Investigational New Drug Applications; Clinical Holds

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

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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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