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U.S. Department of Health and Human Services

Science & Research

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FDA Policy for the Protection of Human Subjects

21 CFR Parts 50 and 56
Informed Consent; Standards for Institutional Review Boards for Clinical Investigations
[Docket No. 87N-0032]
56 FR 28025

June 18, 1991

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

SUMMARY: The Food and Drug Administration (FDA) is amending its regulations on institutional review boards (IRB's) and on informed consent to conform them to the "Federal Policy for the Protection of Human Research Subjects" (Federal Policy) published elsewhere in this issue of the Federal Register. Existing FDA regulations governing the protection of human subjects share a common core with the Federal Policy and implement the fundamental principles embodied in that policy.

EFFECTIVE DATE: August 19, 1991.

FOR FURTHER INFORMATION CONTACT: Richard M. Klein, Office of Health Affairs (HFY-20), Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857, 301-443-1382.

TEXT: SUPPLEMENTARY INFORMATION:

I. Background

FDA is charged by statute with ensuring the protection of the rights, safety, and welfare of human subjects who participate in clinical investigations involving articles subject to section 505(i), 507(d), or 520(g) of the Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 355(i), 357(d), or 360j(g)), as well as clinical investigations that support applications for research or marketing permits for products regulated by FDA, including food and color additives, drugs for human use, medical devices for human use, biological products for human use, and electronic products.

In the Federal Register of January 27, 1981, FDA adopted regulations governing informed consent of human subjects (21 CFR part 50; 46 FR 8942) and regulations establishing standards for the composition, operation, and responsibilities of IRB's that review clinical investigations involving human subjects (21 CFR part 56; 46 FR 8958). At the same time, the Department of Health and Human Services (HHS) adopted regulations on the protection of human research subjects (45 CFR part 46; 46 FR 8366). The FDA and HHS regulations share a common framework.

In December 1981, the President's Commission for the study of Ethical Problems in Medicine and Biomedical and Behavioral Research (the commission) issued its "First Biennial Report on the Adequacy and Uniformity of Federal Rules and Policies, and their Implementation, for the Protection of Human Subjects in Biomedical and Behavioral Research, Protecting Human Subjects." The commission recommended that all Federal departments and agencies adopt the HHS regulations (45 CFR part 46).

In May 1982, the President's Science Advisor, Office of Science and Technology Policy (OSTP), appointed an ad hoc Committee for the Protection of Human Research Subjects (the committee), under the auspices of the Federal Coordinating Council for Science, Engineering, and Technology (FCCSET), to respond to the recommendations of the commission. The committee, composed of representatives and ex officio members from departments and agencies that conduct, support, or regulate research involving human subjects, developed responses to the commission in consultation with OSTP and the Office of Management and Budget (OMB).

The committee agreed that uniformity of Federal regulations on human subject protection is desirable to eliminate unnecessary regulations and to promote increased understanding by institutions that conduct federally-supported or regulated research. The committee developed a model policy which OSTP later modified and, with the concurrence of all affected Federal departments and agencies, published as a proposal in the Federal Register of June 3, 1986 (51 FR 20204). More than 200 comments were submitted in response to the proposal. Published elsewhere in this issue of the Federal Register is the final rule on the Federal Policy.

FDA concurs in that final rule. In the Federal Register of November 10, 1988 (53 FR 45678), the agency proposed to amend its regulations in 21 CFR parts 50 and 56 to conform them to the Federal Policy to the extent permitted by the act. The agency is committed to being as consistent with the final Federal Policy as it can be, given the unique requirements of the act and the fact that FDA is a regulatory agency that rarely supports or conducts research under its regulations. However, as explained in the proposed rule, FDA must diverge from §§ XXX .101(h) and XXX .116(d) of the Federal Policy.

FDA received 22 comments on the proposed rule from sponsors of regulated research, institutional review board members and staff, academic institutions, medical societies, and lawyers. Several comments were prepared by organizations, each representing a consortia of institutions that had been polled concerning the proposed rule.

A. General Comments

1. The majority of comments supported the agency's efforts to conform to the Federal Policy.

2. The majority of comments received concerned the proposal to amend § 56.108(b) to require that IRB's follow written guidelines for ensuring the reporting of scientific misconduct and of unanticipated problems to the IRB, institutional officials, and FDA. Two comments noted that this provision would make the IRB the institutional body that investigates alleged fraud, severely damaging the IRB/investigator relationship and possibly diminishing the effectiveness of the IRB in protecting human subjects. Several comments noted that the proposed additional reporting requirements would duplicate investigator and sponsor reporting requirements and would be difficult for the IRB to enforce. One comment said that this section may adversely affect the IRB/institution relationship and asked how FDA intended to ensure that reporting occurred. One comment interpreted the provision as applicable to animal studies and wondered whether IRB's would be responsible for contacting sponsors. One comment expressed concern that the workload of the IRB would increase and adversely affect the recruitment of new members. One comment sought to exclude Adverse Drug Reaction reports. One comment argued that the reporting requirement was unauthorized by law.

Two comments from sponsors requested that sponsor notification be added under proposed § 56.108(b), noting that an investigator engaged in misconduct is unlikely to report that misconduct to the IRB, and that the sponsor is the entity that frequently detects misconduct through its extensive monitoring practices. In addition, these comments requested clarification of the office in FDA to which scientific misconduct should be reported. Several comments requested that FDA define or clarify "scientific misconduct" and "unanticipated problems."

Since the proposed model policy was published, the Public Health Service published a final rule concerning fraud and misconduct in science (54 FR 32446, August 8, 1989). Because that rule directs institutions to establish provisions for the investigation of alleged scientific fraud and misconduct, the mention of "scientific misconduct" has been deleted, as unnecessary, from the model policy. Because FDA only proposed to require that IRB's report scientific misconduct to be consistent with the model policy, it has deleted this requirement from its final rule. This action should allay many of the concerns expressed in the comments.

Moreover, FDA believes that the comments misconstrued the intent of § 56.108(b). This section requires simply that an IRB have procedures by which it checks to ensure in reviewing each study presented, that provision has been made in the study to notify the IRB, appropriate institutional officials, and FDA in the specified circumstances. Section 56.108(b) does not require that the IRB itself provide the notification to either the institution or to FDA, unless such reporting would not otherwise occur. Although FDA's regulations include reporting requirements for certain types of investigational articles (see, e.g., 21 CFR parts 312 (investigational drugs) and 812 (investigational devices)), there are no such provisions for other articles that may be the subject of an investigation (e.g. food additives). Because all regulated research to be conducted at an institution will come before the IRB, FDA finds that the IRB is the appropriate entity to charge with the responsibility for ensuring that reporting of the specified problems to the IRB, the institution, and the agency will occur.

3. One comment urged FDA to move toward the adoption of an assurance system as established for the other agencies within HHS to guarantee compliance with regulations for the protection of human subjects.

FDA continues to believe that it would be inappropriate for it to adopt this mechanism. As stated in the final rule in the Federal Register of January 27, 1981 (46 FR 8959, comment 2), the benefits of assurance from IRB's that are subject to FDA jurisdiction, but not otherwise to HHS jurisdiction, do not justify the increased administrative burdens that would result from an assurance system. FDA relies on its Bioresearch Monitoring Program, along with its educational efforts, to assure compliance with these regulations.

4. One comment expressed concern over FDA's proposed divergences from sections 101(h) and 116(d) of the Federal Policy. The comment contended that it is sometimes impossible to obtain informed consent, as defined by FDA's regulations, in foreign clinical trials.

As stated in the proposed rule (53 FR 45679), FDA does not have the authority to accept the procedures followed in a foreign country in lieu of informed consent as required by the act for studies that are conducted under a research permit that it grants. The comment did not provide any information that would compel a different conclusion.

B. Comments on Definitions

5. One comment suggested that the word "discomfort" used in proposed §§ 50.3(i) and 56.102(i) is difficult to define and is subjective.

FDA believes that the meaning of "discomfort" is sufficiently clear. FDA interprets this term to have its ordinary meaning; that is, to mean the extent to which a subject may be made uncomfortable by the article that is the subject of the research.

6. One comment asserted that proposed § 56.102(m), the definition of "IRB approval," suggests an intent to change the procedural requirements of IRB approval.

FDA proposed to add this definition to make the regulations conform to the Federal Policy and to clarify the meaning of the phrase "IRB approval" under this rule. The addition of this definition is not intended to effect a substantive change in part 56. In the preamble to its August 8, 1978 proposal of the IRB regulation (43 FR 35186 at 35197), FDA presented a thorough discussion of its authority to require IRB review.

7. One comment stated that the reference to "other institutional and Federal requirements" in proposed § 56.102(m) goes beyond FDA's ability to determine other institutional requirements and may be counterproductive where there is conflict between the institutional requirements and FDA or HHS requirements. The suggestion is made to delete "and other institutional * * * requirements."

This definition is intended to make clear that IRB approval is to be based on a determination that the proposed research is acceptable under any applicable institutional requirements, applicable law, and standards of professional conduct and practice. If there are conflicts between the institutional requirements and Federal law, those conflicts obviously must be resolved in favor of the Federal law. However, institutional requirements often address matters not addressed by Federal law. Therefore, FDA finds it appropriate to mention both institutional and Federal requirements in this definition.

8. One comment suggested substituting "clinical investigation" for the word "research" in § 56.102(m).

FDA rejects the suggestion. FDA has defined "clinical investigation" in § 56.102(c) to be synonymous with "research" (46 FR 8976). Because FDA desires to conform to the Federal Policy and in the absence of a compelling argument to diverge from it, FDA is using the word used in the Federal Policy.

9. Several comments suggested deleting "at an institution" from § 56.102(m), contending that this phrase may confuse the original intent of the meaning of IRB approval. Another comment noted that much research today is conducted outside the institutional setting.

FDA rejects the comments. In 1981, when FDA adopted the IRB regulations, FDA intentionally defined "institution" broadly to include "any public or private entity or agency" (§ 56.102(f); 46 FR 8963, comment 27). Thus, § 56.102(m) is consistent with the original intent of the IRB regulations.

10. One comment suggested revising § 56.102(m) to read "IRB approval means * * * that the research has been reviewed for undue risk to the subject and may be conducted * * *."

FDA rejects the suggestion. The suggested change does not adequately describe the role of the IRB. The IRB's review of studies and informed consent documents includes numerous considerations in addition to whether the study presents undue risks to the human subjects involved.

C. Comments on Exemptions From IRB Requirements

11. One comment requested that no exemptions from IRB requirements be granted for those populations already identified as vulnerable.

FDA did not propose that studies involving vulnerable populations be exempt from IRB review. The only exemptions from the IRB review requirements were established in the 1981 final rule (46 FR 8942; 21 CFR 56.104). The use of an investigational article is exempt from IRB review if the investigation started before July 27, 1981, before the requirement of IRB review was in effect, or if it involves an emergency use of the test article, in which case there is not time for IRB review before the article is used. The agency found that in these circumstances, the considerations that support granting an exemption outweigh those that would support denying it (46 FR 8965, comment 48). The comment did not provide any basis for reconsidering or revising this judgment. The agency points out that the latter consideration (emergency use), which is the only basis on which a new study would be exempt, applies only to particular uses of an article and would not provide the basis for an exemption for the use of an article in a particular population. Therefore, FDA finds that this comment provides no basis for modifying its regulations.

12. One comment suggested that FDA completely exempt "minimal risk" studies from IRB review.

FDA rejects the comment. The determination of minimal risk can be made only by members of the IRB, not the investigator or the sponsor. The burden of an expedited review of a protocol to determine if it presents minimal risk is not so great as to justify the requested exemption.

D. Comments on IRB Membership

13. Three comments suggested that FDA define in § 56.107 the specific members to be included on an IRB. Several comments suggested that FDA define, in new § 56.107(c), "non-scientific" and "scientific." Two comments suggested that the IRB include "one member who has an understanding of the medical risks involved." Another comment suggested that § 56.107(c) be clarified to include a statement requiring that at least one member of the IRB have an understanding of the scientific method.

FDA rejects these comments. FDA has chosen not to prescribe professional membership requirements for IRB members. The regulations allow for flexibility in the makeup of the IRB (see 46 FR 8966, comment 55). They require, however, that there be at least one member whose concerns are in nonscience areas and one member who has the professional competency to review the proposed research, such as a physician. FDA interprets "competency" in this context to include the ability to understand the scientific method. The agency believes that the membership requirements that it has adopted are adequate to ensure that an IRB will be able to fully consider the issues presented by a study.

14. One comment suggested that the proposed change in § 56.107(a), allowing IRB's that regularly review studies that involve vulnerable categories of subjects to consider including as a member an individual knowledgeable about, and experienced in, working with vulnerable populations, will afford less human subject protection than the current regulation.

The current regulation states that an IRB that regularly reviews research involving vulnerable populations should include as members individuals who are primarily concerned with the welfare of vulnerable subjects. Revised § 56.107(a) lists categories of subjects who are considered vulnerable and requires that the institution, or other authority, consider including individuals knowledgeable and experienced in working with these types of subjects as voting members on the IRB. This revision is not intended to lessen in any way the protections for vulnerable populations under FDA's regulations. As explained in the proposal (53 FR 45679), FDA is making this change only to conform to the language of the Federal Policy.

FDA on its own initiative is adding parenthesis to the word "reviewers" in § 56.110(b)(1) to permit a continuance of existing IRB review procedures.

E. Comments on IRB Functions and Operations

15. Several comments sought clarification of new § 56.108(b)(1) with regard to the definition and interpretation of "any unanticipated problems involving risks to human subjects and others" and the level of risk to be reported.

FDA interprets this phrase to mean an unexpected adverse experience that is not listed in the labeling for the test article. Such experience includes an event that may be symptomatically and pathophysiologically related to an event listed in the labeling but that differs from the event because of greater specificity or severity. The word "others" has previously been defined as persons who are participating in clinical trials under the same or similar protocols or who may be affected by products or procedures developed in those trials (see 53 FR 45661, 45665; November 10, 1988).

F. Comments on Expedited Review Procedures

16. One comment read the parenthetical change in § 56.110(b), "of one year or less," as affecting a change from the current regulations.

FDA disagrees with the comment. Under current regulations, the IRB may approve a study that will continue beyond 1 year, such as a longitudinal followup study. The IRB is obligated, however, under § 56.109(e) (21 CFR 56.109(e)), to conduct continuing review of the research at intervals appropriate to the degree of risk that it presents but not less than once a year.

17. One comment stated that expedited review procedures should never be used in research that involves vulnerable populations.

FDA disagrees with the comment. Expedited review procedures may only be used to review research that involves minimal risk as defined in § 56.102(i) or to review minor changes in previously approved research (§ 56.110(b)). The determination that such conditions apply must be made by the chairperson of the IRB, or by one or more experienced members of the IRB designated by the chairperson. Thus, research involving vulnerable populations will not be subject to expedited review unless a member of the IRB has affirmatively determined that the subjects will not be exposed to any greater risk of harm than they encounter in daily life or during routine physical or psychological examinations or tests, or that a change in research that has been reviewed by the whole IRB is minor. Obviously, in making these determinations, the IRB member must consider the nature of the subject population. Moreover, if expedited review is undertaken, the reviewer may exercise all the authority of the IRB, including the authority under § 56.111(a)(3) to ensure that any special problems of vulnerable populations have been addressed. Thus, FDA believes that vulnerable populations will not be involved in research that has been subject to expedited review procedures without full consideration of whether such research should be subject to expedited review at all and, if so, of their interests. Therefore, FDA does not agree with the comment.

G. Comments on Criteria for IRB Approval of Research

18. One comment suggested deleting "* * * economically or educationally disadvantaged persons * * *" from new § 56.111(a)(3), stating that it would be impossible for the IRB or the clinical investigator to make that determination.

FDA disagrees with the comment. As stated in § 56.111(b), FDA expects the IRB to make sure that adequate protections are included in those clinical investigations in which vulnerable subjects will be participating. There is no requirement for the IRB to make a determination that individual subjects are disadvantaged. However, the IRB is required to determine whether it is likely that vulnerable individuals will be involved in the study, and, if so, whether adequate safeguards have been included to protect the study subjects or whether additional safeguards are necessary.

II. Environmental Impact

The agency has determined under 21 CFR 25.24(a)(8) that this action is of a type that does not individually or cumulatively have a significant effect on the human environment. Therefore, neither an environmental assessment nor an environmental impact statement is required.

III. Economic and Regulatory Assessments

FDA has examined the economic consequences of the final amendments to its regulations pertaining to IRB's and to informed consent in accordance with the criteria in section 1(b) of Executive Order 12291 and found that these amendments would not be a major rule under the Executive Order. The agency also has considered the effect that the final rule would have on small entities including small businesses in accordance with the Regulatory Flexibility Act (Pub. L. 96-354). The agency certifies that there will not be a significant economic impact on a substantial number of small entities. FDA explained the basis for these conclusions in the proposal (53 FR 45681). The agency did not receive any comments that suggest contrary conclusions. This final rule contains information collections subject to the Paperwork Reduction Act of 1980. These information collections have been approved under OMB control number 0910-0130.

List of Subjects in

21 CFR Part 50
Prisoners, Reporting and recordkeeping requirements, Research, Safety.

21 CFR Part 56
Reporting and Recordkeeping requirements, Research, Safety.

Therefore, under the Federal Food, Drug, and Cosmetic Act and the Public Health Service Act, 21 CFR parts 50 and 56 are amended as follows:

PART 50 -- PROTECTION OF HUMAN SUBJECTS

1. The authority citation for 21 CFR part 50 continues to read as follows:

Authority: Secs. 201, 406, 408, 409, 502, 503, 505, 506, 507, 510, 513-516, 518-520, 701, 706, 801 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 346, 346a, 348, 352, 353, 355, 356, 357, 360, 360c-360f, 360h-360j, 371, 376, 381); secs. 215, 301, 351, 354-360F of the Public Health Service Act (42 U.S.C. 216, 241, 262, 263b-263n).

2. Section 50.3 is amended by revising paragraph (l) to read as follows:

§ 50.3 Definitions.

* * * * *

(l) Minimal risk means that 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.

* * * * *

PART 56 -- INSTITUTIONAL REVIEW BOARDS

3. The authority citation for 21 CFR part 56 continues to read as follows:

Authority: Secs. 201, 406, 408, 409, 501, 502, 503, 505, 506, 507, 510, 513-516, 518-520, 701, 706, 801 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 346, 346a, 348, 351, 352, 353, 355, 356, 357, 360, 360c-360f, 360h-360j, 371, 376, 381); secs. 215, 301, 351, 354-360F of the Public Health Service Act (42 U.S.C. 216, 241, 262, 263b-263n).

4. Section 56.102 is amended by revising paragraph (i) and by adding new paragraph (m) to read as follows:

§ 56.102 Definitions.

* * * * *

(i) Minimal risk means that 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.

* * * * *

(m) IRB approval means the determination of the IRB that the clinical investigation has been reviewed and may be conducted at an institution within the constraints set forth by the IRB and by other institutional and Federal requirements.

5. Section 56.104 is amended by adding new paragraph (d) to read as follows:

§ 56.104 Exemptions from IRB requirement.

* * * * *

(d) Taste and food quality evaluations and consumer acceptance studies, if wholesome foods without additives are consumed or if a food is consumed that contains a food ingredient at or below the level and for a use found to be safe, or agricultural, chemical, or environmental contaminant at or below the level found to be safe, by the Food and Drug Administration or approved by the Environmental Protection Agency or the Food Safety and Inspection Service of the U.S. Department of Agriculture.

6. Section 56.107 is amended by revising paragraphs (a), (b), and (c) to read as follows:

§ 56.107 IRB membership.

(a) Each IRB shall have at least five members, with varying backgrounds to promote complete and adequate review of research activities commonly conducted by the institution. The IRB shall be sufficiently qualified through the experience and expertise of its members, and the diversity of the members, including consideration of race, gender, cultural backgrounds, and sensitivity to such issues as community attitudes, to promote respect for its advice and counsel in safeguarding the rights and welfare of human subjects. In addition to possessing the professional competence necessary to review the specific research activities, the IRB shall be able to ascertain the acceptability of proposed research in terms of institutional commitments and regulations, applicable law, and standards or professional conduct and practice. The IRB shall therefore include persons knowledgeable in these areas. If an IRB regularly reviews research that involves a vulnerable catgory of subjects, such as children, prisoners, pregnant women, or handicapped or mentally disabled persons, consideration shall be given to the inclusion of one or more individuals who are knowledgeable about the experienced in working with those subjects.

(b) Every nondiscriminatory effort will be made to ensure that no IRB consists entirely of men or entirely of women, including the instituton's consideration of qualified persons of both sexes, so long as no selection is made to the IRB on the basis of gender. No IRB may consist entirely of members of one profession.

(c) Each IRB shall include at least one member whose primary concerns are in the scientific area and at least one member whose primary concerns are in nonscientific areas.

* * * * *

7. Section 56.108 is amended by revising paragraph (a), by removing paragraph (c), by redesignating paragraph (b) as paragraph (c), by adding a new paragraph (b), and by adding a parenthetical statement to the end of the section to read as follows:

§ 56.108 IRB functions and operations.

(a) Follow written procedures: (1) For conducting its initial and continuing review of research and for reporting its findings and actions to the investigator and the institution; (2) for determining which projects require review more often than annually and which projects need verification from sources other than the investigator that no material changes have occurred since previous IRB review; (3) for ensuring prompt reporting to the IRB of changes in research activity; and (4) for ensuring that changes in approved research, during the period for which IRB approval has already been given, may not be initiated without IRB review and approval except where necessary to eliminate apparent immediate hazards to the human subjects.

(b) Follow written procedures for ensuring prompt reporting to the IRB, appropriate institutional officials, and the Food and Drug Administration of: (1) Any unanticipated problems involving risks to human subjects or others; (2) any instance of serious or continuing noncompliance with these regulations or the requirements or determinations of the IRB; or (3) any suspension or termination of IRB approval.

* * * * *

(Information collection requirements in this section were approved by the Office of Management and Budget (OMB) and assigned OMB control number 0910-0130)

8. Section 56.110 is amended by revising paragraph (b) to read as follows:

§ 56.110 Expedited review procedures for certain kinds of research involving no more than minimal risk, and for minor changes in approved research.

* * * * *

(b) An IRB may use the expedited review procedure to review either or both of the following: (1) Some or all of the research appearing on the list and found by the reviewer(s) to involve no more than minimal risk, (2) minor changes in previously approved research during the period (of 1 year or less) for which approval is authorized. Under an expedited review procedure, the review may be carried out by the IRB chairperson or by one or more experienced reviewers designated by the IRB chairperson from among the members of the IRB. In reviewing the research, the reviewers may exercise all of the authorities of the IRB except that the reviewers may not disapprove the research. A research activity may be disapproved only after review in accordance with the nonexpedited review procedure set forth in § 56.108(c).

* * * * *

9. Section 56.111 is amended by revising paragraphs (a)(3) and (b) to read as follows:

§ 56.111 Criteria for IRB approval of research.

(a) * * *

(3) Selection of subjects is equitable. In making this assessment the IRB should take into account the purposes of the research and the setting in which the research will be conducted and should be particularly cognizant of the special problems of research involving vulnerable populations, such as children, prisoners, pregnant women, handicapped, or mentally disabled persons, or economically or educationally disadvantaged persons.

* * * * *

(b) When some or all of the subjects, such as children, prisoners, pregnant women, handicapped, or mentally disabled persons, or economically or educationally disadvantaged persons, are likely to be vulnerable to coercion or undue influence additional safeguards have been included in the study to protect the rights and welfare of these subjects.

10. Section 56.115 is amended by revising paragraph (a)(6) and by adding a parenthetical statement to the end of the section to read as follows:

§ 56.115 IRB records.

(a) * * *

(6) Written procedures for the IRB as required by § 56.108 (a) and (b).

* * * * *

(Information collection requirements in this section were approved by the Office of Management and Budget (OMB) and assigned OMB control number 0910-0130)

Dated: March 29, 1991.

David A. Kessler,
Commissioner of Food and Drugs.

Louis W. Sullivan,
Secretary of Health and Human Services.

[FR Doc. 91-14260 Filed 6-17-91; 8:45 am]

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