[Federal Register Volume 61, Number 8 (Thursday, January 11, 1996)]
[Notices]
[Pages 1032-1033]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 96-417]



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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Investigational Biological Product Trials; 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 Biologics Evaluation and Research (CBER) has placed 
on certain investigational biological product trials. CBER held its 
first clinical hold review meeting on May 17, 1995. FDA is inviting any 
interested biological product company to use this confidential 
mechanism to submit to the committee for its review the name and number 
of any investigational biological product 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 February 1996. Biological product 
companies may submit review requests for the February meeting by 
January 30, 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: Joy A. Cavagnaro, Center for Biologics 
Evaluation and Research (HFM-2), Food and Drug Administration, 1401 
Rockville Pike, Rockville, MD 20852-1448, 301-827-0379.
SUPPLEMENTARY INFORMATION: FDA regulations in part 312 (21 CFR part 
312) provide procedures that govern the use of investigational new 
drugs and biologics 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 product. The IND must contain the study protocol, a 
summary of human and animal experience with the product, and 
information on the product's characterization, chemistry, pharmacology, 
and toxicology. FDA reviews an IND to help ensure the safety and rights 
of human subjects of research and to help ensure that the quality of 
any scientific evaluation of a drug is adequate to permit an evaluation 
of the product's efficacy and safety.

[[Page 1033]]

    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 or biologic 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 or biologic 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 or biologic, and 
patients already in the study should stop receiving therapy involving 
the investigational drug or biologic 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 clinical 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. -
    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 clinical hold applies 
and explains the basis for the action. The clinical hold order may be 
made by telephone or other means of rapid communication, or in writing. 
Following notification of the clinical hold by telephone or other means 
of rapid communication, CBER promptly provides the sponsor with a 
written explanation of the basis for the clinical hold.
    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 without notification, 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, the sponsor may request a meeting with 
the review staff and management to discuss the clinical 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 for Drug Evaluation and Research's (CDER's) practices in 
imposing clinical holds. First, CDER completed a centerwide review of 
clinical holds recorded in their management information system. While 
some differences in practice and procedure were discerned among 
divisions in CDER, it appeared that the procedures specified in the 
regulations were, in general, being followed, and that clinical 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 met quarterly 
through 1992. The committee currently meets semiannually as a regular 
program.
    CBER began a similar process to evaluate the consistency and 
fairness of CBER's practices in imposing clinical holds by instituting 
a review committee to review clinical holds. CBER also plans to conduct 
further quality assurance oversight of the IND process. CBER held its 
first clinical hold review committee meeting on May 17, 1995, and 
intends to make the clinical hold review process a regular, ongoing 
program. The committee last met in October 1995. 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 clinical hold 
to have that clinical hold considered ``anonymously.'' The committee 
consists of senior managers of CBER, a senior official from CDER, and 
the FDA Chief Mediator and Ombudsman.
    Clinical holds to be reviewed will be chosen randomly. In addition, 
the committee will review clinical holds proposed for review by 
biological product sponsors. In general, a biological product 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 CBER staff, 
with the exception of the FDA Chief Mediator and Ombudsman, are never 
advised, either in the review process or thereafter, which of the 
clinical 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 CBER 
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, may be requested in writing from 
the Freedom of Information Office (HFI-35), Food and Drug 
Administration, rm. 12A-16, 5600 Fishers Lane, Rockville, MD 20857, 
approximately 15 working days after the meeting, at a cost of 10 cents 
per page. If the status of a clinical hold changes following the 
committee's review, the appropriate division will notify the sponsor.
    FDA invites biological product companies to submit to the FDA Chief 
Mediator and Ombudsman the name and IND number of any investigational 
biological product trial that was placed on clinical hold during the 
past 12 months that they want the committee to review at its February 
1995 meeting. Submissions should be made by January 30, 1996, to Amanda 
B. Pedersen, FDA Chief Mediator and Ombudsman (address above).

    Dated: January 4, 1996.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 96-417 Filed 1-9-96; 9:27 am]
BILLING CODE 4160-01-F