[Federal Register Volume 60, Number 163 (Wednesday, August 23, 1995)]
[Notices]
[Pages 43804-43805]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 95-20812]




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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration


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 June 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 will be held in October 1995. Drug companies may 
submit review requests for the October meeting before September 22, 
1995.

 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, 301-443-1306.

FOR FURTHER INFORMATION CONTACT: Deborah A. Wolf, Center for Drug 
Evaluation and Research (HFD-362), Food and Drug Administration, 7500 
Standish Pl., Rockville, MD 20855, 301-594-1046.

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 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 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 in 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 or on behalf of the 

[[Page 43805]]
director of the 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 
30 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 30 
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 in Sec. 312.48 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. First, CDER 
completed a centerwide review of clinical holds recorded in the 
management information system. While some differences in practice and 
procedure were discerned among divisions, it appeared that the 
procedures specified in the regulations were, in general, being 
followed, and that holds were scientifically supportable.
    Second, FDA established 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 June 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 from the FDA 
Chief Mediator and Ombudsman. 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 October meeting. Submissions should 
be made by September 22, 1995 to Amanda B. Pedersen, FDA Chief Mediator 
and Ombudsman (address above).

    Dated: August 15, 1995.
William K. Hubbard,
Acting Deputy Commissioner for Policy.
[FR Doc. 95-20812 Filed 8-22-95; 8:45 am]
BILLING CODE 4160-01-F