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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)
827-16857 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