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addition to the direct costs described in Application which clarifies the efforts to expand access to paragraph (d)(1)(i) of this section, a circumstances in which charging for an investigational drugs for treatment use. sponsor may recover the costs of investigational drug in a clinical trial is Before 1987, there was no formal monitoring the expanded access IND or appropriate, sets forth criteria for recognition of treatment use in FDA’s protocol, complying with IND reporting charging for an investigational drug for regulations concerning INDs, but requirements, and other administrative the different types of expanded access investigational drugs were made costs directly associated with the for treatment use described in this final available for treatment use informally. expanded access IND. rule, and clarifies what costs can be In 1987, FDA revised the IND (3) To support its calculation for cost recovered for an investigational drug. regulations in part 312 (21 CFR part recovery, a sponsor must provide DATES: This rule is effective October 13, 312) to explicitly provide for one supporting documentation to show that 2009. specific kind of treatment use of the calculation is consistent with the FOR FURTHER INFORMATION CONTACT: investigational drugs (52 FR 19466, May requirements of paragraphs (d)(1) and, if Colleen L. Locicero, Center for Drug 22, 1987). Section 312.34 authorized applicable, (d)(2) of this section. The Evaluation and Research, Food and access to investigational drugs for a documentation must be accompanied by Drug Administration, 10903 New broad population under a treatment a statement that an independent Hampshire Ave., Bldg. 22, rm. 4200, protocol or treatment IND when certain certified public accountant has Silver Spring, MD 20993–0002, criteria were met. Section 312.35 reviewed and approved the calculations. 301–796–2270; or described the submission requirements Dated: July 20, 2009. Stephen M. Ripley, Center for for such treatment use. The 1987 IND Jeffrey Shuren, Biologics Evaluation and Research regulations also implicitly acknowledged the existence of other Associate Commissioner for Policy and (HFM–17), Food and Drug Planning. Administration, 1401 Rockville kinds of treatment use, notably use in individual patients, by adding a [FR Doc. E9–19004 Filed 8–12–09; 8:45 am] Pike, Rockville, MD 20852, 301– 827–6210. provision for obtaining an BILLING CODE 4160–01–S SUPPLEMENTARY INFORMATION: investigational drug for treatment use in an emergency situation (§ 312.36). Table of Contents DEPARTMENT OF HEALTH AND However, § 312.36 did not describe HUMAN SERVICES I. Background criteria or requirements that must be II. Overview of the Final Rule Including met to authorize individual patient Food and Drug Administration Changes to the Proposed Rule treatment use. A. Overview In response to criticisms that this lack 21 CFR Parts 312 and 316 B. Changes to the Proposed Rule of criteria and submission requirements III. Comments on the Proposed Rule resulted in inconsistent policies, [Docket No. FDA–2006–N–0238] (formerly A. General Comments on the Proposed Docket No. 2006N–0062) Rule inequitable access, and preferential access for certain categories of patients, RIN 0910–AF14 B. Comments Related to Proposed Rule as Congress included in the Food and Drug a Whole Administration Modernization Act of Expanded Access to Investigational C. Comments on Specific Provisions of the 1997 (FDAMA) (Public Law 105–115), Drugs for Treatment Use Proposed Rule which amended the Federal Food, Drug, IV. Legal Authority AGENCY: and Cosmetic Act (the act), specific Food and Drug Administration, V. Environmental Impact HHS. provisions concerning expanded access VI. Analysis of Economic Impacts to investigational drugs for treatment ACTION: Final rule. A. Objectives of the Final Action B. Nature of the Problem Being Addressed use (Expanded Access to Unapproved SUMMARY: The Food and Drug C. Baseline for the Analysis Therapies and Diagnostics, section 561 Administration (FDA) is amending its D. Nature of the Impact of the act (21 U.S.C. 360bbb)). regulations on access to investigational E. Benefits of the Final Rule FDA proposed this rule in December new drugs for the treatment of patients. F. Costs of the Final Rule 2006 to further address the concerns The final rule clarifies existing G. Minimizing the Impact on Small Entities that motivated the FDAMA changes, regulations and adds new types of H. Alternatives including problems of inconsistent expanded access for treatment use. VII. Paperwork Reduction Act of 1995 application of access policies and A. The Final Rule Under the final rule, expanded access to B. Estimates of Reporting Burden programs and inequities in access based investigational drugs for treatment use VIII. Federalism on the relative sophistication of the is available to individual patients, setting in which a patient is treated or including in emergencies; intermediate- I. Background on the patient’s disease or condition. By size patient populations; and larger In the Federal Register of December describing in detail in the final rule the populations under a treatment protocol 14, 2006 (71 FR 75147), FDA proposed criteria, submission requirements, and or treatment investigational new drug to amend its regulations permitting safeguards for the different types of application (IND). The final rule is access to investigational drugs to treat expanded access for treatment use of intended to improve access to patients with serious or immediately investigational drugs, FDA hopes to investigational drugs for patients with life-threatening diseases or conditions increase awareness and knowledge of serious or immediately life-threatening when there is no comparable or expanded access programs and the diseases or conditions who lack other satisfactory alternative therapy to procedures for obtaining investigational therapeutic options and who may diagnose, monitor, or treat the patient’s drugs for treatment use. The agency benefit from such therapies. Elsewhere disease or condition. believes that the final rule appropriately in this issue of the Federal Register, As discussed in greater detail in the authorizes access to promising drugs for FDA is publishing the final rule on preamble to the proposed rule (71 FR treatment use, while protecting patient Charging for Investigational Drugs 75147 at 75148 to 75149), there have safety and avoiding interference with Under an Investigational New Drug been several statutory and regulatory the development of investigational

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drugs for marketing under approved B. Changes to the Proposed Rule insurance companies, hospitals, a trade applications. The final rule has been revised in organization representing hospitals, and In 2007, after the proposed rule on response to comments received on the a professional society representing expanded access was published, proposed rule. The responses are oncologists. Congress passed the Food and Drug discussed in section III of this A. General Comments on the Proposed Administration Amendments Act of document. The final rule: Rule 2007 (FDAAA) (Public Law 110–85). • Revises proposed § 312.300(a) to Most of the comments strongly One provision, codified in 505–1(f)(6) of clarify that subpart I is intended to the act (21 U.S.C. 355–1(f)(6)), requires supported the goal of expanding access apply not only to the use of to investigational drugs for treatment the Secretary of Health of Human investigational new drugs but also to Services (the Secretary) to promulgate use. The vast majority of these approved drugs whose availability is comments expressed strong support for regulations concerning how a physician limited because the drugs are subject to may provide a drug under the the proposed rule as a way to expand a risk evaluation and mitigation strategy access. As a category, the largest volume mechanisms of section 561 when the (REMS) in accordance with section 505– drug is subject to elements to assure safe of comments came from individuals, 1(f)(6) of the act. and the vast majority of those supported use under a risk evaluation and • Also revises proposed § 312.300(a) the proposed rule. Healthcare and mitigation strategy (REMS). The to clarify that subpart I is intended to expanded access mechanisms described consumer advocacy organizations apply to all those with a serious disease provided the next largest volume of in this final rule can be used by a or condition, regardless of whether the patient seeking access to a drug with a comments. Comments from these patient would currently be considered organizations spanned the spectrum REMS in the event that the drug is not seriously ill with that disease or available to the patient under the from strongly supportive to strongly condition. negative. Many healthcare and criteria of the REMS, provided the drug • Revises proposed § 312.300(b) to consumer advocacy organizations and the patient meet the criteria for an include a definition of ‘‘serious disease expanded access program. Therefore, commented that they believe the rule or condition.’’ strikes the appropriate balance between this rule fulfills the FDAAA • Revises proposed § 312.305(c)(5) to requirement. increased access and patient safety clarify that a sponsor should make an without impeding enrollment in clinical This final rule applies both to drug investigator’s brochure available to products that are subject to section 505 trials or otherwise jeopardizing the licensed physicians in an expanded development of new drugs for marketing of the act (21 U.S.C. 355) and biological access program whenever such a products subject to the licensing approval. brochure exists. Healthcare and consumer advocacy provisions of the Public Health Service • Revises proposed § 312.310(a)(2) to organizations who opposed the Act (42 U.S.C. 201 et seq.) and 21 CFR omit the words ‘‘type of.’’ proposed rule had widely divergent part 601. This is consistent with the • Revises proposed § 312.310(c)(2) to views. Some of these commenters previous regulations on treatment use, clarify that the summary of the expressed the view that the rule did not which applied to both drug and expanded access use should include all go far enough in removing the obstacles biological products. adverse effects, not merely unexpected to patient access to investigational drugs II. Overview of the Final Rule Including ones, and that the summary should be for treatment use and argued that, after Changes to the Proposed Rule submitted to FDA. phase 1 safety testing, there should be • Revises proposed § 312.310(d)(2) to largely unfettered access to A. Overview extend the time in which to make investigational drugs for patients with The final rule amends FDA written submissions to 15 working days serious or immediately life-threatening regulations by removing the current after FDA’s authorization of emergency diseases or conditions and no sections on treatment use of use. alternative therapies. One of these investigational drugs (§§ 312.34, 312.35, The agency did not propose to amend organizations urged that the rule be and 312.36), revising § 312.42 on the text of § 316.40. However, because withdrawn and a substantially more clinical holds, and adding subpart I of § 316.40 references the requirements of permissive access policy (one that part 312 on expanded access. Subpart I § 312.34, which is being withdrawn, affords individual patients greater describes the following ways that FDA has revised § 316.40 to remove the autonomy) be developed and expanded access to treatment use of reference to § 312.34. implemented. investigational drugs are available: Some healthcare and consumer III. Comments on the Proposed Rule • Expanded access for individual advocacy organizations expressed the patients, including in emergencies; The agency received 119 comments view that the proposed rule went much • Expanded access for intermediate- on the proposed rule. Comments were too far in making investigational drugs size patient populations (smaller than received from individuals (persons with available to patients for treatment use. those typical of a treatment IND or serious or immediately life-threatening One comment argued that expanded treatment protocol); and diseases or conditions, persons with access as described in the proposed rule • Expanded access treatment IND or family members with such diseases or would eliminate the incentive for treatment protocol (described in conditions, and other interested patients to enroll in clinical trials that previous §§ 312.34 and 312.35). persons), healthcare and consumer provide the evidence necessary to make The final rule provides the following: advocacy organizations, healthcare effective use of new therapies, would be (1) Criteria that must be met to authorize professionals (physicians and harmful to patients exposed to therapies the expanded access use, (2) pharmacists), pharmaceutical and for which there is limited safety and requirements for expanded access biotechnology companies, trade effectiveness information, and raises submissions, and (3) safeguards to organizations representing issues of fairness because of the protect patients and preserve the ability pharmaceutical and biotechnology potential that the supply of the drug to develop meaningful data about companies, health insurance companies, may not be adequate to make it available treatment use. a trade organization representing health to all those seeking access. Some

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comments argued that there should be may not be satisfactory to all; sometimes disseminating information to the lay access only in the very late stages of it is not possible to reconcile the more public or their healthcare providers and clinical development, ideally not until disparate views. FDA has made its best complained that the proposed rule did phase 3 testing had been completed. effort to set forth a regulatory policy that not mention any additional efforts to Comments from pharmaceutical and is consistent with its statutory mandate, disseminate the new policies. biotechnology companies and their taking into account the views of those Several comments recommended that trade organizations were the next largest who commented. FDA believes it has FDA do more to publicize its expanded category of comments. These comments addressed these competing issues in a access regulations, educate and train were generally supportive of the goal of way that affords patients a meaningful physicians, and/or improve expanding access, but expressed and reasonable measure of autonomy communications with patients and concern about the potential for over their own healthcare decisions patient advocacy organizations. One expanded access, as described in the while preserving the integrity of the comment stated that patients are proposed rule, to impede drug drug approval process and protecting sometimes confused about the reasons development and add new patient safety. they are not able to enroll in an administrative burdens or expense for Specific issues raised by the expanded access program or obtain companies. comments and the agency’s responses individual access and urged FDA to FDA’s response to these general follow. consider ways to improve comments is that we believe the final communication to patients about the rule appropriately addresses the B. Comments Related to the Proposed standards for expanded access to competing concerns surrounding Rule as a Whole minimize this confusion. One comment expanded access. As discussed in detail 1. Public Awareness and Physician and recommended that training materials in the preamble to the proposed rule (71 Patient Education Programs and information be made available to FR 75147 at 75160), the key question in the general public in an easily making investigational drugs available (Comment 1) In the preamble to the accessible format and medium, such as for treatment use is how to address the proposed rule (71 FR 75147 at 75149), on FDA’s Web site, so that patients and various interests—individual patients’ FDA stated that the major goals of this patient advocates can obtain the desires to make their own decisions rulemaking are to broaden the scope of instructions for submitting an expanded about their healthcare, including expanded access and to address access request. Another comment from decisions about using experimental concerns about inequities in access to a patient advocacy group recommended therapies in advance of such treatments investigational drugs under expanded that FDA provide guidance on each of being approved for marketing, society’s access programs. FDA explained that by the specific types of expanded access. interest in the efficient development of describing in detail in regulation the The comment stated that not all new therapies to treat serious and criteria, submission requirements, and physicians will have the time or immediately life-threatening diseases or safeguards for the different types of inclination to inform themselves about conditions, and the need to protect expanded access programs, FDA hoped the expanded access mechanisms and vulnerable patients from unnecessary to increase knowledge and awareness of processes and, therefore, it is important and unacceptable risks. FDA recognizes expanded access programs and the that patients and patient advocates be that these issues are complex and can procedures for obtaining investigational informed about expanded access and have life-or-death implications, both for drugs under such programs and, as a FDA’s requirements for expanded access individuals seeking access to result, facilitate wider availability of so that they can inform their physicians. investigational drugs and for large investigational drugs in appropriate (Response) FDA believes that clearly populations of patients with a given circumstances. FDA also explained that specifying in regulations the disease or condition who desire that it wished to address concerns that in the mechanisms and processes for obtaining innovative therapies for their disease or past, access to investigational drugs has investigational drugs for treatment use condition be developed and marketed as been primarily available to patients with is the essential and fundamental quickly as possible. Therefore, it is not certain serious or immediately life- platform on which to build awareness surprising that there are a range of threatening diseases or condition— of, and accessibility to, expanded access perspectives about how best to reconcile particularly cancers, Human programs. FDA agrees, however, that these competing interests and highly Immunodeficiency Virus (HIV) disease, new expanded access regulations alone impassioned defenses of the various and HIV-related conditions—and hoped will not be sufficient to increase perspectives. that the greater awareness and clarity knowledge and awareness about FDA’s perspective in attempting to fostered by this rulemaking would expanded access to an extent that will address and, where possible, reconcile facilitate access to investigational drugs meet FDA’s goals for broader and more these different views, is intended to be for patients with serious or immediately equitable access. Therefore, in consistent with its statutory mandate to life-threatening diseases or conditions conjunction with publication of this ensure that drug therapies developed who may have been underserved in the final rule, FDA intends to develop and and marketed for serious and past. engage in a broad range of publicity and immediately life-threatening diseases or Several comments expressed the view educational efforts in a variety of forums conditions are safe and effective (which that this rulemaking alone would not be and media to increase awareness of the requires substantial evidence from sufficient to accomplish these goals. mechanisms for obtaining clinical trials) and that individuals One comment argued that promulgating investigational drugs for treatment use. exposed to investigational therapies expanded access regulations is an (Comment 2) Some comments stated under an IND, whether in a clinical trial ineffective vehicle to increase that additional steps would be needed or for an expanded access use, are not knowledge and awareness of expanded to address complaints that access to subject to unnecessary and unacceptable access programs because FDA investigational drugs was biased toward risks. FDA acknowledges the varied regulations are not widely read by cancer and HIV disease patients. One positions expressed on access to healthcare providers and consumers. comment recommended that FDA work investigational drugs for treatment use. Another comment stated that Federal more closely on early access programs The agency recognizes that this rule Register notices are not the best way of with disease-specific institutes at the

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National Institutes of Health (NIH) in clinical trials (i.e., other than phase 1 perceived as burdensome, may be a addition to the National Cancer Institute trials in which one group of participants deterrent to obtaining access to and the Office of AIDS Research in the is given an investigational drug subject investigational drugs for treatment use. National Institute for Allergy and to FDA’s jurisdiction, while the control However, FDA believes the evidentiary, Infectious Disease. One comment group receives either a standard submission, and data collection recommended outreach to better inform treatment for the disease or a placebo). requirements are generally non-labor minorities about access to If expanded access is for an intensive, straightforward, and investigational drugs for treatment use. investigational drug that is not the appropriate to the kind of assurances The comment suggested a program subject of certain controlled clinical needed to permit treatment use of specifically directed at African- trials, the statute does not require investigational drugs. We acknowledge American women because of their low information about the expanded access that compliance with the expanded rates of cancer survival relative to white in ClinicalTrials.gov. Thus, for example, access requirements might pose women. information about an expanded access particular challenges for physicians FDA’s Office of Special Health Issues program for an intermediate-size patient (whether in academic or nonacademic (OSHI) works closely with individual population for a drug that is being settings) who are not very familiar with patients and patient organizations, developed (see § 312.315(a)(2)) would IND and IRB regulations, as well as for including minority and special disease be included in ClinicalTrials.gov as long medical centers in which existing groups, and with the healthcare as the other requirements for inclusion administrative burdens already test the provider community and organizations. are met. However, information about an limits of available resources. However, The office responds to questions about expanded access program for an we believe that the burdens associated expanded access and directs inquiries intermediate-size patient population for with IND compliance and IRB review for specific treatment uses of a drug that is not being developed under under expanded access programs have investigational products to the a clinical trial (see § 312.315(a)(1)) and been minimized to the extent possible appropriate staff within FDA. The office therefore is not subject to the mandatory while still ensuring patient safety. maintains a Web site with general registration provisions in section 402(j) The majority of the data necessary to information about expanded access and of the PHS Act would not be required satisfy the IND submission requirements other ways of getting promising to be included in ClinicalTrials.gov. for a licensed physician obtaining an therapies to seriously ill patients (see IND for an individual patient will, in http://www.fda.gov/ForConsumers/ 2. Administrative Burdens Associated ByAudience/ForPatientAdvocates/ With Obtaining Expanded Access most cases, be provided by reference to SpeedingAccesstoImportant (Comment 4) A number of comments, the content of an IND held by a sponsor NewTherapies/default.htm). particularly from patient advocacy who is developing the investigational (Comment 3) Some comments urged groups, stated that the administrative drug for marketing. (In the case of that all expanded access INDs and burdens associated with expanded treatment access to an approved drug protocols be listed on ClinicalTrials.gov access could undermine FDA’s efforts to that is subject to a REMS, reference to (http://www.clinicaltrials.gov), the Web broaden access. The general concern a sponsor’s IND may not be necessary.) site maintained by NIH that is intended was that the requirements, particularly Therefore, in making an IND to include a listing of controlled clinical for physicians seeking individual submission, the physician will trials for drugs in development. One patient INDs, are too onerous and, ordinarily only be required to provide a comment asked that FDA clarify therefore, physicians will be reluctant or narrative explaining the rationale for the whether the public notification unwilling to seek investigational drugs intended use and dose, why there are no provision (the provision that describes for treatment use for their patients. Two comparable or satisfactory therapeutic what should be listed on comments argued that the burden would alternatives, a description of the ClinicalTrials.gov) applies to access be greatest in nonacademic settings patient’s disease or condition (including programs for intermediate-size patient because physicians in those settings are recent medical history and previous populations. typically not as familiar with IND treatments), and the monitoring, testing, (Response) ClinicalTrials.gov is regulations and Institutional Review or other procedures needed to minimize governed by section 402(j) of the Public Board (IRB) requirements. The the risks of the drug to the patient. For Health Service Act (PHS Act) (42 U.S.C. comments recommended that the the post-treatment submission, the 282(j)). The law, as amended by requirements for expanded access for physician must provide a written FDAAA, requires the registration of individual patients be simplified and summary of the results of the expanded certain controlled clinical trials on disconnected from compliance with access use, including adverse effects. ClinicalTrials.gov and specifically other sections of part 312 (e.g., The information needed for each of requires information to be included investigator and sponsor responsibilities these submissions is the same kind of about whether expanded access to an in subpart D (Responsibilities of information that is captured during investigational drug under section 561 Sponsors and Investigators)). Another routine patient care and, consequently, of the act is available for those who do comment stated that administrative is already known to the physician or can not qualify for enrollment in the clinical burdens are a particular problem in the be readily accessed. Therefore, FDA trial and how to obtain information academic research setting, where does not consider these submission about such access (section intensive IRB approval and oversight, requirements to be a burden that is out 402(j)(2)(A)(ii)(II)(gg) of the PHS Act). combined with the data collection of proportion with the risks inherent in The ClinicalTrials.gov provisions only requirements of the protocols, have using an investigational product for apply to certain controlled clinical trials forced some centers to forego treatment use (see response to comment (see definition of ‘‘applicable drug participation in expanded access 60 for discussion of IRB review issues). clinical trial’’ in section 402(j)(1)(iii) of programs until they can find a source of FDA intends to engage in educational the PHS Act). Thus, information about funding. efforts to help physicians understand expanded access is required to appear in (Response) FDA shares the concern the individual patient requirements and ClinicalTrials.gov when the drug at that the requirements for obtaining how to navigate those requirements in a issue is the subject of certain controlled access to investigational drugs, if way that minimizes the administrative

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burdens. These efforts will be directed investigational drugs for treatment use eligible patients receive care, provided at physicians in both academic and more accessible for diseases and there are appropriate controls and nonacademic settings. conditions and in clinical settings that oversight, as set forth in this final rule. For multi-patient expanded access have purportedly been underserved by 4. Supplies of Investigational Drugs INDs, FDA agrees that there are steps expanded access programs. that could be taken to minimize (Comment 5) Several comments (Comment 7) Several comments were administrative burdens at participating agreed that certain diseases, conditions, concerned that there seemed to be an sites. As with any use of investigational and regions have been underserved by implicit assumption in the proposed agents, FDA encourages the use of expanded access programs. Some rule that there will be an adequate centralized IRBs and standardized data comments maintained that minority supply of an investigational drug to collection documentation across populations, in particular African- meet the demand for the drug generated expanded access IND sites when there Americans and women, have been by potentially broader access over an are multiple sites. As part of its ongoing underserved by expanded access indefinite period of time. Some outreach efforts on expanded access, programs and that these populations comments pointed out that increasing FDA intends to work with constituents should be the focus of efforts to make demand for an investigational drug in patient advocacy, clinical settings, access to investigational drugs for could create supply constraints, which and the pharmaceutical industry to treatment use more equitable. could make it impossible to provide a minimize the burdens associated with (Response) FDA agrees that regions, drug for treatment use to all those who multi-patient expanded access programs diseases, or populations that have been seek it and could also threaten the generally, as well as the burdens underserved by expanded access completion of clinical studies of the associated with specific multi-patient programs should be the focus of efforts drug. One comment argued that access programs as they arise. to ensure more equitable access. FDA’s expanded access programs should focus FDA does not believe that licensed OSHI is committed to working with any on investigational drugs with an physicians and sponsors should be underserved constituencies to help adequate supply to meet the potential exempt from compliance with the address inequities in the access to demand. Two comments stated that sponsor and investigator requirements investigational drugs for treatment use. access should be fair and equitable in in subpart D of part 312. It is crucial to (Comment 6) One comment expressed situations in which the supply cannot keep in mind that expanded access concern that the implications of one of meet the demand. One comment involves use of an investigational FDA’s stated goals—to improve access recommended that the treatment IND therapy in a vulnerable population, so to investigational therapies outside provisions in the final rule include a the rationale for oversight, monitoring, academic medical centers—are way to ensure fair and equitable access recordkeeping and human subject unknown and may be harmful. The in situations in which there is not protections applicable to clinical trials comment suggested that a possible enough supply of a drug to meet the is equally applicable in the treatment reason that access to investigational demand. use context. Accordingly, § 312.305(c) of drugs for treatment use is more likely in (Response) FDA agrees that, in cases the final rule provides that investigators, academic medical centers is that these when there is not sufficient supply of an sponsors, and sponsor-investigators centers tend to treat more patients with investigational drug to make it available must comply with the responsibilities serious and immediately life-threatening to all patients who seek it, access to the for sponsors and investigators set forth diseases or conditions who have drug for treatment use should be as in subpart D of part 312 to the extent exhausted all available conventional equitable as reasonably possible. FDA they are applicable to the expanded treatment options. The comment noted does not agree that expanded access access use. Section 312.305(c)(1) that there is a lack of information in the programs should be limited to only provides that a licensed physician proposed rule concerning differences in those situations in which there is an under whose immediate direction an patient outcomes between patients adequate drug supply for all potential investigational drug is administered or treated with investigational drugs in subjects. Mechanisms to fairly allocate dispensed for an expanded access use is academic medical centers and those limited drug supply (e.g., lotteries) have considered an investigator. Section treated elsewhere and suggested that, been used in the past to provide drugs 312.305(c)(2) provides that an absent such data, it is not necessarily to at least some of the patients who individual or entity that submits an desirable for the use of investigational could benefit. FDA supports the use of expanded access IND or protocol is drugs for treatment use to become these mechanisms where they are considered a sponsor. Section significantly more prevalent outside needed. 312.305(c)(3) provides that a licensed academic medical centers. However, FDA does not believe that it physician under whose immediate (Response) FDA acknowledges that is necessary to include in the final rule direction an investigational drug is patients who have the diseases or a requirement that fair and equitable administered or dispensed, and who conditions for which treatment use of distribution mechanisms be used to submits an IND for expanded access investigational drugs is generally sought allocate an investigational drug in the use, is considered a sponsor- may be found in greater numbers in event of insufficient supply. Current IRB investigator. academic medical centers specializing regulations require an IRB to determine in the treatment of serious and that selection of subjects, in this case 3. Equitable Access immediately life-threatening conditions. patients to be treated, is equitable (21 The preamble to the proposed rule (71 FDA does not agree, however, that the CFR 56.111(a)(3)). FDA believes that FR 75147 at 75149) explains that, by intent to facilitate access in all settings provision is adequate to ensure describing in detail the categories of requires data on comparative quality of equitable access in cases in which the expanded access use and the criteria care across different settings, any more drug supply is not adequate to meet the and submission requirements for such than it would require such a comparison demand. use, and otherwise increasing awareness among academic centers in geographic FDA anticipates that the most of the mechanisms and processes for regions. FDA believes it is important to appropriate distribution mechanism for obtaining investigational drugs for foster use of investigational drugs for a drug with limited supply will be very treatment use, FDA hopes to make treatment use in all settings in which case specific, for example, requiring

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identification of threshold clinical 6. Data Obtained from Expanded Access a population not exposed to the drug in parameters for possible access and a Use clinical trials. However, a control group mechanism to randomly select from (Comment 9) One comment asked is more important to the utility of those who meet the parameters. whether data generated in expanded effectiveness data than safety data. Therefore, FDA believes it is advisable access programs must be submitted to Because expanded access programs are for the sponsor to work with the the NDA for the drug product and, if so, typically uncontrolled exposure (with relevant patient or disease advocacy how FDA evaluates this information limited data collection), it is very organizations, professional societies, when determining the safety and unlikely that an expanded access IND and other affected constituencies to efficacy of the drug for the proposed would yield effectiveness information devise the most appropriate mechanism indication and patient population. that would be useful to FDA in for allocating a limited drug supply in Another comment stated that FDA’s considering a drug’s effectiveness. a specific situation. However, it should historical reluctance to consider efficacy However, if a sponsor believes that be noted that FDA has no authority to information from expanded access uses effectiveness information from compel sponsors to participate in that as evidence of efficacy in an NDA or expanded access use can contribute to a collaboration or to make their supplemental NDA has been a determination that there is substantial investigational products available for disincentive for some companies to evidence of effectiveness, it should treatment use. make a product available for expanded submit the information and an explanation of its relevance to FDA. access. The comment maintained that it 5. Industry Support or Incentives to There are examples in which FDA has would be appropriate to consider safety Broaden Expanded Access made use of adverse events information (Comment 8) Some comments argued and efficacy information from an from expanded access use in the safety that the proposed rule would not expanded access IND or protocol in assessment of a drug. There are a small increase expanded access because a assessing the safety and effectiveness of number of cases in which an important substantial increase in access would a drug when the use and patient adverse event was first identified during require industry support. Some population in the expanded access IND expanded access use and those adverse comments suggested that FDA offer or protocol are similar to the use and events were included in product financial incentives to industry, such as population for which approval is labeling. This is not a negative from a extending periods of exclusivity or sought. The comment asked that FDA public health perspective—the sooner expediting drug review, to encourage revise the proposed rule to explicitly important adverse events are identified drug companies to make drugs available inform sponsors, investigators, patients, the better. Even from the sponsor’s for treatment use. and patient representatives that any viewpoint, early discovery of a rare (Response) FDA is aware that, for a safety and efficacy data collected in adverse event is, on the whole, a benefit. variety of reasons, there may be expanded access are expected to be Although adverse events first identified reluctance among pharmaceutical and reported in the initial NDA seeking during expanded access use of certain biotechnology companies to make approval for the drug or biological drugs have been included in the drugs’ investigational drugs available under product. One comment argued that a approved product labeling, we are expanded access programs. FDA’s company that makes a drug available for unaware of any cases in which adverse charging rule, published elsewhere in treatment use under an expanded access event information obtained from this issue of the Federal Register, is IND or protocol runs the risk of being expanded access use has resulted in intended to address concerns about adversely affected by unfavorable safety denial of approval for a product. financial barriers to providing access by observations from use in the expanded (Comment 10) One comment observed allowing companies to charge an access population, notwithstanding that that data from expanded access might amount for an investigational drug that the patients receiving the drug under an provide helpful information about use enables them to recover the costs expanded access IND or protocol are of a drug in patients who are sicker than associated with making the drug often sicker, nonresponders to prior those patients enrolled in clinical trials. available. Other financial incentives are treatments, and otherwise not (Response) FDA agrees that expanded beyond the scope of this regulation and representative of the population access use in a population with a FDA’s statutory authority. For example, evaluated in controlled clinical trials, particular disease or condition that is FDA’s existing authority to extend but there is no commensurate benefit to sicker than the population in the marketing exclusivity to induce certain the company from favorable efficacy clinical trials might yield some helpful behavior derives from congressional observations in the expanded access insights into the tolerability profile, but mandates. population. typically would not provide insight into FDA also does not believe that a (Response) As with any IND, sponsors the response to the drug (effectiveness) promise to expedite review of new drug of expanded access INDs must provide because of the uncontrolled nature of applications (NDAs) is a reasonable FDA with information on patient the access program and limited data option to encourage broader access to outcomes and adverse events observed collection. investigational drugs for treatment use. during an expanded access use. This (Comment 11) Some comments The types of drug products that meet the information must be included in IND recommended that investigational drugs requirements for treatment use— annual reports (§ 312.33) and/or IND be made available for expanded access investigational therapies to treat serious safety reports (§ 312.32) and, typically, only under protocols that are designed and immediately life-threatening an NDA must also contain at least a to capture some scientific knowledge. diseases or conditions—are likely to summary of the expanded access One comment recommended that the already be eligible for the shortest experience with a drug. The information final rule require all categories of review times currently available (6 obtained from an expanded access use expanded access to be conducted under months). Given the complexity of NDAs, can be useful to a drug’s safety a clearly defined research protocol. The FDA does not believe it can routinely assessment. For example, a relatively comment recommended that the final review applications in less time while rare adverse event might be detected rule require that: (1) An appropriate maintaining the integrity of the review during expanded access use, or such use sponsor be responsible for collecting process. might contribute safety information for patient outcomes data, (2) reports be

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submitted in a timely fashion to FDA, access uses (those involving applicable investigational drugs available to large and (3) patients be required by FDA to drug clinical trials) will be included in populations for treatment use, participate in official data-gathering the ClinicalTrials.gov results database particularly by identifying such processes within a formal cohort study (see response to comment 3 and http:// programs as ‘‘open-label safety studies.’’ or patient registry. www.clinicaltrials.gov). The goal of an open-label safety study (Response) FDA does not agree that is to better characterize the safety of a 7. Assessing the Impact of Expanded investigational drugs should be made drug late in its development. However, Access available only under expanded access in practice, many studies that are protocols designed to obtain meaningful (Comment 13) One comment described as open-label safety studies scientific data, or contingent on encouraged FDA to develop a tracking have characteristics that appear to be enrolling patients in a formal cohort system to evaluate how well the more consistent with treatment INDs or study or registry. As explained in expanded access program is working treatment protocols. FDA stated that, in § 312.300(a) of this final rule, the and to identify factors, such as the future, it intends to evaluate primary purpose of expanded access is economic obstacles, that might be submissions identified as open-label to diagnose, monitor, or treat a patient’s impeding access to investigational drugs safety studies to determine whether disease or condition, not to generate for treatment use. The comment those studies are more characteristic of scientific data intended to characterize recommended that the system include treatment INDs or treatment protocols. the drug. However, FDA agrees that information on patients and The proposed rule stated that a study there should be efforts to optimize the investigators, whether or not requests described as an open-label safety study information obtained from expanded for expanded access are granted, and if that provides broad access to an access exposures with an eye toward not, the reason for not granting such investigational drug in the later stages of detecting any unexpected outcomes or requests, the outcomes of the development, but lacks planned, events. treatments, and costs, if any, to patients systematic data collection and a design (Comment 12) FDA received several who pay for their treatments. appropriate to evaluation of a safety comments advocating more systematic (Response) FDA believes this final issue, is likely to be considered a collection of data on outcomes of rule, in conjunction with treatment IND or treatment protocol. expanded access programs, including implementation of electronic format (Comment 14) Several comments adverse events. One comment INDs and the expanded expressed support for FDA’s position maintained that current data collection ClinicalTrials.gov information, will that programs that make investigational practices for expanded access programs make it easier for the agency to compile drugs available to large populations for rarely yield useful information and that information about the types of diseases treatment use should be treatment INDs better collection of safety data might or conditions that are or are not being or treatment protocols, not open-label identify previously unknown safety treated under expanded access INDs. safety studies. One comment stated that concerns. One comment stated that data That information could, for example, mischaracterizing a treatment IND as an collection should focus on elements identify disease categories that appear to open-label safety study afforded the such as drug start and stop dates, dose, be underserved by expanded access study more credibility than it deserved. patient treatment outcomes, and INDs. FDA does not foresee that such Several comments opposed FDA’s significant adverse events, and that information would be able to position, stating that open-label safety collection of adverse events could use specifically identify economic or other studies are important in elucidating the standardized reporting forms (e.g., obstacles to obtaining access for certain safety profile of investigational drugs MedWatch), which might promote more diseases or conditions, but it could be prior to approval, the time required for consistent collection of reliable used to initiate discussions among formal review could affect expediting information. One comment also stated patient and disease advocacy drug development, and FDA’s plan that FDA should consider compiling a organizations, the relevant medical would result in fewer expanded access database of evidence derived from specialty professional society, programs. expanded access uses for use by pharmaceutical companies with (Response) In enunciating this policy, patients, clinicians, manufacturers, and products that could possibly be made FDA did not intend to limit the conduct researchers to help identify areas that available for expanded access, FDA, and of open-label safety studies intended to researchers might pursue for new other interested parties to help identify evaluate particular safety concerns, such treatments and therapies. barriers to access. As to the comment’s as long-term followup of subjects (Response) FDA agrees that more specific recommendation that a tracking initially enrolled in a randomized trial, standardized data collection methods system include information on patients safety studies in pediatric development and forms could ease some of the and investigators, whether or not programs, and other safety studies. documentation burdens associated with requests for expanded access are These types of studies are legitimate expanded access. However, FDA does granted, and if not, the reason for not open-label protocols and are an integral not believe it is in a position, at this granting such requests, the outcomes of part of a drug development program. time, to be able to describe in regulation the treatments, and costs, if any, to FDA will continue to encourage such or guidance the form and content of data patients who pay for their treatments, studies as appropriate. collection programs specific to FDA does not believe that such a system However, FDA continues to believe expanded access uses. FDA is willing to is necessary at this time, nor do that the treatment IND process is a more participate in collaborative efforts with resources permit establishment of such appropriate vehicle for providing access interested constituents to develop better a system. to investigational drugs for treatment data collection methods. FDA does not use to large populations outside believe that data collected from 8. Open-Label Safety Studies controlled clinical trials late in a drug’s expanded access use would, in most In the preamble to the proposed rule development. The treatment IND cases, be in a form that would be useful (71 FR 75147 at 75155), FDA expressed provides appropriate patient safeguards for hypothesis generation. It is concern that sponsors have used and permits FDA the necessary important to note, however, that programs other than treatment INDs or oversight over the development information about some expanded treatment protocols to make program. And as FDA explained in the

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preamble to the proposed rule (71 FR administration of the investigational associated with investigational drugs 75147 at 75155), authorization of drug. and ancillary care provided under expanded access use is subject to a more One comment from a health insurance expanded access programs. FDA agrees formal review process that explicitly company stated that the design of that drugs made available under considers the impact of expanded access insurance benefits already recognizes expanded access programs are typically on enrollment in any ongoing clinical that some patients should receive investigational and not approved for trials and the progress of drug benefit coverage for treatments that are marketing. However, FDA takes no development generally. The time for not yet supported by clinical evidence, position on how the terms ‘‘reasonable,’’ review of a treatment use program both in clinical trials and as treatment ‘‘necessary,’’ or ‘‘medically necessary’’ should not affect the timing of drug for promising but unproven treatments in health insurance contracts should be development because the need for such for life-threatening illnesses outside of interpreted. an expanded access program and the clinical trials. The comment asked FDA to clarify in the rule that therapies 10. Waiver of Liability for Harm Related protocol for the program can be to Expanded Access considered in advance and put in place provided under expanded access when needed. Therefore, FDA does not programs are experimental and not (Comment 17) One comment from a believe this policy will result in fewer FDA-approved and that making these pharmaceutical company stated that the expanded access programs. therapies available for treatment use proposed rule does not address the (Comment 15) One comment asked does not provide evidence that such significant liability issues for sponsors whether only patients with a serious treatments are ‘‘reasonable,’’ and investigators arising from making disease or condition could be enrolled ‘‘necessary’’ or ‘‘medically necessary,’’ investigational drugs available for expanded access. Many comments from in open-label studies that FDA would as defined in benefit documents. The individuals stated that receiving consider to be treatment INDs. comment stated that third-party payers would welcome a more standardized investigational drugs under expanded (Response) One of the threshold approach to the treatment of diseases access programs should be premised on criteria for a treatment IND is that the without established therapies, a patient’s waiver of liability for harm population to be enrolled has a serious particularly because these rules raise resulting from treatment with the or immediately life-threatening disease questions about responsibility for investigational drug. These comments or condition. Therefore, only protocols routine costs associated with otherwise maintained that liability should be intended to treat patients with serious excluded care. waived for doctors, hospitals, drug or life-threatening diseases or (Response) FDA’s intent in manufacturers, and FDA. conditions are subject to this promulgating the expanded access (Response) FDA does not believe it is requirement. regulation is to foster the availability of appropriate to insulate investigators or It should be noted that FDA has not investigational drugs for treatment use sponsors, whether they are treating taken the position that the agency will to as many patients with serious and physicians, hospitals or other clinical consider all open-label safety studies to life-threatening diseases as possible who settings, or drug manufacturers, from be treatment INDs. FDA will not lack known effective therapies for their potential liability arising from the consider an open-label safety study to disease or condition. FDA recognizes administration or provision of be a treatment IND when the purpose of that determinations that investigational investigational drugs for treatment use. the study is actually to study the safety drugs made available under expanded In fact, FDA’s informed consent profile of the drug. access programs, and patient care regulation, 21 CFR 50.20, states, ‘‘No 9. Insurance Coverage for Investigational related to administration of those drugs, informed consent, whether oral or Drugs and Related Patient Care Drug are not reimbursable would be likely to written, may include any exculpatory Coverage limit access to such therapies for some language through which the subject or patients (e.g., those who lack the the representative is made to waive or (Comment 16) Several comments were financial resources to pay out-of- appear to waive any of the subject’s concerned about the potential pocket). It is FDA’s hope, therefore, that legal rights, or releases or appears to implications of the proposed rule on health insurers and other third-party release the investigator, the sponsor, the coverage decisions by health insurers payers will make well-reasoned institution, or its agents from liability and other third-party payers. Some reimbursement decisions that will not for negligence.’’ The scope of FDA’s comments were concerned that, because impinge on the availability of liability, if any, for any harm resulting the drug made available is investigational drugs for treatment use. from decisions concerning expanded investigational, third-party payers To the extent that it is an insurer’s access to investigational drugs for would deny coverage for the drug and policy that care necessitated by treatment use is determined by statute may also deny coverage for patient care administration of an investigational and cannot be modified by a waiver necessitated by use of the drug. One drug in a clinical trial is reimbursable, provision in a regulation. comment noted an example of a patient FDA believes that care associated with seeking expanded access to an administration of an investigational 11. Inconsistency Between Subpart I investigational drug who would be drug in an expanded access program and Subpart E required to have frequent, expensive should be treated similarly for The expanded access regulations use monitoring, including reimbursement purposes. However, the terms ‘‘immediately life threatening electrocardiograms (EKGs) and monthly FDA recognizes it has no inherent disease or condition’’ and ‘‘serious Computed Tomography (CT) scans, and authority to dictate reimbursement disease or condition.’’ who might not be able to obtain access policy. (Comment 18) One comment if health insurance did not reimburse for FDA also recognizes that this final suggested that there was a discrepancy the required monitoring. One comment rule may have implications for health between terminology used in the argued that the goals of expanded access insurance coverage decisions because of proposed rule (subpart I of part 312) and are illusory if third-party payers do not existing language in health insurance terminology used in subpart E of part reimburse for drug costs (if any) and contracts and how that language is 312. The proposed rule uses the term routine patient care necessitated by interpreted with respect to costs ‘‘immediately life-threatening,’’ while

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subpart E uses the term ‘‘life- REMS, FDA did not intend that an when the drug is subject to elements to threatening.’’ The proposed rule uses expanded access IND under subpart I be assure safe use under a REMS. We will the term ‘‘serious,’’ while subpart E uses used to provide the approved drug to assess the impact of this rule on the term ‘‘severely debilitating.’’ The patients with a serious disease or expanded access to drugs subject to a comment recommended that this final condition when the approved drug is REMS and, if appropriate, will consider rule clear up the confusion arising from being used for an unapproved issuing a guidance on this matter. the use of similar but different terms in indication. Regardless of whether an In response to the comment on FDA regulations. approved drug is being tested in a insurance reimbursement, we note that (Response) The subpart I regulations clinical trial to treat a serious disease or FDA does not have jurisdiction over are being issued in response to a condition that is not part of the current coverage decisions by health insurance provision of FDAMA, now codified in approved indication, use of an approved companies and, in any case, is not section 561 of the act (21 U.S.C. drug off-label for an unapproved aware that allowing expanded access to 360bbb). The terms used in this final indication within the practice of an already approved drug under subpart rule are consistent with and drawn from medicine (i.e., to treat a patient in a I would influence coverage decisions by the terminology in section 561. clinical setting) is not subject to part 312 health insurance companies. Accordingly, any change to make the (the IND regulations), including subpart (Comment 20) One comment notes terms consistent would require revision I. By definition, in such a case, the drug that § 312.300(a) states that the intent is to subpart E. This final rule deals only is already being legally marketed. to make investigational drugs available with subpart I, and thus the comment However, in at least two situations, to ‘‘seriously ill patients,’’ while the asks for a remedy that is outside the expanded access under subpart I may be general criteria in § 312.305(a) require scope of this rule. appropriate for drugs that are already that patients to be treated with an Moreover, we note that subpart E and approved: First, it is conceivable that a investigational drug have ‘‘a serious or subpart I have different purposes. sponsor developing an approved drug immediately life-threatening disease or Subpart E provides procedures to for a new indication for treatment of a condition.’’ The comment pointed out expedite the development, evaluation, serious or immediately life-threatening that a patient can have a serious disease and marketing of new therapies. Subpart disease or condition may want to make or condition and not be seriously ill, for I provides procedures for making the approved drug available for the new example, in the early stages of a investigational drugs available when the indication under a treatment IND. For progressive disease. primary purpose is to diagnose, example, if the new indication involves (Response) FDA acknowledges that monitor, or treat a patient’s disease or a different route of administration or the use of the term ‘‘seriously ill’’ in the condition. Nonetheless, if subpart E dosage form, the sponsor may prefer to provision describing the intended scope were to be amended, FDA would then provide the new dosage form under a of the access provision could be consider the propriety of the treatment IND if it believes that failure interpreted as narrower in scope than terminology used in subpart E. to make the drug available under a was intended, and thus inconsistent treatment IND could lead to with the term ‘‘serious or immediately C. Comments on Specific Provisions of compounding of the drug (e.g., life-threatening disease or condition.’’ the Proposed Rule preparation of a new dosage form of a Therefore, FDA has changed 1. Scope (§ 312.300 and 312.300(a)) drug by a compounding pharmacist § 312.300(a) to make clear that subpart using the active ingredient of an I is intended to apply to all those with Proposed § 312.300(a) describes the approved drug product) and that such a serious disease or condition, whether intended scope of subpart I of part 312. compounding could expose patients to or not the patient would currently be It makes clear that the purpose of unnecessary risks. FDA would be considered seriously ill with that subpart I is to describe processes for amenable to receiving treatment INDs disease or condition. making investigational drugs available for unapproved uses of approved drugs in situations in which the primary in situations in which the sponsor 2. Definitions (§ 312.300(b)) purpose is to diagnose, monitor, or treat would prefer the use of a treatment IND a. Immediately life-threatening a serious or immediately life-threatening to make the drug available for treatment disease or condition. disease or condition in a patient who use outside the ongoing or completed Proposed section 312.300(b) defines has no comparable or satisfactory controlled trials of the unapproved use. the term ‘‘immediately life-threatening alternative therapeutic options. Second, for drugs that are subject to disease’’ as a stage of disease in which (Comment 19) Three comments asked a REMS, expanded access under subpart there is a reasonable likelihood that that FDA clarify whether it intended I may be available to allow treatment of death will occur within a matter of that an expanded access IND be used to patients who do not otherwise meet the months or in which premature death is make an approved drug available for an criteria under the REMS to receive the likely without early treatment. unapproved indication in a situation in drug. (Comment 21) One comment which a sponsor is conducting a clinical For these reasons, we have revised expressed support for the proposed trial of the approved drug under an IND § 312.300(a) to state that subpart I rule’s definition of the term for a new indication to treat a serious contains the requirements for the use of ‘‘immediately life-threatening disease’’ disease or condition. Two of these investigational new drugs and approved and encouraged FDA to include this comments urged that FDA modify the drugs where availability is limited by a definition in the final rule. One proposed rule to make clear that it REMS when the primary purpose is to comment maintained that the proposed applies to unapproved uses of approved diagnose, monitor, or treat a patient’s definition of immediately life- drugs. The comments believed that such disease or condition. This fulfills the threatening was unnecessary because modification would make it more likely mandate, codified in 505–1(f)(6) of the immediately life-threatening conditions that health insurance companies would act, for the Secretary of Health of are a subset of serious conditions and reimburse for unapproved use of Human Services to promulgate thus need not be defined. approved drugs. regulations concerning how a physician (Response) The proposed rule defined (Response) In general, for an already may provide a drug under the the term ‘‘immediately life-threatening approved drug that is not subject to a mechanisms of section 561 of the act disease’’ because the evidentiary criteria

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for authorizing a treatment IND under meant by the term would make access deliberations concerning what should proposed § 312.320 vary depending on to investigational drugs for treatment be considered a serious disease or whether the disease or condition is use overly broad. One of those condition and has served the agency merely serious or is also immediately comments argued that a definition well in its implementation of the Fast life-threatening. There is a lower would promote more consistent Track legislation. The Fast Track evidentiary threshold for a treatment application of the rule. One comment guidance (p. 4) states that whether a IND for an immediately life-threatening recommended that the definition err on disease or condition is serious ‘‘is a condition. The evidentiary distinction the side of inclusiveness. One comment matter of judgment, but generally is and definition are carried over from the asked for clarification of what is meant based on its impact on such factors as previous treatment IND regulation and by serious disease or condition because survival, day-to-day functioning, or the reflect the distinction between section it is unclear what serious conditions likelihood that the disease, if left 561(c)(6) and (c)(7) of the act. Because would have an important effect on untreated, will progress from a less the final rule retains the lower functioning or other aspects of quality of severe condition to a more serious one. evidentiary standard for authorizing a life as well as persistent or recurrent * * * For a condition to be serious, the treatment IND for an immediately life- morbidity. condition should be associated with threatening condition, FDA believes it is Some comments provided morbidity that has substantial impact on necessary to retain the definition. recommendations or specific language day-to-day functioning. Short-lived and (Comment 22) One comment from an on how to define serious disease or self-limiting morbidity will usually not organization representing epilepsy condition. Two comments be sufficient but the morbidity need not centers asked the agency to define recommended relying on existing be irreversible, provided it is persistent immediately life-threatening in such a language in the Fast Track guidance (pp. or recurrent.’’ FDA believes this way that it would include status 3 to 4). One comment recommended definition is also conceptually epilepticus and pointed out that the defining serious disease or condition consistent with the criteria identified in mortality rate from status epilepticus is based on the following criteria in a 1999 the IOM report, the definition of serious up to 6 percent. Institute of Medicine (IOM) Report adverse drug experience in the IND (Response) A disease or condition entitled ‘‘Definition of Serious and safety reporting regulation, and the with an acute mortality rate of six Complex Medical Conditions.’’ The IOM description of serious disease or percent would be considered an report gave the following examples of condition in the preamble to 21 CFR immediately life-threatening condition descriptive criteria for serious and part 314, subpart H (Accelerated for purposes of subpart I. complex medical conditions: Approval of New Drugs for Serious or b. Serious disease or condition. • Conditions that cause serious Life-Threatening Illnesses). Therefore, In the preamble to the proposed rule disability, such as stroke or closed head we have adopted this definition of (71 FR 75147 at 75151), the agency or spinal cord injuries. serious disease or condition in explained that, because of the difficulty • Conditions that cause significant § 312.300(b). in specifically describing regulatory pain or discomfort that can cause FDA recognizes, based on its own criteria that characterize a ‘‘serious serious interruptions to life activities, experience in trying to define and disease or condition,’’ the proposed rule such as arthritis and sickle cell disease. describe what is meant by serious does not provide a definition for the • Conditions that may require disease or condition, that this definition term. Because it is difficult to define frequent monitoring, such as will be subject to various ‘‘serious disease or condition’’ without schizophrenia and other psychotic interpretations. FDA intends to be appearing to exclude diseases or illnesses. flexible in its interpretation of the term conditions that should be considered • Conditions whose treatment carries to ensure that the definition does not serious or include those that should not, the risk of serious complications, such thwart access to an investigational drug FDA in the proposed rule elected to as most cancers or conditions requiring in a situation where access would be describe and illustrate by example what complex surgery. desirable. It is foreseeable that there is meant by serious disease or condition Another comment recommended that might even be situations in which a in other regulatory settings where the the definition of serious disease or serious health risk in the absence of seriousness of a disease or condition is condition be made consistent with the active serious disease should be an issue (e.g., Fast Track, Accelerated definition of serious adverse drug considered a serious condition. For Approval) (see FDA’s guidance for experience in § 312.32(a) (the definition example, it may be desirable to make an industry entitled ‘‘Fast Track Drug used for the IND safety reporting experimental vaccine available as a Development Programs—Designation, requirements), which defines a serious prophylactic measure to laboratory Development, and Application Review’’ adverse drug experience as including workers who have been inadvertently (Fast Track guidance) (63 FR 64093, inpatient hospitalization or exposed to a deadly pathogen but have November 18, 1998)). The preamble prolongation of existing hospitalization, not yet contracted the disease. solicited comment on this approach for a persistent or significant disability/ Notwithstanding the potential pitfalls in purposes of expanded access— incapacity, or a congenital anomaly/ defining serious disease or condition, implicitly asking whether the term birth defect. based on the views expressed in the should be defined or the agency’s (Response) Because of the support for comments received, FDA believes that previous practice of describing the defining the term ‘‘serious disease or stating a definition is preferable to concept and illustrating by example was condition’’ in the comments, FDA is providing only an explanation and acceptable. providing a definition in the final rule. illustration of the concept of serious (Comment 23) Several comments As recommended by some comments, disease or condition and will facilitate stated that FDA should define ‘‘serious FDA is basing the definition on the more consistent and equitable disease or condition.’’ No comments description of a serious disease or application of the expanded access recommended not defining the term. condition in the Fast Track guidance. regulations. Three comments stated that not defining That description and illustration of (Comment 24) One comment stated the term and relying on existing serious disease or condition was the that intractable epilepsy should be descriptions and illustrations of what is result of prolonged and careful considered a serious disease or

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condition. Another comment was b. Risk/benefit assessment— not be made by FDA reviewers. The concerned that in situ breast cancer evidentiary standards. comment also stated that this provision would not be considered a serious Proposed § 312.305(a)(2) provides that ‘‘represents a sea change’’ in FDA’s disease or condition for purposes of the FDA must determine that the potential policy because it would regulate the expanded access regulations. patient benefit justifies the potential practice of medicine. (Response) FDA agrees that risks of the treatment use and that those Another comment stated that the risk- intractable epilepsy and in situ breast risks are reasonable in the context of the benefit decision to be made for cancer would be considered serious disease or condition to be treated. For individual patient expanded access conditions for purposes of the expanded individual patients, proposed should be made only by the patient’s access regulations as each would § 312.310(a)(1) further provides that the physician, not also by FDA. The unquestionably cause morbidity and physician seeking access for a patient comment objected to the proposed potentially premature mortality if left must also determine that the probable criterion that FDA determine that the untreated. risk to the person from the potential patient benefit justifies the investigational drug is not greater than potential risks of the treatment use and 3. Requirements for All Expanded the probable risk from the disease or that those potential risks are not Access (§ 312.305) condition. For intermediate-size patient unreasonable in the context of the Proposed § 312.305 contains the populations, proposed § 312.315(b)(1) disease or condition to be treated general criteria for determining whether further provides that FDA must (§ 312.305(a)(2)). The comment argued access to investigational drugs for determine that there is enough evidence that, in interposing itself into the risk- treatment use is appropriate under the that the drug is safe at the dose and benefit decision, FDA had expanded access uses described in duration proposed for expanded access impermissibly changed the statutory subpart I (§ 312.305(a)), the general use to justify a clinical trial of the drug standard for deciding whether to grant submission requirements for the in the approximate number of patients individual patient expanded access. The expanded access INDs described in expected to receive the drug under comment recognized that section subpart I (§ 312.305(b)), and safeguards expanded access, and proposed 561(b)(2) of the act requires the applicable to those expanded access § 312.315(b)(2) provides that FDA must Secretary to determine that there is uses (§ 312.305(c)). determine that there is at least sufficient evidence of safety and Proposed § 312.305(a)(1) states that preliminary clinical evidence of effectiveness to support the use of the FDA must determine that the patient or effectiveness, or of a plausible investigational drug in an individual population to be treated has a serious or pharmacologic effect of the drug, to patient. However, the comment stated immediately life-threatening disease or make expanded access use a reasonable that this provision does not empower condition and there is no comparable or therapeutic option in the anticipated FDA to make a risk determination. (Response) FDA disagrees with the satisfactory alternative therapy to patient population. For treatment INDs or treatment protocols, § 312.320(a)(3)(i) recommendation to remove the diagnose, monitor, or treat the disease or further provides that for a serious requirement that the agency determine condition. disease or condition, there must be whether the potential patient benefit a. Comparable or satisfactory sufficient evidence of safety and justifies the potential risks and whether alternative therapy. effectiveness to support the use, which those risks are reasonable in the context (Comment 25) One comment from a would ordinarily consist of data from of the disease or condition to be treated. cancer patient appeared to assert that phase 3 trials but could consist of FDA also rejects the characterization of there should be more flexibility in compelling data from completed phase this policy as a ‘‘sea change.’’ This assessing whether there are comparable 2 trials. Section 312.320(a)(3)(ii) policy reflects the essence of FDA’s satisfactory or alternative therapies. The requires that, for an immediately life- long-standing approach to using comment stated that certain comparable threatening disease or condition, the investigational drugs for treatment use, alternative therapies may be more toxic available scientific evidence taken as whether under individual patient INDs and patients exposed to those therapies whole must provide a reasonable basis or multi-patient INDs, and reflects the may become too sick to survive any to conclude that the investigational drug act’s requirement of FDA involvement subsequent treatment, thus barring them may be effective for the expanded access in a determination of the propriety of from access to a promising experimental use and would not expose patients to an the expanded access use (see section treatment. unreasonable and significant risk of 561(b)(2), (b)(3), (c)(6), and (c)(7) of the (Response) FDA shares the comment’s illness or injury. Such evidence would act). The practice-of-medicine concern that existing alternative ordinarily consist of clinical data from exemption in the IND regulations therapies may have greater toxicity than phase 3 or phase 2 trials, but could be applies to use of an approved drug for an experimental treatment option, based on more preliminary clinical an unapproved use in a clinical setting, especially in the oncology setting. FDA evidence. not to the use of an unapproved drug. believes that the relative toxicity of (Comment 26) One comment from a With regard to treatment access to an potential alternative therapies is clearly physician with investigational drug approved drug subject to a REMS, an element to be considered in whether experience asked that FDA remove the because the risk profile of such a drug there are comparable or satisfactory requirement that the agency must means that it is not available for alternative therapies for a given patient. determine that the potential patient unrestricted use, FDA maintains a role, The potential lower toxicity of an benefit justifies the potential risks of the consistent with sections 505–1(f)(6) and experimental therapy would be treatment use and those potential risks 561 of the act, in assessing the considered in light of the more are not unreasonable in the context of appropriateness of the drug for established effectiveness profile of the the disease or condition to be treated. treatment use analogous to its role approved therapy, the patient’s ability The comment maintained that the regarding treatment access to to tolerate the approved therapy, and seriously ill patient and his/her investigational drugs. other clinical factors in assessing physician should be the ones to decide As to the comment that FDA has whether the approved therapy is a whether or not to accept the risks of the impermissibly aggregated to itself the satisfactory alternative therapy. treatment and that the decision should risk benefit decision to be made for

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individual patient expanded access, the there should no expanded access until standard is warranted. FDA believes comment itself acknowledges that the completion of phase 2 testing, and that to require less evidence would section 561(b)(2) of the act states that then only if the phase 2 data are significantly increase the likelihood that the criteria for individual patient compelling. Another comment patients would be more harmed than expanded access include that the recommended that there be no benefited by use of experimental Secretary determines that there is expanded access until evidence of a therapies. ‘‘sufficient evidence of safety and drug’s safety and effectiveness has been Conversely, FDA does not believe that effectiveness to support the use of the demonstrated in clinical trials that will there should categorically be a specified investigational drug.’’ If FDA were to be submitted for approval, which would minimum amount of data, such as data accede to the comment’s interpretation usually be data from phase 3 trials but from completed phase 2 or 3 trials, that the risk determination belongs may include phase 2 data. Other before any expanded access is solely to the physician, it would comments were concerned that the permitted. As detailed in the preamble effectively read out of existence section proposed rule required too much to the proposed rule (71 FR 75147 at 561(b)(2) of the act. In that section, evidence to obtain an investigational 75168), FDA believes there needs to be Congress expressly directed FDA to drug for treatment use. Those comments flexibility in the evidentiary standards make a determination regarding the believe that the evidentiary standards to be applied to the varied types of sufficiency of the evidence of both would inappropriately deny access to expanded access INDs and expanded safety and effectiveness to justify investigational drugs to some patients. access protocols that the agency is likely treatment use of an investigational (Response) The assessment of the to receive. Moreover, even if a specified product. While section 561(b)(1) of the risks and benefits of investigational minimum amount of data for expanded act requires a physician to make a therapies in the absence of complete access were desirable, FDA believes that determination that the probable risk to data about the safety and effectiveness completion of phase 2 or 3 testing is the patient is not greater than the of those therapies is challenging and more than should be required for certain probable risk from the disease or subject to varied interpretations and types of expanded access INDs and condition, this finding is a necessary, viewpoints. FDA believes the proposed expanded access protocols. rule strikes an appropriate balance and but not in itself sufficient, prerequisite (Comment 28) One comment argued sets forth a reasonable approach to to providing a drug for individual that access has the potential to increase balancing risks and benefits. That treatment use. Section 561(b)(2) of the the risk to patients with the possibility approach, as outlined in the discussion act clearly contemplates a determination of no commensurate benefit. The above, requires an assessment of risk by FDA regarding safety and comment maintained that safety issues and benefit based on the relative effectiveness, and the agency cannot related to exposure to an investigational seriousness of the disease or condition choose to ignore that responsibility. drug are best addressed in the context and the size of the population to be of clinical trials and asked FDA to (Comment 27) Some comments were treated under the expanded access IND require that access be provided only concerned that the proposed rule did or protocol—with the evidentiary not provide an adequate balance requirements decreasing as seriousness under a defined protocol, by a qualified between risks and benefits and, in increases and the size of the population investigator, with defined dosage range particular, did not provide a sufficiently decreases. Increasing the amount of and adverse event monitoring high evidentiary standard for providing evidence needed as the size of the procedures, and with specified time access, and as a result would expose population exposed increases is based intervals for assessing response. patients to unnecessary risks. One on FDA’s considerable experience with (Response) FDA agrees that access comment stated that because many of the clinical development of drugs that protocols should provide a detailed plan the drugs that would be made available demonstrates the need to cautiously for the conduct of the protocol, under access programs are highly likely increase the size of exposure in order to including plans for data collection and to prove ineffective in further clinical detect serious toxicities that occur in patient monitoring commensurate with testing, exposure to such drugs may not small percentages of those exposed (and the size of the population to be treated improve patients’ conditions and, in are thus not likely to be detected in a and the nature of the use (e.g., short- some cases, may increase patient small population exposure). Decreasing term versus long-term). However, suffering and hasten death. One the amount of evidence needed as the because of the broad range of potential comment provided an apparent seriousness of the disease or condition populations for which access may be illustration of the potential harm. The increases simply acknowledges that provided under an expanded access comment pointed out that autologous patients in greater peril are willing to protocol—from an individual patient to bone marrow transplants were assume greater risks. many thousands of patients—and the performed on approximately 30,000 FDA recognizes that investigational wide range of potential risks and women with advanced breast cancer drugs have risks, including unknown resulting need for variations in the before it was established that such risks, and that it is likely that some intensity of monitoring, it would not be treatment did more harm than good and drugs made available for treatment use good policy to require the same level of that, as a result, some of the women will ultimately be shown to have no detail and specificity for each protocol. who received this treatment had benefit, and in fact cause harm. As a The amount of detail and specificity increased suffering and shortened lives. result, there is the potential for some required will increase with increasing One comment stated that a patient patients to be harmed by such drugs. size of the population, increasing should have some assurance that an However, FDA believes that, on balance, complexity of the disease being treated, investigational drug may be potentially more patients are likely to gain some and greater risks associated with the use life-saving that would outweigh any benefit from investigational drugs than of the drug. For the same reasons, the potential negative risks of using the be harmed by them and, therefore, amount of data to be collected and the drug. Some comments maintained that, patient interests are best served by potential utility of that data might vary. until there is a certain threshold of data making such drugs available under Accordingly, FDA believes it would not available, there should be no access appropriate programs. FDA does not be useful to promulgate specific and whatsoever. One comment argued that believe that a lesser evidentiary uniform data collection and monitor

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requirements for all expanded access evidentiary threshold for individual (Comment 30) Two comments protocols. patient expanded access be evidence recommended that FDA have different i. Individual Patient Evidentiary from the clinical trials intended to evidentiary standards for individual Standard demonstrate safety and effectiveness for patient expanded access for patients Proposed § 312.310(a)(1) provides that marketing approval (which would with a serious disease or condition and the physician seeking access for a ordinarily be phase 3 studies but could the subset of those patients with an patient must determine that the include phase 2 studies that support immediately life-threatening disease or probable risk to the person from the approval). The comment added, condition. For immediately life- investigational drug is not greater than however, that this category could be threatening diseases or conditions, one the probable risk from the disease or used to provide continuity of care for a comment recommended that there be condition. Concerning the evidence patient who appeared to benefit from a data from completed phase 1 testing at needed before treating an individual drug during participation in an earlier doses similar to those to be used in the patient with an immediately life- clinical trial. treatment use and preliminary evidence threatening illness or disease or (Response) FDA agrees that making an suggesting possible effectiveness. The condition, the preamble to the proposed investigational drug available to an other comment recommended that the rule stated that to support expanded individual patient in the absence of any evidentiary standard that applies to access for an individual patient when clinical data to support the use may treatment INDs for immediately life- the patient has an immediately life- carry substantial risk. FDA does not threatening diseases or conditions apply threatening condition that is not believe, however, that access under to individual patient treatment use for responsive to available therapy, such circumstances should be entirely such conditions (i.e., the available ordinarily, completed phase 1 safety foreclosed by the expanded access scientific evidence taken as whole testing in humans at doses similar to provisions. FDA believes—and our provides a reasonable basis to conclude those to be used in the treatment use, experience has demonstrated—that that the investigational drug may be together with preliminary evidence there are circumstances in which such effective for the expanded access use suggesting possible effectiveness, would use may be appropriate. These and would not expose patients to an be sufficient to support such a use. circumstances might involve a patient unreasonable and significant risk of However, the preamble further stated with an imminently life-threatening illness or injury). Such evidence would that in some cases, there may be no disease or condition, a novel therapy ordinarily consist of clinical data from relevant clinical experience, and the that has a plausible pharmacologic phase 3 or phase 2 trials, but could be case for the potential benefit may be rationale suggesting it may potentially based on more preliminary clinical based on preclinical data or on the be beneficial for that disease or evidence. For individual patient mechanism of action (71 FR 75147 at treatment use for serious diseases or 75151). condition, and robust nonclinical safety data to support the use. FDA does agree conditions, both comments (Comment 29) Several comments were recommended that there be evidence of concerned that the evidentiary that use of an investigational drug for treatment purposes in an individual safety and effectiveness from phase 3 standards applicable to individual trials, although in some circumstances patient in the absence of any clinical patient expanded access allow for the compelling data from phase 2 trials may data should be extremely rare. FDA possibility of making a drug available to be sufficient (the same standard that anticipates that authorizing an a patient without evidence from clinical applies to treatment INDs for serious individual patient treatment use of a experience. One comment stated that ‘‘it diseases or conditions). is wrong to permit use in the absence of drug in the absence of clinical data on (Response) As discussed in the evidence in humans and to present this use of the drug for that indication would previous response, FDA believes that scenario as ‘treatment’ even for be more likely to occur when there was the suggested evidentiary requirements desperately ill patients.’’ Another some clinical data on the drug (e.g., are too high a barrier to access for comment stated that ‘‘it seems from a study for another use) but no individual patient treatment use. Where inappropriate and possibly dangerous to clinical data in the population or the population exposed to an permit this relatively uncontrolled disease for which treatment use is experimental therapy is small (in this access to an investigational drug to sought. case, a single individual), the amount of represent the first human exposure to a However, FDA does not agree that safety and effectiveness evidence drug.’’ Another comment recommended there should be no expanded access to needed to support the use is less than that there be at least preliminary clinical an investigational drug for anyone until would be needed to allow exposure in evidence (such as phase 1 safety testing) the evidence needed to support the size population that might be treated before there be any expanded access use approval is developed, which ordinarily under a treatment IND (often more than regardless of the number of patients. would not occur until the completion of 1,000 patients). One comment recommended that the phase 3 clinical testing. In addition, In contrast to treatment INDs, which final rule state that proceeding with FDA does not believe the expanded usually occur very late in a drug’s treatment use in an individual patient access provisions in subpart I are development, individual patient should be a rare circumstance that necessary to provide continuity of care treatment use may be sought quite early requires, at a minimum, submission to for patients who seemed to have in a drug’s development, and at any FDA of robust evidence from responded to an investigational therapy point during the development. nonclinical studies to show that it is during a clinical trial. A protocol Therefore, FDA also believes it is reasonably safe to proceed with the amendment adding a continuation important to have flexibility in the proposed treatment use, and phase to the clinical trial would evidentiary standards to permit it to information forming the basis from ordinarily be the preferred mechanism respond appropriately to wide nonclinical toxicokinetic studies and for providing an investigational therapy variations in the amount and nature of nonclinical pharmacology studies for to clinical trial participants who wish to evidence that might be presented in selecting dosage, dosage interval, and continue to receive the drug after the support of an individual patient IND. duration of treatment for use in patients. completion of the controlled phase of Thus, FDA would prefer to avoid One comment recommended that the the clinical trial. evidentiary standards pegged to data

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from specific phases of drug might be presented in support of an access under treatment INDs to development. FDA also believes a two- intermediate-size population IND. Thus, programs initiated very late in the drug tiered evidentiary standard—one FDA rejects the recommendation to development process. The comment standard for serious diseases and have evidentiary standards pegged to noted that if phase 3 data are required, conditions and a lower standard for data from a specific phase or phases of a treatment IND would typically only immediately life-threatening diseases or drug development. Again, because of provide access to the investigational conditions—is unnecessary for the flexibility inherent in the drug for a matter of months (i.e., the individual patient INDs because the evidentiary standards for intermediate- time between the initiation of a relative seriousness of the disease or size patient population INDs, FDA does treatment IND and approval of a drug condition is an implicit component of not believe it is necessary or useful to for marketing would be relatively short) the risk-benefit assessment for have different standards for serious and thus would not meet the needs of individual patient INDs, and the current diseases or conditions than for patients or substantially help small evidentiary standard allows for immediately life-threatening diseases or biotech companies. The comment considerable flexibility in the amount conditions. argued that to be truly useful, either and nature of evidence needed to iii. Treatment IND or treatment treatment INDs or treatment protocols support an individual patient IND. protocol evidentiary standards. need to be available based upon phase ii. Intermediate-size patient Proposed § 312.320(a)(3)(i) provides 1 data (at least in cases where population evidentiary requirements. that for a treatment IND or treatment appropriate because of the severity of Proposed § 312.315(b)(1) provides protocol for a serious disease or the disease and a relatively benign that, for expanded access under condition, there must be sufficient safety profile for the drug), the intermediate-size population INDs or evidence of safety and effectiveness to intermediate population programs need protocols, FDA must determine that support the use, which would ordinarily to be able to go well above 100 patients there is enough evidence that the drug consist of data from phase 3 trials, but (i.e., up to 500 or 1,000 patients), or is safe at the dose and duration could consist of compelling data from there needs to a fourth category between proposed for expanded access use to completed phase 2 trials. Section the intermediate and the large justify a clinical trial of the drug in the 312.320(a)(3)(ii) provides that, for an populations programs. Another approximate number of patients immediately life-threatening disease or comment stated that the proposed rule’s expected to receive the drug under condition, the available scientific evidentiary requirements for a treatment expanded access. Proposed evidence taken as whole must provide IND raise the bar to a level effectively § 312.315(b)(2) provides that FDA must a reasonable basis to conclude that the equivalent to the amount of data determine that there is at least investigational drug may be effective for required to obtain marketing approval. preliminary clinical evidence of the expanded access use and would not effectiveness or of a plausible expose patients to an unreasonable and (Response) FDA believes that the pharmacologic effect of the drug to significant risk of illness or injury. Such proposed evidentiary requirements for make expanded access use a reasonable evidence would ordinarily consist of authorizing treatment use under a therapeutic option in the anticipated clinical data from phase 3 or phase 2 treatment IND effectively balance patient population. trials, but could be based on more making an investigational drug available (Comment 31) One comment preliminary clinical evidence. to a substantial number of patients who recommended that FDA have different (Comment 32) Two comments were might benefit from the drug with evidentiary standards for intermediate- concerned that the proposed evidentiary simultaneously protecting those patients size expanded access for serious standards for authorizing a treatment from unreasonable risks associated with diseases or conditions and intermediate- IND or treatment protocol were not the drug. Our experience with this size expanded access for immediately sufficiently rigorous to protect patients. standard—spanning more than two life-threatening diseases or conditions. One comment recommended that, for decades—supports this assessment. For INDs for immediately life- treatment INDs or treatment protocols Moreover, the evidentiary standards threatening diseases or conditions, the for serious diseases or conditions, only provide a certain amount of flexibility, comment stated that there should be data from phase 3 clinical trials should particularly in the case of a treatment some preliminary evidence of clinical be used to assess the potential benefits IND to treat an immediately life- effectiveness. For INDs for serious and risks of the drug. The comment also threatening disease or condition, so that diseases or conditions, the comment recommended that for a treatment IND FDA can make investigational therapies recommended that there be evidence of or treatment protocol for immediately- available to substantial numbers of safety data from completed phase 1 life threatening diseases or conditions, patients as early in the development testing at doses similar to those to be only data from phase 3 clinical trials or process as is reasonably possible. FDA used in the treatment use and compelling data from phase 2 trials believes that more rigorous or inflexible preliminary evidence suggesting should be considered. One comment standards would present an possible effectiveness. objected to the proposed evidentiary inappropriate barrier to obtaining a (Response) Because intermediate-size standard for a treatment IND or a treatment IND in some cases. FDA also population INDs can occur earlier in treatment protocol for an immediately believes that relaxing these standards drug development than treatment INDs life-threatening disease or condition could potentially expose significant and because there are three different because it would permit authorization numbers of patients receiving intermediate-size population access of expanded access on the basis of investigational drugs under a treatment scenarios (for a drug being developed, clinical data more preliminary than IND to unnecessary harm. A key tenet for a drug not being developed, and for phase 2 or 3 data. of drug development is to gradually an approved or related drug that is not Two comments were concerned that increase the size of the population available through marketing channels), the evidentiary standards for a treatment exposed to an investigational drug so as FDA must have flexibility in the IND were overly rigorous. One comment to be able to detect relatively low- evidentiary standards to permit it to stated that requiring safety and frequency, serious toxicity as early as respond appropriately to variations in effectiveness data from phase 3 or phase possible, and before very large numbers the amount and nature of evidence that 2 studies limits the use of expanded of patients have been exposed. This

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principle applies with equal force to the stringent evidentiary standard for a a treatment IND for a serious disease or use of investigational drugs for treatment IND or treatment protocol for condition in § 312.320(a)(3) of this final treatment use. a serious disease or condition than was rule. FDA wishes to emphasize that the contained in FDA’s previous regulation c. Non-interference with drug evidentiary standards for a treatment in § 312.34. Section 312.34 was not development. IND are not the functional equivalent of specific about the nature of the evidence Proposed § 312.305(a)(3) states that, the amount and type of data needed for that would be needed to support a for all expanded access uses, FDA must marketing approval. The standards treatment IND for a serious, as opposed determine that providing the provide a degree of flexibility that to immediately life-threatening, disease investigational drug for the requested enables FDA to authorize a treatment or condition. Rather, the general use will not interfere with the initiation, IND on the basis of data often well short discussion in § 312.34(a) suggested an conduct, or completion of clinical of that needed to obtain marketing earliest point in time at which such a investigations that could support approval. FDA also does not believe that treatment IND could be allowed to marketing approval of the expanded there needs to be a fourth category of proceed (‘‘in appropriate circumstances, access use or otherwise compromise the treatment use in between an a drug may be made available during potential development of the expanded intermediate-size patient population phase 2’’). FDA has always interpreted access use. For a treatment IND, IND and a treatment IND. As discussed that requirement to mean that a proposed § 312.320(a)(1) also requires elsewhere in this preamble, FDA treatment IND for a serious, but non-life- FDA to determine that the drug is being intends that there be sufficient threatening, disease or condition would investigated in a controlled trial under flexibility in the size of the population have to be supported by some phase 2 an IND designed to support a marketing that might be treated under an data (controlled trial data on the disease application for the expanded access use, intermediate-size population IND to of interest), but that phase 2 did not or that all clinical trials of the drug have enable treatment of as many patients as have to be completed. Or, to put it been completed, and that the sponsor is is supported by the available evidence another way, at least one phase 2 trial actively pursuing marketing approval of of safety and effectiveness. would have to have been completed, but the drug for the expanded access use (Comment 33) One comment objected others could be ongoing. FDA has never with due diligence. to the proposed rule’s evidentiary interpreted this provision to mean that (Comment 34) Several comments standard for a treatment IND or a treatment IND for a serious disease or expressed concern that the proposed treatment protocol for a serious disease, condition could proceed without any rule would seriously impede the asserting that it was higher than both phase 2 data. Therefore, FDA believes initiation and completion of clinical the statutory and current regulatory that stating in this final rule that data trials and drug development generally. standards and thus further restricted needed to support for a treatment IND A number of comments stated that, access. The comment noted that section for a serious disease or condition could given a choice, patients would be more 561(c)(1) of the act only requires consist of compelling data from phase 2 likely to try to obtain an investigational ‘‘sufficient’’ evidence of safety and trials is consistent with the statement drug under an expanded access IND or effectiveness. The comment also noted that a drug may be made available for protocol than to participate in a clinical that § 312.34(a) of FDA’s current treatment use during phase 2. trial of the drug (and, for example, risk regulations allows drugs to be made FDA also does not agree that randomization to another treatment). available during Phase 2 ‘‘in appropriate characterizing the phase 2 data needed Two comments argued that making circumstances.’’ The comment pointed to support an treatment IND for a drugs more widely available under out that § 312.320(a)(3) of the proposed serious disease or condition as expanded access INDs would have a rule provides that the evidence needed compelling raises the bar compared to domino effect in which decreased for a treatment IND or treatment that in § 312.34. That provision made enrollment in clinical trials would lead protocol would ordinarily consist of clear that a treatment IND for a serious to less rigorous trial protocols, less data from phase 3 trials, but could disease or condition would ordinarily useful data, and ultimately decrease the consist of compelling data from not be permitted until some point amount of safety and efficacy completed phase 2 trials. The comment during phase 3 or at a point when all information on approved drugs. stated that, under the proposed rule, controlled trials were completed. To (Response) FDA believes that the phase 2 trials would have to be permit a treatment IND to proceed provisions in the proposed rule completed, not merely ongoing, thus during phase 2 was plainly intended to requiring that expanded access raising the standard for expanded access be an exceptional circumstance. FDA programs not impede clinical for treatment INDs and treatment does not believe that ambiguous, development of the investigational drug protocols. The comment also stated that inconclusive, or marginally statistically that is being made available for FDA has also raised the standard significant phase 2 data would justify treatment use are adequate to mitigate because the data would have to be the exceptional circumstance of the impact of expanded access on ‘‘compelling’’ The comment suggested permitting a treatment IND for a serious clinical development. In the case of that because of design limitations, many disease or condition based on phase 2 individual patient expanded access phase 2 trials could be considered not data. Therefore, FDA believes it is INDs, an individual patient is not compelling. The comment suggested reasonable to characterize the phase 2 eligible to obtain access under an that the proposed rule may result in data needed as compelling. FDA also individual patient expanded access IND treatment INDs and treatment protocols disputes the contention that the design if the patient can participate in a being less frequent than under FDA’s of a typical phase 2 could not yield clinical trial of the drug or obtain the current regulations. The comment stated compelling data. drug under a larger access IND. In the that the final rule should use the For the reasons stated previously, case of an intermediate-size patient language in § 312.34(a) of FDA’s current FDA also does not agree that there will population IND for a drug being regulation instead of the new proposed be fewer treatment INDs and treatment developed, the intent of such an IND is language in § 312.320(a)(3). protocols for serious disease or to make a drug available to patients who (Response) FDA does not agree that conditions because of the way FDA cannot enroll in a clinical trial; the proposed rule articulates a more articulated the evidentiary standard for therefore, there would be no effect on

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drug development. The other two of noninterference with clinical trials. finding that FDA must make under intermediate-size patient population First, the comment asserted that with section 561(c) of the act, which applies IND scenarios do not involve drugs that regard to ‘‘widespread’’ treatment INDs, to treatment INDs. are being actively developed. In the case the criteria imposed by § 312.305(a)(3) The comment seems to be based on of a treatment IND, in FDA’s experience, were broader than the authority in the mistaken assumption that under sponsors usually do not initiate section 561(c)(5) of the act and section 561(c)(5), the only treatment INDs until the clinical studies impermissibly permitted FDA to refuse determination that FDA must make is needed to support approval are to approve requests for expanded access whether an investigational drug will completed or fully enrolled. However, it for reasons other than the proposed ‘‘interfere with the enrollment of is possible to authorize a treatment IND treatment use’s effect on enrollment of patients in ongoing clinical before clinical trials needed to support clinical trials. The comment referred to investigations.’’ However, under section marketing approval are fully enrolled. In the proposed rule’s criterion that 561(c)(4) of the act, FDA also must such cases, it would be important for providing expanded access will not determine that the sponsor of the FDA to closely monitor the implications interfere with the initiation, conduct, or controlled clinical trial is actively of the treatment IND on the rate of completion of clinical investigations pursuing marketing approval of the accrual of subjects into the clinical trial that could support marketing approval investigational drug with due diligence. and other clinical development of the expanded access use or otherwise Such active pursuit of marketing milestones. compromise the potential development approval with due diligence implicitly (Comment 35) Some comments asked of the expanded access use includes a determination that the FDA to specify how it will determine (§ 312.305(a)(3)), and urged that the treatment use will not interfere with the that making an investigational drug final rule use statutory language rather initiation, conduct, or completion of available for treatment use will not than that used in the proposed rule. clinical investigations that could interfere with clinical trials or drug Second, in a section related to support marketing approval for the development generally. One comment individual patient access to investigational drug, which is why FDA stated that the expanded access rule investigational drugs, the comment included those particular terms in the should contain more explicit criteria for argued that FDA lacks statutory regulation. FDA could have simply determining that expanded access does authority for the proposed rule’s restated the statutory language in the not detrimentally affect clinical trials. product development criteria. regulation, but since the regulation (Response) FDA believes the criteria Specifically, the comment noted that in implementing the statute is aimed, in are sufficiently explicit to enable FDA to the case of the single patient IND, part, at shedding light on how FDA meaningfully assess the impact of an Congress gave FDA authority to interprets the statute, the agency expanded access program on authorize a single patient IND if the believes the proposed language provides development, and also provide FDA the Secretary determines that ‘‘provision of more helpful guidance than merely flexibility to ask for varied types of the investigational drug * * * will not restating the terms from the statute assurances that access will not impede interfere with the initiation, conduct, or without more. development, depending on the completion of clinical investigations to Regarding the argument that the particular situation. For example, before support marketing approval.’’ The statutory language does not allow FDA authorizing a treatment IND for an comment objected to the phrase ‘‘or to require a determination that investigational drug for which clinical otherwise compromise the potential provision of the investigational drug for trials are ongoing, FDA could seek development of the expanded access treatment use will not ‘‘otherwise specific assurances from the sponsor use’’ in proposed § 312.305(a)(3). compromise the potential development that the treatment IND would not (Response) FDA disagrees with the of the expanded access use,’’ FDA interfere with accrual of patients in the comment. Regarding the first assertion, disagrees for reasons similar to those clinical trial. FDA would likely request that FDA has applied a more stringent explained previously. In § 312.305(a)(3), that the sponsor submit a provision on noninterference with which is applicable to all treatment comprehensive investigational plan clinical trials than is called for in the uses, FDA included this term to with a timetable and milestones to its section of the act relating to expanded generically address other criteria IND (if it had not done so already), so access for treatment INDs, FDA required under different sections of that FDA could periodically assess disagrees that the language in section 561, including section 561(b)(4), whether the treatment IND is having an § 312.305(a)(3) impermissibly expands (c)(3) and (c)(4). FDA does not intend to effect on accrual or other parameters the grounds on which FDA may reject use this catchall language as a limitless related to the pace of clinical a proposed treatment IND. Section means to deny treatment use of development. If FDA determines that 312.305(a)(3) provides that, for all types investigational drugs. Rather, the intent the treatment IND is slowing the pace of of expanded access, FDA must is to endow the implementing drug development or the sponsor is not determine that providing the regulation with sufficient flexibility to actively pursuing marketing approval investigational drug for the requested allow FDA to address situations where with due diligence, FDA can place the use ‘‘will not interfere with the potential development of the treatment treatment IND on clinical hold. It is also initiation, conduct, or completion of use would be compromised by a worth noting that it is likely not in the clinical investigations that could particular treatment proposal, for sponsor’s interest to delay development support marketing approval of the instance, where a proposed use would because it delays marketing approval expanded access use or otherwise usurp the entire population of patients and commercial sale of the drug. compromise the potential development who might be studied in controlled Therefore, sponsors are unlikely to of the expanded access use.’’ While clinical trials. This particular regulatory provide expanded access in situations admittedly much of this language language is motivated by one of the core in which drug development would be matches terminology found in section notions underlying the act—namely, impeded. 561(b)(3) of the act, which applies to recognition that the best form of access (Comment 36) One comment raised individual patient treatment access and to a drug is full marketing approval. two objections to the provisions of the access by small groups of patients, it d. Impeding development of related proposed rule relating to FDA’s finding also generally describes the type of drug products.

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(Comment 37) One comment because such approval would impede enrollment or the demographics of the expressed concern about the potential development of a competing product is trial because those patients would not for expanded access to impede clearly not in the best interests of the have been able to participate in the development of other drug products public health because it would deny clinical trial because of geographical being developed for the same or a patients access to a proven effective constraints. similar indication as the investigational therapy. There do not appear to be any (Comment 40) One comment asked drug being sought for treatment use. The other regulatory options that could whether there have ever been any comment recommended that requests mitigate the impact on development or investigational drugs made available for expanded access include a statement approval of a related drug. through a treatment IND that were not that the public list of clinical trials has (Comment 38) One comment stated subsequently approved for marketing. been reviewed and the patient is not that expanded access would be more (Response) Yes, there have been drugs eligible or is otherwise unable to likely to impede development in the that were made available under a participate (e.g., because of distance) in early stages of drug development and treatment IND that did not obtain available studies. Another comment the development of orphan drugs. marketing approval. However, for these cited an example of a situation in which (Response) FDA agrees that expanded drugs, the failure to obtain marketing enrollment in a clinical trial had access has greater potential to impede approved was not due to the treatment decreased following accelerated development when a drug is available IND interfering with the clinical approval of drugs for the same use under an access IND early in development program. under subpart H. development, particularly if the access (Response) FDA acknowledges the is widespread. For this reason, FDA 4. Expanded Access IND Submission possibility that a large expanded access must determine that a patient seeking Requirements IND for a given product could impede access to an investigational drug under Section 312.305(b) describes the concurrent development of other an individual patient expanded access content of an IND submission or products for the same or a similar IND cannot participate in a clinical trial protocol amendment for expanded indication because trials for those of the drug or obtain the drug under a access. In the event that a licensed products would be competing with the larger expanded access IND or protocol physician, as opposed to a commercial access program for the same patient (§ 312.310(a)(2)). Similarly, an sponsor, is making the IND submission, population. However, requiring that the intermediate-size patient population it provides that the licensed physician sponsor of a proposed expanded access IND intended for a drug being may provide some of the required IND demonstrate that the expanded developed is intended to make the drug information by obtaining a right of access use will not impede development available only to those who cannot reference to the content of the existing of not only its drug but of any other participate in a clinical trial of the drug IND. Proposed § 312.305(b)(2) requires drug in clinical development for the (§ 312.315(a)(2)). FDA believes that that an expanded access submission same use would seem to present an these provisions should minimize the include: unreasonable obstacle to access. For potential for these types of expanded • A cover sheet (Form FDA 1571) example, it is not clear how a sponsor access INDs to impede drug meeting the requirements of § 312.23(a); would be able to demonstrate no effect development. • The rationale for the intended use on the development of a related therapy FDA also agrees that expanded access of the drug, including a list of absent some proprietary knowledge for drugs for orphan diseases has added therapeutic options that would about the development plans of the potential to impede drug development ordinarily be tried before resorting to related therapy. Because there is no due to the relatively smaller population the investigational drug or an obvious way that the sponsor of a from which clinical trial subjects can be explanation of why the use of the proposed expanded access plan could drawn. FDA will carefully evaluate any investigational drug is preferable to the provide proof that the plan would have expanded access submission for an use of available therapeutic options; no effect on another company’s orphan drug to ensure that the data • The criteria for patient selection or, development program, such needed to support approval of the for an individual patient, a description determinations would have to rely orphan product will not be of the patient’s disease or condition, primarily on conjecture. For that reason, compromised by the expanded access including recent medical history and such a requirement would likely be use. previous treatments of the disease or applied inconsistently and, as a result, (Comment 39) One comment condition; could unnecessarily deny access to maintained that expanded access would • The method of administration of the patients in desperate circumstances. be more likely to decrease clinical trial drug, dose, and duration of therapy; FDA also does not believe that the participation in more rural communities • A description of the facility where sponsor of a competing therapy under and that even if clinical trials were still the drug will be manufactured; development should have the ability to able to accrue adequate numbers of • Chemistry, manufacturing, and cause an ongoing expanded access IND subjects, the demographics of controls information adequate to ensure to be put on hold, as would be the case participation in clinical trials could be proper identification, quality, purity, if FDA were to require a sponsor to skewed toward more urban populations. and strength of the investigational drug; show that the expanded access IND (Response) FDA disagrees. The agency • Pharmacology and toxicology would not interfere with another believes that expanded access programs information adequate to conclude that company’s development program, and would have a neutral effect on clinical the drug is reasonably safe at the dose the other company were to demonstrate trial enrollment in rural areas because and duration proposed for the treatment such interference. the same criteria apply in rural and use (ordinarily, information that would FDA also acknowledges the potential more urban settings. Admittedly, be adequate to permit clinical testing of for marketing approval of a related patients in rural areas are more likely to the drug in a population of the size product for the same or a similar be unable to enroll in a clinical trial expected to be treated); and indication to impede development of because of geographical constraints, but • A description of clinical drugs for that indication. However, providing access to those patients procedures, laboratory tests, or other denial or delay of marketing approval would have no effect on clinical trial monitoring necessary to evaluate the

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effects of the drug and minimize its population if there is no existing IND or submission requirements present an risks. if the sponsor of the IND will not obstacle to the vast majority of patients (Comment 41) One comment asked provide the information needed to who seek to obtain investigational drugs whether the proposed submission support the expanded access request. for treatment use under the expanded requirements for expanded access apply The comment added that physicians access regulations, and the agency is to both sponsors and sponsor- may not know whether an IND exists or convinced that the requirements are an investigators. The comment also asked how to find that out. essential component of human subject whether some of the required (Response) In FDA’s experience, the protection. information could be incorporated into vast majority of expanded access INDs (Comment 43) Two comments the protocol rather than provided as for individual patients are for expressed the view that many parts of separate documents in the IND investigational drugs in development, Form FDA 1571 may not be appropriate submission, including the rationale for and submissions are made on behalf of for use by an individual doctor for the intended use of the investigational patients unable to participate in clinical expanded access purposes. The drug with a list of generally available trials. In these situations, the comments asked that FDA provide a treatment options and an explanation as submission requirements are not streamlined version of Form FDA 1571 to why they are not preferable, criteria onerous. The commercial sponsor that is that is specific to individual patient for patient selection, a description of the developing the drug may make a expanded access. One comment patient’s disease or condition (including submission for individual patient access recommended that FDA encourage or recent medical history), and previous as a protocol amendment to its existing require standard nomenclature on treatment use (for an individual patient IND, in which case the licensed expanded access submissions so such submission). physician must only provide the submissions could be readily (Response) The submission sponsor with the required information distinguished from non-expanded requirements are sponsor requirements about the individual patient. access submissions. The comment and thus are intended to apply to both Alternatively, the commercial sponsor stated that for a treatment IND, the sponsors and sponsor-investigators. The may elect only to provide the drug and sponsor should make two entries to Item listing of general submission require the physician to submit his or 11 of the 1571: Check the box for requirements in § 312.305 is not her own IND. In this situation, the INITIAL INVESTIGATIONAL NEW intended to convey the impression that commercial sponsor routinely permits DRUG APPLICATION, and enter each element of the submission be the licensed physician to refer to any ‘‘OTHER: Treatment IND’’ on the blank contained in a separate document. As needed information in its existing IND, line. For an expanded access protocol the comment points out, certain so, again, the licensed physician usually under an existing IND, the comment required submission elements are topics only has to provide the relevant suggested that the sponsor also make that are appropriate for inclusion in a information about the physician’s two entries to Item 11 of the 1571: single protocol. Other elements, such as patient. In each of these scenarios, the Check the box for PROTOCOL pharmacology/toxicology and information the licensed physician must AMENDMENT: NEW PROTOCOL, and chemistry, manufacturing, and controls provide is ordinarily readily available in enter ‘‘OTHER: New Protocol for (CMC), may more typically be found in patient medical records. Expanded Access’’ on the blank line. separate documentation. FDA’s primary In rare circumstances, a licensed (Response) FDA agrees that it is concern is not with the number of physician may seek to obtain access for desirable to be able to readily individual documents submitted, but an individual patient to an distinguish expanded access that the required elements be submitted investigational drug not being submissions from non-expanded access in a form that makes the information developed. If a drug is not being submissions. FDA does not believe, readily accessible and leaves no developed and has never been the however, that a new form specific to question that the submission contains subject of an IND, the submission expanded access is necessary to the necessary information. requirements become more complex. accomplish this task. FDA believes that a. Submissions for individual patient There may be other sources that could instructions for filling out Form FDA expanded access. provide some of the necessary 1571 for expanded access purposes and (Comment 42) Several comments information (e.g., materials data sheets) standardized nomenclature will suffice, expressed concern that individual to minimize the burden on the helping sponsors to complete the form physicians would not be able to comply physician to an extent. However, FDA appropriately and helping FDA to with the submission requirements for must have reasonable assurances about readily identify expanded access expanded access for an individual the integrity and safety of the product, submissions. FDA may develop patient. The comments stated that most so the IND submission will require a guidance to provide instructions for individual physicians will not have significant amount of information completing Form FDA 1571 and sample access to the drug’s CMC or concerning the manufacturing of the completed forms for each type of pharmacology and toxicology product and its pharmacology/ expanded access. information. One comment stated that toxicology profile for FDA to permit use b. Intermediate-size population IND FDA sometimes raises difficult of the drug for the expanded access use. submission requirements. manufacturing, pharmacology, FDA’s guidance for industry entitled In addition to the general submission toxicology, pharmacokinetic, clinical, ‘‘Content and Format of Investigational requirements, proposed § 312.315(c) and statistical issues, and these issues New Drug Applications (INDs) for Phase describes requirements specifically sometimes result in physicians 1 Studies of Drugs, Including Well- applicable to submissions for withdrawing expanded access requests. Characterized, Therapeutic, intermediate-size population expanded One comment opined that the Biotechnology-derived Products,’’ access INDs. Proposed § 312.315(c)(1) submission requirements for individual provides some insight into the amount requires that the submission state patient expanded access may have the and nature of the information that whether the drug is being developed or unintended effect of rendering the would be required in these situations. not being developed. For a drug not proposed rule relatively meaningless for However, because these situations are being developed, proposed the vast majority of the patient rare, FDA does not believe that the § 312.315(c)(2) requires that the sponsor

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explain why the drug cannot currently (Comment 46) One comment asked expanded access IND or protocol under be developed and under what where in the electronic common subpart I is considered a sponsor for circumstances the drug could be technical document (eCTD) to include purposes of part 312) use the term developed. the submission information that is ‘‘person’’ rather than ‘‘individual or (Comment 44) One comment specific to intermediate-size patient entity.’’ The comment pointed out that requested that the requirements in population INDs. ‘‘person’’ is defined in the act and proposed § 312.315(c)(2) and (c)(3) be (Response) The eCTD does not includes ‘‘individual, partnership, removed because they do not seem distinguish INDs of different-size corporation, and association.’’ relevant to the determination of whether patient populations. The information (Response) The term ‘‘individual or access is appropriate for the specific to an intermediate-size patient entity’’ is based on, and intended to be intermediate-size group. population IND would go in the same shorthand for, language in the definition (Response) FDA disagrees. One of location as one for a treatment IND or of a ‘‘sponsor’’ in § 312.3(b) that states FDA’s primary concerns with making a single patient treatment IND. that a sponsor may be an ‘‘individual or investigational drugs available for pharmaceutical company, governmental 5. Safeguards for Expanded Access treatment use is the potential for agency, academic institution, private treatment use to prevent the Proposed § 312.305(c) explains how organization, or other organization.’’ development of information necessary the responsibilities of sponsors and Because the term relates to an existing to demonstrate safety and effectiveness investigators set forth in subpart D definition of sponsor in the IND by usurping a population that could (Responsibilities of Sponsors and regulations, and because in FDA’s have been enrolled in a clinical trial. Investigators) of part 312 apply to experience that definition has been clear FDA believes that section 561 of the act expanded access INDs. Proposed and effective in describing who or what contemplates that expanded access to § 312.305(c)(1) states that a licensed may be considered a sponsor for investigational drugs is not appropriate physician under whose immediate purposes of part 312, FDA prefers to when that access prevents the direction an investigational drug is retain the language in the proposed rule. development of important safety and administered or dispensed for expanded b. Sponsor and investigator effectiveness information that could access use is considered an investigator responsibilities. have been developed if there were no for purposes of part 312 and, therefore, Proposed § 312.305(c)(5) provides that expanded access. Requiring a sponsor to must comply with the responsibilities for all expanded access INDs, sponsors explain why no development is possible for investigators set forth in subpart D are responsible for submitting IND when a drug is not being developed at to the extent they are applicable to the safety reports and annual reports (when all, or why a clinical trial cannot be expanded access use. Proposed the IND or protocol continues for 1 year conducted to study the treatment use § 312.305(c)(2) states that an individual or longer) to FDA as required by when a drug is being developed for a or entity that submits an expanded §§ 312.32 and 312.33, ensuring that use other than the treatment use, access IND or protocol under subpart I licensed physicians are qualified to squarely addresses FDA’s concerns. is considered a sponsor for purposes of administer the investigational drug for (Comment 45) One comment part 312 and must comply with the expanded access use, providing licensed recommended that before concluding responsibilities for sponsors set forth in physicians with the information needed that a patient or patient population is subpart D to the extent they are to minimize the risk and maximize the ineligible to enroll in a clinical trial for applicable to the expanded access use. potential benefits of the investigational purposes of this requirement, the Proposed § 312.305(c)(3) states that a drug (e.g., providing the investigator’s investigator, sponsor, and FDA should licensed physician under whose brochure if there is one), maintaining an carefully consider whether the clinical direction an investigational drug is effective IND for the expanded access study protocol could be amended to administered or dispensed, and who use, and maintaining adequate drug include the patient population submits an expanded access IND, is disposition records and retaining contemplated for treatment use without considered a sponsor-investigator and records in a manner consistent with the affecting the safety of the subjects or the must comply with the responsibilities of requirements of § 312.57. integrity of the study. sponsors and investigators in subpart D Proposed § 312.310(c)(3) further (Response) FDA agrees that the to the extent applicable to the expanded provides that FDA may also require optimal solution would be to somehow access use. sponsors to monitor an individual incorporate the potential intermediate- Proposed § 312.305(c)(4) provides that patient expanded access use if the use size treatment use population in an for all expanded access INDs, is for an extended duration. Proposed ongoing clinical trial by modifying the investigators are responsible for § 312.315(d)(2) states that the sponsor is inclusion/exclusion criteria while not reporting adverse events to the sponsor, responsible for monitoring the compromising safety or study integrity, ensuring that the informed consent intermediate-size population expanded or to enroll that population in a new requirements in part 50 (21 CFR part 50) access protocol to ensure that licensed study. FDA expects that sponsors would are met, ensuring that an IRB review of physicians comply with the protocol have explored all reasonably possible the expanded access use is obtained in and the regulations applicable to avenues for studying the patient a manner consistent with the investigators. Proposed § 312.320(c) population before seeking an expanded requirements of part 56 (21 CFR part states that the sponsor is responsible for access IND for treatment use in that 56), and maintaining accurate case monitoring the treatment protocol to population and that the submission histories and drug disposition records ensure that licensed physicians comply would explain why those avenues were and retaining records in a manner with the protocol and the regulations foreclosed. By requiring the sponsor to consistent with the requirements of applicable to investigators. explain why the population for which § 312.62. (Comment 48) One comment stated an intermediate-size expanded access a. ‘‘Person’’ v. ‘‘individual or entity.’’ that making physicians investigators for IND is sought is not eligible to be (Comment 47) One comment purposes of part 312 will be daunting enrolled in a clinical trial, FDA is recommended that proposed and extremely time-consuming and that encouraging, at least implicitly, this § 312.305(c)(2) (which states that an the typical gastroenterologist not thought process. individual or entity that submits an affiliated with a large teaching or

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research hospital will not be able to manufacturer/supplier, FDA sees no concern that may affect the risk-benefit satisfy these requirements. obstacle to the drug manufacturer/ assessment. (Response) FDA disagrees. For a supplier requiring, as a condition of (Response) FDA strongly disagrees. licensed physician providing access making the drug available to the FDA believes that all adverse events under an individual patient IND, the physician, that the physician agree to identified in expanded access uses responsibilities of an investigator provide the drug manufacturer/supplier should be reported to FDA in the closely parallel those necessary for with copies of all adverse event reports manner described in §§ 312.32 and providing routine patient care. For provided to FDA. 312.33. FDA’s primary interest is the example, the information about a In addition, in the preamble to the expedited reporting of serious and patient that a physician is required to proposed rule (71 FR 75147 at 75153), unexpected events as required by submit to obtain an IND would usually FDA expressed a strong preference for § 312.32(c). Data collected on be derived from the patient history and having commercial sponsors make nonserious or expected events from progress notes. In most cases, the investigational drugs available for expanded access use, in particular from remaining IND submission requirements treatment use under amendments to exposure of an individual patient or would be largely satisfied by obtaining their INDs rather than requiring small number of patients to a drug, is a right of reference to an IND physicians to obtain their own INDs. In not as useful as data collected from maintained by a commercial sponsor, that scenario, the physician is required controlled trials that may identity which is usually easily obtained. Any to report adverse events to the differences in event rates across required monitoring of the course of commercial sponsor under § 312.64. treatment groups (e.g., control group, treatment with the investigational drug (Comment 50) One comment across different doses). Nonetheless, would be similar to the type of suggested that adverse events for information from expanded access monitoring provided as part of routine individual patient INDs should be exposures on these types of adverse patient care. The patient outcomes addressed in a separate section of the events can still contribute to the safety information required to be submitted NDA or biologics license application assessment of a new molecular entity after treatment with the investigational (BLA) instead of being included in the (e.g., corroborate observations in other drug would closely parallel the content integrated summary of safety. The settings). In general, FDA believes it is of a typical discharge summary. comment stated that this approach important that a drug’s safety Therefore, FDA believes that, in most would help alleviate manufacturers’ assessment consider adverse events cases, the IND obligations imposed on concerns that allowing individual observed in the entire population licensed physicians by this final rule patient INDs (typically involving exposed to a drug. would not be significantly more especially sick patients) would (Comment 52) One comment inquired burdensome than the recordkeeping and exaggerate adverse events for the about how to report adverse events for patient evaluation required in the broader population. approved drugs made available under course of routine clinical care of a (Response) FDA does not believe it is an expanded access IND. patient. necessary or helpful to exclude adverse (Response) For an approved drug c. Adverse event reporting. events information from individual made available under an expanded (Comment 49) One comment from a patient INDs from the integrated access IND (e.g., in a circumstance in pharmaceutical company asked whether summary of safety (ISS) in an NDA. The which an approved drug is subject to a licensed physicians who obtain an ISS is intended to evaluate adverse restricted distribution agreement that investigational drug for expanded access events information from the total limits prescribing to a certain disease or use under their own INDs are required population exposed to a drug. The condition, and a patient is seeking to report adverse events to both the analysis takes into account the relative access to the drug for another use), pharmaceutical company supplying the strength of the data and the adverse events must be reported to FDA drug and FDA. The comment characteristics of subjects who under the IND in accordance with maintained that it is important for the experienced adverse events that may § 312.305(c)(5). pharmaceutical company developing bear on causality. For example, data d. Obtaining Informed Consent for the drug to be informed of any adverse indicating that an adverse event Expanded Access Use. events observed in expanded access use. occurred in multiple subjects in the (Comment 53) Many comments from (Response) Because the physician IND drug treatment arm of a controlled trial individual consumers stated that it is holder is both investigator and sponsor is much more reliable than adverse particularly important for patients in this scenario, the physician is not events information from uncontrolled, receiving investigational drugs in required by the IND regulations to individual patient expanded access expanded access programs to receive report adverse events to the drug exposures in patients who are very ill. full disclosure of the risks, and to fully manufacturer who provided the drug to The implication that inclusion of understand the risks, associated with the physician. The regulations require adverse events information from the investigational therapy. Two only that adverse events observed by the individual patient expanded access comments were very concerned that investigator (the physician) be reported exposures over-emphasizes negative patients receiving investigational drugs to the sponsor, who is also the safety information is unfounded and for treatment use not be misled about physician in this scenario. The plainly inconsistent with the the likelihood that the treatment will be physician, in his or her capacity as a methodology FDA uses to analyze drug beneficial. One comment stated that sponsor, is required to report adverse safety. many patients are led to believe that events to FDA and other investigators (Comment 51) Two comments stated access to an investigational intervention (not relevant for individual patient that, for investigational new molecular is their best hope, but often it is a false access), including reporting of serious entities, adverse event reporting for hope. Another comment stated that and unexpected adverse events in an expanded access use should be limited patients with immediately life- expedited manner. However, although to serious adverse events and deaths threatening conditions are extremely there is no regulatory provision that unless there are specific adverse events vulnerable and may not fully would require physicians to report that are identified a priori because they comprehend the information they are adverse events to the drug are related to an identified safety provided about a drug by health care

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practitioners. Another comment expanded access problems, in particular related to obtaining access, and the recommended that FDA provide issues concerning informed consent in particular concerns related to obtaining guidance on how to obtain informed vulnerable populations (see, e.g., parts informed consent from patients consent from patients who are 50 and 56). receiving investigational drugs for candidates to receive an investigational (Comment 55) One comment stated treatment use. FDA does not believe, drug for treatment use. that informed consent documents must however, that it is necessary to require (Response) FDA agrees that patients reflect that patients cannot expect to in regulation that IRBs have special who are candidates to receive personally benefit from the drug, but processes and procedures for reviewing investigational drugs under expanded that the knowledge gained from the expanded access protocols. Existing access programs, because they have experiment will help other patients in regulations already require IRBs to serious or immediately life-threatening the future. consider the vulnerable nature of the diseases or conditions and have (Response) FDA disagrees. The population that will receive an exhausted other treatment options, are a comment seems to misunderstand the investigational drug and to ensure that particularly vulnerable population. overarching purpose of expanded risks are minimized (which would Therefore, they should be afforded a access—to make investigational drugs necessarily involve some consideration rigorous informed consent process that available for treatment purposes to of whether there are any lower-risk effectively communicates the risks and patients with serious or immediately treatment options), and § 50.25(a)(4) potential benefits of any investigational life-threatening diseases or conditions requires that an informed consent therapy to be used for treatment use in and with no other treatment options disclose appropriate alternative a way that does not raise false because the investigational drugs could procedures or courses of treatment, if expectations about a positive outcome conceivably benefit these patients—not any, that might be advantageous to the from treatment and makes clear what is to systematically investigate the use of subject. unknown about the drug. Because of the the drug for the disease or condition. (Comment 57) One comment stated vulnerable nature of expanded access Treatment use under an expanded that a patient receiving expanded access patients, FDA encourages submission of access mechanism, in contrast to should be competent to give informed informed consent documents intended evaluation of an investigational drug in consent. to be used for expanded access a clinical trial, is not intended primarily (Response) While FDA agrees that programs to FDA for review. FDA will to develop data that could be used to valid informed consent is a necessary also consider whether guidance on how benefit future patients. However, as prerequisite to receiving an to obtain informed consent from such FDA made clear in response to comment investigational product in an expanded patients is needed. 54, patients receiving investigational access setting, FDA does not agree that (Comment 54) One comment stated drugs for treatment use should be access to investigational drugs under that because expanded access does not afforded a rigorous informed consent expanded access programs should be technically involve ‘‘research’’ or a process that is careful not to overstate limited to only those who are competent ‘‘clinical investigation,’’ the the expected benefits of the to give their own informed consent, if requirements and principles for investigational drug and is otherwise that is the intended implication of the obtaining the informed consent of cognizant of the inherent vulnerabilities comment. FDA’s regulations concerning subjects participating in clinical and information needs of patients protection of human subjects informed investigations in part 50 may not seeking access to investigational drugs consent (part 50) recognize that a adequately address the range of issues for treatment use. subject may not be competent to give that would arise in obtaining the (Comment 56) One comment informed consent and that valid informed consent of patients receiving recommended that before an IRB can be informed consent may be given by the investigational drugs under expanded allowed to review expanded access subject’s legally authorized access programs. The comment programs, FDA should require the IRB representative. Section 50.20 defines recommended that the expanded access to establish special criteria to ensure ‘‘legally authorized representative’’ as regulations include requirements that physicians have discussed all an individual or judicial or other body concerning the specific information that treatment options with patients as part authorized under applicable law to must be included in informed consent of the informed consent process and consent on behalf of a prospective documents for expanded access that patients and their families fully subject to the subject’s participation in programs. understand the experimental and the procedure(s) involved in the (Response) Again, because of the investigational nature of a drug or other research. The same definition should vulnerable nature of the typical patient therapy, the types and degrees of apply to treatment with an or population to receive an unknown risks, and the potential investigational product under an investigational drug under an expanded positive and negative health outcomes. expanded access program. access program, FDA agrees that (Response) Because patients seeking (Comment 58) One comment patients in expanded access programs access to investigational drugs for recommended requiring that IRBs should be afforded a rigorous informed treatment use are a particularly establish criteria for the length and consent process tailored to the unique vulnerable group and the intent is readability of informed consent issues that arise in the expanded access treatment of a disease or condition, as documents. context. FDA does not believe, however, opposed to a clinical investigation of the (Response) This comment is beyond that it is necessary to add specific use, FDA believes it is important for IRB the scope of this rule. The rule does not informed consent requirements to the review to be particularly sensitive to the address the requirements on IRBs and expanded access regulations or to unique issues raised by use of the comment raises a concern broader amend the informed consent regulations investigational drugs in expanded than expanded access. to incorporate specific requirements for access programs. FDA agrees that it e. IRB review of expanded access use. expanded access. FDA believes that would be useful for an IRB that is likely (Comment 59) Some comments were existing informed consent regulations to review expanded access use to be concerned that the requirement for IRB adequately address the range of issues familiar with the nature of expanded review was a potential obstacle to relevant to informed consent for access protocols, the rules and processes making investigational drugs available

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for treatment use under expanded FDA does not believe that current protections provided clinical trial access INDs, particularly for individual regulations provide authority for IRB participants by the IRB review process. patient INDs. One comment maintained review of individual patient expanded FDA equally strongly believes that all that the IRB review process is slow, access INDs by less than the full IRB. patients considering treatment with an tedious, cumbersome, and requires too The IRB regulations provide for investigational therapy under an much documentation, and that expedited review—under which an IRB expanded access IND should be fully physicians are not familiar with the IRB review may be done by only one or a informed about the risks and potential process. The comment suggested that small number of IRB members—of new benefits of the experimental therapy, some type of centralized IRB may be INDs or protocols only under minimal including disclosure that safety and needed for small- to medium-sized risk situations (§ 56.110(b)). Use of an effectiveness have not been established, access programs. Another comment investigational drug for treatment and give their informed consent prior to noted that in academic research settings, purposes would not be considered being treated with an investigational there is intensive IRB approval and minimal risk and, therefore, does not therapy. Patients seeking access to oversight, and recommended that FDA meet the criteria for expedited review. investigational therapies under explore standardizing expanded access Revising the IRB regulations to provide expanded access programs often are in program protocols so that some of the for a more limited IRB review of somewhat dire clinical circumstances administrative work, in particular IRB individual patient expanded access and thus are a particularly vulnerable submissions, can be lessened. One INDs involves significant human subject population. Therefore, such patients are, comment recommended that, for protections issues that were not arguably, even more in need of the individual patient expanded access considered in this rulemaking and, human subjects protections provided by INDs, FDA reduce or limit the scope of therefore, such revision is beyond the IRB review and informed consent than the requirement for IRB review because scope of this rulemaking. many clinical trial participants. (Comment 60) One comment stated of the time, difficulty, and, in some (Comment 61) One comment that FDA should eliminate the proposed cases, the expense (e.g., when a recommended the elimination of the requirements for IRB review and commercial IRB must be used) of requirements for prior IRB review and obtaining informed consent for obtaining IRB review. The comment approval in accordance with part 56 and individual patient treatment use INDs. recommended that FDA permit review the requirement for written informed The comment maintained that the use of by a subset of the full IRB or waive IRB consent in accordance with part 50 for an investigational drug for treatment use review if a drug has completed phase 1 individual patient expanded access use safety testing (see response to comment is not part of a clinical investigation and therefore beyond the intended scope of (but recommended the retention of these 60 for discussion of why waiver of IRB requirements for intermediate-size review is not a viable option). parts 56 and 50. The comment further argued that these safeguards are population and treatment INDs). The (Response) FDA recognizes that there unnecessary for individual patient comment argued that use of an are circumstances in which IRB review treatment use because there is an investigational drug for the emergency for an expanded access use, particularly established physician-patient treatment of individual patients is not an individual patient use, may be relationship and, therefore, individual part of a clinical investigation and thus difficult to obtain because an patient treatment use is analogous to the is not consistent with the scope of parts institution’s IRB cannot or will not physician-patient relationship in a 50 and 56. The comment stated that provide a timely review or because the typical clinical setting in which such eliminating the requirement would hospital or other clinical setting does safeguards are unnecessary. solve problems and avoid confusion not have an affiliated IRB. FDA (Response) FDA does not agree that it related to differences between FDA’s recommends that IRBs affiliated with lacks legal authority to require IRB IRB regulations and IRB regulations institutions that are likely to have review and informed consent for applicable to Federal agencies and patients seeking access to individual patient expanded access use grantees under 45 CFR part 46 (the so- investigational drugs for treatment use or any other expanded access use. called ‘‘Common Rule’’). Current FDA under individual patient access INDs Expanded access use involves regulations (§§ 56.104(c) and 50.23) consider establishing processes or administration of unapproved products allow for the emergency use of an procedures to facilitate timely IRB that have not yet been shown to be safe investigational drug without prospective review of these INDs. In addition, use of and effective, and raises sufficiently IRB review and approval and a waiver centralized IRB review and other similar concerns to clinical research that of the requirement for prospective cooperative arrangements could informed consent and IRB review are informed consent of the involved facilitate IRB review at these institutions warranted. Moreover, section 561 of the patient-subject, but the Common Rule as well as in settings that are not act contains numerous references to specifies that all research involving affiliated with IRBs. FDA fully supports ‘‘conditions determined by the human subjects must be prospectively centralized IRB review under Secretary’’ and to protocol compliance reviewed and approved by a convened appropriate circumstances and with ‘‘regulations promulgated under IRB committee (with the exception of encourages sponsors to help make this section 505(i)’’ (which include informed certain minimal risk categories of option available where possible. FDA consent and IRB regulations), indicating research, which do not include believes these mechanisms could ease that Congress intended FDA to require expanded access use). The comment the burdens associated with obtaining conditions such as informed consent maintained that the Common Rule IRB review of individual patient INDs and IRB review, consistent with FDA’s applies unless the requested emergency and limit the need to rely on long-standing practice regarding use is considered ‘‘treatment’’ rather commercial INDs. Therefore, FDA is not treatment use with investigational than ‘‘research’’ and thus is not subject persuaded that obtaining IRB review is products. In addition, FDA strongly to prior IRB review and approval under an excessive burden and potential believes that recipients of the Common Rule. The comment obstacle to obtaining access to investigational products under any type maintained that prior FDA review of investigational therapies under of expanded access IND should be individual patient expanded access expanded access INDs. afforded the same human subject would suffice to ensure patient safety

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and compliance with the protocol and investigational drug would be consistent (Response) FDA does not believe the applicable regulations. with the investigator reporting recommended language is necessary or (Response) Although FDA agrees that requirements in § 312.64(b). desirable. Section 312.305(c)(5) requires it is accurate to characterize the use as (Response) FDA agrees that the simply that sponsors assure themselves ‘‘expanded access’’ or ‘‘treatment use’’ licensed physician may be unaware of that the licensed physicians who will be rather than a ‘‘clinical investigation’’ of what events are expected or unexpected participating in an expanded access the drug, which places individual and, therefore, should be required to program are qualified to administer the patient INDs outside the scope of the include information on all observed drug for the expanded access use. FDA Common Rule, FDA disagrees that prior adverse events. Therefore, section believes the requirement concerning the FDA review, without additional review 312.310(c)(2) has been revised to state qualifications of the licensed physician- by a qualified third party, provides that at the conclusion of treatment, the investigator is narrowly focused on the adequate safeguards. The types of licensed physician or sponsor must most germane issue—whether the patients that would typically be eligible provide FDA with a written summary of physician is qualified to administer the to obtain investigational drugs under the results of the expanded access use, drug for the expanded access use. FDA expanded access programs are including adverse effects. believes the language proposed in the vulnerable and have somewhat (Comment 63) One comment stated comment minimizes the qualifications desperate clinical circumstances and, that adverse event reporting for of the licensed physician to too great an therefore, are in particular need of the expanded access use should take extent because it eliminates even the protections afforded by IRB review and advantage of technological cursory inquiry as to whether the the informed consent process. FDA modernization in adverse event physician is qualified to administer the acknowledges that in emergency reporting, such as by using a centralized drug. situations involving individual patient electronic database. The comment stated h. Investigator’s brochure. access, there is not always prospective that such a database could provide Proposed § 312.305(c)(5) also requires IRB review. However, FDA believes that access to basic tabulation and analysis the sponsor to provide the licensed some type of retrospective IRB review is of the voluminous serious adverse event physician with information needed to still important in most cases, especially reports that, in their present form, are minimize the risk and maximize the if treatment with the investigational virtually useless to individual site potential benefits of the investigational drug is ongoing. FDA also believes that investigators and site IRBs. drug, including ‘‘providing the informed consent is an important (Response) FDA has no plans to investigator brochure, if there is one.’’ element of any treatment use, even in implement an electronic data capture (Comment 65) One comment emergency situations. From a medical and analysis system for adverse events requested that this language be revised ethics perspective, the need for that is devoted exclusively to adverse to state that the sponsor provide the informed consent increases with the events observed during expanded access investigator’s brochure ‘‘if required seriousness of the disease or condition use. FDA is actively involved in efforts and the exigency of the clinical under § 312.55 (Informing to develop and implement electronic situation, so it would be all the more investigators).’’ data systems for adverse event reporting important in emergency situations with (Response) FDA does not agree with generally, for both pre- and individual patients. The purported the proposed change because it would advantages of eliminating any postmarketing adverse event reporting. appear to narrow the circumstances in prospective third-party IRB review and FDA believes these systems will also which a sponsor would be required to informed consent are not enough to contribute to improved data collection provide an investigator’s brochure. It offset the potential harm. and analysis of adverse events could be interpreted as requiring that a f. Investigator reporting information obtained from exposure to sponsor make the investigator’s responsibilities for individual patient investigational drugs in expanded brochure available only if the treatment INDs. access programs. use is the same use as is being Proposed § 312.310(c)(2) states that g. Qualifications of licensed developed (i.e., the use for which the ‘‘at the conclusion of treatment, the physicians to participate in expanded investigator’s brochure was written). licensed physician or sponsor must access. FDA believes that the investigator’s provide a summary of the results of the Proposed § 312.305(c)(5) requires, brochure would typically contain expanded access use, including among other things, that sponsors information that would be important for unexpected adverse effects.’’ ensure that licensed physicians any proposed use of the investigational (Comment 62) One comment participating in expanded access drug (e.g., information about adverse recommended that the licensed programs are qualified to administer the events associated with use of the drug) physician be required to provide a investigational drug for the expanded and, therefore, should be made available summary of ‘‘all adverse effects possibly access use. by the sponsor to licensed physicians in related to the investigational drug’’ (Comment 64) One comment an expanded access program whenever rather than only ‘‘unexpected adverse recommended that FDA revise an investigator’s brochure exists. To effects.’’ The comment stated that it is § 312.305(c)(5) to state: ‘‘In general any more accurately express this intent, likely that many private practice licensed physician may participate in an FDA has revised the provision in the physicians requesting expanded access expanded access protocol. Additional final rule to state as follows: ‘‘In all for the emergency treatment of their specific qualifications may be necessary expanded access cases, sponsors are individual patients will not be familiar in some situations.’’ The comment responsible for * * * providing with all of the current information recommended that FDA clarify its licensed physicians with the related to the adverse event profile of expectations about investigator information needed to minimize the risk the investigational drug and/or FDA’s qualifications for expanded access and maximize the potential benefits of regulatory definition of ‘‘unexpected programs to reduce the burden for the investigational drug (the adverse effects.’’ The comment added sponsors and facilitate broader investigator’s brochure must be that requiring physicians to report all physician participation in expanded provided if one exists for the drug) adverse effects possibly related to the access programs. * * *’’

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i. Monitoring of expanded access may not need onsite monitoring). is limited to the use of an INDs. Therefore, it is reasonable to require investigational drug in an established The proposed rule makes the sponsor monitoring for individual patient physician-patient relationship. responsible for monitoring of expanded protocols of extended duration and (Response) FDA does not believe the access INDs or protocols. Proposed necessary for appropriate patient name of the category needs to be § 312.305(c)(2) states that an individual protection. changed. In FDA’s experience, or entity that submits an expanded (Comment 67) Two comments individual patient treatment use arises access protocol or IND is a sponsor for questioned why an industry sponsor in the context of an established purposes of part 312 and, therefore, should be required to monitor an physician-patient relationship, so FDA must comply with the responsibilities individual patient IND when the does not think that point needs for sponsors concerning the oversight of licensed physician holds the IND. clarification. Moreover, FDA is clinical investigations in subpart D of (Response) Where the licensed uncertain how the recommended name part 312, including monitoring of physician is the IND holder for an change would clarify that issue. ongoing protocols (§ 312.56). Proposed individual patient expanded access IND, Proposed § 312.310(a)(1) states that a § 312.310(c)(3) provides that FDA may as opposed to the entity that is licensed physician seeking to obtain an require sponsors to monitor an providing the investigational drug for investigational drug for treatment use individual patient expanded access use the expanded access use, the entity for a patient must determine that the if the use is for an extended duration. providing the drug is not a sponsor with probable risk to the person from the (Comment 66) One comment respect to that IND and, therefore, has investigational drug is not greater than maintained that the requirement that no sponsor responsibilities under part the probable risk from the disease or sponsors monitor the conduct of 312. condition. FDA must also determine individual patient expanded access Proposed § 312.315(d)(2) provides that the potential patient benefit protocols is impractical and that the sponsor is responsible for justifies the potential risks of the burdensome and should be eliminated. monitoring the conduct of an treatment use and those potential risks Another comment objected to the intermediate-size patient population are not unreasonable in the context of requirement to monitor individual access protocol to ensure that licensed the disease or condition (proposed expanded access when the use is for an physicians who are providing the drug § 312.305(a)(2)). extended duration. The comment stated to their patients are complying with the (Comment 70) Some comments were that this provision inappropriately protocol and applicable regulations. concerned that the licensed physician interfered with the patient-physician (Comment 68) One comment would typically lack sufficient relationship and implied that the requested that FDA eliminate the information about an investigational individual physician may be incapable requirement for sponsor monitoring of drug to make an informed decision of monitoring the patient for an intermediate-size access programs. The about the risk to the patient from the extended duration. comment urged FDA to replace the investigational drug versus the risk from (Response) FDA does not believe the monitoring requirement with additional the disease or condition. One comment provision that gives FDA the option to information about the criteria for stated that the very nature of require monitoring for an individual selection of investigators, the method experimental drugs limits patients’ and patient access protocol of extended for data collection by investigators, the physicians’ abilities to know and fully duration is overly burdensome or circumstances under which a understand the risks and benefits of a impractical. The provision is intended commercial IRB might be used to particular drug. One comment to provide the option to monitor for provide IRB oversight for investigators maintained that it is also unlikely there relatively long-term use, such as chronic who practice in a setting without an IRB would be any published literature or open-ended use that is likely to (and also in settings that have an IRB), other sources of information available to continue for many months. In FDA’s and the sponsor’s prospective plan for physicians for drugs that are early in experience, the majority of individual demonstrating due diligence in development. To address this problem, patient treatment uses do not go on for obtaining data from investigators. the comment requested that FDA revise an extended duration, so the number of (Response) FDA does not believe that the final rule to include a requirement instances in which FDA is likely to the provisions the comment suggests that FDA provide information to the require monitoring is small. Moreover, adding to the intermediate-size patient medical profession and patient uses that go on for an extended duration population IND submission are advocacy organizations about the are likely to have greater potential risk adequate to replace real-time monitoring availability of investigational drugs for and, therefore, warrant higher scrutiny. intended to determine whether expanded access, including a full Also, the monitoring need not be investigators are complying with the accounting of the scientific evidence resource-intensive. Guidance protocol and their investigator supporting expanded access uses. concerning acceptable monitoring responsibilities. FDA believes such (Response) The requirement that the practice in the International Conference monitoring is important to ensure licensed physician determine that the on Harmonisation guidance document appropriate use of the investigational probable risk to the person from the entitled ‘‘E6 Good Clinical Practice: drug and patient safety. investigational drug is not greater than Consolidated Guideline’’ provides that the probable risk from the disease or the sponsor should determine the extent 6. Issues Specific to Individual Patients, condition originates in Congress’s and nature of monitoring needed based Including Emergency Use mandate in FDAMA to expand access to on considerations such as the objective, (Comment 69) One comment investigational drugs for treatment use purpose, design, complexity, blinding, recommended that FDA change the (section 561(b)(1) of the act) and is size, and endpoints of the trial. These name of this expanded access category intended to provide greater autonomy to factors are either absent from an from ‘‘individual patients, including for individual patients and their physicians extended duration individual patient emergency use’’ to ‘‘individually in decisions about expanded access use. treatment use or favor low-intensity identified patients for treatment use, The underlying premise of the monitoring (e.g., n = 1), so minimal including for emergency use’’ to make it requirement is that physicians know monitoring would likely suffice (e.g., clear that this expanded access category more about the clinical situations of

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their patients than does FDA and, therapy, but additional courses are specifically to the IND. FDA has revised therefore, should have considerable warranted. the language to clarify who should input into the assessment of risks and (Response) FDA does not believe it is receive this summary as follows: ‘‘At the benefits. FDA acknowledges that there necessary to describe in the regulations conclusion of treatment, the licensed is often limited information available to specific requirements and processes for physician or sponsor must provide FDA physicians about the risks and benefits submissions to extend an expanded with a written summary of the results of of an investigational drug and no access treatment for an individual the expanded access use, including practical way to provide the physician patient. FDA anticipates that, in most adverse effects.’’ the information at FDA’s disposal cases, the submission would require a Proposed § 312.310(c)(4) provides that (information is typically proprietary and minimal amount of information to when a significant number of similar generally can only be disclosed to a demonstrate that the criteria for the individual patient expanded access member of the public on consent of the expanded access use continue to be met requests have been submitted, FDA may commercial sponsor). and would focus primarily on the ask the sponsor to submit an IND or That the physician will often have response to treatment to date, including protocol for the use under § 312.315 or limited information does not, however, any adverse events. § 312.320. make access to investigational drugs for (Comment 73) One comment stated (Comment 75) One comment objected individual patients inherently that the proposed rule’s requirement to this provision because it may increase dangerous. In these situations, in that the duration of an individual the amount of time it takes for an addition to the licensed physician’s patient treatment use generally be individual to obtain access and, because determination, FDA must determine limited to a single course of therapy there is a higher evidentiary standard that the potential benefit to the patient unless FDA expressly authorizes for authorizing an intermediate-size justifies the potential risks of the multiple courses or chronic therapy population IND than for an individual treatment use and that those potential usurps the physician’s role, restricts patient IND, may make a drug less risks are not unreasonable in the context access, and therefore should be accessible for treatment use. (Response) FDA does not believe that of the disease or condition to be treated. eliminated. (Response) FDA disagrees. This rule § 312.310(c)(4) will increase the amount FDA has access to considerably more provides for treatment use of an of time it takes for an individual patient information about the investigational investigational drug in a vulnerable to obtain access. The intent of this drug and can evaluate the potential population, often on the basis of very provision is to make access more benefits and risks of the therapy in light little information about effectiveness efficient at the point it becomes of the information provided by the and safety. To fairly weigh the risks and apparent that there will be more than a physician about risks and benefits in benefits of an investigational drug for few isolated requests for expanded relation to the individual patient’s use in this setting, FDA believes there access by individual patients. By condition. FDA believes that its has to be a clear understanding between obtaining a submission for an expanded knowledge of the drug combined with the treating physician and FDA about access IND that can enroll multiple the licensed physician’s knowledge of the planned course of therapy. For patients, FDA believes this provision the patient’s clinical condition will lead example, to fairly evaluate the risks, it will decrease the amount of time needed to expanded access decisions for will usually be necessary to consider the to get an investigational drug to any individual patients that are in the best planned dose and duration of therapy in patient seeking access under the multi- interests of those patients. relation to what is known about the patient IND because it avoids the Proposed § 312.310(a)(2) states that occurrence of toxicity for that dose and submission and review of many FDA must determine that the individual duration of therapy. For the same individual patient INDs. In addition, patient for whom expanded access use reason, it will usually be necessary to even at the point FDA believes it is is sought cannot obtain the drug under consider the extent of prior exposure appropriate to request a submission of a another type of IND or protocol. and the planned duration of subsequent multi-patient access IND under (Comment 71) One comment therapy before authorizing additional § 312.315 or § 312.320, FDA does not recommended that the word ‘‘type’’ be courses of an investigational drug intend to delay responding to individual deleted from the language in beyond the original treatment plan. patient submissions that are received § 312.310(a)(2) that ‘‘FDA must Therefore, FDA does not believe it is during the time it takes a sponsor to determine that the patient cannot obtain reasonable or wise to authorize access of prepare a submission for an the drug under another type of IND or unspecified duration at the discretion of intermediate-size population expanded protocol.’’ the treating physician. FDA also does access IND. (Response) FDA agrees that the intent not believe this provision unreasonably FDA agrees that the evidentiary of § 312.310(a) is accurately conveyed restricts access. FDA believes that requirement is somewhat higher as the when the words ‘‘type of’’ are omitted subsequent courses of therapy will size of the population to be treated and has revised the provision routinely be permitted where under the access IND increases (e.g., accordingly. appropriate. from individual patient to intermediate- Section 312.310(c)(1) of the proposed Proposed § 312.310(c)(2) requires, size population IND). However, FDA rule states: ‘‘Treatment is generally among other things, that ‘‘the licensed does not foresee that this will be an limited to a single course of therapy for physician or sponsor must provide a obstacle to obtaining access. FDA will a specified duration unless FDA written summary of the results of the not request submission of an expanded expressly authorizes multiple courses or expanded access use.’’ access IND that can enroll multiple chronic therapy.’’ (Comment 74) One comment stated patients until there has been some (Comment 72) One comment that the proposed rule should make volume of experience under several recommended that the final rule clear to whom—presumably FDA—the individual patient INDs. Therefore, at describe submission requirements and written summary of the results of the time FDA requests submission of a processes to extend the treatment use in treatment use must be submitted. multi-patient expanded access IND those instances where the initial (Response) FDA agrees. The written under § 312.315 or § 312.320, FDA will authorization was for a single course of summary should be submitted to FDA, have probably already concluded that

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there is enough patient experience (Response) FDA’s intent in without a written submission, that the under individual patient INDs and other articulating criteria for when it is licensed physician or sponsor explain evidence to justify broader exposure appropriate to consider authorizing how the expanded access use will meet under an IND that can enroll multiple access without a written submission is the requirements of §§ 312.305(a) and patients (e.g., to permit treatment of 10 intended to differentiate true emergency 312.310(a) and, further, that the licensed patients under an intermediate-size situations in which treatment must physician or sponsor make a written population IND). occur within a fairly narrow time frame submission that complies with the (Comment 76) One comment pointed from situations in which there is requirements of §§ 312.205(b) and out an apparent discrepancy between sufficient time to make a written 312.310(b) within 5 working days of the the codified language in § 312.310(c)(4) submission. The emergency process is, onset of the use. of the proposed rule and the preamble by its exigent nature, not as deliberative (Comment 79) Two comments discussion of the section. Section and thorough a consideration of the expressed concern about the 312.310(c)(4) states that ‘‘* * * FDA risks and benefits of a proposed requirement to make a written may ask the sponsor to submit an IND treatment use in an individual patient as submission within 5 working days in or protocol for use under § 312.315 or is afforded by a review of a written situations in which a commercial § 312.320.’’ However, the preamble submission. Therefore, the emergency sponsor has agreed to make the drug states that ‘‘* * * FDA will consider procedures may expose patients to available under its own IND (as opposed whether to request that a potential somewhat higher risk than a more to making the licensed physician obtain sponsor submit an intermediate-size deliberative, non-time-sensitive review an IND). These comments stated that in patient population IND or protocol for and, therefore, should be used only in these situations the commercial sponsor the expanded access use and, possibly, true emergencies. FDA is confident, is dependent on the licensed physician conduct a clinical trial of the expanded however, that the rule as proposed will to obtain the information needed to access use.’’ The comment stated that it permit evaluation of all true emergency make a written submission and, in their appears that the preamble goes beyond treatment use requests using the experience, it takes approximately 30 the language of the regulation and asks emergency procedures. days to obtain all the information what is meant by ‘‘conduct a clinical (Comment 78) One comment noted needed to complete the written trial of expanded access use’’ in the that the proposed regulations on submission from the licensed physician. preamble. emergency INDs require that licensed They ask that FDA provide a longer time (Response) FDA does not believe physicians obtaining an IND take on period in which to make a submission. there is an inconsistency between the responsibilities more commonly (Response) FDA acknowledges that in two statements in the preamble and associated with commercial sponsors situations in which a commercial proposed § 312.310(c)(4). If FDA asks such as monitoring, reporting adverse sponsor makes an investigational drug the sponsor to submit an IND or events, and submitting annual reports available for treatment use under its protocol for use under § 312.315 for a (where applicable). The comment was own IND, it is dependent, to a certain drug being developed, that submission concerned that these responsibilities extent, on the patient’s physician to would have to address why the patients may make physicians less willing to obtain the information needed to make to be treated under the intermediate-size obtain investigational drugs for their the submission. Therefore, FDA agrees expanded access IND cannot be enrolled patients. that the time to make a written in a clinical trial and under what (Response) The agency recognizes that submission should be extended. FDA circumstances the sponsor would the licensed physician who must obtain believes that 15 working days should be conduct a clinical trial in these patients. his or her own IND to make a drug sufficient time to obtain whatever Based on the information submitted, available for treatment use to an information is needed to make a written FDA must conclude that enrollment in individual patient, whether or not in an submission. FDA is concerned that a clinical trial is not possible before the emergency situation, is subject to providing a longer period of time, such intermediate-size population expanded regulatory obligations usually as 30 days, may reduce compliance with access protocol can begin. However, applicable to commercial sponsors and the written submission requirement and FDA might reasonably conclude, based with which the physician may not be may negatively impact patient safety. on that information, that a clinical trial familiar. However, the agency believes FDA also believes it is inefficient and in the intended treatment population is that for an individual patient IND, these potentially confusing to have different possible and ask the sponsor to conduct obligations will not be too onerous time frames for making a written a clinical trial of the treatment use, because they closely parallel the type of submission for a commercial sponsor either in lieu of, or in addition to, an monitoring and documentation that are who must obtain information from a intermediate-size population expanded routine in a clinical practice (e.g., patient’s physician to complete a access IND. routine patient care, progress notes, submission and a licensed physician Proposed § 312.310(d) sets out discharge summary) and, therefore, are who must complete his or her own IND emergency procedures for expanded not a substantial added burden. FDA submission. Therefore, 15 working days access for individual patients. If there is also believes these obligations are will be the time for making a written an emergency that requires a patient to essential elements of human subject submission for each of these situations. be treated before a written submission protection. In addition, FDA can Accordingly, the § 312.310(d)(2) has can be made, FDA may authorize the provide assistance to licensed been revised to provide 15 working days use of the drug without a written physicians in complying with their for making a written submission submission. The proposed rule provides expanded access IND regulatory following emergency authorization to that emergency use can be authorized by requirements (e.g., FDA’s Office of treat an individual patient with an telephone. Special Health Issues is a good resource investigational drug. (Comment 77) One comment was for physicians concerning expanded (Comment 80) One comment stated concerned that emergency use might be access (see http://www.fda.gov/oashi/ that there were a number of too narrowly defined and thus home.html)). administrative steps FDA should take to unnecessarily restrict access in a true Proposed § 312.310(d)(2) requires, as a make expanded access for individual emergency. condition for authorizing emergency use patients easier to obtain. The comment

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stated that different divisions at FDA (Response) FDA agrees that a intended to address a situation in which had different requirements concerning potential advantage is to reduce the an investigational drug once available expanded access. The comment burdens of individual physicians trying under a treatment IND would no longer suggested that FDA make its internal to obtain access for individual patients. be available under a treatment IND, but requirements for individual patient Ideally, only a limited number of would then become available under an expanded access consistent among the physicians would make submissions for intermediate-size patient population divisions. The comment also stated that individual patients before patients expanded access IND. FDA believes this FDA should post the name and contact receiving the investigational drug for the would be an unusual circumstance, but information of the person in each expanded access use could be a foreseeable one, and that the rule as division who is responsible for helping consolidated under an intermediate-size proposed could accommodate that physicians submit individual patient population IND. That consolidation circumstance. For example, clinical expanded access requests. would ease the burden considerably for trials of an investigational drug (Response) One of the purposes that subsequent physicians seeking the drug available under a treatment IND might will be served by this final rule is to for treatment use because they would demonstrate lack of effectiveness on a improve consistency in the way not have to make their own IND primary endpoint that is compatible expanded access INDs are handled submissions. with the expanded access use under the within FDA. FDA believes that (Comment 82) One comment treatment IND, but also provide including clear criteria and submission recommended that this expanded access preliminary evidence of effectiveness on requirements in the regulations should category be renamed from secondary endpoints or in subset help improve consistency in the ‘‘Intermediate-size patient populations’’ analyses, and such evidence could individual patient expanded access to ‘‘Limited patient populations for support a different expanded access use process. In addition, FDA intends to treatment use.’’ The comment (e.g., a more narrowly defined educate reviewers and other review maintained this change would clarify population within a disease or a division staff on these new rules. FDA that the intent of this expanded access different indication) under an also plans to assess the implementation category is to provide ‘‘compassionate’’ intermediate-size population expanded of these rules and will determine at a treatment use of the investigational drug access IND. In this circumstance, some later time whether additional guidance and involves only a limited number of of the patients who were receiving the is needed. prospective patients. drug under the treatment IND might be (Response) FDA does not believe it is eligible to receive the drug under the 7. Issues Specific to Intermediate-Size necessary to further clarify the intent of Patient Populations intermediate-size population IND on the this category of expanded access or of basis of lesser evidence than supported Proposed § 312.315 provides for expanded access generally. Section the treatment IND. However, FDA does expanded access use for multiple 312.300(a) plainly describes the intent not see why this would be a problem patients under a single IND or protocol of expanded access. It states that ‘‘[t]his (e.g., expose any patient to unreasonable for patient populations smaller than subpart contains the requirements for risk), provided the evidence is adequate those typical in treatment INDs or the use of investigational new drugs to support the size population to be treatment protocols, and sets forth the when the primary purpose is to treated under the intermediate-size criteria, submission requirements, and diagnose, monitor, or treat a patient’s population IND. safeguards specific to expanded access disease or condition.’’ Moreover, it is b. Number of patients. INDs for intermediate-size patient apparent throughout the various The preamble to the proposed rule populations. The primary purpose of the requirements set forth in this subpart stated that FDA anticipates that the intermediate-size patient population that the intent is treatment rather than typical intermediate-size patient IND or protocol is to consolidate assessment of the safety and population treatment use IND or expanded access under a single IND to effectiveness of an investigational drug protocol will provide access to between promote better monitoring, oversight, in a controlled setting. In addition, FDA 10 and 100 patients. and ease of administration for an believes the term ‘‘intermediate-size (Comments 84) Some comments were expanded access use compared to population’’ better reflects the intent to concerned that FDA’s estimated range multiple individual patient INDs. describe an expanded access category for the number of patients that could be a. General comments. intended to accommodate populations enrolled in an intermediate-size patient (Comments 81) Several comments in between individual patients and the population IND was too narrow. One expressed approval for the creation of large populations that are typical of comment stated that FDA substantially the intermediate-size patient population access to investigational drugs under underestimated the sizes of the potential IND to formally bridge the gap between treatment INDs or treatment protocols. populations that would need access to individual patient access and large (Comment 83) One comment stated an investigational drug under an population access under treatment INDs that the proposed rule does not address intermediate-size patient population, late in development. One comment the situation in which an investigational and that the estimated range (between agreed that this category would promote drug being made available under a 10 and 100 patients) leaves a significant greater efficiency by aggregating various treatment IND would no longer be gap between the intermediate-size types of individual requests. Another available under a treatment IND because population IND and the treatment IND. comment stated that creation of this of new information about the drug, but The comment recommended the category might diminish the burdens of could still be made available under an creation of a fourth category of individual physicians in complying intermediate-size patient population expanded access IND to bridge this gap. with the expanded access submission IND. The comment was concerned that, One comment asked FDA to clarify the requirements for individual patient in that situation, the evidentiary difference in size of population between INDs, presumably because individual threshold for expanded access would the intermediate category and larger physicians would not have to make actually be lower than for the treatment populations under treatment INDs or submissions once the individual patient IND. protocols because FDA did not provide INDs have been consolidated under an (Response) FDA agrees that the any estimate of the lower end of the intermediate-size population IND. proposed rule was not specifically range for a treatment IND. Two

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comments stated that, although the be used to provide access to greater than believes, therefore, that the criteria set proposed rule contemplated that 100 patients. forth in § 312.315 are adequate to ensure § 312.315(a)(3)(i) and (a)(3)(ii) would be Because there is a need for flexibility that the risks associated with use of for an intermediate-size population of to provide access to greater than 100 drugs made available in each of these 10 to 100 patients, the situations patients under an intermediate-size four situations are minimized and the described in these subsections could population IND in some circumstances, potential benefits maximized across a easily involve much larger numbers of FDA has elected not to provide a variety of different treatment use patients. specific estimate of the population range situations and size populations. (Response) The population range (10 for this category in this final rule. FDA (Comment 86) One comment to 100) for the intermediate-size patient continues to believe that the population recommended deleting the option to population IND identified in the range identified in the proposed rule— make an investigational drug available preamble to the proposed rule is simply 10 to 100 patients—would under an intermediate-size population an estimate and is not intended to accommodate most intermediate-size IND when the drug is not being exclude the possibility that more (or population INDs. However, FDA developed. The comment argued that fewer) patients could be treated under believes foremost that the size because the disease is so rare that it is an intermediate-size patient population population that can be treated under an not possible to recruit patients for a IND. For a drug being developed, it is intermediate-size population IND clinical trial, the sponsor would not possible that more than 100 patients should be dictated by the available ordinarily maintain an active IND, nor could be treated under an intermediate- evidence—the amount of exposure that would the sponsor be manufacturing size population IND. However, our the evidence will support—and the investigational drug supplies (so, experience suggests that programs circumstances of a given case, rather presumably, there is no reason for the substantially larger than this are best than by a somewhat arbitrary estimate of category). The comment stated that the administered under a treatment IND. the size of the upper bound of the proposed rule also implies that this FDA expects that there would ordinarily population. situation may be an open-ended be a seamless transition from c. Sub-categories of intermediate-size commitment to expanded access, which intermediate-size population IND to patient population expanded access. is likely to further deter commercial treatment IND at the point when there Proposed § 312.315 provides for sponsors. One comment asked how FDA was adequate evidence to support the access to an intermediate-size would determine that the drug is the treatment IND, adequate progress with population in four situations: only promising therapy for the people • To provide a drug that is not being drug development, a sponsor willing to with a rare condition without clinical developed to patients who may benefit make the drug available to a larger data to support the use. The comment from the drug (typically patients with a stated that this provision of the population under a treatment IND, and rare disease or condition) proposed rule would further erode the sufficient numbers of patients who need (§ 312.315(a)(1)) possibility of conducting a controlled the drug to justify a treatment IND. • To make a drug that is being clinical trial in this situation. For a drug not being developed, there developed available to patients who (Response) This category of expanded is also the possibility that greater than cannot participate in clinical trials of access use is based on FDA’s experience 100 patients will need access to an the drug (§ 312.315(a)(2)) with situations in which there has been investigational drug under an • To provide an approved drug that no alternative but to make a drug not intermediate-size patient population has been withdrawn for safety reasons, being developed available under an IND IND. Although FDA anticipates that a or cannot be marketed due to failure to to a small number of patients who could relatively small number of patients meet the conditions of the approved benefit from it. In FDA’s experience, it would be receiving access at any given application (usually a manufacturing has not been difficult to determine that point in time under such an IND, it is problem) to a limited number of patients a drug is the treatment of choice for a foreseeable that, for some drugs in this who are dependent on the drug discrete group of patients with a category, conditions will never be right (§ 312.315(a)(3)(i)) particular rare disease or condition. For for development, and over a period of • To provide a drug that is related to example, some antivenins and drugs for years the IND will provide access to an approved drug, but is not approved tropical diseases are not commercially more than 100 patients. However, if for marketing in the United States, in marketed in the United States because substantially more than 100 patients situations where there is a shortage of there is simply not a large enough seek or continue to need access under the approved drug or the approved drug market to develop the product for this category within a fairly narrow time is unavailable due to failure to meet the marketing, but these products are frame, FDA believes there would likely conditions of the approved application nonetheless needed on occasion by be an adequate number of potential (§ 312.315(a)(3)(ii)) readily identifiable patients. FDA has subjects to initiate a clinical trial and (Comment 85) One comment objected made other products available to treat formal development of the drug. to the range of situations in this obscure conditions when the population When a drug has been withdrawn for category, stating that the situations are is seemingly too small for even orphan safety reasons or in a drug shortage too diverse to be accommodated in a drug development. For example, situation, it is also foreseeable that there single expanded access category. thalidomide was made available for a will be greater than 100 patients who (Response) FDA disagrees. Because variety of conditions under several of may need access to the drug—for the amount of evidence needed to make these types of INDs before there was patients in whom the benefits of the an investigational drug available under sufficient data to approve it. Currently, withdrawn drug continue to exceed the an intermediate-size population IND is there are INDs for products not being risks associated with the drug or based on the size of population actively developed that are ongoing, and patients who need to rely on a drug not anticipated to be treated under the IND, FDA anticipates that it will encounter approved for marketing in the United the category can accommodate situations in the future in which this States to substitute for an approved drug situations with significant variations in type of IND is needed. Because these in short supply. In those cases, the the size of the treatment population (see types of INDs exist, and because one of intermediate-size population IND could also preceding comment response). FDA FDA’s goals with this rulemaking to

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make the agency’s various mechanisms studied for one cancer available to treat would permit access to patients who for expanded access transparent and patients with another type of cancer have not previously been treated with thereby make investigational drugs more before there is definitive evidence of the drug, even though the drug is unsafe widely available to those who might effectiveness in the other type of cancer. for marketing. However, a manufacturer benefit, the agency believes it is As discussed above, FDA also believes may be reluctant to make an open-ended important to describe this type of it is important to be able to provide commitment to provide a drug that has expanded access in the regulations. access to multiple patients in a been withdrawn for safety reasons to a FDA recognizes that a commercial controlled manner under an subset of patients when there is no sponsor might not be inclined to be a intermediate-size patient population commercial benefit to the manufacturer. sponsor for this type of IND or to make IND at a point in time in which the use This reluctance could also affect a potentially open-ended commitment for which the drug is being made whether new patients would be able to to manufacture products to provide to available would not yet meet the criteria obtain the drug. another sponsor under this type of IND. for a treatment IND. In FDA’s (Comment 89) One comment In FDA’s experience, these types of experience, it has been helpful from an recommended that the final rule clarify INDs are not usually held by administrative, clinical safety, and that some situations in which a commercial sponsors. They are more monitoring perspective to provide for a marketed drug is found to benefit only commonly held by government agencies multi-patient expanded access IND to a subset of the population for which it and academic institutions. So the fact bridge the gap between individual was approved can be addressed through that this type of IND is of little interest patient INDs and treatment INDs. a restricted distribution program of the to a commercial sponsor is no reason to (Comment 88) One comment stated FDA-approved product in accordance remove it from the expanded access that it is not clear why patients should with subpart H of part 314, rather than regulations, particularly when it meets a receive expanded access to a drug that through withdrawal of the drug for demonstrated public health need. is no longer marketed for safety reasons. safety reasons and use of an FDA also recognizes that this type of The comment stated that a clinical trial intermediate-size patient population access could potentially usurp the entire is the appropriate setting to identify IND to make the drug available to the population that could possibly be patients for whom the potential benefits subset population. enrolled in a clinical trial of a drug. of a drug outweigh the risks. One (Response) FDA agrees that, in However, FDA thinks this situation is comment agreed that, when a drug is situations in which a drug is found to not very likely because drugs are rarely withdrawn from marketing because of be beneficial in only a subset of the developed (at least not in the United safety reasons, there may be a subset of population in which it was originally States) for the types of indications for patients for whom the benefits of approved, it may be possible to allow which drugs are made available under treatment would outweigh the risks. The continued marketing of the drug under this category. Nonetheless, where comment also pointed out that by a restricted distribution program appropriate, FDA intends to make every stating in the preamble to the proposed (Lotronex was originally marketed effort to encourage potential sponsors to rule that those patients for whom the without restrictions and is now study such a drug in a clinical trial benefits of treatment are believed to marketed under a restricted distribution rather than provide it under an outweigh the risks ‘‘could continue to program). In these situations, there expanded access IND. receive the drug under an intermediate- would usually be more compelling data (Comment 87) One comment stated size patient population IND,’’ FDA to support the use in the subset that there was no reason to have an implied that only patients who were population than would be needed for an intermediate-size population expanded already receiving the drug when expanded access IND (i.e., a more access IND for a drug being developed. marketing ceased could obtain the drug rigorously defined subset population). The comment stated that there is no under such an IND. The comment asked The appropriate mechanism for making justification for allowing access under FDA to clarify whether this provision is a drug available to the subset of patients such an IND for a disease different from intended to make a drug available only in whom the benefits continue to the one being studied in the clinical to patients who were receiving the drug outweigh the risks would depend on the trials. For the other situations in which when it was withdrawn for safety circumstances of the particular case. a patient is unable to participate in the reasons or if it would also be possible FDA is always willing to explore the full clinical trial (different disease stage, to provide the drug to patients who had range of options with the manufacturer patient otherwise fails to meet not yet received it. of such a drug. enrollment criteria, enrollment is (Response) In FDA’s experience, there d. Drug shortage. closed, or the trial site is not are multiple examples of situations in (Comment 90) One comment stated geographically accessible), the comment which a drug has been withdrawn from that it is not clear that the expanded stated that the treatment IND would be the market for safety reasons and there access rule would be the right the appropriate vehicle for expanded has been a need to make the drug mechanism for access in a drug shortage access. available to a subset of patients in situation because the numbers of (Response) FDA believes there is whom the benefits of treatment patients needing access could be well in adequate justification for allowing outweigh the risks. Although those who excess of the 100 patients that the expanded access under an intermediate- receive the drug will ordinarily be those preamble suggests are the upper bound size patient population IND for a disease who were already receiving the drug at of the intermediate-size population IND different from the one being studied in the time of withdrawal and appear to category. the clinical development program. For have benefited, it was not FDA’s intent (Response) FDA is retracting a an oncology drug, for example, the to absolutely foreclose the possibility statement in the preamble to the characteristic of a cancer that is the that new patients could receive a drug proposed rule suggesting that there is a target of a given chemotherapeutic agent that had been withdrawn from 100-patient upper bound on the (e.g., specific receptor or enzyme) may marketing for safety reasons. It is population for an intermediate-size be present in other types of cancers. In possible that a population in whom expanded access IND. FDA agrees that that situation, it may be appropriate to benefits continue to outweigh risks a drug shortage situation could result in make an investigational drug being could be characterized in a way that a need for access in more than 100

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patients and more patients than could continue to describe the type of regulated (e.g., surgery) and (2) off-label reasonably be accommodated by an expanded access for treatment use that use (i.e., not labeled for use for the intermediate-size expanded access IND. makes investigational drugs available to relevant condition or disease, but In such situations, FDA would be more large populations as the ‘‘treatment supported by compelling literature likely to exercise its enforcement IND’’ or ‘‘treatment protocol.’’ reference) (71 FR 75147 at 75151). To discretion, the effect of which would be (Comment 92) One comment avoid this perceived problem, the to permit marketing of a related product expressed the view that, despite 20 comment suggested that FDA take one that did not meet the FDA approval years of use, these terms are confusing. of three steps: (1) Put the definition of requirements to substitute for the drug The comment recommended that the ‘‘available therapy’’ stated in FDA’s in short supply until supply issues for terminology be changed to ‘‘large-size guidance for industry entitled the FDA-approved product were patient populations’’ to be consistent ‘‘Available Therapy’’ in a formally resolved. FDA included the drug with the names of the other two issued rule, (2) revert back to the shortage provision in the expanded categories of expanded access. requirement that the investigational new access regulations to address a situation (Response) FDA continues to believe drug must only be measured against in which there is a relatively small, that it would be preferable to retain the other FDA-approved marketed products, discrete population affected by a drug terms ‘‘treatment IND’’ and ‘‘treatment or (3) approve the unapproved therapy shortage. Which mechanism would be protocol.’’ Because these terms have for the new indication so that its use appropriate to make a related drug been in use for more than 20 years, FDA becomes ‘‘on-label.’’ available in a drug shortage situation— believes they have become so strongly (Response) The Available Therapy an intermediate-size population IND or associated with making investigational guidance (p. 4) states that ‘‘available enforcement discretion—would depend drugs available to large populations that therapy (and the terms existing on the circumstances of that situation. to replace the terms would generate treatments and existing therapy) should e. Good manufacturing practices needless confusion. FDA recognizes that be interpreted as therapy that is (GMP) issues. the term ‘‘treatment use’’ is now widely specified in the approved labeling of (Comment 91) One comment used to refer generically to use of an regulated products, with only rare suggested that expanded access was not investigational drug for treatment exceptions.’’ This guidance was the appropriate vehicle for providing purposes outside of a clinical trial, and intended to apply to the use of the term access to a drug that is approved but is not just to use under a treatment IND or in § 312.34(b)(1)(ii) of FDA’s current not being manufactured in a manner protocol. However, FDA believes the regulations concerning treatment INDs consistent with the approval. The confusion that would result from and treatment protocols. That regulation comment stated that because the drug is changing the name of the treatment IND includes the criterion that ‘‘[t]here is no not investigational, access should be outweighs any potential confusion comparable or satisfactory alternative handled under a different mechanism. resulting from use of the word drug or other therapy available to treat The comment added that there should ‘‘treatment’’ in the title of the large that stage of the disease in the intended be assurance of close oversight of the population expanded access IND but not patient population.’’ Section manufacturer to minimize harm to in the other expanded access categories. 312.34(b)(1)(ii) is intended to apply patients. Another comment asked how it (Comment 93) One comment noted equally to the use of the term in new would be determined that the risk due that FDA’s current regulation subpart I. FDA believes this guidance to manufacturing problems is concerning the submission requirements has effectively addressed confusion acceptable. The comment pointed out for a treatment protocol (§ 312.35(a)(ii)) associated with use of the term that the IND would have to cross- provides that a submission for a ‘‘available therapy’’ in the varied reference the NDA for CMC information treatment protocol must explain why contexts in which it is used in FDA’s and also describe the good the use of the investigational drug is regulations. Therefore, FDA does not manufacturing practices (GMP) issues. preferable to the use of available believe it is necessary at this time to (Response) As in the case of a drug marketed treatments. The comment promulgate a regulation defining the shortage, GMP issues for a product pointed out that § 312.305(b)(2)(ii) of the term or revise the guidance so that only could create a need for access in a proposed rule provides that submissions approved therapies could be considered population too large to be for all expanded access uses must available therapy. Nor would it be accommodated under an intermediate- explain why the use of the appropriate to simply approve the size expanded access IND. As with a investigational drug is preferable to the unapproved therapy for the new drug shortage, in these situations FDA use of available therapeutic options. The indication for use, apparently without would be more likely to use comment interpreted this provision of regard to the evidence supporting the enforcement discretion to make the drug the proposed rule as permitting use, so that its use becomes ‘‘on-label.’’ available to a very large number of expanded access for a treatment 9. Clinical Holds of Expanded Access patients. FDA agrees that, whether protocol only when the treatment INDs enforcement discretion or an expanded protocol explains why the use of the access IND is used, there must be investigational drug is preferable to any Proposed § 312.42(b)(3) specifies the careful consideration of the safety approved or unapproved therapies, not conditions under which FDA may place implications of the manufacturing just preferable to any available marketed an expanded access IND or protocol on concerns, including possible monitoring treatment. The comment contended that clinical hold. Proposed § 312.42(b)(3)(i) mechanisms to ensure that patients are this provision could be interpreted to allows FDA to place a proposed not being harmed by a product that has require companies to show that the expanded access use on clinical hold if GMP concerns but is nonetheless being product to be used for treatment use is the pertinent criteria in subpart I for made available to patients. better than both approved and authorizing the use are not met (e.g., unapproved therapies because the non-serious disease or condition, 8. Issues Specific to Treatment IND and preamble states that ‘‘available therapy’’ satisfactory or comparable therapies are Treatment Protocol includes not just FDA-approved available, insufficient evidence to The proposed rule specifically products for that indication, but also support the use) or the IND does not solicited comment on FDA’s decision to includes (1) treatments not FDA- comply with the pertinent submission

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requirements in subpart I. Proposed patients already being treated with a investigational drugs will be used as § 312.42(b)(3)(ii) allows FDA to place an drug to continue treatment) where first-line therapy, second-line therapy, ongoing expanded access IND on appropriate. monotherapy, and combined therapy clinical hold if the agency determines with FDA-approved medications. The 10. Comments on Analysis of Impacts that the pertinent criteria in subpart I comment stated that the aggregate are no longer satisfied. (Comment 95) Three comments from additive cost per year to all U.S. private- (Comment 94) One comment pharmaceutical companies and a trade sector payers would be $273,600,000. emphasized the importance of providing association stated that the rule would The comment maintained that these a high degree of clarity about the likely increase sponsors’ administrative, estimates actually understate the burden reasons for imposing a clinical hold on medical, and regulatory burdens to private-sector payers because they an access program to assure that other associated with expanded access. The exclude potential annual costs to studies of the investigational drug are comments specifically mentioned the Medicare Advantage plans. not unintentionally affected. The costs of providing the investigational (Response) Based on our analysis, we comment stated that lack of clarity drug, conducting clinical laboratory concluded that the costs of this final could shut down an entire development tests, and monitoring, collecting, rule should be small. The cost estimate program and suggested that in the final processing, analyzing, and summarizing provided in the comment appears to rule, FDA cite specific reasons for data. include costs for investigational drugs imposing a clinical hold on an access (Response) Based on our analysis, we under provisions of the charging final program. The comment asserted that conclude that the final rule will not rule published elsewhere in this issue of FDA should apply the same level of have a substantial economic impact. the Federal Register. In response to the rigor for imposing holds on access The final rule clarifies and expands on comment, we have included estimates programs as is applied to clinical holds regulations in place since 1986 but does of the number of individual patients of clinical trials. Another comment not substantially change those with access to investigational drugs suggested that FDA propose an regulations; therefore, the overall under current rules and the number of approach for supplying drugs to patients economic impact should be small. additional patients we expect to gain who are clearly benefiting from Treatment use of investigational drugs is expanded access to investigational treatment and are participating in an relatively uncommon and a particular drugs under this final rule. FDA’s expanded access program that is put on sponsor would be expected to submit a estimates indicate that, on average, as clinical hold. treatment use request only infrequently. many as 53,159 patients per year have (Response) FDA does not believe it is Therefore any additional regulatory access to investigational drugs under necessary or desirable to cite in the burden is expected to be small and current rules. In addition, we estimate regulations specific potential reasons for widely dispersed among affected that as many as 3,095 additional a clinical hold of an expanded access entities. Most treatment use requests are patients will gain expanded access to IND. Section 312.42(b)(3) makes clear for individuals or single patients for investigational drugs under this final that failure to meet any of the criteria or which the drug, clinical laboratory rule. These estimates are based on submission requirements pertinent to testing, monitoring, data processing, and assumptions used in our Analysis of authorizing any of the expanded access reporting costs are expected to be small. Impacts for the proposed rule that were IND categories may be a basis for a The proposed rule does not require not substantively challenged in any clinical hold. It also makes clear that if sponsors to make investigational drugs comments received. It appears that the any of the criteria that were the basis for available for treatment use. Such a estimate of 67,500 patients per year in authorizing an expanded access IND are decision is the sponsor’s alone and will the comment draws no distinction no longer satisfied, FDA may place an presumably be based on a number of between patients receiving ongoing expanded access IND on factors, including cost. If the sponsor investigational drugs under current clinical hold. If FDA were to cite can demonstrate that the clinical trial rules and the additional patients who specific potential reasons for a hold, it could not be conducted unless the will have expanded access under this could give the misimpression that sponsor is able to charge for the final rule. In assessing the impact of the failure to meet criteria or submission investigational drug, the sponsor may final rule, it is the incremental effect, or requirements not expressly mentioned request permission to charge patients additional patients that will gain would not be a basis for a hold. and recover the direct costs associated expanded access, that must be FDA anticipates that clinical holds for with the treatment use. considered. Patients with access to expanded access INDs will be handled (Comment 96) A comment from an investigational drugs under current in the same manner as for INDs for insurance company provided an rules are not relevant to an analysis of clinical trials. That is, the clinical hold estimate of the costs to enrollees in impacts for this final rule. The only letter will cite the relevant regulation commercial private health plans direct costs that are relevant to this final and explain in detail how the criteria associated with the expanded access rule are the costs to drug sponsors to that are the basis for the hold are not rule that indicates the costs to be much prepare and submit expanded access met. FDA further anticipates that, in the larger than those stated in the proposed requests. The comment did not provide event that the basis for a clinical hold rule. The comment assumed that an estimate of these costs. is relevant only to an expanded access physicians would request access to (Comment 97) A comment from a IND and not to the clinical development investigational drugs only when capital fund disagreed with the program, the relevant clinical hold available therapies have failed or when proposed rule’s assertion that the rule documentation will make this conventional therapies do not exist. would not have a significant economic abundantly clear. Additional information related to the impact on a substantial number of small In addition, in situations in which an comment and submitted to the docket at entities. The comment stated that FDA ongoing expanded access IND is placed FDA’s request indicated that ‘‘* * * the had overlooked the extensive role of on hold, FDA will carefully consider the grand total number of patients projected small biotech companies in developing needs of patients already receiving the to utilize INDs under these proposals novel kinds of investigational drugs that drug. FDA will not hesitate to use a each year is approximately 67,500.’’ The are often the most sought-after therapies partial clinical hold (which permits comment also stated its belief that for expanded access. The comment also

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stated that small biotech companies overly optimistic because Federal therapy available and the probable risk severely lack funding and also face Register notices are not the best way of to the person from the investigational special difficulties in getting their disseminating information to the lay drug is not greater than the probable risk therapies to the stage where they are public or their physicians and the from the disease or condition; (2) FDA able to obtain significant partnering proposed rule did not mention any must determine that there is sufficient arrangements. The comment stated that additional efforts to disseminate evidence of safety and effectiveness to such companies could be substantially information about expanded access. support the use of the investigational helped by expanded access programs by (Response) Issuance of the final rule drug in the particular case; (3) FDA permitting them to reach larger numbers is not the only way FDA plans to must determine that provision of the of patients sooner and to generate larger disseminate information on expanded investigational drug will not interfere amounts of supporting data sooner. The access programs to the lay public and with the initiation, conduct, or comment stated that the most powerful physicians. FDA intends to develop and completion of clinical investigations to boost for small biotech companies and engage in a broad range of publicity and support marketing approval; and (4) the the patients seeking their new therapies educational efforts in a variety of forums sponsor or clinical investigator of the would come from combining expanded and media to increase awareness of the investigational drug must submit a access programs with policies allowing mechanisms for obtaining clinical protocol consistent with the cost recovery and reimbursement (the investigational drugs for treatment use. provisions of section 505 of the act (21 subject of the charging proposed rule). IV. Legal Authority U.S.C. 355) describing the use of the The comment also advocated minimal investigational drug in a single patient efficacy requirements for expanded The agency believes it has the or a small group of patients. The final access and stated that such a policy authority to impose requirements rule sets forth factors that FDA will would not impose substantial costs on regarding expanded access to consider in making the necessary investigational drugs under various society or the healthcare system because determinations and explains the sections of the act, including sections sponsors would be paying for the costs procedures and criteria for physicians, 505(i), 561, 701(a) (21 U.S.C. 371(a)), of producing and supplying the therapy sponsors, and/or investigators to make and 505–1(f)(6). in most expanded access programs. The the necessary representations and comment added that if such programs Section 505(i) of the act directs the 1 submissions to FDA. enable a product to reach marketing agency to issue regulations exempting Section 561(c) of the act specifically approval sooner than otherwise, that from the operation of the new drug authorizes expanded access under a would greatly reduce the costs that approval requirements drugs intended treatment IND if FDA makes the sponsors must recoup in pricing solely for investigational use by experts following determinations: (1) Under the products for commercial sale. qualified by scientific training and (Response) The comment suggests expertise to investigate the safety and treatment IND, the investigational drug that investigational drugs produced by effectiveness of drugs. The final rule is intended for use in diagnosing, small biotech companies are often the explains procedures for obtaining FDA monitoring, or treating a serious or most sought-after therapies for authorization for expanded access uses immediately life-threatening disease or expanded access, but provides no of investigational drugs and factors condition; (2) there is no comparable or examples. While small biotech relevant to making necessary satisfactory alternative therapy available companies may face a number of determinations. to diagnose, monitor, or treat that stage difficulties—including a lack of funding Section 561 of the act, added by of the disease or condition in the and partnering opportunities—such FDAMA, provides significant additional population of patients to which the obstacles are neither the subject of this authority for this final rule. Section investigational drug is intended to be final rule nor the responsibility of FDA. 561(a) of the act states that FDA may, administered; (3) the investigational The purpose of the proposed expanded under appropriate conditions drug is already under investigation in a access rule is not to help sponsors reach determined by the agency, authorize the controlled clinical trial for the same use larger numbers of patients and generate shipment of investigational drugs for the under an IND under section 505(i) of the larger amounts of supporting data diagnosis, monitoring, or treatment of a act, or all clinical trials necessary for sooner. The agency believes that these serious disease or condition in approval of that use of the goals are best pursued through the emergency situations. This final rule investigational drug have been normal drug development process. FDA sets forth factors that the agency will completed; (4) the sponsor of the believes that cost recovery for expanded consider in determining whether to controlled clinical trials is actively access—the subject of the charging authorize shipment of investigational pursuing marketing approval of the proposed rule—is appropriate only in drugs in emergency situations. investigational drug, with due diligence, limited circumstances. Further, the Section 561(b) of the act allows any for the same intended use; (5) provision agency has determined that the amount person, acting through a physician of the investigational drug will not to be charged should be limited to the licensed in accordance with State law, interfere with the enrollment of patients direct costs of providing the to request from a manufacturer or in ongoing clinical investigations under investigational drug for the treatment distributor an investigational drug for section 505(i) of the act; (6) in the case use. Cost recovery through charging is the diagnosis, monitoring, or treatment of serious diseases, there is sufficient not intended as a mechanism through of a serious disease or condition if four evidence of safety and effectiveness to which sponsors may generate funds to conditions are met: (1) The physician support the intended use; and (7) in the support drug development generally. must determine that the person has no case of immediately life-threatening The agency agrees with the comment comparable or satisfactory alternative diseases, the available scientific that the proposed rule would not evidence, taken as a whole, provides a impose substantial costs on society or 1 In light of section 903(d) of the act (21 U.S.C. reasonable basis to conclude that the the healthcare system. 393(d)) and the Secretary’s delegations to the investigational drug may be effective for Commissioner of Food and Drugs, statutory (Comment 98) One comment stated references to ‘‘the Secretary’’ in the discussion of its intended use and will not expose that the estimates of increased expanded legal authority have been changed to ‘‘FDA’’ or ‘‘the patients to an unreasonable and use in the Analysis of Impacts appeared agency.’’ significant risk of illness and injury. The

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final rule sets forth factors that FDA will that does not individually or result from increased patient access to consider in making the necessary cumulatively have a significant effect on investigational drugs generally and from determinations. the human environment. Therefore, expanded access being made available Section 561 of the act further requires neither an environmental assessment for a broader variety of disease that protocols submitted under section nor an environmental impact statement conditions and treatment settings. 561 be subject to section 505(i) of the act is required. Private benefits will accrue to including regulations issued under individual patients receiving drugs for VI. Analysis of Economic Impacts section 505(i). Section 561(d) of the act expanded access use, whereas social permits the agency to terminate FDA has examined the impacts of the benefits will accrue if information expanded access for failure to comply final rule under Executive Order 12866 obtained contributes to the development with the requirements of section 561 of and the Regulatory Flexibility Act (5 of new therapies generally. Due to the act. The final rule sets forth the U.S.C. 601–612), and the Unfunded uncertainty with respect to the potential conditions under which FDA will place Mandates Reform Act of 1995 (Public magnitude of such benefits, and a lack an expanded access use on clinical Law 104–4). Executive Order 12866 of necessary data, FDA did not generate hold. directs agencies to assess all costs and quantitative estimates of expected This final rule establishes three benefits of available regulatory benefits. categories of expanded access. While alternatives and, when regulation is authority for individual patient access is necessary, to select regulatory A. Objectives of the Final Action based on section 561(b) of the act, and approaches that maximize net benefits FDA is proposing this action to authority for treatment INDs and (including potential economic, describe in greater detail all of the ways treatment protocols is based on section environmental, public health and safety, patients may obtain expanded access to 561(c) of the act, there is also authority and other advantages; distributive investigational drugs for treatment use. in the statute for FDA to issue impacts; and equity). The agency Specifically, the final rule establishes regulations for intermediate-size patient believes that this final rule is not an eligibility criteria, submission populations. Section 561(b)(4) of the act economically significant regulatory requirements, and safeguards for the requires submission of a protocol for the action under the Executive Order. expanded access use of investigational expanded access use that is consistent The Regulatory Flexibility Act drugs by individual patients, including with the requirements of the IND requires agencies to analyze regulatory in emergencies; intermediate-size regulations describing the use of the options that would minimize any patient populations; and larger investigational drug in a single patient significant impact of a rule on small populations under a treatment protocol or a small group of patients. The entities. Our economic analysis for the or treatment IND. The proposal is also provisions of the final rule concerning proposed rule did not indicate any intended to increase public knowledge expanded access for intermediate-size significant new regulatory burden, and and awareness of expanded access and, patient populations address the use of we did not receive any comments that thus, to make investigational drugs more the investigational drug in the small would cause us to reconsider this widely available. In addition, by groups of patients mentioned in the determination. Therefore, the agency establishing clear eligibility criteria and statute. certifies that the final rule will not have submission requirements, the final rule Section 701(a) of the act provides a significant economic impact on a will ease administrative burdens on general authority to issue regulations for substantial number of small entities. physicians seeking investigational drugs the efficient enforcement of the act. By Section 202(a) of the Unfunded for their patients and on sponsors who clarifying the criteria and procedures Mandates Reform Act of 1995 requires are willing to make promising relating to expanded access to that agencies prepare a written unapproved therapies available for investigational products, this final rule statement, which includes an treatment use. is expected to aid in the efficient assessment of anticipated costs and benefits, before proposing ‘‘any rule that B. Nature of the Problem Being enforcement of the act. Addressed Finally, section 505–1(f)(6) of the act, includes any Federal mandate that may added by FDAAA, states that ‘‘[t]he result in an expenditure by State, local, The fundamental problem addressed mechanisms under section 561 to and tribal governments, in the aggregate, by the final rule is one of incomplete provide for expanded access for patients or by the private sector, of $100,000,000 information. In some circumstances, a with serious or life-threatening diseases or more (adjusted annually for inflation) lack of clearly defined eligibility criteria or conditions may be used to provide in any one year.’’ The current threshold and submission requirements has access for patients with a serious or life- after adjustment for inflation is $133 created inefficiencies that limit patient threatening disease or condition, the million, using the most current (2008) access to potentially beneficial treatment of which is not an approved Implicit Price Deflator for the Gross investigational drugs. The final rule is use for the drug, to a drug that is subject Domestic Product. FDA does not expect also intended to address concerns that, to elements to assure safe use under this this final rule to result in any 1-year historically, cancer and Acquired subsection.’’ FDA ‘‘shall promulgate expenditure that will meet or exceed Immunodeficiency Syndrome (AIDS) regulations for how a physician may this amount. patients have had better access to provide the drug under the mechanisms The agency estimates that the total investigational drugs than patients with of section 561.’’ Because the expanded costs to drug sponsors and physicians to other serious diseases or conditions, and access mechanisms in this final rule submit the additional expanded access that patients under the care of may be used by patients seeking access submissions expected under this final physicians based in academic medical to a drug that is subject to elements to rule will be between $1.5 million and centers are more likely to obtain such assure safe use, this rule fulfills the $3.0 million per year. Because a typical access than patients whose physicians FDAAA requirement. sponsor will submit an expanded access practice outside such centers. In use request only infrequently, these addition, the lack of clearly defined V. Environmental Impact costs are expected to be widely eligibility criteria and submission The agency has determined under 21 dispersed among affected entities. The requirements has led some physicians CFR 25.30(h) that this action is of a type benefits of the final rule are expected to and drug sponsors to devote more

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resources than necessary to the under a treatment protocol or treatment record of the number of submissions in preparation of expanded access IND. this category. However, based on an internal survey of drug review divisions, submissions. Through this final rule, the C. Baseline for the Analysis agency seeks to correct these FDA estimates that approximately 55 shortcomings. During the period 1997 through 2005, other expanded access submissions FDA received an average of 2,046.6 were received each year between 2000 The final rule establishes general INDs per year. Of this number, on and 2002. While it is not possible to eligibility criteria, submission average, approximately 659, or 32.2 determine the precise number that will requirements, and safeguards for the percent (0.322 = 659 / 2,046.6) were be considered intermediate-size patient expanded access use of investigational individual patient or emergency INDs. population expanded access drugs. The requirements that apply to In addition, FDA received submissions, FDA experts believe that all types of expanded access use are approximately 4.6 treatment IND or most of the 55 other submissions each discussed in section III.C.3 of this treatment protocol submissions per year year will fall under this category. document. The final rule also describes during this time period. Thus, treatment Thus, approximately 2.7 percent more specific eligibility criteria, IND or treatment protocol submissions (0.0269 = 55 / 2,046.6) of all INDs submission requirements, and represent about 0.2 percent (0.0022 = received by FDA each year may be safeguards for three specific categories 4.6 / 2,046.6) of all INDs received by the associated with intermediate-size of expanded access: (1) Expanded access agency each year. Because expanded patient population expanded access for individual patients, (2) expanded access for intermediate-size patient requests. The information presented access for intermediate-size patient populations is not currently established previously is summarized in table 1 of populations, and (3) expanded access in the regulations, FDA does not have a this document.

TABLE 1.—BASELINE DATA FOR THE NO. OF INDS AND EXPANDED ACCESS REQUESTS BY CATEGORY

Individual Patient or Treatment IND Category Total INDs Emergency IND or Protocol Other

Number 2046.6 659 4.6 55

Percent of all INDs 100 32.2 0.2 2.7

One comment submitted in response under single patient or emergency INDs. patients. Thus, an average of 4.6 to the proposed rule provided an FDA believes that it is reasonable to treatment IND or protocol submissions estimate of the number of patients that assume that a typical expanded access could affect between 460 and 46,000 might be affected by this rule. As part submission for an intermediate-size individuals. Based on this information, of our response, we have generated patient population will affect between FDA estimates that between 1,669 and estimates of the number receiving 10 and 100 individuals. Given that FDA 52,159 individuals currently receive investigational drugs under current currently receives an average of 55 such investigational drugs through expanded expanded access programs, in place submissions per year, we estimate that access programs. The wide range of since 1986. between 550 and 5,500 individuals these estimates reflects significant Based on the information presented currently receive investigational drugs variation in the number of patients in previously, FDA currently receives an under intermediate-size patient intermediate-size patient populations, average of 659 individual patient or population or other expanded access and treatment INDs or protocols. These emergency INDs per year. Thus, programs. A treatment IND or protocol approximately 659 individuals per year can vary significantly in size and may estimates are summarized in table 2 of currently receive investigational drugs include between 100 and 10,000 this document.

TABLE 2.—APPROXIMATE NO. OF INDIVIDUALS AFFECTED BY EXPANDED ACCESS PROGRAMS IN PLACE SINCE 1986

Average No. No. of Minimum No. Maximum No. Category of Submissions Patients of Individuals of Individuals

Individual Patient or Emergency IND 659 1 659 659

Small Patient Population/Other 55 10 to 100 550 5,500

Treatment IND or Protocol 4.6 100 to 10,000 460 46,000

Total 1,669 52,159

D. Nature of the Impact available to patients, and FDA in its serious and immediately life-threatening The final rule will affect patients who oversight role in the process for making conditions who lack satisfactory lack effective therapeutic alternatives investigational drugs available for therapeutic alternatives. Therefore, FDA and may benefit from access to expanded access use. As discussed in anticipates that the final rule will investigational drugs, physicians the preamble of the proposed rule (71 increase the number of patients who attempting to obtain investigational FR 75147 at 75149 to 75150), a major obtain access to investigational drugs for drugs for their patients, drug sponsors purpose of this rule is to expand access treatment use. This increase in volume who make investigational drugs to investigational drugs for patients with will lead to more expanded access

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submissions from sponsors and patients obtaining investigational drugs From 1997 to 2005, FDA received, on physicians seeking investigational drugs under expanded access INDs or average, approximately 659 individual for their patients and, as a consequence, protocols for individual patients and patient and emergency IND submissions will require FDA to review more intermediate-size patient populations. per year. Although FDA is confident submissions. Given the relatively small Because this final rule does not this final rule will increase this volume, burden associated with expanded access significantly change the existing it is difficult to predict with precision use submissions under the previous regulations concerning treatment INDs the extent of the increase. There is regulations (although such submissions or treatment protocols, the number of uncertainty concerning the extent to are approximately one-third of all IND patients receiving investigational drugs which patients who desire expanded under these mechanisms should be submissions, the vast majority of those access to investigational drugs are largely unaffected. are for individual patients and do not unable to obtain them; the extent to typically require substantial agency 1. Individual Patient Expanded Access which better information about the resources to review), and the small Submissions mechanisms and processes for obtaining additional burden associated with the access to investigational drugs will expanded access provisions in this final By increasing awareness of the ways rule, FDA expects that the economic individual patients can obtain expanded stimulate more patients, or their impact of the final rule will be small. access to investigational drugs for physicians, to seek investigational drugs treatment use, and decreasing the for expanded access use; and the extent The final rule also attempts to perceived difficulty of obtaining such to which drug manufacturers will be minimize the potential administrative access, the final rule should increase the willing to make investigational drugs burdens for physicians, sponsors, and number of individual patients seeking more broadly available for expanded FDA that will result from an increased access to investigational drugs. FDA volume of patients obtaining access use. Although FDA is confident anticipates that this increase in there will be an increase in the volume investigational drugs for expanded individual patient expanded access access use. The final rule encourages the of individual patient expanded access submissions will be greatest in the years use following issuance of this final rule, consolidation of multiple individual immediately following implementation patient INDs or protocols for a given use because of these uncertainties the of the final rule and will at some point agency can provide only an estimate of under an intermediate-size patient level off or possibly even decline. This population IND or protocol. By reducing the range of potential increase. FDA leveling off or decline will occur when believes that, after publication of the the total volume of submissions that a significant volume of individual final rule, it is reasonable to anticipate will have been prepared if all patients patient expanded access has a 40 to 60 percent increase in the were to obtain a drug under individual accumulated for a variety of drugs, and patient INDs or protocols, consolidation the individual patient expanded access volume of individual patient expanded will limit the additional administrative INDs or protocols for those drugs are access submissions by year 3. As burdens from increased patient access. then replaced with intermediate-size discussed previously in this document, In addition, by explicitly clarifying the patient population INDs or protocols we anticipate that growth will be most eligibility criteria and submission that enroll multiple subjects. Making the rapid in the years immediately requirements for expanded access, the transition from multiple individual following publication of the final rule final rule should make the process of patient INDs or protocols to a single and will eventually plateau or possibly obtaining access to investigational drugs intermediate-size patient population even decline. The implications of these more efficient for all affected parties. IND or protocol should reduce the assumptions for the total number of It is expected that any increase in the overall administrative burden associated individual patient expanded access volume of submissions will result with making a particular investigational submissions are summarized in table 3 primarily from greater numbers of drug available for treatment use. of this document.

TABLE 3.—EXPECTED PERCENT INCREASE AND ESTIMATED NO. OF INDIVIDUAL PATIENT EXPANDED ACCESS SUBMISSIONS

Year After Implementation of Final Rule Expected Percent Increase in Individual Pa- Expected No. of Individual Patient Submis- tient Submissions sions1

1 20 to 40 791 to 923

2 30 to 50 857 to 988

3 40 to 60 923 to 1054

4 0 923 to 1054

5 0 923 to 1054 1 Based on the current average of 659 individual patient treatment use submissions per year and the estimated percent increases in column 2.

2. Intermediate-Size Patient Population treatment use. Based on an internal agency anticipates that this final rule Expanded Access Submissions survey of review divisions, FDA will increase the number of such Although intermediate-size patient estimates that for the period 2000 submissions. Because this previously population expanded access has not through 2002 it received approximately informal mechanism will be described previously been described in the 55 submissions per year that would be in the regulations for the first time, there regulations, this general type of considered intermediate- size patient will be greater awareness, which is mechanism has been used informally to population expanded access likely to stimulate submissions. In make investigational drugs available for submissions under the final rule. The addition, the anticipated increase in

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volume of individual patient expanded individual patient expanded access estimate of the range of potential access submissions discussed submissions are likely to be appropriate increase. FDA believes it is reasonable previously in this document is expected for consolidation. to anticipate a 25 to 50 percent growth to increase the number of intermediate- Based on our experience, we believe in the volume of submissions for size patient population expanded access that many of the individual patient intermediate-size population expanded submissions because the final rule expanded access submissions we access INDs or protocols over a 5-year encourages the consolidation of receive will be appropriate for period. multiple individual patient INDs or consolidation. However, some Compared with the growth in protocols for a given expanded access individual patient expanded access individual patient expanded access use. submissions will be for expanded access submissions, this increase is likely to be The extent to which submissions for uses that are sufficiently rare that it is more gradual in the years immediately expanded access for intermediate-size unlikely that there will be enough following implementation of a final patient populations will increase is similar uses to consolidate them under rule, and will increase more sharply uncertain. Section 312.315 of the final an intermediate-size patient population after 2 to 3 years as some of the increase rule concerns expanded access for IND or protocol. There is also in volume of individual patient intermediate-size patient populations. uncertainty about the extent to which expanded access submissions is shifted This section provides that FDA may ask sponsors will be willing to make to intermediate-size population INDs or a sponsor to consolidate expanded investigational drugs available for protocols. As in the case of expanded access under this section when the expanded access use under access for individual patients, growth in agency has received a significant intermediate-size patient population the number of submissions is expected number of requests for individual INDs or protocols. Although FDA is to plateau or even decline after a few patient expanded access to an confident that there will be growth in years. The implications of these investigational drug for the same use. the volume of intermediate-size patient assumptions for the number of FDA does not have historical population expanded access INDs or individual patient expanded access information that will permit us to protocols, because of the uncertainties submissions are summarized in table 4 accurately predict what portion of identified, we can provide only an of this document.

TABLE 4.—EXPECTED PERCENT INCREASE AND ESTIMATED NO. OF INTERMEDIATE-SIZE PATIENT POPULATION EXPANDED ACCESS SUBMISSIONS

Year After Implementation of Final Rule Expected Percent Increase in Intermediate- Expected No. of Intermediate-Size Patient Size Patient Population Submissions Population Submissions1

1 5 to 10 58 to 61

2 10 to 20 61 to 66

3 20 to 40 66 to 77

4 25 to 50 69 to 82

5 0 69 to 82 1 Based on the current average of 55 intermediate-size patient population submissions per year and the estimated percent increases in column 2.

3. Expanded Access under Treatment or treatment protocols or under less Reclassification of an open-label INDs and Treatment Protocols formal open-label (also referred to as protocol as a treatment IND or treatment open-access) protocols. The agency protocol may also increase publicity for, The number of treatment INDs and intends to be more vigilant in ensuring and awareness of, the access program. treatment protocols should be largely that a use of an investigational drug that Sponsors of treatment INDs or treatment unaffected by the final rule. The concept has the characteristics of a treatment protocols may, in certain circumstances, of large access programs is well be required to list those programs at established and most drugs that meet an IND or treatment protocol is submitted and authorized as such, rather than as http://www.clinicaltrials.gov, a Web site unmet medical need for a serious or maintained by the NIH as a resource for immediately life-threatening condition an open-label protocol. While this increased vigilance may increase the patients seeking to enroll in clinical have had some kind of large access trials or obtain access to investigational number of treatment INDs or treatment program late in their development. drugs for treatment use. The additional protocols, any increase will be primarily Therefore, the number of large access exposure generated by this site may programs is primarily a function of the attributable to reclassifying open-label attract more patients than will have had number of new drugs to treat serious safety studies as treatment INDs or access under an open-label protocol. As and immediately life-threatening treatment protocols rather than a net a result, any given treatment IND or conditions that reach the latter stages of increase in the overall number of large treatment protocol may be somewhat drug development (e.g., become NDA access programs. This reclassification more costly than a less-publicized open- submissions). This rule is unlikely to should also improve safety monitoring label protocol due to the volume of influence that number. of large access programs without patients enrolled. FDA is not able to As stated in the preamble of the significantly increasing administrative predict the impact on patient volume as proposed rule (71 FR 75147 at 75155), costs, because the costs for a treatment a result of reclassifying open-label or sponsors have instituted large expanded IND or treatment protocol and an open- open-access protocols as treatment INDs access programs under treatment INDs label protocol are similar. or treatment protocols. However, FDA

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anticipates that there will be some protocols. FDA believes that this action, effectiveness, obtaining the informed economies of scale, so that the along with detailed eligibility criteria consent of the patient, approval of an incremental costs will be relatively and submission requirements IRB, and a careful assessment of the small on a per-patient basis. FDA established in the final rule, will potential risks and benefits to the believes any added costs will be improve access to investigational drugs patient. In addition, the final rule will justified by the potentially greater and result in making expanded access place limits on the scope and duration number of patients who will benefit use more widely available to patients of certain types of expanded access use, from access to investigational drugs. regardless of treatment setting. require that sponsors of such INDs or In formulating the final rule, FDA protocols monitor the expanded access E. Benefits of the Final Rule considered its statutory mandate and use and comply with safety and annual Because FDA currently has no data the interests of individuals and special reporting requirements for INDs, and that will allow us to predict the extent patient populations, drug sponsors, and subject ongoing INDs or protocols to to which the amendments to existing the general public. The agency found periodic reassessment. The agency IND regulations will generate direct that in many situations, individuals or believes these safeguards will benefits for consumers, it is not possible special patient populations have adequately protect the safety and to accurately quantify the magnitude of benefited from increased access to a welfare of patients who will seek, and any expected incremental benefits at drug that has not yet been approved for may benefit from, expanded access to this time. The number of patients marketing (e.g., in the case of cancer or investigational drugs. obtaining expanded access to HIV therapies). These individuals or investigational drugs is expected to patient groups generally have serious or F. Costs of the Final Rule increase. However, because eligible immediately life-threatening conditions To the extent that the final rule results patients will have serious or and have not responded to available in an increase in the number of immediately life-threatening conditions therapies or cannot participate in expanded access submissions, drug that have failed to respond to available ongoing clinical trials for some reason. sponsors and physicians requesting therapies, and because the On the other hand, unrestricted access investigational drugs on behalf of their investigational drugs are unproven, FDA to investigational drugs for treatment patients will incur some additional cannot predict the extent to which use could reduce the patient population costs. Because the final rule does not individual patients will benefit from available for enrollment in the clinical include any new, mandatory reporting access to these drugs. Thus, the trials required to demonstrate safety and requirements, the agency believes that following discussion describes, in efficacy in support of new drug the one-time costs associated with this general terms, the nature of the potential marketing applications. If expanded rule will be negligible. Thus, the benefits associated with the final rule. access to investigational drugs were to incremental burden imposed by this The benefits of the final rule are adversely affect the marketing approval final rule will be in the form of expected to result from improved process, the general population will additional annual or recurring costs patient access to investigational drugs experience diminished social benefits associated with the increased number of generally and from expanded access due to the reduced or delayed expanded access submissions estimated being made available for a broader availability of new therapies approved previously in this document. variety of disease conditions and for marketing by FDA. The agency estimates that preparation treatment settings. In particular, the The final rule addresses these and submission of an individual patient clarification of eligibility criteria and competing interests by allowing expanded access submission will submission requirements will enhance investigational drugs to be made require a total of approximately 8 hours. patient access by easing the available for expanded access use only This time burden will be divided among administrative burdens on individual if providing the drug for the requested physicians (approximately 15 percent or physicians seeking investigational drugs use will not interfere with the initiation, 1.2 hours) and nurses, nurse for their patients and on sponsors who conduct, or completion of clinical practitioners, or medical administrators make investigational drugs available for investigations that could support (approximately 85 percent or 6.8 hours). expanded access use. Expanded access marketing approval, or otherwise According to the U.S. Department of to investigational drugs may generate compromise the potential development Labor, Bureau of Labor Statistics,2 total both private and social benefits. Private of the expanded access use. In this way, employer costs per hour worked for benefits will accrue to individual the final rule effectively balances the employee compensation for registered patients receiving drugs for expanded interests of those patient populations nurses in the health care and social access use, whereas social benefits will who will benefit from having greater assistance sector was $44.21 as of March accrue if these private benefits are also access to investigational drugs with the 2008. Thus, the cost of the estimated 6.8 valued by society at large, or if any broader interests of society in having hours of nurse time required to prepare information obtained contributes to the safe and effective new therapies and submit an individual patient development of new therapies generally. approved for marketing and widely expanded access submission will be The final rule is also designed to available. approximately $301 ($300.62 = $44.21 address concerns that many physicians The agency is also aware that per hour x 6.8 hours). and their patients, particularly those allowing expanded access to Historically, most of the treatment use outside of academic medical centers, are investigational drugs before they are requests submitted to the agency have unaware of the availability of fully evaluated for safety may have been prepared by physicians in the investigational drugs for expanded adverse consequences for the seriously hematology/oncology specialty category. access use. In FDAMA, Congress ill patients who receive them. The Data available on the Internet indicate included language in section 561(c) of safeguards in the final rule are also the act to authorize the Secretary to designed with this concern in mind. 2 See http://www.bls.gov/news.release/ inform medical associations, medical Authorization of a particular expanded ecec.toc.htm, last viewed July 11, 2008. (FDA has verified the Web site address, but FDA is not societies, and other appropriate persons access use is generally contingent upon responsible for any subsequent changes to the Web of the availability of investigational a number of factors, including some site after this document publishes in the Federal drugs under treatment INDs or treatment evidence of the drug’s safety and Register.)

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that the median expected total physician time required to prepare and $301 + $224). Applying this cost figure compensation for a physician in the submit an individual patient expanded to the number of additional individual hematology/oncology specialty category access submission is about $224 patient expanded access submissions was $387,739 as of March 2008.3 This ($223.69 = $186.41 per hour x 1.2 estimated previously in this document median total compensation figure hours). Therefore, the agency estimates suggests the pattern of incremental corresponds to approximately $186 per that the total cost to prepare and submit annual costs summarized in table 5 of hour ($186.41 = $387,739 / 2,080 hours). an individual patient expanded access this document. Thus the cost for the 1.2 hours of submission will be about $525 ($525 =

TABLE 5.—NO. OF ADDITIONAL INDIVIDUAL PATIENT EXPANDED ACCESS SUBMISSIONS AND ESTIMATED ANNUAL COSTS

Expected Cost of Additional Individual Pa- Year After Implementation of Final Rule Expected Increase in the No. of Individual Patient Submissions1 tient Submissions2

1 132–264 $69,300 to $138,600

2 198–329 $103,950 to $172,725

3 264–395 $138,600 to $207,375

4 264–395 $138,600 to $207,375

5 264–395 $138,600 to $207,375 1 Based on increases in the number of individual patient expanded access submissions implied by the estimates presented in table 2 of this document. 2 Based on an estimated cost of $525 per individual patient expanded access submission.

Preparation and submission of an intermediate-size patient population hourly total compensation figure of intermediate-size patient population expanded access submission is about $42 ($41.77 = $86,890 / 2,080 expanded access IND or protocol is approximately $9,120 ($9,120 = 60 hours). Thus, the cost associated with expected to require a total of about 120 hours x $152). the 36 hours of Clinical Research hours of staff time. This time burden Information available on the Internet Associate time required to prepare and will be divided between a Medical also indicates that the median total submit an intermediate-size patient Director or Director of Clinical Research, compensation for a Regulatory Affairs population expanded access submission typically a medical doctor Director is approximately $235,149 per is approximately $1,512 ($1,512 = 36 5 (approximately 50 percent or 60 hours), year. This translates into an estimated hours x $42). a Regulatory Affairs Director hourly total compensation figure of (approximately 20 percent or 24 hours), about $113 ($113.05 = $235,149 / 2,080 Based on the information presented, and a Clinical Research Associate hours). Thus, the cost associated with the agency estimates that the total cost (approximately 30 percent or 36 hours). the 24 hours of Regulatory Affairs to prepare and submit an intermediate- Information available on the Internet Director time required to prepare and size patient population expanded access suggests that the median total submit an intermediate-size patient submission will be approximately compensation for a physician serving as population expanded access submission $13,350 ($13,344 = $9,120 + $2,712 + a Medical Director is about $316,134 per is approximately $2,712 ($2,712 = 24 $1,512). Applying this figure to the year.4 This translates into an estimated hours x $113). increases in the number of intermediate- hourly total compensation figure of Finally, information available on the size patient population expanded access about $152 ($151.98 = $316,134 / 2,080 Internet indicates that the median total submissions estimated previously in hours). Thus, the cost associated with compensation for a Clinical Research this document suggests the pattern of the 60 hours of Medical Director time Associate is approximately $86,890 per annual cost increases summarized in required to prepare and submit an year.6 This translates into an estimated table 6 of this document.

TABLE 6.—NO. OF ADDITIONAL INTERMEDIATE-SIZE PATIENT POPULATION EXPANDED ACCESS SUBMISSIONS AND ESTIMATED ANNUAL COSTS

Expected Increase in the No. of Inter- Year After Implementation After Final Rule mediate-Size Patient Population Submis- Expected Cost of Additional Intermediate- Size Patient Population Submissions2 sions1

1 3 to 6 $40,050 to $80,100

2 5 to 11 $66,750 to $146,850

3 11 to 22 $146,850 to $293,700

3 See http://swz.salary.com/salarywizard/ changes to the Web site after this document but FDA is not responsible for any subsequent layoutscripts/swzl_newsearch.asp, last viewed July publishes in the Federal Register). changes to the Web site after this document 11, 2008. (FDA has verified the Web site address, 4 See http://swz.salary.com/salarywizard/ publishes in the Federal Register.) but FDA is not responsible for any subsequent layoutscripts/swzl_newsearch.asp, last viewed July 5 See footnote 4 of this document. 11, 2008. (FDA has verified the Web site address, 6 See footnote 4 of this document.

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TABLE 6.—NO. OF ADDITIONAL INTERMEDIATE-SIZE PATIENT POPULATION EXPANDED ACCESS SUBMISSIONS AND ESTIMATED ANNUAL COSTS—Continued

Expected Increase in the No. of Inter- Year After Implementation After Final Rule mediate-Size Patient Population Submis- Expected Cost of Additional Intermediate- Size Patient Population Submissions2 sions1

4 14 to 27 $186,900 to $360,450

5 14 to 27 $186,900 to $360,450 1 Based on increases in the number of intermediate-size patient population expanded access submissions implied by the estimates presented in table 3 of this document 2 Based on an estimated cost of $11,000 per intermediate-size patient population expanded access submission.

For reasons discussed previously in Therefore, FDA does not expect the cost burdens associated with this final this document, the agency does not provisions of this final rule regarding rule are summarized in table 7 of this expect that the final rule will have an treatment INDs or treatment protocols to document. impact on the overall number of impose any incremental cost burden. treatment INDs or treatment protocols. The total estimated variable and annual

TABLE 7.—COST SUMMARY

One-Time Fixed 1 Year After Implementation of Final Rule Cost Variable Cost Annual Cost

1 $0 $109,350 to $218,700 $109,350 to $218,700

2 $0 $170,700 to $319,575 $170,700 to $319,575

3 $0 $285,450 to $501,075 $285,450 to $501,075

4 $0 $325,500 to $567,825 $325,500 to $567,825

5 $0 $325,500 to $567,825 $325,500 to $567,825 1 Since estimated one-time fixed costs are negligible, annual costs equal variable costs.

For reasons discussed previously in consolidation should, to some extent, also the drug developer or the developer this document, the agency expects that offset incremental administrative will generally be willing to grant the the total one-time costs of the final rule burdens caused by increased patient request. To the extent that these will be negligible. FDA expects that the access. Making the transition from provisions minimize the informational annual costs of this final rule will range multiple individual patient expanded burden on potential sponsors or from a low of about $109,000 to access INDs or protocols to a single IND physicians, the final rule will enhance $219,000 in the first year following or protocol for an intermediate-size both efficiency and cost effectiveness. publication of the final rule, to a high patient population should reduce for One comment submitted in response of about $325,000 to $568,000 in the sponsors the administrative burdens to the proposed rule provided an fourth and fifth years. These estimates associated with making a drug available estimate of the number of patients that suggest total annual costs for the final for expanded access use. In addition, might be affected by this final rule. As rule of between $1.2 and $2.2 million provisions of the final rule are designed part of our response, we have generated for the 5-year period following to minimize the amount of information estimates of the number additional implementation of the final rule. and paperwork required to support a individuals that will gain access to The agency expects that the estimated particular expanded access request. investigational drugs as a result of the incremental cost burdens associated Physicians and drug sponsors will need final rule. with this final rule are likely to be to review the rule to become familiar Information presented in table 5 of widely dispersed among affected with its provisions and to gather the this document indicates that FDA entities for several reasons. First, given evidence and information necessary to expects this final rule to generate the historical volume of various types of support an expanded access submission. between 132 and 395 additional treatment use submissions, the agency However, in instances where a current individual patient or emergency INDs believes that a particular drug sponsor— IND already exists, a sponsor need only per year. Thus, we estimate that or a physician acting on behalf of a submit an amendment describing the between 132 and 395 additional patient—will submit a request for information relevant to the expanded individuals per year will have expanded expanded access to investigational access protocol. Also, another sponsor access to investigational drugs under drugs fairly infrequently. Second, as or individual physician acting on behalf single patient or emergency INDs as a noted previously, the final rule of a patient may, with the written result of this final rule. Information encourages the consolidation of permission of the original sponsor, presented in table 6 of this document multiple expanded access INDs or reference information in the current IND indicates that FDA expects this final protocols for individual patients for a already on file. The agency believes that rule to generate between 3 and 27 particular expanded access use under an a majority of expanded access additional expanded access submissions intermediate-size patient population submissions will have such a right of for intermediate-size patient expanded access IND or protocol. Such reference, either because the sponsor is populations. As discussed previously,

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we believe that an intermediate-size populations. Finally, because FDA receive investigational drugs through patient population or other expanded expects this final rule to have no impact expanded access programs as a result of access program will generally include on the number of treatment INDs or this final rule. The range of these between 10 and 100 individuals. protocols, the number of patients with estimates reflects significant variation in Therefore, we estimate that between 30 access to investigational drugs will be the number of patients in intermediate- (30 = 3 x 10) and 2,700 (2,700 = 27 x unaffected. Based on this information, size patient populations. These 100) additional individuals per year will FDA estimates that between 162 (162 = estimates are summarized in table 8 of have expanded access to investigational 132 + 30) and 3,095 (3,095 = 395 + this document. drugs under intermediate-size patient 2,700) additional individuals will

TABLE 8.—APPROXIMATE NO. OF ADDITIONAL INDIVIDUALS AFFECTED BY EXPANDED ACCESS PROGRAMS UNDER THE FINAL RULE

Expected No. of No. of Minimum No. of Maximum No. of Category Additional Submissions Patients Additional Individuals Additional Individuals

Individual Patient or Emergency IND 132 to 395 1 132 395

Small Patient Population/Other 3 to 27 10 to 100 30 2,700

Treatment IND or Protocol 0 100 to 10,000 0 0

Total 162 3,095

G. Minimizing the Impact on Small unidentified sponsors for research the probable risk from the disease or Entities purposes. Because nearly all individual condition; and FDA determines that The agency does not believe the final patient treatment use submissions are there is sufficient evidence of safety and rule will have a significant economic made by various types of entities for effectiveness to support the use of the impact on a substantial number of small research purposes, the agency believes investigational drug. FDAMA also entities. Nevertheless, in the proposed that most of these entities will be largely incorporated into the act FDA’s rule, we recognized our uncertainty classified as small entities. current regulation concerning treatment Because there is currently no formal regarding the number and size INDs or treatment protocols under mechanism in place for tracking the distribution of affected entities, as well which large populations currently other types of expanded access (e.g., as the economic impact of the final rule receive investigational drugs for intermediate-size patient population on those entities, and requested detailed treatment use. Because FDAMA did not submissions), no data exist that will comment on these important issues. We require that FDA adopt implementing allow the agency to identify the number received no comments that would cause of sponsors in this category that will regulations, the agency could have us to change our determination that the qualify as small entities. chosen not to do so. final rule will not have a significant Thus, while highly uncertain, the However, the agency believes that economic impact on a substantial agency believes that at least some of the implementing regulations will further number of small entities. entities submitting expanded access improve expanded access to Agency records indicate that the requests will qualify as small entities. investigational drugs for treatment use. majority of submissions for treatment As discussed in section VI.F of this use of investigational drugs (about 78 One of the major criticisms about access document, the agency expects that any to investigational drugs is that the percent) are submitted by commercial incremental burden associated with the drug sponsors. Other entities making criteria for authorizing access are final rule will be small and widely unclear and that there is not broad treatment use submissions include dispersed among affected entities. government agencies (approximately 14 knowledge among affected, or percent), individual physicians (7 H. Alternatives potentially affected, parties about the percent), and academic institutions (1 FDA considered several alternatives mechanisms or procedures to obtain percent). Thus, the agency believes that to the final rule. They are discussed in access. FDA believes the final the vast majority (92 percent) of the following paragraphs. regulations are needed to address these sponsors of expanded access INDs or concerns. The regulations provide to protocols (consisting of commercial 1. Do Not Propose Implementing sponsors, patients, and licensed drug sponsors or government agencies) Regulations for the Expanded Access physicians who will be seeking will not be considered small entities. Provisions of FDAMA investigational drugs for their patients The remaining 8 percent of treatment FDAMA revised the act to specifically clear direction about the criteria for use submissions are made by individual authorize the use of investigational new authorizing expanded access and what physicians and academic institutions drugs by licensed physicians to information must be submitted to the that the agency believes will meet Small diagnose, monitor, or treat individual agency to enable it to evaluate a Business Administration small business patients who have a serious disease or proposed expanded access submission. criteria. condition if, among other things, the Clearer direction and greater knowledge Of the average of 659 individual physician determines that the person of the mechanisms and procedures for patient treatment use submissions has no comparable or satisfactory obtaining investigational drugs for submitted annually, very few are alternative therapy to diagnose, monitor, expanded access use should reduce associated with commercial sponsors. or treat the disease or condition, and barriers to access. The vast majority are submitted by that the probable risk from the individual physicians and various other investigational drug is not greater than

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2. Propose a Regulation Describing Only more transparent about the processes for A. The Final Rule Individual Patient Expanded Access and making drugs available for expanded 1. Submission Requirements for All the Treatment IND or Treatment access. As stated previously, FDA has Expanded Access Uses Protocol used this intermediate category Section 312.305(b) describes the As discussed in the previous informally in the past and believes it submission requirements applicable to paragraphs, FDAMA specifically will have reason to use this category in all types of expanded access. authorized the use of investigational the future. Therefore, FDA believes it is appropriate to formalize and fully Section 312.305(b)(1) states that an new drugs by licensed physicians to expanded access submission is required diagnose, monitor, or treat individual describe in the regulations the intermediate expanded access category, for each type of expanded access. The patients in certain circumstances. submission may be a new IND or a FDAMA also essentially repeated FDA’s as well as the two other categories of expanded access. protocol amendment to an existing IND. current regulation concerning treatment Information required for a submission INDs or treatment protocols under 3. Propose a Regulation Describing More may be supplied by referring to which large populations currently Than Three Expanded Access Categories pertinent information contained in an receive investigational drugs for FDA also considered proposing a rule existing IND if the sponsor of the treatment use. existing IND grants a right of reference FDA could have chosen to adopt that will include more than three expanded access categories, but rejected to the IND. regulations that described only these Section 312.305(b)(2) describes the two categories of expanded access. this alternative. In internal discussions, FDA found that the distinctions expanded access submission However, FDA has had a long history of requirements. The following items must using an informal mechanism to make between the proposed categories and the additional categories it considered were be included: investigational drugs available to • A cover sheet (Form FDA 1571) intermediate-size patient populations. unclear. FDA was concerned that the additional categories would create meeting the requirements of § 312.23(a); This mechanism has been used in • The rationale for the intended use situations in which both: (1) The confusion rather than provide the clarity that is the goal of the final regulations. of the drug, including a list of available expanded access use did not meet the therapeutic options that will ordinarily criteria for a treatment IND under the FDA concluded that the additional categories could be merged into the be tried before resorting to the previous regulation and (2) it would investigational drug or an explanation of have been excessively burdensome for three proposed categories and that these categories will be able to provide access why the use of the investigational drug sponsors and FDA to require large is preferable to the use of available numbers of individual patient INDs for to investigational drugs in all situations FDA is likely to encounter. therapeutic options; the same use. The agency concluded • The criteria for patient selection; or, that, consistent with the terminology of VII. Paperwork Reduction Act of 1995 for an individual patient, a description section 561(b)(4) of the act, it is of the patient’s disease or condition, preferable to establish an intermediate This final rule contains information collection requirements that are subject including recent medical history and category for expanded access, with previous treatments used for the disease additional criteria and monitoring to review by the Office of Management and Budget (OMB) under the Paperwork or condition; requirements, that will be used for more • The method of administration of the Reduction Act of 1995 (44 U.S.C. 3501– than an individual patient, but fewer drug, dose, and duration of therapy; 3520) (the PRA). The title, description, than the large numbers of patients in • A description of the facility where and respondent description of the treatment INDs or treatment protocols. the drug will be manufactured; In FDA’s experience, there is often a information collection provisions are • Chemistry, manufacturing, and need for a middle ground between an shown below with an estimate of the controls information adequate to ensure individual patient IND or protocol and annual reporting burden. Our estimate the proper identification, quality, a treatment IND or treatment protocol. includes the time for reviewing purity, and strength of the For some drugs in development, there is instructions, searching existing data investigational drug; considerable demand for expanded sources, gathering and maintaining the • Pharmacology and toxicology access before the use meets the criteria data needed, and completing and information adequate to conclude that for a treatment IND or treatment reviewing each collection of the drug is reasonably safe at the dose protocol. There are also situations in information. and duration for expanded access use which investigational drugs that are not Title: Expanded Access to (ordinarily, information that will be being actively developed are the best Investigational Drugs for Treatment Use adequate to permit clinical testing of the available therapy for a significant Description: The final rule clarifies drug in a population of the size number of patients and should be made existing regulations and revises them by expected to be treated); and available to patients under an expanded adding new types of expanded access • A description of clinical access process. In these situations, for treatment use. Under the final rule, procedures, laboratory tests, or other making the drug available under a series expanded access to investigational monitoring necessary to evaluate the of individual patient expanded access drugs will be available to individual effects of the drug and minimize its INDs or protocols is burdensome on patients, including in emergencies; to risks. physicians, sponsors, and FDA, and intermediate-size patient populations; makes it difficult to monitor the and to larger populations under a 2. Individual Patient Expanded Access expanded access use to identify treatment protocol or IND. The final rule Section 312.310(b) contains significant safety concerns such as is intended to improve access to additional submission requirements that serious adverse events. investigational drugs for patients with apply to use of an investigational drug Describing this intermediate category serious or immediately life-threatening for the treatment of an individual in the regulations is also consistent with diseases or conditions who lack other patient by a licensed physician. The FDA’s goal of maximizing awareness of therapeutic options and may benefit expanded access submission must expanded access programs by being from such therapies. include information adequate to satisfy

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FDA that the criteria for all expanded studied in a clinical trial, the sponsor submissions (primarily from physicians) access uses and those specific to must explain why the patients to be and a survey of our review divisions on individual patient expanded access treated cannot be enrolled in the clinical the prevalence of individual patient have been met. The individual patient trial and under what circumstances the protocol exception submissions expanded access criteria are: sponsor will conduct a clinical trial in received from commercial drug • The physician must determine that these patients. sponsors. As indicated in the table the probable risk to the person from the below, we expect an increase in the 4. Treatment IND or Protocol investigational drug is not greater than number of individual patient expanded the probable risk from the disease or Section 312.320 describes the access submissions because the final condition, and treatment IND or treatment protocol rule will increase awareness of the • FDA must determine that the currently codified in §§ 312.34 and option for individual patients to gain patient cannot obtain the drug under 312.35. Section 312.320(b) states that access to investigational drugs and another type of IND. the expanded access submission must decrease the perceived difficulty of Section 312.310(b)(1) states that if the include information adequate to satisfy obtaining such access. We anticipate drug is the subject of an existing IND, FDA that the criteria for all expanded that the increase in individual patient the expanded access submission may be access uses and those specific to the expanded access INDs or protocols will made by a commercial sponsor or by a treatment IND or protocol have been be greatest in the years immediately licensed physician. met. The criteria specific to a treatment following implementation of the final Section 312.310(b)(2) states that a IND or treatment protocol are: (1) The rule and will at some point level off or sponsor may satisfy the submission drug is being investigated in a possibly even decline. This leveling off requirements by amending its existing controlled clinical trial designed to or decline will occur when a significant IND to include an individual patient support a marketing application for the volume of individual patient expanded expanded access protocol. expanded access use or all clinical trials access INDs or protocols have Section 312.310(b)(3) states that a of the drug have been completed, (2) the accumulated for a variety of drugs, and licensed physician may satisfy the sponsor is pursuing marketing approval the individual patient expanded access submission requirements by obtaining a of the drug for the expanded access use INDs or protocols for those drugs are right of reference to pertinent with due diligence, and (3) there is then replaced with intermediate-size information in the IND and providing sufficient clinical evidence of safety and patient population expanded access any other required information not effectiveness to support the treatment INDs or protocols that enroll multiple contained in the IND (usually only the use. Such evidence will ordinarily subjects. information specific to the individual consist of data from phase 3 trials, but We estimate that preparation and patient). could consist of compelling data from submission of an individual patient 3. Intermediate-Size Patient Populations completed phase 2 trials. When the expanded access IND or protocol expanded access use is for an submission will require a total of Section 312.315(c) states that an immediately life-threatening disease or approximately 8 hours. expanded access submission for an condition, the available scientific 2. Intermediate-Size Patient Population intermediate-size patient population evidence, taken as a whole, could Expanded Access must include information adequate to provide a reasonable basis to conclude satisfy FDA that the criteria for all that the investigational drug may be Although intermediate-size patient expanded access uses and those specific effective for the expanded access use population expanded access INDs or to intermediate-size patient populations and will not expose patients to an protocols have not previously been have been met. The intermediate-size unreasonable and significant risk of described in regulation, investigational patient population criteria are: (1) There illness or injury. This evidence will drugs have been made available is enough evidence that the drug is safe ordinarily consist of clinical data from informally for treatment use to such at the dose and duration proposed for phase 3 or phase 2 trials, but could be populations. Based on an internal treatment use to justify a clinical trial of based on more preliminary clinical survey of our review divisions, we the drug in the approximate number of evidence. estimate that, for the period 2000 patients expected to receive the drug for through 2002, we received treatment use; and (2) there is at least B. Estimates of Reporting Burden approximately 55 submissions per year preliminary clinical evidence of Our estimate of the amount of time that we consider expanded access for an effectiveness of the drug or of a required to complete an expanded intermediate-size patient population plausible pharmacologic effect of the access submission is based on the under the final rule. As indicated in drug to make expanded access use a assumption that either the submission table 9, we anticipate that this number reasonable therapeutic option in the will be made by the drug developer or will increase under the final rule anticipated patient population. Section the submitter will have obtained a right because there will be greater awareness 312.315(c) contains additional of reference from the drug developer. of this option. In addition, the submission requirements that apply to We expect an increase in the number of anticipated increase in volume of use of an investigational drug for submissions for expanded access for submissions for expanded access for intermediate-size patient populations. individual patients and for individual patients discussed The expanded access submission must intermediate-size patient populations as previously is expected to increase the state whether the drug is being a result of this final rule. number of submissions for expanded developed or is not being developed and access for intermediate-size patient describe the patient population to be 1. Individual Patient Expanded Access populations because the final rule treated. If the drug is not being actively From 1997 to 2005, we received on encourages the consolidation of developed, the sponsor must explain average approximately 659 submissions multiple individual patient INDs or why the drug cannot currently be for the treatment use of investigational protocols for a given expanded access developed for the expanded access use drugs by individual patients per year. use. and under what circumstances the drug This estimate is based on our records of Information provided by our review could be developed. If the drug is being the number of individual patient IND divisions indicates that preparation and

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submission of an intermediate-size do not expect the provisions of this final Table 9 of this document presents the patient population IND will require a rule regarding treatment INDs or annualized reporting burden for the total of approximately 120 hours. treatment protocols to impose any total number of expanded access increased paperwork burden. The 3. Treatment IND or Treatment Protocol submissions by type of expanded access burden for these submissions, as use. The estimates in the table are based We do not expect the final rule to currently required under § 312.35, is on data from section VI of this have an impact on the overall number already approved by OMB under OMB document and are calculated by of treatment INDs or treatment protocols control number 0910–0014. averaging the projected number of because this type of expanded access is Description of Respondents: Licensed submissions for the first 3 years after already established in FDA regulations physicians and manufacturers, implementation of this final rule. at §§ 312.34 and 312.35. Therefore, we including small business manufacturers.

TABLE 9.—ESTIMATED ANNUAL REPORTING BURDEN1

No. of No. of Responses Total Hours per 21 CFR Section Respondents per Respondent Responses Response Total Hours

§§ 312.305 and 312.310(b) 988 1 988 8 7,904

§§ 312.305(b) and 312.315(c) 68 1 68 120 8,160

Total 16,064 1 There are no capital costs or operating and maintenance costs associated with this collection.

The information collection provisions Medical research, Reporting and ■ 6. Section 312.42 is amended by in this final rule have been submitted to recordkeeping requirements. revising paragraph (b)(3) to read as OMB for review. Prior to the effective ■ Therefore, under the Federal Food, follows: date of this final rule, FDA will publish Drug, and Cosmetic Act and under a notice in the Federal Register § 312.42 Clinical holds and requests for authority delegated to the Commissioner modification. announcing OMB’s decision to approve, of Food and Drugs, 21 CFR parts 312 modify, or disapprove the information and 316 are amended as follows: * * * * * collection provisions in this final rule. (b) * * * An agency may not conduct or sponsor, PART 312—INVESTIGATIONAL NEW (3) Clinical hold of an expanded and a person is not required to respond DRUG APPLICATION access IND or expanded access protocol. FDA may place an expanded to, a collection of information unless it ■ displays a currently valid OMB control 1. The authority citation for 21 CFR access IND or expanded access protocol number. part 312 is revised to read as follows: on clinical hold under the following Authority: 21 U.S.C. 321, 331, 351, 352, conditions: VIII. Federalism 353, 355, 360bbb, 371; 42 U.S.C. 262. (i) Final use. FDA may place a ■ FDA has analyzed this final rule in 2. Section 312.30 is amended by proposed expanded access IND or revising paragraph (c) to read as follows: accordance with the principles set forth treatment use protocol on clinical hold if it is determined that: in Executive Order 13132. FDA has § 312.30 Protocol amendments. tentatively determined that the rule (A) The pertinent criteria in subpart I * * * * * of this part for permitting the expanded does not contain policies that have (c) New investigator. A sponsor shall access use to begin are not satisfied; or substantial direct effects on the States, submit a protocol amendment when a (B) The expanded access IND or on the relationship between the new investigator is added to carry out a expanded access protocol does not National Government and the States, or previously submitted protocol, except comply with the requirements for on the distribution of power and that a protocol amendment is not expanded access submissions in subpart responsibilities among the various required when a licensed practitioner is I of this part. levels of government. Accordingly, the added in the case of a treatment agency has tentatively concluded that protocol under § 312.315 or § 312.320. (ii) Ongoing use. FDA may place an the rule does not contain policies that Once the investigator is added to the ongoing expanded access IND or have federalism implications as defined study, the investigational drug may be expanded access protocol on clinical in the order and, consequently, a shipped to the investigator and the hold if it is determined that the federalism summary impact statement is investigator may begin participating in pertinent criteria in subpart I of this part not required. the study. The sponsor shall notify FDA for permitting the expanded access are no longer satisfied. List of Subjects of the new investigator within 30 days of the investigator being added. * * * * * 21 CFR Part 312 * * * * * ■ 7. Part 312 is amended by adding and reserving subpart H, and by adding Drugs, Exports, Imports, § 312.34 [Removed] subpart I, consisting of §§ 312.300 Investigations, Labeling, Medical ■ 3. Section 312.34 is removed. through 312.320, to read as follows: research, Reporting and recordkeeping requirements, Safety. § 312.35 [Removed] Subpart H—[Reserved] 21 CFR Part 316 ■ 4. Section 312.35 is removed. Subpart I—Expanded Access to Investigational Drugs for Treatment Use § 312.36 [Removed] Administrative practice and Sec. procedure, Drugs, Investigations, ■ 5. Section 312.36 is removed. 312.300 General.

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312.305 Requirements for all expanded satisfactory alternative therapy to (3) The expanded access submission access uses. diagnose, monitor, or treat the disease or and its mailing cover must be plainly 312.310 Individual patients, including for condition; marked ‘‘EXPANDED ACCESS emergency use. (2) The potential patient benefit SUBMISSION.’’ If the expanded access 312.315 Intermediate-size patient submission is for a treatment IND or populations. justifies the potential risks of the 312.320 Treatment IND or treatment treatment use and those potential risks treatment protocol, the applicable box protocol. are not unreasonable in the context of on Form FDA 1571 must be checked. the disease or condition to be treated; (c) Safeguards. The responsibilities of Subpart I—Expanded Access to and sponsors and investigators set forth in Investigational Drugs for Treatment (3) Providing the investigational drug subpart D of this part are applicable to Use for the requested use will not interfere expanded access use under this subpart with the initiation, conduct, or as described in this paragraph. § 312.300 General. completion of clinical investigations (1) A licensed physician under whose (a) Scope. This subpart contains the that could support marketing approval immediate direction an investigational requirements for the use of of the expanded access use or otherwise drug is administered or dispensed for an investigational new drugs and approved compromise the potential development expanded access use under this subpart drugs where availability is limited by a of the expanded access use. is considered an investigator, for risk evaluation and mitigation strategy (b) Submission. (1) An expanded purposes of this part, and must comply (REMS) when the primary purpose is to access submission is required for each with the responsibilities for diagnose, monitor, or treat a patient’s type of expanded access described in investigators set forth in subpart D of disease or condition. The aim of this this subpart. The submission may be a this part to the extent they are subpart is to facilitate the availability of new IND or a protocol amendment to an applicable to the expanded access use. (2) An individual or entity that such drugs to patients with serious existing IND. Information required for a submits an expanded access IND or diseases or conditions when there is no submission may be supplied by protocol under this subpart is comparable or satisfactory alternative referring to pertinent information considered a sponsor, for purposes of therapy to diagnose, monitor, or treat contained in an existing IND if the this part, and must comply with the the patient’s disease or condition. sponsor of the existing IND grants a responsibilities for sponsors set forth in (b) Definitions. The following right of reference to the IND. definitions of terms apply to this subpart D of this part to the extent they (2) The expanded access submission are applicable to the expanded access subpart: must include: Immediately life-threatening disease use. (i) A cover sheet (Form FDA 1571) (3) A licensed physician under whose or condition means a stage of disease in meeting the requirements of § 312.23(a); which there is reasonable likelihood immediate direction an investigational (ii) The rationale for the intended use that death will occur within a matter of drug is administered or dispensed, and of the drug, including a list of available months or in which premature death is who submits an IND for expanded therapeutic options that would likely without early treatment. access use under this subpart is ordinarily be tried before resorting to Serious disease or condition means a considered a sponsor-investigator, for the investigational drug or an disease or condition associated with purposes of this part, and must comply explanation of why the use of the morbidity that has substantial impact on with the responsibilities for sponsors investigational drug is preferable to the day-to-day functioning. Short-lived and and investigators set forth in subpart D use of available therapeutic options; self-limiting morbidity will usually not of this part to the extent they are (iii) The criteria for patient selection be sufficient, but the morbidity need not applicable to the expanded access use. or, for an individual patient, a be irreversible, provided it is persistent (4) Investigators. In all cases of description of the patient’s disease or or recurrent. Whether a disease or expanded access, investigators are condition, including recent medical condition is serious is a matter of responsible for reporting adverse drug history and previous treatments of the clinical judgment, based on its impact events to the sponsor, ensuring that the disease or condition; on such factors as survival, day-to-day informed consent requirements of part (iv) The method of administration of functioning, or the likelihood that the 50 of this chapter are met, ensuring that the drug, dose, and duration of therapy; disease, if left untreated, will progress IRB review of the expanded access use (v) A description of the facility where from a less severe condition to a more is obtained in a manner consistent with the drug will be manufactured; serious one. the requirements of part 56 of this (vi) Chemistry, manufacturing, and chapter, and maintaining accurate case § 312.305 Requirements for all expanded controls information adequate to ensure histories and drug disposition records access uses. the proper identification, quality, and retaining records in a manner The criteria, submission purity, and strength of the consistent with the requirements of requirements, safeguards, and beginning investigational drug; § 312.62. Depending on the type of treatment information set out in this (vii) Pharmacology and toxicology expanded access, other investigator section apply to all expanded access information adequate to conclude that responsibilities under subpart D may uses described in this subpart. the drug is reasonably safe at the dose also apply. Additional criteria, submission and duration proposed for expanded (5) Sponsors. In all cases of expanded requirements, and safeguards that apply access use (ordinarily, information that access, sponsors are responsible for to specific types of expanded access are would be adequate to permit clinical submitting IND safety reports and described in §§ 312.310 through testing of the drug in a population of the annual reports (when the IND or 312.320. size expected to be treated); and protocol continues for 1 year or longer) (a) Criteria. FDA must determine that: (viii) A description of clinical to FDA as required by §§ 312.32 and (1) The patient or patients to be procedures, laboratory tests, or other 312.33, ensuring that licensed treated have a serious or immediately monitoring necessary to evaluate the physicians are qualified to administer life-threatening disease or condition, effects of the drug and minimize its the investigational drug for the and there is no comparable or risks. expanded access use, providing licensed

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physicians with the information needed obtaining from the sponsor permission § 312.315 Intermediate-size patient to minimize the risk and maximize the for FDA to refer to any information in populations. potential benefits of the investigational the IND that would be needed to Under this section, FDA may permit drug (the investigator’s brochure must support the expanded access request an investigational drug to be used for be provided if one exists for the drug), (right of reference) and by providing any the treatment of a patient population maintaining an effective IND for the other required information not smaller than that typical of a treatment expanded access use, and maintaining contained in the IND (usually only the IND or treatment protocol. FDA may ask adequate drug disposition records and information specific to the individual a sponsor to consolidate expanded retaining records in a manner consistent patient). access under this section when the with the requirements of § 312.57. (c) Safeguards. (1) Treatment is agency has received a significant Depending on the type of expanded generally limited to a single course of number of requests for individual access, other sponsor responsibilities therapy for a specified duration unless patient expanded access to an under subpart D may also apply. FDA expressly authorizes multiple investigational drug for the same use. (d) Beginning treatment—(1) INDs. An (a) Need for expanded access. courses or chronic therapy. expanded access IND goes into effect 30 Expanded access under this section may days after FDA receives the IND or on (2) At the conclusion of treatment, the be needed in the following situations: earlier notification by FDA that the licensed physician or sponsor must (1) Drug not being developed. The expanded access use may begin. provide FDA with a written summary of drug is not being developed, for (2) Protocols. With the following the results of the expanded access use, example, because the disease or exceptions, expanded access use under including adverse effects. condition is so rare that the sponsor is a protocol submitted under an existing (3) FDA may require sponsors to unable to recruit patients for a clinical IND may begin as described in monitor an individual patient expanded trial. § 312.30(a). access use if the use is for an extended (2) Drug being developed. The drug is (i) Expanded access use under the duration. being studied in a clinical trial, but emergency procedures described in patients requesting the drug for § 312.310(d) may begin when the use is (4) When a significant number of expanded access use are unable to authorized by the FDA reviewing similar individual patient expanded participate in the trial. For example, official. access requests have been submitted, patients may not be able to participate (ii) Expanded access use under FDA may ask the sponsor to submit an in the trial because they have a different § 312.320 may begin 30 days after FDA IND or protocol for the use under disease or stage of disease than the one receives the protocol or upon earlier § 312.315 or § 312.320. being studied or otherwise do not meet notification by FDA that use may begin. (d) Emergency procedures. If there is the enrollment criteria, because (3) Clinical holds. FDA may place any an emergency that requires the patient enrollment in the trial is closed, or expanded access IND or protocol on to be treated before a written submission because the trial site is not clinical hold as described in § 312.42. can be made, FDA may authorize the geographically accessible. § 312.310 Individual patients, including for expanded access use to begin without a (3) Approved or related drug. (i) The emergency use. written submission. The FDA reviewing drug is an approved drug product that Under this section, FDA may permit official may authorize the emergency is no longer marketed for safety reasons an investigational drug to be used for use by telephone. or is unavailable through marketing due the treatment of an individual patient by (1) Emergency expanded access use to failure to meet the conditions of the a licensed physician. may be requested by telephone, approved application, or (a) Criteria. The criteria in facsimile, or other means of electronic (ii) The drug contains the same active § 312.305(a) must be met; and the communications. For investigational moiety as an approved drug product following determinations must be made: biological drug products regulated by that is unavailable through marketing (1) The physician must determine that the Center for Biologics Evaluation and due to failure to meet the conditions of the probable risk to the person from the Research, the request should be directed the approved application or a drug investigational drug is not greater than to the Office of Communication, shortage. (b) Criteria. The criteria in the probable risk from the disease or Outreach and Development, Center for § 312.305(a) must be met; and FDA must condition; and Biologics Evaluation and Research, 301– determine that: (2) FDA must determine that the 827–1800 or 1–800–835–4709, e-mail: (1) There is enough evidence that the patient cannot obtain the drug under [email protected]. For all other drug is safe at the dose and duration another IND or protocol. investigational drugs, the request for proposed for expanded access use to (b) Submission. The expanded access authorization should be directed to the justify a clinical trial of the drug in the submission must include information Division of Drug Information, Center for approximate number of patients adequate to demonstrate that the criteria Drug Evaluation and Research, 301– expected to receive the drug under in § 312.305(a) and paragraph (a) of this 796–3400, e-mail: expanded access; and section have been met. The expanded [email protected]. After normal access submission must meet the (2) There is at least preliminary working hours, the request should be clinical evidence of effectiveness of the requirements of § 312.305(b). directed to the FDA Office of Emergency (1) If the drug is the subject of an drug, or of a plausible pharmacologic Operations, 301–443–1240, e-mail: existing IND, the expanded access effect of the drug to make expanded [email protected]. submission may be made by the sponsor access use a reasonable therapeutic or by a licensed physician. (2) The licensed physician or sponsor option in the anticipated patient (2) A sponsor may satisfy the must explain how the expanded access population. submission requirements by amending use will meet the requirements of (c) Submission. The expanded access its existing IND to include a protocol for §§ 312.305 and 312.310 and must agree submission must include information individual patient expanded access. to submit an expanded access adequate to satisfy FDA that the criteria (3) A licensed physician may satisfy submission within 15 working days of in § 312.305(a) and paragraph (b) of this the submission requirements by FDA’s authorization of the use. section have been met. The expanded

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access submission must meet the (2) The sponsor is responsible for unreasonable and significant risk of requirements of § 312.305(b). In monitoring the expanded access illness or injury. This evidence would addition: protocol to ensure that licensed ordinarily consist of clinical data from (1) The expanded access submission physicians comply with the protocol phase 3 or phase 2 trials, but could be must state whether the drug is being and the regulations applicable to based on more preliminary clinical developed or is not being developed and investigators. evidence. describe the patient population to be § 312.320 Treatment IND or treatment (b) Submission. The expanded access treated. protocol. submission must include information (2) If the drug is not being actively Under this section, FDA may permit adequate to satisfy FDA that the criteria developed, the sponsor must explain an investigational drug to be used for in § 312.305(a) and paragraph (a) of this why the drug cannot currently be widespread treatment use. section have been met. The expanded developed for the expanded access use (a) Criteria. The criteria in access submission must meet the and under what circumstances the drug § 312.305(a) must be met, and FDA must requirements of § 312.305(b). could be developed. determine that: (c) Safeguard. The sponsor is (3) If the drug is being studied in a (1) Trial status. (i) The drug is being responsible for monitoring the treatment clinical trial, the sponsor must explain investigated in a controlled clinical trial protocol to ensure that licensed why the patients to be treated cannot be under an IND designed to support a physicians comply with the protocol enrolled in the clinical trial and under marketing application for the expanded and the regulations applicable to what circumstances the sponsor would access use, or investigators. conduct a clinical trial in these patients. (ii) All clinical trials of the drug have PART 316—ORPHAN DRUGS (d) Safeguards. (1) Upon review of the been completed; and IND annual report, FDA will determine (2) Marketing status. The sponsor is actively pursuing marketing approval of ■ 8. The authority citation for 21 CFR whether it is appropriate for the part 316 continues to read as follows: expanded access to continue under this the drug for the expanded access use section. with due diligence; and Authority: 21 U.S.C. 360aa, 360bb, 360cc, (3) Evidence. (i) When the expanded 360dd, 371. (i) If the drug is not being actively access use is for a serious disease or developed or if the expanded access use ■ 9. Section 316.40 is revised to read as condition, there is sufficient clinical follows: is not being developed (but another use evidence of safety and effectiveness to is being developed), FDA will consider support the expanded access use. Such § 316.40 Treatment use of a designated whether it is possible to conduct a evidence would ordinarily consist of orphan drug. clinical study of the expanded access data from phase 3 trials, but could use. Prospective investigators seeking to consist of compelling data from obtain treatment use of designated (ii) If the drug is being actively completed phase 2 trials; or orphan drugs may do so as provided in developed, FDA will consider whether (ii) When the expanded access use is subpart I of this chapter. providing the investigational drug for for an immediately life-threatening expanded access use is interfering with disease or condition, the available Dated: July 20, 2009. the clinical development of the drug. scientific evidence, taken as a whole, Jeffrey Shuren, (iii) As the number of patients provides a reasonable basis to conclude Associate Commissioner for Policy and enrolled increases, FDA may ask the that the investigational drug may be Planning. sponsor to submit an IND or protocol for effective for the expanded access use [FR Doc. E9–19005 Filed 8–12–09; 8:45 am] the use under § 312.320. and would not expose patients to an BILLING CODE 4160–01–S

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