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Exposing
humans to any drugs, biological agents, chemicals, or any
other non-food substance in support of research typically
makes the research subject to Food & Drug Agency (FDA)
regulations. As a result researchers must comply with additional
FDA requirements before beginning the research. Different
requirements apply depending on the prior approval status
of the agent, how it is being used, the subject population
being used, the affect on the risk/benefit ratio associated
with the use of the drug, if the study is meant to support
a new indication, etc. The following table outlines the
primary different types of research and what if anything
must be done to comply with FDA regulations.
|
Type
of research |
FDA
Requirements? |
| 1 |
Investigational
new drug (no prior FDA approval) |
IND
required - FDA must be contacted <click
here> |
| 2 |
FDA
approved/marketed drug used in accordance with package
insert, approved indications, approved routes of administration,
and/or approved subject populations (prior FDA approval)
in a clinical investigation |
No
IND required |
| 3 |
FDA
approved/marketed drug used in a manner not previously
approved - new indications, different route, different
patient/subject population - in support of clinical
research, regardless of whether the drug is the central
object of the research |
FDA
must be contacted and investigator must either obtain an
(a) IND, or (b) official written determination from
the FDA that an IND is not required.<click
here> |
| 4 |
FDA
approved/marketed drug used in a research protocol that
increases the risk (or decreases the acceptability of
risk) to the subject population engaged in the clinical
investigation. |
FDA
must be contacted and investigator must either obtain
an
(a) IND, or (b) official written determination from
the FDA that an IND is not required.<click
here> |
| 5 |
Any
other chemical, biologic, or non-food item administered
to subjects in support of a clinical investigation,
regardless of whether the item is the central object
of the research. |
FDA
must be contacted and investigator must either obtain
an
(a) IND, or (b) official written determination from
the FDA that an IND is not required.<click
here> |
| 6 |
Non-FDA
regulated chemicals, including both substances given
to induce a physiologic effect and substances that serve
as markers or tracers, regardless of whether the item
is the central object of research |
If
a substance to be used in research is not manufactured
specifically for use in humans and is not listed in
the U.S. Pharmacopeia as intended for use in humans
or is not subject to FDA oversight, the IRB protocol
must contain the following information pertaining to
the substance:
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- A
review, based on the published literature, of the
mechanism of action, potential risks, and accumulated
experience with the use of the substance. If no
animal or human safety data exists, the investigator
must present safety data from a scaled dose test.
Generally, a 500x scaled dose study in mice or rats
will meet this requirement, but other model systems
may be used depending upon the nature of the substance
to be tested.
- A
statement, based on appropriate calculations, as
to whether the substance will be administered in
an amount that would be expected to have a pharmacologic
effect. An estimate should be provided of the size
of the dose to be administered relative to the total
physiologic pool of the substance, in cases where
tracers are used that are analogs of naturally occurring
molecules. Most commonly this would be stated as
a percentage of the total pool.
- A
statement of the source (manufacturer) and whether
the substance is synthetic or purified from biological
sources.
- Documentation
of the purity of the substance to be administered.
The preferred form of documentation is a Certificate
of Analysis from an analytical laboratory. As a
general rule, if the substance contains impurities,
the nature of these impurities must be known and
stated. Purity may be documented by standard methods
such as mass spectroscopy and liquid chromatography.
If a commercial laboratory is used, documentation
should be provided that the laboratory uses FDA
Good Laboratory Practice (GLP) methods. If assays
of purity are performed by a noncommercial laboratory,
the methods should be USP standard, and the appropriate
USP methodology reference provided.
- Documentation
of the sterility and pyrogen-free characteristics
of the specific batch(es) to be used in the research.
The methods used in this determination should be
included in the Research Plan, and follow USP methodologies,
and/or be performed by a GLP laboratory.
- Documentation,
from published literature or specific testing (preferably
using the same method as noted in c.), of the chemical
stability of the substance.
- A
description of the formulation of the substance,
including the physical description of the substance
as received from the manufacturer, what solution
the substance is dissolved in for administration,
how it will be administered, and its expected toxicities.
- For
research involving radioactive isotopes, a separate
application to the appropriate Radioactive Drug
Research Committee (RDRC) - either VA or UCSD--
is required. The RDRC will review the proposed use
under criteria listed in federal regulation 21CFR361.1
and report its decision to the IRB. These criteria
include both pharmacologic and radiation dose limits,
and an assessment of whether the radiation exposure
is justified on a risk-benefit basis.
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FDA
office Center for Drug Evaluation and Research (CDER)
FDA
Regulations: 51 CFR 312 Subchapter D- Drugs for Human Use
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=312
Biopharmaceutical Development Program - Sponsor's Guide to Regulatory Submissions for an Investigational New Drug
The following document provides useful information about what is required to obtain IND approval for new drugs (no prior FDA approval).
http://wwwbdp.ncifcrf.gov/pdf/GuidetoRegSubs.pdf
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