[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
