The IRB Guidebook was last updated in 1993. Developments over the intervening years have made portions of the Guidebook information obsolete, while portions of the information remain valid. There is no errata document to indicate which information has been superseded. OHRP cautions users to verify the current validity of any Guidebook information before relying on the information in a program of human subjects protection.

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Institutional Review Board
Guidebook

* CHAPTER II *
REGULATIONS AND POLICIES


A. Department of Health and Human Services Regulations, Policies, and Assurances

B. Food and Drug Administration Regulations and Policies

Suggestions for Further Reading


A. DEPARTMENT OF HEALTH AND HUMAN SERVICES
REGULATIONS, POLICIES, AND ASSURANCES

i. THE FEDERAL POLICY

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
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

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
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

For information concerning the Federal Policy and FDA regulations, contact:

Dr. Paul W. Goebel, Jr.
Office of Health Affairs (HFY-20)
Food and Drug Administration
5600 Fishers Lane
Rockville, MD 20857
Tel: (301) 827-1685

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:

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]

[Agency for International Development]

24 CFR Part 60 [Department of Housing and Urban Development] 28 CFR Part 46 [Department of Justice] 32 CFR Part 219 [Department of Defense] 34 CFR Part 97 [Department of Education] 38 CFR Part 16 [Department of Veterans Affairs] 40 CFR Part 26 [Environmental Protection Agency] 45 CFR Part 46 [Department of Health and Human Services] 45 CFR Part 690 [National Science Foundation] 49 CFR Part 11 [Department of Transportation]

FDA regulations pertaining to research with human subjects are codified at:

21 CFR Part 50 [Protection of Human Subjects] 21 CFR Part 56 [Institutional Review Boards

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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?
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?

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."

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iii. ASSURANCES

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.
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].

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)
ii. Cooperative Oncology Group Program (COG)
iii. Community Program for Clinical Research on AIDS (CPCRA)

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].

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B. FOOD AND DRUG ADMINISTRATION REGULATIONS AND
POLICIES

i. INTRODUCTION

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
Office of Health Affairs (HFY-20)
Food and Drug Administration
5600 Fishers Lane
Rockville, MD 20857
(301) 443-1382

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 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)
§46.101(h) (DHHS)

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)
§46.102 (DHHS)

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)
§46.108 (DHHS)

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)
§46.109 (DHHS)
§46.117(c) (DHHS)

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)
§46.110 (DHHS)

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)
§46.114 (DHHS)

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)
§46.115 (DHHS)

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)
§46.116(a)(5) (DHHS)

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.

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WAIVER OF IRB REVIEW

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
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

See also FDA Information Sheets: "Waiver of IRB Requirements" and "Emergency Use of an Investigational Drug."

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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."]

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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)
Center for Drug Evaluation and Research
Food and Drug Administration
5600 Fishers Lane
Rockville, MD 20857
(301) 443-4320

For biologic products, contact:

Division of Biological Investigational New Drugs (HFN-823)
Center for Biologic Evaluation and Research
Food and Drug Administration
8800 Rockville Pike
Bethesda, MD 20857
(301) 443-4864

(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."

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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.]

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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.]

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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
Office of AIDS Coordination (HF-12)
Food and Drug Administration
5600 Fishers Lane
Rockville, MD 20857
Tel: (301) 443-0104

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

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SUGGESTIONS FOR FURTHER READING

A. The Federal Policy

B. Food and Drug Administration Regulations and Policies

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Chapter II: Regulations and Policies