Guidance for Industry
Submitting and Reviewing Complete Responses to Clinical Holds
[PDF version of this guidance]
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
October 2000
User Fees
Revision 1
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Guidance for Industry1
Submitting and Reviewing
Complete Responses to Clinical Holds
This guidance represents the Food and Drug Administration_s current thinking on this
topic. It does not create or confer any rights for or on any person and does not operate
to bind FDA or the public. An alternative approach may be used if such approach satisfies
the requirements of the applicable statutes and regulations.
I. INTRODUCTION
Under Food and Drug Administration (FDA) regulations, an investigational new drug
application (IND) is either allowed to proceed or placed on clinical hold (21 CFR 312.42).
A clinical hold is an order issued by the FDA to the applicant to delay a proposed
clinical investigation or to suspend an ongoing investigation. A clinical hold may be
designated either a complete clinical hold or a partial clinical hold. An
applicant may respond to a clinical hold. Once the applicant has submitted a complete
response to the clinical hold, the Agency must evaluate the response and decide whether to
lift the hold. The Agency has committed itself to respond to the applicant within 30 days.
This guidance is intended to describe how applicants should submit responses to clinical
holds so that they may be identified as complete responses and the Agency can track the
time to response.
We have provided a glossary at the end of this guidance to ensure that key terms are
used consistently.
II. BACKGROUND
Section 117(3)(c) of the Food and Drug Administration Modernization Act of 1997
(Modernization Act) provides that "any written request to the Secretary from the
applicant of an investigation that a clinical hold be removed shall receive a decision, in
writing and specifying the reasons therefor [sic], within 30 days after receipt of such
request._2__In addition, in
conjunction with the reauthorization of the Prescription Drug User Fee Act of 1992
(PDUFA), the Agency committed to user fee performance goals incorporating the same
response time. In her letter to Congress regarding reauthorization of PDUFA, the Secretary
of Health and Human Services endorsed the Agency's commitment to respond to an applicant_s
complete response to a clinical hold within 30 calendar days of the Agency_s receipt of
the applicant's complete response. Beginning in fiscal year (FY) 1998, the Agency
committed to respond to at least 75 percent of complete responses within 30 calendar days
of receipt of the complete response. In fiscal years 1999-2002, the Agency's goal is to
respond to at least 90 percent of the complete responses within 30 calendar days of
receipt of the complete
response.
To implement section 505(i)(3)(C) of the Federal Food, Drug, and Cosmetic Act (the Act)
and the PDUFA goals, in the Federal Register of December 14, 1998, FDA amended its
IND regulations to state that the Agency will respond in writing to a sponsor_s request
that a clinical hold be removed from an investigation within 30 calendar days of the
Agency_s receipt of the request and the sponsor_s complete response to the issues that led
to the clinical hold (21 CFR 312.42(e)).
III. POLICIES AND PROCEDURES
The regulations in 21 CFR 312.42(c) require that when FDA concludes there may be
grounds for imposing a clinical hold, FDA will _attempt to discuss and satisfactorily
resolve the matter with the sponsor before issuing the clinical hold order._ FDA
experience is that most potential holds, particularly those based on inadequate patient
monitoring, can be resolved through such discussion. However, if FDA determines that a
study must be placed on clinical hold, it becomes subject to section 505(i)(3) of the Act.
A. What happens when the Agency imposes a clinical hold?
The Agency communicates the clinical hold to the sponsor, usually in a teleconference.
After an IND has been placed on clinical hold, the study may not be initiated until the
applicant has received a communication (via phone, fax, letter, or e-mail) from the Agency
allowing the study to proceed (21 CFR 312.42(e)).
Within 30 days from the date of the teleconference placing an IND on clinical hold, the
Agency must send the sponsor a clinical hold letter, signed by the Division Director or
Acting Division Director, that describes in detail the reasons for the clinical hold (21
CFR 312.42(d)). The name of the responsible FDA contact will be included in the clinical
hold letter.
The Agency may discuss additional nonhold issues regarding the IND in the clinical hold
letter, or address them in a separate letter to the sponsor. If FDA addresses nonhold
issues in the clinical hold letter, they should be in a separate section of the letter and
be clearly marked as nonhold issues.
If the sponsor addresses all of the clinical hold issues identified in the Agency's
clinical hold letter (a complete response), the Agency must respond to the sponsor
within 30 days of receipt of the complete response (§ 312.42(e)). The 30-day response
clock does not begin until a complete response to the clinical hold is received by the
Agency.
B. How will the FDA measure the PDUFA goals on clinical holds?
The FDA will measure the PDUFA performance goals outlined in the Secretary's letter to
Congress regarding Agency response to sponsors_ complete responses to clinical holds based
on commercial INDs.
C. How will the Agency handle clinical holds that were imposed prior to the
publication of this guidance?
All clinical holds will be tracked for Modernization Act purposes and will be handled
under the procedures described in this guidance, regardless of whether they were initiated
before or after issuance of this guidance.
D. Can I address nonhold issues in my response to the Agency's clinical hold letter?
No, even if the Agency includes nonhold issues in the clinical hold letter, you should
ensure that the complete response to a clinical hold letter contains no material
related to issues other than the IND clinical hold. If you wish to address any nonhold
issues raised by the Agency, please do so in a separate amendment or letter.
E. What else should I include in my response to the clinical hold letter?
If you believe you have responded to all of the issues raised in the clinical hold
letter (i.e., that you are submitting a complete response), you should state this in the
cover letter. Please type in large, bold letters at the top of the cover letter of the
complete response: CLINICAL HOLD COMPLETE RESPONSE.
F. How should I send my response to ensure a timely review by the Agency?
You should send the complete response by a method that ensures that it has been
received by the appropriate FDA document room. To facilitate a response to your
submission, submit the response in triplicate to the IND. You can ensure your submission
is received and handled in a timely way by faxing a copy of the cover letter to the FDA
contact listed in the clinical hold letter who is responsible for the IND.
G. What happens if I think my response is complete, but the FDA disagrees?
If FDA finds that your response is not complete, FDA will notify you as soon as
possible by phone or other means of rapid communication, but no later than 30 days after
receipt of your response. The Agency will tell you what information is needed to
make it a complete response. The 30-day clock will not start until the FDA receives what
it believes to be a complete response to the clinical hold letter.
H. How will the FDA handle an amendment providing additional information to the
complete response that is submitted after the 30-day review clock has started? Will FDA
extend the 30-day review clock?
No. Such an amendment received during the 30-day review process will not extend the
clock. The division may choose to review the amendment in the time remaining, or stop the
30-day clock and start a new 30-day clock based on the receipt date of the amendment.
Amendments to the IND on nonclinical hold issues will be handled in the usual way.
I. What happens once the Agency receives the complete response?
The FDA will review your complete response within 30 calendar days after the receipt of
a complete response, indicating whether the hold is lifted and, if not, specifying the
reasons why not. After an IND has been placed on clinical hold, the study may not be
initiated until the Agency has contacted you (via phone, fax, letter, or e-mail) telling
you that the study may proceed (21 CFR 312.42(e)). (Communications by phone, fax, or
e-mail will be followed by a letter.)
J. What happens if the Agency does not meet the 30-day response deadline?
As soon as possible after the review team determines that it will not meet the 30-day
deadline, the Agency will telephone you and discuss the review progress to date and what
is being done to facilitate completion of the review.
GLOSSARY
Agency's Response to an Applicant's Complete Response: A letter to the applicant
from the Agency in response to an applicant's complete response in which the applicant (1)
is allowed to proceed under the IND as proposed by the applicant (i.e., the clinical hold
is lifted), (2) is allowed to proceed with specific restrictions not proposed by the
applicant (i.e., a partial hold), or (3) is informed that studies under the IND may still
not proceed. In the latter two cases, the letter will set forth why the clinical hold is
being maintained. This letter should be issued to the applicant within 30 calendar days of
receipt of the applicant_s complete response.
Applicant_s Complete Response to an IND Clinical Hold: A response from the
applicant in which all clinical hold issues identified in the clinical hold letter have
been addressed.
Clinical Hold: An order issued by FDA to the sponsor of an IND to delay or to
suspend a clinical investigation for reasons described in 21 CFR 312.42. A clinical
hold may be either a complete clinical hold or a partial clinical hold.
A clinical hold (including a partial clinical hold) involves the Agency (1) requiring
additional information and/or data, (2) reviewing the additional information and/or data,
and (3) after the review, informing the sponsor that they can proceed. The Agency has not
imposed a clinical hold if it requests additional information and/or data from the
sponsor, but the sponsor does not have to wait for FDA review and authorization to proceed
before initiating a new protocol.
_ Complete Clinical Hold: A delay or suspension of all clinical work requested
under an IND.
_ Partial Clinical Hold: A delay or suspension of only part of the clinical work
requested under the IND (e.g., a specific protocol or part of a protocol is not allowed to
proceed; however, other protocols or parts of the protocol are allowed to proceed under
the IND).
Commercial IND: An IND for which the sponsor is usually a corporate entity.
Other INDs may be designated as commercial if it is clear the sponsor intends the product
to be commercialized at a later date. INDs from the National Institutes of Health (NIH)
will not be classified as commercial INDs until such time as the division determines that
commercial development is being pursued.
30-day Response Clock: The FDA is required by the Modernization Act to respond
in writing to the applicant within 30 calendar days after receipt of the applicant's
complete response to a clinical hold (§ 312.42(e)).
1 This guidance has been prepared by
the Review Management Working Group comprising individuals from the Center for Drug
Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER)
at the Food and Drug Administration. (OMB control number 0910-0445)
On June 1, 1998, the President instructed all Federal agencies to ensure the use of
plain language in all new documents. This guidance reflects Agency efforts to comply with
the President's plain language initiative.
2 Section 117(3)(c) of the
Modernization Act is codified in the Federal Food, Drug, and Cosmetic Act at 505(i)(3)(C).
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