[Federal Register Volume 59, Number 27 (Wednesday, February 9, 1994)]
[Unknown Section]
[Page 0]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 94-2882]


[[Page Unknown]]

[Federal Register: February 9, 1994]


-----------------------------------------------------------------------


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.

-----------------------------------------------------------------------

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. The experimental phase of the committee process has 
concluded, and FDA has decided that the committee will now meet 
semiannually as a regular program. 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 March 1994. Drug companies may 
submit review requests for the March meeting before March 11, 1994.

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 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 at 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 at 21 CFR 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 which 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 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 this 
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 21 CFR 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 center-wide 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 agency now has decided to make the clinical hold committee 
review process 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 FDA's Chief Mediator and Ombudsman. The 
committee will meet semiannually. The March meeting will be the second 
meeting after the close of the experimental stage of the committee.
    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 request review when it disagrees with 
the agency's scientific conclusions.
    Requests for committee review of a clinical hold should be 
submitted to FDA's Chief Mediator and Ombudsman, who is responsible for 
selecting clinical holds for review. The committee and CDER staff (with 
the exception of the 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 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 March meeting. Submissions should 
be made by March 11, 1994, to Amanda B. Pedersen, FDA Chief Mediator 
and Ombudsman (address above).

    Dated: February 2, 1994.
Michael R. Taylor,
Deputy Commissioner for Policy.
[FR Doc. 94-2882 Filed 2-8-94; 8:45 am]
BILLING CODE 4160-01-F