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  1. Clinical Trials and Human Subject Protection

New Drug, Antibiotic, and Biologic Drug Product Regulations

21 CFR Parts 312, 314, 511, and 514
New Drug, Antibiotic, and Biologic Drug Product Regulations
[Docket No. 82N-0394]
52 FR 8798

March 19, 1987

AGENCY: Food and Drug Administration.

ACTION: Final rule.

SUMMARY: The Food and Drug Administration (FDA) is revising its regulations governing the submission and review of investigational new drug applications (IND's). The new regulations (called the IND Rewrite) will ensure FDA's ability to monitor carefully the safety of patients participating in clinical investigations, while also facilitating the development of new beneficial drug therapies. The improvements will also help sponsors of clinical investigations prepare and submit high quality IND applications and permit FDA to review them efficiently and with minimal delay. This action is one part of a larger effort by FDA to improve the agency's drug approval process, including the earlier publication of companion regulations governing new drug applications (NDA's) for marketing approval. Elsewhere in this issue of the Federal Register, FDA is reproposing procedures governing: (1) Availability of investigational drugs for treatment use; and (2) sale of investigational drugs. Both of these issues had been addressed in the IND Rewrite proposal.

DATES: These final regulations are effective June 17, 1987. FDA will, however, accept applications until March 19, 1988, that are in the format required under either the current regulations or this final rule. For additional information concerning this effective date, see "Paperwork Reduction Act" appearing in the preamble of this document. Comments regarding "Outside Review Boards" by April 20, 1987.

ADDRESS: Written comments on the revised regulations to the Dockets Management Branch (HFA-305), Food and Drug Administration, Rm. 4-62, 5600 Fishers Lane, Rockville, MD 20857.

FOR FURTHER INFORMATION CONTACT: Steven H. Unger, Center for Drugs and Biologics (HFN-362), Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857, 301-295-8046.


I. Introduction

This final rule continues the rulemaking efforts by the Department of Health and Human Services and FDA to revise Federal regulations governing the new drug approval process. This phase of the regulations (called the IND Rewrite) makes final new procedures in 21 CFR Part 312 for FDA review of investigational new drug applications and for monitoring the progress of investigational drug use. The IND Rewrite was issued as a proposal in the Federal Register of June 9, 1983 (48 FR 26720). The first phase of these regulatory revision efforts (called the NDA Rewrite) covers FDA procedures in 21 CFR Part 314 for FDA review of new drug and antibiotic applications for marketing. This first phase was completed with publication of final regulations in the Federal Register of February 22, 1985 (50 FR 7452). Collectively, the IND and NDA Rewrites conclude an effort begun when FDA made concept papers available for public comment (44 FR 58919; October 12, 1979) and held a public meeting on November 9, 1979, to discuss them. These regulations are promulgated under the Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 301 et seq.).

The objectives of the IND Rewrite final rule are to establish an efficient investigational drug process in order both: (a) To focus FDA's attention during the early phase of clinical research on protecting the safety of human test subjects and to give sponsors greater freedom to design, revise, and implement clinical research studies; and (b) to facilitate consultation between FDA and drug sponsors, once the preliminary human studies have been completed and a drug appears to have marketing potential, to help ensure that the design of major clinical trials is acceptable and will support marketing approval if the test results are favorable. These regulations are also intended to encourage innovation and drug development while continuing to assure the safety of test subjects. In addition, through better planning and closer consultation, FDA's later review of applications for marketing should proceed more efficiently. These changes will benefit the consumer by enhancing the prompt marketing availability of safe and effective therapies.

In preparing the final rule, FDA carefully reviewed more than 50 comments received from pharmaceutical manufacturers, trade associations, health professionals, professional societies, and consumer organizations. In addition, FDA managers met with agency employees in order to gain their views as part of the internal decisionmaking process. The agency also considered the recommendations of the Congressionally sponsored Commission on the Federal Drug Approval Process. In preparing the final rule, therefore, the agency has considered views of persons representing virtually all groups having an interest in the investigational drug process.

Like the IND and NDA Rewrite proposals and the NDA Rewrite final rule, the IND final rule has been reviewed in accordance with Executive Order 12291 (46 FR 13193; February 19, 1981) and the policy objectives outlined above.

FDA's IND Rewrite final rule complements the revised NDA regulations. For example, one of the themes of the IND/NDA Rewrites is to establish a continuing dialogue between FDA staff and drug sponsors/applicants. Accordingly, the regulations codify a sequence of four standard conferences targeted at key stages of the drug approval process. These are (in the IND regulations) the "end-of-Phase 2 conference" and the "pre-NDA conference" and (in the NDA regulations) the "ninety-day conference" and the "end-of-review conference." In addition, both the IND and NDA regulations provide for other communication between FDA staff and sponsors/applicants on an as needed basis, as well as a strong commitment to resolve any disputes in a timely manner.

In the Federal Register of September 27, 1977 (42 FR 49612), FDA proposed to issue rules (21 CFR Part 52) governing the obligations of sponsors and monitors of clinical investigations. In a related document, published in the Federal Register of August 8, 1978 (43 FR 35210), FDA proposed comprehensive rules governing the obligations of clinical investigators (21 CFR Part 54). While restating and clarifying many of the obligations of sponsors and clinical investigators previously set forth in the IND regulations (ß 312.1), these two documents also proposed to: (a) Change some existing requirements covering the conduct and review of clinical investigations; and (b) extend the requirements to persons who conduct clinical investigations of any product regulated by FDA. On the assumption that these two proposals would be made final before, or at the same time as, the IND Rewrite final rule, the agency in the IND Rewrite proposal did not systematically address issues relating to sponsor and clinical investigator responsibilities.

Because those proposals to establish Parts 52 and 54 have not been made final, FDA has retained in new Part 312 most of those existing requirements governing clinical investigator and sponsor/monitor obligations that were to have been transferred to proposed Parts 52 and 54. The responsibilities of sponsors and clinical investigators prescribed in this final rule are substantially the same as those set forth in the existing IND regulations.

In connection with issuance of the IND and NDA Rewrites, FDA has significantly expanded the use of guidelines. FDA has recently issued guidelines on how to fulfill certain technical requirements in order to provide applicants with greater guidance in these areas. These guidelines, which apply to regulatory requirements for both NDA and IND applications, should materially assist implementation of the new regulations.

Elsewhere in this issue of the Federal Register, FDA is reproposing new rules on: (i) The distribution of drugs for treatment use and (ii) the sale of investigational drugs. Comments received on these issues are addressed in the reproposal. Pending the adoption of new rules on the sale of investigational drugs, FDA has retained in this final rule the current provisions on sale.

Highlights of the final IND rule, the agency's economic analysis, and a discussion of related issues are contained in the following introductory sections. The remainder of this preamble is devoted to a section-by-section analysis of comments received, responses to them, and the contents of the final regulations.

II. Highlights of the Final Rule

The guiding principle in the IND Rewrite final rule is that different stages of the IND process will be regulated differently. Safety concerns will predominate at the beginning of the process to ensure that research subjects are not exposed to unreasonable risks. In the later phases of drug investigation, FDA will also evaluate the scientific merit of study protocols to ensure that planned clinical studies are capable of producing valid information on safety and effectiveness necessary to obtain marketing approval. In response to comments and further internal deliberations, the final rule has modified certain provisions of the proposal to meet these objectives better. The major provisions of the final rule are summarized as follows:

  1. Regulation of the early phase of human research. The final rule incorporates the proposed revisions designed to give drug sponsors greater freedom during the early phase of human research (Phase 1) by permitting such research to proceed unless it presents an unreasonable and significant risk to test subjects. Thus, the final rule narrows the scope of FDA's review of Phase 1 studies to focus on the safety of human test subjects and permit clinical investigators in Phase 1 to modify protocols on the basis of experience gained during the investigation without prior notification to FDA. Moreover, the final rule emphasizes to drug sponsors that the amount of toxicology and chemistry information required in the initial IND submission depends on the nature and extent of the proposed clinical studies. These changes are intended to encourage innovation in drug development while continuing current safeguards governing the safety of test subjects.

    In the proposed rule, FDA solicited comments on the merits of adopting a dual track system for Phase 1 studies in which drug firms would have the option of submitting IND's either to FDA or to nongovernmental "Outside Review Boards" (ORB's). As discussed later in this preamble, FDA has decided to solicit further comment on the feasibility of ORB's, focusing in particular on the possible establishment of a pilot program.

  2. Format for IND submission. The final rule establishes a new format for IND submissions, similar to that in the proposal, that will result in better organized applications and thus facilitate agency review. The revised format focuses on the proposed human studies so that supporting toxicology and chemistry information can be reviewed in light of the proposed clinical investigations. The new IND will consist of a greatly simplified IND form that serves as a cover sheet, a brief overview of the investigational plan, and the protocols and supporting technical information on the drug's chemistry, pharmacology, and toxicology.

  3. IND safety reports. The final rule specifies a drug company's obligations in reviewing and reporting adverse drug reaction information, clarifying the proposal in several respects. The rule requires that sponsors promptly review and evaluate all safety information received by the sponsor and that the sponsor report to FDA within 10 working days all adverse drug reactions that are both serious and unexpected. In addition, the final rule requires the sponsor to notify FDA by telephone of any unexpected death or life-threatening experience no later than 3 working days after the sponsor first learns of the experience. This telephone call will provide an early warning of the most serious kinds of adverse experiences and will enable FDA to discuss with the sponsor the need, if any, to modify or discontinue the study. These safety report provisions should significantly improve FDA's ability to monitor the safety of clinical studies.

  4. Amendment procedures. Like the proposal, the final rule divides the IND amendment procedures into three distinct categories: (i) Protocal amendments, for new protocols and changes in existing protocols; (ii) information amendments, for additional data as they develop; and (iii) IND safety reports, as described above. Appropriate reporting intervals apply to each category depending upon the need for prompt agency review. The final rule also clarifies the scope of the annual reports, which are intended to provide an overview of the progress to date and future plans for the IND.

  5. Meetings between FDA and drug sponsors. The final rule codifies FDA's proposal to extend to the sponsor of any IND an opportunity for an "end-of-Phase 2" conference with FDA to obtain concurrence on an overall plan for the conduct of Phase 3 trials and the design of specific studies. The final rule also codifies the policy that gives IND sponsors and opportunity to meet with FDA for a "pre-NDA" conference to discuss appropriate formats for data presentation in a marketing application.

  6. "Clinical hold" procedures. The final rule adopts procedures essentially the same as those contained in the proposal pertaining to FDA's instituting a "clinical hold." A clinical hold is an order either not to begin or not to continue a clinical study. The final rule limits clinical holds in Phase 1 studies to situations where there is an unreasonable and significant risk to human subjects. In Phases 2 and 3, FDA's authority to issue a clinical hold would extent to serious defects in study design that would render the study incapable of producing valid evidence of safety and effectiveness. All clinical holds must be approved by the director of the division in FDA's Center for Drugs and Biologics with responsibility for review of the IND.

  7. Exemptions for certain studies on marketed drugs. The final rule exempts from most IND requirements certain investigations conducted with drugs already approved for marketing. The exemption applies where safety is not an issue (because of a similarity in dose, route of administration, and patient population with the approved labeling) and where the investigation is not being conducted for the purpose of changing the drug labeling (for example, where the study is not for purposes of adding a new indication or comparative safety claim). The agency expects that this exemption will apply primarily to researchers in academic or other institutions. This exemption is intended to reduce burdens on researchers while permitting FDA resources to be devoted to monitoring clinical investigations requiring FDA oversight and to reviewing marketing applications. Although exempt from most IND requirements, the investigations would nonetheless be subject to the general prohibition against promotion of investigational drugs (ß 312.7), and to the other regulations designed to protect the rights and safety of patients, such as the institutional review board (21 CFR Part 56) and informed consent (21 CFR Part 50) regulations.

  8. Dispute resolution. The final rule has been significantly revised to emphasize, similar to the NDA final rule, the use of informal meetings and other informal communications as the means for resolving differences between FDA and sponsors. For administrative and procedural issues, the final rule establishes an ombudsman whose function will be to facilitate timely and equitable resolutions of administrative and managerial disagreements about IND's. For scientific and medical disputes, the final rule encourages applicants to seek resolution through informal meetings with appropriate agency staff and management representatives as the need may arise. The final rule also provides for the participation of outside experts at these informal meetings when feasible. This procedure supersedes the appeals process described in the IND Rewrite proposal.

III. Economic Analysis

FDA has examined the economic consequences of the changes implemented by the final rule in accordance with Executive Order 12291 and the Regulatory Flexibility Act (Pub. L. 96-354). The agency concludes that these revisions will have favorable economic impacts on the health care system, drug sponsors, and the agency without compromising the safety of human subjects. Although some of these favorable impacts are quantifiable, others with greater potential for savings can only be characterized in a very generalized, nonquantitative manner at this time.

Quantifiable impacts include an estimated net annual savings of $4.9 million to sponsors, arising from a simplified IND format; reduced and/or staged submission of manufacturing and controls data; a reduction in the number of amendments that are submitted during the first year that an IND is active; savings in start-up expenses associated with studies that would no longer be placed on clinical hold under the revised criteria; and savings of sponsor-investigator resources currently used to prepare IND's that will no longer be necessary. The only projected cost increase is modest by comparison and arises from requirements to improve the quality of annual reports. These revisions will also produce some savings in agency review resources.

A potential for substantially larger savings is presented by the provisions for increased use of guidelines, meetings, and informal advice to aid commercial IND sponsors in assembling the data for those IND's that lead to the submission of a marketing application. These initiatives, taken together, could result in substantial savings from fewer deficiencies being noted in the NDA review process due to better designed clinical trials, as well as further savings from the elimination of some unnecessary or poorly designed clinical studies. For example, gaining advice on the proper protocol for a major clinical study could save a year or more in the process if it prevents the need to redo certain key research as a result of faulty study design.

As stated in the proposal, the agency concludes that these revisions are not a major rule as defined in Executive Order 12291. The agency also certifies that the changes will not have a significant impact on a substantial number of small entities. The net savings, described above, will accrue to all sponsors, regardless of size, and the preponderance of unquantifiable savings will probably accrue to the public and to sponsors of commercial IND's, most of whom are not small entities. A copy of the agency's revised assessment of economic impact is on file with the Dockets Management Branch (HFA-305), Food and Drug Administration, Rm. 4-62, 5600 Fishers Lane, Rockville, MD 20857.

The revisions to the IND regulations have a significance well beyond the specific cost reductions summarized above. As noted earlier, these regulations are part of a comprehensive review of the new drug approval process designed to accelerate the development and marketing of new drug therapies without compromising the safety and effectiveness of new drugs. Collectively, FDA's new regulations, guidelines, procedures, and policies should produce considerable benefits. A quicker, more efficient drug development process means that the American public will have more safe and effective drugs sooner. A less costly drug development process means that the pharmaceutical industry will be able to develop more new drugs with the same number of research dollars, or alternatively to market less costly drugs. Either outcome will be of direct benefit to the American public. Most importantly, the prompt availability of safe and effective drug therapies has enormous potential benefit to patients and the public in terms of improving the length and quality of life and in reducing health care and hospital costs.

IV. Paperwork Reduction Act of 1980

This final rule contains information collection requirements that were submitted for review and approval to the Director of the Office of Management and Budget (OMB), as required by section 3507 of the Paperwork Reduction Act of 1980. The requirements were approved and assigned OMB control number 0910-0162.

Only ß 312.33 contains changes that are different from the proposal that was submitted to OMB that may require a change in the reporting burden. Revised information collection estimates reflecting these changes will be submitted for approval to OMB. The reporting requirements of ß 312.33 will not be effective until FDA obtains OMB approval. FDA will publish a notice concerning OMB approval of these requirements in the Federal Register prior to June 17, 1987.

V. Comments on the Proposed Rule

Applicability of IND Requirements (ß 312.2)

  1. Changes permitted to marketed product. Many comments asked for clarification of the proposed exemption in ß 312.2. The exemption would permit a sponsor to conduct a study with a lawfully marketed drug without having to submit an IND if the study did not involve use of the drug in a way that significantly increased the risks associated with use of the product, and if certain other conditions were met. These comments in general were interested in knowing to what extent a sponsor could change the drug product or the conditions of the drug's use and remain within the terms of the exemption. Specifically, one comment asked whether it would be permissible to conduct a study with a capsule of a drug that is lawfully marketed in tablet form. Other comments urged that the exemption permit modifications in the packaging or labeling of a marketed drug that do not affect a product's quality, safety, or effectiveness.

    The exemption was not intended to require an investigator to use the drug in exactly the dosage form, dosage levels, and patient populations described in the marketed labeling for the product, but rather to permit changes to the lawfully marketed drug product that do not increase the risks (or, as explained in response to paragraph 8 below, the acceptability of the risks) over the risk presented by use of the product in conformance with its marketed labeling. Because assessing the risks involved in specific uses of a product depends on a number of variable factors, the agency cannot in advance describe precisely the degree to which particular drug products might be altered through dosage level changes, dosage form changes, or changes in the intended patient population and stay within the exemption. As guidance, the agency will, on request, provide advice on the applicability of the exemption to particular drug uses, and will provide public notice when specific situations are identified that would require an IND.

    Some general examples may nonetheless be stated. The agency believes that, in general, the use in a clinical investigation of a drug in capsule form that is lawfully marketed in tablet form should not, in itself, raise safety concerns necessitating submission of an IND. Of course, there may be exceptions. For example, the agency can foresee circumstances in which reformulation to capsule form of a drug product might so affect its bioavailability as to raise safety concerns warranting submission of an IND. There might also be significant problems involved in grinding up and encapsulating enteric-coated or film-coated tablets. Apart from these exceptions, however, FDA believes that the change from tablet to capsule should rarely result in the removal of a study from the terms of the ß 312.2 exemption. In contrast, FDA would presume that any change from one dosage form to an intravenous (I.V.) dosage form (including a change from an intramuscular (I.M.) dosage form to an I.V. dosage form) would significantly increase the risk so as to warrant an IND.

    FDA also believes that the substitution of an investigational label for an approved label should rarely, if ever, raise safety concerns triggering the need to submit an IND. Similarly, modifications in packaging and labeling that do not impair a drug's stability or quality should not remove a product from the terms of the exemption. Indeed, because the study will be investigational, it is expected that the labeling for the drug will be changed to some extent for purposes of the investigation.

  2. One comment argued that studies of over-the-counter (OTC) drugs involving dosage levels of the active ingredient lower than the marketed level should be exempted because such studies would invariably pose fewer risks for subjects than would be posed by the marketed version of the drug.

    The agency does not believe it is desirable to indicate, apart from the general rule, specific situations in which an IND will not be required. Applying the general rule, however, there would appear to be few situations in which use of an OTC drug at a dosage level lower than the marketed level would raise safety concerns. However, where a drug is used to treat a life-threatening illness or to prevent irreversible damage, safety concerns might appropriately trigger the need to submit an IND.

  3. The proposal defined "investigational new drug" to include "a marketed drug that is used for any purpose or in any way other than that described in its labeling * * *." Given this definition, one comment asked whether FDA intended a postapproval study of a labeled indication -- an indication that, by definition, would not be deemed investigational -- to be subject to IND requirements.

    The agency believes that a postapproval study of an indication contained in a marketed product's labeling (whether conducted by a commercial sponsor or otherwise) is, and should be, subject to all relevant requirements governing the investigational use of drugs, including the requirements of Part 312. All studies, including those involving use of a marketed drug for a labeled indication, pose risks that patients' interests will be subordinated to the interests of the study, and therefore implicate FDA's responsibilities for the rights and safety of human subjects. To clarify the agency's view that it has jurisdiction over all clinical studies, the definition of "investigational new drug" has been revised to make clear that it includes any drug used in a clinical investigation.

    It should be emphasized that even though a study of a marketed drug involving an indication contained in the product's approved labeling would be subject to all relevant requirements governing the use of investigational drugs, such a study would, like a study of a marketed drug for an unlabeled indication, be exempt from IND submission requirements if it met the conditions of ß 312.2.

  4. Several comments expressed concern that the proposed exemption from IND submission requirements did not extend to studies intended to support a significant change in the advertising for the drug. One comment argued that studies used to support advertising claims are rarely submitted to FDA and that it is the responsibility of the party making the claim to ensure that support for the claim is adequate. Another comment contended that the reference to advertising in the prohibition is inappropriate as current regulations provide that advertising must be based on drug's approved labeling and many studies are done for the purposes of making comparative statements within the parameters of approved labeling. This comment urged that the exemption from IND submission requirements should apply unless the purpose of the study is to make a significant change in the approved product's labeling. Finally, one comment argued that, given Federal Trade Commission jurisdiction over advertising for OTC drugs, a study to support an advertising claim for a nonprescription drug is not a study subject to the general jurisdiction of FDA.

    The agency disagrees with the suggestion that it lacks authority to regulate studies of OTC drugs in human subjects that are conducted for the purpose of modifying drug advertising. Such studies, like clinical studies intended to change prescription drug advertising, involve the use of a human drug for an investigational purpose and are, therefore, appropriately subject to all rules administered by FDA governing the protection of human subjects. However, given that FDA does not routinely become involved in reviewing OTC advertising content, the case for requiring IND's for OTC advertising studies is not as compelling as it is for prescription drug advertising studies. For this reason, FDA has revised the final rule to exempt OTC advertising studies from IND submission requirements.

  5. Several comments requested assurance that the results of a study conducted under the exemption in ß 312.2 could later be submitted in support of a marketing application. One comment contended that a refusal to accept studies would be unnecessarily wasteful of limited resources and would expose human subjects to unnecessary clinical experimentation.

    FDA advises that a study that is conducted in good faith under the terms of the exemption in ß 312.2 (i.e., without the filing of an IND) will later be acceptable to the agency in support of an IND or marketing application. Therefore, where the agency finds that a study was conducted under the exemption on the reasonable belief that each of the significant elements of the exemption applied, the FDA will not subsequently raise any objections to its acceptance, assuming adequate guarantees of the ethical propriety and scientific validity of the study. On the other hand, where there is evidence that the sponsor had no reasonable basis for concluding that a study should have been exempted, FDA may take other regulatory action, as appropriate.

    As FDA is willing to discuss and advise sponsors on the applicability of the exemption to planned clinical investigations, the agency believes there should be few occasions for determining after the fact that a study did not qualify for the exemption, but should have been conducted under an IND.

  6. One comment recommended that the proposal be clarified to indicate that the exemption for lawfully marketed drug products was confined to drug products lawfully marketed in the United States.

    Because approval requirements may differ among countries, the agency intended to limit the exemption to studies involving drugs lawfully marketed in the United States. FDA has revised the regulation accordingly.

  7. One comment expressed concern that the determination of whether a drug study "increased the risks" of the drug was very judgmental, and that the degree of judgment involved would lead conscientious investigators routinely to solicit agency help in determining whether an IND is needed. On the other hand, another comment suggested that the provision is so ambiguous that its usefulness is likely to be limited by fear of transgressing. The comment claimed that without a definition of what is meant by "significantly increases the risks," the provision could well tie an investigator to the dose, route of administration, and patient population identified in the approved labeling.

    The exemption is not intended necessarily to tie the investigator to the dose, route of administration, and patient population(s) described in the product's approved labeling, but rather is designed to permit deviations from the approved labeling to the extent that such changes are supported by the scientific literature and generally known clinical experiences. As noted in the preamble to the proposed rule, FDA recognizes that a considerable amount of professional judgment must be exercised in determining whether the conditions of an investigation "significantly increase" the risk associated with use of the drug. Because the assessment of risks involved in a therapeutic procedure is an everyday part of the practice of medicine, the individual investigator should usually be able to determine the applicability of the exemption. As noted, FDA will provide advice on the question when requested.

  8. One comment argued that in some cases where a drug is approved for use at a high dosage level to treat a very serious illness, it may not be appropriate to use it investigationally at that dosage level in the study of a less serious condition. The comment suggested that such uses should not be exempted from IND requirements.

    The comment correctly identifies a defect in the proposed exemption scheme. Under the proposal, an IND would be required only if a change "significantly increase[d] the risks associated with use of the drug." However, in the case cited in the comment, a change in patient population arguably would not affect the risks at all ("risks" understood as the incidence or seriousness of adverse drug reactions), but would plainly affect the acceptability of those risks ("acceptability" incorporating the notion of drug benefit and understood as the willingness of a patient to run the risks associated with the drug to undertake the proposed therapy). FDA concludes that a change that significantly diminishes the acceptability of the risk raises safety concerns that necessitate submission of an IND, and has revised the regulation to incorporate this concept.

  9. A comment urged that "patient population" as used in proposed ß 312.2(b)(1) be defined specifically. The comment asked whether "patient population" referred solely to demographics, such as age, sex, or race, or also referred to disease groups, such as heart patients or kidney dialysis patients. The comment claimed that if disease groups were intended to be included, it could be that any use outside the labeled indications would constitute use in a different patient population, and that the inherent risk of failure for the nonlabeled use could constitute a significant risk.

    "Patient population" was intended to include groups defined in terms of demographic characteristics (e.g., geriatric patients, pediatric patients) and in terms of disease processes (e.g., heart patients or kidney dialysis patients). Therefore, a significant increase in risk (or significant decrease in acceptability of risk) resulting from the clinical use of a drug in either a demographic or disease group that is not identified in the marketed labeling for the drug would necessitate submission of an IND.

    The agency advises that the risk that a drug will not be effective in a patient population should not ordinarily trigger the need to submit an IND. Of course, there should be some evidence to support the reasonableness of a drug's administration for its investigational use. Also, where the consequence of therapeutic failure is irreversible injury or death, an IND would clearly be required. In other cases, because the possibility that a drug may not be effective is obviously relevant to an evaluation of its benefits and risks, the possibility of therapeutic failure should be considered in determining the acceptability of risk of an investigational use (see response to paragraph 8, above).

  10. One comment contended that not all IRB's consider their involvement necessary in the circumstances described in proposed ß 312.2 under which a drug study would be exempted from IND requirements.

    FDA has retained a requirement for IRB review as a condition for the exemption because the agency considers review of such studies to be necessary to protect the rights and welfare of subjects. FDA believes that the generalized concern about IRB unwillingness to review studies is more theoretical than real. In the past, FDA has found little reluctance on the part of IRB's to review studies that are subject to agency regulations mandating such review. However, even if an investigator is faced with an IRB unwilling to review a planned study, the investigator may relocate the investigation to an institution whose IRB is willing to review the study or may request a waiver of IRB review (perhaps for the reasons that lead the unwilling IRB to conclude review was unnecessary). Therefore, the agency believes there should be adequate alternative means of complying with the conditions for exemption.

  11. One comment objected to the statement in proposed ß 312.2(d) that the investigational drug regulations do not apply to the use of a lawfully marketed drug in the practice of medicine for an unlabeled indication. The comment argued that such an exemption deprived the agency of the control required to ensure the safest possible use of the drug, and also deprived the public of useful information about the drug's nonlabeled uses.

    As noted in the preamble to the proposed rule, it was clearly the intent of Congress in passing the Federal Food, Drug, and Cosmetic Act that FDA not regulate the practice of medicine, which the agency has consistently viewed as including the use by physicians of marketed drugs for unlabeled indications in the "day-to-day" treatment of patients. Once a drug product has been approved for marketing, a physician may, in treating patients, prescribe the drug for uses not included in the drug's approved labeling. Control of the practice of medicine in these cases is primarily exercised through State laws affecting medical licensing and practice and through products liability law.

    While FDA does not regulate physicians' uses of approved drugs for unlabeled indications, the agency does continue to receive information about the drug's unlabeled uses. This information is obtained from a variety of sources, including physicians' adverse reaction reports, reports of sponsors' postmarketing surveillance activities, and reports of studies conducted by practitioners and researchers that are published in the medical literature.

  12. Section 312.2 deals with exemptions from IND requirements for biological in vitro diagnostic products. As proposed, the section specified the criteria for exemption -- exempting products intended to be used in a diagnostic procedure that confirmed the diagnosis made by another, medically established, diagnostic product or procedure -- but did not specify the particular products that would meet these criteria and therefore be exempt from the otherwise applicable provisions of Part 312. To ensure that the scope of this exemption is not misinterpreted, FDA has revised ß 312.2(b)(2) by adding new ß 312.2(b)(2)(ii) to identify the specific classes of product that, in the agency's view, meet the criteria for exemption. As thus revised, the regulation lists three classes of exempted products: blood grouping serum, reagent red blood cells, and anti-human globulin. A sponsor of a study involving an investigational biological in vitro diagnostic product not on this list who nonetheless believes the product meets the criteria for exemption should discuss with FDA the appropriateness of extending the exemption to that product. If FDA agrees with the sponsor, the sponsor's product will be added to the codified list of exempted products. A sponsor of a clinical investigation involving a biological in vitro diagnostic product that is not listed in ß 312.2(b)(2)(ii) must submit an IND for that investigation.

    The exemption for clinical investigations involving in vitro biological diagnostic products is conditioned on compliance with the labeling and recordkeeping requirements of ß 312.160. FDA has revised ß 312.160 by adding labeling and record retention requirements appropriate for in vitro biological diagnostic products. Accordingly, as revised, the section requires that shipments of in vitro biological diagnostic products be labeled as follows: "CAUTION: Contains a biological product for investigational in vitro diagnostic tests only." In addition, ß 312.160(a)(3) has been revised to require that records of shipments of exempted in vitro biological products be retained for the same record retention period as applies to shipments of investigational drugs subject to IND requirements.

    1. A placebo used in a clinical investigation is an "investigational new drug" as defined in this rule. As a technical matter, this means that an IND would be required for shipment and use of the placebo in a clinical study even when use of the active treatment drug in the study does not require an IND. FDA does not believe that asking for an IND in such cases serves a useful purpose. Therefore, on its own initiative, FDA has added new ß 312.2(b)(5) to state that an IND is not required when a placebo is used in a clinical study that does not otherwise require submission of an IND.

Definitions and Interpretations (ß 312.3)

  1. Several comments criticized the use of the term "investigational new drug application" to identify the sponsor's submission. One comment contended that the use of a term like "investigational new drug exemption" would be more consistent with the applicable statutory provisions and with FDA's decision not to adopt an affirmative approval mechanism. Another comment contended that the term "investigational new drug application" carries the connotation that the submitter of an IND is an applicant rather than a sponsor and must wait for the agency's approval prior to instituting the proposed research. This comment recommended that the term "investigational new drug notice" be adopted.

    As noted in the preamble to the proposal, the phrase "investigational new drug application" was adopted because it has come to be almost universally preferred over the more cumbersome, official term -- "Notice of Claimed Investigational Exemption for a New Drug." FDA believes the phrase is consistent with the pertinent provisions of the act and is also consistent with the mechanisms by which an IND goes into effect. Notwithstanding that submitters of IND's do not need to obtain approval, investigational drug studies are still subject to agency review prior to their initiation. Finally, FDA notes that to the extent that "investigational new drug application" carries a connotation for some that affirmative approval is required, the agency has revised the final regulation to define the phrase as synonymous with the former title, i.e., "Notice of Claimed Investigational Exemption for a New Drug." Therefore, FDA believes that little possibility for misunderstanding remains.

  2. Although no comments were submitted on the IND Rewrite's proposed definition of "sponsor" and "sponsor-investigator," comments were received on the very similar definitions of these terms that were included in the proposed rule governing the obligations of sponsors and monitors (proposed 21 CFR Part 52). Because of the relevance of those comments to this rulemaking, the comments are summarized and discussed below.
  3. One comment urged that a person who provides financial support, but who has no right to receive reports in return, be excluded specifically from the definition of "sponsor." The comment expressed concern about how the definition would affect grants to research institutions.

    The agency concludes that no changes in the definition of sponsor are necessary. The definition of "sponsor" does not include the concept of financial support as a characteristic of the sponsor relationship. Someone must, however, conceive of a particular study; someone must plan the study, arrange for financing, facilities, personnel, and other necessities; someone must serve as the focal point for negotiations with other bodies such as suppliers, laboratories, and IRB's; and, if an application for the research is required under the act, someone must assume the responsibilities of a sponsor and be identified as such in the application. Clearly, not all of these tasks need to be undertaken by the same person, but generally one person accepts the principal responsibility for completing these chores. The definition of "sponsor" does not force any particular person to accept this responsibility. Rather, it is flexible enough to permit the parties involved to decide what entity will serve as the sponsor of a particular study. Thus, a person who makes a grant to support an investigational study would not necessarily be a sponsor, unless identified as such in an application for a research permit. Instead, the recipient of the grant or some other entity may assume the responsibilities of a sponsor.

  4. Another comment suggested that the word "initiates" in the definition of "sponsor" be replaced by "requests" to avoid any implication that the sponsor conducts any part of the study. One comment suggested the definition be explicit in excluding universities and medical schools in all but special circumstances.

    The word "initiates" is appropriate. The definition of "sponsor" clearly states that the sponsor (other than a sponsor-investigator) does not actually conduct the investigation. The suggestion to substitute the word "requests" for the word "initiates" is rejected.

    No basis exists for excluding universities and medical schools from the definition of "sponsor." Although these institutions may seldom initiate a clinical investigation, it is possible that they may do so. When they do, they should be subject to the regulations to assure protection of the rights of human subjects, the safety of all subjects, and the quality and integrity of data resulting from the investigation.

  5. One comment objected to the exclusion of corporate sponsors from the definition of "sponsor-investigator" and stated that the creation of a double standard of enforcement for sponsors and sponsor-investigators is both confusing and a violation of equal protection because no need for the differential treatment had been demonstrated. The comment argued that pharmaceutical companies often conduct their own investigations, and that they, as well as independent individual investigators, should not be required to police themselves.

    The definition of "sponsor-investigator" is not intended to create a double standard or to discriminate against any one. Rather, the definition reflects the practical necessity of distinguishing between the situation in which a single individual both initiates and conducts a clinical investigation and the situation in which a corporation initiates an investigation that is conducted by its employees. The definition of "sponsor" specifically states that employees of a corporate or agency sponsor are considered to be investigators. In the case of a single individual, it would not be appropriate for that individual to comply with certain sponsor obligations. It would be senseless, for example, to require that the sponsor-investigator monitor himself or herself. This need for special provisions does not exist in cases where a sponsoring corporation or other entity conducts its own investigations with full-time staff employees. In these cases, the sponsor may assign other employees, or use a contractor, to serve as monitors. Monitoring of such a study is thus possible and feasible.

Labeling (ß 312.6)

  1. One comment asked whether the "investigational caution" statement required to appear on each drug label must appear on the labels of small, single-dose containers for which there may be significant space limitations.

    FDA believes that the inclusion of the required cautionary statement on the investigational label alerts all persons involved in a drug's distribution and dispensing to the drug's investigational status. As the utility of this message is not a function of the size of the package bearing the label, FDA does not believe it should exempt unit dose packages or other small packages from the requirement. At the same time, FDA is aware that space limitations may occasionally make it difficult to include all required information on the smallest drug package containers, and the agency will consider requests for waivers under ß 312.10 of label and labeling requirements on a case-by-case basis.

  2. One comment urged that the immediate container label of an investigational drug intended for self-administration include the name and emergency telephone number of the investigator. The comment contended that this provision would facilitate treatment of serious adverse reactions associated with investigational drugs.

    FDA is not aware of any problems attributable to the absence of emergency identifier information on investigational drug labels. The agency believes that human subjects have little difficulty in obtaining additional information about investigational drugs when the need arises. In addition, the agency notes that the informed consent form, a copy of which is given to each subject of an investigation, is required to identify the person to contact in the event of a research-related injury. For these reasons, while FDA would strongly encourage sponsors and investigators to develop a system to simplify the process by which subjects may obtain information and assistance in a drug-related emergency, the agency does not believe it should mandate identification of an emergency name and number.

Prohibition Against Prolonging an Investigation (ß 312.7(c))

  1. Several comments objected to the prohibition in proposed ß 312.7(c) against a sponsor prolonging an investigation after finding that the results of the investigation appear to establish sufficient data to support a marketing application. These comments suggested that there may be good reasons to delay submission of a marketing application, including a finding that additional data are needed to support an effective marketing plan. One comment suggested that the final regulation retain the current provision of the regulations that allows the sponsor to give reasons for not submitting an NDA.

    FDA believes that subjects should not be exposed unnecessarily to an investigational drug when sufficient data to support a marketing application have been obtained. This view is the basis of the proposed requirement. While sponsors will presumably submit marketing applications after deciding that the results of clinical studies support the applications, FDA concedes that there may be sound scientific or other reasons for delaying the submission of an application, and that such decisions are within the discretion of the sponsor. Therefore, the final rule, while continuing to prohibit a sponsor from unduly prolonging an investigation after finding that the results appear to support an application, will no longer require the submission of an application. FDA believes this change meets the concerns of the comments.

  2. The final sentence of proposed ß 312.7(c) would have required a sponsor to withdraw its IND if it determined that the data would support a marketing application. One comment suggested that there may be valid reasons for continuing a study, even though the results obtained are considered sufficient to support an NDA.

    FDA has deleted this provision. FDA agrees that there may be sound reasons for a sponsor to continue an investigation even after determining that the data will support a marketing application. For example, a sponsor might conclude that further studies would be desirable to obtain additional safety data or to study new indications.

Sale of Investigational Drugs (ß 312.7(d))

  1. Elsewhere in this issue of the Federal Register, FDA is reproposing new rules regarding the sale of investigational drugs. Comments received on this issue are addressed in that reproposal. Pending the adoption of a new final rule based on that reproposal, FDA has retained in this final rule the current provisions on sale.

Waivers (ß 312.10)

  1. Proposed ß 312.10 described the procedures under which FDA may waive any applicable requirement of the IND regulations. One comment complained that the provisions would give FDA too much discretion to dispense with otherwise applicable regulatory requirements. Other comments contended that because waivers should be relatively rarely needed, the granting of a waiver should be a matter of public notice and discussion.

    FDA believes the first comment misconstrued the purpose of the waiver provision. The waiver provision was intended to give applicants flexibility to seek alternative ways of complying with the regulatory requirements governing the conduct of clinical studies. The provision does not authorize FDA to waive statutory requirements; nor will the agency waive regulatory requirements, particularly those concerning the protection of the safety and welfare of human subjects, unless sponsors comply fully with the stated condition justifying waivers.

    FDA's requirements for the confidentiality of information apply to the existence of IND's and extend to waiver requests that are part of IND submissions. Moreover, FDA believes that the administrative burdens involved in routinely giving notice of requests for waivers would represent a needless encumbrance on the review process and would, given the limited nature of the waiver process, outweigh whatever benefits might flow from such disclosures.

  2. One comment suggested that the waiver regulation identify the specific person or office to be contacted to obtain a waiver.

    In general, waiver requests regarding IND's should be directed to the division with responsibility for review of the IND. Because this is the same for IND submissions and contacts generally, the agency does not consider it necessary to list the contact point in the rule itself.

Guidelines (ß 312.145)

  1. Many comments contended that, to ensure the integrity and scientific validity of technical guidelines, the public should be provided with an opportunity to participate in the creation or modification of these guidelines.

    Because FDA recognizes the significant contribution the industry, the medical community, and other members of the public can make to the development of scientifically sound guidelines, FDA has routinely solicited comment on previous scientific guidelines. With respect to the guidelines that have already been developed to implement the NDA and IND Rewrites, FDA did issue them as draft guidelines before making them final. Any future guidelines will be similary developed. FDA believes these actions should provide an appropriate degree of public input into the process.

  2. A number of comments approved of the proposed policy to issue a list of guidelines applicable to the regulations administered by the Center for Drugs and Biologics. Additionally, one comment recommended that the list of guidelines be published at least once per year in the Federal Register. Another comment recommended the establishment of the centralized public archive of guidelines.

    The Center for Drugs and Biologics has prepared a list of guidelines that apply to all regulations administered by the Center. The list may be obtained from the Legislative, Consumer, and Professional Affairs Branch, Division of Regulatory Affairs (HFN-365), Office of Compliance, Center for Drugs and Biologics, 5600 Fishers Lane, Rockville, MD 20857. Given the ready availability of this list, the agency does not believe its annual publication in the Federal Register is necessary.

    With respect to the request for a centralized archive of guidelines, the agency advises that a public file of guidelines is now maintained by the agency's Dockets Management Branch. In accordance with ß 10.80 of the agency's regulations, the file maintained by that Branch includes all public comments received in developing the guidelines.

Investigational New Drug Application

Requirement for an IND (ß 312.20)

  1. One comment noted that, historically, reviewing divisions of the Center for Drugs and Biologics have required a separate IND to be filed for each dosage form of a drug substance under clinical investigation. The comment recommended revising this policy to permit a sponsor to conduct clinical investigations of several different dosage forms under a single IND.

    The comment is not correct regarding current agency policy. FDA does not routinely require separate IND's for different dosage forms of a drug substance under clinical investigation. The agency may require separate IND's if separate applications will simplify agency review of the submissions -- for example, if different dosage forms of an investigational drug are assigned to different reviewing divisions. A sponsor with any questions about the appropriateness of submitting a single IND in this situation should discuss the matter with the division responsible for review of the initial IND submission.

Outside Review Boards

  1. In the preamble to the proposed rule, FDA discussed the issue of, and solicited comments on, establishing a "dual track" system in which drug sponsors would have the option of submitting IND's either to FDA or to third party, nongovernmental bodies -- "Outside Review Boards" (ORB's). ORB's would parallel FDA in performing a "scientific review" of proposed human research studies involving pharmacology, toxicology, chemistry, and clinical issues. The IND's being considered for this dual track system were the initial IND's that cover the first introduction of a drug into humans and the early clinical pharmacology and effectiveness studies (Phase 1). FDA's preliminary view, as stated in the preamble to the proposed rule, was that the dual track system may be unnecessary in light of the many changes contained in the agency's proposed rule.

    Six comments supported the ORB concept while 12 comments opposed adopting a dual track ORB system. These comments, both those in favor of and opposed to ORB's, did not raise new issues or arguments from those noted and discussed by FDA in the preamble to the proposed rule. For example, several comments in favor of ORB's stated that the concept was worth trying on a pilot basis, though acknowledging that even a pilot test would require FDA to establish standards or guidelines for their operation. One comment's endorsement of the ORB concept, however, included a recommendation for extension of ORB review to Phase 2, or at least early Phase 2, trials. Comments against the dual track system cited essentially the same arguments previously noted by FDA in the proposal: that there would be no obvious benefit to the use of ORB's in shortening the review time of IND's as FDA now reviews IND's promptly; that "permissive" ORB's might surface, thereby allowing drug sponsors to "shop around" to find favorable reviewers; and that the independence of ORB's might be questioned where the drug sponsor provides large financial grants to the institution establishing the ORB.

    FDA has carefully considered three comments and concludes that it would be desirable to consider further the merits of undertaking a pilot project in this area. However, because the comments submitted represented diverse views, even within the regulated community, the agency is now soliciting comments on the following points in order to determine if a pilot test of ORB's should be undertaken and, if so, to identify the best possible candidates for such a pilot program:

    (1) Which institutions, organizations, or other entities would be interested in participating in such a pilot program?

    (2) Which drug categories should be involved in a pilot program? For example, should the pilot program focus on one category of drugs or should it include a broader spectrum?

    (3) What should FDA's responsibilities be, if any, in monitoring the participating ORB in ensuring that there is no conflict of interest of ORB members, and in evaluating the IND's being considered.

    (4) To whom would the ORB be accountable (e.g., FDA, Congress, or other oversight organizations)?

    (5) What would be the legal liability, if any, of ORB members or their affiliated institutions, for the consequences of the ORB's decisions?

    (6) How long should such a pilot program last, what should be the criteria for assessing its success or failure, and who, in addition to FDA, should participate in the evaluation?

    (7) Who should fund the ORB participating in any pilot program?

    Interested persons are invited to submit specific proposals for participating, including the make-up of its proposed ORB. Proposals should be submitted by April 20, 1987.

Phases of an Investigation (ß 312.21)

  1. Several comments contended that both previous and proposed divisions of a clinical investigation into three phases created "uncertainty and ambiguity." One comment recommended adopting instead a two-tiered system in which the earliest clinical pharmacology stages of research -- defined to include those closely supervised studies conducted to obtain basic information about pharmacology, toxicology, and pharmacokinetics, and preliminary information about safety and effectiveness -- would be subject to less FDA regulatory control. The comments argued that during this "clinical pharmacology" stage FDA should rely more heavily than in the past upon the expertise of investigators and the safeguards employed by institutions conducting clinical pharmacology studies. The comments concluded that FDA should focus its review on the "clinical development" stages of research, which would include the later stages of research, in which large numbers of subjects are studied to develop evidence necessary to support a marketing application.

    Except for the question of whether there ought to be "two" versus "three" phases, the approach of the final rule is generally consistent with that recommended by the comments, both in terms of how the phases of a clinical investigation are defined and how they are regulated. FDA agrees that the clinical investigation process should be divided into an early clinical pharmacology stage (Phase 1) and a later clinical development stage (Phases 2 and 3), and that FDA's control of the earliest studies should be significantly less than over the later stages.

    With respect to the question of two versus three phases, to the extent that the entire process is organic and evolutionary, any division into phases or stages is somewhat arbitrary. However, the agency believes that the definition adopted corresponds as well as any with the significant divisions of the investigational process.

  2. Several comments recommended that the proposed definitions of the phases delete all references to the size of the subject population that would usually be expected to participate in the three phases of a study. One comment expressed concern that the numbers used to characterize each of the phases for illustrative purposes might come to be viewed as rigid requirements or limits for the number of patients in each phase. Other comments objected that the definitions of the phases did not necessarily apply to studies of biologic drugs, "orphan" drugs, diagnostic products, dosage forms other than the oral dosage form, or to marketed drugs tested for a new use.

    The purpose of including these definitions in the regulations is to provide a general yardstick for the development process for new drugs. The agency agrees that the description of the phases may not apply to certain classes of clinical investigations as well as it applies to studies of the classic, previously untested, drug in oral dosage form. However, that fact does not, in the agency's view, reduce the value of the descriptions as guidance in generally describing the nature of each phase. The agency assures sponsors that the description of the phases are not intended as rigid requirements, and that sponsors whose studies do not conform to the norms described in the regulation will not be disadvantaged in the review of their applications.

General Principles of the IND Submission (ß 312.22)

  1. This section states that the agency's primary objectives in reviewing an IND are, in all phases of the investigation, to assure the safety and rights of subjects, and, in Phases 2 and 3, to help assure that the quality of scientific evaluation of drugs is adequate to permit an evaluation of drugs' effectiveness and safety. Accordingly, the agency's review of Phase 1 submissions focuses on assessing the safety of the investigations while the review of Phases 2 and 3 also includes an evaluation of the scientific quality of the investigation and the likelihood that the investigations will yield data capable of meeting statutory standards for marketing approval.

  2. Several comments took issue with the agency statement of its objectives in reviewing clinical investigations. One comment argued that it is inappropriate for FDA to review and otherwise regulate the scientific design of Phase 2 and Phase 3 studies to determine whether such studies are likely to yield data capable of meeting statutory standards of marketing approval. The comment argued that "it is in fact expert opinion [that] is necessary to determine if substantial evidence has been provided," that such conclusions "rarely can be made at the outset" of a clinical development study, and that FDA "should not interject itself into the sponsor's developmental program unless there exists risks relative to patients." On the other hand, another comment suggested that it is inappropriate not to consider the scientific quality of a study, even in Phase 1. The comment suggested that concerns about the safety and rights of human subjects and concerns about scientific validity of a study are, in fact, not distinguishable because, according to the comment, "experiments which are poorly designed scientifically expose subjects to unreasonable risks and are, by definition, unsafe."

    FDA believes that the final rule, like the proposal, strikes the proper balance between these two extremes. First, the agency believes that its review of the quality of the sponsor's study design in the later stages of an investigation is in the public interest. Such review should preclude unnecessary exposure of human participants to risks in investigations that will ultimately have no scientific or regulatory value. In addition, by screening out poorly designed studies before they are conducted, FDA review should reduce the time required to obtain the valid evidence to make a decision on a drug's availability. As discussed later in this preamble, however, FDA would not place a clinical hold on a Phase 2 or 3 study, because of study design, unless the design was so deficient that the study could not meet its stated objective of establishing the product's safety and effectiveness.

    Agency authority to consider questions of study design in regulating clinical investigations is well-established. The premarketing approval provisions of the statute require that the evidence proferred to demonstrate a drug product's effectiveness consist of adequate and well-controlled trials. The most cost-effective time to make that determination is before a study begins. Indeed, it would be unreasonable for FDA not to advise a drug sponsor, in advance, if the agency determined that a particular study would not yield data capable of meeting statutory standards for marketing approval.

    The decision to narrow the focus in Phase I review to issues of safety alone reflects the desirability of reducing regulatory impediments to scientific creativity at this early stage of drug development. Because approximately 80 percent of all early investigations do not lead to marketing applications, the investment of resources that would be needed to assure the best possible scientific design of such studies is not justified, so long as research subjects are not put at risk. Moreover, Phase 1 studies are generally not considered pivotal to marketing approval, but rather are superseded by the later Phase 2 and Phase 3 studies. Of course, Phase 1 issues of study design that impact on research subject safety will remain part of FDA's purview.

  3. Several comments addressed the statement in proposed ß 312.22(c) that, to aid communications and minimize paperwork, information and data in IND's should, with some exceptions, be submitted only in summary form. While expressing agreement with the thrust of the principle, several comments were not certain what the exceptions referred to in the proposed section were. These comments asked that FDA identify the specific data items that would require detailed information.

    FDA believes that the statement fairly reflects the rule's overall approach to submission requirements. However, FDA concludes that the statement should be deleted as it provides no more guidance on submission requirements than can be obtained from an examination of the various specific provisions of the regulation. Additional guidance may also be obtained from relevant guidelines and from discussions with agency reviewers. FDA has revised the final rule accordingly.

  4. One comment, while appreciating the need to eliminate unnecessary paperwork, contended that eliminating raw data from IND submissions would serve to delay, rather than expedite, completion of the IND. The comment contended that raw data are needed to check sponsor and investigator interpretations of data, to spot check, and otherwise to gain a better insight into the application. The comment stated that raw data are especially important in an IND process in which a decision to permit an investigation to begin must be made within 30 days of submission of the application.

    The agency believes that the detail and comprehensiveness of information required to be submitted in the IND are adequate to permit successful oversight of the safety and quality of clinical studies. While the agency does not require submission of "raw data" to the IND, information that is of most direct relevance to agency review -- including information on the most important animal tests, on previous human experience with the investigational drug, and on adverse experiences during the course of the study -- must be submitted in sufficient detail to permit close scientific review. To require routine submission of raw data would not only impose additional burdens on study sponsors without any evident corresponding benefits to FDA, but could well impair FDA's oversight by overloading reviewers with extraneous and irrelevant information.

  5. Proposed ß 312.22(d) states that when a sponsor-investigator uses a drug that is already subject to a manufacturer's IND, the sponsor may ordinarily refer to the manufacturer's IND to provide the technical information supporting the proposed clinical investigation. One comment, noting that the preamble to the proposal indicated that such incorporation would occur only when permission is granted by the commercial sponsor, urged that the final regulation require the commercial sponsor's permission to be in writing.

    FDA agrees that a sponsor-investigator should not be able to rely on proprietary information submitted by a commercial drug firm unless the sponsor-investigator has received authorization to do so. Therefore, FDA has revised the final regulation to condition such reliance on the sponsor-investigator obtaining appropriate authorization from the commercial sponsor.

  6. Proposed ß 312.22(d) only expressly discussed the possibility that a sponsor-investigator might incorporate by reference information contained in a commercial sponsor's investigational application. One comment noted that under some circumstances incorporation by reference of information in a marketing application might also be appropriate. The comment urged that the final regulation be revised to accommodate this possibility.

    FDA agrees that under certain circumstances -- for example, when a marketed drug is studied for a new indication -- it would be appropriate to incorporate information contained in a marketing application into a sponsor-investigator's IND. FDA has revised the final regulation accordingly.

IND Cover Sheet (ß 312.23(a)(1))

  1. The proposal contained a requirement that the sponsor identify in the application cover sheet the phase or phases of the clinical investigations to be conducted. One comment asked whether the requirement pertained only to those studies to be initiated 30 days after submission of the IND, or whether it also referred to those studies to be conducted under the IND in the future.

    The cover sheet should reflect the phase or phases of the study that are intended to be covered by the IND submission. This submission (including protocols and supporting information) may be limited to the studies that will begin immediately after the IND goes into effect or may cover, at the sponsor's option, any or all of the remaining studies planned.

  2. The cover sheet includes a commitment by the sponsor that the investigation will be subject to the initial and continuing review and approval of an institutional review board (IRB), and that investigators will not make any deviations from the research plan without IRB approval. Several comments asserted that a sponsor cannot make these commitments for an investigator. The comments suggested that the sponsor should only be required to make a commitment to inform all investigators of applicable requirements, and to monitor them in accordance with applicable regulations.

    A sponsor's obligation to monitor its studies to ensure compliance with pertinent regulatory requirements, including IRB review requirements, has been part of the IND regulations for many years, and is now widely accepted as an appropriate sponsor responsibility. Therefore, FDA does not regard as unreasonable requiring the sponsor to commit to ensure compliance by investigators with pertinent IRB review and approval requirements. FDA does not view this commitment as a guarantee by the sponsor of investigator compliance in every case, but rather as an undertaking to ensure that investigators are fully informed of their responsibilities and to adopt monitoring procedures to minimize the possibility of investigator noncompliance.

  3. Proposed ß 312.23(a)(1)(vii) would require the sponsor to list the name and title of the person responsible for evaluating adverse reactions or other evidence of risks obtained from clinical investigators. Several comments recommended that this requirement be deleted, suggesting that the evaluation of adverse reactions is normally a collective effort, involving a number of individuals from different disciplines. The comments suggested that, in many cases, it would be extremely difficult to identify a single individual responsible for decisionmaking in this area. One comment suggested that FDA's initial contact point on all issues relating to conduct of the investigation, including adverse reactions reporting, should be the person responsible for monitoring the conduct and progress of the clinical investigation whose name would already have been provided to the IND under ß 312.23(a)(1)(vi).

    The agency believes that the requirement should be retained. The identification of a person (or persons) responsible for evaluating information relevant to the safety of the drug will be of significant help to agency reviewers in obtaining more information from the sponsor about a safety report submitted under ß 312.32, when such followup is necessary.

    FDA acknowledges that the evaluation of safety information may involve more than one person. Therefore, if a number of persons from different disciplines are involved in the evaluative effort, FDA would have no objection to the sponsor identifying any one or more of these individuals. FDA does not believe that it is consistent with the requirement for the sponsor to identify here the person identified in ß 312.23(a)(1)(vi) as charged with monitoring the conduct and progress of the investigation unless that person is also, in fact, responsible for review and evaluation of safety information.

    As proposed, the regulation would have required the identification of the person responsible "for evaluating adverse reactions or other evidence of risk * * * ." This has been revised to require the identification of the person (or persons) responsible for "review and evaluation of information relevant to the safety of the drug." The change conforms this section to the provisions in ß 312.32 governing review and reporting of safety information.


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