[Federal Register Volume 60, Number 188 (Thursday, September 28, 1995)]
[Pages 50207-50208]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 95-24072]



Food and Drug Administration

Investigational New 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.


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 new biological product trials. CBER held its 
first clinical hold review committee meeting on May 17, 1995. FDA is 
inviting any interested biological company to use this confidential 
mechanism to submit to the committee for its review the name and number 
of any investigational new biological products trial placed on clinical 
hold during the past 12 months that the company wants the committee to 

DATES: The meeting will be held in October 1995. Biological companies 
may submit review requests for the October meeting before October 10, 

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 and 
pharmacology. 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.
    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 
    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. 
Irrespective of the 30-day time limit permitted by Sec. 312.42(d), CBER 
policy provides that within 15 days of the notification of the clinical 
hold by telephone or other method of rapid communication, the sponsor 
will be provided with a written explanation of the basis for the 
clinical hold. In addition to providing a statement of reasons, this 
ensures that the clinical hold is recorded in CBER'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 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 

[[Page 50208]]
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. The committee last met in June 1995.
    CBER has now begun a similar process to evaluate the consistency 
and fairness of CBER's practices in imposing clinical holds. CBER is 
beginning by instituting a review committee to review recent 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 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 
FDA's 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 FDA's 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 
    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 biological product companies to submit to the FDA Chief 
Mediator and Ombudsman the name and IND number of any investigational 
new biological product trial that was placed on clinical hold during 
the past 12 months that they want the committee to review at its 
October 1995 meeting. Submissions should be made by October 10, 1995, 
to Amanda B. Pederson, FDA Chief Mediator and Ombudsman (address 

    Dated: September 20, 1995.
William K. Hubbard,
Acting Deputy Commissioner for Policy.
[FR Doc. 95-24072 Filed 9-27-95; 8:45 am]