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U.S. Department of Health and Human Services

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New Drug, Antibiotic, and Biologic Drug Product Regulations: part 3

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

Clinical Holds and Requests for Modification (ß 312.42)

104. Several comments supported codifying clinical hold procedures in the regulations. However, a number of comments objected to the proposed criteria for imposing a clinical hold and also to the proposed procedures under which clinical holds would be implemented. These specific objections are discussed in detail below.

105. One comment suggested that the standard for a clinical hold based on a finding that the investigator brochure is "misleading, erroneous, or materially incomplete" (proposed ß 312.42(b)(1)(iii)) be reworded to require a finding that "the investigator brochure is materially misleading, erroneous, or incomplete."

The agency believes that any information in an investigator brochure that is "misleading" or "erroneous" is presumptively "material" in terms of significance, and therefore the explicit qualifier suggested by the comment is unnecessary. However, the "incompleteness" of an investigator brochure may be of minimal significance and, therefore, an insufficient basis for imposing a hold without a further finding that the deficiency is material with respect to the function of the brochure. Therefore, the agency concludes that this provision should be retained as proposed.

106. Under proposed ß 312.42(b)(2)(ii), a clinical hold may be imposed on a Phase 2 or 3 study where "the plan or protocol for investigation is clearly deficient in design to meet its stated objectives." One comment objected to the omission of this grounds for clinical hold from the criteria applicable to Phase 1 studies. The comment contended that the safety of a study cannot be evaluated without a critical inquiry into its scientific merits and concluded that it would be difficult to assure subject safety absent a carefully drawn research protocol. In contrast, several comments objected to the retention of this criteria for studies in any phase. These comments contended that FDA's mandate does not extend to stopping a clinical investigation based solely on the agency's views of the scientific deficiencies of the investigation. Finally, one comment contended that it is inappropriate to interrupt the course of a planned clinical investigation, which may involve the investment of significant amounts of time and financial resources, unless there is a well-founded concern for the safety of study subjects.

As discussed in paragraph 31 above, FDA has both the authority and responsibility to establish conditions, including a review of study design, to ensure that a study that is conducted to develop evidence of a drug's safety and effectiveness is designed to achieve its objectives. Review of study design may prevent unnecessary mistakes, may assure the adequacy of a study, and may otherwise increase the likelihood that completion of the study will generate the kind of data needed to make a final determination about the drug's safety and effectiveness.

FDA is sensitive to the potential costs and disruptiveness of a clinical hold, and will not impose a hold because of design problems unless it finds the study to be "clearly deficient in design to meet its stated objectives." This intentionally places a substantial burden on FDA to show that a design defect is critical with respect to the purposes of the study. The criterion is a guarantee that FDA will not casually impose clinical holds for trivial or easily correctable design problems. When this standard is met, however, imposing a clinical hold will preclude exposure of human subjects to risks in an investigation that FDA concludes would ultimately have no scientific or regulatory value. It will also save substantial drug development time, in the long run, by preventing continuation of a study that could not possibly support marketing approval.

The agency discussed previously its reasons for "narrowing" the focus of Phase 1 review to matters of subject safety alone. As noted in that discussion, the narrow focus reflects a desire to remove impediments to innovation at this early stage of drug discovery. While the narrower focus may mean that some poorly designed studies will be conducted that would otherwise have been placed on clinical hold, FDA believes the likelihood of this happening is slight, and that the safety considerations arising from such an occurrence are not significant in that FDA will still have reviewed the study for subject safety generally. On balance, therefore, FDA believes it appropriate to defer to sponsors on matters of Phase 1 study design.

FDA notes that a number of potentially safety-related criteria are listed as bases for terminations, but are not listed as bases for clinical holds. Thus, for example, while ß 312.44(b)(1)(iii) authorizes FDA to terminate a study on finding that the methods, facilities, and controls used for manufacturing the drug "are inadequate to establish and maintain appropriate standards of identity, strength, quality, and purity as needed for subject safety," this factor is not listed among the bases for clinical holds under ß 312.42(b). The omission of such specific criteria from the listed criteria for clinical holds is not intended to suggest that they would not be a basis for a clinical hold, if the particular deficiency posed an unreasonable and significant risk of illness and injury to human subjects. To the contrary, FDA would view the deficiency to be a proper basis for a clinical hold under the provisions of ß 312.42(b) (1)(i) and (2)(i).

107. Several comments urged the creation of additional procedural safeguards and a better appeals mechanism relating to the imposition of clinical holds. One comment claimed that the promise in proposed ß 312.42(c) that FDA will, before issuing the clinical hold order, attempt to discuss and satisfactorily resolve the matter with the sponsor, can be interpreted to mean anything from a casual attempt at telephone communication to a requirement for a formal meeting. Given the potential significance of a clinical hold for a sponsor's drug development plans, the comment urged that the sponsor be given 48-hour notice of a hold imposed for safety reasons and longer notice for holds imposed for nonsafety reasons. In either case, the comment urged that a sponsor be given the right to meet or talk by telephone with the responsible reviewing official before the hold goes into effect. Another comment, while conceding that it may be appropriate to impose an immediately effective hold where the safety and rights of human subjects are at stake, recommended that in all other cases a clinical hold not become effective until the sponsor has exhausted all appeals rights including, ultimately, the right to a regulatory hearing before the agency under Part 16.

The procedures governing the imposition of clinical holds are tailored to the needs of a regulatory process that gives reviewers little time to decide whether proposed studies should begin or ongoing studies continue: studies under an IND may begin 30 days after FDA is given notice by the sponsor, and these same studies, once begun, may be significantly changed in direction or scope under protocol amendments without any advance notice to FDA. The relative informality and flexibility of the clinical hold procedures, criticized by the comments, are thus, in the agency's view, dictated by the nature of the process.

While the agency is committed to making a good faith attempt to discuss and satisfactorily resolve deficiencies in an IND before considering the need to impose a clinical hold, it does not believe that it is obligated to establish procedural safeguards of the types suggested by the comments. The nature of the agency contact with sponsors will depend on the imminence of hazard to human subjects, on the availability of key agency and sponsor personnel, and on a variety of other factors.

For similar reasons, FDA believes that it cannot in the abstract specify the extent of notice that can appropriately be given a sponsor before making a hold effective.

108. Several comments urged that the clinical hold provisions make clear the agency's obligation to explain the reasons for a hold when it is imposed.

Agency practice has been to explain briefly the basis for a clinical hold when it is imposed, and to follow up this initial communication with a written explanation of the agency's action. FDA has revised the final rule to reflect this practice.

109. One comment urged that the procedures governing the resumption of a clinical investigation placed on clinical hold be revised to permit the order rescinding the hold to be made by or on behalf of the Division Director. (The proposal provided that such rescission order could only be made by the Division Director.) The comment also recommended that the clinical hold procedures specifically permit FDA to authorize resumption of a study by telephone or by other means of rapid communication.

FDA agrees with these suggestions and has revised the regulation accordingly.

110. Proposed ß 312.45(a) would give the agency the authority to convert an IND to inactive status if all clinical investigations covered by the IND remain on hold for 1 year or more. Several comments recommended revising this to state that any IND on clinical hold will be placed on inactive status only in the event that the clinical hold is no longer contested by the sponsor of the investigation.

FDA believes that as a matter of administrative efficiency -- to "clear the books" -- it is appropriate that the agency retain the authority to place an IND on inactive status if all studies under the IND have been on clinical hold for at least 1 year. The 1 year between imposition of the clinical hold and transfer to inactive status should generally be more than sufficient time to raise and attempt resolution of the deficiencies that prompted the agency to place the studies on clinical hold.

It should be noted that inactivation of a study under the circumstances described by the comment is not automatic. Under ß 312.45(a), if FDA seeks to place a study on inactive status, it must give the sponsor notice of the proposed action and an opportunity to respond as to why the IND should remain active. The fact that issues surrounding a clinical hold order remain under dispute may be a legitimate basis for a sponsor request to continue an investigation as "active."

111. One comment urged that FDA elaborate on the scope of a clinical hold. The comment claimed that it would not be reasonable to halt a study with six investigators when only one had been found to be inadequately qualified to participate in it.

If FDA finds that only one of several investigators named in an IND is not qualified to conduct the investigation, the clinical hold order would ordinarily be limited to the study conducted by that investigator. This concept is noted in ß 312.42(a) of this final rule, which states that the clinical hold order may apply to one or more of the investigations covered by an IND.

To ensure that the sponsor is informed of the precise limits of the clinical hold order, FDA has revised the final rule to require the Division Director (or the Director's designee) to specify in the initial communication to the sponsor the studies to which the hold applies.

As proposed, the clinical hold procedures (ß 312.42) gave FDA 15 days from the date of imposition of a clinical hold to provide the sponsor with a written explanation of the basis for the action. On reconsideration, FDA concludes that 15 days may not allow the agency sufficient time to provide the sponsor with a complete written explanation of the basis for its action. Accordingly, ß 312.42(d) has been revised to require the agency to provide a written explanation "As soon as possible, and in any event within 30 days of the imposition of the clinical hold."

Termination (ß 312.44)

112. Under proposed ß 312.44(b)(1)(iv), FDA would be able to terminate an investigation on a finding that clinical investigations are not being conducted in accordance with the plan or protocol submitted. One comment suggested that minor departures from these protocols and plans should not be the basis for terminating an IND, and recommended conditioning such actions on a finding that the investigations are being conducted in a manner "substantially different" from the plan or protocol submitted.

The agency agrees and has revised the final rule accordingly.

113. Under ß 312.44(b)(2)(ii), FDA may terminate a Phase 2 or 3 investigation if it finds that the investigational plan is not reasonable as a bona fide plan to determine whether or not the drug is safe and effective for use. One comment urged that this standard not be used to prevent or preclude pilot studies or exploratory research that might not, taken alone, be satisfactory to establish safety and effectiveness. Another comment objected to the standard on the grounds that it would permit FDA to prevent clinical investigations "merely on the basis of the agency's opinion as to the value of what FDA anticipates will be their results." This comment urged that a determination under this provision require, in addition, a finding that a continuation of the investigation would subject human subjects to an unreasonable and significant risk of illness or injury.

Proposed ß 312.44(b)(2)(ii) was intended to give FDA grounds for terminating an investigation that was not directed, overall, at evaluating safety and effectiveness of the drug. The criterion would not provide grounds for terminating an investigation simply because one or another study was considered inadequate. A bona fide investigational approach may well include pilot studies, open safety studies, and other studies that would not, by themselves, establish a drug's safety and effectiveness.

114. As proposed, ß 312.44(b)(2)(iii) would authorize FDA to terminate a study on finding that "There is convincing evidence that the drug is effective for the purpose for which it is being investigated." This provision has been corrected in the final rule to read "There is convincing evidence that the drug is not effective for the purpose for which it is being investigated."

115. Under proposed ß 312.44(d), FDA could immediately terminate an IND on finding that the continuation would present a significant danger to the public health. One comment suggested revising this language to condition an immediate termination on a finding of an "unreasonable, direct, and substantial danger to the health of individuals."

The agency believes that the immediate termination procedure should focus more directly on the health of individuals and therefore has revised ß 312.44(d) in this final rule to condition such terminations on a finding of "an immediate and substantial danger to the health of individuals."

Inactive Status (ß 312.45)

116. Several comments objected to the provisions under which FDA could terminate an IND that has been on inactive status for 5 years. One comment suggested that the prospect of termination eliminates the principal value of inactive status to sponsors and will discourage them from seeking it.

FDA believes that the provision for terminating IND's that have been on inactive status for 5 years or more is reasonable to permit the agency to focus its resources upon clinical investigations that are actually being conducted and to keep government records current. Moreover, the termination procedure in ß 312.44 is not automatic: under the procedure, the sponsor has an opportunity to respond to an agency proposal to terminate an IND with an explanation of why it should continue on inactive status. Finally, FDA does not believe sponsors will be adversely affected by termination of an IND that has long been inactive, both because the termination of an IND does not preclude a sponsor from proposing new studies in the future under another IND, and because the agency has, in the NDA Rewrite final rule, amended ß 314.430 governing the disclosure of information in a terminated IND to assure the continued confidentiality of trade secret, confidential commercial, and financial information.

Meetings (ß 312.47)

117. Comments agreed with FDA's view that meetings between a sponsor and the agency are frequently useful in resolving questions and issues raised during the course of a clinical investigation. Noting, however, that under current practice there is sometimes a delay of several months in scheduling meetings, comments urged that meetings be held promptly after a request is submitted. Also, one comment urged that advance written information in support of a meeting should be kept to a minimum, and that requests for such information should balance the sponsor's costs in preparing the material against the expected results.

The agency agrees that sponsors should not be asked to prepare and submit more information in advance of a meeting than is needed to ensure a productive exchange of views at the meeting. This principle does not mean, however, that the amount of advance information can or should always be kept to a bare minimum. To the contrary, the successful conclusion of many meetings may demand a considerable investment of time and resources in developing background information. This is especially true for meetings such as an end-of-Phase 2 conference, whose primary purpose is to evaluate the adequacy and significance of data developed by the sponsor.

FDA also agrees that meetings are most useful if held promptly after requests for them are submitted and after the necessary advance information has been submitted. The agency will make every effort to schedule such meetings as early as is feasible and to the extent that agency resources permit.

118. One comment requested that the final regulation specifically authorize and encourage "pre-IND" meetings, i.e., meetings between sponsors and FDA prior to the actual submission of an IND. The comment contended that such meetings are often needed to answer questions about technical requirements for an IND and may be essential for planning a clinical study.

The final rule identifies two specific points during the drug development process when meetings between a sponsor and FDA can be particularly useful and productive: (a) at the end of Phase 2; and (b) at the end of Phase 3, but prior to submission of a marketing application. FDA has codified those two meetings because they are exceedingly valuable to both agency reviewers and sponsors and because they are useful for a vast majority of IND's. Although "pre-IND" meetings may be useful for a particular case, FDA does not believe their utility will be so generalized as to warrant separate codification. The agency notes, however, that individual sponsors may request such meetings under ß 312.47(a) as the need may arise. FDA encourages such meetings to the extent that they aid in the evaluation of the drug and associated scientific issues.

119. Two comments contended that many NDA approvals are delayed by questions and concerns about manufacturing and control information. The comments recommended that FDA expand the list of subjects for "pre-NDA" meetings to include these kinds of technical issues.

FDA has no objection to sponsors raising for discussion at "pre-NDA" meetings technical problems relating to the chemistry, manufacturing, and control segment of the marketing application. FDA has revised the final rule to make clearer FDA's willingness to discuss these and other technical matters at such meetings.

Sponsors should also be reminded that the NDA final rule (ß 314.50(d)(1)(iv)) has established a procedure specifically authorizing the early submission and review of chemistry, manufacturing, and control information. Under this procedure, applicants may submit the chemistry, manufacturing, and control part of the marketing application 90 to 120 days in advance of the rest of the application. This procedure may frequently be superior to the "pre-NDA" meeting as a means of resolving the highly technical issues involved.

Dispute Resolution (312.48)

120. The IND Rewrite proposal contained a new formal appeals process for resolving disputes between FDA and sponsors. The appeals process was first outlined in the proposed NDA Rewrite and was more fully described in a publicly available FDA Staff Manual Guide 4820.5. Under that process, drug firms could 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 became available for use for both IND's and NDA's through issuance of the Staff Manual Guide noted above.

FDA first received adverse comments on this appeals procedure in the NDA Rewrite rulemaking, and these objections were reiterated in the IND Rewrite rulemaking. The comments suggested that the appeals process was, on the one hand, too complex for resolving minor administrative and procedural disputes, and, on the other hand, too inflexible to handle efficiently major scientific and medical disputes, which, according to the comments, should be referable as a matter of right to one of FDA's standing advisory committees.

FDA in general agreed with these observations about the shortcomings of the formal appeals mechanism. The agency's view of the deficiencies of the process was underlined by the fact that the appeals process was rarely used successfully during the more than 1 year it was effective. For these reasons, in issuing the NDA Rewrite final rule, FDA abandoned the formal process in favor of a more comprehensive approach to dispute resolution. This approach entailed establishing a range of procedural alternatives, each tailored to a specific kind of dispute, and then referring sponsors to whichever of the available procedural mechanisms was best suited to the particular matter under discussion. FDA now concludes that a comparable dispute resolution mechanism should be adopted for the IND process and ß 312.48 of this final rule has been revised accordingly.

There are three chief components of this new appeals process: (1) The use of an ombudsman to deal with administrative and procedural problems; (2) the codification of an informal process for resolving scientific disputes; and (3) the increased use of outside scientific advisers, when feasible and appropriate.

First, the final rule encourages sponsors to seek the help of a designated "ombudsman" to resolve administrative and procedural disputes arising during the course of an investigation. The function of the ombudsman is to investigate the facts and to facilitate a timely and equitable resolution of the issue. Appropriate issues to raise with the ombudsman include resolving difficulties in scheduling meetings, obtaining timely replies to inquires, and obtaining timely completion of pending reviews. Details on the role of the ombudsman are set forth in a publicly available FDA Staff Manual Guide 4820.7. (Other elements of the new dispute resolution mechanism are described in the revised FDA Staff Manual Guide, "Appeals Process: Resolving Scientific Disputes Over Drug Applications" (CDB 4820.5).)

The second component of the dispute resolution mechanism emphasizes the value of informal communications between sponsors and DFA as the best means of resolving important technical and scientific issues quickly and amicably. If scientific or medical disputes arise, the final rule provides that applicants should first discuss the matter directly with the responsible reviewing officials. If these discussions do not resolve the matter, applicants may request an informal meeting with the appropriate reviewers and supervisors. Alternatively, disputes may be appropriately discussed at a more formal, "pre-NDA" or "end-of-Phase 2" meeting.

Finally, the new procedures recognize the advantages of utilizing the advice of outside scientific experts in the dispute resolution process, where it is practicable and feasible to do so. Section 312.48(c)(3) of the final rule therefore provides that, in requesting a meeting with the agency to resolve a scientific or medical dispute, sponsors may suggest that FDA seek the advice of outside experts, in which case FDA may, in its discretion, invite to the meeting one or more of its advisory committee members or other agency consultants, as designated by the agency. The applicant is also free to bring its own consultants.

Section 312.48(c)(3) of the final rule also provides that, for major scientific and medical policy issues not resolved by informal meetings, FDA may on its own initiative refers the matter to one of its standing advisory committees for its consideration and recommendations. Although ß 312.48 does not provide the right to advisory committee review requested by some comments, FDA does intend to integrate outside experts more fully into the IND portion of the drug approval process. FDA believes that providing applicants a right to advisory committee review for any disputed issue is impractical from the standpoint of the potential number of controversial issues and the relatively infrequent number of advisory committee meetings. Moreover, utilization of outside advisory committees is committed to the discretion of the agency, and not properly delegated to members of the public. Nonetheless, by involving individual advisory committee members or consultants in the dispute resolution process on a more informal basis, FDA believes that the goal of interacting with the scientific community can be achieved without the delays, resouces, and scheduling problems associated with full advisory committee involvement.

Responsibilities of Clinical Investigators and Sponsors

122. As noted in the introduction, the proposed IND Rewrite was issued on the assumption that proposed Part 52 governing the obligations of sponsors and monitors and proposed Part 54 governing the obligation of clinical investigations would be adopted as final rules before, or at the same time as, this final rule. As noted, because those proposals have not been made final, FDA has retained in new Part 312 most of those obligations of investigators and sponsors in existing Part 312 that were to be transferred to in Parts 52 and 54. While in general, the obligations of sponsors, monitors, and clinical investigators are the same as those set forth in the existing IND regulations, in three areas, FDA is adopting minor changes that relate to provisions first proposed in the September 27, 1977, and August 8, 1978, proposed rules. These areas are: (a) Obligations assigned to contract research organizations; (b) disclosure of study audits conducted by the sponsor; and (c) the standard for disqualifying clinical investigators. These changes apply to investigational new animal drugs as well as new drugs for human use. They will be discussed in turn.

Contract Research Organizations

The agency is adopting certain provisions relating to contract research organizations based on proposed Part 52 (see proposed ß 52.5 at 42 FR 49623). A contract research organization is an independent organization that contracts with a sponsor of a clinical investigation to assume one or more obligations of the sponsor for the conduct of a clinical study. Use of contract research organizations has grown increasingly common in the United States. Adoption of these provisions represents a regulatory acknowledgment of this common practice.

The final rule: (1) Defines the term "contract research organization" (ß 312.3); (2) authorizes a sponsor to transfer any or all of the sponsor's obligations for the conduct of the clinical study to a contract research organization (ß 312.52(a)); (3) requires that the sponsor keep a written statement that outlines what obligations have been so transferred (ß 312.52(a)); and (4) describes the responsibilities of both the sponsor and the contract research organization, once having made such a transfer (ß 312.52 (a) and (b)). In addition, the final rule requires that the sponsor disclose in the IND whether any obligations have been transferred to a contract research organization, and, if so, that the sponsor list the obligations transferred. Finally, 21 CFR Part 314 is amended by adding new ß 314.50(d)(5)(x) to conform Part 314 to Part 312 with respect to contract research organizations.

The agency is adopting identical changes concerning contract research organizations in the investigational new animal drug (INAD) and new animal drug application (NADA) regulations.

A number of persons commented on the provisions pertaining to contract research oganizations when proposed Part 52 was issued. A summary of these comments and the agency's responses follow:

i. Several comments objected to the proposed requirements that obligations transferred to a contract research organization be specifically described, stating that a general transfer of all obligations should be allowed. These comments argued that because a sponsor is often unable to describe specifically each aspect of an obligation transferred before a study begins, it would be unrealistic to have those obligations that were not specifically described considered not to have been transferred at all.

FDA agrees that when a sponsor transfers all its responsibility for the conduct of a study, a statement of this general transfer of obligations should be allowed. The regulation has been revised accordingly. Therefore, when a sponsor transfers all obligations regarding the conduct of a clinical study to a contract research organization, the written statement may indicate that a general transfer has been made and need not enumerate the specific obligations transferred. However, in other cases, i.e., when less than all obligations are transferred, specificity in describing the transfer of obligations of a sponsor to a contract research organization is essential. In such cases, because a contract research organization is required to comply with the specific regulation applicable to any obligations it assumes for a sponsor, a sponsor must be able to set forth specifically each obligation that it expects the contract research organization to assume. The specification of the transferred obligations ensures that the contract research organization knows exactly what its obligations are before beginning a clinical investigation.

While a contract research organization may assume any or all of the sponsor's responsibility for the conduct of a study, it should be emphasized that the transfer does not relieve the sponsor from responsibility for the quality and integrity of any data derived from the investigation that are submitted to FDA.

ii. One comment requested an explicit statement to the effect that if a contract research organization is subjected to administrative action, the sponsor will not also be subject to this same administrative action if the sponsor complied with all applicable requirements governing the transfer of obligations.

The agency considers such explicit language unnecessary because the written statement identifying what obligations have been transferred will clearly fix the individual sponsor/contract research organization responsibilities. The agency may, therefore, initiate action based upon failure to comply with a regulatory obligation against only the party that has assumed responsibility for, but has not fulfilled, a particular obligation. The agency does not contemplate taking administrative action against a sponsor based solely upon the failure of a contract research organization to perform obligations that have been transferred to it by the sponsor. Sponsors should, therefore, take special care that transferred obligations are described clearly.

iii. One comment asked whether the name of the specific monitor within the contract research organization must be submitted to FDA, along with the name and address of the contract research organization.

The name of the monitor is required to be submitted. See ß 312.23(a)(1)vi) in this final rule.

Disclosure of Study Audits

Proposed Part 52 would have required that a monitor designated by the sponsor visit investigators periodically to, among other things, audit case report forms against individual subject records to assure the accuracy and completeness of the forms (see proposed ß 52.20(b) at 42 FR 49623, 49624). While the agency believes that such audits are extremely important, it has concluded that it should not compel such reviews by regulation.

Rather, the agency has concluded that it should only require that a sponsor, in its submission to the agency of a report of a clinical investigation, state whether the investigator's subject records were audited or reviewed in the course of monitoring a clinical investigation. The agency is adding new ß 314.50(a)(5)(xi) as a necessary conforming amendment to Part 314. The agency is also making an appropriate change to the NADA regulations by adding a new ß 514.1(b)(8)(ix).

As noted above, although FDA has not made the auditing of subject records mandatory in this final rule, FDA concludes that it should know whether such a review has, in fact, been conducted. Knowledge that a sponsor has audited subject records may affect the detail with which FDA conducts its own inspection of the supporting data. Morever, in those cases where an agency inspection is not conducted, e.g., in some foreign countries, whether the sponsor has audited the study is an important factor to be considered in evaluating the study. Thus, FDA believes that disclosure of which studies have been audited will significantly improve the efficiency of the agency's clinical investigator inspection program while representing a minimal additional burden on study sponsors.

Disqualification of Clinical Investigators

123. The agency is retaining all the current standards and procedures governing disqualification of clinical investigators, with only one modification. The existing regulations permit the agency to disqualify an investigator on a finding that "the investigator has repeatedly or deliberately failed to comply with the conditions of the exempting regulations * * * or has repeatedly or deliberately submitted false information to the sponsor of an investigation and has failed to furnish adequate assurance that the conditions of the exemption will be met * * * " (ß 312.1 (c)(2)) (emphasis added). This final rule deletes the provision allowing a clinical investigator to avoid disqualifications through the submisson of "adequate assurances" of future compliance.

This action is based on proposed Part 54, which would have similarly limited the grounds for disqualification (see proposed Part 54, Subpart K, at 43 FR 35227). Under the 1978 proposal, no provision for the submission of assurances was included whereby an investigator could avoid disqualification if the other criteria for disqualification were met. FDA received no comments on this approach.

Based on its more than 20 years of experience with the clinical investigator disqualification procedures, the agency believes that the disqualification procedure will operate more effectively and efficiently if it is limited to objective questions about whether there have been violations of FDA's regulations. The more subjective question of when assurances of future compliance are adequate should be addressed independently of the hearing proceeding. Under the procedures adopted in this final rule, assurances may be presented at several stages of a disqualification proceeding: (1) When the agency initiates a disqualification action, (2) at the informal conference with the Center for Drugs and Biologics offered before any hearing, (3) during the negotiations on a consent agreement, and (4) after an investigator has been disqualified, as part of the efforts to obtain reinstatement. See ß 312.70 of this rule and the guidelines for reinstating the eligibility of clinical investigators to receive investigational articles, announced in the Federal Register of November 19, 1982 (47 FR 52228). Deletion of the submission of "adequate assurances" as a ground for avoiding disqualification will affect only proceedings for which a notice of opportunity for hearing is issued after the effective date of this rule.

FDA acknowledges that proposed Part 54 contained additional criteria for clinical investigator disqualification that are not being adopted in this final rule. These criteria related to the significance of the regulatory violation; i.e., whether the violations adversely affected the validity of the study or the rights or safety of test subjects. The 1978 proposal also provided that the disqualification sanction would not be used if other lesser regulatory actions would be adequate.

FDA believes that these criteria are so subjective as to make them extremely difficult to apply fairly in disqualification proceedings. The agency emphasizes, however, that the agency retains discretion on whether to initiate an action to disqualify a clinical investigator, and that the Commissioner will exercise that discretion and not disqualify an investigator if the violations are insignificant, or if lesser sanctions would be adequate.

124. Several comments received on proposed Part 54 questioned FDA's authority under the act to disqualify clinical investigators. Because these coments are relevant to the disqualification procedures that are described both in the existing regulation and in this final rule, they are summarized and discussed below. One comment argued that none of the sections of the act that FDA cited in the preamble to proposed Part 54, that is, sections 701(a), 505(i), and 507(d), explicitly provides for or even suggests disqualification. Two comments suggested that the unsuccessful efforts of Congress to enact legislation to grant the agency explicit authority to disqualify investigators implies that FDA lacks authority now to disqualify clinical investigators.

FDA believes that the agency clearly has authority to disqualify clinical investigators that violate FDA's regulations. A thorough discussion of this authority is found in the preamble to proposed Part 52 (43 FR 35221). FDA believes it is unnecessary to restate that discussion here. In sum, although the concept of disqualification is not explicitly mentioned in the act, the Supreme Court in Weinbergerv. Bentex Pharmaceuticals, Inc., 412 U.S. 645, 653 (1973) has recognized that FDA has authority that "is implicit in the regulatory scheme, not spelled out in haec verba" in the statute. As stated in Morrow v. Clayton, 326 F.2d 36, 44 (10th Cir. 1963):

[I]t is a fundamental principle of administrative law that the powers of an administrative agency are not limited to those expressly granted by the [ir] statutes, but include, also, all of the powers that may be fairly implied therefrom.

See Mourning v. Family Publications Service Inc., 411 U.S. 356 (1973) and National Petroleum Refiners Association v. FTC, 482, F.2d 672 (D.C. Cir. 1973). See also Weinberger v. Hynson, Westcott & Dunning, Inc., 412 U.S. 609 (1973); National Nutritional Foods Ass'n v. Weinberger, 512 F.2d 688, cert denied, 423 U.S. 827 (1975); United States v. Nova Scotia Food Products Corp., 568 F.2d 246-248 (2d Cir. 1977); American Frozen Food Institute v. Mathews 413 F. Supp. 548 (D.D.C. 1976) aff'd per curiam, 555 F. 2d 1059 (D.C. Cir. 1977); National Confectioners Ass'n v. Califano, 569 F.2d 690 (D.C. Cir. 1978); National Ass'n of Pharmaceutical Manufacturers v. FDA, 637 F.2d 877 (2d Cir. 1981).

Congressional inaction on proposed legislation that would state expressly an agency's authority to act does not support an inference that the agency lacks implicit authority to act under existing legislation. Red Lion Broadcasting Co. v. FCC, 395 U.S. 367, 381-382 n. 11 (1969). See also Leist v. Simplot, 638 F.2d 283, 318 (2d Cir. 1980), affirmed sub nom. Merrill Lynch, Pierce, Fenner & Smith v. Curran, 456 U.S. 353 (1982).

The agency concludes it has ample authority for the promulgation of procedures that govern the disqualification of an investigator of any FDA-regulated product who fails to carry out the requirements of these regulations.

125. The statement of clinical investigator responsibilities in this final rule is essentially the same as that contained in former ß 312.1 with the exceptions noted above. However, in the former regulation, as noted below, clinical investigator responsibilities were described in forms (Forms FD-1572 and FD-1573) that were signed by the investigator and obtained by the sponsor. While FDA believes that the forms adequately stated the investigator's responsibilities, the agency has concluded that a clearer approach is to set forth investigator responsibilities in the body of the text (see ß 312.60 et seq.).

126. FDA recognizes that some may view the decision by the Ninth Circuit Court of Appeals in the United States v. Smith, 740 F.2d 734 (9th Cir. 1984), which involved criminal charges against a clinical investigator, as raising questions about the agency's authority to promulgate enforceable regulations on the obligations of clinical investigators. After considering the court's opinion, FDA concludes that it has ample authority to issue such regulations. The agency points out that the court in Smith noted that under the regulation then in effect (former 21 CFR 312.1(c)), FDA could conduct an administrative hearing to revoke an investigator's entitlement to work with investigational new drugs.

Moreover, FDA believes that both the language of the statute and its legislative history demonstrate that issuance of this final rule is within the scope of authority delegated to the Secretary by Congress under sections 505(i) and 701(a) of the act (21 U.S.C. 355(i) and 371(a)). The statutory language makes clear Congress' intent that clinical investigators be subject to section 505(i) of the act, and that they be required to maintain records. The stated purpose of section 505(i) is to make investigational drugs available "solely for investigational use by experts qualified by scientific training and experience to investigate the safety and effectiveness of drugs." The experts referred to are, in fact, the clinical investigators covered by this final rule, who perform the tests for which the investigational exemption exists. Section 505(i) of the act states that the "Secretary shall promulgate [exempting] regulations * * * [for] drugs intended soley for investigational use by experts * * *." Thus, it does not contain any restriction on who may be subject to such regulations.

The plain meaning of the statute demonstrates that Congress intended the Secretary to have the discretionary authority to impose conditions on investigational drug use in addition to those conditions specified as examples in the statute. The Secretary was explicitly authorized by Congress to impose "other conditions relating to the protection of the public health" by this part of the statute. 21 U.S.C. 355(i).

The legislative history of section 505(i) of the act also demonstrates that Congress intended the Secretary to require clinical investigators to maintain investigational drug study records. Before passage of the Drug Amendments of 1962 (Pub. L. 87-781), Congress was aware that FDA had proposed regulations on new drugs for investigational use, including the requirement that investigators prepare and maintain records. See 27 FR 7990 (1962); 108 Congressional Record 17308 (1962) (remarks of Senator Eastland). The regulations were promulgated in 1963 (28 FR 179; January 8, 1963) and were codified in ß 312.1. The House Committee Report specifically approved the proposed regulations and made clear what section 505(i) of the act was intended to accomplish.

[This section] provides a firm legal basis for greater controls of the distribution of new drugs for investigational use. Existing law directs the Secretary to promulgate regulations providing for exempting new drugs from preclearance for safety on condition that they are labeled and intended soley for investigational use by experts qualified by scientific training and experience to investigate the safety of new drugs. * * * These investigators are required to maintain records on the investigation. The Department has proposed strengthening regulations to provide greater safeguards in investigational drug use. The bill approves strengthening regulations and provides that the regulations may require, among other things, * * * (3) the establishment and maintenance of adequate records, * * * to facilitate the evaluation of the safety and effectiveness of the new drug, when an application is filed * * *. [This section also] amends the prohibited-acts section of existing law, section 301(e), 21 U.S.C. ß 331(e), to forbid the failure to establish or maintain any required record, either on an investigational use of drugs or on clinical experience. * * *

H. Rept. 2464, 87th Cong., 2d Sess. 9-10 (1962) (emphasis added).

FDA views as unreasonable an interpretation of section 505(i) of the act that excludes regulation of clinical investigation from the public health protections provided by the section. A clinical investigator who falsified or destroyed original records of a drug study, and who then submitted false records to a sponsor, would clearly cause the sponsor to maintain false records and to make false reports to FDA. Moreover, were an investigator not required to maintain his or her own records (as distinct from those maintained by the sponsor), FDA would in those cases frequently be precluded from even discovering the falseness of the reports and would then review and perhaps approve drug products on the basis of false data.

Thus, section 505(i) provides ample authority for FDA to adopt these regulations, which have the force and effect of law.

Investigator Statement (ß 312.53(c))

127. Proposed and final ß 312.53(c)(1) transforms the investigator statement (Form FDA-1572) from a detailed description of the responsibilities of all parties to the investigation into a brief form that identifies the regulations governing conduct of a clinical investigation and commits the investigator to comply with these requirements. One comment expressed regret at this change, claiming that, as proposed, the clinical investigator would no longer have available a concise written statement of his or her obligations. The comment suggested that the regulations explicitly require the sponsor to provide the investigator with a written summary of all applicable responsibilities before the investigation begins.

FDA agrees with the comments on the usefulness of providing investigators with a written summary of their responsibilities in conducting a clinical investigation. The agency has therefore prepared an informational leaflet that summarizes investigator responsibilities imposed under this part and other relevant requirements of FDA's regulations. This leaflet can be obtained from the Legislative, Professional, and Consumer Affairs Branch (HFN-365), Center for Drugs and Biologics, Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857 (301-295-8012).

Because FDA is making available a written summary of investigator responsibilities, the agency does not believe that this final rule should require sponsor distribution of similar materials to investigators.

128. Section 312.53(c) requires that the investigator statement identify the name and address of the IRB that is responsible for review and approval of the investigator's study. One comment suggested that it would be inappropriate and impracticable to include this information in the investigator statement.

FDA disagrees with this comment. An investigator is responsible for obtaining IRB approval of a clinical investigation before a study may be initiated, and for keeping the sponsor informed of such IRB approval and subsequent IRB actions concerning the study. FDA does not believe it is a significant additional burden to ask the investigator to inform the sponsor of the IRB's name and address. The cooperation of investigators in this matter will help the sponsor to meet its responsibility to keep the agency informed of the identity of all reviewing IRB's.

129. One comment asked that the proposed commitment of the investigator to "report to the sponsor immediately any unsuspected or serious side effects that occur in the course of the investigation(s)" (proposed ß 312.53(c)(1)(vi)(e)) be revised to require the reporting of any "unexpected or serious side effects."

FDA has revised ß 312.53(c)(1)(vi)(e) to require the investigator to report adverse experiences in accordance with the provisions of ß 312.64. Section 312.64 requires an investigator promptly to report to the sponsor any adverse effect that may reasonably be regarded as caused by, or probably caused by, the drug. If the adverse effect is alarming, the regulation requires the investigator to report immediately. These provisions are taken almost verbatim from former ß 312.1.

130. A comment objected to the provision in ß 312.53(c)(3) that would require the sponsor to obtain a clinical plan from each participating investigator. The comment stated its assumption that the sponsor is ordinarily responsible for developing the plan, and that the sponsor normally provides the plan to participating investigators rather than the other way around. Another comment contended that the use of the term "clinical plan" is confusing, as it usually refers to the overall plan of the sponsor. The comment suggested using "protocol" or "clinical protocol" instead.

FDA agrees that the use of the term "protocol" alone may be less confusing and has revised ß 312.53(c)(3) of the final rule accordingly.

The final rule is not intended to designate whether the investigator or the sponsor originate the protocol under which a study will be conducted. The inclusion of the protocol in the information given by the investigator to the sponsor simply provides added assurance that there has been a "meeting of the minds" between sponsor and investigator on the appropriate course for the study.

Informing Investigators (ß 312.55)

131. One comment contended that the intended relationship between the investigator notification requirements of ß 312.32 dealing with notifying investigators of IND safety reports and those outlined in ß 312.55(b) dealing with important safety information is unclear. The comment contended that ß 312.55 should not require more with respect to notification than is required under the IND safety report requirement. The comment observed that proposed ß 312.55(b) can be read to require that safety information other than that contained in the safety reports be conveyed to investigators on an immediate basis. If that is what was intended, the comment asked the agency to specify what other information should be conveyed to investigators and what need there is for conveying that additional information.

FDA did not intend that ß 312.55(b) differ from ß 312.32 with respect to investigator notification of important safety information. FDA has revised ß 312.55(b) to clarify that important safety information shall be relayed in safety reports to the investigator in accordance with ß 312.32.

Review of Ongoing Investigations (ß 312.56)

132. Proposed ß 212.56 directed sponsors to "evaluate the evidence relating to safety and effectiveness of the drug as it is obtained from the investigators." One comment claimed that, since it is not ordinarily possible to evaluate evidence of effectiveness without breaking the code for blinded studies, the preamble to the final regulation should make clear that, for blinded studies, evidence is not considered "obtained" until the code is broken.

The agency views ß 312.56(c) as requiring a sponsor to: (1) Immediately review all new data received from an investigator regarding the safety of the investigational drug, (2) periodically evaluate all data received from all investigators regarding the safety of the drug, and (3) periodically evaluate the data received from all investigators who have completed their portions of the investigation to ascertain whether the drug is proving to be effective for the intended use. As thus interpreted, a sponsor should not have to "break the code" of a blinded study to evaluate evidence relating solely to the effectiveness of the investigational drug.

133. If an investigation is discontinued for safety reasons, ß 312.56(d) (ß 312.56(c) as proposed) requires the sponsor to notify all reviewing IRB's of the discontinuance. One comment asked whether the sponsor's obligation would be limited to notifying only those IRB's reviewing studies involving the specific dosage level and dosage form of the problem drug, or whether the obligation would extend to notifying all IRB's reviewing studies of the drug at any dosage level or in any dosage form. Two other comments suggested that the responsibility for notifying an IRB should belong with the investigator, not the sponsor.

The notification requirement in ß 312.56(d) applies to all IRB's reviewing clinical investigations with the investigational drug. The notification provides added assurance that reviewing IRB's will be promptly informed of the most serious problems relating to their review.

With respect to the comments suggesting that the investigator, not the sponsor, has the responsibility for IRB notification, FDA recognizes that sponsors usually do not have direct contact with IRB's. FDA believes, however, that under extraordinary circumstances, such as when a sponsor discontinues a study because an adverse drug effect presents an unreasonable and significant risk to subjects, it is not unreasonable to ask the sponsor to notify all reviewing IRB's of the discontinuance. Direct contact between the sponsor and IRB in this situation will permit an IRB to obtain directly from the sponsor all the facts surrounding the sponsor's decision to discontinue the study, information that may not be available from the investigator.

134. Under ß 312.56(d) (ß 312.56(c) as proposed), if a sponsor determines that its investigational drug presents an unreasonable and significant risk to subjects, the sponsor is required to discontinue the investigation as soon as possible, and in no event later than 5 working days after making the determination. One comment agreed that the 5-working-day time limit should apply to the entry of new subjects to the investigation, but argued that the provision should be revised to permit the investigator to take participating subjects off the drug "in a fashion consistent with the health and safety of the subjects."

Once a determination has been made that an investigational drug presents an unreasonable and significant risk to subjects -- the trigger for discontinuance -- the agency believes it is reasonable to expect sponsors to ensure that subjects are taken off the drug as quickly as possible. FDA believes that, as a general rule, 5 working days is sufficient time for patients to be taken off the drug in a fashion consistent with their health and safety. If, in the sponsor's view, there are extraordinary circumstances dictating that some subjects be continued on the drug, FDA will be willing on a case-by-case basis to discuss an extension of the 5-day time limit.

Inspection of Sponsor's Records and Reports (ß 312.58)

135. Proposed ß 312.58(a) would require the sponsor to make available for FDA inspection and copying the records and reports that are required to be maintained by the sponsor under Part 312 and other applicable regulations. One comment argued that reports made by a sponsor's monitor should not be subject to this provision because monitoring, as a quality assurance function, will work most efficiently if it is not subject to government audit. In this way, the comment contended, monitors' reports will be more candid and critical, and thus have more value to the sponsor in assuring that appropriate corrective actions are undertaken as needed.

FDA believes it should retain the authority to inspect records and reports relating to a sponsor's monitoring of clinical investigations under Part 312. Access to these materials helps the agency both to confirm that monitoring is actually taking place and to determine the nature of such monitoring. FDA also is not persuaded that the prospect of agency inspection of monitoring records and reports should significantly influence monitors in recording their observations and recommendations.

As proposed, ß 312.58(a) would have required sponsors to make available to FDA's inspectors "reports required to be maintained under this part and under other applicable parts of this chapter." This might be read as not requiring a sponsor to make available a record or report that is not specifically enumerated in the regulations, even though it is clearly related to the conduct of a clinical investigation. To clarify agency intent, FDA has revised ß 312.58(a) in the final rule to give the agency explicit authority to inspect and copy any record or report relating to a clinical investigation conducted under Part 312.

Imports (ß 312.110(a))

136. The proposal provided that an investigational drug may be imported if it complies with Part 312 and the consignee of the shipment is either the sponsor of the study or is an investigator named in the IND. One comment noted that a domestic agent may act as intermediary for a foreign sponsor, receiving the drug directly from the foreign sponsor, and monitoring and controlling its distribution. The comment suggested that shipment directly to this class of consignees be made expressly allowable.

The agency has no objection to the importation of a drug into the United States going through an agent of a foreign sponsor provided: (a) The intermediary is identified in the IND and (b) the IND describes what, if any, actions the intermediary will take with respect to the imported drug (e.g., repacking or relabeling). FDA has revised the regulation accordingly.

137. One comment asked that FDA give sponsors guidance on the procedures to be followed in importing a new drug for use in laboratory research or for tests in vitro.

The import into the United States of a drug intended for investigational use in laboratory research animals or tests in vitro must comply with the requirements set forth in proposed and final ß 312.160 governing authorization to ship such drug. This section requires the shipper to ensure that the drug is properly labeled, that due diligence is taken to ensure that the drug is shipped only to experts regularly engaged in conducting tests in animals or in vitro, and that accurate records are kept of the drug's distribution. It should be noted that ß 312.160 only governs compliance with the Federal Food, Drug, and Cosmetic Act; a sponsor may face import requirements under other laws and administered by other agencies, such as laws governing importation of controlled substances.

138. One comment suggested that the import provisions of proposed ß 312.110(a) should be revised to allow a sponsor to import an investigational new drug for use as a control in a comparative study involving the sponsor's own drug without requiring a separate IND for the comparison drug. The comment suggested that the importation of the drug could be accommodated by allowing the sponsor to insert all necessary relevant information in the sponsor's existing IND file, thus obviating the need to create a separate IND for the imported drug.

As an administrative convenience and to ensure that information on both the investigational drug and the drug used as an active control are reviewed together, the two drugs should be included in the same IND. The sponsor should, of course, ensure that sufficient information is submitted on the control drug to permit an assessment of the drug's safety for use in the investigation, and to permit the drug to be used as a baseline of effectiveness against which to measure the effectiveness of the principal drug under study. (Sponsors are reminded that when an active treatment control is used, FDA expects such control to be a known effective therapy. See 21 CFR 314.126(b)(2)(iv).)

Exports (ß 312.110(b))

139. Proposed ß 312.110(b)(1) would permit export of an investigational new drug if an IND is in effect for the drug and each person who receives the drug is an investigator named in the application. Several comments contended that, as written, this provision could be interpreted as prohibiting the intra-company export of investigational drugs, a practice which the comment suggested was common under the current regulations. The practice allows a shipment from the United States company to go first to its parent, subsidiary, or affiliate company in a foreign country for final distribution by the foreign affiliate to the clinical investigator. One comment stated that shipping through a foreign affiliate permits the sponsor to save multiple shipping expenses and to ensure proper storage conditions upon receipt. The comment stated its assumption that FDA did not intend to prohibit this practice and urged that the final regulation so state.

The agency has no objection to either a domestic or an export shipment of an investigational drug subject to an IND going through an intermediary on its way to the clinical investigator provided the IND identifies the intermediary and describes what actions, if any, the intermediary will take with respect to the drug. Of course, the IND would still be required to identify and give the qualifications for each participating investigator.

140. One comment questioned the applicability of the IND export provisions to the export of antibiotic drugs. The comment noted that, on its face, the export provisions apply to any investigational new drug including antibiotic drugs. The comment claimed that these provisions could be interpreted to mean that an unapproved antibiotic drug could not be exported except in accordance with the investigational export provisions. The comment claimed that this would be inconsistent with FDA's previously expressed view that the act does not require an IND for the export of an unapproved antibiotic drug intended for use in humans if the standards of section 801(d) of the act (21 U.S.C. 381(d)) are met. The comment asked for clarification of the agency's view in the final regulation.

The comment is correct in noting that antibiotic drug products, including investigational antibiotic drug products, may be exported under the provisions of section 801(d) of the act. FDA has added new ß 312.110(b)(4) to state that, notwithstanding the export provisions of the IND regulations, an investigational antibiotic may be exported if its export conforms to the provisions of section 801(d) of the act.

141. It should be noted that, under the recently adopted Drug Exports Amendments Act of 1986, FDA is authorized to approve applications to export unapproved drugs (including biological products). New section 802 of the Federal Food, Drug, and Cosmetic Act and section 351(h)(1)(A) of the Public Health Service Act describe the conditions that a drug firm must satisfy to obtain FDA approval to export unapproved products for commercial marketing abroad. FDA has revised ß 312.110(b) to make clear that the IND export provisions do not preclude the export of products that are approved for export under the new law.

142. In the Federal Register of January 18, 1984 (49 FR 2095), FDA amended the IND regulations to streamline the process by which the agency may authorize the export of investigational new drugs that are not subject to an effective IND. Specifically, these revisions allow the agency to authorize export in two situations: (a) In response to a request submitted by a drug firm containing sufficient information to demonstrate that the drug is appropriate for investigational use, that the drug will be used for investigational purposes only, and that the drug can legally be used by the consignee in the importing country for the proposed investigational use; and (b) in response to a request submitted by an authorized official of the government of the importing country, submitted directly to FDA, that specifies that the government has adequate information about the drug for the proposed use, that the drug will be used for investigational purposes only, and that the drug can legally be used in the importing country. These two provisions have been incorporated into this final rule (ß 312.110(b)(2)).

Foreign Clinical Studies Not Conducted Under an IND (ß 312.120)

143. One comment noted that a foreign clinical investigation conducted under an IND is required to conform to FDA's current IRB regulations, whereas a foreign study not conducted under an IND is deemed acceptable if it complies with the ethical principles of the Declaration of Helsinki. The comment questioned the disparate treatment of these studies and suggested that the final rule should eliminate the distinction between them so that compliance with the ethical principles of the Declaration of Helsinki would meet the ethical requirements for any foreign study, whether conducted under an IND or not.

The distinction referred to in the comment is not a product of the new regulations, but rather carries forward the past requirement under former ß 312.20. FDA believes this distinction is warranted for the following reasons.

First, the agency believes that any study under an IND, wherever it is conducted, should comply with all applicable requirements governing the conduct of clinical studies, including the requirement for institutional review. To exempt foreign studies under an IND from IRB requirements might encourage sponsors to remove clincial studies from the United States to countries with lesser standards of human subject protection. This would clearly not be in the interest of the public health.

While FDA is unwilling to create a different standard for foreign studies under an IND, the agency will accept in support of an IND or marketing application reports of foreign studies that are not under an IND (and not subject to institutional review), provided there are adequate alternative guarantees of human subject protection. This policy is based on a recognition that much important clinical research is conducted throughout the world, which meets the legal and ethical standards of the countries in which it is conducted, but which is carried on without the kind of institutional review required under FDA's requirements. To insist on absolute adherence to FDA's IRB requirements would obligate the agency to reject valid scientific data generated overseas. Thus, ß 312.120 (like its predecessor ß 312.20) permits FDA to accept a foreign study not subject to institutional review, provided the study was conducted in accordance with the Declaration of Helsinki or the laws of the foreign country in which the research was conducted, whichever affords the greater protection of the individual.

Finally, FDA notes that ß 56.105 of the IRB regulations permits a waiver of IRB review where that is warranted. Thus, foreign research can be conducted under an IND even where IRB review is not available, provided a waiver from the agency is obtained in advance.

On its own initiative, FDA has revised ß 312.120(b) to make clear that the data submission requirements for foreign studies in paragraph (b) apply not only to foreign studies intended to support an IND, but also to such studies when submitted in support of a marketing application. The revision conforms the final rule to previous agency policy.

144. Proposed and final ß 312.120(b)(3) requires that case records from a foreign study be submitted if FDA so requests. One comment suggested that the laws and regulations of some foreign countries may not permit the submission of case records and urged that the final regulation provide for other means of assuring the validity of information in a foreign study.

FDA understands that a sponsor cannot disclose foreign records that are prohibited from disclosure by foreign law. Nevertheless, if the agency believes that access to records is necessary to verify certain data or to validate the study -- and such records are not available because of foreign law -- the sponsor and FDA will need to agree upon an alternative validating procedure if the agency is to rely on the data. Such alternative validation might entail the verification of data by a foreign drug regulatory body or other mutually agreed on procedure.

145. One comment supported FDA's proposals to accept foreign clinical studies in support of IND applications and applications for marketing permits, but urged that the assumption should be that these studies are acceptable unless FDA can demonstrate why the studies are not acceptable.

FDA disagrees with this comment's suggestion that the burden of proof should be on FDA to show why a foreign study is inadequate. As with domestic studies, the burden is on the sponsor to demonstrate that a study is valid. Nevertheless, FDA routinely gives sponsors its reasons for refusing to accept a study, whether foreign or domestic, and that practice will continue.

146. Section 312.120 requires a sponsor who wishes to rely on a foreign clinical study to submit a description of the research facilities used during the study. One comment recommended deleting the requirement, observing that such description is not required for studies under an IND.

FDA disagrees. An assessment of the adequacy of research facilities for a proposed investigation is an important factor in determining the reliability and validity of data generated by a study, wherever the study is conducted. For studies conducted under an IND, this assessment is frequently obtained through on-site inspections of the facilities identified in the IND. However, because of the difficulties in inspecting foreign research facilities and because of the likelihood that FDA will not otherwise be familiar with such facilities, FDA believes it is appropriate to require documentation of the adequacy of foreign facilities. The requirement should not represent a significant burden on sponsors, but will appreciably enhance FDA's review of the quality of foreign studies.

147. One comment recommended that FDA not require a sponsor wishing to rely on a foreign study to submit the names and qualifications of members of that study's reviewing IRB or other independent review committee when such information is not required of a domestic study.

Information about the qualifications of such review committee members is important in assessing the competence of the committee to protect the interests of human subjects. While it is true that the sponsor of a study under an IND is not required to submit the names and qualifications of the members of an independent review committee, the information is routinely obtained through FDA on-site inspections of the IRB. To obtain comparable insight into the quality of institutional review for foreign studies not conducted under an IND, given that inspections of foreign review committees are usually not feasible, FDA believes it is appropriate to ask that the sponsor document the qualifications of the institutional committee members. FDA notes that this provision is not a new requirement, but has been part of FDA's regulations since 1975.

Availability for Public Disclosure of Data and Information in an IND (ß 312.130)

148. Proposed ß 312.130 provided that the existence of an IND will not be disclosed or acknowledged. One comment urged that this section be revised to state that, unless such public disclosure is clear and a matter of public record, existence of an IND will not be disclosed by FDA without consulting with a sponsor. The comment argued that unless FDA has a clear record of a previous disclosure, the sponsor is most likely to know whether the existence of the IND has been publicly divulged.

FDA's longstanding policy has been not to disclose the existence of an IND unless its existence has previously been disclosed. Where there is any doubt about previous disclosure, the burden is placed on the requestor to demonstrate such disclosure. As this procedure for screening requests has worked well, FDA does not believe the suggested change is needed.

Drugs for Investigational Use in Laboratory Research Laboratories or In Vitro Tests (ß 312.160)

149. The proposal provided that if authority to ship a drug for use in laboratory research animals or in vitro is terminated, the person shipping the drug must recall or have destroyed the unused supplies of the drug. One comment contended that there should be no need to destroy supplies that may possibly be in short supply and suggested that the provision be revised to permit disposal of the drug in some other way.

FDA agrees with the comment and has revised the final rule by adding new paragraph (c) to ß 312.160 to permit a shipper of a drug for investigational use in vitro or in research animals to authorize alternative disposition of unused supplies of the investigational drug, once the investigation is ended. The right to provide an alternative disposition is conditioned on the shipper assuring that the unused supplies will not expose humans to risks from the drug, either directly or indirectly.

List of Subjects

21 CFR Part 312
Drugs, Medical research.

21 CFR Part 314
Administrative practice and procedure, Drugs.

21 CFR Part 511
Animal drugs, Medical research, Reporting and recordkeeping requirements.

21 CFR Part 514
Administrative practice and procedure, Animal drugs.

Therefore, under the Federal Food, Drug, and Cosmetic Act and the Public Health Service Act, 21 CFR Chapter I is amended as follows:

1. By reviewing Part 312 to read as follows:

PART 312 -- INVESTIGATIONAL NEW DRUG APPLICATION
Subpart A -- General Provisions

Sec.
312.1 Scope.
312.2 Applicability.
312.3 Definitions and interpretations.
312.6 Labeling of an investigational new drug.
312.7 Promotion and sale of investigational drugs.
312.10 Waivers.

Subpart B -- Investigational New Drug Application (IND)

Sec.
312.20 Requirement for an IND.
312.21 Phases of an investigation.
312.22 General principles of the IND submission.
312.23 IND content and format.
312.30 Protocol amendments.
312.31 Information amendments.
312.32 IND safety reports.
312.33 Annual reports.
312.34 Treatment use of an investigational new drug. [Reserved]
312.36 Emergency use of an investigational new drug.
312.38 Withdrawal of an IND.

Subpart C -- Administrative Actions

Sec.
312.40 General requirements for use of an investigational new drug in a clinical investigation.
312.41 Comment and advice on an IND.
312.42 Clinical holds and requests for modification.
312.44 Termination.
312.45 Inactive status.
312.47 Meetings.
312.48 Dispute resolution.

Subpart D -- Responsibilities of Sponsors and Investigators

312.50 General responsibilities of sponsors.
312.52 Transfer of obligations to a contract research organization.
312.53 Selecting investigators and monitors.
312.55 Informing investigators.
312.56 Review of ongoing investigations.
312.57 Recordkeeping and record retention.
312.58 Inspection of sponsor's records and reports.
312.59 Disposition of unused supply of investigational drug.
312.60 General responsibilities of investigators.
312.61 Control of the investigational drug.
312.62 Investigator recordkeeping and record retention.
312.64 Investigator reports.
312.66 Assurance of IRB review.
312.68 Inspection of investigator's records.
312.69 Handling of controlled substances.
312.70 Disqualification of a clinical investigator.

Subpart E -- Miscellaneous

312.110 Import and export requirements.
312.120 Foreign clinical studies not conducted under an IND.
312.130 Availability for public disclosure of data and information in an IND.
312.140 Address for correspondence.
312.145 Guidelines.

Subpart F -- Drugs for Investigational Use in Laboratory Research Animals or in Vitro Tests

312.160 Drugs for investigational use in laboratory research animals or In vitro tests.

Authority: 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); sec. 351, 58 Stat. 702 as amended (42 U.S.C. 262); 21 CFR 5.10, 5.11.

Subpart A -- General Provisions
ß 312.1 Scope.

(a) This part contains procedures and requirements governing the use of investigational new drugs, including procedures and requirements for the submission to, and review by, the Food and Drug Administration of investigational new drug applications (IND's). An investigational new drug for which an IND is in effect in accordance with this part is exempt from the premarketing approval requirements that are otherwise applicable and may be shipped lawfully for the purpose of conducting clinical investigations of that drug.

(b) References in this part to regulations in the Code of Federal Regulations are to Chapter I of Title 21, unless otherwise noted.

ß 312.2 Applicability.

(a) Applicability. Except as provided in this section, this part applies to all clinical investigations of products that are subject to section 505 or 507 of the Federal Food, Drug, and Cosmetic Act or to the licensing provisions of the Public Health Service Act (58 Stat. 632, as amended (42 U.S.C. 201 et seq.)).

(b) Exemptions. (1) The clinical investigation of a drug product that is lawfully marketed in the United States is exempt from the requirements of this part if all the following apply:

(i) 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 labeling for the drug;

(ii) If the drug that is undergoing investigation is lawfully marketed as a prescription drug product, the investigation is not intended to support a significant change in the advertising for the product;

(iii) The investigation does not involve a route of administration or dosage level or use in a patient population or other factor that significantly increases the risks (or decreases the acceptability of the risks) associated with the use of the drug product;

(iv) The investigation is conducted in compliance with the requirements for institutional review set forth in Part 56 and with the requirements for informed consent set forth in Part 50; and

(v) The investigation is conducted in compliance with the requirements of ß 312.7.

(2)(i) A clinical investigation involving an in vitro diagnostic biological product listed in paragraph (b)(2)(ii) of this section is exempt from the requirements of this part if (a) it is intended to be used in a diagnostic procedure that confirms the diagnosis made by another, medically established, diagnostic product or procedure and (b) it is shipped in compliance with ß 312.160.

(ii) In accordance with paragraph (b)(2)(i) of this section, the following products are exempt from the requirements of this part: (a) blood grouping serum; (b) reagent red blood cells; and (c) anti-human globulin.

(3) A drug intended solely for tests in vitro or in laboratory research animals is exempt from the requirements of this part if shipped in accordance with ß 312.160.

(4) FDA will not accept an application for an investigation that is exempt under the provisions of paragraph (b)(1) of this section.

(5) A clinical investigation involving use of a placebo is exempt from the requirements of this part if the investigation does not otherwise require submission of an IND.

(c) Bioavailability studies. The applicability of this part to in vivo bioavailability studies in humans is subject to the provisions of ß 320.31.

(d) Unlabeled indication. This part does not apply to the use in the practice of medicine for an unlabeled indication of a new drug or antibiotic drug product approved under Part 314 or of a licensed biological product.

(e) Guidance. FDA may, on its own initiative, issue guidance on the applicability of this part to particular investigational uses of drugs. On request, FDA will advise on the applicability of this part to a planned clinical investigation.

ß 312.3 Definitions and interpretations.

(a) The definitions and interpretations of terms contained in section 201 of the act apply to those terms when used in this part:

(b) The following definitions of terms also apply to this part:

"Act" means the Federal Food, Drug, and Cosmetic Act (secs. 201-902, 52 Stat. 1040 et seq., as amended (21 U.S.C. 301-392)).

"Clinical investigation" means any experiment in which a drug is administered or dispensed to, or used involving, one or more human subjects. For the purposes of this part, an experiment is any use of a drug except for the use of a marketed drug in the course of medical practice.

"Contract research organization" means a person that assumes, as an independent contractor with the sponsor, one or more of the obligations of a sponsor, e.g., design of a protocol, selection or monitoring of investigations, evaluation of reports, and preparation of materials to be submitted to the Food and Drug Administration.

"FDA" means the Food and Drug Administration.

"IND" means an investigational new drug application. For purposes of this part, "IND" is synonymous with "Notice of Claimed Investigational Exemption for a New Drug."

"Investigational new drug" means a new drug, antibiotic drug, or biological drug that is used in a clinical investigation. The term also includes a biological product that is used in vitro for diagnostic purposes. The terms "investigational drug" and "investigational new drug" are deemed to be synonymous for purposes of this part.

"Investigator" means an individual who actually conducts a clinical investigation (i.e., under whose immediate direction the drug is administered or dispensed to a subject). In the event an investigation is conducted by a team of individuals, the investigator is the responsible leader of the team. "Subinvestigator" includes any other individual member of that team.

"Marketing application" means an application for a new drug submitted under section 505(b) of the act, a request to provide for certification of an antibiotic submitted under section 507 of the act, or a product license application for a biological product submitted under the Public Health Service Act.

"Sponsor" means a person who takes responsibility for and initiates a clinical investigation. The sponsor may be an individual or pharmaceutical company, governmental agency, academic institution, private organization, or other organization. The sponsor does not actually conduct the investigation unless the sponsor is a sponsor-investigator. A person other than an individual that uses one or more of its own employees to conduct an investigation that it has initiated is a sponsor, not a sponsor-investigator, and the employees are investigators.

"Sponsor-Investigator" means an individual who both initiates and conducts an investigation, and under whose immediate direction the investigational drug is administered or dispensed. The term does not include any person other than an individual. The requirements applicable to a sponsor-investigator under this part include both those applicable to an investigator and a sponsor.

"Subject" means a human who participates in an investigation, either as a recipient of the investigational new drug or as a control. A subject may be a healthy human or a patient with a disease.

ß 312.6 Labeling of an investigational new drug.

(a) The immediate package of an investigational new drug intended for human use shall bear a label with the statement "Caution: New Drug -- Limited by Federal (or United States) law to investigational use."

(b) The label or labeling of an investigational new drug shall not bear any statement that is false or misleading in any particular and shall not represent that the investigational new drug is safe or effective for the purposes for which it is being investigated.

ß 312.7 Promotion and sale of investigational drugs.

(a) Promotion of an investigational new drug. A sponsor or investigator, or any person acting on behalf of a sponsor or investigator, shall not represent in a promotional context that an investigational new drug is safe or effective for the purposes for which it is under investigation or otherwise promote the drug. This provision is not intended to restrict the full exchange of scientific information concerning the drug, including dissemination of scientific findings in scientific or lay media. Rather, its intent is to restrict promotional claims of safety or effectiveness of the drug for a use for which it is under investigation and to preclude commercialization of the drug before it is approved for commercial distribution.

(b) Commercial distribution of an investigational new drug. A sponsor or investigator shall not commercially distribute or test market an investigational new drug.

(c) Prolonging an investigation. A sponsor shall not unduly prolong an investigation after finding that the results of the investigation appear to establish sufficient data to support a marketing application.

(d) Sale of an investigational drug. If the drug is to be sold, the sponsor should submit a notification to FDA providing a full explanation why sale is required and why the sale should not be regarded as the commercialization of a new drug for which an application is not approved.

ß 312.10 Waivers.

(a) A sponsor may request FDA to waive applicable requirement under this part. A waiver request may be submitted either in an IND or in an information amendment to an IND. In an emergency, a request may be made by telephone or other rapid communication means. A waiver request is required to contain at least one of the following:

(1) An explanation why the sponsor's compliance with the requirement is unnecessary or cannot be achieved;

(2) A description of an alternative submission or course of action that satisfies the purpose of the requirement; or

(3) Other information justifying a waiver.

(b) FDA may grant a waiver if it finds that the sponsor's noncompliance would not pose a significant and unreasonable risk to human subjects of the investigation and that one of the following is met:

(1) The sponsor's compliance with the requirement is unnecessary for the agency to evaluate the application, or compliance cannot be achieved;

(2) The sponsor's proposed alternative satisfies the requirement; or

(3) The applicant's submission otherwise justifies a waiver.

52Subpart B -- Investigational New Drug Application (IND)

ß 312.20 Requirement for an IND.

(a) A sponsor shall submit an IND to FDA if the sponsor intends to conduct a clinical investigation with an investigational new drug that is subject to ß 312.2(a).

(b) A sponsor shall not begin a clinical investigation subject to ß 312.2(a) until the investigation is subject to an IND which is in effect in accordance with ß 312.40.

ß 312.21 Phases of an investigation.

An IND may be submitted for one or more phases of an investigation. The clinical investigation of a previously untested drug is generally divided into three phases. Although in general the phases are conducted sequentially, they may overlap. These three phases of an investigation are a follows:

(a) Phase 1. (1) Phase 1 includes the initial introduction of an investigational new drug into humans. Phase 1 studies are typically closely monitored and may be conducted in patients or normal volunteer subjects. These studies are designed to determine the metabolism and pharmacologic actions of the drug in humans, the side effects associated with increasing doses, and, if possible, to gain early evidence on effectiveness. During Phase 1, sufficient information about the drug's pharmacokinetics and pharmacological effects should be obtained to permit the design of well-controlled, scientifically valid, Phase 2 studies. The total number of subjects and patients included in Phase 1 studies varies with the drug, but is generally in the range of 20 to 80.

(2) Phase 1 studies also include studies of drug metabolism, structure-activity relationships, and mechanism of action in humans, as well as studies in which investigational drugs are used as research tools to explore biological phenomena or disease processes.

(b) Phase 2. Phase 2 includes the controlled clinical studies conducted to evaluate the effectiveness of the drug for a particular indication or indications in patients with the disease or condition under study and to determine the common short-term side effects and risks associated with the drug. Phase 2 studies are typically well controlled, closely monitored, and conducted in a relatively small number of patients, usually involving no more than several hundred subjects.

(c) Phase 3. Phase 3 studies are expanded controlled and uncontrolled trials. They are performed after preliminary evidence suggesting effectiveness of the drug has been obtained, and are intended to gather the 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 subjects.

ß 312.22 General principles of the IND submission.

(a) FDA's primary objectives in reviewing an IND are, in all phases of the investigation, to assure the safety and rights of subjects, and, in Phase 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, although FDA's review of Phase 1 submissions will focus on assessing the safety of Phase 1 investigations, FDA's review of Phases 2 and 3 submissions will also include an assessment of the scientific quality of the clinical investigations and the likelihood that the investigations will yield data capable of meeting statutory standards for marketing approval.

(b) The amount of information on a particular drug that must be submitted in an IND to assure the accomplishment of the objectives described in paragraph (a) of this section depends upon such factors as 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.

(c) The central focus of the initial IND submission should be on the general investigational plan and the protocols for specific human studies. Subsequent amendments to the IND that contain new or revised protocols should build logically on previous submissions and should be supported by additional information, including the results of animal toxicology studies or other human studies as appropriate. Annual reports to the IND should serve as the focus for reporting the status of studies being conducted under the IND and should update the general investigational plan for the coming year.

(d) The IND format set forth in ß 312.23 should be followed routinely by sponsors in the interest of fostering an efficient review of applications. Sponsors are expected to exercise considerable discretion, however, regarding the content of information submitted in each section, depending upon the kind of drug being studied and the nature of the available information. Section 312.23 outlines the information needed for a commercially sponsored IND for a new molecular entity. A sponsor-investigator who uses, as a research tool, an investigational new drug that is already subject to a manufacturer's IND or marketing application should follow the same general format, but ordinarily may, if authorized by the manufacturer, refer to the manufacturer's IND or marketing application in providing the technical information supporting the proposed clinical investigation. A sponsor-investigator who uses an investigational drug not subject to a manufacturer's IND or marketing application is ordinarily required to submit all technical information supporting the IND, unless such information may be referenced from the scientific literature.

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