (4th Cir. 1985) 89. Storms v. Reid, 691 S.W.2d 73 (Tex. App. 1985). 106. Wheatley v. Towers, 358 N.E.2d 971 (Ill. App. 90. Thomas, J., Textbook of Roman Law 166 (1976). 1977). 91. Towe Farms, Inc. v. Central Iowa Production 107. Williams v. Board of Education of Clinton Com- Credit Assn., 528 F. Supp. 500 (S.D. Iowa 1981). munity Unit School District No. 15, 367 N.E.2d 549 92. Twin Cities Motor Co. v. Rouzer Motor Co., 148 (Ill. App. 1977). S.E. 461 (N.C. 1929). 108. Wolk v. Nichols, 572 P.2d 1190 (Ariz. 1977).

63-221 0 - 87 - 4 QL 3 chapter 6 Informed Consent and Disclosure

“Every human being of adult years and sound mind has a right to determine what shall be done with his own body.” —Scholendorff v. Society of New York Hospital, 105 N.E. 92, 93 (1914) CONTENTS

Page Consent Requirements for Medical Treatment and Human Research ...... 93 Common Law Consent for Medical Treatment ...... 93 State Statutory Requirements for Medical Treatment ...... 94 Federal Consent Requirements for Human Research ...... 94 State Consent Requirements for Human Research ...... 9S Institutional Review Boards ...... 96 Voluntariness of Consent ...... ,....., ...... 96 Disclosure Requirements ...... 98 Disclosure Requirements in Medical Treatment ...... 98 Disclosure in the Research Setting ...... 100 Disclosure Requirements and Commercial Gain ...... 102 Are Changes Needed in the Consent Process? ...... 106 Federal Research Exclusions ...... 106 Federal Exculpatory Language ...... ,..107 Latent Discovery of Commercial Gain...... ,...... 108 Role of the Institutional Review Board ...... 109 Documentation Requirements ...... , ...... 109 Summary and Conclusions ...... 110 Chapter p references...... 110

Box Box Page D. Physicians’ and Patients’ Views of Informed Consent and Disclosure ...... 99 Chapter 6 Informed Consent and Disclosure

Communication is as important in research as cian agrees to carry it out, the consent process in other professional endeavors. The communi- is usually complete, The practitioner may then cation between a physician or researcher and a perform the procedures that have been author- patient or research subject will vary based on the ized by the patient. situation faced by the parties involved. A physi- Although the consent process is completed prior cian who is removing a tumor from a patient is to undertaking medical treatment, subsequent likely to focus on several issues that differ from diagnostic or therapeutic measures can call for those faced by a researcher who is obtaining blood changes in the treatment plan originally agreed samples from healthy donors for a clinical re- to by the physician and the patient. This situa- search trial. Although the dynamics of these two tion requires new disclosures of pertinent infor- situations differ, an informed consent based on mation, a continuing dialog and exchange of in- the communication of optimal information re- formation, and a new or modified authorization mains the desired result. for treatment. Consent must generally be obtained from pa- Health facilities, legislation, or regulations may tients and research subjects prior to specimen require a written, signed consent. Some type of removal for treatment or experimentation. In- written record of the consent process is often nec- formed consent refers to a person’s agreement essary to satisfy requirements regarding the qual- to allow the activity to happen, based on full dis- ity of treatment, insurance claims, and legal de- closure of the facts needed to make a decision in- fense. A consent form cannot replace the dialog telligently. Informed consent has several compo- between the clinician and patient; its proper role nents: disclosure, comprehension, voluntariness, is to document that an exchange of information competence, and consent (11). Consent is a proc- has taken place. ess, not a form. The process represents a two- way flow of information between caregiver and In any discussion of informed consent, it must patient about the risks and benefits of treatment, be realized that many problems that arise can only leading to an agreement and course of action. be settled on a case-by-case basis. The parties involved often enter the consent process equipped Once there has been a sufficient exchange of with varying degrees of comprehension, compe- information by both parties, and assuming that tence, and voluntariness of action. This chapter the prerequisites of legal and mental capacity and will discuss these problems, as well as investigate voluntariness are in place, the patient is in a posi- the protections available to research subjects and tion to make an informed and voluntary choice. patients, After a choice of treatment is made and the clini-

CONSENT REQUIREMENTS FOR MEDICAL TREATMENT AND HUMAN RESEARCH

Consent requirements take many forms and are Common Law Consent for based on different principles. Professional medi- Medical Treatment cal societies have traditions concerning information exchange with patients. Other requirements Common law has developed two different the- emerge from common law, while others are based ories of consent. The traditional view, based on on State or Federal laws and regulations. the law of battery, holds that unauthorized treat-

93 94 ● Ownership of Human Tissues and Cells

ment is actionable as an intentional tort (3). As Much of the State legislation concerning in- such, there is no need to prove actual harm to formed consent deals with setting requirements the patient. Although the traditional view is fol- for information disclosure. These laws also con- lowed in some jurisdictions, it is now well-recog- tain the permissible grounds for not disclosing in- nized in common law that the law of battery is formation to patients. Nondisclosure provisions generally inadequate to deal with most contem- are often found in statutes that delineate the ele- porary consent issues. Patients who claim they ments necessary for a consent lawsuit or that received inadequate information about a proce- specify valid defenses to consent actions. Medico- dure are not in a position to say that treatment legal emergencies (13,15), therapeutic privilege was not authorized. Unless the patient can dem- (2,28), and requests by patients not to be informed onstrate fraud, misrepresentation, or breach of (9,29) are examples of legislative exceptions to the contract, there is no recourse. requirements for a valid consent. The common law in some States has recognized Federal Consent Requirements for this problem and a new theory of consent law has emerged. Based on the law of negligence, a Human Research patient can claim that the consent was invalid be- Following World War 11, the subject of human cause the authorization was based on inadequate research generated much international, Federal, disclosure of information. There is no need to and State discussion. This produced a wide vari- prove that the defendant had intentionally tried ety of pronouncements (25), guidelines (10), stat- to harm or deceive the patient. Rather, based on utes (20)30), and regulations (45 CFR 46, 21 CFR the law of negligence the plaintiff must prove: 50) governing human research. ● the appropriate standard of disclosure; There are two main bodies of Federal regula- ● that a breach of that standard took place; tions governing human research. Promulgated by ● that as a reasonably foreseeable consequence the Department of Health and Human Services of this breach, the patient was harmed; and (DHHS) and the Food and Drug Administration ● that had the patient been properly informed, (FDA), the regulations detail the elements neces- consent to the procedure would have been sary for informed consent to research and the withheld (24). documentation of that authorization, The DHHS Important elements also include the voluntari- regulations govern research conducted or funded ness of consent, mental capacity, legal capability, by the Department, including the National Insti- scope of disclosure of information, and exceptions tutes of Health (NIH) (45 CFR 46). The FDA regu- to the general rules for consent. lations govern clinical investigations that support applications for research or marketing permits State Statutory Requirements for for products such as drugs, food additives, bio- Medical Treatment logical products, and medical devices (21 CFR 50). The DHHS regulations have been recognized as Several States have enacted so-called “consent being the primary Federal requirements govern- to treatment” legislation. The impetus for many ing the protection of human research subjects. of these laws was the malpractice crisis of the The Interagency Human Subjects Coordinating 1970s. Many State legislatures also have passed Committee, which has representatives of 17 Fed- malpractice reform laws, including provisions eral agencies, has proposed that the DHHS regu- governing consent lawsuits (8) and the require- lations serve as a model policy for all Federal de- ments for a valid consent (33). The negligence the- partments and agencies (51 FR 20204). ory of consent has been given legislative recognition (27), and in some instances the right to bring As with the requirements for consent found in consent actions on the theory of assault or bat- the traditional treatment context, the DHHS reg- tery has been removed, ulations make it clear that consent to research Ch. 6—Informed Consent and Disclosure ● 95

must be obtained from the subject or his legal rep- a general prohibition on using exculpatory lan- resentative in circumstances that minimize the guage to release the investigator, institution, or prospect of coercion or undue influence (45 CFR sponsor from liability for negligence (45 CFR 46,1 16). The regulations specifically address is- 46,116; 21 CFR 50.20). sues such as confidentiality, compensation for Aside from its general consent regulations, research-related injuries, the right to withdraw DHHS has special provisions governing research from research without incurring a penalty or loss using fetuses, pregnant women, and human in of rights, and optional disclosure requirements vitro fertilization (45 CFR 46.201-46,211); prisoners that can be imposed. (45 CFR 46.301-46.306); and children (45 CFR The regulations are quite specific in terms of 46.401-46.409). consent documentation (45 CFR 46.117). In most instances, a written, signed consent is required State Consent Requirements for prior to initiating research. The regulations rec- Human Research ognize two types of consent documents, the so- California, New York, and Virginia have legis- called long form and the short form. The long form lated specific consent requirements for human encompasses all the consent elements required research (5, 18)31). Each of these State laws makes under the Federal regulations. The short form in- it clear, however, that research subject to Federal dicates that the subject or the subject legally au- regulatory requirements is exempt from State pro- thorized representative has been given a verbal visions (7)21,32), other States have less detailed account of the required information. The form legislative provisions regarding human research. must be signed by the research subject or repre- These laws, frequently codified under State nurs- sentative. The subject or representative must also ing home or long-term care statutes, are usually be given a written summary of the oral explana- part of patients’ rights legislation and simply in- tion approved by the Institutional Review Board dicate that informed consent is required for per- (IRB). For such a consent to be valid, the verbal sons enrolled in human research (16,17). other disclosure must be witnessed by another person provisions indicate that individuals may decline who, along with the subject or representative, to participate in human research (4,23). must sign the short-form consent document. The person who obtains the authorization must also The fact that only a few States have enacted sign the short-form consent. detailed legislation governing consent and human research, even though Federal regulations apply In specific situations, the DHHS regulations pro- directly only to federally sponsored research and vide that consent requirements can be waived. clinical investigations, may reflect a belief that the Waiver can occur when the IRB determines that: States are not equipped to regulate or monitor ● there is no more than a minimal risk to human research. It could also be interpreted to subjects; mean that State legislators do not believe the sub- ● the waiver will not have an adverse impact ject is so pressing as to require legislative initia- on the rights and welfare of subjects; tives. Another possible explanation is that Federal ● without the waiver, it would not be practical regulations are so detailed—and that IRBs tend to carry out the research; and to judge all research according to federally man- ● under appropriate circumstances, additional dated standards even if not federally sponsored– details will be given to subjects following their that there is little need for further legal controls participation in the research project (45 CFR at the State level. 46.1 16(d)). Although human research has not generated Under FDA regulations, exceptions to general much legislative response at the State level, the consent requirements are allowed when it is not laws that have been enacted convey a rather clear feasible to secure an authorization prior to using message regarding the well being and needs of the test article or to preserve the life of the re- research subjects, These State laws require a search subject (21 CFR 50.23), However, there is voluntary authorization prior to participation —— ——

96 ● Ownership of Human Tissues and Cells

from either a competent research subject or, in Patients may agree to treatment to avoid con- some instances, the subject’s legal representative, frontation or to satisfy some personal, family, or with a considerable emphasis on a written in- social objective. Indeed, some patients suffering formed consent. from serious medical problems may not be capable of a totally voluntary consent if the alterna- Institutional Review Boards tive to a proposed procedure is the prospect of lingering illness or death. DHHS regulations require institutions perform- When the prospect of commercial gain is intro- ing human subject research to create and use In- duced into the research setting, concern arises stitutional Review Boards to review proposed research projects for compliance with detailed about the voluntariness of consent. Will subjects human subject research regulations if the research be unduly influenced by the knowledge of possi- is funded by the Department or its constituent ble commercial gain? Will researchers unduly in- agencies (45 CFR 46.103(b)). fluence or coerce subjects who are the source of marketable, biological material? If these are gen- Since NIH is the primary source of funding for uine concerns, what steps can be taken to mini- biomedical research undertaken at medical schools, mize the prospect of a less than voluntary con- graduate science programs, and research hospi- sent? tals, the regulations appear at first glance to cover human specimen research. However, research in- Factors Influencing Voluntariness volving pathological or diagnostic specimens is ex- of Consent empt if the specimens are publicly available (for A variety of factors can influence the voluntar- instance, from a tissue culture depository) or if iness of consent to participate in research. Three the information is recorded by the investigator in such a manner that subjects cannot be identi- of these are: fied (46 CFR lo). . satisfying psychological, emotional, or medical needs; OTA commissioned a survey of the IRBs serv- ● ing 23 medical institutions to determine the prac- desire to please others; and ● the prospect of financial gain. tices of these institutions with respect to informed consent for specimen procurement and research. There is no doubt that for many subjects, par- Of 22 responding institutions, none reported any ticipation in human research satisfies some psy- special cases or problems arising with respect to chological, emotional, or medical need. The psy- using human biological materials. The survey sug- chological or emotional impetus for taking part gests that IRBs hold researchers to more strin- in a study may not be clearly defined, but afflic- gent ethical standards than are required by law. tion with or recovery from a serious illness, or All of the IRBs reported that the same standards the loss of a loved one, are sometimes rationales are used to review and justify all research projects for research participation. Taking part in a study in their institutions, regardless of the source of sometimes satisfies a need for attention, In most funding, even though compliance is only man- instances, it is not troublesome that a subject par- dated for federally funded projects. ticipates in a research project to satisfy an emotional or psychological need. However, when re- Voluntariness of Consent searchers who are aware of this inner need exploit it to gain consent, then voluntariness becomes an Voluntariness of consent is an important con- issue. Controlling this problem can be difficult, sideration in treatment and research. For a con- particularly because the undue influence may be sent to be voluntary, the authorization must be quite subtle yet very effective. IRBs and research- given freely. There should be no suggestion of un- ers alike must be diligent to safeguard against this due influence or coercion. In reality, it is hard to problem. insulate the patient or research subject from the most subtle—let alone sometimes overt—institu- The desire to please others can also pressure tional and social pressures. people into participating in research. This is par- — —

Ch. 6—informed Consent and Disclosure ● 97 ticularly of concern among those persons who see interest. Two distinct duties are present: one as their participation as a way to gain the favor of a principal investigator and the other as an at- someone in authority or for whom they have con- tending physician to the patient/research subject. siderable respect. Considerable doubt can be cast The interests of the researcher maybe far differ- on the ability of subjects in a dependent relation- ent from the concerns of the attending physician. ship to achieve a voluntary consent. Prisoners and The researcher may see the subject as an invalu- those in long-term care facilities typify such po- able source of scientific knowledge or perhaps tential subjects. Such concerns are embodied in commercial gain. The physician sees a patient re- the DHHS regulations dealing with prisoners as quiring careful diagnostic testing and treatment. research subjects (45 CFR 46.301-46.306). How- When the researcher and attending physician are ever, this problem can also manifest itself in other the same person, the desire for financial gain could dependent groups (e.g., children, the elderly). overshadow the concern for the well-being of the patient/research subject. Research might be car- The prospect of financial gain may also influ- ried out that would ordinarily be avoided and ence a subject’s decision to give consent. If a treatment that would usually be conducted might researcher places considerable emphasis on the not be pursued. prospect for financial gain with impoverished research subjects, such information may be an un- Commercial gain is not the only motivation for due influence. Even compensation for expenses unduly influencing physician/researchers. For and inconvenience could provide some impetus some, the potential for public or scientific rec- to participate. The question remains whether ognition may be more of an impetus to unduly these influences are inherently bad, or if not, are influence subjects than the thought of reaping fi- so strong as to be unwelcome. If so, safeguards nancial reward. While it may be difficult to dis- could be designed to minimize their effect. cern public or peer recognition as a cause for concern, the potential exists for the physician/ Legal Dynamics of the Physician/ researcher to conduct himself/herself in a man- Researcher and Patient/Research ner that unduly influences the subject. Subject Relationship It is difficult to determine whether or not un- Like the relationship between a physician and due influence is a serious problem in medical- a patient, the physician/researcher liaison with based human research. If it is, there are limits a patient/research subject is one of a fiduciary to what can be done to eliminate it. Educating phy- trust. The physician/researcher owes a special sician/researchers about the proper means of ob- duty of care to patient/research subjects and must taining consent, monitoring the consent process, not act in a way that jeopardizes the rights and requiring consent documentation, and taking ap- welfare of participants. This includes obtaining propriate action when discovering instances of authorizations for participation in research in a undue influence are all practical options. In addi- manner that is free of undue influence and based tion, professional boards can discipline those who on a fair and comprehensive disclosure of infor- have acted improperly. mation. The ability of research subjects to perceive un- The danger of undue influence is as real in the due influence should not be discounted. The ef- research setting as it is in the medical treatment fect of the consumer movement has spread to context. The results can be far worse in the treat- health care and patients have become more reluc- ment context, however, where subjects who agree tant to agree to treatment without first being satis- to unnecessary procedures or tests must pay fied of the need for and the costs of it. Patient- health facilities or clinicians. Moreover, in the research subjects, too, are likely to inquire about treatment setting the institutional and IRB safe- the purpose, needs, and benefits of studies. guards for human subjects are often not present. Finally, when enforced properly, the current For some physician/researchers, the prospect Federal human research regulations provide a con- of commercial gain can represent a conflict of siderable degree of protection against undue in- 98 . Ownership of Human Tissues and Cells fluence in the consent process. Full enforcement therefore be the most practical safeguards against of current provisions along with proper disclo- undue influence with respect to human tissues sure of the prospect for commercial gain may and cells of potential commercial value.

DISCLOSURE REQUIREMENTS

For a consent to be valid, the patient or research patient-need standard considers the probable im- subject must be given an adequate amount of in- pact treatment will have on employment and life- formation with which to reach a reasoned choice, style as well as the financial and emotional costs Perhaps no other aspect of consent has generated to the patient. State courts are increasingly adopt- more case law and discussion among scholars than ing this view in preference to the physician-based the extent of required disclosure of information. standard. Disclosure requirements can vary in different Both approaches to disclosure would generally settings. The following sections consider stand- include the following information in disclosure ards of disclosure in three contexts: disclosure to patients: in the medical treatment setting, disclosure in the ● the nature and purpose of a diagnostic, med- research setting, and disclosure when potential ical, or surgical intervention; commercialization of a product is contemplated. ● probable, foreseeable risks and benefits associated with the intervention; Disclosure Requirements in ● the availability of reasonable, alternative pro- Medical Treatment cedures and the probable, foreseeable risks and benefits associated with these optional In the United States, there are two schools of interventions; thought regarding the disclosure standard in con- ● an explanation of probable complications, dis- sent to treatment. The traditional view, held by comfort, disability, or disfigurement associ- a majority of States, requires disclosure of infor- ated with recommended, as well as optional, mation that the medical community customarily interventions; and discloses to patients (24). This standard is based ● the probable, foreseeable risk(s) associated on what physicians view as important, as well as with foregoing all interventions (24). what facts physicians believe patients should know before agreeing to treatment. Additional disclosure requirements are sometimes needed. For example, it maybe argued that A modern trend, adopted by a minority of States, patients in teaching hospitals should be informed bases disclosure requirements on what a reason- that students, interns, or residents may take an able person in the patient’s position would want active role in their health care because this infor- to know in the same or similar circumstances. Un- mation may be an important consideration for like the physician-oriented approach, this stand- some patients in agreeing to or refusing recom- ard is based on patient need and recognizes that mended therapy. patients want to take a more active role in their treatment. To this end, patients need information Case law recognizes that certain types of infor- that is material or significant to their decisions mation need not be disclosed. For example, un- regarding recommended care (24). der the patient-oriented standard the clinician need not divulge information regarding: The patient-need approach involves the patient in making decisions and it compels physicians to ● risks already known to the patient, communicate with patients. It enlarges the con- ● obvious risks which the patient may be present process to take into account matters beyond sumed to know, the mechanics of a proposed form of care. The ● remote risks with a very low incidence asso- Ch. 6—informed Consent and Disclosure ● 99

ciated with proposed care or testing, and ● risks either unknown to the clinician at the time consent is obtained or that in exercise of reasonable care could not be ascertained (26). Case law involving the physician-oriented standard does not provide a hard and fast rule for what the doctor need not disclose. This is a matter based principally on the facts and circumstances of each case, taking into account customary practice in the medical community. Should litigation ensue in a case controlled by the physician-oriented viewpoint, expert testimony would likely be required to establish what is the acceptable scope of nondisclosure (24). Both standards recognize certain exceptions when the need for disclosure is outweighed by other considerations (26). These include medical emergencies, situations where disclosure could be detrimental to the patient’s well-being, and instances of legal or mental incapacity. Thus, disclosure of information cannot be considered in a vacuum. Whether clinicians follow either the professional or patient-need standard of disclosure, it is imperative for them to take into account the surrounding facts and circumstances of each case. How this information is interpreted and applied helps to differentiate the two standards for disclosure. Several State legislatures have set requirements regarding what information needs to be disclosed (2,22,28,33), the types of information that need not be revealed (29,33), and the circumstances in which disclosure need not be made (13,25,33), Re- mote risks (2) or risks that are commonly known (2,18,29) need not be revealed. Similarly, medico- legal emergencies (13,15,33) and statutory versions of therapeutic privilege (2,9,28) create exemptions from the standard requirement for disclosure of information. The law is far from settled in the area of disclosure standards and some decisions have sparked controversy. For example, how far must a physician go in making certain that a patient’s refusal of care is informed (12)? Moreover, does the duty to reveal information about reasonable alternative procedures include mention of those procedures that are more hazardous than the recommended intervention? The Supreme Court of — . -.

100 Ž Ownership of Human Tissues and Cells

Connecticut has suggested that ‘(reasonable” alter- In addition, the researcher must explain that natives does include description or inclusion of subjects are voluntarily taking part in research more risky options (14). It remains to be seen and that their refusal to participate will not incur whether other courts will adopt that court’s defi- a penalty or loss of benefits to which they are nition of a reasonable alternative. otherwise entitled. Moreover, they must be told that they may withdraw from the study at any What constitutes an appropriate amount of in- time without incurring a penalty or loss of bene- formation disclosed to a patient under the phy- fits to which they are entitled. sician-oriented standard may be as hard to discern as “material” or “significant” information The same States that have detailed statutes on under the patient-oriented approach. The courts consent and human research have similar disclo- have evaded setting precise requirements. As a sure requirements (6)19). However, the Federal result, more, rather than less, case-law develop- regulations are more comprehensive, listing ad- ment can be anticipated in this area of consent. ditional information that should be revealed to research subjects if deemed appropriate (45 CFR I16(b)). This may include: Disclosure in the Research Setting ● situations in which the subject’s role in the Federal law requires far more information to study may be ended by the researcher with- be disclosed to obtain valid consent in a research out regard to the participant’s consent, setting than in a therapeutic setting. Under Fed- ● other costs to the subject that may result from eral regulations (45 CFR 46.116) and some State the research study, statutes (6), all reasonably foreseeable risks and ● the consequences of the participant with- discomforts that subjects might experience must drawing from the project and the means for be disclosed, an orderly conclusion to the subject’s involvement, Risk information is not the only type of infor- ● a statement that significant new findings mation that requires greater elaboration in the achieved in the course of the research relat- research setting. Federal law also mandates dis- ing to the subject’s willingness to carry on closure regarding: in the study will be provided to the subject, ● the nature and purpose of the research; and ● anticipated length of subject’s participation ● the approximate number of persons taking in the study; part in the study. ● procedures to be followed; Although Federal regulations emphasize full and ● identification of experimental procedures; ● candid disclosure of information, there are cir- benefits to the subject or others that maybe cumstances where an IRB may approve practices reasonably anticipated from the study; ● that alter or exclude some or all of the elements alternative procedures or treatments that for consent. To do so, the IRB must document that may be advantageous to the subject; ● the research involves no more than “minimal risk” steps to be taken, if any, to maintain confiden- to subjects, defined in the regulations as: tiality of records identifying participants; ● whether compensation and treatment are [T]he risks of harm anticipated in the proposed available for injury arising in a study where research are not greater, considering probability more than minimal risk is involved; and magnitude, than those ordinarily encountered ● if compensation or/for treatment is available, in daily life or during the performance of routine what it consists of, or where additional de- physical or psychological examinations or tests (45 CFR 46.102(@). tails may be obtained; and ● who should be contacted if subjects have In addition, the IRB must determine and docu- questions regarding the research or their ment that modifying the consent requirements rights, and the contact person in the event will not have an adverse impact on the rights and of research-related injury (45 CFR 46.1 16(a)). welfare of subjects. It must also be shown that Ch. 6—informed Consent and Disclosure ● 101

SAMPLE CONSENT FORM . :..:.:t>;··. • I.R.B. NO: __' ..____ _ : ',~" t •.. ',' This form is for use when the researcb WiII-~"'''''tlc '-- ,,, ~ • , """<-'. - . ~ p""""'"

Coosent to Partiel ...... IN''!h

1. Project Name: 2. Project Director: This research was approved by the 3. The purpose of this research is: 4. The general plan of the research is:

5. The following procedures wiD be performed ~

7. In order to do the research it will be ~to 8. This research may resuh in the following: di8C8t1U01rU!', 9. Participation in this research may involve thEf: 10. Participation in this research may benefit ... 11. As an alternative to participation in thisstudy,lbe 12. The investigators wiD do everything possible tb nnrVlm! to predict everything that might occur. If i partictlpatJlt ••li .. _:ted usual or unexpected is occurfug he/she .baWd conltaCl~:;W

In the event of any injury resulting froJ;Q. any t'AII.. fh1 M,,_ical care will be provided at the usual charge, but no Federal or District of ""ua,' oPUllil be available for compensa· tion. Additional information on this subjeJ:t' may be - 'iI"'l_.. __ of the Medical Director.

Anyone who agrees to participate in this ~ nV.1lime. Refusal to partiCipate or to continue to partic1pate will not harm. an 1ftdiY81 pbJ'sicj.ans, the hospital or those doing the research. They wm do the ·beat· ltwbetfter or not he/she partici- pates in this research. ' )* and I ~ad all of my

Data

Date

Rev. 8/79

SOURCE: Offk:e of Technt;IIogy AleeMmem, 1981. 102 ● Ownership of Human Tissues and Cells

as a practical matter the study could not be pur- prospect of any person achieving commercial gain sued without the consent modification. When as the result of any invasive procedure should be appropriate, however, subjects taking part in disclosed because this information may help a per- studies in which consent requirements have been son decide whether or not to take part in the re- modified must be given relevant information fol- search. While this information may not be perti- lowing their participation (45 CFR 46.116(d)). nent to medical risks and benefits, it can be viewed as a logical extension of the information already The need for a detailed disclosure of risk infor- required for consent. mation in the research setting is also found in case law. As a Federal appellate court wrote: Under current Federal regulations it can also be argued that at some point in the course of re- . . . [F]or a physician to avoid liability by engag- search, disclosure of potential commercial gain ing in drastic or experimental treatment, which exceeds the bounds of established medical stand- is required. The regulations require disclosure ards, his patient must always be fully informed “when appropriate . . . significant new findings of the experimental nature of the treatment and [are] developed during the course of the research of the foreseeable consequences of the treatment which may relate to the subject’s willingness to (l). continue participation” (45 CFR 46.116(b)(5)). It can be argued that the discovery in a subject’s body The common-law approach to disclosure in the of a unique cell line that may be commercially research setting is pragmatic. The degree of in- valuable constitutes a significant new finding. This formation revealed to a subject will vary from case type of information could influence a subject in to case, but some basic principles apply. The deciding whether or not to continue his role in greater the probability of risks and the more novel the research project. As such, under the regula- or experimental the procedure, the more detailed tions it maybe the type of additional information should be the information divulged to research that can be required when deemed appropriate subjects. This is an extension of the basic concepts by an IRB. of consent dealing with personal autonomy and the need for sufficient information to reach a rea- It also can be argued that in a medical treat- soned decision about care. ment context, disclosure of commercial gain should be deemed “material” or “significant” information. Under the patient-need approach to Disclosure Requirements and disclosure, this would require that the patient be Commercial Gain provided with such information. Since greater disclosure is usually required in a research setting, In medical settings, the information disclosed it would follow that disclosure of potential com- to patients traditionally has focused on the risks mercial gain would be required there as well. and benefits of diagnostic tests or treatment, as well as alternative procedures. In the research Arguments Against Disclosure context, the disclosure of information has centered Regarding Commercial Gain on the nature of the study, the involvement of subjects, and any risks involved. However, arguments Arguments can also be made against disclosing over the nature of disclosure arise when the pros- the prospect of commercial gain. One argument pect of commercial gain becomes an issue. opposing disclosure, is that the prospect of commercial gain is highly speculative and to bring up Arguments Favoring Disclosure the subject in a consent dialog may detract from Regarding Commercial Gain the more important aspects of the process. This interference may not rise to the level of undue Several arguments could be proposed to justify influence, but it could impede subjects from tak- why disclosure of potential commercial gain ing an effective role in the consent process. should be required in the research setting. If the right to decide what will be done to one’s own It can be argued that commercial gain should body is to be given full legal recognition, then the not be disclosed if it would hamper the subject’s Ch. 6—informed Consent and Disclosure Ž 103

SAMPLE CONSENT FORM 'ThIs form is for use when th6~:' *.t'!¥'

1. Project Nam~:' 2.. Project Director:

This ~ was aDI1iJtWi.:J.~ 3. The purpose of this resaarch ~: ' 4. The general plan of the ...... is: , " 5. 11te fOllowing prOceClureI1vdI ~ pe'"" 6 ..

7. This research ~y reaUl1. in the, foJlc)Wlf 8. partidpatioDiD:ti. r.SfJJ'Ch ma, 9. The ~toH'wOI do MrR1MhiM'lMD to predict ~ that:might acn"~1tJ usual 'or unexpected i8 OOOUtinI·helsIle~

_rcm":Anl_~~"." "'*~. care wiD be provided at ,. ,beavallahle for compensa\~ , 'of the Medical Director. '\

Anyone who agrees to pal'tidJJa. -~ma"af anytime. Refusal to participate . or to continue to participate will ItIarlllllip,~dth1ttl1her physicians, the hospital or those doing the ~: ThlrvwUlClIOUIe Dlett1!heY itsdiYlduu',l\'b,etbier or not he/she pardd- pates In thiS research."':' ':.: "

~ r I;

I bave read the abowt ..._.,.~ptoJect j ,~(w~reIl~~.e by: ). ADythingfdtcl_~!W~~~8 and I had aD of my questionB answered ,to my satiafadjQp. ,,;~~~ ·.DIrt..

...... I:... tfJ ... .,.l ....

(signed) --...,...... -...- Date

Date

~Date . 104 ● Ownership of Human Tissues and Cells ability to reach an informed choice free of undue Based on a professional disclosure standard, the influence. The prospect of financial security stem- majority viewpoint is concerned with what the ming from marketable products derived from hu- medical community considers necessary informa- man tissues and cells could interfere with some tion for patients to know in making a treatment people’s ability to reach an informed decision, decision. Even with the viewpoint held by a minority of States, based on patient need, it is un- Disclosing information regarding commercial certain whether the prospect of commercial gain gain could jeopardize the health and safety of some would be “material” or “significant” to a patient subjects, as well as the validity of the research contemplating actual treatment or an invasive itself. For example, upon learning of the prospect diagnostic procedure. It will be up to the courts of commercial gain, some potential subjects might or State legislatures to decide whether the possi- be hesitant to relate medical or personal history bility of commercial gain for any interested party information that would otherwise disqualify them requires disclosure where diagnostic tests or ac- from the study. This could result in studies gen- tive treatment is contemplated. erating invalid or skewed data. It could also jeopardize the health and safety of subjects who by In the research setting, where subjects maybe their actions expose themselves to unacceptable enrolled in studies offering little likelihood of di- and unanticipated risks. rect benefit and where there may be serious Requiring researchers to disclose information known or unknown risks, disclosure of commer- about potential commercial gain is arguably in- cial gain may bean important consideration. Such consistent with their professional responsibility information is likely to be particularly important to inform subjects about health-related details. Re- when the marketing of a product containing hu- searchers may not be sufficiently informed them- man tissues and cells is quite probable. It is a fac- selves to realistically explain the prospect of com- tor that goes to the core of personal autonomy mercial gain. In fact, the researcher may not even and a subject’s determination whether or not to be the physician of record who interacts with the be the source of a commercially viable commodity. subject. While an investigator may think there is It should not be assumed that all persons, upon an opportunity to successfully market unique hu- learning that they carry a unique cell strain or man biological materials or products invented other type of biological material, will agree to its from specimens, in fact there maybe little likeli- commercial marketing as a developed cell line. hood of this becoming a reality. For researchers Some people may be opposed to such use (see ch. to divulge such information could convince sub- 8). jects to participate in research on the basis of mis- Safeguards can be developed and put in place information, unreasonable expectation, or for the that minimize any detrimental impact flowing sole purpose of financial gain. This would be con- from disclosure of probable commercial gain, if trary to the general principles of consent and dis- policymakers, IRBs, or researchers determine that closure. such disclosure is desirable. These include deter- Finally, full information regarding potential com- minations regarding the content and timing of mercial gain may be impossible to convey in many such disclosure and the standard for revealing instances since the prospect of such gain is likely such information. The standard determines how to be vague and speculative at the time the sam- much information regarding the treatment or re- ple is obtained. search project will be given to the subject, When the focus shifts to novel or experimental Standard for Disclosing Commercial Gain interventions or research, the standard for disclo- In the medical treatment setting, it is unlikely sure is broadened even further. No longer is the that a court following the viewpoint of disclosure standard tied to conventional medical beliefs or held by most States would require clinicians to the informational needs of a reasonable person. inform patients of the prospect of commercial gain Federal regulations require disclosure of any pro- accruing from the use of patients’ tissues and cells. cedures deemed experimental (45 CFR 46.116(a)(l)) Ch. 6—Informed Consent and Disclosure ● 105 and any foreseeable risks or discomforts stem- if the possibility of commercial gain is not dis- ming from the study (45 CFR 46.116(a)(2)). closed. Moreover, the welfare of such subjects might be given inadequate attention if the pros- The full disclosure requirements found in the pect of commercial gain clouds objectivity. When research setting may be appropriate for most noncommercial gain is probable, the rights and wel- therapeutic or experimental studies. However, fare of subjects may require full disclosure. when a study focuses on human biological material it may well be asked whether the prospect The opportunity to identify potentially market- of commercial gain needs to be disclosed in all able tissues and cells in research may set a new nontherapeutic or research settings or if a less but limited disclosure standard. Rather than re- stringent standard would suffice? quiring disclosure about commercial gain in all cases, it could be limited to those instances where Questions like these arise because in many in- marketable material is reasonably foreseeable. stances tissues and cells can be obtained with a However, when information is available that is minimum of risk to research subjects. In other “material” to a subject’s decision as well as his instances, diseased tissues or cells must be re- rights and welfare, disclosure is imperative. That moved from a patient in order to save life or pro- a subject may garner financial security, experi- tect health. From a practical point of view, it may ence a loss of privacy, or become the target for be unwise and unnecessary to impose upon all commercial ventures as a result of biological sub- human research projects an additional disclosure stances derived from tissues or cells is arguably requirement regarding possible commercial gain. “material” or “significant” information. As such, This view is reinforced by current Federal reg- careful consideration should be given to incor- ulations. Research involving the collection and porating such a “materiality” disclosure require- study of pathological or diagnostic specimens is ment in the human research regulations. specifically exempt from the disclosure regulations if: Content of Disclosure Regarding Commercial Gain . . . these sources are publicly available or if the information is recorded by the investigator in such The need for a full and frank disclosure of the a manner that subjects cannot be identified, di- prospect of commercial gain must be balanced rectly or through identifiers linked to the subjects against the potential impact such a revelation may (45 CFR 46.101@)(5)). have on the ability of potential subjects to reach reasoned judgments about participating in a study. Another Federal provision relates to the author- The content of such a disclosure should be con- ity of IRBs to approve studies in which all of the sistent with other information requirements for elements of informed consent are not present (45 consent (45 CFR 46.116). This would include: CFR 46.l16(d)). This may occur when, among other things, studies involve no more than mini- ● the nature and purpose of using human bio- mal risk and such modifications will not have an logical material obtained in the course of the adverse impact on the rights or welfare of subjects. research; ● the probable risks associated with obtaining If research involves no more than minimal risk the material; to the patient, and commercial gain is not likely, ● the probable benefits flowing from obtain- a blanket requirement to inform subjects about ing the material and the probable benefici- commercial gain may be unnecessary. In such cir- aries of these substances or knowledge de- cumstances, the IRB could be empowered to ex- rived from same; clude reference to commercial gain. ● the possible commercial gain that may result However, if it is probable that research may yield from developing the biological material in a commercially significant product derived from question; a human sample, disclosure may become more ● a description of the method(s) the investigator necessary. In this instance, the pecuniary and intends to use to obtain the biological mate- privacy rights of subjects may be compromised rial from research subjects; 106 ● Ownership of Human Tissues and Cells

● the availability of reasonable, alternative ways might make them ineligible as participants. This of obtaining such material and the probable could result in flawed research results and possi- risks and benefits associated with these alter- bly put the subject and others in the study at seri- natives; ous and unnecessary risk. To overcome this diffi- ● the name and location of persons to be con- culty, potential subjects must be carefully screened tacted if subjects have any questions or con- to make certain that they meet eligibility criteria. cerns during the course of the study; Only then should a full disclosure take place, in- ● the availability of treatment or compensation cluding the reasonably foreseeable prospect of se- for injuries stemming from the study; and curing commercial gain. ● the right of subjects to withdraw from or to participate in the project without prejudic- A second concern relates to the probability of ing their ability to secure treatment to which commercial gain discovered subsequent to the par- they are otherwise entitled. ticipant’s entry into the study. The need for full disclosure continues until the conclusion of treat- Timing of Disclosure Regarding ment or research. Indeed, the duty to advise pa- Commercial Gain tients or subjects may extend much longer, particularly when individuals are at risk as a result Choosing the correct time to tell a subject or of treatment or research procedures. When sig- patient of potential commercial gain presents two nificant discoveries are made in the course of re- different concerns. One is that the prospect of search and they alter the basis of the consent, the commercial gain could unduly influence the sub- investigator should reveal this information to subject. The other is whether a researcher has a jects. The reasonably foreseeable prospect of responsibility to inform subjects whenever new commercial gain determined in the course of a developments alter the original terms on which research study amounts to a “significant new find- the consent was based. ing” that may have an impact on the subject willingness to carry out his role in the project (45 CFR On disclosure of possible commercial gain, some 46.l16(b)(5)). subjects may withhold information they believe

ARE CHANGES NEEDED IN THE CONSENT PROCESS?

The current DHHS regulations contain two pro- searchers are therefore not obliged to disclose visions that concern research involving human their research or commercial interests to provid- biological material. The first excludes certain types ers of specimens in these instances. of specimens from the regulatory requirements (45 CFR 46.101(b)(5)) . The second prohibits the This may pose an ethical problem for some peo- use of exculpatory language through which the ple because researchers might garner commer- subject is made to waive or appear to waive any cial reward from work carried out on unknown legal right (45 CFR 46.116). subjects. From this point of view, it could be argued that the regulations should be amended, ei- Federal Research Exclusions ther by:

The DHHS informed-consent policy applies to 1. prohibiting researchers from reaping finan- virtually all human research funded by the De- cial rewards from such discoveries, partment. However, an exemption exists for re- 2. requiring the application of informed consent search involving the collection or study of exist- requirements to the collection and use of such ing data, documents, or pathological or diagnostic specimen material, or specimens if these are publicly available or if the 3. disclosing to the subject that a specimen might information is recorded by the investigator in such be used in research that mayor may not result a manner that subjects cannot be identified. Re- in the development of a commercial product. —

Ch. 6—Informed Consent and Disclosure Ž 107

From a practical point of view, trying to iden- dled under other legal theories and principles. This tify the human sources of “existing” specimens may include provisions in research contracts, would be cumbersome, if not impossible. In addi- property law, or perhaps professional disciplinary tion, more harm than good may be achieved in laws. trying to secure consent because research efforts can be impeded by trying to overprotect patients Federal Exculpatory Language whose primary interest-diagnosis or treatment— is unrelated to the research. The purpose of the DHHS human research regulations is to safeguard the rights and welfare of If the consent process is changed to include a research subjects. This is particularly apparent disclosure requirement concerning commercial in the consent regulations. This approach includes gain, this disclosure could be limited to those in- a provision which in part bans the use of excul- stances where there is a significant probability patory terms “through which the subject or the of commercial gain (i.e., a high probability or cer- representative is made to waive or appear to waive tainty of a marketable biological material being any of the subject’s legal rights (45 CFR 46.116). extracted) arising from the use of human tissues and cells from an identified research subject. This The intent of this provision is to safeguard sub- information would be conveyed during the con- jects and to make certain that they do not wit- sent process, when the researcher provided other tingly or unwittingly relinquish any legal rights. required details relating to risks, benefits, and This concept reinforces the notion of consent as alternate treatment options. To overcome the po- a communication process arising from the physi- tential for unduly influencing research subjects, cian-patient or researcher/subject relationship. It researchers should be cautious not to give any also reflects the concept of consent as a contrac- more or less emphasis to details regarding com- tual matter in which parties on both sides should mercial gain than is given to other required in- be working from positions of comparable strength. formation. The issue arises, however, as to whether the ban on exculpatory language should be lifted for in- As with other types of information, disclosures stances of potential commercial gain. regarding potential commercial gain should be in understandable terminology, with research sub- Some subjects may not want to reap financial jects receiving a full and understandable expla- benefits as a result of or as a byproduct of their nation regarding the human tissues and cells that participation in research. This may offend their may be developed by a researcher into a market- sense of values and deter them from taking part able resource, as well as the definition of ‘(com- in studies. Moreover, the prospect of sharing pos- mercial gain. ” Subjects should be given ample op- sible financial gain with a subject may have a de- portunity to ask questions and should be given terrent effect on important research. Although sufficient time to carefully consider whether they it is true that a human being may be the source want to participate in a study that might result of a marketable cell line, it is the researcher who in commercial gain. has identified and fostered the discovery. Re- searchers may well question the utility of conduct- While the law of consent is designed to safe- ing such studies, particularly if research subjects guard the rights of the person relating to his or demand a significant share of the financial gain. her body, it has its limits. Consent cannot, and arguably should not, prevent researchers from A possible change in the DHHS informed con- reaping financial reward as the result of research sent regulations could be made to modify the pro- developing tissues and cells collected from another hibition on the use of exculpatory language to per- person. It can only assure subjects of a fair level mit research subjects to waive any rights to of communication regarding their participation commercial gain stemming from research find- in research. The propriety of researchers achiev- ings. This provision should be clearly worded, and ing financial success from manipulating human the waiver of such rights must be free of undue specimens in their research is an issue best han- influence and coercion. Research subjects should 108 ● Ownership of Human Tissues and Cells

Promotional Material Directed to Physicians understand exactly what rights are being waived. They should also understand that should they decide not to waive their rights to commercial gain, they will not be denied treatment to which they are otherwise entitled. In appropriate cases, research subjects should be informed that their decision not to waive their rights to commercial gain may disqualify them as participants. When such situations arise, subjects should be told why a non- waiver is a basis for exclusion from a study and what compensation is available to the subject who agrees to a waiver. This may take the form of an offer of a lump sum of funds to compensate the Informed Consent Systems subject for waiving rights to marketable, human was developed by doctors and research material. lawyers to help eliminate Permitting the use of enforceable, exculpatory doctor/patient litigation. language regarding commercial gain could actually enhance the rights and welfare of subjects. It is possible that researchers and sponsors may The Informed ConsentTM System is: be far more protective of the source of their hu- A Videotape designed to inform a patient man tissues and cells if they need not share fi- about surgical procedures in an easy- nancial gain with subjects. to-understand format. A Legal Support Service designed to Giving subjects the opportunity to waive their supply materials which show that the right to financial gain from marketing products duty to obtain [the patient’s] informed derived from their biological material does not consent was discharged. obviate the need for informed consent. Indeed, SPANISH FORMAT AVAILABLE- with certain safeguards in place, there should be no hesitancy in permitting exculpatory language Features: through which an “informed” subject waives le- + Videotapes explain surgery in a clear and uncomplicated manner, gal right to possible legal rights to financial gain. + Videotapes explain risks and complications but are not designed to scare patients. + Videotapes use diagrams and illustrations Latent Discovery of instead of actual photographs. Commercial Gain + Legal Support Service stores evidential materials and provides access for later If the prospect of financial gain does not become courtroom use. apparent until subjects have become deeply involved in the project, generally accepted princi- Informed Consent™ Systems ples of human research hold that the researcher specialty areas: has a duty to disclose this information as soon + obstetrics/gynecology + orthopedic + as possible. It represents a logical perpetuation + otolaryngology + urologv + of the consent process, particularly when a latent + endarcardiology/vasiculary + discovery may have a dramatic impact on the origi- + general surgery + nal terms of consent.

For more information, or to order, call: Support for this view can be found in the cur- 1-800-FILMTEC rent regulation (45 CFR 46.116(5)) that authorizes VA residents call: 703-471-6891 an IRB to require additional disclosures regard- distributed by Filmtec, Inc. Reston, Va. 22090 ing “significant new findings” that may affect a 1986. Filmtec, lnc subject’s willingness to continue in research. An Ch. 6—informed Consent and Disclosure ● 109 additional disclosure with respect to the effect of tend to disclose to subjects. This could be approved withdrawal from a study could be made based by the IRB along with written information sheets on 45 CFR 46.116(4). and consent documents.

Documentation Requirements Role of the Institutional Review Board Disclosure of potential commercial gain and the use of exculpatory language reinforce the need If additional disclosure requirements and the to accurately document consent. This does not use of exculpatory clauses are added to the con- have to be a so-called ‘(long form” consent; a “short sent process, IRBs will have a greater role. Cur- form” consent document would suffice (45 CFR rent regulations indicate that when potential 46.117(b)). subjects are vulnerable to undue influence or co- The major difficulty with current documenta- ercion, the IRB should make certain that there tion is that the IRB has the ability to waive the are safeguards to protect their rights and welfare requirement for signed consent. This can occur (45 CFR 46.11 l(b)). This role becomes particularly when the only record linking the research with important when potential commercial gain is in- the subject is the consent form and the principal volved. It is equally important when researchers risk involved is a potential breach of confiden- intend to use exculpatory language and seek tiality. Similarly, documentation can be waived waivers from subjects to commercial gain. when a study involves no more than minimal risk What could be included in these added safe- of harm to subjects and involves no procedures guards? The following are examples of additional for which written consent is normally required protections that could enhance the rights and wel- outside of the research context (45 CFR 46. 117(c)). fare of subjects: With the prospect of commercial gain and the ● careful review by the IRB of information to use of exculpatory language, some type of docu- be disseminated to subjects to make certain mentation could be required to safeguard the that it details in comprehensive terms what rights of all concerned. First, IRBs could be pro- constitutes “commercial gain”; hibited from waiving consent form documenta- ● monitoring the consent process on a random tion when studies involve the prospect of com- basis to make certain that subjects are receiv- mercial gain or the use of exculpatory language. ing approved information and that there is This solution, however, does not alleviate the con- no evidence of undue influence or coercion; cern for a potential breach of confidentiality found ● in the case of subjects who may be vulner- in the current regulations. The problem is com- able to undue influence or coercion, the IRB pounded when an additional consent authoriza- could require the appointment of an advo- tion is required for cases in which commercial cate whose duties would be similar to those gain is discovered subsequent to the first consent. for children who are wards under 45 CFR Requiring consent forms in this case could repre- 46.409(b); and sent a serious concern for subject confidential- ● followup procedures, such as random out- ity. A breach of confidentiality in this situation come screening to compare the experience could make the subjects a target for unscrupulous of subjects at the conclusion of the study with persons who for their own financial gain might research protocols, information sheets, and identify the participants carrying marketable bio- consent documentation presented to partici- logical substances. A possible solution to this prob- pants at the outset of the project. lem is to require researchers to use extra safeguards to maintain confidentiality of research Should researchers determine in the course of subject information, but this idea may not be a study that a significant likelihood exists for po- realistic. tential gain, the regulations could require them to report this fact to the IRB. Investigators could Another option is to leave the current regula- then present to the IRB the information they in- tion unchanged, but add a proviso that a waiver 110 . Ownership of Human Tissues and Cells approved by an IRB constitutes a rebuttable pre- link between the subject and the study. With the sumption of valid consent. This would be impor- use of a carefully designed system of identifica- tant if allegations ever arose claiming that the sub- tion codes, a detailed note in the record offers ject was not informed about commercial gain or less chance of identifying a subject than does a that the subject did not waive his right to com- traditional consent form. A detailed note in the mercial gain. Unless the subject could rebut the subject’s record is also a practical means of inference of proper disclosure of information or documenting disclosures and waivers regarding a properly obtained waiver, the presumption of commercial gain made subsequent to the entry valid consent would stand. If such a recommen- of participants into the study. When confronted dation is deemed practical, further review would with a detailed note in his or her record, the sub- be necessary to make certain that it does not of- ject will be hard-pressed to prove lack of disclo- fend Federal evidentiary provisions. sure or a waiver to commercial gain. A detailed note in a subject’s record would have certain ad- A third option would be to require a detailed vantages over a standardized consent form. For note in the subject’s record. This would eliminate instance, a note could contain information tailored the need for consent forms when minimal risk to the specific subject, a feature often impracti- is involved. It also minimizes concern about breach cal in standard forms. of confidentiality when consent forms are the sole

SUMMARY AND CONCLUSIONS

Consent must generally be obtained from pa- required as part of the informed consent proc- tients and research subjects prior to specimen ess. Arguments favoring such disclosure include removal for treatment or experimentation. In- the concept that research subjects should have formed consent represents a two-way flow of in- the right to decide what to do with their own tis- formation between the physician or researcher sues and cells, and that current regulations re- and the patient or research subject in order to quire disclosure of significant new findings de- communicate the facts necessary for the patient veloped during the course of research which may to decide on a method of treatment and for the relate to the subject’s willingness to continue research subject to decide whether to participate participation. Arguments against disclosure rein the research. garding potential commercial gain include the possibility that any commercial gain is highly specula- The common law has developed two different tive, that disclosure would hamper a research theories of consent: the traditional view, based subject from reaching an informed decision free on the law of battery; and a more modern theory of the undue influence that monetary gain might based on the law of negligence. Several States have provide, and the possibility that subjects might enacted consent laws, many of which are con- endanger their health and skew research results cerned with setting requirements for information by hiding facts from researchers so they can par- disclosure. Federal regulations provide protection ticipate in research that may provide financial of human subjects in federally sponsored re- remuneration. search. The Federal policy requires each research institution to establish and operate Institutional Current Federal regulations contain two provi- Review Boards that have oversight authority over sions that concern the marketing of tissues and research using human subjects and sets certain cells. The first excludes certain types of specimens requirements that investigators must follow to ob- (e.g., existing data, documents, records, patholog- tain informed consent prior to and during re- ical exams, or diagnostic specimens, if these search. sources are publicly available or if the information is recorded by the investigator in such a man- Questions arise as to whether disclosing the ner that subjects cannot be identified, directly or prospect of potential commercial gain should be through identifiers linked to the subjects) from ——-—.—

Ch. 6—Informed Consent and Disclosure . 111 the regulatory requirements. The other provision to be used when the prospect of commercial gain prohibits the use of exculpatory language through is relevant. If additional disclosure requirements which the subject is made to waive or appear to and the use of exculpatory clauses are added to waive any of the subject’s legal rights. Either or the consent process, Institutional Review Boards both of these provisions could be revised to will have a greater responsibility in oversight of achieve certain results, or additional disclosure research. requirements could be included in the regulations

CHAPTER 6 REFERENCES

1. ithern v. L’eterank Administration, 537 F.2d 1098, 17. Mont. Code Ann. $53-20-147 (Supp. 1983). 1102, Ioth Cir. 1976. 18. N.Y. Pub. Health Law $$2440-2446 (McKinney 2. Alaska Stat, $09.55.556 (Supp. 1985). %IPP. 1986). 3. American Law Reports, 2d. cd., vol. 56, pg. 695 19. N.Y. Pub. Health Law $2441 (McKinney Supp. 1986). (1957). 20. N.Y. Pub. Health Law ~$2441-2442 (McKinney 4. Ark. Stat. Ann. $59-1416 (Supp 1983). SUPP. 1986). 5. Cal, Health & Safety Code $$24170-24179.5 (West 21. N.Y. Pub. Health Law $2445 (McKinney Supp. 1986). SUPP. 1986). 22. N.Y. Pub. Health Law $2805-d (McKinney Supp. 6. Cal. Health & Safety Code $24173 (West Supp. 1986). 1986). 23. Or. Rev. Stat. $441.605(3) (Supp. 1985). 7. Cal. Health & Safety Code $24179 (West Supp. 24. Rozovsky, F., Consent to Treatment: A Practical 1986). Guide (1984). 8. De]. Code Ann. tit. 18, $6801 (Supp. 1984). 25. See, e.g., the so-called Nuremberg Code enunciated 9. Del. Code Ann. tit. 18, $6852 (Supp. 1984). in, United States of America v. Karl Brandt, No. 10. Medical Research Council of Canada, Ethics in Hu- 1, Trials of War Criminals, vol. 11 and the Decla- man Experimentation, Report No. 6, 1978. ration of Helsinki adopted by the 18th World Med- 11. Faden, R., and Beauchamp, T., A Historuv and The- ical Assembly, Helsinki, Finland, 1964 as revised or-v of Informed Consent (New York: Oxford Uni- by the 29th World Medical Assembly, Tokyo, Ja- versity Press, 1986). pan, 1975. 12. Fagel, B., “The Duty of Informed Refusal,” 9 Legal 26. Sard v. Hardy, 379 A.2d 1014 (Md. Ct. App. 1977). Aspects of Medical Practice 1 (1981), commenting 27. Texas Stat. Ann. $4590-1 (1979). on Truman v. Thomas, 27 Cal.3d 285, 165 Cal. Rptr. 28. Utah Code Ann. $78-14-5 (Supp. 1986). 308, 611 P.2d. 902, (1980). 29. Vt. Stat. Ann. tit. 12, $1909 (Supp. 1984). 13. Ky. Rev. Stat. $304.40-320 (1976). 30. Va. Code ~37.1-234 (1979). 14. Logan v. Greenwich Hospital Association, 465 A.2d 31. Va. Code $$37.1-37.1-241 (1979). 294 (Corm. 1984). 32. Va. Code $37.1-237 (1979). 15. Miss. Code Ann. ~41-41-7 (Supp. 1986). 33. Wash. Rev. Code Ann. ~7.70.050 (Supp. 1986). 16. Mo. Ann. Stat. $198.088(c) (Vernon Supp. 1986). chapter 7 Economic Considerations

“Every time we obtain a sample . . . we make sure there is a piece of paper . . . I take all the risks and put $25 million of investment into the research. I don't want the patient then saying, ‘Yeah, but it came from me.’ “ —Michael S. Ostrach Vice President, Cetus Corp. The Baltimore Sun, Apr. 6, 1986

“In nearly every case, the cells will never yield anything of commercial value. But lotteries do have winners. In exceptional circumstances, one person’s cells will have a special property that makes them uniquely valuable.” —Edward Dolnick The New Republic 195(3739):16, 1986 CONTENTS

Page Payments to Sources ...... $...... ,...115 Equity ...... , ..115 Added Costs ...... 116 Social Goals ...... 117 Safety and Quality ...... 117 Shortages ...... 118 Market v. Nonmarket Systems ...... 119 The Role of Nonprofit Organizations ...... 121 Ahernatives to Nonprofit Institutions ...... ,....122 Nonprofit Institutions and the Government ...... 122 Interaction of For-Profit and Nonprofit Ins itutions ...... 123 Summary and Conclusions ...... 124 Chapter p references ...... 125

Figure Figure No. Page 14. Promotional Material, National Disease Research Interchange ...... 123 —

Chapter 7 Economic Considerations

The fundamental economic question that arises arguments for and against payments for provi- when considering the use of human tissues and sion of human tissues and cells, analyzes the orga- cells in biotechnological research and commerce nization of provision of human biological materi- is that of payments to sources. And if sources are als along market and nonmarket lines, and to be paid, what factors will enter into the price describes the potential role of nonprofit institu- calculation? This chapter summarizes economic tions in brokering human biological materials.

PAYMENTS TO SOURCES

On economic grounds, it is possible to argue both participants are receiving an inequitable return for and against paying the sources of human bio- for their services or products. On the distribu- logical materials. Arguments over payments for tion side, issues arise regarding access to the serv- human biological materials used in biotechnolog- ices or products by parties who seek them. ical research and commerce echo the debate that has gone on for many years over donations of kid- Production of Human Biological neys for transplantation and donations of blood Materials for transfusion and therapeutic products. Five It can be argued that some sources are not enti- principal issues are essential in the debate: tled to the value of the tissues and cells they pro- ● the equity of production and distribution, vide because they do nothing to develop the ma- ● the added costs of payments to sources and terials into a valuable product. Diseased tissue, costs associated with that process, for example, is actually a threat and sources are ● social goals (the merits of an altruistic sys- willing to pay a physician to excise it. By this rea- tem of donations versus a market system), soning, sources perceive such human biological ● safety and quality (both of the source and the materials as less than worthless, and it is only the biological materials), and intervention of the researcher that gives the tis- ● potential shortages or inefficiencies resulting sue value. It is the researcher, therefore, who from a nonmarket system or from changing should legitimately realize the economic value of from a nonmarket system to a market system, the tissue. Of these issues, two appear to be central. Issues On the other hand, it could be argued that the of equity argue in favor of a system of payments sources of tissues and cells are entitled to the value to sources. On the other hand, the added costs of any resources ultimately derived from them. of payments to sources and associated costs ar- This view holds that human beings have the right gue against such a payment system. The factors to treat certain physical parts of their own bod- related to social goals, safety and quality, and ies, particularly regenerative parts, as objects for shortages do not now offer compelling support possession, gift, and trade (I). As the commercial either for or against paying sources. potential of biotechnology emerges, this viewpoint could become increasingly relevant. If it is possi- Equity ble to determine or estimate the potential value of biological materials, then as information is dis- The equity of a system can be considered from tributed, patients, or their agents, will come to both the production and distribution sides. On the know the values of tissues and cells they may pos- production side, one issue is whether any of the sess and they will expect adequate recompense.

115 —

116 . Ownership of Human Tissues and Cells

Distribution of Human Biological cient payment. Thus, payments will likely easily Materials exceed the amount required to draw forth the services of an adequate number of sources. For Researchers desiring human tissues and cells this reason, the actual compensation to sources from other researchers, especially at other insti- is unlikely to have a large economic impact on tutions, must rely on the willingness of other re- the biotechnological uses of human biological ma- searchers and institutions to cooperate. By cus- terials. tom and ideology, the main incentive to this cooperation is the scientific commitment to the The transaction costs associated with paying free flow of ideas and materials. To date, the sys- sources, however, are likely to dwarf the costs tem has operated fairly efficiently. However, as of actual payments to the sources. Studies employ- biotechnological products and processes are being human cell lines, for example, may take years ing commercialized this free flow of information to complete and the final commercial application and materials occasionally is being curtailed and may be the result of accumulated research based, in many cases is becoming more formal. There in part, on a number of different cell lines. The may also be shortages of human tissues and cells transaction costs incurred by a researcher to main- for basic research if the incentives to cooperate tain records of the origin of all the cell lines lead- prove insufficient to motivate researchers to go ing to the development of a particular cell line to the trouble of supplying fellow researchers. with commercial applications could be sizable (6). Furthermore, transaction costs will be incurred When access to a good is not based on market for the many uses of cell lines and cells that do values, other nonmarket forms of distribution can not have direct commercial applications (see ch. arise, One unfortunate feature of many nonmar- 2) or even have no value. For instance, it is possi- ket systems is corruption, sometimes expressed ble that cells from a specific patient will not suc- in side payments. The kidney procurement sys- cessfully become established in culture for tech- tem provides an example. In principle, access to nical reasons. Or cells might become contaminated kidneys is determined on the basis of criteria such with bacteria. Thus, some tissue samples—prob- as length of time on the waiting list, tissue type, ably the overwhelming majority—will never be need, and age. At least one medical center, how- developed into cell lines and yet would incur sig- ever, placed wealthy patients needing kidneys nificant transaction costs (6). ahead of other patients, with equal needs, on its waiting list (9). In addition, because many preliminary experiments must be carried out before a commercial Added Costs application is discovered or developed, it would be difficult to negotiate a value for a particular Two types of additional costs would be incurred human tissue at the time it is obtained. Scientists if sources were compensated for their specimens: also would have considerable difficulty establish- the actual compensation to the sources and the ing the relative value of individual cell lines that cost of administering the program (also called lead to commercial application. Some experiments “transaction costs”). These costs could add signif- with cell lines will contribute more to commer- icant burdens to the process of developing biotech- cial application than others, and it would be diffi- nological products and processes from human tis- cult to assess their value a priori or even after sues and cells. the fact (6). payments to sources could range from large Many of the cell lines used in research are used sums that might be awarded to a handful of for purposes other than developing commercial sources who have rare tissues to small sums given products. Cell lines are used to test whether par- to the many sources of more common tissues. In ticular substances are required for cells to grow either case, because tissues and cells generally are or to test the response of cells to exogenous agents. obtained as byproducts of needed medical treat- The physiology or the morphology of the cell ment, most sources are unlikely to refuse access might be explored, or the cells might be used as to their tissues and cells on grounds of insuffi- a means to propagate viruses. Cells are also used Ch. 7—Economic Considerations ● 117 as model systems for screening carcinogens or because too few donations are made so payment teratogens. In addition, cell lines can be used in is necessary (2). Second, requiring altruism where research from which negative findings contrib- substances of great value are concerned leads to ute to knowledge, but do not result in a commer- black market activity and, in fact, the opposite cial product. Finally, many cell lines are used as of the desired behavior. Third, altruism alone may untreated controls in research as the cell line in not be sufficient motivation to provide enough question is manipulated. Even if any of these ap- materials to meet demand. Altruism is not neces- plications resulted in commercialization, it is likely sarily the primary factor in the decision to do- that many cell lines from many patients would nate, for example, when pressure is placed on a have been used in the research. The transaction sibling or parent to provide a kidney to a relative costs borne by the researcher in tracking the pain need (3,5). tient origin of the cells used for research collat- Inherent in most arguments against paying eral to actual commercialization and negotiating sources for bodily materials is the widespread their value would be high (6). moral repugnance at the notion of a market in Another potential problem associated with a human body parts. This repugnance is most payment system is the harm it could have on in- strongly felt in the case of organ sales, where, for formation exchange among scientists. As the in- example, permanent physical damage to the or- formal distribution system operates today, cell gan vendor may result. An additional argument lines are shared among researchers to confirm relates to the relationship between patient and research results or to begin new research projects, physician (or researcher). Introducing monetary Negotiations over the transfer and value of prop- motives on either part could affect the bond of erty rights for cell lines could reduce the exchange trust between patient and doctor. On the other of information among scientists (6). hand, the altruistic provision of human biological materials by one person to another in order Another area of transaction costs might also to save a life may contribute to the bonds that occur—the cost of negotiating between the re- hold communities together (11). searcher or physician and patient over transferring property rights. These negotiations would create sizable costs for all parties even if the de- Safety and Quality bated cell line never has a commercial applica- The issues of safety and quality probably are tion. For instance, because the patient and the not major concerns for most biotechnological uses researcher or commercial firm have different of human biological materials, Most such tissues degrees of knowledge regarding commercial ap- and cells are removed in the course of needed plications of cell lines, the patient may have to surgery for the patient’s benefit, so the motives retain knowledgeable third parties or consultants. of the source (or payment to him) is not likely to The principle is the same as hiring a knowledge- affect either the source’s safety or the quality of able broker to aid the purchase and sale of stocks the biological materials obtained. and bonds (6), An additional factor is that con- flicts over the distribution and value of rights may In those few instances where provision of hu- impose additional stress on sick patients. man tissues and cells may be discretionary, payment could influence the safety of both the source Social Goals and the recipient of human biological materials. When the procurement activity itself poses risks Social goals also enter into the debate over the to the source, the potential for harm would likely merits of a market system versus a nonmarket, be exacerbated by the promise of payment. Moti- or altruistic, system. Arguments in favor of pay- vated by the promise of payment, for example, ments for human tissues and cells are based on individuals might accept a measure of medical risk three lines of reasoning. First, the primary issue to provide their kidneys for transplantation, in can be viewed as a need to save lives; in the case effect becoming organ mines for wealthier peo- of organs, this need is not met by free donations ple in need of kidneys. Similarly, when commer- 118 ● Ownership of Human Tissues and Cells cial whole blood collectors were in business in by eliminating the altruistic motivation and po- the United States there were numerous reported tential sources would hold out for the highest cases of excessive bleeding of donors and lower bidder. quality blood. Proponents of paying sources, in contrast, ar- The quality of human specimens can affect the gue that if altruism is not the primary motive in safety of the recipient. There has been a dramatic providing human tissues and cells, payments to increase in scientists’ awareness of the potential sources might draw forth a larger supply. One for viral contamination of human derived biolog- example of this was seen in the early years of the ical in recent years. Blood products have trans- whole blood market, when insufficient supply by mitted hepatitis and acquired immune deficiency altruistic donors was supplemented by supplies syndrome, and pituitary hormone preparations from paid donors. Nonprofit blood collectors have have transmitted Creutzfeld-Jakob disease to pre- succeeded in the last 20 years in nurturing the viously healthy recipients. Similar problems can motive of altruism in donors, so now blood short- be expected to arise with any tissues and cells of ages, while still occurring seasonally, no longer human origin. Viewed from one perspective, com- are a major problem. mercial pressures could aggravate quality problems, while altruistic systems could help ensure Those in favor of payments to sources argue good quality (11). On the other hand, quality may the case for a market system most strongly in the be problematic precisely because there is insuffi- context of cadaver organ donations. Patients are cient commercialization and because of the pro- indeed dying because of the shortages of certain tection from liability that voluntarism might af- cadaver organs, such as livers and hearts. Propo- ford to those people responsible for procuring and nents of payments for cadaver organs argue that dispensing human tissues and cells (8). such payments would be virtually certain to increase the number of cadaver organ donations. Shortages Although there might be some decrease in organ donations from people whose primary motivation At present, there is no apparent shortage in the was humanitarian, there would likely be a net gain availability of human tissues and cells for biotech- in the number of organs available (2,3). nological use. Shortages that may develop in the A market system can be the most efficient current nonmarket system are likely to be a func- method of handling shortages because a free mar- tion of inherent shortages of a particular type of ket tends to equate demand and supply at some tissue in the population, or a problem of access equilibrium price level. Systems in which prices and transportation. As the techniques of biotech- are regulated at below market values generally nology and the biotechnology industry mature, suffer shortages, often relying on the altruism of however, this situation may change. In a time of providers or direct coercion to obtain the socially shortages, two mechanisms to draw forth an ade- desired result. Nevertheless, where an economic quate supply of human tissues and cells for re- activity is already organized along nonmarket lines search purposes are: 1) the motivation of sources and the primary motivation of participants is altru- by altruism (e.g., the possibility that the research ism, and where the demand for the item is fixed, will lead to a cure for a serious illness); and 2) any introduction of market activities may not elicit payment to sources. an increased supply of donations—it may even Opponents of payments to sources argue that have the undesired effect of reducing the level a market system could exacerbate shortages of of donations. The precise effect that introducing needed human samples. They fear that any hint a market system would have on supply of human of monetary concerns would discourage donations biological remains a matter of speculation. Ch. 7—Economic Considerations ● 119

MARKET V. NONMARKET SYSTEMS

The present system for developing human- 2) a greater interest in the uses of human tissues derived commercial biotechnology products con- and cells in biotechnology as the commercial prof- tains both market and nonmarket activities, al- itability of the industry begins to be realized (10). though there are few instances of actual payment There are several ways to organize a market among researchers for human tissues and cells. system in human biological materials to minimize Some researchers and physicians, however, do the problems that might arise. For instance, pay- have consulting relationships with biotechnology ments to sources could be made prospectively, or pharmaceutical companies which provide ac- before commercialization is a likely outcome of cess to tissues and cells derived from humans or the research. At that time, neither physician/ products of research involving human materials. researcher nor patient/subject will have reason At university research centers, scientists are to believe that the cells are especially valuable. generally required to share the fruits of their re- People who believe that individual specimen search with the university. Where university resources should share more fully in commercial searchers and biotechnology companies have a successes may object to this approach, however, defined research relationship, the potential value particularly if they are patients (to whom a fidu- of the human biological materials maybe shared. ciary duty is owed). They might prefer to make In many cases, however, biotechnology firms do a large payment to the one fortunate source whose not themselves purchase undeveloped human tis- tissues or cells are ultimately incorporated into sue. Instead, they may negotiate with a researcher an invention, but give no payment to the majority who has already developed a cell line, gene probe, whose specimens were used and discarded. In a or something else of potential value. The struc- way, this is a form of lottery, raising the possibil- ture of these deals can either be direct purchase, ity that participants would be unduly influenced royalty agreements, or any of a number of other by the lure of a prize. Payment to one fortunate possibilities. source also fails to recognize the contributions of those sources whose specimens were also es- By the time a biotechnology company enters the sential components of the research leading to the picture and begins to negotiate with a researcher, final invention, even though not a part of the in- there is generally already reason to believe that vention itself. the product is of potential value. Since the researcher is an informed negotiator, he is likely If a prospective payment approach were used, to recognize the potential value of the undeve- payments could be made on the basis of a flat fee loped tissue. In this situation, the researcher— to patients and research participants for sale of rather than the biotechnoloy company or human their specimens. (While many research subjects source—may reap the value of the undeveloped are now paid for their participation, they are not tissue. Should a market arise where undeveloped explicitly paid for their tissue. Patients generally tissue could be bought and sold, any added value are not paid for their specimens, either.) This pro- that is currently being realized by the researcher, spective payment approach would result in uni- physician, university, or biotechnology company form payments to all specimen sources who do might be recaptured by the source of the human not waive payment and would require only mini- tissues and cells. mal paperwork and recordkeeping. The amount of research money needed to make these pay- At present, there is no widespread movement ments could be calculated from the projected num- toward a change in the existing system of free ber of patient/subject specimens stated in the re- provision of human tissues and cells for use in search proposal. research and commerce in biotechnology. Stimu- lus for such a change may come from: I) judicial Alternatively, payments that vary among decisions resulting from current litigation and any sources could be negotiated by the physician/ additional cases that might arise in the future, and researcher and each patient/subject early in a re- 120 Ž Ownership of Human Tissues and Cells search project. If negotiated before either party research where the objective is to develop a com- knows whether the specimen has valuable char- mercially viable product. Much research, how- acteristics or whether a commercial product will ever, is not directed toward developing a prod- result, the fee is likely to be low. In cases involv- uct. How would researchers engaged in such basic ing common types of cells, no negotiation at all research obtain their tissue? It would clearly be would be necessary: the researcher would budget desirable for these researchers to be given tissue a fixed amount per specimen and would refuse by patients at no cost and undoubtedly some to pay more since there are numerous sources sources will be motivated by altruism. The prob- of appropriate tissue. However, the researcher lem for these sources will be whether to trust the would also have the flexibility to pay a higher fee researcher when he tells them that the goals of to individuals whose tissues and cells have unusual the research are noncommercial. Further com- characteristics. This approach lets market forces plicating the matter is the fact that the researcher affect the transactions between researchers and may not be able to anticipate where the research sources and gives researchers significant discre- will lead and may end up with an unanticipated tion in determining an appropriate payment, but commercial product after all. it may result in increased time resolving negotiations and perhaps even bidding among compet- Other approaches could be used to encourage ing researchers, the researcher to reveal his true intentions regarding his research objectives. For instance, a When tissues or cells are purchased from a researcher might have two informed consent source at the time of surgical excision, rather than forms. If he thinks there is commercial potential, later when a commercial product has been de- then he buys the right from the patient with a veloped, neither the patient nor the researcher commercial consent form. If he thinks that his knows whether the tissue has value and the tis- research has no commercial potential, then he and sue’s value is its expected value. This expected the patient sign a free-donation consent form. value depends on the probability that a commer- However, the noncommercial consent agreement cially viable product can be developed. In princi- would contain clauses with penalties for the ple, then, this value could be estimated at the time researcher should his research lead to a commer- of excision and the amount, probably nominal, cial product. The beneficiary of the penalty might could be paid to the source. The cost would be be the nonprofit university where the research similar to the costs pharmaceutical companies is performed. This structure could provide incen- have incurred in conducting worldwide searches tive to encourage the researcher to reveal his best for chemical samples. An alternative form of agree- guess as to where the research is likely to lead. ment could provide an initial, nominal amount to the source with the promise of a percentage of A market system might also operate on the ba- any future profits if commercial gain is realized, sis of retrospective payment to sources—that is, payment after prospects for commercialization If the patient objects to the payment offered and are recognized or realized. Inherent in a system if the researcher does not value the tissue more of retrospective payment is the possibility that a highly, then no deal would be struck. Since there source could have unrealistic expectations about is no reason to believe a priori that the tissue is the likelihood of commercial success, the degree unusual, neither researcher nor subject would of profitability, or the relative importance (and have concern that something of value was being value) of the raw material as compared to other lost. If the patient has some reason to think his aspects of the research and development effort. tissue is rare, or if he is a risk taker and unwilling Retrospective payments could encourage sources to accept the researcher’s statistically fair offer, to engage in a form of extortion, demanding un- he would have every right to go to the expense reasonable prices for consent to use their speci- of having the tissue examined himself. mens, confident that companies have already in- Prospective payment to sources conceivably vested years of research and development (and could be used by researchers engaged in applied millions of dollars) in the product. A retrospec- Ch. 7—Economic Considerations . 121

tive negotiation process would require the assis- where unpaid and paid donations exist side-by- tance of attorneys representing both parties. side is the blood and plasma donation system currently operating in the United States. For most Neither prospective nor retrospective payment of their activities, the whole blood and plasma sec- appears to be prohibited by the physician’s fidu- tors operate in rather different spheres. However, ciary duty to his patient. What is more likely to the largely nonprofit whole blood sector (which bean unacceptable breach of that duty would be relies on unpaid donations) and the largely com- a failure to disclose information about commer- mercial plasma sector (which pays its sources) do cial potential or provide for some fair system of compete in the sale of finished plasma products. compensation. This example of a hybrid nonprofit/commercial Any design of a feasible system of payments to organization of economic activity may prove in- sources would require further information and structive in considering payments to sources of analysis. A useful and relevant model to consider human tissues and cells for biotechnology uses.

THE ROLE OF NONPROFIT ORGANIZATIONS

Nonprofit organizations may play an important Some nonprofits, such as CARE or the American role in the marketing of human tissues and cells, Red Cross, receive their income primarily in the just as they have in the procurement and distri- form of grants or donations. These organizations bution of blood and organs. A clear and unequivo- are called donative nonprofits. In contrast, com- cal nonprofit organization for procuring and dis- mercial nonprofit) such as many hospitals and tributing human biological materials may be daycare centers, receive their income primarily necessary to preserve the trust between sources from the sale of services. In the case of donative and recipients and ensure the continued provi- nonprofit) the patrons are the donors. The pa- sion of human specimens for research. Provid- trons of commercial nonprofits are the custom- ing tissue to an assuredly nonprofit organization ers receiving the services (i’). may allay the suspicions of sources who want to What characteristics of an activity make it more support basic research but who do not want any suitable to nonprofit than for-profit organization? one person to benefit financially from their con- Why, for example, do people wishing to provide tribution. food assistance to impoverished persons overseas Nonprofit institutions often step in to fill the donate money to an organization such as CARE need when markets fail to deliver a sufficient when they could engage the services of an experi- quantity of certain goods that are clearly in de- enced commercial grocery distributor? The main mand. In many instances, it is a public nonprofit reason appears to be that with certain products institution—the government—that provides the consumers are unable to evaluate accurately service. The government also can intervene less whether the promised good or service has been directly to regulate markets by controlling prices, delivered. In such circumstances the market may requiring that providers be licensed, or declar- provide insufficient discipline for a profit-seeking ing certain goods to be nonmarketable. producer. The key element seems to be trust. In the preceding example, the source does not know Private nonprofit enterprises* are the form of and is not in contact with the party receiving the organization most relevant to the provision and food. Consequently, the source would have great receipt of human tissues and cells. There are two difficulty verifying that the grocery distributor general ways to finance nonprofit organizations. had fulfilled its part of the agreement. The source ‘It is important to note that if profits are defined as the excess therefore needs a trusted organization to fulfill of revenues o~rer costs, then private nonprofit enterprises also earn the agreement. Because of the legal constraints profits. The difference between profit and nonprofit institutions lies in whether the earnings are distributed to those who have con- under which it must operate, a nonprofit is likely trol over them. to serve in that role better than its for-profit coun-

63-221 0 - 87 - 5 QL 3 122 • Ownership of Human Tissues and Cells terpart. Nonprofit enterprises therefore can be by doctors are subject to Federal regulation for seen as a response to a particular kind of market safety and efficacy, Nonprofit distributors are failure. likely to arise where such protective mechanisms have not developed or are inadequate. Commercial nonprofits, such as hospitals, differ from donative nonprofits in that the bulk of Regulation of for-profit organizations can help their income is in the form of payments made by maintain the strengths of for-profit organizations patrons in direct exchange for services. Since the while limiting their flaws. This regulation can ei- recipient of the service is also the source, the type ther be imposed by the government or can be im- of market failure described in the food aid exam- posed contractually through free negotiation di- ple (resulting from the distance between the rectly between the parties. Limits on rates of source and the recipient) does not occur, The con- return, for example, are often imposed on natu- sumer, however, may still prefer to deal with a ral monopolies such as public utilities. Under such commercial nonprofit firm rather than a for-profit regulation, prices are restricted to a level that per- firm because the services sought are of such a mits the firm’s shareholders to earn a specified nature, or provided under such circumstances, rate of return on their investment while protect- that the consumer must necessarily entrust a great ing the public good. Firms subject to regulation deal of discretion to the producer—a discretion of their rates of return can be viewed as special that the consumer may be in a poor position to cases of nonprofit organizations. police. It can be expected that when the profit motive is eliminated, a price is paid in terms of incen- Nonprofit Institutions and the tives. Nonprofit firms are often slower in meet- Government ing increased demand and less efficient in their Nonprofit organizations have four principal in- use of inputs than for-profit firms. Furthermore, herent weaknesses: despite the limitations placed on them, some nonprofit probably do distribute some of their net ● Nonprofit institutions may be severely limited earnings through inflated salaries and perquisites. in their ability to raise capital since they are Nonetheless, where the consumer is in a poor po- unable to sell equity shares. They must rely sition to judge the services he is receiving, any instead on donations, retained earnings, and for-profit organization of production and distri- debt for capital financing. bution is likely to rate second best to a nonprofit ● While commercial nonprofit entities must le- enterprise despite the expected efficiency losses. gally use the entire sum paid by the consumer to produce services, the consumer has no as- Alternatives to Nonprofit surance that the services he pays for will be Institutions provided to him. Patients in private hospital rooms, for example, often subsidize ward pa- Many goods and services are not easily evalu- tients through their high room and board ated by consumers and yet are commonly pro- charges. vided by for-profit firms. Medicinal drugs are one ● Profits are an important motivator of man- example, as are the services of doctors, lawyers, agement efficiency, and nonprofit institutions automobile mechanics, and television repairmen. might be expected to be somewhat less vigi- But these services are generally small and discrete lant in eliminating unnecessary expenses than and consumers can switch suppliers relatively eas- their for-profit counterparts. ily if they become dissatisfied. Furthermore, spe- ● The profit motive is a powerful incentive for cial institutions have arisen to provide additional ensuring that firms enter an industry and ex- protection for consumers. Doctors and lawyers, pand when the demand for the industry’s for example, must be licensed and are subject to product increases. Stripped of this motive, some supervision and discipline from their respec- nonprofit organizations might be more slug- tive professional organizations. Drugs prescribed gish in responding to changed demand. Ch. 7—Economic Considerations • 123

In response to these problems, a number of serv- Figure 14.— Promotional Material, ices commonly provided by nonprofit organiza- National Disease Research Interchange tions are frequently also undertaken by government, such as education and hospital care. The taxing power of the government gives it a strong OF MICE advantage over nonprofits. Government organizations also have access to capital and a degree of accountability not necessarily found in all types of nonprofits. At least one nonprofit corporation that procures and distributes human biological materials is supported by the Federal Government. The National Disease Research Interchange (NDRI); Philadelphia, PA) is a nonprofit corporation founded in 1980 to advance the procurement, preservation, and AND MEN. distribution of tissues and organs for research (figure 7-l). It was established by the National Insti- tutes of Health and the Pew Memorial Trust in response to requests from the biomedical community for regular access to human tissues in order to corroborate animal studies. Since 1981, NDRI has distributed more than 20,000 tissue samples to research laboratories in the United States. Traditional research has long relied on animal tissue studies. And Researchers are asked to reimburse NDRI for tis- from these studies we’ve extrapolated sues. Typical charges range from $10 for eye tis- to fit our human model. sue (e.g., iris) and $200 for pancreatic tissue to But consider how much further variable amounts for intestinal tissue (4). and how much faster our research could go were human tissue available. Then consider that NDRI, a nonprofit organization, now provides a Interaction of For-Profit and variety of autopsy, surgical and brain Nonprofit Institutions dead cadaveric tissues (both normal control and disease). Different types of human tissues and cells are now used for a variety of nonprofit and profit purposes. Human samples are used by the pharmaceutical industry to produce drugs, by trans- . Tissue Procurement “ Tissue Preservation “ Distribution plant surgeons to transplant vital and nonvital or- 215222 NDRI ——————— ——————————.— I gans, and by hospitals to transfuse blood. In each — Please send me an application 1 more information. instance, the human material can be considered 1 and : I mail to: NDRI a factor in a production process. 2401 Walnut St., Phila., PA 19103 I Four key features of these markets, however, ~ Nwe-. -- .-. . . . .__.-_. ~ distinguish human biological materials from many I Affiliation – -- - – I I Address — .— --- —--— I other goods and services. First, there is no neces- I sary connection between the value of the human ~ City - State ___ Zip ---- / 1 biological material and the price of the material. I Phone -– –._ I I By law, certain types of human materials, such L––––—–—––—––—–—————J as organs for transplantation, are not permitted SOURCE: National Disease Research Interchange, Philadelphia, PA. -— —

124 . Ownership of Human Tissues and Cells

to be sold; by fiat, therefore, the price of these the law only specifies that the source does not resources is zero. Diseased human tissues and cells have the right to sell it. The law does not specify used in research have also, by custom, been free who may in fact reap the economic value of the to investigators. For healthy tissue that research- organ. Legislating that the source does not have ers recruit from sources, compensation varies, but the right to sell an organ and that it can only be usually covers only time and inconvenience. Sec- transferred at a price of zero does not, however, ond, there may be nonprice regulation of who reduce the value of the organ to zero. What it may provide human biological materials, how the does, instead, is transfer the value of the organ transaction is to occur (e.g., through informed con- from the source to other parties.2 These could sent), and who receives the final product. Third, be the owners of the other factors of production, even when the price of human specimens is zero, the entity that produces the final product, the pur- there are a significant number of persons with chasers or recipients of the final product, or all altruistic motives who willingly offer their tissue. of these parties. How the parties share in the value Fourth, many of the organizations involved in proof the zero-priced factor depends on the supply ducing the final product are nonprofit organi- and demand conditions prevailing in the market zations. and on the degree of control the producer has over the market. This distribution scheme is a direct consequence of the extraordinarily high symbolic value placed on human tissues and cells that often requires sup- ‘Suppose, for example, that a market for transplantable kidneys pliers of these materials to be motivated by altru- existed. There are three parties to the transaction—the donor, the ism alone. However, while altruism is required surgical/hospital team, and the recipient—and they are able to ac- complish the transaction at prices agreeable to all. The amount re- to be the motivator of supply for many types of quired by the family of the kidney donor to proffer the kidney is human biological materials, no such requirement $50,000, the amount required by the surgicallhospital team to bring is made of other participants in the production forth its services is $100,000, and the kidney recipient is willing to pay $150,000. Suppose further that a law is passed requiring all process, which may at times include for-profit ac- transactions in kidneys to be gifts, thereby prohibiting the kidney tors. To control this production process, some reg- donor’s family from selling the kidney and reaping its economic value ulation of prices, rates of return, and distribution of $50,000. Who will now realize this value? The intent of the legislation was that the value of the kidney be transferred as a gift from may be imposed. The regulation can take several the kidney donor to the recipient, with the transplant ultimately forms and involve public and private nonprofit costing the recipient on.y $100,000. Yet, because nothing is done organizations. to ensure this outcome, a different outcome is possible. Depending on the conditions of the transplantable kidney market, it may be As described in chapter 5, the law is unclear possible for the surgicahospital team to realize the value entirely by charging the recipient $150,000. Of course, this transfer of the in defining the rights relating to human biologi- value of the kidney from the donor to the surgical/hospital team cal materials. In the case of organs for transplant, would be subject to a broad ethical debate.

SUMMARY AND CONCLUSIONS

The traditional relationships between sources likely determine whether a change occurs in the and researchers, and among researchers at differ- current system of free donation of human tissues ent institutions, have been informal and involved and cells for use in biotechnological research and free exchange or transfers. Today, however, the commerce. A change could arise from: 1) judicial techniques of biotechnology and the potential for decisions in present or future cases under litiga- profits and scientific recognition have introduced tion, or 2) a greater public interest in the uses of issues of commercialization into various uses of human biological materials in biotechnology as human tissues and cells. the commercial profitability of the biotechnology industry begins to be realized. At present, there is no widespread sentiment favoring a move toward a market system for hu - From the point of view of equity, a market struc- man tissues and cells. Two principal factors will ture has a strong appeal because it eliminates the —

Ch. 7—Economic Considerations • 125 potential windfall realized by parties receiving the the market price for untested tissue will be free donation. On the other hand, the magnitude nominal. of the transaction costs associated with payment For the present nonmarket system to continue to sources may be sufficient to deter any forays to operate successfully, a clear and unequivocal into a market structure. perhaps the most likely nonprofit organization of procurement and dis- development is that there will be little practical tribution of human tissues and cells may be nec- difference between a market and nonmarket essary to preserve the trust between sources and structure for handling human tissues and cells: takers and to ensure the continued supply of do- because of the great uncertainty about the value of any one sample of human tissues or cells and nations of human biological materials for research purposes. the small percentage of useful tissues and cells,

CHAPTER 7 REFERENCES

1. Ancirews, L. B., “My Body, My Property, ” Hastings 7. Hansmann, H. B., “Three Essays on the Role of Non- Center Report 16(5):28-38, 1986. Profit Enterprise,” unpublished Ph.D. dissertation, 2. Brains, M., “Transplantable Human Organs: Should Yale University, New Haven, CT, 1978. Their Sale Be Authorized by State Statutes?” Am. 8. Kessel, R., ‘(Transfused Blood, Serum Hepatitis, and J. La\ir Med. 3(2):183-195, 1977. the Cease Theorem, ” Blood Policy: Issues and A her- 3 Buc, N. L., and Bernstein, J. Z., “Buying and Selling natives, D.B. Johnson (cd. ) (Washington, DC: Amer- Human Organs Is Worth a Harder Look, ”Heahh - ican Enterprise Institute, 1976). sca~ 1(2):3-5, 1984. 9. Schneider, A., and Flaherty, M. P., “The Challenge 4 . Couture, M. L., research manager, National Disease of a Miracle: Selling the Gift ,“ ~“ttsburgh Press, Nov. Research Interchange, Philadelphia PA, personal 3-10, 1985. communication, July 11, 1986. 10. Thorne, E., and Langner, G., “Uses of Human Bio- 5. Eckert, R. D., “Blood, Money, and Monopoly, ” Se- logical Materials in Biotechnological Research and curinga Safer Blood Supp~y: T}vo \’ie\$rs, -R.D, Eck - Commerce: An Economic Analysis, ” contract pa- ert and E.L. tt~allace (eds. ) (Washington, DC: Amer- per prepared for the Office of Technology Assess- ican Enterprise Institute, 1985). ment, U.S. Congress, 1986. 6 Greenberg, it’., associate professor, Department 11 Titmuss, R., The Gift Relationship (New York: Pan- of Health Services Administration, The George theon Books, 1971). ~1’ashington University, Washington DC, personal communication, May 1986. chapter 5 Ethical Considerations

“It is time to start acknowledging that people’s body parts are their personal property. ” —Lori B. Andrews Hastings Center Report 16:5, 1986

“We may be more than mere protoplasm, but we’re nothing without our bodies (at least in this world). Putting a price on the priceless, even a high price, actually cheapens it. So we don’t approve of selling our body parts; and the body isn’t quite property. ” —Thomas H. Murray Discover, March, 1986 ——

CONTENTS

Page Introduction ...... +...... 129 Hypothetical Case Study ...... 129 List of Ethical Questions ...... 130 The Ethics of Buying and Selling Bodies and Their Parts ...... 130 The Principle of Respect for Persons ...... 130 The Principle of Beneficence ...... 134 Principles of Justice ...... 135 The Moral Status of Bodies and Their Parts ...... 137 Philosophical Perspectives ...... 137 Selected Religious Perspectives ...... 138 Summary and Conclusions ...... 143 Chapter preferences...... 144

Figures Figure No. Page 15. The Human Skeleton v. the Human Person ...... 137 16. Dissection of the Human Corpse ...... 140 —

Chapter 8 Ethical Considerations

INTRODUCTION

The use of human tissues and cells in biological research raises important ethical issues about how these materials are obtained, transformed, and possibly commercialized. Although these issues are new, there are significant moral and ethical traditions from which to develop guide lines about the ways in which human biological materials ought to be developed or exchanged. The absence of established customs or patterns for the development and exchange of these materials is due, at least in part, to the relatively new potential for profits to be derived from the development of human cells and tissue into cell lines or gene probes. This potential creates novel questions about the best courses of action that should be taken by physicians, patients, and others concerning the transfer of human biological materials. The following hypothetical case study indicates some of the ways in which new questions about the proper transfer and use of human tissues and cells can affect the relationship between doctor and patient.

Hypothetical Case Study

It is not farfetched to consider the ways in which modern developments in biotechnology might transform the relationship between doctor and patient. It is now possible to obtain something of value in any medical procedure that involves col- lecting a patient’s tissues or cells. This possibility seems to entail new obligations regarding informed consent, The nature of these obligations, however, is a subject of some debate.

129 —

130 Ž Ownership of Human Tissues and Cells

List of Ethical Questions whether it is ethical for bodily materials to be bought and sold or about how justice should be This chapter addresses the following questions: preserved in the distribution of profits are largely ● Is it ethical for human tissues and cells to be an American phenomenon. In Japan, for example, developed into commercial products? a loan shark gives his clients the “opportunity” ● If it is ethical for human tissues and cells to to repay him in kidneys. In the Philippines, pris- be developed into commercial products, what oners attempt to obtain earlier paroles by “donat- are the necessary ethical conditions for such ing” kidneys. In Bombay, India, a mother sold her transactions? kidney for $7,000 to buy a dowry for her daugh- ● What is the relationship between the iden- ters, a clock, a TV set, and a swivel fan (22). tity of a person and his tissues and cells? ● In this country, the combination of for-profit Are there any limits or restrictions on the use and nonprofit markets encompasses the some- of human tissues and cells? ● times competing values of private enterprise and Does an individual retain rights or interests public good (see ch. 7). If private enterprise and in his tissues and cells after they are cast off the public good were always synonymous, then as waste, surgically extracted, or otherwise the question of whether it is proper or fair for relinquished? researchers to profit from human biological ma- The underlying question is whether or not the terials would not arise. This chapter discusses not buying and selling of undeveloped human cells only whether any harms might result if human or developed cell lines and gene probes could re- tissues and cells are bought and sold, but also how sult in substantial benefits or harms for individ- profits that accrue from any commercialization ual human beings. It may be that anxieties about might be fairly or justly distributed.

THE ETHICS OF BUYING AND SELLING BODIES AND THEIR PARTS

Are human biological materials objects for a ban on such commercialization? Proposals for commerce, things that may properly be bought markets in human tissues, for example, could be and sold? There are three broad ethical grounds justified on the grounds that they would lead to for objecting to or supporting commercial activi- a preponderance of good results over bad. On the ties in human biological materials. These parallel, other hand, objections to the same markets could but only roughly, the generally accepted ethical likewise be couched in consequentialist (outcome- principles of respect for persons, beneficence, oriented), beneficence-based terms. and justice. The third principle is justice. A societal commitment to fairness and equality maybe relevant First is respect for persons: the idea that trade to determining the moral acceptability of com- in human materials ought to be limited to the ex- merce in human body parts. It maybe that much tent that the body is part of the basic dignity of of the public repugnance to a market in human human beings. If the body is indivisible from that tissues stems from a sense that the limit on per- which makes up personhood, the same respect missible inequalities would be breached by such is due the body that is due persons. Conversely, a market. if the body is considered incidental to the essence of moral personhood, trade in the body is not protected by the ethical principle of respect for The Principle of Respect for persons. Persons

The second moral principle is beneficence. The principle of respect for persons can be il- Would commercialization of human materials lustrated by the work of four moral theorists: two (perhaps of specific kinds) be more beneficial than have theological roots, two have secular back- Ch. 8—Ethical Considerations Ž 131

grounds. In addition, two emphasize the moral organic view of the Nazis and the technological, importance of the body, and two view human bi- ‘(spare parts)” mechanistic analogies of the present ology as incidental to the moral nature of human day (18). beings. The theologians are Paul Ramsey and Ramsey criticizes those Protestant and Catho- Joseph Fletcher; the philosophers are Leon Kass lic theologians who, he believes, give too little em- and H. Tristram Engelhardt, Jr. phasis to the fact of human embodiment. They contribute, he says, to the technological view of When these individuals have addressed com- human bodily existence. Their writings simply af- mercialization, it usually has been in the context firm the dualism of person and body that influ- of organs for transplantation. Each, however, has important views about the body and its relation- ences contemporary views. ship to moral personhood that illuminate the ethi- In addition, Ramsey is opposed to commerciali- cal debate about the use of human tissues and zation of the human body, or at least of its vital cells in biotechnology (14). organs. His principle reason stems from his view of the body’s irrevocable connection to the per- Paul Ramsey son; he sees the body as a sacredness in the biological order. This requires that it be treated with Paul Ramsey, a Christian theologian, argues that respect. This view also makes the commercializa- man is a “sacredness” in his bodily life. For Ram- tion of the body morally repugnant. sey, respect for the human body as an insepara- ble part of the person is an important moral duty Ramsey incorporates into his ethics the notion grounded in the respect due to all persons cre- of a “quasi-property right ’’—the right of kin to con- ated by God (18). Ramsey has reservations about trol the disposition of the body for burial in Anglo- the morality of organ donations by living donors, American common law. (See ch. 5 for a discus- He requires that due weight be given to the phys- sion of legal aspects of this right.) He argues that ical harm done to the donor since the only hu- this right is “quasi” in that possession for com- man life we know to respect, protect, and serve mercial purposes is still denied to any claimant in medical care is physical life. In particular, giv- (the man himself or his kin). It is a sort of “prop- ing an organ is an act of charity and never an obli- erty” in that possession for a certain human and gation. familial purpose is legally protected. This purpose is the positive human value and interest at stake—a Ramsey has equally deep qualms about policies protection of the poor or the upwardly mobile that would remove organs from the newly dead from commercial exploitation even with the con- without the consent of the donor while living and sent of the person whose body it is, or was. Ram- the family upon death. Even with consent, he cau- tions that human beings should not begin to think sey states that there is no opposition too strong against the potential abuses of a market in hu- of their bodies as a group of parts to be given, man flesh. taken away, or, worst of all, sold. Ramsey believes that human beings exist in their bodies and Ramsey is so committed to the idea of sacred- that respect for the body is indivisible from ness and bodily integrity that he offers, only half- respect for the person. Ramsey has a basic con- facetiously, the proposal that organs donated by cern about humankind’s tendency to regard the living donors be regarded as merely on loan, to body as an instrument or as incidental to the moral be returned to the giver when the recipient dies. person. He states: Ramsey makes this proposal to emphasize the im- There are many refined and subtle ways by portance of bodily integrity and the wrong done which men [and women] may be encouraged or when integrity is violated-even for such a great allowed to treat themselves as parts only, or col- good as preserving the life of another. For him, lections of parts, in the service of medical progress no great preponderance of good could justify or societal value to come. In terms of our vision harming a live donor against his charitable will. of man and his relation to community, there may His discussion of living organ donors asks: Does be little to choose between the blood and soil, the body belong to the person? His answer: Yes. 132 ● Ownership of Human Tissues and Cells

For living or cadaver donors, may parts of the persons are not non- or anti-artificial; they are body be sold? His answer: No (14). not essentially sexual; and they are not essentially parental (7). In Fletcher’s view, it is reasonable Joseph Fletcher and possible to be thoroughly human and favor technology, to have the human species survive In contrast to Paul Ramsey’s view of the ethical without sexuality, and to be fully personal with- centrality of the human body, theologian Joseph out reproducing. Fletcher gives biology some emphasis, but does not assign much, if any, moral significance to it. Fletcher’s desire to move the body outside of To Fletcher, the body appears to be merely a the moral compass is even more accentuated in necessary condition for the pursuit of the truly subsequent writings reflecting further on indica- important things about being human. Its sig- tors for humanhood. He says that neocortical func- nificance is only instrumental, not essential. tion is the key to humanness, the essential trait A recurrent theme in Fletcher’s work is a prefer- necessary to all other traits (7). ence for human control over natural processes, Given Fletcher’s views about the moral insig- for design and choice over chance, for reason over nificance of the body and his celebration of con- those things indifferent to reason. Fletcher asserts trol and artifice, it is unlikely he would object to that being truly human involves knowing one’s the commercialization of the body or its parts circumstances (e.g., one’s physical nature) and con- based on respect for persons. He might have other trolling circumstances toward rationally chosen objections, but they would have to be on quite ends (5). different grounds. His view of the body and its Fletcher’s equation of artifice and control with relation to the moral person could not support moral stature suggests that he advocates the least any strong objection to using it for commercial natural course as the most morally elevated one, gain. that the artificiality of certain means of conception make them, for that reason, preferable to natural means. He states: Leon Kass To be a person, to have moral being, is to have Leon Kass, a physician and philosopher, objects the capacity for intelligent causal action. It means to those whom he calls corporealists, that is, those to be free of physiology! It is precisely persons— for whom there is nothing but the body. He also and not souls or bodies or glands or human objects to theorists of personhood, consciousness, biology-that count with God and come first in and autonomy who treat the essential human be- ethics (5). ing as pure will and reason, as if bodily life counted The relative unimportance of the body to moral for nothing (10). Kass states that the former con- personhood is reinforced in Fletcher’s seminal ar- fines man too much to mindless nature; the lat- ticle about ‘(indicators of personhood’’(7). He names ter treats man in isolation, even from his own na- 15 positive and 5 negative criteria. Fourteen of ture (10). the fifteen positive criteria are descriptions of vari- In his book, Toward a More Natural Science, ous capacities-e.g., self-awareness, curiosity, Kass develops a philosophy of medicine and med- concern for others. Only one directly addresses ical ethics based on what he believes are insights the body—a functioning neocortex. It is clear that that come from a right understanding of the body. this physiological requirement is important only It is completely secular, and in that respect it is because the neocortex is the physiological sub- distinct from both Ramsey and Fletcher. But in stratum—the enabling condition-of the other 14 its rejection of a mind/body dualism and its em- criteria. brace of a concept of the body that stresses its Of the five negative criteria—those things that dignity, Kass has much in common with Ramsey he asserts are not central to moral personhood– and little with Fletcher. He finds part of his inspi- three may be taken to pertain to the human body: ration in the way physicians regard the body: Ch. 8—Ethical Considerations ● 133

Doctors respect the integrity of the body not has much more in common with the theologian, only because and if the patient wants or allows Fletcher, than with the philosopher, Kass. Human them to. They respect and minister to bodily beings have no interest, he says, in preserving wholeness because they recognize, at least tacitly, mere biological life as an end in itself. In contrast what a wonderful and awe-inspiring—not to say to the brain, and particularly the neocortex, the sacred—thing the healthy living human body is body is a complex, integrated mechanism that sus- (lo). tains the life of the brain, which serves as a basis On secular rather than theological grounds, Kass for the life of a person (4). But all of the body’s stands with Ramsey in tying human embodiment parts, aside from the higher parts of the brain, to human moral worthiness. He states that hu- can be replaced. The particular features of the man dignity rests on acknowledging the neces- body are in this sense more incidental than essen- sity of human embodiment. What is the relation- tial. Engelhardt has no difficulty counting the com- ship of the human being to his body: that of the puter HAL in the movie 2001 as a person. His views owner to property? He does not explicitly answer on personhood and brain transplants are consist- this question but he makes clear his skepticism ent with this (i.e., personhood goes with conscious- about treating the body as commercial property. ness, with the brain and not the body) as well as Discussing reproductive technologies in general his view on the proper definition of death. He and surrogate motherhood for pay specifically, agrees with Fletcher that in humans the person Kass states that the buying and selling of human does not survive the destruction of the neocortex. flesh and the dehumanized uses of the human From all of this, it is clear that for Engelhardt the body ought not to be encouraged (10). This posi- body is morally important only insofar as it em- tion is tied to his general repugnance at the no- bodies the life of the person. Engelhardt stresses tion of owning living nature per se. He doubts the that it is in and through our bodies that we are wisdom of permitting the patenting of life and in the world, have our relations with others, and worries about individuals owning entire living realize our concrete purposes in life (3). Still, per- kinds, e.g., micro-organisms. He sees no natural sons can objectify their bodies, measure them stopping place between bacterium and homo according to personal goals, replace them, and sapiens, once the ownership of living nature is even sell them. permitted. He asks: Because persons are at the core of morality If a genetically engineered organism may be and because persons are in the world through owned because it was genetically engineered, their bodies and have their bodies as their what would we conclude about a genetically al- cardinal possessions, individuals cannot do tered or engineered human being? (10). whatever they please to the bodies of others. Kass refuses to separate the body out from what Engelhardt states that one cannot respect other gives human beings their dignity and offers the moral agents, while being willing to destroy their premise that one can learn a great deal about hu- embodiment or their unique place in the world man dignity and moral conduct from looking care- (4). Respect for persons, then, provides a mini- fully at what the body means. He is reluctant to mal protection against unwanted physical violence permit commercialization of the body or to treat to the bodies of human beings. living nature in general as something that should Engelhardt’s arguments regarding the limits of be reduced to mere property. Taken together, State authority lead to his explicit views on the these views create an argument that links the commercialization of the body. In contrast to body to human dignity so strongly as to raise thinkers like Ramsey and Kass for whom the spe- doubts about the moral acceptability of com- cial dignity of the body places it outside the realm mercializing the human body. of those things that may be bought and sold, En- gelhardt cites the philosophers Hegel and Locke H. Tristram Engelhardt, Jr. to develop his claim that the human body is the H. Tristram Engelhardt, Jr., a physician and phi- quintessential example of property. He then ar- losopher, holds a secular view of the body that gues that we have a right to trade our bodies com- 134 . Ownership of Human Tissues and Cells mercially. In fact, he argues that, if anything, our tity produced to match the quantity demanded right to trade other material objects is inferior at an equilibrium price that reflects the value of to and less clear than our right to trade our bod- the material to sellers and buyers. However, it ies. He also would permit indentured servitude, is important to consider whether there are any as it exists, for example, when one receives sup- beneficence-based reasons to object to a market port for education in exchange for a commitment in human tissues and cells (14). to military service. For Engelhardt, these rights are based on con- Beneficence-Based Objections sent. He states that persons own themselves and to Commercialization own other persons insofar as they have agreed There are two general types of objections to to be owned (4). He explicitly denies the author- commercialization based on the principle of ity of governments to forbid commercial trade in beneficence. The first focuses on basic assump- bodies and their parts. He states that the author- tions about the importance of freedom and ra- ity of governments is suspect, insofar as they “(r)est- tionality; the second grants these assumptions, but rict the choice of free individuals without their argues that wider, indirect effects are preponder- consent” (e.g., attempts to forbid the sale of hu- antly negative (14). man organs) (4). Should the State try to prevent such transactions, he defends a fundamental Arguments of the first type deny that individ- moral right to participate in the black market (4). uals maximize their own well-being through mar- According to Engelhardt, individuals own their ket transactions. There are four objections of this bodies and may commercialize them as they wish. type: There is no State authority for interfering in that 1. Critics of commercialization argue that the commercialization, and there is a moral right, all assumption that people are rational con- else being equal, to defy any such efforts at State sumers is dubious. There is ample evidence control. Engelhardt contends that it cannot be pre- of irrational human behavior in markets and sumed that individuals have consented to such elsewhere. While this may not seem impor- governmental control of their bodies by virtue of tant when the commodity being traded is a their participation in the State. videocassette recorder or cake mix, irrational Although religious views may be thought to be trade in human tissues, cells, and cell prod- the key dividing line between those who consider ucts is a more serious matter. the body an essential and irremovable part of per- 2. While the assumption that people are free and sonhood and those who give it much less moral rational might be reasonable for most adults, weight, this brief analysis of the views of four the- there will be large classes of people, includ- orists shows that this is not the case. Rather, it ing children, the mentally ill, and the men- appears that the idea that the brain and the neo- tally disabled, for whom this assumption is cortex are the morally important stuff of per- clearly unjustified. These people might par- sonhood is held by those who do not oppose ticipate in either production or allocation mar- commercialization of the body. kets. Given their inability to consent to the The Principle of Beneficence use of their body, including invasive procedures necessary to obtain commercially val- The relevance of the principle of beneficence uable materials, their participation as sellers to the debate can be understood by considering seems particularly morally questionable. De- this fundamental question: would commerciali- cisions would need to be made about whether zation of human materials be more beneficial to ban such people as suppliers, make provi- than a ban on such commercialization? Even sions for their limited participation, or endure allowing for imperfections, one could argue that the spectacle of unlimited use of such non- a market in human tissues and cells would be the consenting suppliers. most efficient system of determining production 3. In every human interaction, including all mar- and allocation. A market would permit the quan- ket interactions, there is the possibility of Ch. 8—Ethical Considerations . 135

abuse--fraud, misrepresentation, coercion, they will, on the whole, outweigh the imme- and the like. This is not peculiar to markets diate benefits (12)18). in human materials, but it may be that abuse 4. In the specific case of human biological main this realm is more morally repugnant than terials donated for research to nonprofit in- it would be with other goods, stitutions (e.g., university-based biomedical 4. There may be a discrepancy between what research), the shift from a gift to a market people desire and what they need; that is, be- basis could have damaging consequences in tween what even fully rational and free con- the cost and availability of such materials, sumers might pursue in a market, and what public perception of and generosity toward those individuals need to promote their gen- biomedical researchers, and increased sus- uine well-being. Therefore, it is possible that picion of health providers. a market might be consistent with human desires but inconsistent with the human good. Principles of Justice

The second type of beneficence-based objections Distinct questions of justice as fair and equal go on to ask about the wider effects of commer- treatment arise when considering the acquisition, cialization, particularly of the human body: development, and allocation of human tissues and cells, To complicate matters further, there are sev- I. Commercialization of the body will lead to eral ideals or theories of justice, each of which disrespect and devaluation of the human body commands a certain amount of respect and ad- in general. This argument will not be espe- herents. Since our society appears to subscribe cially persuasive to those who believe that the to several, sometimes incompatible ideals of biological body does not deserve such respect justice, there will be no easy way to list the in the first place (e.g., Fletcher) or who ar- ethical implications of commercializing hu- gue that such regulations fall outside of the man biological from a “correct’) theory of jus~ moral authority of the State (e.g., Engelhardt). tice. It is possible, however, to contrast two im- 2. Commercialization will somehow threaten important, opposed views: the libertarian view and portant ideals of equality, not through any the egalitarian view (14). explicit declaration in favor of inequality, but because in a society where wealth is unequally The Libertarian View distributed, the costs of production and benefits of allocation are likely to be unequally Libertarian theorists emphasize the processes of exchange as based on free consent, they mini- distributed as well. Whether such inequities mize the importance of whatever distribution re- come to be seen as morally unacceptable will sults from a series of fair exchanges, and they hold depend on a number of complex factors hav- that the State does not have the authority to ining to do with the prevailing ideals of the cul- terfere in most market transactions (4,15). On the ture, the history of related decisions, and the other hand, more egalitarian theorists believe that nature of the good being allocated. When the there are constraints on permissible exchanges, poor, for example, are the suppliers of hu- and they also believe that there may be specific man biological materials and the wealthy are limitations on the institutions a just society may the beneficiaries (e.g., if production and allo- have (19) or on the distribution of at least some cation of transplantable kidneys were accomplished through markets), the resulting corre- goods-especially those goods necessary to the ful- fillment of basic human needs (2,24). lation between risks and poverty, benefits and wealth, would challenge a very important con- The libertarian view of justice and the commer- ception of equality in this country. cialization of the body is intimately tied to the im- 3. Moving from the concept of gift to a market portance of the concepts of respect for persons in human tissues and cells carries with it such and private property. This view places a fun- important losses to the common good that damental emphasis on autonomy, understood as 136 ● Ownership of Human Tissues and Cells the free choice of rational persons based on rights facie claims, to be respected even though not ex- to privacy and noninterference by the government plicitly invoked. where parties involved freely consent. The idea These human rights are based on a concept of of property has as its paradigm case one’s owner- individual moral worth as inalienable and as abso- ship of one’s own body (4). Given these premises, lute. According to this view, all humans are of interfering with commercial trade in one’s own equal and immeasurable moral worth. Egalitar- biological materials would be perhaps the clearest ians argue for the proposition that one person’s and gravest affront to justice imaginable. well-being is as valuable as any other’s and one Given the libertarian view, selling oneself freely person’s freedom is as valuable as any other’s. to another does not involve a violation of the prin- From this follows the claim of the prima facie ciple of autonomy, so such transactions should equality of a person’s right to well-being and free- fall within the protected privacy of free individ- dom (24). uals. In addition, if one sells oneself at the right One egalitarian offers this definition of justice: price and under the proper circumstances, one “An action is just if, and only if, it is prescribed would expect to maximize the balance of bene- exclusively with regard to the rights of all whom fits over harms. However, the point in principle it affects” (24). Egalitarians argue that some ine- is that free individuals should be able to dispose qualities can be justified precisely on the grounds of themselves freely (4). of justice; that is, that the very reasons for saying According to this view, if this results in the poor that human beings have equal moral worth and selling and the rich buying, so be it; interfering equal rights to well-being and freedom can also, with the free choices of individuals is a violation under certain empirical circumstances, justify of justice. The pattern of distribution is not rele- limited forms of inequality. vant to justice; indeed, the very notion of “distribu- By showing that certain inequalities maybe justi- tive” justice, of unjust patterns of distribution ob- fied within an egalitarian theory of justice, it is tained from exchanges not in themselves unjust, possible to identify and condemn unjustified ine- seems incoherent in this theory. qualities. This is accomplished by examining practices to see if they deny or diminish the equal moral The libertarian view of justice follows directly worth of individuals or groups of persons, or if from the concept of the personas individual, au- they otherwise enhance or impede satisfying the tonomous, and free, and from the notion that demands of justice. respecting persons means most of all not interfering in whatever transactions to which rational To the extent that commercial trade in human individuals agree. The libertarian theory of jus- tissues and cells makes people feel that they are tice says in effect that commercial trade in inferior to others, this practice would be unjust. body parts is the essence of justice, and that Pricing the body and its parts, which would prob- those who would interfere with it have an ex- ably lead to the poor selling more than the rich, ceedingly heavy burden of proof on their could also have this effect. shoulders. The more traditional maxims of dis- The arguments come full circle. If one believes tributive justice—to each according to need, that the body is merely incidental to what is worth, merit, or work—are replaced by “to each morally significant about persons-their ra- according to the agreements he has freely made” tionality, capacity to choose, and freedom— (4). then those aspects of commercialization likely to lead to differential participation in the body- market will not seem offensive, precisely be- The Egalitarian View cause the body is not particularly connected The egalitarian theory of justice contrasts with to a person’s moral worth. If, on the other the libertarian view. Egalitarian theory is based hand, one believes that respect for persons in- on a powerful and clear view of respect for per- cludes respect for the human body, then those sons. This theory emphasizes concepts of natu- empirical properties of the market do pose a ral or human rights. These human rights are prima threat to justice (14). Ch. 8—Ethical Considerations ● 137

THE MORAL STATUS OF BODIES AND THEIR PARTS

Philosophical and religious traditions offer a others. The donation of brain tissue might be number of alternatives for thinking about the body viewed as more central to the essence of a per- and its parts in relationship to the human person than the donation of skin tissue. son. These traditions provide a basis on which A second alternative to Cartesian dualism is that to gather insights about the uses and transfer of mind or the essence of the human person is inti- human tissues and cells. mately connected to all of the biological material that comprises the human body. In this case, the Philosophical Perspectives essence of the person or identity is tied up in each The nature of the relationship between human and every cell and tissue, so no one type of hu- identity, personhood, and the mind to the body man tissue would be considered more valuable is a problem that has classical roots in Western than any other. In fact, the genetic identity of an philosophy. Although the early Greek Atomists individual person can be discerned from any one held that the human mind was made of actual ma- somatic cell. terial, the idea that the mind is nonspatial has dom- It is not clear that either of these alternatives inated philosophical thinking since the time of to Cartesian dualism necessarily precludes the use Plato. The view that the human mind and body exist as a duality was developed in some detail by Rene Descartes in the 17th century. Cartesian Figure 15.— The Human Skeleton v. dualism holds that the essence of a person is an the Human Person immaterial, nonspatial substance or mind that can, in theory, exist apart from the body. During the lifetime of an individual, mind and body are one but this is incidental and not necessary to the existence of mind. From a Cartesian point of view, human tissues and cells are valuable only to the extent that they provide a temporary substrate or basis for the existence of the human person. The relationship between the human person and a particular tissue or cell is not essential, particularly if these materials are replenishable. This is not to say that Cartesian would be reluctant to attach a monetary value to such materials. In fact, they may be quite inclined to make tissues and cells the object of commerce because there is no great significance attached to such materials in terms of the human mind, personality, or identity. There are at least two primary alternatives to Cartesian dualism. One alternative view is that the human mind and some specific biological material (e.g., the human brain) are intimately connected so that it is impossible for the mind to exist apart from the presence of brain tissues and cells such as neurons. In this case, one might value certain kinds of human tissues and cells above SOURCE: Albinus on Anatomy, by Beverly Hale and Terence Coyle

63-221 0 - 87 - 6 QL 3 138 . Ownership of Human Tissues and Cells

of human tissues and cells in commerce. The of humanity to the neglect of the external body. materialist may in one case attach a higher price Some have even argued that the image of God is to certain kinds of cells or he might hold that each the body, while others have argued that it is a com- and every tissue is so valuable that all human bio- bination of the spiritual and the physical in a psy- logical material should be expensive. In addition, chophysical unity. Jewish and Christian thought whether one is a Cartesian or not, it may be and practice as a whole views the person as an possible to object to the buying and selling of animated body. At times, however, Judaism and human tissues and cells based on social jus- Christianity have also appropriated Hellenistic con- tice or other considerations that are separate victions about the separation of soul and body; from the question of how the essence of a hu- sometimes their beliefs and practices represent man person is related to the body. a combination of themes (25).

Among the numerous ethical implications of Selected Religious Perspectives different interpretations of the image of God, some There are three reasons to examine religious are especially important for this study. The Gen- perspectives when developing public policies in esis passage connects creation in the image of God a pluralistic society. One reason is historical: many with God’s authorization of human “dominion” existing laws regarding bodies and their parts have over the rest of creation. Humans are in, but are been influenced by religious sources. To under- distinguished from, the rest of nature. If, as in stand these laws, it is important to identify the the royal ideology of the ancient Near East, hu- beliefs and values that support them. Second, re- mans are God’s representatives in parts of his king- ligious traditions shape the ethical values of many dom, their rule should be like God’s and should people. These traditions influence whether some never be exploitative. Their dominion is not to uses of bodily parts or materials are viewed as be viewed as domination but as stewardship or ethically acceptable or unacceptable. A third, trusteeship. As stewards and trustees, human closely related reason is that religion and religious beings do not have unlimited power. God has organizations are an important facet of our soci- set limits on what human beings may do with ety and they have to be considered when policy- and to their own bodies and those of others makers try to determine which policies are polit- (1). Genesis 9:6, for example, connects the prohi- ically feasible. Extreme opposition from religious bition of taking human life with creation in God’s organizations sometimes may render a policy in- image. feasible from a political standpoint (l). Arguments against suicide in Judaism and Chris- Because of variations among and within Juda- tianity often draw on analogies between relation- ism, Catholicism, and Protestantism, it is difficult ships between God and human life, on the one to speak of a “Judeo-Christian tradition” unless hand, and ordinary relationships, on the other. that is taken to mean a common source (the He- Many of these analogies involve property relation- brew Bible/Old Testament) and some common, ships (e.g., life is a gift or loan from God) or per- though very general, themes (l). These themes sonal or role relationships (e.g., human beings are are based on the relationship between God and God’s children, servants, or sentinels). While Jew- human beings. ish and Christian traditions rule out suicide and some uses of the body such as prostitution, they The Old Testament states that God created the do not clearly prohibit slavery, even though its world, including human beings, as good. Human convictions, particularly about the creation of all beings themselves were created “in the image of human beings in God’s image, could be invoked God” (Genesis l:26f; cf.5:1 and 9:6). This is the basis in opposition to slavery (l). of the theological doctrine of “imago dei”or the image of God. Although imago dei has been vari- Finally, respect for the cadaver is significantly ously interpreted as reason, free will, or spiritual connected to the human beings’ creation in God’s capacities, some theologians have objected to the image: Jews and Christians respect the body of concentration on intellectual and spiritual aspects the dead as symbolic of the human person and Ch. 8—Ethical Considerations ● 139

his dignity (8). This respect recognizes and sup- idly by the blood of thy neighbor” (Leviticus ports (within limits) the aversion to tampering with 19:16)—and it justifies some actions that would the body, whether living or dead. appear to be prohibited regarding the cadaver. The language of the image of God has often Under Jewish law, autopsies are generally op- focused on what is distinctive about human posed even when performed to establish the cause beings, particularly their use of reason, exer- of death or to increase medical knowledge in gen- cise of will, and making decisions. Respect for eral. An autopsy is permitted, however, to answer persons is one way to state the implications of a specific question that would contribute to the the theological doctrine of the imago dei, but it immediate improved care of patients (21). When entails respect for embodied human beings, not a patient dies, for example, while suffering from simply their wills, and it is not unlimited self- cancer and receiving an experimental treatment, determination or autonomy because it is severely it may be important to determine whether the limited by God’s creation and will. In practice, it drug was in part responsible for the death. The is often very difficult to determine what actions emphasis falls on the immediacy of the benefit are required by the principle of respect for per- to be gained. Within the Jewish tradition, the ca- sons, as an expression of the imago dei (l). This daver merits the same dignity, respect, and con- point is evident in the following analysis of spe- sideration that would be accorded a living patient cific Jewish, Catholic, and Protestant beliefs and undergoing an operation (21). Organs should not practices regarding the body, its parts, and ma- be removed from the body, except where abso- terials. lutely necessary for the information sought, and any removed organs must be returned to the body Judaism for burial except for small sections necessary for pathology examinations. Any part of a dead body In Judaism, as well as in Catholicism and Prot- must be buried because any person who comes estantism, there is little, if any, direct discussion into contact with it is ritually defiled. of the issues arising from the modern use of human tissues and cells. Hence it is necessary to fer- The priority of saving human life allows for con- ret out concepts and principles in the myriad rules siderable flexibility in the application of Jewish that Jewish tradition has developed regarding the law to technological developments such as organ living human body and the cadaver. Several rele- transplantation. The tradition emphasizes that the vant concepts and principles can be discerned in source of the organs must be dead according to the laws of burial. Also relevant is the interpreta- criteria of absence of respiration and absence of tion of the rules of the “halakah” (the body of Jew- cardiovascular pulsation--obviously these criteria ish law supplementing Scripture) through analogi- pose problems for organ transplantation–and it cal arguments about cases. stresses the decedent’s act of donation (though familial donations are not precluded). Some com- According to Jewish law, there are three major mentators view the prohibitions against the use prohibitions regarding the cadaver: it is imper- of a dead body as not applying to a removed or- missible to mutilate the cadaver (and thus, accord- gan which “lives” again when it is successfully ing to many, to cremate it), to use or derive any transplanted into a recipient (20). benefit from the cadaver, and to delay the interment of the cadaver or any of its parts (17,20). Within the Jewish tradition there would appear These prohibitions against desecration derive to be opposition to tissue banks on the grounds from God’s creation of human beings in his own that a recipient is not immediately available, but image (21). How are these prohibitions interpreted cornea banks have been viewed as acceptable on and applied? In particular, are they absolute? Any the grounds that it is highly probable that the cor- prohibition in Jewish law, except for murder, sex- nea will be used immediately because so many ual immorality, and idolatry, may be overridden potential recipients are at hand. It would not be in order to save human life. Saving human life easy, however, to extend this argument to cover is a paramount imperative—’’Thou shalt not stand research on human tissues, cells, and developed 140 . Ownership of Human Tissues and Cc//s

Figure 16.—Dissection of the Human Corpse

AND R E AE V E SAL I I B R V X ELL ENS J S, r N V 1- Uifsimi CAR 0 L I v.lrnpcrJtllris medici, de Hutr'l.lni corporis fabrica Libri fcptem.

SOURCE: De Humani Corporis Fabrica, 1555. Ch. 8—Ethical Considerations Ž 141

cell lines and gene probes because it is difficult From a Catholic perspective, since human be- to predict benefits, which, in any event, would ings are merely the administrators of their lives, only accrue to patients in the future. bodily members, and functions, their power to dispose of these things is limited (11). In this con- It is permissible for living persons to donate a text, the principle of totality limits what people kidney to save someone’s life or to donate blood may do to their bodies and parts. The principle to a blood bank. Even though there are prohibi- of totality indicates that a diseased part of the body tions against intentionally wounding oneself or can be removed for the benefit of the totality or forfeiting one’s life to save another, most inter- whole body (13). This doctrine was subsequently pretations of Jewish law hold that one is allowed applied to the amputation of a healthy human limb. or even obligated to place oneself into a possibly A modern formulation of this doctrine appears dangerous situation to save his fellow man from in Pope Pius XI’s Casti Connubii (1930): certain death (21). This is a risk-benefit analysis, in which the probability of saving the recipient Furthermore, Christian doctrine establishes, life is substantially greater than the risk to the and the light of human reason makes it most clear, donor’s life or health, Blood donation is viewed that private individuals have no other power over similarly, even though the donor may have no spe- the members of their bodies than that which per- cific recipient in mind and the blood maybe stored tains to their natural ends; and they are not free to destroy or mutilate their members, or in any for a time, Here again the needs of potential re- other way render themselves unfit for their nat- cipients are so great that there is a reasonable cer- ural functions, except when no other provision tainty that the blood will be used to save life, while can be made for the good of the whole body. the risks to the donor are minimal. Because this formulation of the principle of to- In general, the requirements for exemption from tality appears to warrant mutilation only for the the prohibitions regarding the cadaver or the liv- physical benefit of the person’s body as a whole, ing person focus on the probability of immediate it also appears to rule out removal of an organ rescue of human life. Both the prohibitions and to benefit another person. However, many the- the exceptions are based on the dignity of human ologians have come to believe that mutilation is beings as created in the image of God. Extensions ethically appropriate when it is for the good of of the exceptions to banking corneas or blood sug- the whole person, not simply of the body. gest that some indirect and delayed possibilities may be available. However, as indicated in the Some critics contend that appeals to psychologi- preceding discussion, it would be difficult–though cal or spiritual benefits to the donor to justify or- not impossible—to extend them so far as to in- gan donation undermines the appropriate moral- clude research and commercialization on human religious constraints on the human use of bodies tissues and cells or cell lines and gene probes. Such and their parts (18). One Jesuit moral theologian an extension would depend on the probability of rejects both of these charges: Richard McCormick significantly benefiting human beings through re- contends, first, that a donor’s benefit (psychologi- search. cal or spiritual wholeness) is not necessarily identical with the donor’s motivation (charity), and second, that these psychological and spiritual at- Roman Catholicism tributes of the donor only establish the moral context of organ donation, not the justifiability of par- In general, the Catholic Church holds that nota- ticular transplants. The justifiability of particular ble or major excised parts of the body should be transplants depends on the proportionality of ben- buried. Transplantation of organs and tissues from efits and burdens to the recipient and to the donor cadavers generally has been accepted. Donation (13). of organs and tissues has been viewed as praise- worthy, though not obligatory, and the benefit of In a statement that invoked an analogy with the donation need not be as direct or as immediate sale of blood, Pope Pius XII refused to rule out as Jewish law suggests. all compensation for organs and tissues: 142 ● Ownership of Human Tissues and Cells

Moreover, must one, as is often done, refuse on son’s mouth or to be castrated in order to make principle all compensation? This question remains a more comfortable living as a singer and so forth. unanswered. It cannot be doubted that grave But to have a dead or diseased organ amputated abuses could occur if payment is demanded. But when it endangers one’s life or to have something it would be going too far to declare immoral every cut off which is a part, but not an organ, of the acceptance or every demand of payment. The case body (e.g., one’s hair) cannot be considered a is similar to blood transfusions. It is commenda- wrong against one’s own person—although a ble for the donor to refuse recompense: it is not woman who cuts her hair in order to sell it is not necessarily a fault to accept it (16). altogether free from guilt (9). Catholicism, like Judaism and Protestantism, em- Protestants generally do not believe that there phasizes the dignity that belongs to human be- are any special limits on what may be done to ings and to their physical remains after death. This cadavers. Protestants, like Jews and Catholics, rec- dignity is derived from their creation in the im- ognize limits expressed in the language of respect age of God. Representing the image of God, hu- and dignity. One Protestant commentator argues man beings are stewards or administrators of their that rituals are needed even after a cadaver’s or- lives but their actions are limited by God’s law. gans have been donated as ‘(a testimony to the Some of these limits have been expanded in re- privileged place of the body in acts of love (12).” cent years in response to technological develop- For the most part, Protestants tend to conceive ments. In general, charitable acts of donation are most of the major ethical problems in this area praised, whether they are directed toward spe- in relation to consent, which they see as a require- cific individuals or tissue banks (e.g., a blood bank), ment of the principle of respect for persons. but they are subject to evaluation from the stand- In the treatment of living persons, Protestants point of proportional or relative good (e.g., kid- tend to emphasize the virtues of love or charita- ney donation). ble consent. Many theologians would grant greater latitude to competent people making decisions Protestantism about their own organs to benefit others than to Although there are variations within both Juda- surrogate decisionmakers donating organs (e.g., ism and Roman Catholicism, they are not as ex- kidneys) from persons such as children or institu- tensive as in Protestantism, which encompasses tionalized, mentally retarded, or insane people. so many different religious groups. After exam- However, several Protestants have argued that ining some Jewish, Catholic, and Protestant posi- charitable consent still allows too much latitude tions in the late 1960s, Joseph Fletcher lamented, in permissible donations. At least one Protestant “as we often find in these matters of specific or theologian appeals to a strand of Biblical tradition, concrete moral questions, there is no Protestant also strongly affirmed by Judaism, that empha- discussion on surgery, autopsy, and other mutila- sizes the integrity of the flesh and opposes Carte- tive procedures—not even on the ethics of trans- sian mentalism and dualism, which he fears could plant donation (6).” Modern Protestants tend to lead, for example, to donation of a heart by a liv- emphasize the principle of respect for persons ing person (18). Although the independent value even more than Catholicism, with its emphasis on of bodily integrity clearly rules out a heart dona- the ends of nature, and Judaism, with its strong tion from a living person, its other limits are not emphasis on the tradition of interpretation of the very clear. As in Judaism and Catholicism, one of law. However, Protestants generally have recog- the main requirements for organ donation would nized limits to what people may do to their bod- be proportionality as expressed in a risk-benefit ies even when they have disagreed about what analysis. those limits are. The philosopher Immanuel Kant In sketching out the implications of these tra- offered one extreme formulation: ditions, it is important to recall the distinction It is a form of partial self-murder to deprive one- between ethically acceptable and ethically self of an integral part, for example, to give away preferable policies and practices. For example, or sell a tooth to be transplanted into another per- some modes of transfer and some uses of human Ch. 8—Ethical Considerations . 143 biological materials may be viewed as ethically fulness, privacy, and confidentiality, might be de- preferable to others without those others being rived from these general principles. From these viewed as ethically unacceptable—for example, principles and others, it is possible to indicate some these traditions put a high premium on explicit judgments about the ethical acceptability and gifts and donations without necessarily exclud- preferability of various policies. ing tacit gifts, sales, abandonment, and appropri- According to the religious traditions ana- ation in all cases (l). lyzed, any of the following modes of transfer of human biological materials-gift (explicit or The Impacts of These Religious presumed), sale, abandonment, or appropria- Traditions tion—is ethically acceptable under some cir- At least two major variables present in these cumstances, but priority is given to explicit religious traditions may affect the use of human gifts In any event, the first three modes of trans- biological materials: the type or kind of materi- fer all depend on voluntary, knowledgeable con- als and the mode of transfer. The significance sent in significant, but different, ways. Thus, they of different modes of transfer (or acquisition, if all recognize some kind of property right by the viewed from the standpoint of the user) and differ- original possessor of the biological materials. A ent materials will hinge on various moral princi- recent prediction for future legislation is not sur- ples, such as: prising: ● respect for persons; Legislation in the future seems likely to follow ● beneficence, or benefiting others; and an uneven course in which systems of voluntary ● justice, or treating others fairly and distrib- consent will be diluted with mixtures of controlled uting benefits and burdens equitable. commerce, contracting out, and limited compul- sory acquisition (23). In addition, several other moral considerations, such as fidelity to promises and contracts, truth-

SUMMARY AND CONCLUSIONS

Ethical choices about how to handle the trans- fied and those who think it is not seems mostly fers of human tissues and cells from patients and to be an argument between those who accept research subjects to physicians and researchers a dualistic view of the separation between are important decisions in two respects. First, body (material, physiological being) and mind these choices will reflect the way in which the (immaterial, rational being), and those who do human body is regarded. If certain human parts not. The former group includes theological and are sacred or dignified, then social traditions sug- secular ethicists such as Joseph Fletcher. The lat- gest that they may be given, but not sold, and ter include such theologians and secular philoso- ownership of them is only of a special, limited kind. phers as Paul Ramsey and Leon Kass. others, such as H. Tristram Engelhardt, Jr., argue that com- Second, like the choice of how to obtain blood mercialization must be tolerated as part of recog- for transfusions, the system that is chosen for ob- nizing the limits of governmental authority to taining human tissues and cells will characterize interfere in private choices, even on behalf of im- relationships among the individuals of our soci- portant goals or special beliefs certain groups may ety. These relationships are mediated through the have about the sacred character of body parts that profit and nonprofit institutions that connect hu- individuals may freely wish to sell. man beings in their mutual quest to relieve suffering and to pursue the common good separately Religious traditions offer insights about the value and together. and significance of the human body. According The dispute between those who believe that to selected religious traditions, the human body commercialization of the human body is justi- is created in the image of God and therefore there 144 . Ownership of Human Tissues and Cells are limits on what human beings can do with their cells are acceptable within the Jewish, Catholic, own bodies and those of others. Although sev- and Protestant traditions, priority is given to ex- eral methods of transferring human tissues and plicit gifts.

CHAPTER 8 REFERENCES 1. Childress, J. F., ‘(The Implications of Major West- (cd.) (New York: Macmillan/Free Press, 1978). ern Religious Traditions for Policies Regarding Hu- 14. Murray, T. H., “On the Ethics of Commercializing man Biological Materials,” contract paper prepared the Human Body,” contract paper prepared for the for the Office of Technology Assessment, U.S. Con- Office of Technology Assessment, U.S. Congress, gress, May 1986. Washington, DC, April 1986. 2. Daniels, N., Just Health Care (New York: Cambridge 15. Nozick, R., Anarchy, State, and Utopia (New York: University Press, 1985). Basic Books, 1974), 3. Engelhardt, H. T., Alind-Boa’y: A Categorical Rela- 16. Papal Teachings: The Human Body (Boston: St. Paul tion (Hague: Martinus Nijhoff, 1973). Editions, 1960) 4. Engelhardt, H.T., The Foundations of Bioethics 17. Rabinovitch, N. L., “What Is the Halakah for Organ (New York: Oxford University Press, 1986). Transplants?” Jewish Bioethics, F. Rosner and J.D. 5. Fletcher, J., Morals and Medicine (Boston: Beacon Bleich (eds.) (New York: Sanhedrin Press, 1979). Press, 1960). 18. Ramsey, P., The Patient as Person (New Haven, CT: 6. Fletcher, J., “Our Shameful Waste of Human Tis- Yale University Press, 1970). sue: An Ethical Problem for the Living and the 19. Rawls, J., A Theory of Justice (Cambridge, MA: Har- Dead, ” Updating Life and Death: Essays in Ethics vard University Press, 1971). and Medicine, D,R. Cutler (cd) (Boston: Beacon 20. Rosner, F., “Organ Transplantation in Jewish Law, ” Press, 1969). Jewish Bioethics, F. Rosner and J. D. Bleich (eds.) 7. Fletcher, J., “Four Indicators of Humanhood—The (New york: Sanhedrin press, 1979). Enquiry Matures, ’’Hastings CenterReport 14(6):4-7, 21. Rosner, F., and Tendler, Rabbi, M.D., Practical Meal- December 1974. ical Halacha, 2d ed. (Jerusalem/New York: Feldheim 8. Hovde, C. A., “Cadavers: General Ethical Concerns)” Publishers, 1980). Encyclopedia of Bioethics, W.T. Reich (cd.) (New 22. Schneider, A., and Flaherty, M. P., The Challenge York: Macmillan/Free Press, 1978). of a Miracle: Selling the Gift (Pittsburgh, PA: Pitts- 9. Kant, I., The Doctrine of Virtue, Part II of the burgh Press, Nov. 3-10, 1985). Metaphysics of Morals, trans. M.J. Gregor (Phila- 23. Scott, R., The Body as Property (New York: The delphia: University of Pennsylvania Press, 1971). Viking Press, 1981). 10. Kass, L. R., Toward a More Natural Science (New 24. Vlastos, G., “Justice and Equality,” Social Justice, York: Free Press, 1985). Richard B. Brandt (cd,) (Englewood Cliffs, NJ: 11. Kelly, G., Medico-Moral Problems (St. Louis, MO: Prentice-Hall, 1962). The Catholic Hospital Association, 1958), 25. Wartofsky, M. W., “On Doing It For Money, ” Bio- 12. May, W. F., “Religious Justifications for Donating medical Ethics, T. Mappes and J. Zembaty (eds.) Body Parts, ’’Hastings Center Report 15:38-42, Feb- (New York: McGraw-Hill, 1981). ruary 1985. 26. Zaner, R., “Embodiment,’’Encycfopedia ofBioethics, 13. McCormick, R. A., “Organ Transplantation: Ethical W .T. Reich (cd.) (New York: Macmillan/Free Press, Principles, ” Encyclopedia of Bioethics, W .T. Reich 1978). — —

Appendixes Appendix A Code of Federal Regulations, Part 46, Subpart A: Basic Policy for Protection of Human Research Subjects, Department of Health and Human Services

Reprinted below is Subpart A of the Department of a Department grant, contract, cooperative agreement Health and Human Services’ regulations concerning or fellowship. basic protection of human research subjects, Other (1) This includes research conducted by Depart- subparts, which are not reprinted here, address re- ment employees, except each Principal Operating search involving fetuses, pregnant women, human in Component head may adopt such nonsubstantive, vitro fertilization, prisoners, and children. procedural modification as may be appropriate from an administrative standpoint. 46.101 To what do these regulations apply? (2) It also includes research conducted or funded 46.102 Definitions by the Department of Health and Human Services 46.103 Assurances outside the United States, but in appropriate cir- 46.104-46.106 Reserved cumstances, the Secretary may, under paragraph 46.108 IRB functions and operations (e) of this section waive the applicability of some 46.109 IRB review of research or all of the requirements of these regulations for 46.110 Expedited review procedures for certain re- research of this type. search (b) Research activities in which the only involvement 46.111 Criteria for IRB approval of research of human subjects will be in one or more of the fol- 46.112 Review by institution lowing categories are exempt from these regulations 46.113 Suspension or termination of IRB approval of unless the research is covered by other subparts of research this part: 46.114 Cooperative research (1) Research conducted in established or com- 46.115 IRB records monly accepted educational practices, such as (i) 46.116 General requirements for informed consent research on regular and special education instruc- 46.117 Documentation of informed consent tional strategies, or (ii) research on the effective- 46.118 Applications and proposals lacking definite ness of or the comparison among instructional plans techniques, curricula, or classroom management 46.119 Research undertaken without intention of in- methods. volving humans (2) Research involving the use of educational tests 46.120 Evaluation and disposition of applications and (cognitive, diagnostic, aptitude, achievement), if in- proposals formation taken from these sources is recorded 46.121 Investigational new drug or device 30 day de- in such a manner that subjects cannot be identi- lay requirement fied, directly or through identifiers linked to the 46.122 Use of Federal funds subjects. 46.123 Early termination of research funding (3) Research involving survey or interview pro- 46.124 Conditions cedures, except where all of the following conditions exist: (i) Responses are recorded in such a 546.101 To what do these regulations apply? manner that the human subjects can be identified, (a) Except as provided in paragraph (b) of this sec- directly or through identifiers linked to the sub- tion, this subpart applies to all research involving hu- jects; (ii) the subject’s responses, if they became man subjects conducted by the Department of Health known outside the research, could reasonably and Human Services or funded in whole or in part by place the subject at risk of criminal or civil liability

147 —..

148 . Ownership of Human Tissues and Cells

or be damaging to the subject’s financial standing (f) No individual may receive Department funding or employability; and (iii) the research deals with for research covered by these regulations unless the sensitive aspects of the subject’s own behavior, individual is affiliated with or sponsored by an institu- such as illegal conduct, drug use, sexual behavior, tion which assumes responsibility for the research un- or use of alcohol. All research involving survey or der an assurance satisfying the requirements of this interview procedures is exempt, with exception, part, or the individual makes other arrangements with when the respondents are elected or appointed the Department. public officials or candidates for public office. (g) Compliance with these regulations will in no way (4) Research involving the observation (includ- render inapplicable pertinent Federal, state, or local ing observation by participants) of public behavior, laws or regulations. except where all of the following conditions exist: (h) Each subpart of these regulations contains a sep- (i) observations are recorded in such a manner that arate section describing to what the subpart applies, the human subjects can be identified, directly or Research which is covered by more than one subpart through identifiers linked to the subjects; (ii) The shall comply with all applicable subparts. observations recorded about the individual, if they (i) If, following review of proposed research activi- became known outside the research, could reason- ties that are exempt from these regulations under para- ably place the subject at risk of criminal or civil graph (b)(6), the Secretary determines that a research liability or be damaging to the subject’s financial or demonstration project presents a danger to the standing or employability; and (iii) The research physical, mental, or emotional well-being of a partici- deals with sensitive aspects of the subject’s own pant or subject of the research or demonstration behavior such as illegal conduct, drug use, sexual project, then Federal funds may not be expended for behavior, or use of alcohol. such a project without the written, informed consent (5) Research involving the collection or study of of each participant or subject. existing data, documents, records, pathological [46 FR 8386, Jan. 26, 1981; 46 FR 19195, Mar. 27, 1981, specimens, or diagnostic specimens, if these sources as amended at 48 FR 9269, Mar. 4, 1983] are publicly available or if the information is recorded by the investigator in such a manner that 46.102 Definitions subjects cannot be identified, directly or through (a) “Secretary” means the Secretary of Health and identifiers linked to the subjects. Human Services and any other officer or employee of (6) Unless specifically required by statute (and the Department of Health and Human Services to except to the extent specified in paragraph (i)), re- whom authority has been delegated. search and demonstration projects which are con- (b) “Department” or "HHS” means the Department ducted by or subject to the approval of the Depart- of Health and Human Services, ment of Health and Human Services, and which (c) “Institution” means any public or private entity are designed to study, evaluate, or otherwise ex- or agency (including Federal, state, and other agencies). amine: (i) Programs under the Social Security Act, (d) “Legally authorized representative” means an in- or other public benefit or service programs; (ii) Pro- dividual or judicial or other body authorized under cedures for obtaining benefits or services under applicable law to consent on behalf of a prospective those programs; (iii) Possible changes in or alter- subject to the subject participation in the procedures) natives to those programs or procedures; or (iv) involved in the research, Possible changes in methods or levels of payment (e) “Research” means a systematic investigation de- for benefits or services under those programs. signed to develop or contribute to generalizable knowl- (c) The Secretary has final authority to determine edge. Activities which meet this definition constitute whether a particular activity is covered by these reg- “research” for purposes of these regulations, whether ulations. or not they are supported or funded under a program (d) The Secretary may require that specific research which is considered research for other purposes. For activities conducted or funded by the Department, but example, some “demonstration” and “service” pro- not otherwise covered by these regulations, comply grams may include research activities. with some or all of these regulations. (f) “Human subject” means a living individual about (e) The Secretary may also waive applicability of whom an investigator (whether professional or stu- these regulations to specific research activities or dent) conducting research obtains (1) data through in- classes of research activities, otherwise covered by tervention or interaction with the individual, or (2) these regulations. Notices of these actions will be pub- identifiable private information. “Intervention” in- lished in the Federal Register as they occur. cludes both physical procedures by which data are App. A—Code of Federal Regulations, Part 46, Subpart A Ž 149

gathered (for example, venipuncture) and manipula- quirement does not preempt provisions of these tions of the subject or the subject’s environment that regulations applicable to Department-funded re- are performed for research purposes. “Interaction” in- search and is not applicable to any research in an cludes communication or interpersonal contact be- exempt category listed in $46.101. tween investigator and subject. “Private information” (2) Designation of one or more IRBs established includes information about behavior that occurs in a in accordance with the requirements of this sub- context in which an individual can reasonably expect part, and for which provisions are made for meet - that no observation or recording is taking place, and ing space and sufficient staff to support the IRBs information which has been provided for specific pur- review and recordkeeping duties. poses by an individual and which the individual can (3) A list of the IRB members identified by name; reasonably expect will not be made public (for exam- earned degrees; representative capacity; indica- ple, a medical record). Private information must be tions of experience such as board certifications, individually identifiable (i.e., the identity of the sub- licenses, etc., sufficient to describe each member’s ject is or may readily be ascertained by the investiga- chief anticipated contributions to IRB deliberations; tor or associated with the information) in order for and any employment or other relationship between obtaining the information to constitute research in- each member and the institution; for example: full- volving human subjects. time employee, part-time employee, member of (g) ‘(Minimal risk” means that the risks of harm an- governing panel or board, stockholder, paid or un- ticipated in the proposed research are not greater, con- paid consultant. Changes in IRB membership shall sidering probability and magnitude, than those or- be reported to the Secretary. dinarily encountered in daily life or during the (4) Written procedures which the IRB will fol- performance of routine physical or psychological ex- low (i) for conducting its initial and continuing re- aminations or test. view of research and for reporting its findings and (h) “Certification” means the official notification by actions to the investigator and the institution; (ii) the institution to the Department in accordance with for determining which projects require review the requirements of this part that a research project more often than annually and which projects need or activity involving human subjects has been reviewed verification from sources other than the investi- and approved by the Institutional Review Board (IRB) gators that no material changes have occurred in accordance with the approved assurance on file at since previous IRB review; (iii) for insuring prompt HHS. (Certification is required when the research is reporting to the IRB of proposed changes in a re- funded by the Department and not otherwise exempt search activity, and for insuring that changes in in accordance with $46.10 l(b). approved research, during the period for which [46 FR 8386, Jan. 26, 1981; 46 FR 19195, Mar. 27, 1981] IRB approval has already been given, may not be initiated without IRB review and approval except 46.103 Assurances where necessary to eliminate apparent immediate (a) Each institution engaged in research covered by hazards to the subject; and (iv) for insuring prompt these regulations shall provide written assurance satis- reporting to the IRB and to the Secretary of unan- factory to the Secretary that it will comply with the ticipated problems involving risks to subjects or requirements set forth in these regulations. others. (b) The Department will conduct or fund research (c) The assurance shall be executed by an individual covered by these regulations only if the institution has authorized to act for the institution and to assume on an assurance approved as provided in this section, and behalf of the institution the obligations imposed by only if the institution has certified to the Secretary that these regulations, and shall be filed in such form and the research has been reviewed and approved by an manner as the Secretary may prescribe. IRB provided for in the assurance, and will be subject (d) The Secretary will evaluate all assurances sub- to continuing review by the IRB. This assurance shall mitted in accordance with these regulations through at a minimum include: such officers and employees of the Department and (1) A statement of principles governing the insti- such experts or consultants engaged for this purpose tution in the discharge of its responsibilities for as the Secretary determines to be appropriate. The protecting the rights and welfare of human sub- Secretary’s evaluation will take into consideration the jects of research conducted at or sponsored by the adequacy of the proposed IRB in light of the antici- institution, regardless of source of funding. This pated scope of the institution’s research activities and may include an appropriate existing code, decla- the types of subject populations likely to be involved, ration, or statement of ethical principles, or a state- the appropriateness of the proposed initial and con- ment formulated by the institution itself. This re- tinuing review procedures in light of the probable 150 ● Ownership of Human Tissues and Cells risks, and the size and complexity of the institution. (f) An IRB may, in its discretion, invite individuals (e) On the basis of this evaluation, the Secretary may with competence in special areas to assist in the re- approve or disapprove the assurance, or enter intone- view of complex issues which require expertise beyond gotiations to develop an approvable one. The Secre- or in addition to that available on the IRB. These indi- tary may limit the period during which any particular viduals may not vote with the IRB. approved assurance shall remain effective or otherwise condition or restrict approval. 46.108 IRB functions and operations (f) Within 60 days after the date of submission to In order to fulfill the requirements of these regula- HHS of an application or proposal, an institution with tions each IRB shall: an approved assurance covering the proposed research (a) Follow written procedures as provided in shall certify that the application or proposal has been 46.103(b)(4). approved by the IRB within 30 days after receipt of (b) Except when an expedited review procedure is a request for such a certification from the Department. used (see $46.110), review proposed research at con- If the certification is not submitted within these time vened meetings at which a majority of the members limits, the application or proposal may be returned of the IRB are present, including at least one member to the institution, whose primary concerns are in nonscientific areas. In order for the research to be approved, it shall receive 46.104-46.106 [Reserved] the approval of a majority of those members present (b) Each IRB shall have at least five members, with at the meeting. varying backgrounds to promote complete and ade- (c) Be responsible for reporting to the appropriate quate review of research activities commonly con- institutional officials and the Secretary any serious or ducted by the institution. The IRB shall be sufficiently continuing noncompliance by investigators with the qualified through the experience and expertise of its requirements and determinations of the IRB. members, and the diversity of the members’ back- [46 FR 8386, Jan. 26, 1981; 46 FR 19195, Mar. 27, 1981] grounds including consideration of the racial and cultural backgrounds of members and sensitivity to such $46.109 IRB review of research issues as community attitudes, to promote respect for (a) An IRB shall review and have authority to approve, its advice and counsel in safeguarding the rights and require modifications in (to secure approval), or dis- welfare of human subjects. In addition to possessing approve all research activities covered by these regu- the professional competence necessary to review spe- lations, cific research activities, the IRB shall be able to ascer- (b) An IRB shall require that information given to tain the acceptability of proposed research in terms subjects as part of informed consent is in accordance of institutional commitments and regulations, appli- with $46.116. The IRB may require that information, cable law, and standards of professional conduct and in addition to that specifically mentioned in 46.116, practice. The IRB shall therefore include persons be given to the subjects when in the IRB’s judgment knowledgeable in these areas. If an IRB regularly re- the information would meaningfully add to the pro- views research that involves a vulnerable category of tection of the rights and welfare of subjects, subjects, including but not limited to subjects covered (c) An IRB shall require documentation of informed by other subparts of this part, the IRB shall include consent or may have documentation in accordance one or more individuals who are primarily concerned with 46.117. with the welfare of these subjects. (d) An IRB shall notify investigators and the institu- (b) NO IRB may consist entirely of men or entirely tion in writing of its decision to approve or disapprove of women, or entirely of members of one profession. the proposed research activity, or of modifications re- (c) Each IRB shall include at least one member whose quired to secure IRB approval of the research activity. primary concerns are in nonscientific areas; for ex- If the IRB decides to disapprove a research activity, ample: lawyers, ethicists, members of the clergy. it shall include in its written notification a statement (d) Each IRB shall include at least one member who of the reasons for its decision and give the investiga- is not otherwise affiliated with the institution and who tor an opportunity to respond in person or in writing. is not part of the immediate family of a person who (e) An IRB shall conduct continuing review of re- is affiliated with the institution. search covered by these regulations at intervals appro- (e) No IRB may have a member participating in the priate to the degree of risk, but not less than once per IRBs initial or continuing review of any project in which year, and shall have authority to observe or have a the member has a conflicting interest, except to pro- third party observe the consent process and the re- vide information requested by the IRB. search. App. A—Code of Federal Regulations, Part 46, Subpart A ● 151

$46.110 Expedited review procedures for certain of the research on public policy) as among those kinds of research involving no more than minimal research risks that fall within the purview of its risk, and for minor changes in approved research responsibility. (a) The Secretary has established, and published in (3) Selection of subjects is equitable. In making the Federal Register, a list of categories of research this assessment the IRB should take into account that may be reviewed by the IRB through an expedited the purposes of the research and the setting in review procedure. The list will be amended, as appro- which the research will be conducted. priate, through periodic republication in the Federal (4) Informed consent will be sought from each Register. prospective subject or the subject’s legally author- (b) An IRB may review some or all of the research ized representative, in accordance with, and to the appearing on the list through an expedited review pro- extent required by 46.116. cedure, if the research involves no more than mini- (5) Informed consent will be appropriately doc- mal risk. The IRB may also use the expedited review umented, in accordance with, and the extent re- procedure to review minor changes in previously ap- quired by 46.117. proved research during the period for which approval (6) Where appropriate, the research plan makes is authorized. Under an expedited review procedure, adequate provision for monitoring the data col- the review may be carried out by the IRB chairperson lected to insure the safety of subjects. or by one or more experienced reviewers designated (7) Where appropriate, there are adequate pro- by the chairperson from among members of the IRB. visions to protect the privacy of subjects and to In reviewing the research, the reviewers may exer- maintain the confidentiality of data. cise all of the authorities of the IRB except that the (b) Where some or all of the subjects are likely to reviewers may not disapprove the research. A research be vulnerable to coercion or undue influence, such activity may be disapproved only after review in as persons with acute or severe physical or mental ill- accordance with the non--expedited procedure set forth ness, or persons who are economically or education- in $46.108(b). ally disadvantaged, appropriate additional safeguards (c) Each IRB which uses an expedited review proce- have been included in the study to protect the rights dure shall adopt a method for keeping all members and welfare of these subjects. advised of research proposals which have been approved under the procedure. 46.112 Review by institution Research covered by these regulations that has been (d) The Secretary may restrict, suspend, or terminate approved by an IRB may be subject to further appro- an institution’s or IRBs use of the expedited review propriate review and approval or disapproval by officials cedure when necessary to protect the rights or wel- of the institution. However, those officials may not ap- fare of subjects. prove the research if it has not been approved by an 546.111 Criteria for IRB approval of research IRB. (a) In order to approve research covered by these 546.113 Suspension or termination of IRB approval regulations the IRB shall determine that all of the fol- of research lowing requirements are satisfied: An IRB shall have authority to suspend or terminate (1) Risks to subjects are minimized: (i) By using approval of research that is not being conducted in procedures which are consistent with sound re- accordance with the IRBs requirements or that has search design and which do not unnecessarily ex- been associated with unexpected serious harm to sub- pose subjects to risk, and (ii) whenever appropri- jects. Any suspension or termination of approval shall ate, by using procedures already being performed include a statement of the reasons for the IRBs action on the subjects for diagnostic or treatment purposes. and shall be reported promptly to the investigator, (2) Risks to subjects are reasonable in relation appropriate institutional officials, and the Secretary. to anticipated benefits, if any, to subjects, and the [46 FR 8386, Jan. 26, 1981; 46 FR 19195, Mar. 27, 1981] importance of the knowledge that may reasonably be expected to result. In evaluating risks and ben- 46.114 Cooperative research efits, the IRB should consider only those risks and Cooperative research projects are those projects, benefits that may result from the research (as dis- normally supported through grants, contracts, or sim- tinguished from risks and benefits of therapies sub- ilar arrangements, which involve institutions in addi- jects would receive even if not participating in the tion to the grantee or prime contractor (such as a con- research). The IRB should not consider possible tractor with the grantee, or a subcontractor with the long-range effects of applying knowledge gained prime contractor). In such instances, the grantee or in the research (for example, the possible effects prime contractor remains responsible to the Depart- —

152 Ž Ownership of Human Tissues and Cc//s

ment for safeguarding the rights and welfare of hu- opportunity to consider whether or not to participate man subjects. Also, when cooperating institutions con- and that minimize the possibility of coercion or un- duct some or all of the research involving some or all due influence. The information that is given to the sub- of these subjects, each cooperating institution shall ject or the representative shall be in language under- comply with these regulations as though it received standable to the subject or the representative. No funds for its participation in the project directly from informed consent, whether oral or written, may in- the Department, except that in complying with these clude any exculpatory language through which the regulations institutions may use joint review, reliance subject or the representative is made to waive or ap- upon the review of another qualified IRB, or similar pear to waive any of the subject’s legal rights, or re- arrangements aimed at avoidance of duplication of leases or appears to release the investigator, the spon- effort. sor, the institution or its agents from liability for negligence. 46,115 IRB records (a) Basic elements of informed consent. Except as pro- (a) An institution, or where appropriate an IRB, shall vided in paragraph (c) or (d) of this section, in seeking prepare and maintain adequate documentation of IRB informed consent the following information shall be activities, including the following: provided to each subject: (1) Copies of all research proposals reviewed, sci- (1) A statement that the study involves research, entific evaluations, if any, that accompany the an explanation of the purposes of the research and proposals, approved sample consent documents, the expected duration of the subject’s participa- progress reports submitted by investigators, and tion, a description of the procedures to be followed, reports of injuries to subjects. and identification of any procedures which are ex- (2) Minutes of IRB meetings which shall be in perimental; sufficient detail to show attendance at the meet- (2) A description of any reasonably foreseeable ings; actions taken by the IRB; the vote on these risks or discomforts to the subject; actions including the number of members voting (3) A description of any benefits to the subject for, against, and abstaining; the basis of requiring or to others which may reasonably be expected changes in or disapproving research; and a writ- from the research; ten summary of the discussion of controverted is- (4) A disclosure of appropriate alternative pro- sues and their resolution. cedures or courses of treatment, if any, that might (3) Records of continuing review activities, be advantageous to the subject; (4) Copies of all correspondence between the IRB (5) A statement describing the extent, if any, to and the investigators. which confidentiality of records identifying the (5) A list of IRB members as required by subject will be maintained; $46.103(b)(3). (6) For research involving more than minimal (6) Written procedures for the IRB as required risk, an explanation as to whether any compensa- by $46.103(b)(4). tion and an explanation as to whether any medi- (7) Statements of significant new findings pro- cal treatments are available if injury occurs and, vided to subjects, as required by 46.116(b)(5). if so, what they consist of, or where further infor- (b) The records required by this regulation shall be mation may be obtained; retained for at least 3 years after completion of the (7) An explanation of whom to contact for an- research, and the records shall be accessible for in- swers to pertinent questions about the research spection and copying by authorized representatives and research subjects’ rights, and whom to con- of the Department at reasonable times and in a rea- tact in the event of a research-related injury to the sonable manner. subject; and [46 FR 8386 Jan. 26, 1981; 46 FR 19195, Mar. 27, 1981] (8) A statement that participation is voluntary, refusal to participate will involve no penalty or loss 546.115 General requirements for informed consent of benefits to which the subject is otherwise enti- Except as provided elsewhere in this or other sub- tled, and the subject may discontinue participation parts, no investigator may involve a human being as at any time without penalty or loss of benefits to a subject in research covered by these regulations un- which the subject is otherwise entitled. less the investigator has obtained the legally effective (b) Additional elements of informed consent. When informed consent of the subject or the subject legally appropriate, one or more of the following elements authorized representative. An investigator shall seek of information shall also be provided to each subject: such consent only under circumstances that provide (1) A statement that the particular treatment or the prospective subject or the representative sufficient procedure may involve risks to the subject (or to App. A—Code of Federal Regulations, Part 46, Subpart A . 153

the embryo or fetus, if the subject is or may be- ical care, to the extent the physician is permitted to come pregnant) which are currently unforeseeable; do so under applicable Federal, state, or local law. (2) Anticipated circumstances under which the [46 FR 8386, Jan. 26, 1981; 46 FR 29883, June 3, 1981, subject’s participation may be terminated by the as amended at 48 FR 9270, Mar. 4, 1983] investigator without regard to the subject’s consent; (3) Any additional costs to the subject that may result from participation in the research; 546.117 Documentation of informed consent (4) The consequences of a subject’s decision to (a) Except as provided in paragraph (c) of this sec- withdraw from the research and procedures for tion, informed consent shall be documented by the use orderly termination of participation by the subject; of a written consent form approved by the IRB and (5) A statement that significant new findings designed by the subject or the subject’s legally author- veloped during the course of the research which ized representative. A copy shall be given to the per- may relate to the subject’s willingness to continue son signing the form. participation will be provided to the subject; and (b) Except as provided in paragraph (c) of this sec- (6) The approximate number of subjects involved tion, the consent form may be either of the following: in the study. (1) A written consent document that embodies (c) An IRB may approve a consent procedure which the elements of informed consent required by does not include, or which alters, some or all of the 46.116. This form maybe read to the subject or elements of informed consent set forth above, or waive the subject legally authorized representative, but the requirement to obtain informed consent provided in any event, the investigator shall give either the the IRB finds and documents that: subject or the representative adequate opportu- (1) The research or demonstration project is to nity to read it before it is signed; or be conducted by or subject to the approval of state (2) A “short form” written consent document stat- or local government officials and is designed to ing that the elements of informed consent required study, evaluate, or otherwise examine: (i) Programs by 46.116 have been presented orally to the sub- under the Social Security Act, or other public ben- ject or the subject legally authorized representa- efit or service programs; (ii) procedures for obtain- tive. When this method is used, there shall be a ing benefits or services under those programs; (iii) witness to the oral presentation. Also, the IRB shall possible changes in or alternatives to those pro- approve a written summary of what is to be said grams or procedures; or (iv) possible changes in to the subject or the representative. Only the short methods or levels of payment for benefits or serv- form itself is to be signed by the subject or the rep- ices under those programs; and resentative. However, the witness shall sign both (2) The research could not practicably be car- the short form and a copy of the summary, and ried out without the waiver or alteration. the person actually obtaining consent shall sign a (d) An IRB may approve a consent procedure which copy of the summary. A copy of the summary shall does not include, or which alters, some or all of the be given to the subject or the representative, in elements of informed consent set forth above, or waive addition to a copy of the “short form. ” the requirements to obtain informed consent provided (c) An IRB may waive the requirement for the inves- the IRB finds documents that: tigator to obtain a signed consent form for some or (1) The research involves no more than minimal all subjects if it finds either: risk to the subjects; (1) That the only record linking the subject and (2) The waiver or alteration will not adversely the research would be the consent document and affect the rights and welfare of the subjects; the principal risk would be potential harm result- (3) The research could not practicably be caring from a breach of confidentiality. Each subject ried out without the waiver or alteration; and will be asked whether the subject wants documen- (4) Whenever appropriate, the subjects will be tation linking the subject with the research, and provided with additional pertinent information af- the subject’s wishes will govern; or ter participation. (2) That the research presents no more than min- (e) The informed consent requirements in these reg- imal risk of harm to subjects and involves no pro- ulations are not intended to preempt any applicable cedures for which written consent is normally re- Federal, state, or local laws which require additional quired outside of the research context. information to be disclosed in order for informed con- In cases where the documentation requirement is sent to be legally effective. waived, the IRB may require the investigator to pro- (f) Nothing in these regulations is intended to limit vide subjects with a written statement regarding the the authority of a physician to provide emergency med- research. 154 ● Ownership of Human Tissues and Cells

546. I 18 Applications and proposals lacking definite device (as defined in 21 CFR 812.3(m)), the institution plans for involvement of human subjects shall identify the drug or device in the certification. Certain types of applications for grants, cooperative The institution shall also state whether the 30-day in- agreements, or contracts are submitted to the Depart- terval required for investigational new drugs by 21 ment with the knowledge that subjects may be involved CFR 312. l(a) and for significant risk devices by 21 CFR within the period of funding, but definite plans would 812.30 has elapsed, or whether the Food and Drug not normally be set forth in the application or pro- Administration has requested that the sponsor con- posal. These include activities such as institutional type tinue to withhold or restrict the use of the drug or grants (including bloc grants) where selection of spe- device in human subjects. If the 30 day interval has cific projects is the institution’s responsibility; research not expired, and a waiver has not been received, the training grants where the activities involving subjects institution shall send a statement to the Department remain to be selected; and projects in which human upon expiration of the interval. The Department will subjects’ involvement will depend upon completion of not consider a certification acceptable until the insti- instruments, prior animal studies, or purification of tution has submitted a statement that the 30 day in- compounds. These applications need not be reviewed terval has elapsed, and the Food and Drug Adminis- by an IRB before an award may be made. However, tration has not requested it to limit the use of the drug except for research described in 46.101(b), no human or device, or that the Food and Drug Administration subjects may be involved in any project supported by has waived the 30-day interval. these awards until the project has been reviewed and approved by the IRB, as provided in these regulations, 46.122 Use of Federal funds and certification submitted to the Department. Federal funds administered by the Department may not be expended for research involving human sub- S46.119 Research undertaken without the intention jects unless the requirements of these regulations, in- of involving human subjects cluding all subparts of these regulations, have been In the event research (conducted or funded by the satisfied. Department) is undertaken without the intention of involving human subjects, but it is later proposed to 46.123 Early termination of research funding: use human subjects in the research, the research shall evaluation of subsequent applications and first be reviewed and approved by an IRB, as provided proposals in these regulations, a certification submitted to the (a) The Secretary may require that Department fund- Department, and final approval given to the proposed ing for any project be terminated or suspended in the change by the Department. manner prescribed in applicable program requirements, when the Secretary finds an institution has $46.120 Evaluation and disposition of applications materially failed to comply with the terms of these reg- and proposals ulations. (a) The Secretary will evaluate all applications and (b) In making decisions about funding applications proposals involving human subjects submitted to the or proposals covered by these regulations, the Secre- Department through such officers and employees of tary may take into account, in addition to all other eligi- the Department and such experts and consultants as bility requirements and program criteria, factors such the Secretary determines to be appropriate. This evalu- as whether the applicant has been subject to a termi- ation will take into consideration the risks to the sub- nation or suspension under paragraph (a) of this sec- jects, the adequacy of protection against these risks, tion and whether the applicant or the person who the potential benefits of the proposed research to the would direct the scientific and technical aspects of an subjects and others, and the importance of the knowl- activity has in the judgment of the Secretary materi- edge to be gained. ally failed to discharge responsibility for the protec- (b) On the basis of this evaluation, the Secretary may tion of the rights and welfare of human subjects approve or disapprove the application or proposal, or (whether or not Department funds were involved). enter into negotiations to develop an approvable one. $46.124 Conditions $46.121 Investigational new drug or device With respect to any research project or any class 30-day delay requirement of research projects the Secretary may impose addi- When an institution is required to prepare or to sub- tional conditions prior to or at the time of funding mit a certification with an application or proposal un- when in the Secretary’s judgment additional conditions der these regulations, and the application or proposal are necessary for the protection of human subjects. involves an investigational new drug (within the meaning of 21 U.S.C. 355(i) or 357(d)) or a significant risk Appendix B Acknowledgments

OTA would like to thank the members of the advisory panel who commented on drafts of this report, the contractors who provided material for this study, and the many individuals and organizations that supplied background information. In addition, OTA acknowledges the following individualstheir reviewfor of drafts of this report:

Jan Almquist Zsolt Harsanyi Gray, Cary, Ames and Frye Porton International Lori Andrews Clark B. Inderlied American Bar Foundation University of Southern California Arthur L. CapIan Philip Jacobs The Hastings Center University of Massachusetts Carl Cranor Eric T. Juengst University of California, Riverside The University of California at San Francisco Timothy D. Leathers H. Tristram Engelhardt, Jr. Northern Regional Research Center, USDA Baylor College of Medicine Frank D. Lee Michael A. Epstein DNAX Research Institute of Molecular and Cellular Weil, Gotshal and Manges Biology, Inc. Brian Ferguson Rachel Levinson The Australian National University National Institutes of Health Frank W. Fitch N. Mu] The University of Chicago Health Council of the Netherlands Joseph Fletcher Donna M. Peehl University of Virginia Stanford University Leonard H. Glantz Paul Ramsey Boston University School of Public Health Princeton University John H. Goddeeris Howard M. Spiro Michigan State University Yale University Richard D. Godown Jan Stepan Industrial Biotechnology Association Swiss Institute of Comparative Law Leonard H. Glantz Janet Trubatch Boston University School of Public Health The University of Chicago David W. Golde Oskar R. Zaborsky University of California, Los Angeles OMEC International, Inc. Susanne M. Gollin Jonathan T. Zackey University of Arkansas for the Medical Sciences Gage, Mazursky, Schwartz, Angelo and Kussman

155 Appendix C Glossary

Abandonment: The surrender, relinquishment, dis- Cell: The smallest component of life capable of carry- claimer, or cession of property or rights. ing on all essential life processes. A single unit is Accession Coming into possession of a right or of- a complex collection of molecules with many differ- fice, including the right to all that one’s own prop- ent activities all integrated to forma functional self- erty produces, whether that property be movable assembling, self-regulating, self-reproducing biologi- or immovable. cal unit. See eukaryote and prokaryote. Actionable: Furnishing legal ground for a proceed- Cell culture The propagation of cells removed from ing in a court of justice. organisms in a laboratory environment that has Amino acid: One of 20 molecules that are linked to- strict sterility, temperature, and nutrient require- gether in various combinations to form proteins. ments; also used to refer to any particular individ- Each different protein is made up of a specific se- ual sample. See cell and cell line. quence of these molecules with the unique sequence Cell line: A sample of cells that has undergone the coded for by DNA. process of adaptation to artificial laboratory culti- Aneuploid: An abnormal number-either an excess vation and is capable of sustaining continuous, long- or deficiency-of chromosomes in a cell. See diploid. term growth in culture. See cell and cell culture. Antibody: A protein molecule, also called immuno- Chattel: An article of personal property, more com- globulin, produced by the immune system in re- prehensive than “goods” because it includes animate sponse to exposure to a foreign substance. An anti- as well as inanimate property. body is characterized by a structure complementary Chromosome: The physical, threadlike structure to the foreign substance, the antigen, that provoked within the nucleus of a cell composed of a DNA- its formation and is thus capable of binding specifi- protein complex and containing the hereditary ma- cally to the foreign substance to neutralize it. See terial, i.e., genes. In bacteria, it is the DNA mole- antigen and monoclinal antibodies. cule—a single, closed circle (no associated protein)— Antigen: A molecule introduced into an organism and comprising the cell’s total genetic information. recognized as a foreign substance, resulting in the Cloning: The process of asexually producing many elicitation of an immune response (antibody pro- copies of a biological material, all identical to the duction, lymphokine production, or both) directed original ancestor. In tissue and cell culture technol- specifically against that molecule. See antibody and ogy, the process by which a culture is grown and monoclinal antibodies. amplified starting from a single cell; in recombinant Autoimmune disease: A disease in which the body’s DNA technology, the process of using a variety of defenses (its immune system) fail to distinguish the recombinant DNA procedures to produce multiple body’s own tissue from foreign matter with the copies of a single gene or segment of DNA. result that the body’s own tissue is attacked and Common law: Law created by judicial decisions, as damaged. distinguished from law created by the enactments Autonomy: Derived from the Greek “autos” (self) and of legislatures. In the United States, common law “nomos” (rule, governance, or law), first used in encompasses that portion of the common law of reference to self-rule or self-governance in Greek England (including such acts of parliament as were city-states. In ethics, it is the principle that independ- applicable) that had been adopted and was in force ent actions and choices of an individual should not here at the time of the American Revolution. be constrained by others. Conversion: Any unauthorized interference in the B lymphocyte: A specialized white blood cell in- right of ownership over goods or personal chattels volved in the immune response of vertebrates that belonging to another resulting in the alteration of originates in the bone marrow and produces anti- their condition or the exclusion of the owner’s body molecules after challenge by an antigen. In rights; any unauthorized act that deprives an owner hybridoma technology, these cells contribute anti- of his property permanently or for an indefinite body-producing capability to a hybridoma. See T period of time. lymphocyte. Deoxyribonucleic acid: See DNA. Beneficence Mercy, kindness, or charity. In ethics, it Diploid: The state of having two complete sets of is the principle that one has a duty to confer benefits match-paired chromosomes-one set of paternal ori- or to help others further their legitimate interests. gin, the other of maternal origin–in all normal cells

156 App. C—Glossary . 157

in higher organisms, except sex cells. In normal hu- a particular type of immortal tumor cell line, a my- man cells, this number is 46. See aneuploid. eloma, with an antibody-producing B lymphocyte. Distributive justice: Theories and principles for the Cultures of such cells are capable of continuous fair allocation of resources in general and scarce growth and specific (i.e., monoclinal) antibody pro- resources in particular. See justice. duction. DNA (deoxyribonucleic acid): The molecule that Imago dei: From Latin, meaning in the image of God. is the repository of genetic information in all organ- Immunization: The injection of an antigen into an isms (with the exception of a small number of viruses organism resulting in an immune response that may in which the hereditary material is ribonucleic include the production of antibodies. acid—RNA). The information coded by DNA deter- Immunoglobulin: See antibody. mines the structure and function of an organism. In vitro: Literally, ‘(in glass. ” Refers to a process, test, Enzyme: A protein that acts as a catalyst, speeding or procedure in which something is measured, ob- the rate at which a biochemical reaction proceeds, served, or produced outside a living organism af- but not altering its direction or nature. ter extraction from the organism. See in vivo. Equity: Fairness and equality. In economics, the mone- In vivo: Literally, “in the living.” Refers to a reaction tary value of a property, or of an interest in a prop- that is being observed or investigated using an in- erty, in excess of claims or liens against it. In law, tact organism. See in vitro. a body of law separate from common law that is Justice: Generally refers to fair and equal treatment. designed to achieve a lawful result when legal pro- In ethics, it is the principle that one should act in cedure is inadequate. such a manner that no one person bears a dispro- Eukaryote: An organism with well-developed or- portionate share of benefits or burdens. See dis- ganelles and whose genetic material (DNA) is en- tributive justice. closed within membrane-bound, structurally dis- Lymphocytes: See B lymphocyte and T lymphocyte. crete nuclei. Eukaryotes include all organisms Lymphokine: A group of proteins that modulate the except viruses, bacteria, and blue-green algae. See immune response and that are necessary for proper prokaryote. function of the entire immune system. Interferon Exculpatory: Clearing or tending to clear from al- and interleukin-2 are lymphokines. leged fault or guilt; excusing. Microphage: A large specialized cell that originates Fiduciary: Of or founded in confidence or trust; also in the bone marrow and is involved in many stages a person having a duty to act in scrupulous good of the immune response, including consumption of faith primarily for another’s benefit. foreign particles such as viruses and lymphokine For-profit: Referring to an organization primarily de- production. signed to pay dividends on invested capital; an in- Market: The available supply of or potential demand stitution organized to yield an excess of returns over for specified goods or services. expenditures. See nonprofit. Monoclinal antibodies: Identical antibodies that Gene: The fundamental unit of heredity; an ordered recognize a single, specific antigen and are produced sequence of nucleotide base pairs which produce by a clone of specialized cells. Commercial quanti- a specific product or have an assigned function. ties of these molecules are now produced by hybri- Gene probe: A molecule of known structure or func- domas. See antibody, antigen, and hybridoma. tion, labeled with a tracer substance such as a dye Myeloma: A malignant tumor of an antibody-produc- or radioactive label, that is used to locate and iden- ing cell. In hybridoma technology, some of these tify a specific region or base sequence of DNA or tumor cells have been adapted to cell culture, and RNA. In this report, a gene probe as an end prod- these cells contribute immortality to a hybridoma uct refers to a cloned DNA sequence. cell line. Host: In recombinant DNA technology, the organism Nonmaleficence: Generally associated with the used for growth and reproduction of virus, plas- maxim “primum non nocere’’—from Latin, mean- mid, or other foreign DNA. ing above all, do no harm. In ethics, it is the princi- Hybridization: In cell culture, the formation of new ple that one has a duty not to inflict evil, harm, or cells as a result of the fusion of whole cells or cell risk of harm. parts of different parental origin. In recombinant Nonprofit: Referring to an organization primarily de- DNA, a procedure in which single-stranded nucleic signed not to pay dividends on invested capital; an acid segments are allowed to bind to identical or organization not conducted or maintained for the nearly identical sequences, forming hybrid double- purpose of yielding an excess of returns over ex- stranded helices. penditures in a transaction or series of transactions. Hybridoma: A new cell resulting from the fusion of See for-profit. 158 . Ownership of Human Tissues and Cells

Nucleus: The membrane-enclosed structure in eu- somal RNA—responsible for translating the genetic karyotes that contains the chromosomes. information encoded by an organism (i.e., DNA) into Organelle: A structure outside the nucleus of a cell a protein product; the hereditary material of some that is specialized in its ultrastructure and biochem- viruses. ical composition to serve a particular function (e.g., somatic: Pertaining to the cells of an organism ex- mitochondria, endoplasmic reticulum, chloroplast). cept for those of the germ line (i.e., sex cells—sperm Pathogenic: Able to cause disease; often used to ex- and eggs). press lethality. Specification: In law, relating to patents, machin- prokaryote: An organism lacking organelles and in ery, and building contracts, a particular or detailed which the genetic material (DNA or RNA) is not en- statement of the various elements involved. closed within a membrane-bound, structurally dis- Statute: A law enacted and established by the legisla- crete nucleus. Bacteria and blue-green algae are tive branch of the government. prokaryotes. See eukaryote. T lymphocyte Specialized white blood cell involved Protein: A molecule composed of a few to hundreds in the immune response of vertebrates that origi- of amino acids linked in a specific sequence deter- nates in the bone marrow, matures in the thymus mined by the sequence of a gene in the DNA. These gland, and produces some Iymphokines. Subclasses molecules are required for the structure and func- of T lymphocytes are important to antibody pro- tion of all living organisms. duction and the enhancement or suppression of an Recombinant DNA: A broad range of techniques immune response. See B lymphocyte and mic- involving the manipulation of the genetic material rophage. of organisms; often used synonymously with genetic Tissue culture: See cell culture. engineering; also used to describe a DNA molecule Tort law: Derived from legal principles governing constructed by genetic engineering techniques and wrongful acts, except those involving a breach of composed of DNA from different individuals or contract, committed against a person or property species. for which civil action will be valid. Res nullius: The property of no one. A thing which Transaction cost: An outlay associated with carry- has no owner, either because a former owner has ing out a business deal. finally abandoned it, because it has never been Undue influence: Any improper constraint on a per- appropriated by any person, or because it is not son particularly susceptible to persuasion which susceptible to private ownership. deprives the person being influenced from acting Restriction endonuclease: An enzyme isolated with free will. from bacteria that selectively recognizes and clips Uniform Commercial Code (UCC): A model act, double-stranded DNA at specific sequences. More begun in 1942 by the American Law Institute and than 400 different restriction enzymes are known the National Conference of Commissioners, to re- to recognize over 100 different DNA sequences. place most existing statutes relating to commercial Restriction enzyme: See restriction endonuclease. transactions. Adopted in part or whole by every Ribonucleic acid: See RNA. State. RNA (ribonucleic acid): A molecule existing in three Vector: A DNA molecule used to introduce foreign forms–messenger RNA, transfer RNA, and ribo- DNA into host cells. ——...... —— — —

Index Index

Key: t = table; f = figure; ph = photo industry, 8, 52, 56-63, 119 issues, iii Abandonment Biotherapeutics, Inc. law of conversion and trespass to chattel, 82 fee-for-service research, 62 Access to human biological materials Blood and blood products interested parties, 49-64 donation, 52, 117-118, 141, 212 Accession law lymphokine content, 39-40 source of rights relating to human biological materials, marketing, 12, 24, 76-78, 87, 117-118 83-84, 87 ownership, 26 Adrenalin crystals Bodies and their parts patentable, 71 moral status, 130-134, 136, 137-144 Aging, human Bone marrow, human study with primary cell cultures, 33 collection and payment by the National Institutes of Agricultural doctrine Health, 52 applicability to cases involving human biological mate- Brenner v. Manson rials, 83-84, 85 Supreme Court decision on patentability, 71 Alabama commercial code Cadavers implied warranties in sales of human blood and tis- dissection, 140f sues, 77 emotional distress claims, 72-75 tax on blood sales, 78 "Judeo-Christian tradition,” 138-139, 141, 142 American Law Institute law, 72-75, 87 on wrongful acts toward cadavers, 73 sources of human tissue, 7, 51 Andrews, Lori B. wrongful acts toward, 72-73 on property rights to body parts, 127 California law Angiogenin accession, 85-86 commercialization, 60 disposal of human biological materials, 80 research and development, 60, 61f Cancer cells Antibodies fusion with T lymphocytes to produce hybridomas, 40 composition and structure, 37 National Cancer Institute network, 53 monoclonal, 5, 37-38, 39f, 44, 62 Cancer treatment polyclonal, 37 fee-for-service research, 62 production and function, 5, 35, 37, 38 Carcinogenesis Autonomy use of cell fusion in research, 35 libertarian view of justice, 135-136 Cartesian philosophy Autopsies moral status of bodies and their parts, 137-138, 142 Law and religion, 72-75, 87, 139 Case histories Availability of human biological materials angiogenin development, 60, 61f effect of commercialization, 116, 124-125, 135 Chakrabarty-Patent and Trademark Office organism equity, 12 patentability case, 49 coerced tissue donation, 77 B lymphocytes Hagiwara case, 4, 26 hybridomas, 38 hypothetical case concerning effect of commercializa- immune response, 37 tion on doctor-patient relationship, 14 Battery law hypothetical case concerning proper transfer and use applicability to consent issues, 93-94, 110 of human biological materials, 129 Beneficence ownership of human cells, 24-26 ethics of buying and selling bodies and their parts, Stanford University cell line ownership case, 25 134-135 University of California, Los Angeles—Hoffman- Bernard, Claude LaRoche cell line ownership case, 25-26 on research on biological materials, 29 University of California, Los Angeles-Moore ownership Biopharmaceuticals case, 26 commercial potential, 50-51 Catholicism development and testing, 31, 58-59, 59t, 60, 61f, 154 moral status of bodies and their parts, 141-142 estimated U.S. marketing dates, 58t CCPA. See Court of Customs and Patent Appeals, U.S. ]icensing, 61 Cell culture Biotechnology commercialization, 3, 4, 16-17, 116 definition, 24 development and technology, 5, 8, 25f, 31-35, 36f, 40, history and development, iii, 23 44, 55-56

161 162 ● Ownership of Human Tissues and Cells

ownership, 3, 4, 17, 25 Confidentiality patentability, 49-50 agreements, 78-79 repositories, 52-53 Federal consent and disclosure regulations, 95, 100, trade secrets, 78 109-110 transfers, 12, 52 Congress use, 35, 116-117 effect of actions on sources of human tissue, 51 Cell fusion establishment of President’s Commission for the Study development and use, iii, 35, 38 of Ethical Problems in Medicine and Biomedical Cells, human and Behavioral Research, 99 applicability of cadaver law, 73 House Committee on Science and Technology, 50, 52 commercial interest, 7, 24, 49-51, 54, 56-62 National Organ Transplant Act, 75-76 emotional distress claims, 73-75 patent policy, 50, 70 genetic content and engineering, 6, 41-42 policy on use of human biological materials, 15-19 ownership, 24-27, 69-87 Connecticut supreme court repositories, 52-53 on disclosure, 99-100 storage, 33 Consent of source of human biological materials trade secrets, 79, 87 ethical considerations, 131, 134, 135-136, 142 uses, 7, 52, 54-55 legal considerations, 73, 74-75, 93-94 Cells, mammalian market system for human biological materials, 120 compared with microbial cells, 31t physicians’ obligations and patients’ rights, 14, 99 Chakrabarty-Patent and Trademark Office case policy considerations, 10-11 patentability of organisms, 49, 50, 71 requirements, 17-19, 93-111, 113, 129, 152-153 Christianity Scholendorff v. Society of New York Hospital, 91 moral status of bodies and their parts, 138-139, Contract law 141-143 relevance to human biological materials, 9, 17 Cloned genes, human Conversion law repositories, 52-53 relevance to use of human biological materials, 79-83, uses, 34, 40, 44 84-86, 87 Clonetics Corp. Copyright law marketing of normal cloned human skin cells, 24 source of rights relating to human biological materials, Commerce in human biological materials 78, 87 development of biotechnology products, 8, 50-51, 55- Corruption 56, 60, 113, 119-121 possibility in distribution of human biological materi- effects on costs, 12-13, 116-117, 135 als, 116, 117 emotional distress claims, 74 Court of Customs and Patent Appeals, U.S. equity of distribution, 116, 124-125 Chakrabarty-Patent and Trademark Office organism ethical considerations, 13-15, 127, 129-144 patentability case, 49 hypothetical case study, 14 In re Bergey decision, 49-50 informed consent, 17-19, 96 interest in research and inventions, 49-51, 56-62 legal considerations, 9, 50-51, 70, 72, 76-78, 83, 87 Deoxyribonucleic acid. See DNA market system, 12, 119-121, 123-125, 134 Department of Commerce, U.S. physician/researcher and patient/subject relationship, revised regulations, 50n 97 Department of Health and Human Services, U.S. principle of beneficence, 134-135 regulation of research, 10, 11, 17-18, 94-95, 96, 97, principles of justice, 135 106, 107, 147-154 role of Federal Government, 15-19 Descartes, Rene safety and quality, 117-118 development of view of mind-body duality, 137 Commissioners on Uniform State Laws Diamond v. Chakrabarty Uniform Anatomical Gift Act, 75 Supreme Court organism patentability decision, 49, 50, Common law 71 physician’s fiduciary duty, 82-83 Disclosure to source of human biological materials re- property rights in corpses, 72 quirements, 10-11, 102, 104-106, 110-111 relevance to use of human tissues and cells, 9, 69, Scholendorff v. Society of New York Hospital, 91 86-87 DNA. See also Recombinant DNA res nullius, 82 composition and function, 41-42 rights of sources of human biological materials, 80, 93- copyrightability, 78 94, 102, 110-111 Dobson, Matthew Compensation. See Payments experiment with human biological materials, 23 Index • 163

Dolnick, Edward Genentech on commercial potential of human cells, 113 development and ownership of KG-1 cell line, 25 General Electric Economic considerations organism patentability case, 49 biotechnology, 63 Genes use of human biological materials, 11-13, 113, 115-125 clones, 6, 40, 41-44, 45, 52 Egalitarian view of justice composition and function, 41-42 ethics of buying and selling bodies and their parts, excision with restriction endonucleases, 42-43 136 expression, 42f Emotional distress probes, 16-17, 43-44 caused by acquisition and use of human biological ma- quantity in human cells, 41-42 terials, 72-75 use of monoclinal antibodies in research, 38 Employers’ rights Genetic engineering. See Recombinant DNA “hired to invent” doctrine, 70-71 Government Engelhardt, H. Tristram, Jr. interference in commercialization of human biological principle of respect for persons, 133-134 materials, 133-134, 135-136, 143 Equity relationship with nonprofit institutions, 122-123 effects of commerce in human biological materials, 12, Growth hormone, human 13, 115-116, 124-125, 135-136 production and use, 45 Ethical considerations use of human biological materials, 13-15, 127, 129-144 Hagiwara hybridoma development and ownership dispute, 4, 26 Families’ rights Harvard University Medical School cadavers, 72-75, 131 angiogenin research and development, 60 Federal Government “Hired to invent” doctrine interest in human biological materials, 7, 15-19, 50 patent law, 70-71 support for National Disease Research Interchange, Hoffman-LaRoche 123 development and ownership of KG-1 cell line, 25-26 Federal law and regulations House Committee on Science and Technology blood and semen sales, 76 survey of research use of human tissues and cells, 52 blood plasma as property, 78 House Committee on Science and Technology Investiga- conversion and trespass to chattel, 79 tions and Oversight Subcommittee 1985 survey on copyright, 78 patent applications, 50 human research, 10-11, 17-18, 94-95, 96, 97, 100, 102, HT-29 human tumor cell line 104-110, 147-154 angiogenin development, 60 ownership rights, 25 Human rights patents, 49, 50, 70-72, 87 egalitarian view of justice, 136 personal rights, 70, 86 Hybridomas testing of biotechnology products, 61, 154 commercial product, 3 use of human tissues and cells in biotechnology, 17-18 fee-for-service research, 62 Fee-for-service research ownership, 4, 26 interested parties, 62 technology, 5, 6, 35, 37-40, 44, 52 patients’ costs, 62 Financial gain from human biological materials “Imago dei” doctrine disclosure of prospect to source of human biological moral status of bodies and their parts, 138, 139 materials, 10-11, 102, 104-106, 110-111 Immunity effect on voluntariness of consent, 96, 97 higher animals, 35, 37 ethical distribution, 130 hybridoma technology, 35, 37-40 Federal Government’s rights, 17 In re Bergey interested parties, 49-63 organism patentability, 49-50 sources’ rights, 16-17 Industry Fletcher, Joseph acquisition of human biological materials, 52 on moral status of bodies and their parts, 132, 142 effects of 1980 patent law changes, 50-51 Food and Drug Administration, U.S. exploitation of biomedical research, 50 regulations of biological materials and human re- interest in human tissues and cells, 8, 56-62 search, 10, 54, 60-61, 94, 95 payments to researchers and physicians, 61-62, 119 For-profit institutions product development, 59t, 61 interaction with nonprofit institutions, 123-124 profits from government-funded research, 17 regulation, 122 relationships with universities, 7, 54, 61-62, 119 164 ● Ownership of Human Tissues and Cells

transfers of human biological materials, 52 specimen users, 4 use of rodent monoclinal antibodies, 38 tissue conversion cases, 86 Informed consent. See Consent trade secrets law, 78 Injuries Libertarian view of justice law of conversion and trespass to chattel, 81-82 commercialization of human biological materials, 135 rights relating to human biological materials, 69-70 “Liver Tissue Procurement and Distribution System” “Innovation lag” in commercial exploitation of research establishment and purpose, 53 congressional concern, 50 Lymphocytes Institutional Review Boards immune response, 37 approval of research, 17-18, 95, 96, 100, 102, 105, 109- Lymphokines 110, 149-151 fee-for-service research, 62 Insulin, human function in immune response, 38-39 production and use, 45 technology, 5, 37, 38-40 Insurance therapeutic use, 40 ownership and use of human biological materials, 4, 27 Macrophages Interagency Human Subjects Coordinating Committee function in immune response, 38-39 regulation of human research, 94 McCormick, Richard Interferon on organ donations, 141 occurrence in human blood, 39-40 Medical Research Council’s Laboratory of Molecular Biol- production and therapeutic use, 6, 25-26, 40, 44, 45 ogy discovery of hybridoma production technique, Interleukin-2 38 therapeutic use, 40, 62 Medical treatment Inventions consent and disclosure requirements, 93-100, 102, 104, biological, 7, 24, 49-51, 63 110-111 inventors’ rights, 16, 70-72, 87 Mendel legal definition, 71-72 principles of genetics, 41 Micro-organisms Judaism as trade secrets, 78 moral status of bodies and their parts, 138-139, 141 ownership, 133 “Judeo-Christian tradition” Milstein, Cesar moral status of bodies and their parts, 138-139 discovery of hybridoma production technique, 38 Justice “Mo” cell line ethics of buying and selling bodies and their parts, 13- development and ownership, 26 14, 15, 135-136 Monoclinal antibodies technology and use, 5, 37-38, 39f, 44, 62 Kant, Immanuel Monsanto Co. on moral status of bodies and their parts, 142 angiogenin research and development, 60 Kass, Leon R. Moore, John on control of biomedical research, 47 congressional testimony on patients’ rights, 21 principle of respect for persons, 132-133 development and ownership of “Mo” cell line, 26 KG-1 cell line Morality. See Ethical considerations development and ownership, 25-26 Murray, Thomas H. Kidney procurement system congressional testimony on sharing of profits from hu- corruption, 116 man biological materials with sources, 67 Kohler, Georges on sale of body parts, 127 discovery of hybridoma production technique, 38 National Cancer Institute Legal considerations development and ownership of KG-1 cell line, 25 biotechnology, 63 establishment of cancer tissue network, 53 injuries to persons versus injuries to property, 69-70 experimental cancer treatments, 62 market for human biological materials, 124 National Disease Research Interchange ownership of human biological materials, 9, 24-27, 52 establishment and operations, 53, 123 possible sources of rights relating to human biological National Institutes of Health materials, 70-84, 87 collection of blood and bone marrow for research, 52 remedies, 84-86 establishment of National Disease Research Inter- use of human biological materials, 9, 69-87 change, 123 Liability ownership dispute over WI-38 cell line, 25 blood and semen sales, 76-77 patent policy, 50 insurance, 27 regulation of human research, 94 Index . 165

support of human-related research, 52 Philosophy support of repositories of human biological materials, moral status of bodies and their parts, 132-134, 137- 53 138, 142, 143 National Organ Transplant Act Physicians model for statute prohibiting buying and selling hu- acquisition of human biological materials, 52, 73-75 man tissues and cells, 16 consulting relationships with biotechnology and regulation of human organ donation and sales, 3, disclosure requirements, 18-19, 93-111 75-76 fiduciary duty, 82-83, 97, 121 Negligence law pharmaceutical companies, 119 applicability to consent issues, 94, 110 relationship with patients, 14, 51, 97-98, 117, 129 Nonmarket system Pituitary hormone preparations development and production of human biological ma- transmission of Creutzfeld-Jakob disease, 118 terials, 119-121, 125 Pius XI Nonprofit organizations on moral status of bodies and their parts, 141 patenting federally funded inventions, 50 Pius XII role in procurement and distribution of human bio- on compensation for organs and tissues, 141-142 logical materials, 13, 121-124, 125 Policy on human biological materials effect of religion on law and public opinion, 14, 138 Office of Technology Assessment issues and options for Congress, 15-19 “New Developments in Biotechnology ” series, iii President’s Commission for the Study of Ethical Prob- survey of Institutional Review Boards, 96 lems in Medicine and Biomedical and Behavioral Oldham, R.K. Research foundation of Biotherapeutics, Inc., 62 study of informed consent, 99 Organ donations “Product of nature” doctrine ethical considerations, 130, 131-132, 139, 141, 142, 143 patentability of cell lines, 50 law and regulations, 3, 75-76, 87 Profits. See Financial gain payments for, 75-76, 87, 118 Property law Ostrach, Michael S. relevance to use of human tissues and cells, 9 on documentation of consent, 113 Property rights human biological materials, 24-27, 69-87, 127 Patent and Trademark Amendment Act Presser, William patenting and licensing of products of government- on wrongful acts toward cadavers, 72-73 sponsored research, 7, 50 Protection of Human Subjects (45 CFR Part 46) Patent and Trademark Office guidelines position on patentability of organisms, 49, 50 adequacy for regulation of use of human tissues and Patent law cells in biotechnology, 17-18 effect on transfers of human biological materials, 12, Protestantism 50-51, 52 moral status of bodies and their parts, 142-143 relevance to human biological materials, 7, 16-17, 24n, Public domain 49-50, 63, 70-72, 81, 87 unregistered cell lines, 17 Patients. See also Sources of human biological materials rights and interests, 7, 16-19, 21, 26, 51, 63, 71, 78-87, 93-111 Ramsey, Paul Payments for human biological materials principle of respect for persons, 131-132 relation to value, 123-124 Recombinant DNA to physicians and researchers, 119 copyrightability, 78 to sources, 12-13, 15-16, 55-56, 75-76, 100, 108, 115- gene probe, 43-44 121, 125, 141-142 increased use of human specimens, 52 Pearson v. Dodd mechanism, 42-43 applicability to subcultures from existing cell lines, 81 synonymous with genetic engineering, 41 Pew Memorial Trust technology, iii, 5-6, 35, 41-45 establishment of National Disease Research Inter- use with monoclinal antibody technology, 38 change, 123 Religion Pharmaceutical industry impact on use of human biological materials, 13-15, acquisition of human biological materials, 52, 55-56 138-144 effects of 1980 patent law changes, 50-51 Remedies interest in human tissues and cells, 56-62 cases involving human biological materials, 84-86 payments to researchers and physicians, 119 Repositories research and development, 61 supplying human biological materials to researchers, testing, 35, 54, 154 52-53 166 ● Ownership of Human Tissues and Cells

Res nullius payment, 12-13, 15-16, 55-56, 62, 75-76, 115-120, law of conversion and trespass to chattel, 82-83 124-125 Research rights, 4, 9, 16-17, 67, 70-84, 87, 119, 124, 130 commercial interest, 3, 8, 49-51 Specification doctrine consent and disclosure requirements, 93-98, 100-106, law of accession, 84 110-111 Stanford University emotional distress claims, 73-75 ownership dispute over WI-38 cell line, 25 ethical considerations, 129-144 State law fee-for-service, 62 blood and semen sales, 76, 87 funding, 50, 63, 154 consent and disclosure requirements, 94, 95-96, 98- Judaism, 139, 141 100, 104, 110-111 patent law, 70-72, 87 conversion and trespass to chattel, 79, 80, 85-86, 87 purposes, 54 cultures and micro-organisms as trade secrets, 78 regulation, 10, 11, 17-19, 47, 107-108, 110-111, 149-154 implied warranties in sales of human blood and use of human biological materials, 8, 54-55, 62-63 semen, 77 Research subjects. See also Sources of human biological organ donation, 75 materials personal rights, 69-70 interests, 51 tax on blood sales, 78, 87 legal dynamics of relationship with researchers, 97-98 Storage not considered inventors, 71 human cells, 33, 34ph payment, 62 Supply. See Availability rights, 16-19, 83, 93-111, 147-154 Supreme Court, US. Researchers Brenner v. Manson patentability decision, 71 acquisition of human biological materials, 52 Diamond v. Chakrabarty organism patentability consulting relationships with biotechnology and phar- decision, 49, 50, 71 maceutical companies, 119 effect of actions on sources of human tissue, 51 interests, 8, 52-56 1980 ruling on patentability of new life forms, 7 relationship with sources of human tissue, 51, 97-98 responsibilities to subjects, 93-111 T cell hybridomas rights, 4, 12, 70-72, 83-84, 107, 115, 119, 130 lymphokine production, 40 transfers of human biological materials, 52 T lymphocytes wrongful acts, 73-75 function and use, 38-40 Respect for persons Tax law ethics of buying and selling human biological materi- sale of blood, 78, 87 als, 130-134 Tennessee Supreme Court justice, 135-136 tax on blood sales, 78 Protestantism, 142 Theology Roche Institute of Molecular Biology use of human biological materials, 131-132, 138, 139, development and ownership of KG-1 cell line, 25 142, 143 Roman Catholicism Thomasson, Mildrene C. moral status of bodies and their parts, 141-142 on research use of human biological materials, 21 Tissue culture technology, 5, 31-55 Scholendorff v. Society of New York Hospital Tissues, human informed consent and disclosure, 91 applicability of cadaver law, 73 Scientists. See Researchers as property, 69-87 Semen sales difficulty in establishing value, 116 law, 76-77, 87 donation, 139, 141 Silvestri v. Grant emotional distress claims, 73-75 patentability decision, 71-72 House Committee on Science and Technology survey Slavin, Ted of research use, 49-56 marketing blood, 24 industry interest, 56-62 Sources of human biological materials. See also Research reasons for removal, 51 subjects; Patients relative rarity, 55-56 basis of researchers’ choices, 54 repositories, 52-53 coercion of, 44, 77, 96-98, 109, 134-135 sources, 7-8 collection and compensation, 52 sources’ interests, 51 emotional distress claims, 73-75 trade secrets, 79, 87 identification, 4 Tort law interests, 51 relevance to use of human biological materials, 9, 69, not considered inventors, 71 70, 72-73, 87 Index ● 167

Totality University of Alabama moral status of bodies and their parts, 141 project on availability of tissues for research, 53-54 Trade secrets law University of California, Los Angeles Medical Center source of rights relating to human biological materials, cell line development, 25-26 78-79, 87 University of California, San Diego Transfer of human biological materials development and ownership of Hagiwara hybridoma, among researchers, 52 26 confidentiality agreements, 78-79 University of Minnesota Hospital effect of payments to sources on equity, 116, 117 “Liver Tissue Procurement and Distribution System,” impact of religious traditions, 143 53 moral and ethical considerations, 15, 129, 143-144 organ donation law, 75, 87 Waiver of consent requirements ownership rights, 52 Federal regulations, 95 Trespass-to-chattel law Waiver of patient’s and research subjects’ rights source of rights relating to human biological materials, Federal regulations, 107, 110-111 79-83, 87 fee-for-service research, 62 removal of ban in Department of Health and Human Undeveloped human biological materials Services regulations, 18 distinct from biological inventions, 24 University of California, Los Angeles-Moore ownership Uniform Anatomical Gift Act case, 26 regulation of human organ donation, 3, 75 warranties) implied uniform Commercial Code blood and semen sales, 76-77 applicabilitv to blood and semen sales, 76-78, 87 West, W.H. Uniform Trade Secrets Act foundation of Biotherapeutics, Inc., 62 applicability to human tissues and cells, 79 White blood cells. See Lymphocytes Universities WI-38 normal human cells increased patent applications after 1980 patent law development and ownership, 25 changes, 50 profits from government-funded research, 17 relations with industry, 7, 50, 54, 61-62, 119 168 ● Ownership of Human Tissues and Cells

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