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THE COMMITTEE ON HUMAN RESEARCH
UCSF GUIDANCE ON RESEARCH TOPICS AND ISSUES
INVESTIGATIONAL NEW DRUGS AND BIOLOGICS (IND)
(June
2004, Revised May 2006, Revised February 2008)
Brief Overview
Food and Drug Administration (FDA) regulations 21 CFR
312 (drugs) and 601 (biologics) contain procedures and requirements governing
the use of investigational new drugs and biologics. All clinical research
projects involving drugs or biologics which are not FDA-approved for marketing
must be reviewed by the FDA. This is done by filing an Investigational
New Drug Application (IND).
When is an IND
Required?
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Any use of a drug or
biologic not approved for marketing by the FDA, even if no study
is being
conducted. |
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Studies involving a drug or biologic that
is not approved by the FDA. |
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Studies involving an approved (i.e., commercially
available) drug or biologic that is being tested to support a
new indication or significant change in labeling of the drug
or biologic. |
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Studies involving an approved drug or biologic
that is being tested to support a significant change in advertising
for the drug or biologic. |
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Studies involving an approved drug or biologic
that is being used or tested in a new route of administration,
new dosage level, or new patient population that may increase
the risk of the drug or biologic. |
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When is
an IND Not Required?
Please review the HRPP information sheet, Exemptions from IND Requirements for a complete list of all types of investigations which are exempt from FDA IND requirements, according to 21 CFR 312.2.
Additional discussion is provided below for clinical research of approved drugs or biologics.
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Clinical Studies: Any clinical
investigation of a marketed drug or biologic requires CHR review
and approval. An IND is not required if all of the following conditions
are met: |
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It is not intended to be reported to the FDA
in support of a new indication for use or to support any other
significant change in the labeling; and |
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It is not intended to support a significant
change in the advertising for the product; and |
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It does not involve a route of administration
or dosage level, use in a subject population, or other factor that
significantly increases the risks (or decreases the acceptability
of the risks) associated with the use of the product; and |
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It is conducted in compliance with the requirements
for IRB review and informed consent [21 CFR parts 50 and 56 respectively];
and |
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It is conducted in compliance with
the requirements concerning the promotion and sale of drugs [21
CFR 312.7].
NOTE: Even when there is no immediate intent
to change product labeling or advertising, investigators who
are planning rigorous, carefully controlled clinical investigations
of an off-label uses of approved drugs or biologics should obtain
an IND for the study. The CHR has serious concerns about conducting
such studies without an IND because the data, even if positive
and important for public health, will not be considered by the
FDA.
Example: An investigator
proposes a small pilot study of an approved drug for a novel
use and states that an IND is not needed because the data will
not be submitted to the FDA. The investigator explains that if
the pilot data looks promising a larger trial will be submitted
with an IND. The CHR is likely to approve the pilot study without
an IND because a small pilot study is an appropriate first step
in determining whether a change in labeling should be sought.
Example: An investigator proposes a multicenter
randomized trial of an approved drug for a novel use and states
that an IND is not needed because the data will not be submitted
to the FDA. The CHR is not likely to approve the study without
an IND because the data could be important and should be considered
by the FDA. |
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Off-Label Prescriptions:
Neither an IND nor CHR review is required for off-label use of
a marketed drug or biologic as long as such use is strictly for
clinical purposes, and the results are not presented as research. |
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Types of IND Applications
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Timing the IND
Submission
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Pre-IND Advice: Investigators
considering submitting an IND application to the FDA should consult
the FDA’s
Office
of Drug Evaluation IV (ODE IV) Pre-IND Consultation Program before submitting an IND application. |
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The IND Submission: The IND submission to the FDA
and the CHR application should be initiated at the same time. The
FDA has 30 days to review the IND application. Likewise, the CHR
typically reviews an application within a 30-day window, but it
may take longer to secure approval. Subjects may not be recruited
or enrolled before FDA and CHR approval. |
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CHR Application
Requirements
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IND Number - When an investigation
requires an IND number, the CHR will not issue final approval until
the IND number is reported to and verified by the CHR. Verification can be accomplished by providing a copy of the sponsor's protocol with the IND number listed, or by submitting correspondence from the sponsor or FDA indicating the IND number for the study. However, the CHR will review
the research before the IND application is submitted to the FDA. The
FDA does not require local IRB approval before issuing IND numbers. |
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Investigator’s Brochure - For
any study involving an investigational drug or biologic, one copy
of the Investigator’s Brochure must be submitted with the CHR
application. |
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Protocol – If there
is a sponsor’s, multicenter, or “full” protocol,
one copy of that protocol must accompany the CHR application. |
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FDA Form 1572 – This form is required for FDA
purposes and does not need to be submitted to the CHR. |
Consent Form
Requirements
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Purpose and Background Section: |
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Must include a clear statement that the drug
or biologic is investigational and has not been approved or, if
studying an approved drug or biologic, that it is approved but
not for the use being studied. |
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Should include a brief lay description of what
the drug or biologic is and how it is thought to act. |
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Must not state or imply that the issuance of
an IND is an approval or endorsement by the FDA. |
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Confidentiality Section: |
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Must state that the FDA may review subjects’ medical
records and research records which identify the subjects. |
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Alternatives Section: |
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If studying an approved drug or biologic, must
explain that subjects can receive drug or biologic without participating
in the study. An exception to this may be granted if the off-label
prescription of the drug or biologic is unrealistic or unsafe outside
of a carefully controlled clinical study. |
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Costs Section: |
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Must state how the costs of the study drug or
biologic will be covered. |
Control of Investigational
Drugs and Biologics
Local Dispensing Policies and Regulations
Hospitals or other clinical settings have their own
policies regarding the use of investigational drugs and biologics in
order to assure patient safety and comply with JCAHO standards, California
law, and California Department of Health Services regulations. Investigators
conducting research in clinical settings other than those listed below
should consult those local policies and the personnel charged with
compliance with those policies. Consultation should take place before
preparing the budget for the clinical study.
UCSF Medical Center Policies can be found at:
InvestigationalNewDrugs.pdf
| Investigational Drug Pharmacists: |
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Parnassus / Mt Zion campus: |
Scott Fields, PharmD 415.353.1798 |
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UCSF/Mt Zion Cancer Center: |
Monica Lee, PharmD 415.353.7052 |
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San Francisco VAMC: |
Henry Leung, PharmD 415.221.4810 x 2925 |
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San Francisco General Hospital: |
David Dupre, PharmD 415.206.4926
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Investigator Responsibilities for Control of Investigational
Drugs/Biologics
Investigators conducting studies in which an investigational drugs/biologics
will be used must ensure adequate control of the drug or biologic.
Adequate control and handling of investigational drug/biologic include
all of the following:
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The investigator should ensure that
the investigational drug/biologic is used only in accordance with
the CHR-approved protocol. |
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An investigator must administer the investigational
drug/biologic only to participants under the investigator’s
direct personal supervision or under the supervision of a sub-investigator
directly responsible to the investigator. |
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The investigator must not supply the investigational
drug/biologic to any person not authorized to receive it. |
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An investigator is required to maintain adequate
records of the disposition of the investigational drug/biologic,
including dates of dispensing, quantity currently maintained for
dispensing, and amount of the investigational product dispensed
to participants. |
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If the investigation is terminated, suspended,
discontinued, or completed, the investigator must return any unused
supplies of the investigational drug/biologic to the study sponsor,
or otherwise provide for disposition of the unused supplies as
directed by the sponsor. |
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If the investigational drug is subject to the
Controlled Substances Act, the investigator must take adequate
precautions, to prevent theft or diversion of the substance into
illegal channels of distribution. These precautions include: storage
of the investigational drug in a securely locked, substantially
constructed cabinet, or other securely locked, substantially constructed
enclosure to which access is limited. |
Sample Investigational Agent Accountability Record
Adverse Event
Reporting Under federal regulations for the protection
of human subjects in research both the Committee on Human Research
(CHR) and the FDA require that adverse events associated with research
participation be reported in an expedited manner.
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Investigator’s
Responsibilities: All investigators have an obligation to report
certain adverse events (AE) directly to the IRB. Please review
the CHR Guidelines on Adverse Event Reporting for a detailed
description of the CHR reporting requirements.
When an IND is issued, there are additional and separate federal
requirements for reporting adverse events to the FDA. When
the study sponsor holds the IND, investigators need to report
all adverse events to the sponsor and the sponsor will submit
appropriate reports to the FDA.
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Investigator-Sponsor
Responsibilities: An Investigator who files an IND is also said
to “hold the IND” for the specific study protocol.
Investigators who hold an IND (investigator-initiated/investigator-sponsor
IND) have responsibilities for reporting AEs to the FDA as well
as the CHR. In addition to reporting to the CHR, an investigator-sponsor
must directly report the following AE information to the FDA: |
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Within 7 calendar days after
the study sponsor’s
initial receipt of the information. The sponsor should notify
the FDA by telephone or by facsimile transmission of any unexpected
fatal or life-threatening experience associated with the use
of the drug. |
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Within 15 calendar days after
the sponsor’s
initial receipt of the information. The sponsor should notify
the FDA and all participating investigators in a written IND
safety report of:
(A) Any adverse experience associated with the use of the drug that is both serious
and unexpected; or
(B) Any finding from tests in laboratory animals that suggests a significant
risk for human subjects including reports of mutagenicity, teratogenicity, or
carcinogenicity. |
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Additionally, an investigator-sponsor is
responsible for reporting safety information to the FDA: |
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“The sponsor shall promptly review all
information relevant to the safety of the drug obtained or otherwise
received by the sponsor from any source, foreign or domestic,
including 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 agency
by the sponsor” (21 CFR 321.32(b)). |
Additional
Reporting Obligations for Investigators-Sponsors
When an Investigator files an IND, the Investigator is considered
the Sponsor and as such carries all of the FDA regulatory responsibilities
and reporting obligations of both the Investigator and Sponsor as outlined
below described in the FDA regulations 21
CFR 312 (drugs) and
21
CFR 601 (biologics). Please refer to the regulations for complete information.
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FDA reporting obligations
of investigators under an IND include: |
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Drug disposition |
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Case histories |
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Progress reports |
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Safety reports |
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Final report |
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Financial disclosure report |
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Specific record keeping and record retention |
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FDA reporting obligations
of sponsors under an IND include: |
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Protocol amendments |
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Information amendments |
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IND Safety Reports |
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Annual Reports |
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Withdrawal of an IND |
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Specific record keeping and retention |
Resources
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