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Last revised 8-31-07
Required Reports to a FDA-Accepted Investigational
New Drug (IND) Application
IND Safety Reports
A. Adverse Event Definitions
1. Adverse event
2. Associated with the use of the drug or study treatment(s).
3. Disability.
4. Life-threatening adverse event.
5. Serious adverse event.
6. Unexpected adverse event.
B. Review of Safety Information: Sponsor Responsibilities
C. IND Safety Reports: Notification Requirements and Format
1. Requirements for written IND Safety Reports.
2. Requirements for telephone or facsimile transmission of IND Safety
Reports.
3. Requirements for followup to submitted IND Safety Reports.
4. Alternate IND Safety Report formats and frequency.
II. IND Annual Reports
A. Individual Clinical Study Information
B. Summary of Investigational Drug Information
C. General Investigational Plan
D. Investigator Brochure Revisions
E. Phase 1 Protocol Modifications
F. Foreign Market Developments
G. Outstanding FDA Business
III. IND Withdrawal or Discontinuation Notice
A. Notification Requirements: General
B. Notification Requirements: Safety Issues
I. IND Safety Reports 1
A. Adverse Event Definitions:
1. Adverse event. Any untoward medical occurrence in a clinical study;
regardless of the causal relationship of the event with the
investigational drug or study treatment(s).
2. Associated with the use of the drug or study treatment(s). There is a
reasonable possibility that the experience may have been caused by
the drug or study treatment(s).
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21 CFR Section 312.32
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Last revised 8-31-07
3. Disability. A substantial disruption of a person’s ability to conduct
normal life functions.
4. Life-threatening adverse event. Any adverse event that places the
patient or subject, in the view of the investigator, at immediate risk of
death from the reaction as it occurred (i.e., does not include a reaction
that, had it actually occurred in a more severe form, might have caused
death).
5. Serious adverse event. Any adverse event occurring at any dose that
results in any of the following outcomes: death, a life-threatening
adverse event, inpatient hospitalization or prolongation of existing
hospitalization, a persistent or significant disability/incapacity, or a
congenital anomaly/birth defect.
Important medical events that may not result in death, be life-
threatening, or require hospitalization may be considered a serious
adverse event when, based upon appropriate medical judgment,
they may jeopardize the patient or subject and may require medical
or surgical intervention to prevent one of the outcomes listed in this
definition. Examples of such medical events include allergic
bronchospasm requiring intensive treatment in the emergency room
or at home, blood dyscrasias or convulsions that do not result in
inpatient hospitalization, or the development of drug dependency or
drug abuse.
6. Unexpected adverse event. Any adverse event, the frequency,
specificity or severity of which is not consistent with the current
investigator brochure; or, if an investigator brochure is not required or
available, the frequency, specificity or severity of which is not
consistent with the risk information described in the general
investigational plan or elsewhere in the current application, as
amended.
For example, under this definition, hepatic necrosis would be
unexpected (i.e., by virtue of greater severity) if the current version
of the investigator brochure (or investigational plan or IND
application) only referred to elevated hepatic enzymes or hepatitis.
Similarly, cerebral thromboembolism and cerebral vasculitis would
be unexpected (i.e., by virtue of greater specificity) if the current
version of the investigator brochure (or investigational plan or IND
application) only listed cerebral vascular accidents.
“Unexpected” as used in this definition, refers to an adverse event
that has not been previously observed (i.e., addressed in the
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investigator brochure and/or in the investigational plan or IND
application) rather than from the perspective of such an event not
being anticipated from the pharmacological properties of the
pharmaceutical product.
B. Review of Safety Information: Sponsor Responsibilities 2
The sponsor of the corresponding IND application shall promptly
review all information relevant to the safety of the drug that is obtained
or otherwise received by the sponsor from any source, foreign or
domestic, include information derived from any clinical or
epidemiological investigations, animal investigations, commercial
marketing experience, reports in the scientific literature, and
unpublished scientific papers; as well as reports from foreign
regulatory authorities that have not already been previously reported to
the FDA by the sponsor.
Note: The requirements of the sponsor for the reporting of adverse
drug experiences to the FDA (see below, C. IND Safety Reports:
Notification Requirements and Format) differ from the requirements of
the investigator for the reporting of adverse events to the sponsor (see
Investigator Responsibilities) and may differ from the requirements of
the investigator for the reporting of adverse events to the reviewing
Institutional Review Board (IRB). Investigator-sponsors of IND
applications are subject to compliance with both the adverse event
reporting requirements of the sponsor and the requirements of the
investigator.
C. IND Safety Reports: Notification Requirements and Format
1. Requirements for written IND Safety Reports.
The sponsor shall notify the FDA and all participating investigators
in a written IND Safety Report of:
o Any human adverse event that is (i) Associated with the use of
the drug or study treatment(s); and (ii) both Serious and
Unexpected.
Note: A sponsor of a clinical research study of a marketed
drug is not required to make a Safety Report for any adverse
event that occurs as a result of the use of the drug outside of
the respective clinical research study. 3
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21 CFR Sec. 312.32 (b)
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21 CFR Sec. 312.32 (c)(4)
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Last revised 8-31-07
o Any finding from tests in laboratory animals that suggests a
significant risk for human subjects including reports of
mutagenicity, teratogenicity, or carcinogenicity.
Each written IND Safety Report shall be made as soon as possible
and in no event later than 15 calendar days after the sponsor’s
receipt of the respective adverse event information or laboratory
animal data.
Written IND Safety Reports addressing a human adverse event
should be submitted on a FDA Form 3500A; written reports of
animal data shall be submitted in narrative format.
o Each written IND Safety Report shall bear prominent
identification of its contents; i.e., “IND Safety Report”.
o Each written IND Safety Report shall be submitted to the
applicable new drug review division within the FDA’s Center for
Drug Evaluation and Research (CDER) or product review
division within the FDA’s Center for Biologics Evaluation and
Research that has responsibility for review of the respective IND
application.
o In each written IND Safety Report, the sponsor shall identify all
previously submitted IND Safety Reports concerning a similar
adverse event and shall analyze the significance of the adverse
event in light of the previous, similar reports.
2. Requirements for telephone or facsimile transmission of IND Safety
Reports.
In addition to the subsequent submission of a written IND Safety
Report, the sponsor shall notify the FDA by telephone or by
facsimile transmission of any human adverse event that is (i)
Associated with the use of the drug; (ii) Unexpected; and (iii) Fatal
or Life-threatening.
o Note: A sponsor of a clinical research study of a marketed drug
is not required to make a Safety Report for any adverse event
that occurs as a result of the use of the drug outside of the
respective clinical research study. 4
The telephone or facsimile transmission of applicable IND Safety
Reports shall be made as soon as possible but in no event later
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21 CFR Sec. 312.32 (c)(4)
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Last revised 8-31-07
than 7 calendar days after the sponsor’s initial receipt of the
respective human adverse event information.
o Telephone or facsimile transmission of applicable IND Safety
Reports shall be to the applicable new drug review division
within the FDA’s Center for Drug Evaluation and Research
(CDER) or product review division within the FDA’s Center for
Biologics Evaluation and Research that has responsibility for
review of the respective IND application.
3. Requirements for follow-up to submitted IND Safety Reports.5
All safety information received by the sponsor shall be promptly
investigated.
Follow-up information to an IND Safety Report shall be submitted to
the applicable review division of the FDA as soon as the relevant
information is available.
If the results of a sponsor’s investigation show that an adverse drug
experience that was initially determined to not require a written IND
Safety Report does, in fact, meet the requirements for reporting; the
sponsor shall submit a written IND Safety Report as soon as
possible, but in no event later than 15 calendar days after the
determination is made.
Results of a sponsor’s investigation of other safety information shall
be submitted, as appropriate, in an Information Amendment or
Annual Report.
4. Alternate IND Safety Report formats and frequency.
The FDA may request a sponsor to submit IND Safety Reports in a
format or at a frequency that differ from the standard requirements
outlined above. The sponsor may also propose and adopt a different
IND Safety Report format or frequency; provided that the change is
agreed to in advance by the director of the new drug review division of
the FDA’s Center for Drug Evaluation and Research (CDER) or
product review division of the FDA’s Center for Biologics Evaluation
and Research that has responsibility for review of the respective IND
application.
II. IND Annual Reports 6
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21 CFR Sec. 312.32 (d)
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21 CFR Sec. 312.33
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A sponsor shall annually submit, within 60 days of the anniversary date that
the IND application was accepted by the FDA, a brief report of the progress of
the investigation that includes:
A. Individual Clinical Study Information
To include a brief summary of the status of each clinical study in progress
and each study completed during the previous year. The summary is
required to include the following information for each study:
1. The title of the study (with any appropriate study identifiers such as a
protocol number);
2. The purpose of the study;
3. A brief statement identifying the patient population;
4. A statement as to whether the study is ongoing or completed;
5. The total number of subjects initially planned for inclusion in the study;
6. The total number of subjects entered into the study to date, tabulated
by age group, gender, and race;
7. The number of subjects for whom participation in the study was
completed as planned;
8. The number of subjects who dropped out of the study early for any
reason; and
9. If the study has been completed, or if interim results are known, a brief
description of any available study results.
B. Summary Investigational Drug Information
To include a summary of information about the investigational drug
obtained during the previous year’s clinical and nonclinical investigations;
including:
1. A narrative or tabular summary documenting the most frequent and
most serious adverse reactions by body system;
2. A summary of all IND Safety Reports submitted during the previous
year;
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3. A list of subjects who died during participation in the investigation (i.e.,
inclusive of all studies conducted under the IND) whether or not
thought to be related to the investigational drug, with the cause of
death listed for each subject;
4. A list of subjects who dropped out during the course of the
investigation (i.e., inclusive of all studies conducted under the IND) in
association with any adverse experience (co-listed), whether or not
thought to be related to the investigational drug.
5. A brief description of what information, if any, was obtained that is
pertinent to an understanding of the drug’s actions; including, for
example, information about dose response, information from controlled
trials, and information about bioavailability.
6. A list of the preclinical studies (including in-vitro and animal studies)
completed or in progress during the past year and a summary of the
major preclinical findings.
7. A summary of any significant manufacturing or microbiological
changes made during the past year.
C. General Investigational Plan
To include a description of the general investigational plan for the coming
year (i.e., to replace the general investigational plan submitted the
previous year). The general investigational plan shall contain the following
information:
2. The rationale for the drug or the research study;
3. The indication(s) to be studied;
4. The general approach to be followed in evaluating the drug;
5. The kinds of clinical trials to be conducted in the following year (if plans
are not developed for the entire year, the sponsor should so indicate);
6. The estimated number of patients or subjects to be given the drug in
those studies; and
7. Any risks of particular severity or seriousness anticipated on the basis
of the toxicological data in animals or prior studies in humans with the
drug or related drugs.
D. Investigator Brochure Revisions
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If the investigator brochure (if applicable) has been revised, include a
description of the revision and a copy of the new brochure.
E. Phase 1 Protocol Modifications
To include a description of any significant Phase 1 protocol modifications
made during the previous year and not previously reported to the IND in a
protocol amendment.
F. Foreign Market Developments
To include a brief summary, if applicable, of significant foreign market
developments with the drug during the past year; such as approval of
marketing in any country or withdrawal or suspension from marketing in
any country.
G. Outstanding FDA Business
If desired by the sponsor, include a log of any outstanding business with
respect to the IND for which the sponsor requests or expects a reply,
comment or meeting from or with the FDA.
III. IND Withdrawal or Discontinuation Notice 7
At any time, a sponsor may withdraw an effective IND without prejudice.
A. Notification Requirements: General
If an IND is withdrawn by the sponsor, the sponsor shall so notify the FDA,
all current participating investigators, and all reviewing Institutional Review
Boards (IRBs).
1. All clinical investigations conducted under the IND shall be terminated.
2. All stocks of the investigational drug shall be returned to the sponsor or
otherwise disposed of at the request of the sponsor. (See Sponsor
Responsibilities: Investigational Drug Accountability)
B. Notification Requirements: Safety Issues
If an IND is withdrawn because of a safety reason, the sponsor shall
promptly so notify the FDA, all (current and past) participating
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21 CFR Sec. 312.38
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investigators, and all reviewing Institutional Review Boards (IRBs); to
include the safety issue(s) leading to the decision to withdraw the IND.
1. All clinical investigations conducted under the IND shall be terminated.
2. All stocks of the investigational drug shall be returned to the sponsor or
otherwise disposed of at the request of the sponsor. (See Sponsor
Responsibilities: Investigational Drug Accountability)
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