[Federal Register Volume 63, Number 239 (Monday, December 14, 1998)]
[Proposed Rules]
[Pages 68710-68712]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-33030]


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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.

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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adverse comment, the direct final rule will be withdrawn, and the 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