Return to Index Page
Institutional Review Board * CHAPTER II * A. Department of Health and Human Services Regulations, Policies, and Assurances
B. Food and Drug Administration Regulations and Policies
Waiver of IRB Review Treatment Investigational New Drug Exemption Suggestions for Further Reading
A. DEPARTMENT OF HEALTH AND HUMAN SERVICES OVERVIEW Until 1991, federal departments and agencies that conduct, support, or regulate research
used a variety of policies and procedures to protect human research subjects. To eliminate
confusion and promote uniformity, each of these departments and agencies has adopted as
regulation a common Federal Policy for the protection of human research subjects. The
Federal Policy applies to research involving human subjects that is conducted, supported,
or otherwise subject to regulation by any of the following sixteen federal departments and
agencies: Department of Agriculture The FDA has concurred in the Federal Policy, but has not adopted the Policy in its entirety.
Instead, the FDA has made selected changes to its IRB and informed consent regulations
that correspond to the Federal Policy. [See Federal Register 56 (June 18, 1991):
28025-28029.] Where a protocol is subject to review under more than one department or agency's
regulations, the requirements of each set of regulations must be met. This situation may
arise, for example, with Treatment INDs, or when applying the provisions on waiver of
documentation of informed consent, in cases where both the FDA and DHHS have
jurisdiction over the research. (See, e.g., Guidebook Chapter 2, Section B, "Food and Drug
Administration Regulations and Policies," discussing Treatment INDs, and Chapter 2,
Section A(ii), "45 CFR 46: Most Frequently Asked Questions," question 10.) The adoption of the Federal Policy by these departments and agencies implements a
recommendation of the President's Commission for the Study of Ethical Problems in
Medicine and Biomedical and Behavioral Research (established by Act of Congress on
November 9, 1978) that all federal departments and agencies "adopt as a common core the
regulations governing research with human subjects issued by the Department of Health and
Human Services (codified at 45 CFR 46), as periodically amended or revised, while
permitting additions needed by any department or agency that are not inconsistent with these
core provisions." The resulting Federal Policy was drafted by the Ad Hoc Committee for
the Protection of Human Research Subjects and the Interagency Human Subject
Coordinating Committee, appointed under the auspices of the Federal Coordinating Council
for Science, Engineering and Technology. The Federal Policy is based on Subpart A of the DHHS regulations for the protection of
human research subjects, adopted by DHHS in 1981. The Federal Policy now replaces
Subpart A of the 1981 DHHS regulations; Subparts B and C remain unchanged; Subpart D
has been modified to accommodate renumbering changes in Subpart A. [See 45 CFR
46.401(b).] Regulations for DHHS and the other departments and agencies listed above are
now, in effect, identical (not including the FDA, which has regulations that differ in some
significant respects, or the CIA, which follows the DHHS human subjects regulations
through an Executive Order, but has not itself adopted specific human subjects regulations).
Adoption of the Federal Policy incorporates DHHS's basic considerations for the
protection of human subjects; the provisions of Subparts B, C, and D of the DHHS
regulations are applicable to research supported or conducted by these departments and
agencies at institutions that have MPAs approved by and on file with OPRR. IRBs familiar with DHHS regulations prior to adoption of the Federal Policy will want to
note the following changes (this list is not, however, exhaustive; IRB members must
familiarize themselves with the Federal Policy in its entirety): §101(b): Exemptions. Some of the previous exemptions have been combined,
rephrased, and renumbered; there is also a new exemption for "taste testing."
Institutions claiming exemptions should be careful to cite appropriate
exemptions in grant applications and contract proposals. §101(h): Research in foreign countries. This is a new provision that allows a
department or agency head to determine that if procedures prescribed by a
foreign institution afford protections at least equivalent to those in the
regulations, the department or agency head may approve the substitution of
foreign procedures in lieu of the procedural requirements in the regulations.
Claims that foreign sites employ "at least equivalent" protections should be
forwarded to OPRR. [Note that this provision was not adopted by the FDA. See
description in Chapter 2, Section B(ii), "Comparing FDA and DHHS
Regulations."] §102: Definitions. The wording in the definition of "minimal risk" has been
slightly altered [§102(i)]. Definitions for "IRB" and "IRB approval" have been
added [§102(g) and (h)]. §103: Assurances. There are several minor modifications in this Section,
primarily because federal departments and agencies must accept
DHHS-approved Multiple Project Assurances (MPAs). §103(f): Certification. The regulations no longer explicitly list a "grace
period" of 60 days for receipt of certification of IRB review and approval from
MPA institutions. The National Institutes of Health and other Public Health
Service agencies extended the current policy of providing a "grace period" for
competing applications and proposals via administrative announcement. §107: IRB Membership. Several wording changes have been made, but the
modifications from the 1981 language do not represent a change in the care with
which institutions select IRB members. See, particularly, §107(a) and (b) for
wording changes from the 1981 regulations. (See also, Department of Education
Interim Final Regulations published at Federal Register 56 (June 18, 1991):
28029-28032.) §114: Cooperative research. Significant wording changes clarify the
definition of cooperative research and the responsibilities of the institutions
involved. Joint review or other arrangements geared toward avoiding
duplication of effort are desirable, but must be approved by the department or
agency head. Each participating institution remains responsible for safeguarding
the rights and welfare of human subjects and for complying with the regulations. For information concerning the Federal Policy and DHHS regulations, contact: Dr. Gary B. Ellis For information concerning the Federal Policy and FDA regulations, contact: Dr. Paul W. Goebel, Jr. A description of major differences between DHHS and FDA regulations on research
involving human subjects is given in Chapter 2, Section B, "Comparing FDA and DHHS
Regulations." APPLICABLE LAWS AND REGULATIONS Federal Register 56 (June 18, 1991): 28002-28032 [Federal Policy for the Protection of
Human Subjects; Notices and Rules] Codification of the Federal Policy for each of the departments and agencies adopting it is as
follows: [Agency for International Development] FDA regulations pertaining to research with human subjects are codified at: ii. 45 CFR 46: MOST FREQUENTLY ASKED QUESTIONS DHHS receives many requests for assistance in interpreting and applying its human subjects
research regulations, which are codified at 45 CFR 46. This Section provides answers to
the twenty-eight most frequently asked questions. 1. Question: What is OPRR's function in the DHHS regulations? Answer: The Office for Protection from Research Risks (OPRR) is a unit
within the Department of Health and Human Services (DHHS) that implements
the regulations on behalf of the Secretary, HHS. It is located in the Office of the
Director, Office of Extramural Research, National Institutes of Health (NIH),
Bethesda, Maryland. The Public Health Service Act required DHHS to issue regulations for the
protection of human subjects of research and to implement a program of
instruction and guidance in ethical issues associated with such research. The
regulations are codified at Title 45 Part 46 of the Code of Federal Regulations,
Protection of Human Subjects (45 CFR 46), last revised on June 18, 1991. 2. Question: How is 45 CFR 46 implemented? Answer: DHHS regulations require institutions to assure their compliance with
45 CFR 46 before initiating participation in DHHS-conducted or - supported
research involving human subjects. The terms of these written institutional
assurances are negotiated with OPRR and constitute binding commitments to
comply with the provisions of 45 CFR 46. Each negotiated commitment is
called an Assurance document and is entered into by the institution and OPRR,
representing DHHS. There is more than one type of Assurance document,
depending on the nature of the research and other considerations. Each
Assurance document stipulates the method(s) by which the institution will
protect the rights and welfare of research subjects in accordance with the
regulations [45 CFR 46.103]. [See Guidebook, Chapter 2, Section A(iii),
"Assurances."] 3. Question: To what activities does 45 CFR 46 apply? Answer: The regulations for the protection of human participants in research
apply to all research involving human participants that is conducted or
supported, in whole or in part, by DHHS in foreign or domestic settings. Note
that any support provided by DHHS, e.g., supplying a drug for research
purposes, may trigger applicability of the regulations [45 CFR 46.101]. 4. Question: If an IRB reviews a protocol that is closed to accruals before the institution
initiates involvement in the research, must the IRB retain its records on the project for three
years beyond the completion of the research [45 CFR 46.115]? Answer: While most records (e.g., the protocols) need not be retained, some,
(e.g., any IRB minutes in which the project is discussed) should be preserved.
Institutional policy, however, may stipulate that all IRB records are to be kept
for three years. 5. Question: Must an IRB perform continuing reviews of protocols in which patient
accruals have been closed and the research interventions are completed, but investigators
are still collecting follow-up data? Answer: Yes. So long as data are being collected for an organized research
project, the IRB must continue to review the status of the protocols and the
details of the continuing data gathering activity. If the continuing research meets
the requirements for expedited review, the expedited review process may be
used, if desired by the IRB. 6. Question: Why would a standard cooperative research protocol or a standard informed
consent document need review at the local level when it has already been reviewed by
another national organization (e.g., the National Institutes of Health, the National Cancer
Institute, or a cooperative research group), or even by the IRB of another institution with an
approved Assurance? Answer: Cooperative protocol requirements may be standard, but the research
setting is not standard across institutions. In addition, one should not assume
that because a protocol or informed consent document has been reviewed by
another entity, it necessarily conforms to pertinent regulations, local laws, or
the local research setting. For example, local laws, institutional policies and
constraints, professional and community standards, and population differences
are all factors that can influence the research setting. [See 45 CFR 46.103(d),
46.107(a), and 46.111(a)(3), noting the relevance of the particular setting in
which the research is to take place.] 7. Question: Certain research involving prisoners or children can be approved only upon
review by the Secretary, HHS, in consultation with a panel of experts (specified in the
regulations) [45 CFR 46.306(2)(c)-(d) (prisoners) and 46.407 (children).] Also, certain
research involving fetuses, pregnant women, and human in vitro fertilization requires
review by an Ethics Advisory Board established by the Secretary [45 CFR 46.204 and
46.211]. When a MPA-holding institution reviews research that is neither supported nor
conducted by DHHS, does it have to meet these special review requirements? Answer: The institution's Assurance requires the institution to protect the rights
and welfare of human research subjects whether or not the research is
supported or conducted by DHHS [Federal Policy §___.103(b)(1)]. Further,
institutions are encouraged to treat all research involving human subjects with
the same level of review, regardless of the source of funding. In the case of
research that would receive a second level of review if it were
DHHS-supported, institutions should appoint a special review panel composed
of the same kinds and quality of experts who would likely have advised the
Secretary. 8. Question: What role does an advocate play in the review of research involving children
who are wards of the state? Answer: An advocate for a child who is a ward of the state has a fiduciary
relationship (one of trust and confidence) to the child. In other words, the
advocate must act with the child's interest as the primary consideration. 9. Question: Why must foreign sites abide by DHHS regulations? Why isn't the Declaration
of Helsinki or another international code acceptable? Answer: DHHS wants to ensure that all DHHS-supported or -conducted
research involving human subjects provides subjects with protections that are at
least equivalent to those afforded by DHHS regulations. Many international
guidelines, such as the Declaration of Helsinki, provide general principles and
are a good place to start, but do not describe the specific procedures through
which those principles are to be realized. Through its negotiations with the
foreign institution, OPRR ensures that those Assurances provide procedures
that are equivalent to those required by 45 CFR 46. 10. Question: FDA will consider waiving local IRB review for Treatment INDs (if waiver
is in the best interests of the subjects and adequate alternative mechanisms for human
subject protection are provided, e.g., to avoid duplication when a national review body has
already reviewed the Treatment IND). [See 21 CFR 312.34; FDA, "IRB Information Sheet:
Waiver of IRB Requirements" (February 1989).] Do DHHS regulations require local IRB
review for Treatment INDs, even when FDA does not? Answer: If both the FDA and DHHS have jurisdiction over the research
activities, IRBs must meet the requirements of both sets of regulations. Where
the FDA has granted a waiver of local IRB review, DHHS regulations would
still require local IRB review if: (1) an MPA-holding institution that has agreed
to follow DHHS regulations for all research is involved; or (2) the research is
supported by a DHHS component. Furthermore, grant of an FDA waiver of
local IRB review gives permission to the local IRB to forego review; local
IRBs retain the right to review the research if they so choose. The Secretary
may grant a waiver of DHHS regulations, and will consider waiving some part
of 45 CFR 46 for Parallel Track protocols. [See Guidebook Chapter 2, Section
B, "Food and Drug Administration Regulations and Policies."] 11. Question: Exemption 4 [45 CFR 46.101(b)(4)] covers research involving the
collection or study of existing data, documents, records, pathological specimens, or
diagnostic specimens. When are data, documents, records, and specimens considered to be
existing for the purposes of this exemption? Can an investigator use, for instance, blood
specimens that have been drawn for another purpose? Answer: To qualify for this exemption the data, documents, records, or
specimens must be in existence before the project begins. An example might be
helpful. Suppose Investigator A wishes to screen blood samples at a rural
hospital for incidence of HIV infection. She does not want to draw specimens
specifically for this purpose; rather she proposes to use specimens that were
drawn for some other purpose but which remain in the hospital laboratory. If
Investigator A proposes to use specimens that had been drawn prior to the
initiation of her research and are, for some reason, "on the shelf," the protocol
will qualify as exempt under 46.101(b)(4), assuming the other requirements of
46.101(b)(4) are met (i.e., the sources are either publicly available or the
information is recorded by the investigator in such a manner that subjects cannot
be identified, directly or through identifiers linked to the subjects). If she
proposes to use specimens that will be drawn after the start date of her project
for reasons unrelated to her research, the protocol is not exempt from IRB
review, even though the specimens will be drawn regardless of her use of the
excess blood. The protocol may, however, qualify for expedited review. In the behavioral sciences, suppose Investigator B wishes to examine court
records of involuntary commitments to psychological institutions. If he uses
court records that were on file before the initiation of his research, the protocol
will qualify as exempt under 46.101(b)(4). If he proposes to use records filed
after the initiation of the project, the protocol is not exempt from IRB review,
although it may qualify for expedited review. The principle behind this policy is that the rights of individuals should be
respected; subjects must consent to participation in research. When specimens
and other data or records have yet to be collected, consent may be more easily
sought. Where circumstances warrant, however, the investigator may seek a
waiver of informed consent in accordance with the regulations [Federal Policy
§___.116(d)]. 12. Question: If an investigator is conducting a "masked" study, are the exemptions of
46.101(b) applicable, since no identifiers will be used? Answer: It is a misnomer that subjects are not identified in masked studies.
Research records do reflect the identity of subjects, either directly or through
identifiers (codes) that can be linked to them. What is "masked" in a
single-masked study is the identity of the intervention the subject receives: the
subject does not know whether she is receiving the investigational intervention
or a standard intervention. In a double-masked study, neither the subject nor the
investigator knows which intervention the subject receives. 13. Question: Do the exemptions apply to Subparts B (fetuses, pregnant women, and human
in vitro fertilization) and C (prisoners)? Answer: No. In addition, with respect to research involving children (Subpart
D), the exemption provided in 46.101(b)(2) for research involving survey or
interview procedures or observation of public behavior does not apply, except
for research involving observations of public behavior when the investigator(s)
does not participate in the activities being observed. 14. Question: Can an IRB use an expedited procedure for the review of administrative
changes to Cooperative Oncology Group (COG) protocols and related documents when the
risks are minimal or less than minimal (e.g., for follow-up calls when gathering initial data
by telephone, collecting changes in addresses and telephone numbers, or altering the
specification of individuals assigned to particular tasks in the protocol) [45 CFR 46.110]? Answer: Yes. Such reviews would constitute review of minor changes in
previously-approved protocols. It is important, however, to distinguish
between those changes that are and are not truly "minor." Any change that
would materially affect the assessment of risks and benefits should not be
considered minor. 15. Question: Can IRBs use an expedited review procedure when applying for a Single
Project Assurance (SPA) from OPRR [45 CFR 46.110]? Answer: No. Since SPAs are used by institutions that do not regularly engage in
DHHS-supported research involving human subjects, special care must be
taken to ensure that the subjects' welfare is fully considered. Institutions holding
MPAs have established records of experience in reviewing human subjects
research that SPA institutions may not have. OPRR policy is therefore to
require that all research activities requiring an SPA be reviewed by the full
IRB. 16. Question: Must investigators provide subjects with all of the information listed in 45
CFR 46.115(a) (basic elements) and (b) (additional elements) as part of the informed
consent process unless the IRB specifically provides otherwise? Answer: The additional elements of informed consent listed in 45 CFR
46.115(b) are required when they are appropriate to the research being
conducted. It is necessary for the IRB to determine explicitly their
inapplicability. 17. Question: Why are Multiple Project Assurances (MPAs) sometimes restricted? Answer: OPRR will sometimes indicate that an IRB at an MPA-holding
institution must acquire additional expertise before certain research activities
can be reviewed and certified by issuing a restriction code. Restriction codes
appear as a suffix to the MPA number (e.g., M2345-01XM). If the institution
has only one IRB, the restriction applies to the overall MPA. If there is more
than one IRB, each IRB has associated with it a unique restrictive suffix code.
This policy may result in institutions holding MPAs that are not restricted
overall because of offsetting capabilities of two or more IRBs. An "XM" suffix indicates that the IRB has an insufficient number of members
with expertise in medicine. An IRB with an XM restriction on its MPA cannot
certify proposed research activities requiring medical expertise to assess risks,
benefits, and the adequacy of safeguards. To certify such research, the IRB
membership must include at least two voting members who possess appropriate
medically-related degrees. OPRR will remove the restriction when the IRB
notifies OPRR of the addition of the appropriate number of medical members
and provides OPRR with a revised IRB membership list. An "XB" suffix indicates that the IRB has an insufficient number of members
with expertise in the behavioral sciences. Requirements parallel to those
described for IRBs reviewing medical research exist for IRBs reviewing
behavioral research. In contrast with the education requirements for members
with medical expertise, members with expertise in the behavioral sciences must
either possess degrees in the behavioral sciences or have related experience in
behavioral research activities. 18. Question: What considerations should institutions address when arranging for review
of research involving human subjects? For example: a. Must an institution establish its own IRB? Answer: The answer to each of (a)-(d) is "not necessarily." The federal
regulations allow institutions to use joint reviews, reliance on the review of
another qualified IRB, or similar arrangements to avoid duplication of effort
[45 CFR 46.114, relating to cooperative research projects]. Similarly,
institutions at which it is not practical to set up an IRB, but which are not
participating in cooperative research as required by §46.114, may be permitted
to use another IRB acceptable to OPRR. Institutions wishing to use another
institution's IRB for DHHS-supported research should contact OPRR for
details. Institutions should bear in mind several considerations when contemplating the
use of another institution's IRB to review its protocols. Specifically, local
laws, institutional policies and constraints, professional and community
standards, and population differences are all relevant factors to IRB
deliberations. Review by an institution in another geographical, cultural, or
professional setting may not take into account pertinent local factors defined by
the research setting. [See 46.103(d), 46.107(a), and 46.111(a)(3).] For
example: When an institution wishes to use another institution's IRB to review its
protocols, OPRR requires documentation to verify for itself whether the IRB is
able to determine the acceptability of proposed research in terms of the
institutional commitments of the institution at which the research will take
place. [See 45 CFR 46.107(a).] If OPRR is not convinced that the IRB is
properly constituted for making these judgments, OPRR may require that
institutional representatives or other persons act as consultants for the IRB's
review. For further information, contact: Division of Human Subject Protection
(DHSP): (301) 496-7041. See also Guidebook Chapter 2, Section A(iii), "Assurances." 19. Question: Section 46.114 of the DHHS regulations allows for reliance upon "the
review of another qualified IRB." Does "qualified" mean that the other institution must have
an Assurance on file with OPRR? Answer: Usually, yes. However, possession of an MPA or other
OPRR-approved Assurance does not guarantee acceptability of the IRB for a
given research activity. Each situation is unique and requires evaluation by
OPRR. Contact the Assurance Branch, DHSP for details [(301) 496-7041]. 20. Question: What options are typically available to an institution seeking to avoid
duplication of IRB effort in the conduct of cooperative projects? Answer: In addition to having each institution conduct its own review, several
options exist, each of which OPRR has found to comply with the letter and
intent of both 45 CFR 46.114 and the regulations as a whole. First, institutions that are close enough geographically to contribute membership
to a common IRB can share in bearing the costs of operation while
simultaneously providing review for protocols that may be used by
investigators at some of all of the sites. This approach results in the
establishment of one IRB that can be cited as the IRB of record by all
institutions that contribute to its membership. A second approach is for one IRB to host reviews for other nearby institutions,
with consultative representation from each institution present for all initial and
continuing reviews of cooperative protocols. In this approach only the host
institution has its own IRB. The other institutions rely on another's IRB, but in
such a way as not to defeat the intent of 45 CFR 46. 21. Question: How can independent investigators (i.e., investigators not associated with an
Assurance-holding institution) who wish to engage in cooperative research in their private
practices obtain local IRB approval for their research? Answer: One possible approach is for the independent investigator to seek
permission from OPRR (and the institution) to rely upon the IRB of a local
institution with an applicable OPRR-approved Assurance for the research in
question. If no such local institution is available or permission is denied, the
independent investigator must identify another IRB that holds an appropriate
Assurance for reviewing the research. It will be important for the investigator
to ensure that the IRB he or she selects can evaluate the research in accordance
with the needs of the research setting (e.g., local laws, professional and
community standards, and cultural differences due to different geographical or
research settings). 22. Question: What is the difference between "compassionate" use, "emergency" use, and
"Treatment INDs?" Answer: The term "compassionate use" has been used in the past to refer to the
provision of investigational drugs outside of an ongoing clinical trial to a
limited number of patients who are desperately ill and for whom no standard
alternative therapies are available. The term "compassionate use" does not,
however, appear in FDA or DHHS regulations; its plausible application to
various access mechanisms causes more confusion than it does assistance. It is
preferable, instead, to use the names of the specific access programs when
discussing the use of investigational articles outside of formal clinical trials. First, the FDA human subjects regulations allow for a test article to be used in
emergency situations without prior IRB approval provided that the emergency
use is reported to the IRB within five working days; subsequent use of the test
article must be reviewed by the IRB [21 CFR 56.104]. An emergency is
defined as a life-threatening situation in which no standard acceptable treatment
is available and in which there is not sufficient time to obtain IRB approval [21
CFR 56.102(d)]. [See Guidebook Chapter 2, Section B, "Food and Drug
Administration Regulations and Policies."] Second, various FDA regulations and policies allow certain persons not
enrolled in clinical trials to obtain access to investigational drugs: See Guidebook Chapter 2, Section B, "Food and Drug Administration Regulations and
Policies" for a more detailed description of these mechanisms. 23. Question: Why does DHHS not allow for an emergency exception to IRB review as
does the FDA? [See 21 CFR 50.23 and 56.104(c), and Guidebook Chapter 2, Section B,
"Food and Drug Administration Regulations and Policies."] Answer: DHHS regulations require that research involving human participants
receive full IRB review and approval, except where expedited review is
specifically permitted, prior to initiation of the research [45 CFR 46.103(b)].
Physicians do, however, retain the authority to provide emergency medical care
to their patients [45 CFR 46.116(f)]. On May 15, 1991, OPRR issued the
following statement clarifying emergency treatment of a patient by a physician
when that patient is also a research subject: Whenever emergency care is initiated without prior IRB review
and approval, the patient may not be considered to be a research
subject. Such emergency care may not be claimed as research, nor
may the outcome of such care be included in any report of a
research activity. Simply stated: [D]HHS regulations for the
protection of human subjects do not permit research activities to be
started, even in [an] emergency, without prior IRB review and
approval. If the emergency care involves drugs, devices, or biologics that are
considered to be investigational by the Food and Drug
Administration (FDA), then it may be necessary to meet FDA
requirements to use the investigational article for emergency
purposes. Thus, the distinction for DHHS-supported or - conducted research is that while
the physician may, without prior IRB approval, treat the patient/subject using a
test article (if the situation meets the FDA requirements), the subject may not be
considered a research subject; data derived from use of the test article may not
be used in the study. 24. Question: The FDA regulations allow an exception from the general requirements for
informed consent for life-threatening situations where the subject's consent or that of his or
her legal representative cannot be obtained because of an inability to communicate with any
of the requisite parties. Why don't the DHHS regulations provide for waiver of consent
requirements in such emergency circumstances? Answer: DHHS regulations permit the waiver of informed consent
requirements only in the case of research that presents no more than minimal
risk [45 CFR 46.116]. As with emergency use of a test article without prior
IRB approval, physicians retain the authority to provide emergency medical
care to their patients. [See Question 23.] Unless, however, prior consent has
been obtained, or the IRB waives the consent requirement after determining that
the research presents a minimal risk, the patient cannot be considered a
research subject; any data derived from the emergency use of the test article
cannot be used in the study. 25. Question: What must be reported to DHHS? Answer: Any of the following occurrences: 26. Question: Must the IRB itself report instances of noncompliance with the regulations to
DHHS? Answer: Not necessarily. Each institution must have in place written
procedures that ensure that instances of serious or continuing noncompliance
will be reported to the IRB, appropriate institutional officials, and the head of
the department or agency supporting the research (here, DHHS) [45 CFR
46.103(b)(5)]. The IRB is only responsible for doing the reporting if it is
required to do so under the institution's written procedures. [NOTE: FDA
requires that the IRB report to FDA if such reporting would not otherwise occur
(Federal Register 56 (June 18, 1991): 28026).] 27. Question: Can treatment of a single patient constitute "research?" Answer: Yes, if there is a clear intent before treating the patient to use
systematically collected data that would not ordinarily be collected in the
course of clinical practice in reporting and publishing a case study. Treating
with a research intent should be distinguished from the use of innovative
treatment practices. 28. Question: If the research is subject to both DHHS and FDA human subjects regulations,
which regulations should the IRB follow? Answer: Where a protocol is subject to review under more than one department
or agency's regulations, the requirements of each set of regulations must be met.
This situation may arise, for example, with Treatment INDs, or when applying
the provisions on waiver of documentation of informed consent, in cases where
both the FDA and DHHS have jurisdiction over the research. [See, e.g.,
Guidebook Chapter 2, Section B, "Food and Drug Administration Regulations
and Policies," discussing Treatment INDs, and Guidebook Chapter 3, Section
D, "Privacy and Confidentiality," under the heading "Confidentiality of
Research Data" (discussing waiver of documentation of informed consent
where the data are sensitive and the existence of a consent form may place the
subject at risk).] See also Guidebook Chapter 2, Section B, "Food and Drug Administration Regulations and
Policies." An Assurance is an agreement or contract between the institution and OPRR, on behalf of
the Secretary, HHS, stipulating the method(s) by which the institution will protect the
welfare of research subjects in accordance with the regulations. The Assurance, approval
of which is a condition of receipt of DHHS support for research involving human subjects,
spells out the institution's responsibilities for meeting the requirements of 45 CFR 46 [45
CFR 46.103]. The existing types of Assurances include: a. Multiple Project Assurance (MPA). A standing agreement on file with
OPRR that is approved for five-year intervals. An MPA is designed for
institutions that are engaged in a significant amount of health-related research
(i.e., institutions that usually have several federally-funded research projects
under way at any given time.) Institutions with an MPA on file may also
negotiate an Inter-Institutional Amendment (IIA). An IIA covers
DHHS-sponsored research conducted at a neighboring affiliated institution by
employees of an institution with an MPA on file with OPRR. b. Single Project Assurance (SPA). An agreement covering a single research
project involving human subjects. An SPA is often used for institutions that do
not have an MPA on file with OPRR. c. Cooperative Project Assurance (CPA). An agreement covering
participation in OPRR-recognized Cooperative Protocol Research Programs
(CPRPs). CPRPs involve multi-protocol, multi-site research in which data from
standardized protocols are pooled across institutions. These protocols are
approved and monitored by DHHS Protocol Review Committees, which are
recognized by OPRR as satisfactorily addressing the adequacy of human subject
protections. Once approved, the CPA is valid for participation in all
OPRR-recognized CPRPs. d. Cooperative Research. In the past, a variety of Assurances were used for
certain cooperative research projects. Examples include: i. Clinical Community Oncology Program (CCOP) These Assurances are being replaced with CPAs as they expire. Contact OPRR for
information regarding these and other subject-specific cooperative Assurances [Assurance
Branch, DHSP (301) 496-7041]. B. FOOD AND DRUG ADMINISTRATION REGULATIONS AND The Food and Drug Administration (FDA) regulates but does not, for the most part, support
or conduct research. Its regulatory mandate, therefore, differs substantially from other
DHHS agencies and other departments and agencies that conduct and support a significant
amount of research. While the structural and functional requirements for IRBs in the FDA
regulations are identical to DHHS regulations, the substantive provisions differ in several
significant respects. IRBs should note that where a protocol is subject to review under
both FDA and DHHS human subjects regulations, both sets of regulations apply, and
the requirements of both sets of regulations must be met. This situation may arise, for
example, with Treatment Investigational New Drug Exemptions (see discussion of
Treatment INDs, below) or when applying the provisions on waiver of documentation of
informed consent, in cases where both the FDA and DHHS have jurisdiction over the
research. FDA regulations pertaining to human subjects research are codified at 21 CFR 50
[Protection of Human Subjects (containing the informed consent requirements)] and 21 CFR
56 [Institutional Review Boards]. In addition to the information provided in this Section, see the various FDA Information
Sheets and guidelines (e.g., IRB Information Sheets, Clinical Investigator Information
Sheets, Guideline for the Monitoring of Clinical Investigations, and Compliance
Program Guidance Manual: Chapter 48, Bioresearch Monitoring - Human Drugs,
Institutional Review Board). For further information on FDA human subjects research
regulations, contact: Mr. Richard M. Klein ii. COMPARING FDA AND DHHS HUMAN SUBJECTS REGULATIONS The DHHS regulations (45 CFR 46) apply to research involving human subjects conducted
by DHHS or supported in whole or in part by DHHS. The FDA regulations (21 CFR 50 and
56) apply to all research involving products regulated by the FDA, including research and
marketing permits for drugs, biological products, or medical devices for human use, food
and color additives, or electronic products. Federal funds do not need to be involved. When
research involving products regulated by the FDA is funded by DHHS, both DHHS and
FDA regulations apply. This Section describes significant differences between FDA and
DHHS regulations, including departures from the new Federal Policy. COMPARISON OF REGULATIONS IRB Regulations §312.120 (FDA) The FDA regulations provide criteria for accepting foreign clinical studies not
conducted under an Investigational New Drug Application (IND). The DHHS
regulations allow a department or agency head to determine that if procedures
prescribed by a foreign institution afford protections at least equivalent to
DHHS regulations, the department or agency head may approve the substitution
of foreign procedures. [See also 21 CFR 812.1.] §56.102 (FDA) FDA definitions are included for terms specific to the type of research covered
by the FDA regulations (test article, application for research or marketing
permit, clinical investigation). A definition for emergency use is provided. The
definition of "IRB approval," added as a result of the Federal Policy,
substitutes the term "clinical investigation" for the term "research" used in the
Federal Policy [§56.102(m)]. FDA also adopted the Federal Policy's new
wording for the definition of "minimal risk" ("the probability and magnitude of
harm or discomfort anticipated in the research are not greater in and of
themselves than those ordinarily encountered in daily life or during the
performance of routine physical or psychological examinations or tests")
[§56.102(i)]. §46.103 (DHHS) DHHS requires that institutions provide an Assurance of Compliance with
human subjects regulations, which is negotiated with OPRR. FDA does not
require Assurances of Compliance, but does require that IRBs have written
policies and procedures. §56.104 (FDA) Unlike DHHS, FDA exempts from prospective IRB review the "emergency use"
of a test article in specific situations. FDA added the Federal Policy's new
"taste testing" exemption at §56.104(d). §56.105 (FDA) FDA provides for sponsors and sponsor-investigators to request a waiver of
IRB review requirements (not informed consent requirements). DHHS
regulations do not have a similar provision. §56.108 (FDA) DHHS requires prompt reporting of unanticipated problems to the Secretary.
FDA does not specify that a similar report be made by the IRB to the FDA
Commissioner, but that the IRB have and follow written procedures to ensure
that such reporting is done by the sponsor and clinical investigator. §56.109 (FDA) Unlike DHHS, FDA does not provide that an IRB may waive the requirement
for signed consent when the principal risk is a breach of confidentiality because
FDA does not regulate studies that would fall into that category of research.
(Both regulations allow for IRB waiver of documentation of informed consent
in instances of minimal risk.) §56.110 (FDA) FDA does not include research on behavior or characteristics of groups or
individuals such as studies of perception, cognition, game theory, or test
development (DHHS activity #9) in its list of research activities that may be
reviewed through expedited review procedures, because those types of studies
are not regulated by FDA. §56.114 (FDA) FDA regulations do not discuss administrative matters dealing with grants and
contracts because they are irrelevant to the scope of the Agency's regulation.
(Both regulations make allowances for review of multi-institutional studies.) §56.115 (FDA) DHHS, but not FDA, requires the IRB or institution to report changes in
membership. FDA has neither an assurance mechanism nor files of IRB
membership; there is therefore no reason for FDA to be informed about changes
in membership. §56.115(c) (FDA) FDA may refuse to consider a study in support of a research or marketing
permit if the IRB or the institution refuses to allow FDA to inspect IRB records.
DHHS has no such provision because it does not issue research or marketing
permits. §§56.120-124 (FDA) FDA regulations provide sanctions for noncompliance with regulations. There
is no parallel DHHS regulation, other than §46.123, which permits early
termination of research support and evaluation of applications and proposals in
light of prior noncompliance. Informed Consent Regulations §50.3(l) FDA adopted the Federal Policy's new wording for the definition of "minimal
risk" ("the probability and magnitude of harm or discomfort anticipated in the
research are not greater in and of themselves than those ordinarily encountered
in daily life or during the performance of routine physical or psychological
examinations or tests") [§56.102(i)]. §50.23 (FDA) FDA, but not DHHS, provides explicit guidance for an exemption from the
informed consent requirements in emergency situations. The provision is based
on a statutory requirement in the Medical Device Amendments of 1976, and
may be used in investigations involving drugs, devices, and other
FDA-regulated products in situations described in §50.23. §46.116(c) and (d) (DHHS) DHHS provides for waiving or altering elements of informed consent under
certain conditions. FDA has no such provision because the types of studies that
would qualify for waiver or alteration are either not regulated by FDA or are
covered by the emergency treatment provisions of §50.23. §50.25(a)(5) (FDA) FDA explicitly requires that subjects be informed that FDA may inspect the
records of the study because FDA may occasionally examine a subject's
medical records as they pertain to the study. While DHHS has the right to
inspect records of studies it funds, it does not impose the same informed
consent requirement because of the infrequency with which the Department
actually inspects subject records. FDA regulations allow the agency to waive any of the requirements contained in Part 56 of
the regulations (governing IRBs), including the requirement of IRB review, for specific
research activities or for classes of research activities otherwise covered by the
regulations. Sponsors or sponsor-investigators must apply directly to FDA for such waivers
[21 CFR 56.105]. The waiver provision does not apply to informed consent requirements
(see description, below). [See also "Treatment INDs," below.] For emergency situations,
the regulations on emergency use of a test article [§56.104, '50.23], rather than waiver of
IRB review apply. Even if a waiver from the FDA requirement of IRB review is requested
and granted, an institution may still require IRB review of the study. Requests for a waiver associated with an IND should be submitted to the Division in the
Center for Drug Evaluation and Research (CDER) or to the Division in the Center for
Biologic Evaluation and Research (CBER) responsible for reviewing the IND. If the
identity of the responsible Division is unknown, the waiver request may be sent to: Mr. William Lampkin See also FDA Information Sheets: "Waiver of IRB Requirements" and "Emergency Use of
an Investigational Drug." WAIVER OF CONSENT REQUIREMENTS Unlike the Federal Policy, FDA regulations do not permit modifications or waivers of the
informed consent requirements, except for emergency use of test articles, which are exempt
from prior IRB review (see description, below). [See also, Guidebook Chapter 3, Section
B, "Informed Consent."] EMERGENCY USE OF A TEST ARTICLE Emergency use is defined as the use of a test article (e.g., investigational drug or biologic)
on a human subject in a life-threatening situation in which no standard acceptable treatment
is available and in which there is not sufficient time to obtain IRB approval for the use. The
investigator is still required to obtain informed consent under these circumstances. FDA exempts from IRB review the emergency use of a test article so long as the emergency
use is reported to the IRB within five working days of its occurrence. Any subsequent use of
the test article is subject to IRB review [21 CFR 50.23; 21 CFR 56.104(c)]. "Subsequent
use" means any use of the test article that occurs after its initial emergency use. When an
IRB receives a report by a clinical investigator of an emergency use, the IRB must examine
each case to assure itself and the institution that the emergency use was justified. Although 21 CFR 56.104 is designed to permit only a single emergency use of a test article
for the treatment of one patient by one physician within an institution, the regulation is not
intended to limit the authority of a physician to provide emergency care in a life-threatening
situation. Should a situation arise which would require the emergency use of the test article
for a second patient, either by the same or a second physician, for the same test article,
subsequent emergency use should not be withheld for the purpose of gaining IRB approval.
If it appears probable that similar emergencies will require subsequent use of the test
article at the institution, every effort should be made either to sign on to the sponsor's
protocol or to develop a protocol for future emergency use of the article at the institution.
Either of these protocols would need to be prospectively reviewed and approved by the
IRB for future use of the test article. In emergency circumstances, it may not be feasible to obtain informed consent prior to using
the test article. The regulations therefore provide an exemption from the informed consent
requirement for such situations. Emergencies qualifying for this exemption are defined as:
(1) life-threatening situations necessitating use of the test article; (2) where the subject is
unable to provide effective consent; (3) there is insufficient time in which to obtain consent
from the subject's legal representative; and (4) there is no available alternative method of
approved or generally recognized therapy of equal or greater likelihood of saving the
subject's life [21 CFR 50.23(a)(1)-(4)]. Special procedures for documenting the infeasibility of obtaining consent apply as follows:
The investigator and a physician who is not participating in the clinical investigation must
certify in writing the existence of all four conditions listed above before use of the test
article [21 CFR 50.23(a)]. If in the investigator's opinion immediate use of the test article is
necessary to save the life of the subject and there is insufficient time to obtain the
independent determination required by §50.23(a) before using the test article, the
investigator is to make his or her own written determinations, then obtain the written review
and independent evaluation of a physician who is not participating in the clinical
investigation within five working days after the use of the test article [21 CFR 50.23(b)].
The documentation required by either §50.23(a) or §50.23(b) must be submitted to the IRB
within five working days after the use of the test article [21 CFR 50.23(c)]. The use of a test article in an investigation designed to be conducted under emergency
conditions (e.g., emergency room research) usually does not qualify for the emergency use
exemption. For drug products, contact: Document Management Reporting Branch (HFD-53) For biologic products, contact: Division of Biological Investigational New Drugs (HFN-823) (Nights and weekends: (202) 857-8400 - FDA Division of Emergency and Epidemiological
Operations) See also, FDA Information Sheets: "Emergency Use of an Investigational Drug" and
"Guidance for the Emergency Use of Unapproved Medical Devices." EXPANDED AVAILABILITY OF INVESTIGATIONAL DRUGS Treatment Investigational New Drug Exemption (Treatment INDs). The use of
investigational drugs is usually limited to subjects enrolled in clinical studies covered by
INDs. In 1987, the FDA established new procedures under which promising investigational
new drugs may be made available to patients with life-threatening or other serious diseases
for which no satisfactory alternative drug or other therapies exist. The purpose of the
Treatment IND exemption is to facilitate the availability of promising new drugs to
desperately ill patients as early in the drug development process as possible (before
marketing begins) and to obtain additional data on the drug's safety and effectiveness. A
Treatment IND is a treatment protocol that is added to an existing investigational new drug
application (IND). It allows physicians to treat qualifying patients according to the
protocol. FDA permits Treatment INDs only for drugs that show some promise of therapeutic benefit.
Two standards exist: For serious diseases, applications for Treatment INDs must show
sufficient evidence of safety and effectiveness to support the use. Ordinarily, this standard
means that a drug may be made available for treatment use either during Phase 3
investigations or after all clinical trials have been completed. For immediately
life-threatening diseases, the evidence, taken as a whole, must show (i.e., there must be
sufficient data reasonably to conclude) that the drug may be effective for its intended use in
its intended patient population and would not expose the patients to whom the drug is to be
administered to an unreasonable and significant additional risk of illness or injury. Under
this standard, investigational drugs for treating immediately life-threatening diseases may be
made available for treatment use earlier than Phase 3, but ordinarily not earlier than Phase 2
[21 CFR 312.34(a), 312.34(b)(2), and 312.34(b)(3)]. Treatment INDs must be reviewed by an IRB prior to their submission and must comply
with the regulations governing informed consent (21 CFR Part 50) and IRBs (21 CFR Part
56) [21 CFR 312.34(c)]. The FDA will, however, consider waiving local IRB review for
Treatment INDs, if waiver is in the best interests of the subjects and adequate alternative
mechanisms for human subject protection are provided (e.g., to avoid duplication when a
national review body has already reviewed the Treatment IND). The effect of the FDA
waiver is to give permission to the local IRB to forego review; local IRBs may, as a matter
of institutional policy, choose to review protocols for which an FDA waiver has been
obtained by the sponsor or sponsor-investigator. Note also that if both the FDA and DHHS
have jurisdiction over the Treatment IND activities, local IRB review will be required
despite the FDA waiver. DHHS regulations apply if: (1) an MPA-holding institution that
has agreed to review the research according to DHHS regulations is involved in the
research; or (2) the research is supported by a DHHS department or agency [45 CFR
46.101, 45 CFR 46.103]. The sponsor and investigators must also comply with all applicable provisions of 21 CFR
Part 312, including distribution of the drug through qualified experts, maintenance of
adequate manufacturing facilities, and submission of IND safety reports. A description of Treatment INDs and the requirements for receiving approval for treatment
use is contained in the FDA's Clinical Investigator Information Sheet titled "Treatment
Use of Investigational Drugs" (May 1989). Charging for Treatment Use of Investigational Drugs. Ordinarily, sponsors or
investigators may not charge for investigational drugs involved in clinical trials. FDA
considers the cost of distributing drugs for investigational purposes to be part of the normal
cost of doing business (unless the sponsor can show that charging subjects for the cost of the
drug is necessary to enable the sponsor to undertake the clinical trial) [21 CFR
312.7(d)(1)]. Treatment use, however, is not part of a clinical trial and is therefore not
considered to be a normal cost of doing business. Rather, the Treatment IND was created to
encourage drug manufacturers to make potentially lifesaving drugs available before they
receive FDA approval. Before charging for investigational drugs, the sponsor must notify
FDA in writing in an information amendment submitted under §312.31. FDA may withdraw
authorization to charge for treatment use drugs if it finds that the requirements of §312.7 are
no longer being met [21 CFR 312.7(d)(4)]. Commencing Treatment Use. Treatment use may begin 30 days after FDA receives the
application unless the request is denied by FDA [312.35(a)]. The required contents of a
treatment protocol are provided in 21 CFR 312.35. Once approved for treatment use, the
investigational drug may be prescribed by physicians who have been specially designated
in the application. The physicians must agree to follow the treatment protocol, keep clinical
records, and report adverse drug reactions to the FDA. The Role of the IRB. The primary responsibility of the IRB in reviewing a Treatment IND
is the same as in reviewing any proposed investigation involving human subjects: to
determine whether the proposed use exposes the subjects to unreasonable or unnecessary
risk, to review the informed consent forms and process, and to monitor the progress of the
Treatment IND. Informed consent is especially important in treatment use situations because the subjects are
desperately ill and particularly vulnerable. They will be receiving medications, which have
not been proven either safe or effective, in a clinical setting. Both the setting and their
desperation may work against their ability to make an informed assessment of the risk
involved. IRBs must ensure that potential subjects are fully aware of the risks involved in
participation. IRBs should also pay particular attention to Treatment INDs in which the subjects will be
charged for the cost of the drugs. The question here is one of equitable selection and the
involvement in research of vulnerable populations, particularly economically
disadvantaged persons [21 CFR 56.111(a)(3)]. If subjects will be charged for use of the
test article, economically disadvantaged persons will likely be excluded from participation.
The stated purpose of the Treatment IND exemption is to facilitate the availability of
promising new drugs to desperately ill patients while obtaining additional data on the drug's
safety and effectiveness. Charging for participation may preclude economically
disadvantaged persons as a class from receiving access to test articles. IRBs will need to
balance this interest against the possibility that unless the sponsor can charge for the drug, it
will not be available for treatment use until it receives full FDA approval [See also
Guidebook Chapter 3, Section C, "Selection of Subjects," and Chapter 3, Section G,
"Incentives for Participation."] Both the research and ethics communities have expressed concern about the effect of the
Treatment IND on the ability of investigators to attract subjects to clinical trials for Phase 3
testing. As one scientist put it, "Why would patients who are sophisticated, demanding, and
willing to participate in experiments take a chance on receiving a placebo when they want
the active compound?" IRBs should be concerned with the effect that the availability of an
investigational drug product outside of a clinical trial will have on the ability of the
investigator to recruit study subjects. As already mentioned, the cost of the drugs that
sponsors can pass on to subjects under the Treatment IND, but not under a regular IND, will
likely have an effect on subject recruitment, particularly since third-party payers usually
will not reimburse the cost of investigational drugs. As mentioned above, this disparity
raises ethical concerns about the equitable selection of subjects. In response to these concerns, the FDA has recently revised the "clinical hold" provisions
of the Treatment IND regulations to allow FDA to place such investigations on clinical hold
if it finds that there is reasonable evidence that the investigation is "impeding enrollment in,
or otherwise interfering with the conduct or completion of a study that is designed to be an
adequate and well-controlled investigation of the same or another investigational drug"
[Federal Register 57 (April 15, 1992): 13249, adding paragraph b(4)(i)-(vii) to 21 CFR
312.42]. Also addressing these concerns, the revised regulations allow the FDA to place a
Treatment IND on clinical hold if insufficient quantities of the investigational drug exist
adequately to conduct both the controlled trial and the Treatment IND, if one or more
"adequate and well-controlled investigations" strongly suggest lack of effectiveness, and if
another drug (either under investigation or approved) for the same indication and available
to the same patient population has demonstrated a better potential risk/benefit balance [21
CFR 312.42(b(4)(iii-v)]. For Additional Information. The FDA's Clinical Investigator Information Sheets provide
further useful information, and also describe the differences between a "single patient use"
situation (see description, below) and a Treatment IND, and between an "emergency use"
situation and a Treatment IND. [See pp. 29-35.] Single Patient Use. Another mechanism through which practitioners may obtain
investigational drugs for treatment use outside of a controlled clinical trial is what is called
a "single patient use." Usually, the patient is in a desperate situation and unresponsive to
other therapies, or in a situation where no approved or generally recognized treatment is
available. Further, there is usually little evidence that the proposed therapy is useful, but
may be plausible on theoretical grounds or anecdotes of success. Access to investigational
drugs for use by a single, identified patient may be gained either through the sponsor under a
treatment protocol, or through the FDA, by first obtaining the drug from the sponsor and then
submitting a treatment IND to the FDA requesting authorization to use the investigational
drug for treatment use [21 CFR 312.35]. [See also the FDA's Clinical Investigator
Information Sheet entitled, "Treatment Use of Investigational Drugs" for more detail.] Parallel Track. The FDA has devised another mechanism to make available promising
investigational agents as quickly as possible to persons with AIDS and other HIV-related
diseases while generating data on the safety and effectiveness of the drug [Federal Register
57 (April 15, 1992): 13250-13259]. Under the FDA policy, persons with AIDS and
HIV-related diseases who are not able to take standard therapy or for whom standard
therapy is no longer effective, and who are not able to participate in ongoing controlled
clinical trials, would have access to promising investigational drugs. Recipients of the new
drugs would be participants in studies without concurrent control groups to monitor drug
safety that are conducted in parallel with the principal controlled investigations. This
mechanism of expanded availability is therefore called "Parallel Track." Parallel Track protocols are accomplished under the Treatment IND mechanism, which is
described above, and should be thought of as a subset of the Treatment IND. They are
distinguished from Treatment INDs by the amount of evidence of effectiveness required.
Treatment INDs may be granted after sufficient data have been collected to show that the
drug "may be effective" and does not have unreasonable risks, but before marketing
approval has been granted. According to the FDA, Parallel Track protocols "might be
approved for promising investigational drugs when the evidence for effectiveness is less
than that generally required for a Treatment IND" [Federal Register 57 (April 15, 1992):
13256]. In other words, Treatment INDs have represented an attempt to move drugs from
late Phase 2 into Phase 3, and Parallel Track represents an attempt to move drugs from late
Phase 1 into Phase 2, both with the intended purpose of making promising new agents
available to persons with life-threatening diseases who cannot participate in controlled
clinical trials and for whom there are no satisfactory alternative therapies. In addition, the
Parallel Track mechanism is available only for AIDS and other HIV-related diseases, while
the Treatment IND is available for a number of serious or life-threatening conditions. Applications for consideration of experimental therapies for Parallel Track expanded
availability must be submitted to the FDA as amendments to existing INDs. The Role of the IRB. FDA human subjects protections regulations (21 CFR 50 and 56),
which apply to all investigational drug studies, and DHHS human subjects protections
regulations (45 CFR 46), which pertain to all institutions that receive DHHS support for
research involving human subjects, apply fully to Parallel Track protocols. The Parallel
Track policy, however, recognizes the difficulty that would be involved in meeting DHHS's
requirements for local IRB review and the negotiation of written Assurances from each
organization or individual practitioner involved in the research and not affiliated with an
assured institution. While local IRBs retain the option of reviewing the expanded
availability side of a Parallel Track protocol, to deal with these difficulties, the Secretary,
HHS, will consider, on a protocol-by-protocol basis, waiving the provisions of 45 CFR 46
where adequate protections are provided through other mechanisms. The mechanism
established by the FDA to meet this need is a national human subject protections review
panel that will provide for patient protection, including approval of consent procedures and
documentation, and will also provide for continuing ethical oversight of each Parallel Track
protocol. The FDA regulations also allow for waiver of its IRB requirements, where the FDA
determines that waiver is in the best interests of the subjects, and that the national human
subjects panel would provide an adequate mechanism for protecting patients. The
Commissioner of Food and Drugs will consider requests by sponsors of Parallel Track
protocols for waivers of the provisions of 21 CFR 56 dealing with local IRB review.
Again, individual institutions retain the option of requiring that their IRBs review Parallel
Track protocols when a study is conducted by the institution or its affiliated investigators. In keeping with FDA and DHHS regulations, local IRBs will continue to review protocols
on the controlled clinical trial side of the "parallel track" [Federal Register 57 (April 15,
1992): 13259]. One of the primary concerns of IRBs that do review the "noncontrolled" side of a Parallel
Track study is the informed consent process. It is vital that participating physicians fully
appreciate the importance of obtaining adequate informed consent, that subjects be informed
of the of the potential risks and benefits of the investigational drug and of other treatment
options in appropriate language to enable the individual patient to make an informed
decision, and that the consent document be kept up-to-date with new information regarding
toxicity and adverse reactions. The eligibility criteria, both for subjects and physicians, are
intended to provide additional protection for individuals against the uncertainties presented
by using drugs that are still in the early stages of development. For example, physicians
must be familiar with potential adverse effects, willing to instruct patients in the early
recognition of these effects, and willing to monitor their patients closely. Charging for Parallel Track Drugs. Charging for investigational drugs is addressed in the
section on Treatment INDs, above. For further information on the FDA's Parallel Track policy, contact: Mr. Donald Pohl APPLICABLE LAWS AND REGULATIONS Waiver of IRB Review 21 CFR 50.23 [Informed consent: Exception from general requirements] 21 CFR 56.104 [Exemptions from IRB requirement] 21 CFR 56.105 [Waiver of IRB requirement] Emergency Use 21 CFR 50.23 [Informed consent: Exception from general requirements] 21 CFR 104 [Exemptions from IRB requirement] Treatment INDs 21 CFR Part 50 [Informed consent] 21 CFR Part 56 [Institutional Review Boards] 21 CFR 56.111 [Criteria for IRB approval of research] 21 CFR 312.7(d) [Charging for and commercialization of investigational drugs] 21 CFR 312.34 [Treatment use of an investigational new drug] 21 CFR 312.35 [Submissions for treatment use] 21 CFR 312.42 [Clinical holds and requests for modification] Federal Register 57 (April 15, 1992): 13249, adding paragraph b(4)(i)-(vii) to 21 CFR
312.42 Single Patient Use 21 CFR 312.35 [Submissions for treatment use] Parallel Track Federal Register 57 (April 15, 1992): 13250-13259 SUGGESTIONS FOR FURTHER READING A. The Federal Policy B. Food and Drug Administration Regulations and Policies Return to Index Page
________________________
Guidebook
REGULATIONS AND POLICIES
Waiver of Consent Requirements
Emergency Use of a Test Article
Expanded Availability of Investigational Drugs
Single Patient Use
Parallel Track
REGULATIONS, POLICIES, AND ASSURANCES
Department of Energy
National Aeronautics and Space Administration
Department of Commerce
Consumer Product Safety Commission
International Development Cooperation Agency
Agency for International Development
Department of Housing and Urban Development
Department of Justice
Department of Defense
Department of Education
Department of Veterans Affairs
Environmental Protection Agency
Department of Health and Human Services
National Science Foundation
Department of Transportation
Central Intelligence Agency
Office for Protection from Research Risks
National Institutes of Health
6100 Executive Blvd.
Suite 3B01, MSC 7507
Rockville, MD 20892-7507
Tel: (301) 496-7005
Office of Health Affairs (HFY-20)
Food and Drug Administration
5600 Fishers Lane
Rockville, MD 20857
Tel: (301) 827-1685
7 CFR Part 1c [Department of Agriculture]
10 CFR Part 745 [Department of Energy]
14 CFR Part 1230 [National Aeronautics and Space Administration]
15 CFR Part 27 [Department of Commerce]
16 CFR Part 1028 [Consumer Product Safety Commission]
22 CFR Part 225 [International Development Cooperation Agency]
21 CFR Part 50 [Protection of Human Subjects]
21 CFR Part 56 [Institutional Review Boards
b. Must there be "compelling reasons" for using another institution's IRB rather
than one's own IRB?
c. Must the reviewing IRB be "local" (within the geographic proximity of the
research participants)?
d. When using another institution's IRB for the review of research, must there be
a representative or consultant appointed to the IRB from the institution
requesting the review so that he or she can provide information about the local
conditions where the research is to take place?
A modified SPA is used when an institution plans to use another institution's
IRB to review its human subjects research. The reviewing institution must
either have an MPA on file with OPRR or submit an SPA for this project for
OPRR approval. The institution proposing to do the research submits a
modified SPA; the institution whose IRB will have responsibility for reviewing
the research submits an SPA, unless it has an MPA on file. OPRR must approve
this arrangement; contact the Assurance Branch prior to submission of the
Assurance [(301) 496-7041].
ii. Cooperative Oncology Group Program (COG)
iii. Community Program for Clinical Research on AIDS
(CPCRA)
POLICIES
Office of Health Affairs (HFY-20)
Food and Drug Administration
5600 Fishers Lane
Rockville, MD 20857
(301) 443-1382
§46.101(h) (DHHS)
§46.102 (DHHS)
§46.108 (DHHS)
§46.109 (DHHS)
§46.117(c) (DHHS)
§46.110 (DHHS)
§46.114 (DHHS)
§46.115 (DHHS)
§46.116(a)(5) (DHHS)
Bioresearch Monitoring Staff
Office of the Associate Commissioner for Regulatory Affairs (HFC-30)
Food and Drug Administration
5600 Fishers Lane
Rockville, MD 20857
(301) 443-2390
Center for Drug Evaluation and Research
Food and Drug Administration
5600 Fishers Lane
Rockville, MD 20857
(301) 443-4320
Center for Biologic Evaluation and Research
Food and Drug Administration
8800 Rockville Pike
Bethesda, MD 20857
(301) 443-4864
Office of AIDS Coordination (HF-12)
Food and Drug Administration
5600 Fishers Lane
Rockville, MD 20857
Tel: (301) 443-0104
Chapter II: Regulations and Policies