[Federal Register: December 14, 1998 (Volume 63, Number 239)] [Proposed Rules] [Page 68710-68712] From the Federal Register Online via GPO Access [wais.access.gpo.gov] [DOCID:fr14de98-21] ======================================================================= ----------------------------------------------------------------------- DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration 21 CFR Part 312 [Docket No. 98N-0979] Investigational New Drug Applications; Clinical Holds; Companion Document to Direct Final Rule AGENCY: Food and Drug Administration, HHS. ACTION: Proposed rule. ----------------------------------------------------------------------- SUMMARY: The Food and Drug Administration (FDA) is proposing to amend its regulations governing investigational new drug applications (IND's) for human drug and biological products. This proposed action would amend the IND clinical hold requirements to state that the agency will respond in writing to a sponsor's request that a clinical hold be removed from an investigation within 30-calendar days of the agency's receipt of the request and the sponsor's complete response to the issue(s) that led to the clinical hold. This proposed action is being taken in accordance with provisions of the Food and Drug Administration Modernization Act of 1997 (the Modernization Act). This proposed rule is a companion document to a direct final rule published elsewhere in this issue of the Federal Register. If FDA receives any significant adverse comment, the direct final rule will be withdrawn, and the comments will be considered in the development of a final rule using usual notice-and-comment rulemaking based on this proposed rule. [[Page 68711]] DATES: Comments must be received on or before March 1, 1999. ADDRESSES: Submit written comments to the Dockets Management Branch (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. FOR FURTHER INFORMATION CONTACT: Murray M. Lumpkin, Center for Drug Evaluation and Research (HFD-2), Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857, 301-594-5417, or Rebecca A. Devine, Center for Biologics Evaluation and Research (HFM-10), Food and Drug Administration, 1401 Rockville Pike, Rockville, MD 20852, 301-827-0373. SUPPLEMENTARY INFORMATION: I. Background On November 21, 1997, President Clinton signed into law the Modernization Act (Pub. L. 105-115). Section 117 of the Modernization Act amends the Federal Food, Drug, and Cosmetic Act (the act) by codifying in section 505(i) (21 U.S.C. 355(i)) several of the procedures and requirements governing the use of investigational new drugs that are already set forth in FDA regulations (parts 50 and 312 (21 CFR parts 50 and 312)). Section 505(i)(2) of the act, as amended by the Modernization Act, provides that if a sponsor of an IND that has been placed on clinical hold requests in writing that the clinical hold be removed and submits a complete response to the issue(s) identified in the clinical hold order, FDA is required to respond in writing to the sponsor within 30- calendar days of receipt of the complete response. This proposed rule would amend Sec. 312.42(e) to reflect this new statutory requirement and to clarify when a sponsor may resume an investigation after FDA issues a clinical hold order. II. Additional Information This proposed rule is a companion to the direct final rule published elsewhere in this issue of the Federal Register. The companion proposed rule and the direct final rule are identical. This companion proposed rule will provide the procedural framework to finalize the rule in the event the direct final rule receives significant adverse comment and is withdrawn. The comment period for the companion proposed rule runs concurrently with the comment period for the direct final rule. Any comments received under the companion proposed rule will be treated as comments regarding the direct final rule. The amendments in this proposed rule are a direct result of the new provisions in section 505(i)(2) of the act. If no significant adverse comment is received in response to the direct final rule, no further action will be taken related to this companion proposed rule. Instead, FDA will publish a confirmation document within 30 days after the comment period ends confirming that the direct final rule will go into effect on April 28, 1999. If FDA receives significant adverse comments, the agency will withdraw the direct final rule. FDA will proceed to respond to comments received regarding the rule and, if appropriate, the rule will be finalized under this companion proposed rule using usual notice-and-comment procedures. For additional information, see the corresponding direct final rule published elsewhere in this issue of the Federal Register. All persons who wish to comment should review the detailed rationale for these amendments set out in the preamble discussion of the direct final rule. A significant adverse comment is one that explains why the rule would be inappropriate, including challenges to the rule's underlying premise or approach, or would be ineffective or unacceptable without a change. A comment recommending a rule change in addition to this rule will not be considered a significant adverse comment, unless the comment states why this rule would be ineffective without the additional change. III. Environmental Impact The agency has determined under 21 CFR 25.30(h) that this action is of a type that does not individually or cumulatively have a significant effect on the human environment. Therefore, neither an environmental assessment nor an environmental impact statement is required. IV. Analysis of Impact FDA has examined the impacts of this companion proposed rule under Executive Order 12866, the Regulatory Flexibility Act (5 U.S.C. 601- 612), and the Unfunded Mandates Reform Act of 1995 (Pub. L. 104-4). Executive Order 12866 directs agencies to assess all costs and benefits of available regulatory alternatives and, when regulation is necessary, to select regulatory approaches that maximize net benefits (including potential economic, environmental, public health and safety, and other advantages; distributive impacts; and equity). Executive Order 12866 classifies a rule as significant if it meets any one of a number of specified conditions, including having an annual effect on the economy of $100 million or adversely affecting in a material way a sector of the economy, competition, or jobs, or if it raises novel legal or policy issues. The agency believes that this proposed rule is consistent with the regulatory philosophy and principles identified in the Executive Order. In addition, the proposed rule is not a significant regulatory action as defined by the Executive Order and so is not subject to review under the Executive Order. The Regulatory Flexibility Act requires agencies to analyze regulatory options to minimize any significant impact on small entities. The agency has considered the effect that this rule will have on small entities, including small businesses, and certifies that the proposed rule will not have a significant economic impact on a substantial number of small entities. Therefore, under the Regulatory Flexibility Act, no further analysis is required. The Unfunded Mandates Reform Act requires an agency to prepare a budgetary impact statement before issuing any rule likely to result in a Federal mandate that may result in expenditures by State, local, and tribal governments or the private sector of $100 million (adjusted annually for inflation) in any 1 year. This proposed rule will not result in an expenditure of $100 million or more on any governmental entity or the private sector, so no budgetary impact statement is required. V. Paperwork Reduction Act of 1995 FDA tentatively concludes that this proposed rule contains no collections of information. Therefore, clearance by the Office of Management and Budget under the Paperwork Reduction Act of 1995 is not required. VI. Request for Comments Interested persons may, on or before March 1, 1999, submit to the Dockets Management Branch (address above) written comments regarding this proposal. Two copies of any comments are to be submitted, except that individuals may submit one copy. Comments are to be identified with the docket number found in brackets in the heading of this document. Received comments may be seen in the office above between 9 a.m. and 4 p.m., Monday through Friday. List of Subjects in 21 CFR Part 312 Drugs, Exports, Imports, Investigations, Labeling, Medical research, Reporting and recordkeeping requirements, Safety. [[Page 68712]] Therefore, under the Federal Food, Drug, and Cosmetic Act, the Public Health Service Act, and under authority delegated to the Commissioner of Food and Drugs, it is proposed that 21 CFR part 312 be amended to read as follows: PART 312--INVESTIGATIONAL NEW DRUG APPLICATION 1. The authority citation for 21 CFR part 312 is revised to read as follows: Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 371; 42 U.S.C. 262. 2. Section 312.42 is amended by revising paragraph (e) to read as follows: Sec. 312.42 Clinical holds and requests for modification. * * * * * (e) Resumption of clinical investigations. An investigation may only resume after FDA (usually the Division Director, or the Director's designee, with responsibility for review of the IND) has notified the sponsor that the investigation may proceed. Resumption of the affected investigation(s) will be authorized when the sponsor corrects the deficiency(ies) previously cited or otherwise satisfies the agency that the investigation(s) can proceed. FDA may notify a sponsor of its determination regarding the clinical hold by telephone or other means of rapid communication. If a sponsor of an IND that has been placed on clinical hold requests in writing that the clinical hold be removed and submits a complete response to the issue(s) identified in the clinical hold order, FDA shall respond in writing to the sponsor within 30- calendar days of receipt of the request and the complete response. FDA's response will either remove or maintain the clinical hold, and will state the reasons for such determination. Notwithstanding the 30- calendar day response time, a sponsor may not proceed with a clinical trial on which a clinical hold has been imposed until the sponsor has been notified by FDA that the hold has been lifted. * * * * * Dated: December 4, 1998. William B. Schultz, Deputy Commissioner for Policy. [FR Doc. 98-33030 Filed 12-11-98; 8:45 am] BILLING CODE 4160-01-F