[Federal Register Volume 63, Number 239 (Monday, December 14, 1998)]
[Rules and Regulations]
[Pages 68676-68678]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-33029]


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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

AGENCY: Food and Drug Administration, HHS.

ACTION: Direct final rule.

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SUMMARY: The Food and Drug Administration (FDA) is amending its 
regulations governing investigational new drug applications (IND's) for 
human drug and biological products. This action amends 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. FDA is taking this action in accordance with provisions of the 
Food and Drug Administration Modernization Act of 1997 (the 
Modernization Act). Elsewhere in this issue of the Federal Register, 
FDA is publishing a companion proposed rule under FDA's usual procedure 
for notice-and-comment rulemaking to provide a procedural framework to 
finalize the rule in the event the agency receives significant adverse 
comments and withdraws this direct final rule.

DATES: This regulation is effective April 28, 1999. Submit written 
comments on or before March 1, 1999. If no timely significant adverse 
comments are received, the agency will publish a document in the 
Federal Register before March 29, 1999, confirming the effective date 
of the direct final rule. If timely significant adverse comments are 
received, the agency will publish a document of significant adverse 
comment in the Federal Register withdrawing this direct final rule 
before March 29, 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, 
301-594-5400, 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. Discussion

A. Introduction

    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's 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 direct final 
rule amends 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.
    In the Federal Register of May 14, 1998 (63 FR 26809), FDA 
announced the availability of a guidance document entitled ``Submitting 
and Reviewing Complete Responses to Clinical Holds.'' This guidance to 
industry describes how applicants should submit responses to clinical 
holds so that they may be identified as complete responses.

B. Background

    The procedures and requirements governing the use of 
investigational new drugs, including the submission and review of 
IND's, are set forth in part 312. An investigational new drug is a new 
drug or biological drug that is used in a clinical investigation. A 
clinical investigation is an experiment in which a drug is administered 
or dispensed to, or used involving, one or more human subjects. An 
investigational new drug that meets the requirements of part 312 is 
exempt from the premarket approval requirements that are otherwise 
applicable, and may be shipped lawfully for the purpose of conducting 
clinical investigations of the drug.
    Part 312 applies to all clinical investigations of products that 
are subject to section 505 of the act, or to the licensing provisions 
of section 351 of the Public Health Service Act (42 U.S.C. 262), with 
one principal exemption--certain clinical investigations of drugs that 
have received premarket approval and are lawfully marketed.
    The person who takes responsibility for and initiates a clinical 
investigation of an investigational new drug is the IND sponsor. The 
sponsor may be an individual, a pharmaceutical company, a government 
agency, an academic institution, or other entity. The individual who 
actually conducts a clinical investigation and administers the 
investigational drug to patients is the investigator (the investigator 
may also be the sponsor). Responsibilities of a sponsor include: (1) 
Notifying FDA of any serious and unexpected adverse experience 
associated with the use of the drug; (2) selecting qualified 
investigators and overseeing the conduct of those investigators; (3) 
ensuring that the investigations are performed in accordance with the 
investigational plan and protocols contained in the IND; (4) providing 
investigators with an investigator's brochure; and (5) submitting an 
annual report to FDA.
    A sponsor may not begin clinical testing with an investigational 
new drug until an IND is submitted to FDA and is in effect for that 
drug. The IND content and format requirements are set forth in 
Sec. 312.23. An IND automatically becomes effective 30-calendar days 
after FDA receives the initial IND submission (or earlier upon FDA's 
notification), unless FDA informs the sponsor that the investigation 
may not proceed (i.e., a clinical hold is issued).
    A clinical hold is an order that FDA issues to the sponsor to delay 
a proposed clinical investigation or to suspend an ongoing 
investigation. Section 505(i) of the act, as amended by the 
Modernization Act, verifies FDA's authority to issue a clinical hold 
and

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endorses FDA regulations that describe the grounds upon which a 
clinical hold may be issued. Under such regulations, codified in 
Sec. 312.42, the basis for a clinical hold depends on the phase of the 
clinical study. FDA may place a proposed or ongoing Phase 1 
investigation on clinical hold if it finds any of the following: (1) 
Unreasonable and significant risk of illness or injury; (2) unqualified 
clinical investigators; (3) a misleading, erroneous, or materially 
incomplete investigator brochure; or (4) insufficient information in 
the IND to assess the risks to subjects. A Phase 2 or Phase 3 study may 
be suspended for any of these reasons or, in addition, because it is 
deficient in design to meet its stated objectives. The clinical hold 
regulations specify additional grounds for placing a hold on a 
treatment IND or treatment protocol or any study not designed to be 
adequate and well-controlled (Sec. 312.42(b)(3) and (b)(4)). An 
investigation that has been placed on clinical hold may resume only 
after the deficiency that prompted the clinical hold is corrected by 
the sponsor and the hold has been released by FDA.

C. Description of the Direct Final Rule

    Current Sec. 312.42(e) describes when a clinical investigation may 
resume after a clinical hold has been imposed by FDA. An investigation 
may resume after the Division Director with responsibility for review 
of the IND notifies the sponsor that the investigation may proceed. 
This notification is usually made after the sponsor corrects the 
deficiency or deficiencies that resulted in the clinical hold. 
Resumption of an investigation may be authorized by telephone or other 
means of rapid communication. Under the current regulation, no 
timeframe is given within which FDA will notify the sponsor that an 
investigation may resume after the sponsor has submitted answers to the 
deficiencies that resulted in the clinical hold and has requested that 
FDA remove the clinical hold.
    As explained previously, FDA is now required under section 
505(i)(2) of the act to respond to a written request from a sponsor 
that a clinical hold be removed within 30-calendar days of receipt of 
the request and the sponsor's complete response to the issue(s) that 
led to the clinical hold. Therefore, FDA is amending Sec. 312.42(e) to 
reflect this requirement. In requesting that the clinical hold be 
removed, the sponsor of the IND must address all of the clinical hold 
issues that the agency noted in the clinical hold order. FDA may notify 
the sponsor of its decision on the request to release the clinical hold 
by telephone or other means of rapid communication, but a written 
response will be issued within 30-calendar days of receipt of the 
sponsor's request and complete response to the issue(s) that led to the 
clinical hold. If FDA determines that the clinical hold will be 
maintained, the written response will state the reasons for such 
decision.
    In addition, under current Sec. 312.42(e), the terms of certain 
clinical holds may permit an investigation to resume without FDA's 
prior notification once the correction or modification that caused the 
clinical hold is made. FDA is deleting the first sentence of current 
Sec. 312.42(e) because it does not accurately reflect the agency's 
practice in imposing a clinical hold. The types of concerns that FDA 
might raise with regard to a clinical investigation that could be 
remedied and implemented without prior agency notification do not 
require the imposition of a clinical hold. Such concerns are generally 
resolved through discussions between the sponsor and FDA. FDA generally 
imposes a clinical hold on an investigation if the deficiencies are 
such that the study's resumption would require prior approval by the 
agency. This revision will help eliminate any confusion regarding 
whether a clinical hold has been placed and the process of removing a 
clinical hold from an investigation and any inconsistent treatment of 
IND's by different units within FDA.

II. Direct Final Rulemaking

    FDA has determined that this amendment to the agency's regulations 
governing IND's for human drug and biological products is suitable for 
a direct final rule. The actions taken should be noncontroversial and 
the agency does not anticipate receiving any significant adverse 
comments. This direct final rule amends Sec. 312.42(e) to reflect 
section 117 of the Modernization Act and current agency practice in 
imposing a clinical hold.
    If FDA does not receive significant adverse comment on or before 
March 1, 1999, the agency will publish a document in the Federal 
Register before March 29, 1999, confirming the effective date 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. If timely significant adverse comments are received, 
the agency will publish a notice of significant adverse comment in the 
Federal Register withdrawing this direct final rule before March 29, 
1999.
    Elsewhere in this issue of the Federal Register, FDA is publishing 
a companion proposed rule, which is identical to the direct final rule, 
that provides a procedural framework within which the rule may be 
finalized in the event the direct final rule is withdrawn because of 
significant adverse comment. The comment period for the direct final 
rule runs concurrently with that of the companion proposed rule. Any 
comments received under the companion proposed rule will be treated as 
comments regarding the direct final rule. Likewise, significant adverse 
comments submitted to the direct final rule will be considered as 
comments to the companion proposed rule and the agency will consider 
such comments in developing a final rule. FDA will not provide 
additional opportunity for comment on the companion proposed rule.
    If a significant adverse comment applies to part of this rule and 
that part may be severed from the remainder of the rule, FDA may adopt 
as final those parts of the rule that are not the subject of a 
significant adverse comment. A full description of FDA's policy on 
direct final rule procedures may be found in a guidance document 
published in the Federal Register of November 21, 1997 (62 FR 62466).

III. Environmental Impact

    The agency has determined under 21 CFR 25.30(h) that this action is 
of a class of actions that do 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 direct final 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

[[Page 68678]]

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 rule is 
consistent with the regulatory philosophy and principles identified in 
the Executive Order. In addition, the 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 
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 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

    This direct final 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 rule. 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.
    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, 21 CFR part 312 is 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. 98-33029 Filed 12-11-98; 8:45 am]
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