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  1. Clinical Trials and Human Subject Protection

Proposed New Drug, Antibiotic, and Biologic Drug Product Regulations

21 CFR Part 312
Proposed New Drug, Antibiotic, and Biologic Drug Product Regulations
[Docket No. 82N-0394]
48 FR 26720

June 9, 1983

AGENCY: Food and Drug Administration.

ACTION: Proposed rule.

SUMMARY: The Food and Drug Administration (FDA) is proposing to revise its regulations governing the review of investigational new drug applications and the monitoring of the progress of investigational drug use. FDA is taking this action to improve the investigational drug development process while maintaining high standards of human subject protection. The improvements are intended to assist sponsors of clinical investigations to prepare and submit high quality applications and to permit FDA to review them efficiently and with minimal delay. This action is one part of a larger effort to review and improve all aspects of FDA's drug regulatory process.

DATE: Comments by August 8, 1983.

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

FOR FURTHER INFORMATION CONTACT: Steven H. Unger, National Center for Drugs and Biologics (HFN-7), Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857, 301-443-5220.


This proposal is the second phase of efforts by the Department of Health and Human Services (HHS) and FDA to revise Federal regulations governing the new drug approval process. The first phase was a proposal published in the Federal Register of October 19, 1982 (47 FR 46622) to streamline the procedures in 21 CFR Part 314 for FDA review of new drug applications for marketing (NDA Rewrite). The second phase, contained in this document, addresses FDA's procedures in 21 CFR Part 312 for reviewing investigational new drug applications and for monitoring the progress of investigational drug use (IND Rewrite). Collectively, the IND/NDA Rewrite culminates an effort begun several years ago when FDA made concept papers available for public comment (44 FR 58919; October 12, 1979) and held a public meeting to discuss them (November 9, 1979).

The IND portion of the Rewrite reflects the continuing commitment of HHS Secretary Richard S. Schweiker and FDA Commissioner Arthur Hull Hayes, Jr., M.D., to facilitate the development, evaluation, and approval of safe and effective new therapies without compromising the underlying standards of safety and effectiveness upon which the American public has come to depend. Towards this end, the proposals reflect two major policy objectives. First, during the early phase of investigational research, FDA should focus on protecting the safety of human test subjects and give sponsors greater freedom to design, revise, and implement clinical research studies. This change should encourage innovation in drug development without compromising the safety of test subjects. Second, once the preliminary human studies have been completed and the durg appears to have marketing potential, FDA and drug sponsors should consult more closely to help ensure that the design of the major clinical trials are acceptable and will support marketing approval if the test results are favorable. 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 availability of safe and effective therapies.

Like the NDA portion of the Rewrite, the IND regulations have been reviewed by a special task force appointed by the Secretary, and chaired by the Commissioner, whose specific charge has been to review these regulations in accordance with Executive Order 12291 (46 FR 13193; February 19, 1981), the mandate of the President's Task Force on Regulatory Relief, and the policy objectives outlined above. Many of these issues were also previously reviewed by a separate FDA task force, which the Commissioner also chaired.

FDA's IND Rewrite proposal is designed to complement the October 19, 1982 NDA Rewrite proposal. That document proposed the following: a new streamlined format for marketing applications; the substitution of concise tabulations of essential clinical data in lieu of most case report forms; a new automatic appeals process for the prompt resolution of scientific disputes; a new policy on the acceptance of foreign data; more definite time frames for agency review; fewer supplements to approved applications along with fewer recordkeeping and reporting requirements; safety update reports while a marketing application is under review by the agency; and a strengthened adverse drug effect surveillance system after drugs have been approved for use by consumers.

These IND/NDA Rewrite proposals are part of a larger, overall effort to reform the drug development and review process. For example, FDA has instituted management changes aimed at enhancing accountability, improving utilization of personnel, and promoting timely communications with drug sponsors. The agency has also instituted some organizational changes, including the formation of the National Center for Drugs and Biologics, and the creation of a separate Office of Orphan Product Development within the Office of the Commissioner. Finally, as described in more detail below, FDA plans to issue guidelines on application format and on how to fulfill testing requirements. FDA believes that these initiatives, taken as a whole, should significantly improve the new drug approval process.

Highlights of this IND proposal, related issues, a description of the investigational new drug process, and the agency's economic analysis are summarized in the following introductory sections. The remainder of this preamble is devoted to a section-by-section analysis of the proposed regulatory changes.

Highlights of This Proposal

The major theme of the proposed IND regulations is that different stages of the IND process would be regulated differently. Safety concerns would predominate at the beginning of the process to ensure that research subjects are not exposed to unreasonable risk. In the later phases of drug investigation, FDA would also evaluate the scientific merit of study protocols to ensure that the planned clinical studies are capable of producing valid information on safety and effectiveness necessary to obtain marketing approval. This change in emphasis reflects the reality that only 20 percent of new chemical entities studied under an IND ever reach the NDA stage. Accordingly, FDA requirements and advice geared toward the development of a marketing application should wait until the drug has undergone the initial safety tests in human subjects and has shown some marketing potential. This proposal also clarifies the IND format, simplifies reporting requirements, and seeks to foster open, frank communications between FDA staff and drug sponsors. Finally, the regulations would give formal recognition to the idea of "treatment use" of certain drugs within the investigational context and would also exempt certain studies on marketed drugs from most IND requirements (except Institutional Review Board review and informed consent). The specific changes are summarized as follows:

1. Greater freedom during the early phase of human research. The agency proposes 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. FDA proposes to narrow the scope of its review of Phase 1 studies to focus on the safety of human test subjects. The proposal also articulates the flexibility available to clinical investigators in Phase 1 to modify protocols on the basis of experience gained during the investigation without prior notification to FDA, and further emphasizes to drug sponsors that the amount of toxicology and chemistry information required to be submitted in an IND depends on the nature and extent of the proposed clinical studies. As noted above, these changes to FDA's regulation of early research are intended to encourage innovation in drug development without compromising the safety of test subjects.

2. Clearer format for IND submission . The agency proposes to clarify the format for submission of an IND to create better organized applications and thereby facilitate agency review. This new format includes a greatly simplified cover sheet (Form FDA-1571), a brief overview of the investigational plan, and a brief introductory statement about the drug. The proposed format would also focus attention on the proposed human studies so that the supporting toxicology and chemistry information can be reviewed in light of the proposed clinical investigations.

3. Clarified amendment procedures . The agency proposes to clarify its amendment procedures by dividing amendments into several distinct categories: (i) Protocol amendments, for new protocols and changes in existing protocols; (ii) information amendments, for additional data as they develop; and (iii) IND safety reports. Each of these categories carries with it appropriate reporting intervals, depending upon the promptness needed for agency review. FDA also proposes to clarfify the scope of the annual reports to provide an overview of the progress to date and future plans for the IND, and to provide FDA with an update of the most significant safety information.

4. Creation of explicit "clinical hold" procedures . The agency proposes to codify procedures for instituting a "clinical hold," an order not to commence or continue a clinical study. For Phase 1 studies, FDA proposes to limit clinical holds to situations where there is an unreasonable and significant risk to human subjects. In later phases, the criteria would also include serious defects in study design that would render the study incapable of producing valid evidence of safety and effectiveness. To ensure uniform application of these criteria to similar drugs, all clinical holds would need to be approved by the director of the applicable reviewing division.

5. Closer consultation between FDA and drug sponsors . Although FDA has for several years offered "end-of-phase 2" conferences for drugs likely to provide significant and modest therapeutic advances, FDA now proposes to give the sponsor of any IND an opportunity to hold such a conference with the agency. The purpose of this meeting is to obtain concurrence on an overall plan for the conduct of Phase 3 trials and the design of specific studies. Such a "meeting of the minds" should significantly reduce the possibility of disputes later on after submission to FDA of a marketing application. FDA also proposes to place in its regulations the opportunity for a "pre-NDA" conference to discuss appropriate format and data presentation in a marketing application.

6. Treatment use of investigational drugs . The agency proposes to codify and state the conditions under which investigational drugs may be used to accomplish a treatment purpose in addition to an investigational purpose. This provision is designed primarily for drugs that have completed Phase 2 testing, when sufficient evidence of safety and effectiveness has already been obtained to justify making available an investigational drug for a treatment use. Such treatment uses would be limited to patients with serious diseases or conditions, for whom alternative therapies do not exist or cannot be used. Under these criteria, orphan drugs would be leading candidates for such treatment use. Accordingly, this provision implements a corresponding section of the recently enacted Orphan Drug Act, as described elsewhere in this preamble. FDA also proposes to simplify the procedures for obtaining investigational drugs for treatment use once these conditions are met.

7. Exemptions for certain studies on marketed drugs. Finally, FDA proposes to exempt from most IND requirements contained in Part 312 certain investigations conducted with drugs already approved for marketing for other uses. These would be limited to situations 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 investigations are not being conducted as a "pivotal study" for the purpose of changing the drug's labeling or advertising (e.g., adding a new indication or comparative safety claim). The exemption would apply primarily to researchers in academic or other institutions who are beginning to explore new uses for marketed drugs (i.e., not pivotal studies), or who are using the drug as a research tool. This provision is intended to reduce burdens on researchers and to permit FDA resources to be devoted to clinical investigations requiring FDA oversight and to review new drugs intended for marketing. Though exempt from most IND requirements in Part 312, such investigations would still be subject to other regulations designed to protect the rights and safety of patients, such as review by Institutional Review Boards (21 CFR Part 56) and informed consent (21 CFR Part 50), as these investigations are still subject to section 505 of the Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 355).

Related Issues

1. Guidelines. During the middle and late 1970's, the agency, with the help of its standing advisory committees, prepared over 25 guidelines devoted to the design of adequate and well-controlled clinical studies on different classes of drugs. These guidelines have facilitated high quality drug research and have been well received by drug sponsors. Therefore, FDA intends to expand the use of guidelines into other areas.

In the IND context, in addition to these clinical testing guidelines, the most pertinent guidelines are those related to animal toxicology testing and to chemistry and manufacturing controls requirements. As discussed elsewhere in this preamble, FDA intends to limit the scope of toxicology and chemistry submissions to that which is necessary to support the scope and duration of the proposed human testing. The guidelines are intended to help describe the scope of such submissions in the more common and expected circumstances. The new toxicology guidelines will update the current guidelines on this subject. The chemistry guidelines will be entirely new.

FDA recognizes that it is important, in issuing such guidelines, to solicit the views of experts throughout the scientific community, including government, industry, and academia. Accordingly, FDA plans to hold public workshops about what should be in these guidelines to gain the views of members of the scientific community. The agency will publish the details of these workshops in future issues of the Federal Register.

FDA is also developing guidelines on appropriate formats for IND's. These guidelines should aid sponsors in organizing and presenting their submissions in a fashion most suitable for efficient agency review.

FDA believes that the planned revisions to existing guidelines and the creation of new guidelines should materially assist in the implementation of the new regulations. Thus, as noted above, the NDA Rewrite, IND Rewrite, and implementing guidelines are very much interrelated and should be viewed as a whole as increasing the efficiency of the new drug approval process.

2. Outside review boards. One option still under consideration by the agency, though not being proposed at this time, is the establishment of a "dual track" system whereby drug sponsors would have the option of submitting initial IND's either to FDA or to third party nongovernmental bodies. These outside groups would fall under the umbrella term of "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 are the initial IND's that cover the first introduction of the drug into man and the early clinical pharmacolgy and effectiveness studies (Phase 1). Even under this dual track system, drug sponsors would still be required to submit their proposed human studies to local Institutional Review Boards (IRB's) for an "ethical review" and to ensure that research subjects give their informed consent.

The specifics of this outside review concept have varied over time. In the Federal Register of September 11, 1981 (46 FR 45538), FDA published a request for information, soliciting views as to whether local IRB's could assume the responsibility for reviewing certain IND's instead of FDA. Over 200 comments were received on that notice from hospitals, university medical centers, testing laboratories, IRB's, pharmaceutical manufacturers, academic and professional associations, and others. The concept of an IRB having sole responsibility for review of IND's was not favored by any category of comments. Most comments cited the lack of specialized scientific expertise of IRB's (especially regarding toxicology, chemistry, and pharmacology), the increased expense of expanding IRB's to gain the needed expertise, liability concerns, and the possibility that IRB's could take more time than FDA to review submissions. A number of comments, however, did suggest an optional system whereby a willing and expanded IRB could assume such review responsibility in lieu of an FDA review. Accordingly, FDA has redirected its consideration to this type of optional system which falls under the general umbrella term, ORB's.

Arguments in favor of ORB's are that FDA now tends to "overregulate" the early stages of human testing by delving into areas, such as study design, that should not concern FDA until later in the process when the drug has shown marketing potential. These arguments suggest that outside experts will be more prone to focus only on the central question of patient safety and leave these other matters to the discretion of the drug sponsor. ORB's are also perceived as a means of saving agency resources without compromising patient safety, as many drugs never advance beyond Phase 1 and so would never need to be seen by the agency.

Arguments against the dual track system start with the fact that FDA now reviews IND's promptly, and that in 90 percent of the cases the research may proceed within 30 days of the initial IND submission. Lengthy review times are therefore not often involved. Opponents also express concern about the possibility that "permissive" ORB's will surface, thereby letting drug sponsors "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. Finally, any FDA resource savings in IND review personnel may be more than offset by the additional resources necessary to develop standards for, inspect, and regulate ORB's.

FDA's preliminary view, apart from the possible advantages and disadvantages noted above, is that the dual track system may be unnecessary in light of the many other reforms contained in this proposal. As noted above, the agency itself is seeking to streamline the regulation of early research by narrowing the scope of Phase 1 review and by maximizing the flexibility with which drug sponsors may carry out early human investigations. By making these changes at FDA, the agency believes that the major goals of the dual track system can be achieved without the possible disadvantages noted above.

This issue, however, still remains under consideration by the agency. Therefore, FDA is soliciting comments as to whether, in light of the other changes being proposed in this document, the dual track system is worth pursuing, either on a permanent or pilot basis. In commenting on this issue, FDA requests responses to the following questions:

a. What specific benefits are attainable under a dual track system that are not attainable by making internal changes at FDA?

b. How can potential conflicts of interest be avoided? For example, should an individual drug sponsor be permitted to have its studies reviewed by an ORB whose institution receives financial assistance or grants from that drug sponsor?

c. What would be the appropriate degree of FDA oversight over ORB's, in terms of licensing, standard setting, and inspections?

d. Should FDA receive any concurrent notification (and, if so, in how much detail) or IND's submitted to ORB's for review?

e. If the dual track system were to be tried on a pilot basis, how long should the pilot program be tried, and how should the parameters of the pilot program be defined (e.g., by drug class and/or by authorizing a limited number of ORB's to operate)?

In addition, with respect to the possibility of a pilot program, FDA would like commenting institutions and drug sponsors to state whether they would be willing to participate in such an experiment.

FDA will carefully consider comments received on this proposal before reaching any final decision on whether to propose regulations involving Outside Review Boards.

3. Bioresearch monitoring regulations. The IND Rewrite proposal is intended to complement the agency's bioresearch monitoring regulations. Those regulations are the protection of human subjects in clinical investigations (21 CFR Part 50), the composition, operation, and responsibility of institutional review boards that review clinical investigations (21 CFR Part 56), and good laboratory practice for conducting non-clinical laboratory studies (21 CFR Part 58). In addition, the agency has also proposed regulations defining the obligations of clinical investigators (proposed 21 CFR Part 54; 43 FR 35210; August 8, 1978) and obligations of sponsors and monitors (proposed 21 CFR Part 52; 42 FR 49612; September 27, 1977).

The IND Rewrite proposal has been prepared on the assumption that clinical investigator and sponsor/monitor regulations will be made final before, or at the same time as, the IND Rewrite regulations. Accordingly, this proposal summarizes only the most essential clinical investigator and sponsor/monitor obligations and its completely silent on other issues (e.g., clinical investigator disqualification) that will be covered by the forthcoming bioresearch monitoring final regulations.

The Investigational New Drug Development Process

Almost all new drugs in the United States are developed by large pharmaceutical firms. These companies discover biologically active new molecules primarily by screening large numbers of synthetic compounds and natural products for various types of pharmacological activity. Those compounds that look promising are then subjected to short-term animal toxicity testing (1 week to 3 months, depending upon the anticipated duration of clinical testing) before being studied in humans. The preclinical testing is conducted to predict whether initial human studies will be acceptably safe and to predict, if possible, the drug's likely therapeutic activity. If the drug looks promising, human clinical studies are proposed in an investigational new drug application (IND).

Once an IND is filed with FDA, the sponsor must wait 30 days before testing the drug in humans. During this period, FDA reviews the submission to make sure the human subjects will not be subjected to unreasonable risks. If the agency is satisfied that the study does not pose such risks, the sponsor may begin testing the drug in humans. However, if FDA is concerned about the safety of the drug, or finds that more information is necessary to assess the safety issue, the agency notifies the drug sponsor not to begin human testing until the problems are resolved.

IND's are also reviewed by local IRB's for ethical acceptability. One goal of this review is to assure that human subjects are provided with sufficient information to be able to give their informed consent, a requirement that is statutorily mandated. IRB's are composed of scientific, medical, and lay personnel and are usually associated with the university, hospital, or clinic where the clinical research is to be undertaken. IRB's are regulated by FDA under regulations in Part 56.

Clinical investigations on new drugs are usually conducted by academic physicians working in university medical centers and by physicians in private practice. These investigations are frequently conducted on behalf of sponsoring drug firms, and the results may be published in the medical literature. Clinical testing proceeds progressively in three phases (called Phases 1, 2, and 3), each phase more extensive than its predecessor. (As noted below, the definitions of these phases are being revised in this proposal to reflect current practice.) As revised, these phases may be summarized as follows:

a. Phase 1 includes the initial introduction of the investigational new drug into humans. Phase 1 studies, which may be conducted in patients or normal volunteeer subjects, are designed to determine the metabolism and other pharmacologic actions of the drug, the side effects associated with increasing doses, and, if possible, to gain early evidence on effectiveness. Phase 1 also includes research studies on drug metabolism, pharmacokinetics, structure-activity relationships, and mechanism of action in humans. Total Phase 1 exposure is quite small, generally in the range of 20 to 80 persons.

b. Phase 2 includes the early controlled clinical studies conducted to evaluate the effectiveness of the drug for a particular indication in patients with the disease and to determine the common short-term side effects snd risks associated with the drug. Phase 2 trials are typically well controlled, closely monitored, and conducted in a relatively small number of patients (usually not more than several hundred).

c. Phase 3 studies are the expanded controlled and uncontrolled trials. They are performed after preliminary evidence of effectiveness of the drug has been established, and are intended to gather additional information about effectiveness and safety that is needed to evaluate the overall benefit-risk relationship of the drug and to provide an adequate basis for physician labeling. Phase 3 studies usually include from several hundred to several thousand patients.

Animal testing is also conducted during the human testing phases. As the human studies enlarge in scope and duration, further toxicology studies are needed to support them. Also, use of women of child bearing potential as test subjects must usually be preceded by reproductive performance and teratology studies in animals. Finally, once a drug appears to have marketing potential, long-term (chronic) animal studies, aproximately 1 to 2 years in duration, are usually conducted to predict possible latent human toxicities, including carcinongenicity.

FDA monitors the progress of an IND by reviewing IND amendments and annual reports submitted by the drug sponsor. Prompt reporting is required for significant safety findings, including certain adverse drug experiences in humans and important findings from animal toxicity studies. Such findings may result in the temporary suspension of a particular study or the termination of the entire IND if the safety subjects is placed in doubt. The agency also reviews new protocols submitted to the IND. In addition, when the sponsor so requests, agency officials assist in developing the overall clinical plan and designing specific protocols, most typically during an "End-of-Phase 2" conference with the drug sponsor, to ensure that planned studies are appropriate for the support of a marketing application.

Once the major IND studies are completed and the sponsor believes the data show the drug to be safe and effective under specified conditions, the sponsor submits to FDA an application to obtain the agency's approval for general marketing. Submission of a marketing application, however, usually does not mean that the IND file is closed. Some patients from earlier studies may still be receiving the investigational drug, or new clinical trials may have been commenced to study the drug for new indications. Accordingly, the IND remains active as long as patients are receiving the drug in an investigational context.

The process just described applies to a "commercial IND" -- that is, an IND submitted by a pharmaceutical company or research center for the purpose of collecting safety and efficacy data necessary to gain marketing approval. In addition, FDA reviews "sponsor-investigator IND's" and "treatment IND's" which normally do not go through the entire three-phase IND process.

A "sponsor-investigator IND" is submitted by an individual researcher, often associated with an academic institution, in order to conduct exploratory therapeutic research or to use the drug as a research tool. A sponsor-investigator IND may involve either an unapproved drug or an approved drug for an unapproved use. If results from this research suggest marketing potential for the drug, further studies are usually conducted under the auspices of a commercial IND.

The term "treatment IND" applies to a request by a practicing physician to administer an unapproved drug primarily for treatment purposes within the investigational context. Such treatment use may be appropriate for patients with serious disease conditions who are not responsive to approved therapies, such as in the case with orphan drugs. Ordinarily, a drug may be available for treatment use only after Phase 2 investigations have been completed.

In terms of overall number, FDA receives approximately 1,100 IND's for new drug and biological products each year. Of these, about 25 percent are commercial IND's, 30 percent are treatment IND's, and the remaining 45 percent are sponsor-investigator IND's. Accordingly, although most of the provisions in this proposal relate to commercial IND's, other provisions relate specifically to treatment IND's and certain sponsor-investigator IND's as well.

Economic Analysis

FDA has examined the economic consequences of the proposed changes in accordance with Executive Order 12291 and the Regulatory Flexibility Act (Pub. L. 96-354). The agency concludes that these revisions would 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 $3.3 million to sponsors, arising from a simplified IND format; reduced and/or staged submission of manfacturing 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 accepted. The only projected cost increase is modest by comparison and arises from requirements to improve the quality of annual reports. These revisions would 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, advice, and an appeals process 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.

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 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 have considerable benefits. A quicker, more efficient drug development process means that the Amercian 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 in public terms of improving the length and quality of life and in reducing health care and hospital costs. In addition, the provisions governing treatment use should be of special, if unquantifiable, benefit to patients with serious conditions who do not have adequate alternative therapies available to them, consistent with the goals of the recently enacted Orphan Drug Act.

Section-by-Section Analysis

FDA proposes to establish six new subparts in Part 312. Subpart A contains general provisions describing the scope of the regulations and the kinds of investigations that are exempt from IND requirements. It also describes the waiver provisions, labeling requirements, and requirements relating to the promotion and sale of investigational products. Subpart B describes the different kinds of applications and format, content, and reporting requirements for each of them. Subpart C contains regulations governing FDA review and action upon applications submitted under Subpart B, including clinical holds and terminations of IND's. Subpart D contains the general responsibilities of sponsors and clinical investigators during the course of a clinical investigation. Subpart E contains provisions on import and export of investigational drugs and a provision on the acceptability of foreign data in support of investigational and marketing applications. Finally, Subpart F describes requirements concerning the use of drugs in vitro and in animal testing.

Definitions. Under current regulations, "IND" stands for "Notice of Claimed Investigational Exemption for a New Drug." However, "IND" has come to be understood as standing simply for "investigational new drug application" and the proposed definition of "IND" would codify the simpler phrase.

As the IND regulations apply not only to "new drugs" but also to antibiotic drugs and biological products, "investigational new drugs" would be defined to include all members of these three categories of drugs that are either not approved for marketing or, if approved, are used in an investigational context outside of medical practice. Similarly, in identifying the submission needed to obtain approval to market a product, the proposal speaks in generic terms of a "marketing application" rather than specifically identifying the application appropriate to the drug (i.e., a new drug application (NDA) for new drugs, a request to provide for certification of an antibiotic (Form 5) for antibiotics, or a product license application for biological products.

The proposal would also define "clinical investigation" to mean any experiment in which an investigational new drug is administered or dispensed to, or used involving, one or more human subjects. In this context, an experiment is any drug use other than the use of a marketed drug in the practice of medicine.

The proposal would adopt definitions of "sponsor," "sponsor-investigator," "investigator," and "subject" that are like those used in the bioresearch monitoring regulations.

Finally, the proposal would revise the definitions of the phases of a clinical investigation to conform them to the current working understanding of the distinctions between them. The regulations now consider both "Phase 1" and "Phase 2" to be parts of "clinical pharmacology," "Phase 1" involving studies in normal subjects, and "Phase 2" involving studies in patients. "Phase 3," under the current regulations, includes all clinical trials. The proposed revision would redefine Phase 1 to include clinical pharmacology testing both in normal subjects and in patients with the condition under investigation. What is currently "Phase 3" under the regulations would, under the revision, be divided into a new "Phase 2," representing the first small, rigidly controlled, clinical studies and a new "Phase 3," representing the expanded clinical trials. The proposed redefinitions in the regulations parallel current usage in the agency's clinical guidelines.

IND Format and Content

This section describes the format in which IND's should be submitted and the types of information IND's should contain.

Currently, IND format and content requirements are set forth in the IND Form FDA-1571, the application submitted by the sponsor to FDA. The form identifies in some detail the kinds of information a sponsor must submit in an IND. In general, such submission is required to include information on the drug's chemistry and manufacture, information about the pharmacology and toxicology of the drug derived mainly from animal studies, sufficient information about each clinical investigator to show that he or she is qualified to undertake the proposed investigations, information about any previous human experience with the drug, and protocols for each proposed study. The current form also performs several other functions, such as describing the sponsor's obligations with respect to the conduct of the investigation, describing some of the administrative actions FDA may take with respect to an IND, and defining the phases of an investigation.

FDA believes there are several deficiencies in the current content and format regulations that should be remedied. First, the statement of what is required to be submitted is needlessly complex and confusing and may lead some sponsors to submit more information than is actually required. Second, current applications are frequently submitted without the kinds of "abstracts" or introductory summaries that are of considerable help to the review process. Third, the current regulation fails to make clear that the technical information should be tailored to the nature and scope of the proposed clinical trials. Accordingly, the proposed revisions in IND format and content are intended to clarify IND submission requirements, to encourage the use of introductory and summary statements to facilitate administrative processing and review, and to emphasize that submission requirements vary with the phase and scope of the proposed clinical investigations.

More important than the actual structural changes, however, are the general principles set forth to guide sponsors in submitting IND's and FDA staff in reviewing them. FDA recognizes that many complaints with the IND system reflect not so much the regulations themselves as the superstructure that has grown up around them in practice. For example, although drugs and biologics have long been governed by the same IND regulations, drug IND's are usually at least twice as extensive as biologics IND's. Accordingly, the following principles are enunciated in the proposed regulations themselves in order to aid in the interpretation of the specific provisions.

The first such principle would be the FDA's primary objectives in reviewing an IND would be, 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 the scientific evaluation of drugs is adequate to permit an evaluation of the drug's effectiveness and safety. Therefore, FDA's review of Phase 1 submissions would focus on assessing the safety of Phase 1 investigations. FDA's review of Phase 2 and Phase 3 submissions, however, would also include an assessment of the scientific quality of the clinical investigation and the likelihood that the investigations will yield data capable of meeting statutory standards for marketing approval. This principle is intended to reflect the agency's underlying policy goals to: (1) Encourage innovation by narrowing the scope of FDA regulation over early human research; and (2) increase the efficiency of the NDA review process through a heightened emphasis on advance FDA/sponsor consultation regarding the design of the major clinical trials.

The second basic principle is that the amount of information on a particular drug that must be submitted in an IND would depend upon the novelty of the drug, the extent to which it has been studied previously, the known or suspected risks, and the developmental phase of the drug and similar factors. This principle is intended to reflect the fact that flexibility in submission requirements is a function not only of the developmental phase of the research, but also of these other aspects of the drug itself.

The third principle is that the central focus of the first IND submission would be on the general investigational plan and the protocols for specific human studies. Subsequent amendments to the IND that contain new or revised protocols would build logically on previous submissions and would be supported by additional information including the results of animal toxicology studies or other human studies as appropriate. Annual reports to the IND would serve as the focus for reporting the status of studies being conducted under the IND and would update the general investigational plan for the coming year. This principle underscores the point that it is the scope and nature of proposed protocols that are of central importance in determining how much information needs to be submitted and in focusing on the degree of safety that needs to be shown.

The new IND format itself would consist of a cover sheet (revised Form FDA-1571), a table of contents, some introductory material intended to provide an overview of the investigation, the protocols for each study, and the technical information to support those specific protocols. This format may be further described, as follows:

1. Cover sheet (Form FDA-1571). FDA proposes to transform the IND Form FDA-1571 from a repository of the regulations to simply a cover sheet for the IND. The new Form FDA-1571 would only identify the phase or phases to be conducted and would contain essential "identifier" information about the sponsor and monitor of the investigation. When signed by the sponsor or the sponsor's representative, the application would commit the sponsor to comply with all applicable provisions governing the investigational use of drugs, as described in Part 312 as well as Parts 50, 52, 54, and 56. If the sponsor does not reside in the United States, the sponsor would designate an agent who resides or maintains a place of business in the United States who would also sign the form. This provision regarding foreign sponsors would correspond to a similar provision in the NDA Rewrite proposal.

2. Introductory sections. The proposed IND format would begin with a table of contents and a brief introductory statement. The introductory statement, which the agency believes should not usually be more than two or three pages in length, would give a broad overview of the proposed investigation. It would give the drug's name, its pharmacological class, a short statement of the objectives of the proposed study, and a brief summary of previous human experience with the drug, including any foreign experience. FDA believes that the statement would be of considerable benefit in facilitating review by helping assign IND's to the appropriate reviewing division in an expeditious manner and by quickly orienting reviewers to the contents of the IND. Following the introductory statement, the IND would contain a general plan for the proposed investigation. This document would give a "blueprint" for drug development -- that is, the kind and number of studies to be conducted in the following year, the general approach to be followed, and an estimate of the number of subjects to be involved. This "blueprint" is one mechanism for focusing attention on the scope and extent of the proposed human studies, both for sponsor submission and FDA review purposes.

3. Protocols. The general investigation plan would be followed by a protocol for each study the sponsor intends to begin at the end of FDA's 30-day review period. Protocols for later studies may be submitted in the initial IND or in protocol amendments as the investigation progresses. The detail of Phase I protocols now submitted by drug sponsors provides one of the best examples of where current practice has superseded the actual letter of the regulations. Although the current regulations require only a "general outline" of Phase 1 studies, in practice most Phase 1 studies have been submitted in the kind of detail more appropriate for Phase 2 or 3 protocols. Accordingly, in drafting revised regulations, FDA has sought to emphasize the difference in requirements between Phase 1 protocols and protocols for Phases 2 and 3.

Although the proposal would require protocols for all phases to contain information on subject selection criteria, on investigator qualification, on proposed procedures for monitoring the clinical effects of the drug, and so on, the proposal would stress that the amount of detail needed on each aspect of the protocol would vary with the phase of the investigation. The revision would reflect FDA's focus in Phase 1 on safety issues and would make clear that FDA expects Phase 1 protocols to be submitted in an outline form that would need to contain sufficient detail to permit a reliable assessment of subject safety, but not more than necessary for an adequate review.

The revision would also stress the flexibility a sponsor has to modify a Phase 1 protocol as experience dictates without having to submit protocol amendments to FDA (provided such modification is described in the next annual report). This flexibility reflects the truly experimental nature of early research and is consistent with the broad policy objective of maximizing sponsor freedom during this stage. Although this flexibility is available under current requirements, it has not been fully appreciated in practice by FDA or investigators and sponsors.

As noted above, FDA's review of Phase 2 and Phase 3 submissions has a broader scope. At this stage FDA is concerned not only with subject safety, but also with an assessment of the scientific quality of studies and the likelihood that the studies will produce the kind of data that can be considered in determining whether to approve a drug for marketing. Therefore, to decrease the chance that such studies will not meet statutory standards for marketing approval, much more detailed information about study design is required for Phase 2 and 3 investigations. FDA has prepared over 25 clinical guidelines for different classes of drugs that describe appropriate ways of designing and conducting these Phase 2 and Phase 3 trials.

One additional minor change should be mentioned. Under current regulations, protocols for early phase studies must identify "any expert committees or panels to be utilized," although protocols for later phases need not. The justification for this difference is no longer evident, and the IND Rewrite would require that each protocol, regardless of phase, identify the name and address of its reviewing institutional review board (IRB). This minor change will provide FDA with immediate access to the identity of a particular IRB, if necessary.

4. Chemistry, manufacturing, and control information. This section states the requirements regarding the submission in the application of information about the composition of the drug substance and drug product, their specifications, and their methods of manufacture and control. The section would clarify rather than substantially revise current requirements. FDA is preparing guidelines on the scope and content of chemistry, manufacturing, and control submissions. The language of the proposed regulation is intended to be general in nature so that it may accommodate changes that might be made as a result of the guideline development process.

The proposed revision emphasizes that chemistry, manufacturing, and control information should be tailored to the scope and duration of the proposed clinical investigation. For example, if relatively short-term clinical tests are planned, the stability information required would be limited to that needed to demonstrate that the product would be stable for the short duration of the investigation.

The revision would continue to require the submission of sufficient information about the drug substance and drug product to ensure its identity, potency, quality, and purity and to ensure that there is a sufficient continuity in the product so that information obtained from previous clinical and nonclinical studies can be considered in assessing the safety of future studies. It would also require a description of the method of preparation (or isolation) of the drug substance and a brief general description of the manufacturing and packaging of the drug product.

5. Pharmacology and toxicology information. FDA also does not propose to change significantly the substance of the current requirements regarding submission of animal and in vitro test results. The results of such tests serve primarily to support FDA's assessment of the safety of proposed clinical investigations. These studies are directed toward defining the drug's safety, toxicity, and pharmacological action rather than its efficacy. They are meant to predict effects which might be expected when the drug is administered to human subjects.

The proposal would retain the current requirement for "adequate information" on the basis of which the sponsor has concluded that it is reasonably safe to begin the proposed study. The proposal, like the current regulation, would note that the kind, duration, and scope of such tests would depend on the nature of the proposed investigations. The proposal would identify only in a general way the kinds of tests that sponsors would ordinarily submit in an IND. Detailed information on what kinds of tests may be submitted to support specific kinds of clinical investigations is contained in toxicology guidelines. The agency is reviewing its toxicology guidelines, and, as noted earlier, plans to develop new guidelines with the help of scientific experts from both inside and outside of government.

The proposal would also specify an appropriate format for toxicology submissions. The sponsor would be required to submit an integrated summary of the toxicological effects of the drug in animals and in vitro and, for each study submitted primarily to support the safety of a proposed investigation, a full tabulation of the data. The latter provision reflects the fact that, unlike most other technical data, the usefulness of much toxicology data is largely confined to the investigational stages of drug development. Because such data's utility is greatest at this early stage, it is appropriate that it be submitted in the kind of detail appropriate for careful scrutiny.

6. Sponsor-investigator IND's. It should be emphasized that the proposed application section describes the information a commercial sponsor must submit for a previously unstudied new molecular entity. In general, it does not describe the kinds of technical information needed to support a sponsor-investigator research study of a previously studied drug product. FDA expects that in most such cases technical information previously submitted to FDA by the commercial sponsor will be incorporated by reference into the sponsor-investigator's IND, assuming permission is granted by the commercial sponsor. FDA will make available guidelines to assist sponsor-investigators in preparing IND's.

Amendments to the IND

This section describes the types and timing of IND amendments that must be submitted during the time that a drug is under investigational status. These amendments fall into three categories: (1) Protocol amendments, (2) information amendments, and (3) adverse drug experience reports. The proposed revisions are intended to rationalize the flow of information to an active IND file, to clarify when amendments are required, and to establish formatting requirements that will simplify their processing and review.

1. Protocol amendments. Current regulations require that a sponsor conducting an investigation adhere to the protocols described in the IND submission. If the sponsor intends to expand the scope of the investigation or to alter its direction, the sponsor is required to amend the IND to reflect the change. The current regulations, however, do not specify when an amendment should be submitted, for what kinds of changes amendments are required, or what the amendment should contain. The lack of specificity in the regulations means all too frequently that amendments are submitted in such a fashion that it is extremely difficult for reviewers to gain an understanding of their significance or their relationship to previous or subsequent submissions, except by reviewing the complete IND file. This difficulty in tracking an IND once an investigation begins may explain in part current emphasis on the initial IND submission.

The proposal would make clear that FDA is interested only in learning contemporaneously about the kinds of changes that bear directly on its review and monitoring responsibilities. Thus, under the protocol amendment procedures, amendments would be required only for new protocols, for protocol changes that significantly relate to the agency's assessment of an investigation's safety, and, for Phase 2 and Phase 3 studies, also for protocol changes that significantly relate to the scope of an investigation or to its scientific quality. Additionally, a protocol amendment would be required to list a new investigator that is added to an already submitted protocol. FDA reviews each new investigator to ensure that the investigator is qualified to conduct the proposed research and to verify that the investigator is eligible to receive investigational new drugs.

The proposal would also clarify the proper timing of submissions. The current IND regulations require the sponsor to notify FDA before beginning a substantially modified protocol or a new protocol, but do not require sponsors to pause before proceeding, so long as local IRB approval has been obtained. The IND Rewrite would explicitly retain this current process. The only change being made here is that protocol amendments which merely list a new investigator to an already submitted protocol would be sent to FDA under the timetable described below for information amendments.

Finally, FDA proposes to create a standard format for protocol amendments that would make them much easier to process and review. The flow of protocol amendments to the IND under current requirements is such that it is frequently difficult to determine the contents of an amendment, the sequence of amendments, or even to determine what specific protocol in an IND a submission is intended to amend. To remedy these deficiencies, the proposed revision would require that all protocol amendments be prominently identified, that they be numbered iin sequence of submission, and that protocol changes plainly indicate what specific protocols they are amending. The proposal would also require that a protocol amendment cite any specific technical data that support the proposed new protocol or protocol change. If, for example, the sponsor proposed to undertake a new long-term trial of 6 months' duration, where all previous trials had not exceeded 1 month, the sponsor would be required to cite the specific animal studies that supported a trial of this length. Such supporting data would either have been previously submitted to the IND or would be concurrently submitted in an information amendment.

2. Information amendments . The current regulation provides that the IND may be "amended or supplemented from time to time on the basis of experience gained with the * * * drug." The regulation contains no other guidance on the submission of additional technical information after the initial IND is submitted. The IND Rewrite would add specificity by establishing an "information amendment" as a means for conveying to FDA information on significant changes in the technical content of the IND file. Information amendments would provide specific technical information, including chemistry, toxicology, and pharmacokinetic data. Information amendments would serve primarily two functions: (i) They would provide the technical support (usually essential toxicological or chemistry information) for new or modified clinical protocols; and (ii) they would be a mechanism for keeping current the information contained in the IND file. The format of information amendments would be similar to that of protocol amendments.

Thus, information amendments would be required to bear prominent identification of their contents and to be serially numbered by discipline. Additionally, to facilitate FDA review, information amendments would be required to contain a statement of the nature and purpose of the amendment and to be submitted in a fashion appropriate for scientific review.

The proposal would also establish a new system for timing of information amendment submissions. Currently, the frequency and number of separate amendments and other communications submitted to an IND file places a significant workload on the agency. This results in delaying the routing of documents to the reviewing divisions. The proposal therefore encourages sponsors to group together information amendments and to submit them together at 30-day intervals instead of submitting these amendments individually. The grouping of amendments should ease both the agency's administrative burdens and the organizational and shipping burdens placed on sponsors. Of course, the agency recognizes that in some cases the progress of an investigation may not permit the grouping of amendments, such as when information amendments are needed to support a protocol amendment that must be submitted more promptly. However, even when submissions are needed more often than every 30 days (so as not to impede the progress of the investigation), FDA encourages sponsors to group submissions as much as possible in order to improve the functioning of FDA document control.

To alleviate the administrative difficulties described above, FDA requests sponsors to group amendments at 30-day intervals (or earlier, if necessary) on an interim basis, pending completion of the notice and comment rulemaking proceeding. FDA believes such implementation is permissible prior to publication of a final rule because the change only affects the timing, not the content, of the submissions.

3. IND safety reports . The IND Rewrite contains a separate section on safety reports to highlight the importance of monitoring patient safety throughout the IND process. The proposal retains the current requirement for sponsors to notify FDA and all participating investigators about any information the sponsors receive associated with the use of the drug that may suggest significant hazards, contraindications, side effects, or precautions; the proposal states that, in meeting this requirement, the sponsor is required to review all information relevant to the safety of the drug obtained or otherwise received by the sponsor from any source, foreign or domestic, including information derived from clinical investigations, animal investigations, commercial marketing experience, reports in the scientific literature, and unpublished scientific papers. (Under the proposed rule defining the obligations of clinical investigators, an investigator is responsible for relaying to the reviewing IRB information received from the sponsor about adverse effects.) The proposal defines "information relevant to the safety of the drug" to include information about related drugs. The proposal also defines "associated with the use of the drug" to mean there is a reasonable possibility that the event may have been caused by the drug. To meet this definition, the causal relationship between the drug and the adverse event need not be known with any degree of certainty and, when doubt exists, the regulation should be construed to require submission of an IND safety report.

In addition, the proposal specifies time frames within which a sponsor would be required to relay safety reports to FDA. The current requirement is that an "alarming" finding must be reported "immediately" and that all other findings must be reported "promptly." Under the proposal, a sponsor would be required to notify FDA about fatal or life-threatening clinical experiences not previously reported as soon as practical and in no event later than 3 working days after the sponsor initially receives the information. Other serious adverse events would be required to be relayed to FDA as soon as possible and in no event later than 10 working days after the sponsor initially receives the information.

To ensure that this information is rapidly transmitted to FDA, the proposal would require the sponsor to relay the 3-day and 10-day IND safety reports by telephone at the same time as Written notifications are submitted. Telephone calls are to be made to the FDA division with review responsibility for the IND. written notifications are to be prominently identified to facilitate expedited processing by the agency.

The proposal would also retain the requirement obliging sponsors to investigate thoroughly all safety related information received by them. Although FDA understands that these investigations will not ordinarily be completed within the time limits prescribed for the IND safety reports, the proposal would require sponsors to submit relevant followup information to the 3-day and 10-day reports as expeditiously as practicable in an information amendment. Followup information on incidents not triggering a 3-day or 10-day report would be submitted, as appropriate, in either an information amendment or an annual report.

Annual Reports

This section describes content requirements for annual reports. Current regulations require a sponsor to submit accurate progress reports of the investigation and significant findings together with any significant changes in the investigator brochure at reasonable intervals, not exceeding once a year. FDA has found such reports to be a valuable means of monitoring the progress of investigations and therefore proposes to retain the provision in the rewrite. However, because current regulations provide inadequate guidance on what should be included in a progress report, the quality of such reports has varied considerably. Annual reports have varied from a very brief and conclusory statement about a sponsor's activities to a comprehensive statistical analysis of all data collected. Accordingly, some sponsors submit too much information and others submit too little.

The revision would clarify what FDA regards as the minimum amount of information needed to monitor satisfactorily the progress of drug development. It would require a brief summary of the status of each clinical study in progress, a brief summary of safety information obtained in the previous year, and a description of the general investigational plan for the following year. As part of the summary of safety information from the previous year, the annual report would contain a listing of patients who died or dropped out of clinical studies, because these patients are likely to provide the most important safety information. (The annual update of safety information would necessarily summarize all IND safety reports submitted to FDA throughout the previous year.) This requirement is consistent with a provision in the NDA Rewrite proposal that would require the routine submission of case report forms for those patients meeting these same criteria (i.e., persons who died or dropped out). Finally, as an aid in fostering better communication between FDA and the sponsor, the sponsor could use the annual report to identify any outstanding business about which the sponsor would like to meet with FDA or to have a written reply or comment from the agency.

Use of Investigational Drugs for Treatment

This section codifies a special procedure authorizing the "treatment use" of investigational drugs in an investigational context.

When reports in the medical literature begin to appear that a new investigational drug shows promise for a serious disease, a demand for the drug for the benefit of patients frequently develops. FDA has responded to this demand by permitting physicians to obtain investigational drugs for treatment use either under physician sponsored IND's or under protocols that are part of commercially sponsored IND's. In addition to providing patients with needed drug therapy, such treatment uses are a valuable adjunct to the investigation as well, frequently providing sponsors and FDA with valuable safety data. Although the agency has for many years permitted selected investigational drugs to be distributed primarily for treatment use under these circumstances, the current IND regulations do not specifically authorize the practice. The proposed revisions would expressly authorize this use of investigational drugs, define the universe of drugs eligible for treatment use, and describe the procedures by which these drugs can be obtained.

Under this proposal, a drug would be obtainable for treatment use either under a treatment protocol submitted by the sponsor of an active commercial IND for that drug or under a separate treatment IND submitted by a licensed medical practitioner. The proposal would make plain that the primary purpose of a treatment protocol or treatment IND is to provide patients with a drug to treat a serious disease condition not treatable satisfactorily with alternative therapies. The criteria for authorizing the use of an investigational drug for treatment would reflect this purpose. Thus, FDA would only authorize use of a drug under a treatment protocol/IND if it found: (1) That the proposed use is intended for a serious disease condition in patients for whom no satisfactory approved drug or other therapy is available; (2) that the potential benefits of the drug's use outweigh the potential risks; and (3) that there is sufficient evidence of the drug's safety and effectiveness to justify its intended treatment use. These criteria would ordinarily mean that a drug would not be a candidate for a treatment use until it had gone through the kind of studies conducted during Phase 2. Thus, investigational drugs would ordinarily only become available for a treatment use at the end of Phase 2 or during Phase 3 of an investigation.

FDA believes that there are several reasons for generally confining the availability of investigational drugs for treatment use to drugs in this time frame. First, the kind of evidence necessary for FDA to be able to make an adequate assessment of the drug's potential benefits is usually not available until this time frame. Second, the agency wants to ensure that the treatment protocol/IND system does not undermine patients' interest in participating in controlled clinical trials. If access to investigational drugs for "treatment" becomes too widespread too early in the process, this could impede the collection of the type of data necessary to obtain marketing approval. Accordingly, FDA believes that the model for treatment protocol/IND use should be a drug in Phase 3 when the major clinical trials are completed or underway and where the evidence to date is favorable toward subsequent approval for marketing. The "Group C" system at the National Cancer Institute has followed these same principles and has achieved considerable success.

FDA anticipates that the proposed criteria for making a drug available under a treatment IND/protocol will be adequate to meet the vast majority of treatment use requests. Where compelling circumstances warrant, however, FDA will consider permitting treatment use earlier in the IND process.

Under the proposed criteria, "orphan drugs" would be leading candidates for treatment use by virtue of their being intended for rare diseases without satisfactory alternative therapy. As stated in the Orphan Drug Act (Pub. L. 97-414; January 4, 1983), sponsors of IND's for orphan drugs should be encouraged to design clinical studies that permit the inclusion of patients who wish to receive the drug for treatment purposes. (See section of Pub. L. 97-414 entitled, "Open Protocols for Investigations of Drugs for Rare Diseases or Conditions.") Accordingly, the treatment use section of the proposed regulations serve to implement the corresponding provisions of the Orphan Drug Act.

FDA has been criticized for not adequately informing the medical commuity about the availability of certain investigational drugs for treatment use. The proposal is intended to improve physician (and patient) access to these investigational drugs in three ways. First, by placing the procedures in the regulations, the necessary steps for obtaining such drugs will be made clear and more generally known. Second, as described below, FDA is encouraging commercial sponsors to develop treatment protocols so that, in most instances, the individual physician should not even have to come to FDA. Third, when separate treatment IND's do need to be submitted to the agency, the necessary paperwork is minimal, designed primarily to ensure patient safety, and the type of information needed to be submitted should be readily accessible to the treating physician. Accordingly, this provision should provide considerable benefits to consumers.

For some of the most promising investigational drugs, requests for the drug for treatment of individual patients can extend into the hundreds. The regulation would encourage drug companies to accommodate such requests under company-developed treatment protocols rather than to act simply as a supplier to many individual physicians, each of whom would otherwise have to submit a separate treatment IND. A company-sponsored treatment protocol has several advantages. Such a protocol can be readily designed to collect important, useful, and easily interpreted data about the drug, especially regarding safety.

It would certainly be in the public interest to utilize that additional premarketing data base. In addition, by channeling a number of physicians' requests for a drug for treatment into a single treatment protocol, scarce agency resources may be saved which can then be devoted to other IND's and marketing applications. In this regard, it should be noted that treatment IND's submitted by individual physicians now account for approximately 30 percent of all IND's received by FDA in a typical year.

Whether the request for use of an investigational drug in treatment were to be submitted in a treatment protocol or in a treatment IND, FDA' requirements would be minimal, consistent with patient safety and proper use. The protocol for each would include an explanation of the rationale for use of the drug, a brief description of the criteria for patient selection, a description of the clinical procedures, laboratory tests, or other measures to be taken to monitor the effects of the drug and to minimize risk, and a description of the proposed dosage and administration. Such protocols might be written by either the drug firm supplying the drug or an individual physician sponsor, with input from FDA as necessary to aid patient safety and proper use.

Because toxicology, chemistry, and other technical information should already be available for FDA review in the commercial sponsor's IND, in general little or no additional supporting information would be required for either a treatment protocol or a treatment IND. In the case of a treatment IND submitted by a individual physician, however, the physician needs permission from the commercial sponsor for FDA to cross-reference such technical information from the commercial sponsor's IND into the physician's treatment IND. In the normal course, if a commercial sponsor chooses to provide the individual physician with the investigational drug, FDA would view that shipment of the drug as authorization by the commercial sponsor to permit FDA to incorporate by reference the technical information in the commercial sponsor's IND into the physician's treatment IND. Such incorporation by reference makes the information available to FDA for review purposes, but does not authorize disclosure to the physician of the information so incorporated.

The obligations of sponsors and investigators on the conduct of investigational uses under treatment protocols/IND's would in general be identical to those imposed on other sponsors and investigators. Thus, the requirements regarding the control of the drug, recordkeeping, and reporting of safety information would apply in the treatment protocol/IND context as well. Although investigators are normally obliged under the IRB, regulations in Part 56 to obtain the review and approval of a local IRB, FDA would carefully consider granting waivers from that requirement in a treatment setting, on the grounds that review by an IRB for conformance with ethical principles designed for the research setting is not always necessary in a treatment context. For treatment protocols covering many patients, the IRB review requirement (or waiver therefrom) applies only once to the initial protocol, not to each patient that is added to it. Of course, FDA waiver of an IRB requirement would not preclude a local IRB from requiring physicians to obtain IRB review for all experimental procedures conducted in the institution.

When FDA does waive IRB review requirements, it may require as a condition of such waiver that the sponsor submit adequate assurance that the treatments use is to be conducted in conformity with all applicable requirements regarding the ethical conduct of an investigation. In particular, FDA may require the submission of sample informed consent forms to demonstrate that adequate and informed consent will be obtained. This is especially important when IRB review has been waived because IRB review is the chief means of assuring adequate informed consent of patients.

It should be emphasized that the treatment IND or treatment protocol is suitable only as a mechanism to obtain a drug that is not otherwise obtainable. The mechanism would not be appropriate as a means of obtaining a commercially available approved drug for a treatment use that is not described in the product's package insert. Such uses of marketed products, if within the practice of medicine, are beyond FDA's authority to require submission of an IND. The applicability of IND requirements to the use of marketed drugs is discussed elsewhere in this preamble.

Emergency Procedures

The need for an investigational drug may arise in an emergency situation that does not allow time for compliance with applicable IND submission requirements. The proposal would formally establish the mechanism now used for obtaining a drug in an emergency. The proposal would permit FDA to authorize shipment of a drug for a specified use before submission of an IND. Such requests would usually be made over the telephone. FDA's authorization would typically require the person who obtains the drug on an emergency basis to followup the initial request with a full written IND submission.

Administrative Actions on an IND

FDA proposes to describe in the regulations administrative actions the agency may take in reviewing an initial IND and in monitoring the progress of investigations that are conducted under an effective IND.

As noted in the introductory section of this preamble, under current requirements FDA has 30 days to review an initial IND submission. FDA's reviewers are asked to decide whether the information submitted in the application supports initiation of the proposed clinical investigations. If the reviewers find that some deficiency in the application justifies delaying the commencement of human studies, a "clinical hold" may be imposed instructing the sponsor not to begin the studies. The kinds of deficiencies that would justify a clinical hold are not described in the current regulations. Unless otherwise notified, a sponsor may begin human studies 30 days after FDA receives the IND.

Once clinical investigations begin, the principal mechanisms of further FDA regulation are deficiency letters, which point out specific technical problems in the application; clinical holds, which are orders to stop or limit specifically identified studies under an IND; and terminations, which are orders that prohibit all investigational activity under an IND.

Current regulations impose no obligations on FDA to explain actions taken with respect to an IND, provide no effective procedures for appealing decisions during the IND process, and fail to explain the regulatory significance of agency deficiency letters and other communications sent to the sponsor during the pendency of an IND. Also, current regulations concerning administrative actions do not describe the proper scope of FDA review during the different phases of the IND process. Therefore, FDA believes that a comprehensive revision and restatement of IND procedures and standards for administrative actions should be undertaken.

The proposal would attempt to remedy these omissions, among other ways, by specifying clinical hold and termination procedures that reflect the changing focus of FDA's concerns in reviewing IND's for different phases, by clarifying the regulatory status of FDA's communications to sponsors, and by codifying an appeals mechanism.

The proposal would also retain the 30-day period for review of initial IND submissions. FDA believes that the 30-day period imposes little if any delay on the drug development process while providing FDA with adequate time to fulfill the agency's responsibilities in monitoring and assessing the safety of proposed human studies. At the same time, FDA concludes that it is unnecessary to establish an affirmative approval mechanism for IND's, i.e., a mechanism under which a sponsor could only begin a study after receiving written notification from FDA. FDA believes the current mechanism has worked well and should not be changed.

1. Deficiency letters. Under current practice, FDA frequently sends letters to sponsors outlining deficiencies in the IND or requesting additional data or information. These "deficiency letters" may follow FDA review of the initial IND or a subsequent amendment, and the letters ae usually not accompanied by a "clinical hold" order. Accordingly, the regulatory status of such letters has been unclear, and some sponsors have apparently interpreted such letters as imposing regulatory "requirements." Under the proposal, the practice of sending deficiency letters to sponsors would be retained, but the regulatory status of these letters would be clarified. Specifically, the proposal states that such letters would be advisory only and would not require any action by sponsors, unless accompanied by a "clinical hold" order. FDA believes this provision should provide both sponsors and agency staff with clear notice of their rights and responsibilities regarding these communications.

2. Clinical holds. The proposal would define the standards for imposing a clinical hold during the different phases of the investigation. Standards for Phase 1 clinical holds would reflect FDA's focus on safety. Thus, a hold in Phase 1 could only be imposed if FDA found one of the following: (1) Human subjects would be exposed to an unreasonable and significant risk of illness or injury (without commensurate benefit to the subject); (2) the clinical investigators were not adequately qualified to conduct the investigation; (3) the investigator's brochure was misleading, erroneous, or materially incomplete; or (4) the IND did not contain enough information to assess the risks to human subjects. This narrowed scope of review would mean that FDA could not impose a clinical hold on a proposed Phase 1 study on concluding that the study was poorly designed or without a proper scientific rationale, unless those deficiencies had a direct bearing on safety. The purpose of this standard is to give sponsors greater freedom to design, revise, and implement early clinical research, as long as patients are not put at risk. Phase 1 studies are almost never considered pivotol for marketing approval, so FDA's responsibility is met at this stage once safety is established. The agency estimates that these narrowed clinical hold criteria would reduce the number of commercial IND's placed on clinical hold by approximately 30 percent. In contrast, during Phases 2 and 3, FDA would be able to stop or delay a study not only for safety, but also if the agency found that the study was "clearly deficient in design to meet its stated objective." The purpose of this different standard is to eliminate the wasteful expenditure of resources by sponsors in undertaking major clinical studies which, on their face, are simply incapable of producing data to support marketing approval.

The proposal would make clear FDA's authority to impose a clinical hold, not only prior to the beginning of a study, but at any time during the course of a clinical investigation. The proposal would also establish procedures to standardize the imposition of clinical holds. First, a clinical hold could only be imposed following a decision by the director of the division that is responsible for reviewing the IND, and the division director would be required to give the sponsor a written explanation of the basis for the hold within 15 days. Second, the clinical hold order would specify whether the study may be commenced or resumed as soon as stated deficiencies are corrected or whether the study's resumption must await the responsible division director notifying the sponsor that the study may proceed. Finally, as described below, if all investigations under an IND remain under a clinical hold order for 1 year or more, FDA could place the IND on inactive status.

In the clinical hold area, as elsewhere, the proposed regulation stresses the agency's commitment to seek the resolution of problems through informal discussions and meetings before resorting to formal regulatory mechanisms. Thus, the proposal provides that whenever FDA believes that a clinical hold should be imposed, it would attempt within the 30 days to discuss and resolve the matter with the sponsor before imposing the hold.

3. Termination of an IND. The proposed revisions of the "terminations" provisions should be viewed as an extension of the proposed revisions regarding "clinical holds." As described above, a clinical hold is an order not to commence or continue a clinical study. The order is viewed as a temporary measure until the problems affecting the specific studies placed on clinical hold can be resolved. In contrast, a termination order is viewed with a greater sense of finality. It is an order that affects all studies being conducted under an IND. In general, an IND would not be terminated if FDA felt there was any real prospect of continuing the investigation. Historically, the termination provision has been used only rarely, but FDA believes it is a necessary sanction to permit FDA to exercise its responsibilities in monitoring adequately the IND process.

The proposal would restate the general grounds for termination of an IND contained in the current regulations, but would tailor the grounds to the specific phases of the investigation. during Phase 1, terminations would be limited to issues involving the safety of subjects or substantial noncompliance with the regulations. In addition to these grounds, the proposal would permit the agency to terminate an IND during Phase 2 and Phase 3 investigations if the plan or protocol were not reasonable as a bona fide scientific plan for determining whether the drug is safe and effective, or if there exists convincing evidence that drug is ineffective for the purpose for which it is being investigated. These latter two criteria (i.e., "not reasonable as a bona fide scientific plan" and "convincing evidence that the drug is ineffective") are expected to apply only in rare cases.

The proposal would retain the current procedures for terminating an IND. Under those procedures, when FDA proposes to terminate an IND, it first notifies the sponsor in writing and gives the sponsor an opportunity to correct any deficiencies or explain why it believes termination of the IND is unwarranted. The sponsor then has 30 days to provide a written response or request a conference with FDA to respond to the agency's proposal. Lacking any response, FDA will terminate the IND. If the sponsor provides a response that the agency finds unacceptable, it will give the sponsor an opportunity for a regulatory hearing under 21 CFR Part 16 of FDA's administrative practice and procedure regulations on the question of whether the IND should be terminated. If FDA's proposed grounds for termination are sustained, the IND is terminated. Following termination, the sponsor is required to discontinue all ongoing studies and properly dispose of supplies of the investigational drug. FDA will, in general, only initiate termination proceedings after first attempting to resolve differences informally or, when appropriate, through the clinical hold procedures described above.

Finally, the proposal would retain the provision in the current regulations that permit FDA to terminate an IND immediately if the agency concludes that continuation of an investigation presents a significant danger to the public or patient health. Although this procedure has only rarely been utilized, FDA believes it represents a valuable procedural complement to the other mechanisms available for ending studies conducted under an IND.

4. Inactive status. FDA proposes to establish an inactive status: (1) For IND's for which no subjects have been entered into clinical studies for a period of 2 years or more; or (2) for which all investigations under the IND have been on clinical hold for 1 year or more. Under the proposal, FDA could place an IND on inactive status on the request of the sponsor or on the agency's own initiative. If FDA acts on its own initative, it would first give the sponsor notice of the proposed action and an opportunity to show that clinical investigations under the IND are being conducted and therefore that the IND should remain active. No clinical studies would be permitted under an inactive IND, but neither would the sponsor be required to comply with the annual reporting requirement applicable to IND's. Resumption of clinical studies would require the submission of amendments describing the proposed investigations. Finally, the agency could terminate an IND that remains inactive for 5 years or more.

This change is intended to help FDA keep track of IND's that are no longer considered active and would also benefit drug sponsors who now make nonsubstantive submissions in the form of annual reports to IND's for which no clinical studies are ongoing or planned. Sponsors believe these submissions are necessary to prevent their applications from being considered abandoned, which under current regulations would make all data and information in the IND available for public disclosure unless extraordinary circumstances exist (see current 21 CFR 312.5(b) and 314.14(f)). This proposal would eliminate the need to submit those reports for inactive IND's. FDA would presume an inactive IND to be in effect for purposes of the public disclosure of data and information in the IND.

The Pharmaceutical Manufacturers Association (PMA) Petitioned FDA to provide for an inactive status for IND's for which sponsors have discontinued clinical investigations. The PMA petition and this proposal are similar in that both would provide for a sponsor to request that an IND be considered inactive, both would eliminate the requirement for annual reports for inactive IND's, and both would protect trade secrets and confidential commercial and financial information from public disclosure.

FDA's proposal differs from the PMA petition, however, in several respects. First, under FDA's proposal, the agency could place an IND on inactive status without the sponsor's consent. The agency believes that this provision is necessary to keep government records current so that agency resources can appropriately be directed to IND's under which clinical investigations are actually being conducted. Second, under the proposal, to resume a study placed on inactive status, a sponsor would have to submit a protocol amendment and wait 30 days for FDA review, paralleling the procedure for initial IND's. FDA believes a 30-day pause before resumption of studies under an inactive IND is necessary because the general accumulation of scientific knowledge during the period of inactivity may affect the risk assessment of studies under the IND. Thus, a reassessment of the potential risks to subjects as well as the potential scientific usefulness of Phase 2 and Phase 3 studies is appropriate after a substantial period of inactivity.

5. Request for reconsideration or clarification. FDA recently adopted a new appeals process under which the sponsor of an NDA or IND can appeal a request or opinion from the division monitoring the application. This procedure, which is more fully described in a publicly available FDA Staff Manual Guide (NCDB 4820.5), was first outlined in the agency's proposal to revise its new drug and antibiotic application procedures (see 47 FR 46622, 46633-46634; October 19, 1982). Sponsors can use the procedure to appeal requests by agency employees for specific additional studies or information, requests to modify or delay a study, or unfavorable agency responses to sponsors' requests for waivers or special technical approaches to scientific problems. The procedure is marked by the sponsor's submission of a written request for reconsideration or clarification to the division responsible for reviewing the IND, the division's prompt response to the sponsor, and, if the division's response is not acceptable, automatic review of the issue by management of the National Center for Drugs and Biologics. FDA will attempt to issue a final decision within 60 days of a sponsor's initial request. The IND Rewrite would simply codify the applicability of this procedure to the IND process. This procedure has already been implemented for both NDA's and IND's through the staff manual guide noted above.


This section describes the use of meetings to improve communications between FDA and sponsors of clinical investigations and thus to facilitate the drug development and approval process. FDA proposes to expand and codify its current practices with respect to meetings with IND sponsors during the course of clinical investigations and in preparation for submission of a marketing application. Although FDA encourages frank and open communication with sponsors throughout the drug development and approval process, it has found that discussions held at the end of Phase 2 of an investigation ("end-of-Phase 2" meetings) and meetings held before submission of a marketing application ("pre-NDA" meetings) are most helpful in facilitating drug development and marketing.

Under the proposal, any IND sponsor may request and obtain an end-of-Phase 2 meeting with reviewing officials, with a special emphasis on new chemical entities under development. FDA's current practice is to encourage end-of-Phase 2 meetings for new chemical entities offering major or modest therapeutic gains over existing drugs. (Type IA and IB drugs under the agency's classification system). FDA's success with these meetings has led it to conclude that the development of other drugs, especially other new chemical entities, would most likely benefit from such early consultation as well. Although other new chemical entities are classified as providing little or no therapeutic gain over existing drugs (Type IC), these products may still provide improved therapeutic benefits for some patients who do not respond well to available therapy. In addition, increase availability of similar drugs should help increase competition in the marketplace.

The primary objective of the end-of-Phase 2 meeting would be for FDA and the sponsor to reach an agreement on the overall plan for Phase 3 clinical investigations and the objectives and designs of particular studies. Minutes of the meeting would reflect the agreements reached. Unless a significant scientific development requires otherwise, the sponsor would be assured that studies performed in accordance with the agreements would be acceptable to FDA (in design and objectives) for purposes of an application for marketing approval.

FDA believes that the kind of collaborative planning that takes place in such meetings is one of the best means available for facilitating drug development without compromising the safety or effectiveness of marketed drugs. One of the greatest sources of delay in the review of marketing applications is when sponsors submit reports from "pivotal" studies that are found to have significant flaws in design. In this situation, prolonged discussions frequently follow on whether the studies are "adequate and well-controlled" and whether the results are scientifically credible. Sponsors, understandably, are dismayed at the prospect of having to re-do major studies, but FDA cannot approve a drug for marketing that does not meet the statutory standards. FDA's experience is that questions of study design can almost always be worked out and agreed upon -- if the discussion takes place before the studies have been conducted. Accordingly, although increased availability of end-of-Phase 2 meetings will create more resource demands on the agency and on sponsors, FDA believes that resources spent increasing the efficiency of the drug development process are well worth spending.

The proposal would specifically provide that both sponsors and the agency may bring outside expert consultants to end-of-Phase 2 conferences. FDA has sought in the past to involve outside experts in end-of-Phase 2 meetings, where practicable, and the agency's experience has been that such expertise is often of considerable benefit in planning the design of Phase 3 studies. FDA, therefore, plans to continue this policy.

FDA also proposes to codify its procedures for "pre-NDA" meetings that are held to discuss new drug and antibiotic applications and biological product license applications. The agency has found these meetings to be useful in ensuring that marketing applications present data in a manner suitable for efficient agency review. "Pre-NDA" meetings are another mechanism whereby advance planning can facilitate the drug review process.

Applicability of IND Requirements to Marketed Drugs

This section describes the applicability of IND requirements to marketed drugs. Specifically, the proposal: (1) Would clarify that the act does not regulate the "practice of medicine" so that a licensed physician may prescribe an approved drug for an unapproved indication; (2) would also clarify that the act does regulate "clinical investigations" using marketed drugs; but (3) would create a new category of clinical investigations using marketed drugs that would no longer require an IND.

Current regulations are silent on the act's applicability to the use of approved drugs for unapproved uses. This issue has caused considerable confusion both inside and outside the agency. In the Federal Register of August 15, 1972 (37 FR 16503), the agency proposed a regulation that would have put forth the legal status of approved labeling; although no final rule has been issued on this subject, the agency has continued to apply the principles set forth in the preamble to the 1972 proposal. In FDA's Drug Bulletin of April 1982, the agency sought to clarify and reiterate the position that the act does not regulate the "practice of medicine." 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. The primary legal constraints in that situation are State laws on medical practice and products liability law. The IND Rewrite proposal would codify the agency's longstanding position that the regulations do not apply to the "practice of medicine," though the proposal does not purport to define with specificity such practice in terms of the act.

A different issue arises when physicians, usually affiliated with academic institutions, seek to conduct "clinical investigations" using marketed drugs, either to look for new uses or to use the drug as a research tool. FDA's position has been, and continues to be, that such investigations are subject to section 505(i) of the act (21 U.S.C. 355(i)). Thus, the agency has received numerous IND's each year covering these types of studies. FDA, however, has reevaluated the utility of reviewing these IND's and has concluded that the agency's review of certain categories of them, as described below, is not necessary to assure patient protection. Accordingly, FDA proposes to exempt from the IND requirements of Part 312 clinical investigations using marketed drugs that meet the following two criteria: (1) The investigation does not involve a route of administration or dosage level or use in a patient population that significantly increases the risk associated with use of the drug product; (2) the investigation is not intended to be reported to FDA as a well-controlled study in support of a new indication for use, nor intended to be used to support any other significant change in the advertising or labeling for the drug.

The first criterion embodies the view that, where a marketed drug is investigated in a way consistent with its approved labeling, FDA review is not needed to protect the safety of research subjects. The agency's approval of a new drug product for marketing is based on a substantial body of scientific information demonstrating the drug's safety in certain doses, routes of administration, and, sometimes, in certain patient populations. That information is conveyed to physicians through detailed professional labeling Administration of the drug under circumstances similar to those described in the approved labeling would not, therefore, be expected normally to produce any significant safety problems necessitating FDA review under the IND process.

FDA recognizes that the safety standard in the proposal contains an element of professional judgment in determining whether the conditions of the investigations "significantly increase" the risk associated with use of the drug. In applying this test, physicians should rely upon the contents of the approved labeling, reports in the medical literature, and their own experience in medical practice. For example, safety concerns necessitating submission of an IND would ordinarily arise where: (1) A drug is to be administered in a dosage many times greater than the labeled amount (new dosage level); (2) a drug approved for use in an oral dosage form is to be used in an intravaneous solution (new dosage form); or (3) an anticancer drug is to be used in patients with nonmalignant disease (new patient population). As an adjunct to these general criteria, FDA would also provide public notice when specific situations are identified that would require an IND.

The second criterion in the proposed regulation is aimed at helping ensure that investigations intended to be submitted to FDA for labeling or advertising changes are adequate in design to serve that purpose. This is the same reason the agency evaluates the design of Phase 2 and Phase 3 studies, and why FDA encourages close consultation with sponsors through participation in "End-of-Phase 2" conferences. As noted earlier, such review by FDA in advance adds considerable efficiency to the drug development process.

Persons conducting exempted studies would still be required to conform to all ethical principles applicable to the conduct of clinical investigations, including the statutory requirement for informed consent. Thus, a study's exemption under the proposal would be conditioned on a sponsor obtaining appropriate informed consent as well as the review and approval of a local IRB. Finally, the sponsor would still be prohibited from commercializing the investigation or promoting the product for its investigated use, except on specific approval by FDA.

The agency considered several alternatives to exempting such studies from IND submission requirements. For example, FDA considered requiring the submission to FDA of an "abbreviated IND" for this subset of uses. Such an IND would simply identify the investigational use the sponsor proposed to study and explain why the study met the criteria for exemption. This notification scheme would arguably permit FDA to play a more active role in regulating these investigations and would allow the agency, if a proposed study failed to meet the criteria for exemption, to stop it prior to its beginning. FDA is concerned, however, that such a system woud actually slow down the process because an abbreviated IND is unlikely to contain sufficient information to verify the criteria. Because reviewers are likely to ask for additional information and delay commencement of the studies, FDA does not consider this to be the best available option. The agency also considered expressly requiring IND's for these studies but, for the reasons stated above, FDA believes agency review is unnecessary to meet FDA's regulatory responsibilities.

The exempted group would include many, if not most, studies conducted by individual investigators in which marketed drugs are used as research tools or in exploratory therapeutic trials. The exemption would also apply to commercially sponsored studies if they fell into the exempted category. The agency would not accept IND's for exempt studies. FDA anticipates that there may be questions raised about the exempt status of certain kinds of investigations. FDA will provide assistance to interested persons who are uncertain whether a proposed study falls under the terms of this exemption.

FDA believes that the exemption for studies of marketed drugs should significantly reduce administrative burdens placed on research conducted by individual investigators without compromising patient safety. FDA should also benefit because studies that would be exempted under the proposal constitute a significant fraction (over 15 percent) of all IND's received by FDA in a given year. Thus, review time and other staff time that are now spent on these IND's would be saved and redirected toward commercial IND's for new products under development, FDA reviews, and other review functions.

Responsibilities of Sponsors and Investigators

FDA proposes to summarize in the regulations the requirements concerning the responsibilities of sponsors and investigators under an IND. These provisions are intended to supplement more detailed requirements contained in FDA's proposed regulations defining the obligations of sponsor and monitors (42 FR 49612; September 27, 1977; proposed Part 52) and of clinical investigators (43 FR 35210; August 8, 1978; proposed Part 54). As noted earlier in this preamble, the IND proposal has been prepared on the assumption that sponsor/monitor and clinical investigator regulations will be made final either before, or at the same time as, the final IND Rewrite. Responsibilities of sponsors and/or clinical investigators are also contained in current FDA regulations on: (1) Informed consent (21 CFR Part 50), (2) institutional review boards (21 CFR Part 56), and (3) good laboratory practice for conducting nonclinical laboratory studies (21 CFR Part 58). To the extent that apparent inconsistencies may develop between the IND regulations and the bioresearch monitoring regulations, the bioresearch regulations would control and the IND regulations would be appropriately clarified when published in final form.

The IND proposal would retain current requirements for a sponsor to (1) select qualified investigators, (2) provide them with the information they need to conduct an investigation properly, (3) ensure proper monitoring of the investigation, (4) ensure that the investigation is conducted in accordance with the general investigational plan and protocols contained in the IND, (5) maintain an effective IND with respect to the investigation, and (6) ensure that FDA and all participating investigators are promptly informed of significant new safety information with respect to the drug. The proposal would also retain current requirements for an investigator to ensure: (1) That the investigation is conducted according to the investigator's statement that was provided to the sponsor, the investigational plan, and applicable FDA regulations; (2) the rights, safety, and welfare of subjects under the investigator's care are protected; and (3) that the drugs used in the investigation are kept under careful control.

One of the primary responsibilities of sponsors under an IND is to select investigators and a monitor who are qualified by training and experience to investigate the drug and monitor the investigations. In this regard the sponsor is required to obtain from each clinical investigator an investigator's statement containing information about the investigator, the facilities where the study will be conducted, and commitments by the investigator with respect to his or her involvement in the study. The sponsor is also required to obtain a curriculum vitae for each investigator and an outline of the plan of investigation.

Unlike most FDA regulations, the current content requirements for an investigator statement are contained in Form FDA-1572 (for investigators involved in clinical pharmacology) and Form FDA-1573 (for investigators involved in clinical trials). The forms, which are reprinted in the regulations, identify in detail the kinds of information the investigator must provide to the sponsor and contain specific commitments the investigator makes with respect to the investigation. The agency proposes to combine the forms into a single investigator statement Form FDA-1572 and to revise the form to make it simply a checklist of the investigator's submission. The agency would provide guidelines to help investigators compile necessary information and provide it to the sponsor.

As described more fully above, the sponsor would be required, as now, to provide each investigator with an investigator brochure containing the information the investigator needs to conduct the investigation properly. In addition, the sponsor is under a continuing obligation to keep each participating investigator informed about new information about the drug, particularly with respect to safety information and the drug's safe use. The important safety information should be communicated orally to investigators with a written followup.

Under the proposal, a sponsor would continue to monitor an investigation by securing compliance of noncomplying investigators with the investigational plan and ending an investigator's participation if he or she refuses to comply with the plan. In addition, the sponsor must monitor the progress of investigations, evaluate safety and effectiveness information, and make reports to FDA regarding adverse drug experiences. All records of the investigation would of course be available for inspection by authorized Federal employees. If a sponsor determines that an adverse drug effect presents an unreasonable and significant risk to subjects, the sponsor must (1) discontinue the investigation and notify FDA and all investigators, (2) dispose of all stocks of the drug, and (3) provide FDA with a full report of the actions taken. Although current regulations require that the sponsors take this action promptly, the proposal would require a sponsor to discontinue an investigation as soon as possible, but in no event later than 5 working days after determining it should be discontinued.

Miscellaneous Provisions

1. Sale of investigational drugs. The proposal would retain, essentially unchanged, the current provisions prohibiting promotion and commercialization of investigational drugs. The proposal would also retain the current policy of not permitting sale of an investigational drug unless a full and satisfactory explanation is given why the sale should not be regarded as commercializing the drug. However, while this policy applies to sale of any investigational drug, the procedure for implementing the policy is different for investigational biological products than it is for investigational new drugs and antibiotics. For biologics, sale is not permitted until the sponsor is notified of FDA's approval of the sale. With respect to new drugs and antibiotics, there is no written current policy, and therefore the issue is subject to differing interpretations and applications, although in practice FDA usually does make affirmative decisions on whether to permit sale. The proposal would extend the procedure for sale of biological products to all investigational drugs so that no sale would be permitted except upon written approval of the Director, National Center for Drugs and Biologics. Centralizing these decisions in one individual would ensure uniform application of the agency's policy in this area.

2. Imports and exports. FDA proposes to codify its current policy on imports and exports of investigational new drugs. The Federal Food, Drug, and Cosmetic (the act) prohibits, under sections 301(d) and 505(a) (21 U.S.C. 331(d) and 355(a)), the introduction or delivery for introduction into interstate commerce of any new drug without an approved application under section 505(b) or an exemption under section 505(i). That prohibition extends to imports and exports of unapproved new drugs under the act's definition of the term "interstate commerce" (section 201(b)) (21 U.S.C. 321(b)). Thus, an unapproved new drug may not be imported into, or exported from, the United States unless it is subject to an exemption provided by FDA for an investigational new drug.

The proposal would simplify the agency's regulations governing imports by requiring an investigational new drug offered for importation into the United States to be subject to an effective IND and require the consignee within the United States to be either the sponsor of the IND or an investigator named in the IND. If the sponsor did not reside in the United States, the sponsor would be required to designate a domestic agent to act on behalf of the sponsor.

The proposal would retain the agency's current policies on exports of an investigational new drug by providing that such drug may be exported from the United States if an IND is in effect for it and each person to whom it is exported is an investigator named in the IND. The proposal would also modify the procedures under which FDA may authorize export of an investigational new drug that is not subject to an IND. Currently, requests for export under these procedures may only be processed through the Department of State.

The proposal would streamline this process by permitting these requests to be submitted directly to FDA by an authorized official of the importing foreign government. As an alternative procedure, the proposal would also permit requests to be submitted by an official of the company that proposes to export the drug. In either case, FDA will authorize shipment only if it is satisfied that the drug is appropriate for investigational use in human subjects, that the drug will be used for investigational purposes only, and that the drug may legally be used by the consignee in the importing country. The amount of information needed to satisfy these criteria will vary depending on the nature of the drug and FDA's prior familiarity with it.

FDA will coordinate export authorization with the appropriate governmental officials of the importing countries. As in the past, FDA will give considerable deference to letters by foreign governments specifically requesting shipment of the drug into their country. Where the request is made by the exporter, FDA will notify the foreign government of any export authorizations that are made.

Finally, the agency emphasizes that these procedures do not permit export of an investigational drug for commercial marketing or for use in routine medical practice.

3. Foreign clinical studies. The proposal would retain current policy on FDA's acceptance for IND purposes of foreign clinical studies not conducted under an IND. The regulation itself has been redrafted to provide greater clarity. FDA accepts well-designed and well-conducted investigational studies that are performed by qualified investigators in accordance with ethical principles acceptable to the world community. Studies meeting these criteria may be used to support clinical investigations in the United States as well as subsequent marketing approval. Marketing approval of a new drug or antibiotic drug based solely on foreign clinical data, however, would be governed by the agency's regulations on new drug applications in Part 314 (see the proposal in 47 FR 46622, 46642-46644, and 46655; October 19, 1982).

4. Public availability of data and information in an IND. FDA proposes no substantive change in the specific regulations applicable to the availability for public disclosure of data and information in an IND. (Although, as noted above, FDA does propose to treat an IND on inactive status as an active IND for purposes of the public disclosure of data and information.) The proposal would retain the current provisions which (i) prohibit FDA disclosure of the existence of an IND, (ii) apply to IND's the same provisions for public release of data and information in a new drug application (NDA) under Part 314, and (iii) specifically provide for the disclosure to an individual patient who received an investigational new drug of a copy of any adverse reaction report relating to the use of the drug in that individual.

5. Address for correspondence. FDA proposes a new section in the regulations to identify the appropriate agency offices to which IND's should be sent. The regulation would also require the outside wrapper of each IND submission to identify the submission (for example, as the original IND submission, protocol amendment, information amendment, adverse drug experience report, or annual report).

6. Guidelines. This section simply states that the agency prepares guidelines to help persons comply with the regulations. As stated in § 10.90(b), guidelinnes do not establish legal requirements but a person may be assured that by following an agency guideline his or her submission will be in a form acceptable to the agency. A person may also choose to use alternative procedures or standards even though they are not provided for in a guideline. A person who chooses to use alternative procedures or standards may discuss the matter in advance with FDA to prevent an expenditure of money and effort on work that may later be found unacceptable. The agency also proposes to establish and make publicly available a list of guidelines that apply to the IND regulations.

7. Use in laboratory research animals or in vitro tests. Although an IND is not required, the agency proposes to retain, with some editorial changes, its current regulations governing the proper labeling and control of investigational new drugs intended solely for use in laboratory research animals, or for tests in vitro.

Environmental Impact

The agency has determined under 21 CFR 25.24(b)(17) (proposed December 11, 1979; 44 FR 71742) that this proposed action is of a type that does not individually or cumulatively have a significant impact on the human environment. Therefore, neither an environmental assessment nor an environmental impact statement is required.

Paperwork Reduction Act of 1980

This proposed rule contains a number of information collection requirements. As required by section 3504(h) of the Paperwork Reduction Act of 1980, FDA has submitted a copy of this proposed rule to the Office of Management and Budget (OMB) for its review of these information collection requirements. Other organizations and individuals desiring to submit comments on the information collection requirements should direct them to FDA's Dockets Management Branch (address above) and to the Office of Information and Regulatory Affairs, OMB, New Executive Office Building (Rm. 3208), Washington, DC 20503, ATTN: Richard Eisenger.

FDA proposes that the final regulation be effective 60 days after its date of publication in the Federal Register.

List of Subjects in 21 CFR Part 312

Drugs, Medical research.

Therefore, under the Federal Food, Drug, and Cosmetic Act (secs. 501, 502, 503, 505, 506, 507, 701, 52 Stat. 1049-1053 as amended, 1055-1056 as amended, 55 Stat. 851, 59 Stat. 463 as amended (21 U.S.C. 351, 352, 353, 355, 356, 357, 371)) and the Public Health Service Act (sec. 351, 58 Stat. 702 as amended (42 U.S.C. 262)) and under 21 CFR 5.11 as revised (see 47 FR 16010; April 14, 1982), it is proposed that Part 312 be revised to read as follows:

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