[Federal Register Volume 61, Number 65 (Wednesday, April 3, 1996)]
[Notices]
[Pages 14797-14798]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 96-8165]



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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Investigational New Drugs; Procedure to Monitor Clinical Hold 
Process; Meeting of Review Committee and Request for Submissions

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) is announcing a meeting 
of the clinical hold review committee, which reviews the clinical holds 
that the Center for Drug Evaluation and Research (CDER) has placed on 
certain investigational new drug trials. The committee was established 
as a 1-year experiment in August 1991. The committee met quarterly 
through 1992 and currently meets semiannually as a regular program. The 
committee last met in November 1995. FDA is inviting any interested 
drug company to use the confidential mechanism to submit to the 
committee for its review the name and number of any investigational new 
drug trial placed on clinical hold during the past 12 months that the 
company wants the committee to review.

DATES: The meeting is currently scheduled for June 1996. Drug companies 
may submit review requests for the June meeting before May 3, 1996.

ADDRESSES: Submit clinical hold review requests to Amanda B. Pedersen, 
FDA Chief Mediator and Ombudsman, Office of the Commissioner (HF-7), 
Food and Drug Administration, rm. 14-105, 5600 Fishers Lane, Rockville, 
MD 20857, 301-827-3390.

FOR FURTHER INFORMATION CONTACT: Janet M. Jones, Center for Drug 
Evaluation and Research (HFD-4), Food and Drug Administration, 5600 
Fishers Lane (WOC II rm. 6020), Rockville, MD 20857, 301-594-5445.

SUPPLEMENTARY INFORMATION: FDA regulations in part 312 (21 CFR part 
312) provide procedures that govern the use of investigational new 
drugs in human subjects. These regulations require that the sponsor of 
a clinical investigation submit an investigational new drug application 
(IND) to FDA outlining the proposed use of the investigational drug. 
The IND must contain the study protocol, a summary of human and animal 
experience with the drug, and information about the drug's chemistry 
and pharmacology. FDA reviews an IND to help ensure the safety and 
rights of subjects and, in phases 2, 3, and 4 of drug development, to 
help ensure that the quality of any scientific evaluation of drugs is 
adequate to permit an evaluation of the drug's efficacy and safety. An 
investigational new drug for which an IND is in effect 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.
    If FDA determines that a proposed or ongoing study may pose 
significant risks for human subjects or is otherwise seriously 
deficient, as discussed in the investigational new drug regulations, it 
may impose a clinical hold on the study. The clinical hold is one of 
FDA's primary mechanisms for protecting subjects who are involved in 
investigational new drug trials. A clinical hold is an order that FDA 
issues to a sponsor to delay a proposed investigation or to suspend an 
ongoing investigation. The clinical hold may be placed on one or more 
of the investigations covered by an IND. When a proposed study is 
placed on clinical hold, subjects may not be given the investigational 
drug as part of that study. When an ongoing study is placed on clinical 
hold, no new subjects may

[[Page 14798]]
be recruited to the study and placed on the investigational drug, and 
patients already in the study should stop receiving therapy involving 
the investigational drug unless FDA specifically permits it.
    FDA regulations at Sec. 312.42 describe the grounds for the 
imposition of a clinical hold. When FDA concludes that there is a 
deficiency in a proposed or ongoing clinical trial that may be grounds 
for the imposition of a hold order, ordinarily FDA will attempt to 
resolve the matter through informal discussions with the sponsor. If 
that attempt is unsuccessful, the agency may order a clinical hold. In 
CDER, a clinical hold is ordered by the director of the new drug 
division that is responsible for review of the IND. The order 
identifies the studies under the IND to which the hold applies and 
explains the basis for the action. The hold order may be made by 
telephone or other means of rapid communication, or in writing. Within 
5 working days of the imposition of the clinical hold, the division 
director provides the sponsor with a written explanation of the basis 
for the hold. Any sponsor who has not received a written explanation 
within 5 working days should notify the division and request that it be 
issued. In addition to providing a statement of reasons, this ensures 
that the hold is recorded in CDER's management information system.
    The clinical hold order specifies whether the sponsor may resume 
the affected investigation without prior notification by FDA once the 
deficiency has been corrected. If the order does not permit the 
resumption, an investigation may resume only after the division 
director or his or her designee has notified the sponsor that the 
investigation may proceed. Resumption may be authorized by telephone or 
other means of rapid communication. If all investigations covered by an 
IND remain on clinical hold for 1 year or longer, FDA may place the IND 
on inactive status.
    FDA regulations at Sec. 312.48 and CDER's Manual of Policies and 
Procedures (MAPP 6030.1) provide dispute resolution mechanisms through 
which sponsors may request reconsideration of clinical hold orders. The 
regulations encourage the sponsor to attempt to resolve disputes 
directly with the review staff responsible for the review of the IND. 
If necessary, a sponsor may request a meeting with the review staff and 
management to discuss the hold.
    Over the years, drug sponsors have expressed a number of concerns 
about the clinical hold process, including concerns about the 
scientific and procedural adequacy of some agency actions. FDA 
undertook several initiatives to evaluate the consistency and fairness 
of the Center's practices in imposing clinical holds.
    One initiative undertaken by FDA was the establishment of a 
committee in CDER to review selected clinical holds for scientific and 
procedural quality. The committee held pilot meetings in 1991 and 1992. 
The trial phase of the committee review process confirmed the agency's 
view that the divisions in CDER impose clinical holds in a manner that 
is generally consistent with FDA's procedural requirements and that 
holds are imposed on scientifically supportable grounds.
    The clinical hold committee review process is now a regular, 
ongoing program. The review procedure of the committee is designed to 
afford an opportunity for a sponsor who does not wish to seek formal 
reconsideration of a pending hold to have that hold considered 
``anonymously.'' The committee consists of senior managers in CDER, a 
senior official from the Center for Biologics Evaluation and Research, 
and the FDA Chief Mediator and Ombudsman. The committee now meets 
semiannually. The committee last met in November 1995.
    Clinical holds to be reviewed will be chosen randomly. In addition, 
the committee will review holds proposed for review by drug sponsors. 
In general, a drug sponsor should consider requesting review when it 
disagrees with the agency's scientific or procedural basis for the 
decision.
    Requests for committee review of a clinical hold should be 
submitted to the FDA Chief Mediator and Ombudsman, who is responsible 
for selecting clinical holds for review. The committee and CDER staff, 
with the exception of the FDA Chief Mediator and Ombudsman, are never 
advised, either in the review process or thereafter, which of the holds 
were randomly chosen and which were submitted by sponsors. The 
committee will evaluate the selected clinical holds for scientific 
content and consistency with agency regulations and CDER policy.
    The meetings of the review committee are closed to the public 
because committee discussions deal with confidential commercial 
information. Summaries of the committee deliberations, excluding 
confidential commercial information, will be available through the 
Freedom of Information Staff (HFI-35), Food and Drug Administration, 
5600 Fishers Lane, Rockville, MD 20857. If the status of a clinical 
hold changes following the committee's review, the appropriate division 
will notify the sponsor.
    FDA invites drug companies to submit to the FDA Chief Mediator and 
Ombudsman the name and IND number of any investigational new drug trial 
that was placed on clinical hold during the past 12 months that they 
want the committee to review at its June meeting. Submissions should be 
made by May 3, 1996, to Amanda B. Pedersen, FDA Chief Mediator and 
Ombudsman (address above).

    Dated: March 28, 1996.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 96-8165 Filed 4-2-96; 8:45 am]
BILLING CODE 4160-01-F