Problematic Variation in Local Institutional Review of a Multicenter Genetic Epidemiology Study

ORIGINAL CONTRIBUTION

Rita McWilliams, MPH Context Sequencing of the human genome provides an immense resource for stud- Julie Hoover-Fong, MD ies correlating DNA variation and epidemiology. However, appropriately powered ge- Ada Hamosh, MD, MPH netic epidemiology studies often require recruitment from multiple sites. Objectives To document the burden imposed by review of multicenter studies and Suzanne Beck, MD to determine the variability among local institutional review boards (IRBs) in the ap- Terri Beaty, PhD proval of a multicenter genetic epidemiology study. Garry Cutting, MD Design A PubMed search was performed to determine the frequency of citations of multicenter studies by 5-year intervals from 1974 through 2002. A 7-question survey ROTECTION OF HUMAN SUB- was sent to all participating study centers to obtain information on frequency of IRB jects in research is an evolv- meetings, dates for submission and approval, use/nonuse of a specific consent form, ing process. The current sys- type of review performed, types of consent forms required, preparation time, and num- tem of institutional review ber of changes requested by the IRB at each center. Centers also provided a copy of boardP (IRB) assessment of human sub- all consent forms they generated and IRB correspondence regarding the study. jects protection was established in 1974 Setting and Participants Thirty-one of 42 cystic fibrosis care centers in this single in response to highly publicized hu- US multicenter genetic epidemiology study of cystic fibrosis replied, yielding a 74% man research scandals in the 1960s and response rate. early 1970s.1,2 Federal regulation of re- Main Outcome Measures Frequency of published research studies and consis- search conduct and IRB function was tency among IRBs. implemented in 1979. When IRBs were Results The number of all published single-center studies has increased 1.3-fold since created, the common paradigm for hu- 1985, while the number of published epidemiology and genetic epidemiology multi- man subjects research consisted of a center studies increased by 8- and 9-fold, respectively, during this same period. Evalu- single investigator at one institution en- ation of the risk of the same genetic epidemiology study by 31 IRBs ranged from mini- rolling local participants, with the ma- mal to high, resulting in 7 expedited reviews (23%) and 24 full reviews (77%). The number of consents required by the IRBs ranged from 1 to 4; 15 IRBs (48%) required jor emphasis of regulation on the re- 2 or more consents, while 10 (32%) did not require assent for children. The most com- view of clinical trials. mon concern (52%) of IRBs pertained to the genetic aspects of the study. Over the past 25 years, research strat- egies and technologies have changed, Conclusions Review of a protocol for a multicenter genetic epidemiology study by local IRBs was highly variable. Lack of uniformity in the review process creates uneven often bringing together investigators human subjects protection and incurs considerable inefficiency. The need for reform, from multiple institutions to enroll geo- such as the proposed centralized review, is underscored by the ever increasing rate of graphically diverse pools of partici- genetic discoveries facilitated by the Human Genome Project and the unprecedented pants into epidemiological studies. opportunity to assess the relevance of genetic variation to public health. However, IRB procedures and their fed- JAMA. 2003;290:360-366 www.jama.com eral underpinnings have not corre- 2,3 spondingly kept pace. Because of the Author Affiliations: Bloomberg School of Public Health Johnson and Johnson, SciClone Pharmaceuticals, de focus of IRBs on clinical trials, others (Ms McWilliams and Dr Beaty) and McKusick-Nathans Code, Discovery Labs, and Osteotech. Dr Cutting owns Institute of Genetic Medicine (Drs Hoover-Fong, Ha- stock in Invitrogen and Life Technologies and has con- have asserted that IRBs “often have little mosh, and Cutting), Johns Hopkins Medical Institu- sulted for Roche Molecular Systems. insight into the needs of epidemiol- tions, Baltimore, Md; Department of Pediatrics, Drexel Corresponding Author and Reprints: Garry Cutting, 4 University College of Medicine, and St Christopher’s MD, McKusick-Nathans Institute of Genetic Medi- ogy.” Indeed, it is worth noting that Hospital for Children, Philadelphia, Pa (Dr Beck). cine, CMSC 1004, 600 N Wolfe St, Baltimore, MD one infamous human subjects re- Financial Disclosure: Ms McWilliams owns stock in 21287 (e-mail: [email protected]).

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search scandal—the Tuskegee Syphi- ent in the interpretation of regulations and consent form was provided as a lis Study—involved an epidemiology by the estimated 3000 to 5000 IRBs in template for the IRB application at each study rather than a clinical trial.1 the United States.2 To assess the bur- center. Each center was provided with The incorporation of genetic infor- den imposed by review of all types of additional information that included the mation into clinical and epidemiologi- multicenter studies, we determined the guidelines for genetic banking pro- cal studies has raised additional prob- yearly volume of single-center and mul- vided by the American Society of Hu- lems for the current IRB system. There ticenter studies published in the litera- man Genetics.10 are few standards set by the Office for ture since 1974. One method of evalu- To document the process of IRB Human Research Protections for ge- ating the impact on the current IRB approval, a 7-question survey (avail- netic studies, and substantial disagree- multicenter process is to submit a com- able on request from the authors) was ment exists within the research common protocol to multiple IRBs.7 sent to all participating CF centers ask- munity about what constitutes minimal We are conducting a multicenter ge- ing the study staff to provide informa- risk in studies that are not clinical trials.5 netic epidemiology study to identify tion on the following: frequency of IRB According to Greely,6 “Research into hu- modifiers of cystic fibrosis (CF). Imple- meetings, dates for submission and man genetics has stretched current regu- mentation of this study required the approval, use/nonuse of the Johns Hop- lations of human subjects research be- participation of CF care centers across kins University consent form, type of yond the breaking point.” The inherent the United States. Institutional review review performed, types of consent rarity of the outcome and the large num- board review of the same study proto- forms required, preparation time, and ber of subjects needed to unravel com- col varied considerably. Here, we pre- number of changes requested by the IRB plex gene-gene and gene-environment sent results of a survey of participat- at each CF center. Each center was also relationships often require a multi- ing CF centers to document current IRB asked to provide a copy of all consent center study design to attain sufficient issues in conducting a multicenter ge- forms generated at their center and all statistical power to generate meaning- netic epidemiology study. IRB correspondence regarding the CF ful results. study. Variability among IRBs regard- Although Silverman et al7 have METHODS ing approval of this study was derived reported variability in the review of mul- A PubMed search was performed to from review of IRB correspondence and ticenter clinical trials, there have been no assess the number of English-language approved consent forms. Issues raised published reports examining IRB human multicenter studies in the litera- by centers and differences among con- approval for sites involved in multi- ture since 1974.9 Abstracts, letters to the sent forms were categorized and tabu- center genetic epidemiological studies. editor, review articles, and publication lated. In addition, current regulations are not types not containing original results were A matrix of consensus statements well suited to the complex issues raised excluded. In addition, collaborative stud- published from 1987 through 2001 was by genetic studies. According to Jam- ies of disease mechanism, disease treat- created to assess the most frequently rozik, “The current systems of ethical ment, or health care delivery were cited guidelines for genetic studies and oversight designed primarily to regu- excluded. The frequencies of citations to illustrate variability in use of these late intervention studies involving indi- of published, multicenter, English- statements in the consent forms. Data vidual patients associated with single language human studies in PubMed from on number of beds, obtained from the institutions have been completely over- 1974 through 2002 were tabulated in American Hospital Association, were taken by developments in clinical, 5-year increments. (The algorithm used used as a proxy for the size of the in- molecular, and epidemiological in the PubMed search is available on stitution.11 Extramural research rev- research.”4 When IRB committees do not request from the authors). enues obtained from the National In- allow a consistent method of consent The CF Twin and Sibling Study is a stitutes of Health (NIH) were used as among the participants, “selection bias multicenter genetic epidemiology study a surrogate for volume of research per- may be introduced and statistical power that was used as a case study to illus- formed at each institution.12 Number of is certainly decreased.”4 Therefore, IRBs trate variability in IRB review. The study beds and level of NIH extramural fund- are largely without guidance in the review involved collection of medical record ing in centers that did and did not re- of studies that incorporate genetics. data along with a blood sample from CF spond to the survey were compared by The current method of multicenter re- patients who attended CF care centers t test. t Tests were also performed to as- view involves approval by each local IRB throughout the United States. A study sess differences in number of days to involved in the study. This results in protocol and consent form developed approval between centers requiring full variability in the type of review, type of by the researchers at Johns Hopkins review vs those that used expedited re- consent form, time to approval, changes Medical Institutions and approved by view and between centers with chil- requested, and the quality of human sub- the Johns Hopkins University School of dren vs those with adults. PϽ.05 was jects protection afforded.7,8 Compound- Medicine IRB, Baltimore, Md, was dis- considered statistically significant. A ing the problem is the variability inher- tributed to each center. This protocol stepwise linear regression analysis was

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Table 1. Frequency of Multicenter Studies in PubMed, 1974-2002* Multicenter Studies

All Studies Genetic Nonmulticenter Studies Epidemiology Epidemiology Interval, mo/d/y No. No./yStudies, No. (%)† Studies, No. (%)† No. No./y 1/1/74-12/31/79 385 64 19 (4.9) 1 (0.2) 499 917 83 319 1/1/80-12/31/84 990 198 99 (10.0) 1 (0.1) 545 534 109 107 1/1/85-12/31/89 3016 603 245 (8.1) 17 (0.6) 680 170 136 034 1/1/90-12/31/94 5541 1108 789 (14.2) 39 (0.7) 777 493 155 499 1/1/95-12/31/99 8632 1726 2007 (23.2) 156 (1.8) 940 360 188 072 1/1/00-12/31/02 6521 2174 1904 (29.2) 154 (2.4) 634 443 211 481 1/1/00-12/31/04 (Projected) 10 870 NA 3173 (NA) 257 (NA) 1 057 405 NA Abbreviation: NA, not applicable. *Data compiled as of May 12, 2003. †Percentage of all multicenter studies.

performed with number of days to ap- in the protocol to be of minimal risk and to obtain approval for a full review was proval as the outcome variable. All sta- eligible for expedited review based on 81.9 days (range, 13-252 days). The tistical analyses were performed using their interpretation of the federal regu- range of preparation time for the full re- SAS software.13 lations.14 Twenty-nine centers (94%) review varied from 2 hours to as many as quired use of consent forms from their 40 hours. Predictably, the mean prepa- RESULTS own institution. Three centers (10%) re- ration time for an expedited review was The overall number of multicenter stud- quired 4 forms (adult, minor, parental, shorter than that for a full review (5.8 ies and the number of epidemiological and assent). The number of centers re- vs 14.8 hours) and the mean number of and genetic epidemiological research quiring 2 or more consent forms was 15 changes requested was lower for an ex- multicenter studies published since the (48%). Ten centers (32%) did not re- pedited review (5.7 vs 8.6). Prepara- establishment of IRBs are presented in quire an assent for children. Of the 21 tion time was not separated into time to TABLE 1. The number of citations for centers that did require an assent, 10 initial submission to the IRB and time multicenter studies increased by 1.6- to (48%) provided a separate assent form to make changes and resubmit to the 3-fold for each of the 5-year periods that included an explanation of the IRB. This information may be useful in from 1985 to 1999. However, the num- study; the rest required a signature or future studies of this type. Prior to re- ber of epidemiology and genetic epi- initials of assent on a consent form writ- gression analysis, correlation analyses demiology multicenter studies in- ten for an adult. The specific age range were conducted for all variables regard- creased 4- to 5-fold every 5 years during of patients for which assent was re- less of review type, all variables for cen- the same period. Between 1985 and quired varied considerably among centers using full review, and all variables 1999, the number of multicenter epi- ters. Ages specified for assent ranged for centers using expedited review. demiology and multicenter genetic epi- from a minimum of 7 years to a vari- Days to approval, an indicator of the demiology studies increased approxi- able maximum of 12 to 18 years. Nine difficulty of review, correlated with the mately 8- and 9-fold, respectively, while assent forms (43%) did not specify age. number of changes requested when both the increase in single-site studies in the There were no statistical differences be- review types were combined (P=.004) literature was 1.3-fold. Numbers for tween centers with children vs centers and with full review (P=.01) when the 2000 through 2002 are consistent with with adults. The number of consents re- data were stratified by review type. No this trend continuing. Thus, multi- quired by a center was independent of other significant correlations were ob- center studies of epidemiology and ge- whether the review was full or expe- served. t Tests were performed for com- netic epidemiology comprise an in- dited. To assess the issue of response bias parison of the full and expedited re- creasing fraction of the multicenter due to differences in the familiarity of view groups. There were no significant studies reviewed by IRBs. centers with human subjects research, differences between the groups except Thirty-one of 42 CF care centers in- the number of beds and the level of NIH in preparation hours (P=.01). How- volved in a multicenter genetic epide- extramural funding in the centers were ever, the paucity of numbers for the ex- miology study replied to the survey of compared between the those who did pedited review groups requires cau- their IRB approval process, yielding a and did not respond to the survey; no tious interpretation of this result. 74% response rate. Twenty-four (77%) differences were found. Although the sample size was small, a of the 31 institutions required full IRB The mean time to obtain approval for stepwise regression analysis was per- reviews, and 7 (23%) considered the an expedited review was 32.3 days formed with number of days to ap- blood draw and medical record review (range, 9-72 days), and the mean time proval as the outcome variable. Num-

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ber of changes required was the only each center was provided with DNA erature has been dramatic. This in- variable that predicted number of days banking guidelines10 and other guide- crease has raised researchers’ con- to approval. lines were available, few consent forms cerns about the adequacy of human The large variability in days to ap- contained information relating to pur- subjects protection.17,18 In 1998, the proval was not explained by the vari- pose/advantage, location, use, and con- deputy inspector general issued a re- ability in meeting schedules, hours of fidentiality procedures or withdrawal port calling for the reform of IRBs. The preparation, number of consent forms, procedures (TABLE 3). report noted the inability of IRBs to cope size of the institution, or volume of re- with rapid advances in biomedical research dollars received by the institu- COMMENT search and changes in the research en- tion. The large variability in the con- Since the early 1980s, the growth of vironment, from conduct of small tent of the consent forms and the multicenter studies in the scientific lit- single-institution studies to larger multi- number of changes requested was explained in part by differences in the Table 2. Issues Raised During Local Institutional Review Board Review amount of genetics-related informa- No. (%) No. of Mean No. of Items tion provided and the high percentage Issue Category of Centers Items per Center (Range) of questions regarding the genetic as- Administrative/grammar/spelling/punctuation* 12 (39) 41 3.4 (1-6) pect of the study. Institutional review Language level 7 (22) 10 1.4 (1-5) boards from smaller institutions with Total DNA/genetic 16 (52) 68 4.2 (1-12) lower research revenues tended to ask Banking 11 (69) 30 2.7 (1-8) more questions, which, in turn, led to Risk-benefit/privacy 10 (62) 23 2.3 (1-4) longer preparation time. Results† 6 (38) 6 1.0 Review of correspondence between Miscellaneous‡ 7 (44) 9 1.3 (0-2) the IRB and the study principal inves- Confidentiality 11 (35) 23 2.1 (1-8) tigator at each center revealed that a All other§ 18 (58) 77 4.3 (0-11) substantial fraction (52%) of issues Check-boxes࿣ 13 (42) 31 2.4 (1-7) raised by local IRBs related to genet- Genetic 10 (77) 16 1.6 (1-3) ics. Most genetics questions related to Other 7 (54) 15 2.1 (1-4) *An example of administrative issues is verification of human subjects training. DNA banking and risk-benefit analy- †Issues concerning results of genetic studies (eg, who should receive results). sis (TABLE 2). Questions related to non- ‡Other genetic issues (eg, need to list all candidate genes to be investigated). §For example, need to submit written assent. genetic issues of confidentiality ac- ࿣Provision of check-boxes on consent form to opt in or out of various aspects of the study (eg, for genetic studies: “I agree that my anonymized DNA may be used by other researchers”; for other studies: “I verify that my participation counted for only 35%. There were also is voluntary”). several questions that referred to clinical trial design tools that were not a part of this observational study. Only 2 cen- Table 3. Use of DNA Banking Guidelines by IRBs ters (6%) explained that the study was Source of Guidelines, Guidelines Reference No. No. (%) of IRBs observational and that there would be Right to and procedure for withdrawal 10, 22, 25, 27, 30 8 (26) no treatment involved. Certificate of confidentiality 16, 25, 28, 30 0 A review of consent forms consis- Anonymous storage (coded) 16, 29, 30 14 (45) tently revealed language required by Description of genetic risk 10, 22, 25, 28 11 (35) each individual IRB for all studies at Commercial development 22, 27, 30 7 (22) their institution. In general, the required Right to refuse genetic results 22, 26, 30 6 (19) templates were not well suited to a Duration of bank 10, 22, 25, 30 5 (16) 15 genetic epidemiology study. For Operation and quality assurance of bank 10, 22, 25, 28 1 (3) example, most consent templates pro- Benefit of bank 10, 16, 25, 27 1 (3) vide information regarding data and Location of bank 10, 25, 30 10 (32) safety monitoring boards. An IRB in this Oversight of sample access 16, 22 4 (13) study requested that this information Ownership of DNA 10, 25, 26 2 (6) be included in its consent form despite Rules for release to researchers 10, 22, 25 1 (3) the fact that this study did not contain Research limitations on samples 10, 25 24 (77) an intervention for it to monitor. In Obtaining results 30 20 (64) addition, items necessary for genetic Purpose of bank 29 3 (10) studies are not found in the templates, Procedure for unexpected findings 10, 25 3 (10) such as assurances of confidentiality for Sample reidentification 30 3 (10) family members, since families are a unit Depositor communication with bank 10, 25 1 (3) of research in genetics. Finally, although Abbreviation: IRB, institutional review board.

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institution studies, and inadequacy of mous data were involved and when any exemplified by variability in the as- reviews due to increased workload, due genetic information was involved. The sent requirement. Institutional review in part to an increase in multicenter definition of minimal risk in research boards are required to set ages of mi- studies, lack of resources, and insuffi- has been a source of debate during the nority and majority based on local laws cient scientific expertise, with many last decade.5,7 Many IRBs struggle with and their own judgment, taking age, IRBs spending “only 1 to 2 minutes of the ideas of risk and benefit in nonin- maturity, and psychological state into review per study.”19 tervention studies. Researchers and consideration.14 State definitions of mi- The dramatic increase in the num- ethicists are divided as to whether ge- nority age range from at least 12 years ber of all multicenter research studies netic studies should always be consid- to at least 17 years, while age of major- supports previous reports of the im- ered to be of higher risk than other ity ranges from 18 to 21 years.33 Most pact of this research strategy on re- forms of research.22 IRBs appear to apply the local legal defi- view of clinical trials.17,19-21 The num- All participants in this study were pa- nition when preparing assents. ber of multicenter genetic epidemiology tients with a well-defined genetic dis- We observed that some IRBs pre- studies found by our search of the order, CF. However, IRBs seemed con- pared an assent form with a grade 2 to PubMed database may be underesti- fused about what risk information they grade 4 reading level, while others only mated because of the infrequency of the needed to provide the participants. It furnish a space for a signature on a con- term genetic epidemiology in the data- has been noted that IRBs lack experi- sent form requiring greater reading base during the early years. This limi- ence in finding the equipoise in a risk- skills. This practice introduces consid- tation was in part overcome by use of benefit analysis in which the risk is psy- erable variability in the level of protec- a series of Medical Subject Heading chosocial and any benefit is solely tion afforded to children participating terms that describe epidemiological scientific knowledge and, hence, indi- in the same research. Thus, variability studies (eg, case-control) and by com- rect.23 Genetics introduces probabilis- in multiple local IRB reviews uncov- bining them with multiple genetic de- tic risk information that incorporates ered differences in review criteria that scriptors (eg, hereditary). Indeed, a re- the concepts of penetrance and vari- could lead to uneven protection of hu- view of 10% of the results of the search able expressivity24 and, often, uncon- man subjects. In addition, the ineffi- strategy yielded a maximum of 8% false- firmed estimates of risk perception, ciency of multiple and variable IRB re- positive results. which further complicates determin- views of a single research protocol It was not possible to differentiate be- ing risk-benefit ratios. These issues were postponed the time to study initiation tween multicenter studies with sepa- illustrated by considerable variability in and resulted in redundant allocation of rate IRB approval and studies in which how IRBs dealt with DNA banking valuable IRB resources without add- review was performed only at the origi- within their consent forms. ing substantially to the protection of hu- nating center. Because of the nature of As shown in Table 3, guidelines for man subjects. the PubMed database, publication bias consent for genetic studies have been A possible solution would be the cre- may also reduce the number of genetic issued by several organizations.10,25-30 ation of an independent national mul- epidemiology studies found in our However, these guidelines are not con- ticenter IRB review system overseen by search. However, this would result in an sistent. Sometimes conflicting guid- the Office for Human Research Protec- underestimate of the numbers, thus im- ance has been offered, which, we specu- tions. An independent but federally ac- plying stronger results. Although the late, contributes to the observed credited central multidisciplinary IRB number of multicenter studies consti- inconsistency among the IRBs. As noted program for multicenter studies could tutes a small fraction of all research stud- by Francis Collins, “Many groups have obviate concerns regarding inad- ies, the amount of work involved in the made recommendations; researchers equate staffing and education of IRBs, multiple reviews of a multicenter study and IRBs are still confused. The IRB the burden multicenter review places imposes a disproportionate burden on Guidebook is dusty and out of date for on local IRBs, variability among IRB re- the IRB system. Thus, the rapid in- genetics research.”31 views, continuity of human subjects crease in use of the multicenter re- The National Bioethics Advisory protections among all participating in- search strategy underscores the ur- Commission found considerable dis- stitutions, IRB availability at smaller in- gency for changing the current process agreement across IRBs regarding “when stitutions, and institutional conflict of of IRB review of multicenter studies. informed consent should be required, interest.34 Membership could be drawn Using a single multicenter genetic and what constitutes proper con- from a pool of qualified individuals with epidemiology study as a case study, we sent.”32 Variability in IRB review was various levels and types of expertise. To observed considerable variability in lo- also revealed in this study by the types ensure the quality of the review, mem- cal IRB assessment of type of review re- and numbers of consent forms re- bership should be recognized within the quired. There were differences among quired and the content of the consent scientific community with the same local IRBs as to what constituted mini- forms. In this study, the lack of con- level of recognition attributed to mem- mal risk when coded rather than anony- sensus among IRBs regarding assent was bership in a study section at the NIH.

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Local IRBs would review multicenter re- HIPAA, thus adding another layer of tors at the CF centers for their participation, Sharon Krag, PhD, for critical review of an early version of the search approved by a federally accred- variability in the review of multi- manuscript, Adele Gilpin, PhD, JD, for guidance on ited, independent central IRB in an ex- center studies and further complicat- ethics, Holly Harden at the Welch Medical Library, Bal- timore, Md, for assistance with PubMed, and Tricia pedited fashion. Full local IRB review ing the execution of studies evaluat- Cornwall for secretarial assistance. would be undertaken only if the expe- ing the contribution of genetic variation dited review revealed a potential for ad- to common disease. verse effects on a community within REFERENCES their catchment area, conflict with lo- CONCLUSION 1. Reilly PR. Rethinking risks to human subjects in genetic research. 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Cary, NC: SAS Institute Inc; 2001. mation.” Concerns regarding a crite- McWilliams, Cutting. 14. Department of Health and Human Services. rion for minimal privacy risk seem to Acquisition of data: McWilliams, Hoover-Fong, Beck. Protection of human subjects. 1991. Codified at 45 Analysis and interpretation of data: McWilliams, CFR §46. Revised November 13, 2001. Available echo those previously expressed, and Hamosh, Beaty, Cutting. at: http://ohrp.osophs.dhhs.gov/humansubjects unanswered, regarding minimal risk in Drafting of the manuscript: McWilliams, Beaty, Cutting. /guidance/45cfr46.htm. Accessibility verified June 16, 41 Critical revision of the manuscript for important in- 2003. federal research regulations. No at- tellectual content: Hoover-Fong, Hamosh, Beck, 15. MacFadyen U. Electronic rapid response to: Lux tempt has been made to create a stan- Cutting. AL, Edwards SW, Osborne JP. Responses of local re- dard individual privacy authorization Statistical expertise: McWilliams, Beaty. search ethics committees to a study with approval from Obtained funding: Cutting. a multicentre research ethics committee. BMJ. 2000; or data use agreement. This leaves the Administrative, technical, or material support: Beck. 320:1182-1183. Available at: http://www.bmj.com regulation and the language to inter- Study supervision: Cutting. /cgi/eletters/320/7243/1182. Accessibility verified Funding/Support: This work was supported by grants June 16, 2003. pretation at each institution. Based on CUTTIN00A0 from the Cystic Fibrosis Foundation, 16. Office for Protection From Research Risks. Is- our experience with IRB review in this HL68927 from the National Heart, Lung, and Blood sues to consider in the research use of stored data or Institute, and R01 DK44003 from the National Insti- tissues. November 7, 1997. Available at: http://ohrp study, we anticipate that local IRBs tute of Diabetes and Digestive and Kidney Diseases. .osophs.dhhs.gov/humansubjects/guidance/reposit will differ in their interpretation of the Acknowledgment: We thank the research coordina- .htm. Accessibility verified June 2, 2003.

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The soul of man is divided into three parts, intelligence, reason, and passion. Intelligence and passion are possessed by other animals, but reason by man alone. —Pythagoras (fl sixth century BC)

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