35186 PROPOSED RULES 

[4110-03] 

DEPARTMENT OF HEALTH, 


EDUCATION, AND WELFARE 


Food and Drug Adminlstrotion 

[21 CFR Parts 16, 56, 71, 171, 180,310,312,314, 

320, 330, 361, 430, 431, 601, 630, 1003, and 

1010] 

£Docket No. 77N-0350l 

STANDARDS FOR INSTITU.TIONAL REVIEW 

BOARDS fOR CLINICAL INVESTIGATIONS 

Proposed Establishment of Regulations 

AGENCY: Food and Drug Administration. 

ACTION: Proposed rule. 

SUMMARY: This is a proposal to clarify existing regulations governing the 

activities of institutional review boards 

<IRB> that review clinical investigations involving human subjects and 

new human drug products. The proposed rule would extend these regulations to include IRB's that review 

clinical investigations involving human 

subjects and articles other than new 

human drug products regulated by the 

Food and Drug Administration <FDA>. 

The proposed regulations are intended 

to provide greater protection of the 

rights and safety of ·subjects involved 

in clinical investigations and to help 

assure the quality and integrity of the 

resulting data that are submitted to 

FDA in support of applications for 

permission _to conduct further research or to market regulated products. 

DATES: Comments by December 6, 

1978. 

ADDRESS: Written comments, prefer­ ably four copies and identified by 

docket No. 77N-0350, may be submitted to the office of the Hearing Clerk 

(FHA-305), Food and Drug Administration, room 4-65, 5600 Fishers Lane, Rockville,~d.20857. 

FOR FURTHER INFOR~TION 

CONTACT: 

John Petricciani, Division of Pathology <HFB-400), Food and Drug Administration, Department of Health, 

Education, and Welfare, 8800 Rockville Pike, Bethesda, Md. 20014, 301­

496-5491. 

SUPP~ENTARY INFOR~TION: 

Although informed consent is an important part of the protection of 

human subjects participating in clinical investigations, this proposal is 

being published without a comprehensive definition of "informed consent" 

to provide an early opportunity for interested persons to review and comment on the proposed standards and 

procedures for institutional review. 

The agency will be publishing shortly 

a companion proposal that will define 

"informed consent." 

The agency also intends to hold 

three open hearings to give the public 

an opportunity to make oral comments on both proposals. A notice of 

the date and location of these hearings will be published later ·with the 

proposed definitions of "informed consent." 

The comment period for this proposal will close on December 6, 1978. However, the Commissioner of Food and 

Drugs recognizes that· it may not be 

·possible to publish the "informed consent" proposal, and schedule and hold 

the public hearings on both proposals 

within that time period. The Commissioner advises interested persons that 

he is prepared to extend the comment 

period on this proposal as appropriate. 

The Commissioner believes that a 

complete revision of FDA requirements relating to IRB's is needed because: (1) Current regulations have 

not been comprehensively reviewed in 

7 years, <2> actions by the Department 

of Health, Education, and Welfare 

<HEW>, the Congress, and the World 

Medical Assembly suggest a need to 

extend IR.B requirements to types of 

clinical investigations involving human 

subjects other than those on new 

human drugs, (3) wherever possible, 

IRB -requirements adopted by FDA 

should be identical to or compatible 

with HEW regulations as well as IRB 

regulations issued by other Federal 

agencies, < 4) the General Accounting 

Office <GAO> has recommended 

changes in current FDA regulations, (5) Congress, in enacting the Medical 

Device Amendments of 1976 <Pub. L. 

94-295), provided for IRB's in clinical 

investigations of devices intended for 

human use, and <6> the new FDA bioresearch monitoring program, designed 

to assure compliance with FDA requirements to protect human research 

subjects and·reinforce the validity and 

reliability of clinical data submitted to 

FDA, can be more efficiently and effectively conducted with the utilization of IR.B's and with · uniform, 

agencyYJide regulatory standards regarding IRB's. Each "of these matters 

is discussed in further detail below. 

Since 1971, FDA has required institutional review of clinical investiga­ tions- subject to regulation by the 

agency and involving institutionalized 

human subjects or 

noninstitutionalized subjects where an 

institution agrees to assume responsi­ bility for the investigation. The benefits of institutional review include appraisal of local conditions and standards, acquaintance with investigators, 

subject groups, and the setting in 

which the investigation is proposed to 

be conducted, independence from competing interests, and sensitivity to 

ethical and scientific concerns in the 

community and the society at large, In 

addition, IRB's can review ongoing in· 

vestigations and oversee the continu· 

ing safety of the subjects as well ns 

the adherence of the investigation to 

the approved protocol and other un· 

derstandings and regUlations. current 

FDA requirements for IRB review are 

set forth in the texts of the forms FD1571, FD-1572, and FD-1573 used for 

exemptions for investigational new 

drug studies (21 CFR 312.l<a)(2), form 

FD-1571, item 10.c.; 21 CFR 

312.1(a)(12), form FD-1572, item 3,; 

and 21 CFR 312.l<a)(13> form FD1573, item 2a.). When originally adopt· 

ed, the agency iridicated that it was 

considering extending these require­

,ments to all other drug investigations 

under FDA jurisdiction (36 FR 5037; 

March 11, 1971). The Commissioner 

has for some time also desired to 

review and codify existing require· 

ments. Since 1971, several events have 

indicated increased acceptance of and 

reliance upon the concept of local, in· 

dependent review of human research 

to evaluate the scientific justification for E>.nd ethical acceptability of expos• 

ing human beings to risk. These devel· 

opments, which increase the advisabil· 

ity of a substantial revision and exten• 

sion of current FDA regulations, in· 

elude: 

(1) HEW guidelines on institutional 

review for research involving human 

subjects that is supported by HEW 

grant or contract were codified in 1974 

into regulation form, after public 

notice and extensiv.e comments from 

interested persons (45 CFR part 46, 

subpart A: see 39 FR 18914;, May 30, 

1974>. These regulations \'/ere subject 

to technical amendments in 1975 (40 

FR 11854; March 13, 1975>. These reg. ulations reflected experience that 

HEW had gathered under earlier 

guidelines, guidelines which were also 

the source of FDA's 1971 regulations. 

The new HEW rules modified and im· 

proved upon the older ones, but ere· 

ated certain inconsistencies between 

FDA's standards regarding regulated 

research and the Department's stand· 

ards regarding funded research. Since 

1974, the HEW regulations have 

served as a model for other Federal 

agencies that support human expert· 

mentation. See, e.g. 10 CFR part 745 

adopted by the Energy Research and 

Development Administration in the 

FEDERAL REGISTER of November 30, 

1976 (41 FR 52434) and regulations 

proposed by the Consumer Product 

Safety Commission in the FEDERAL 

REGISTER of September 2, 1976 (41 FR 

37120). The Commissioner believes 

that, wherever possible, FDA's regulations should be compatible with, if not 

identical to, HEW's and those of other 

Federal agencies. A multiplicity of dis· 

similar and inconsistent Federal requirements is burdensome to institu· 

FEDERAL REGISTER, VOL 43, NO 153-TUESDAY, AUGUST 8, 197B 
.tions, m:B•s, and the-process of clinical 

-investigation. 

~ (2) Congress endorsed the concept of 

institutional review in section 212(a) 

of the National Research Act of 1975 

(42 U.S.C. 747<a>>. which directs the 

Secretary of HEW to require IRB 

review of all biomedical and behavioral research involving huma.il subjects 

conducted at or sponsored by an institution receiving a grant or contract 

under the Public Health Service Act. -Although this includes biomedical r~ 

search involving human subjects when 

such research is regulated or reviewed 

by FDA under the Federal Food, 

Drug, and Cosmetic Act <the "act"> if 

it is conducted by a Public Health 

Service grantee or contractor, it does 

not extend to institutions not receiv­

-ing such financial support. The Commissioner believes that it would be 

consistent with the congressional 

intent for FDA to use its existing statutory authority to apply an IRB 

review requirement wherever it is both 

reasonable and feasible. 

<3> The Declaration of Helsinki, a set 

of principles adopted by the World 

Medical Assembly Can international 

body of experts concerned with health 

and scientific matters) was revised in 

1975 to recommend that every biomedical research protocol be given "to a 

specially appointed independent com-' · mittee for reconsideration, comment, 

...--and 	guidance" <sec. !(2)). <A copy of 

the amended declaration is on display 

in the Office of the Hearing Clerk 

<HFA-305), Food and Drug Administration, Room 4-65, 5600 Fishers Lane, 

Rockville, Mel. 20857.) The agency has 

previously acknowledged the declaration as reflecting the most widely accepted standards for biomedical research involving human subjects. <See 

38 FR 24220 <Sept. 6, 1973>; 40 FR 

16053, .<Apr. 9, 1975>; and 21 CFR 

312.20.> Although it might be argued that the process by which FDA reviews the investigational use of newdrugs and will, in the future, review 

certain medical devices fulfills this 

• 	 recommendation, the Commissioner 

believes the declaration contemplates 

a committee more closely acquainted 

with the investigator and the setting in which the clinical investigation will 

be conducted. 

<4> When the Medical Device 

Amendments of 1976 were enacted, 

reference to institutional review was 

incorporated for the first time in the 

act, in section 520Cg) (21 U.S.C 

360j(g)). Congress clearly approved - such review as a means of protecting subjects while encouraging research in 

medical devices for numan use. In the 

FEDERAL REGISTER of August 20, 1976 

(41 FR 35282), the Commissioner proposed regulations governing investigational device exemptions <IDE> under 

section 520Cg) of the act, including imPROPOSED RULES 

plementing institutional reView requirements. <See 21 CFR part 812, subpart D of that proposal.) Comments 

filed on that proposal have been reviewed and utilized in preparing this 

notice. In the FEDERAL REGISTER of 

May 12, 1978 <43 FR 20726) the Commissioner issued portions of the IDE 

proposal as a tentative final regulation. Those provisions in the IDE pro­ posal that duplicate or overlap substantially with the requirements proposed in this document have been deleted from the tentative final regulation. The Commissioner will review 

comments on this proposed rule 

promptly and will issue in final form 

at least those proposed provisions that 

are essential to the promulgation of 

comprehensive final regulations governing the investigational use of medical deVices. 

(5) The General Accounting Office 

<GAO> published a report- entitled 

"Federal Control of New Drug Testing 

Is Not Adequately Protecting Human 

Test Subjects and the Public" (July 

15, 1976>; chapter 4 of this report evaluated institutional reView requirements and made recommendations for 

improvement. A copy of this report is 

also on display in the Office of the 

Hearing Clerk, Food and Drug Admin· 

istration. This proposal is a step in implementing some of the GAO recommendations. 

(6) Finally, FDA has recently reassessed its responslbUtles, needs, and 

priorities in the entire area of biomedical research, including safety testing of substances in animals, monitoring 

of clinical investigations by sponsors, the role of institutional reView boards, 

and the obligations of clinical investigators. The agency, the Congress, and 

others have recently become concerned about the validity and reliability of scientific data on the safety and 

effectiveness of products regulated by 

FDA. Much of the history of this 

review, with special emphasis on tbe 

quality and integrity of safety data. derived from nonclinicallaboratory studies, is discussed in the preamble to the 

proposal on goocJ, laboratory practices published in the FEDERAL REGISTER of 

November 19, 1976 C41 FR 51206). Congressional and Presidential action in 

the summer of 1976 appropriated to 

FDA $16.3 million and authorized over 

600 new positions to carry out expanded activities in the area of bioresearch 

monitoring. 

In conjunction with this legislative 

action, the Commissioner has established a "Bioresearch Monitoring Program" to develop and Implement an 

agencywlde program for all aspects of 

preclinical testing and clinical research relating to FDA-regulated products. The program is managed by 

an intra-agency steering committee 

that oversees seveml task forces as35187 


signed to consider specific matters. 

The Institutional Review Board Task 

Force has the responsibility for: Cl> 

Developing an agency strategy to 

define the responsibilities of IRB's in 

cllnlcalinvestlgations h)volving hUman 

subjects which are regulated by FDA-. 

or which involve products regulated by 

FDA and C2> assuring that these duties 

are adequately and reliably performed. 

To meet these goals, the task force 

proposed the following: 

1. Promulgation of agencywide regu- · lations that would set forth the responsibilities of IRB's and enforcement procedures; these proposed regu­ lations are based upon existing FDA 

regulations for investigational new 

drug studies, proposed regulations for 

investigational use of medical devices 

and comments received on them, and 

FDA experience. 

2. Issuance of an agencywide compliance program that would include enforcement policies, regular inspections 

of IRB's, and special inspections initiated by FDA to audit particular investigations. 

3. Development of appropriate organizational structures or mechanisms 

and data. systems to be used for plan­ ning and scheduling inspections under 

the compliance program and for reviewing and evaluating the results of 

individual inspections as well as the 

overall program. 

PlmPOSES OF !NsrrrtrnONAL REviEw 

Institutional reView began when a 

few institutions treating patients or. 

conducting medical research established internal committees to review 

research grant applications and other 

proposed cllnlcalinvestigations, and to 

advise responsible officials within the 

institution on whether the proposed 

projects should be permitted. Reviews 

and adVice origlnally emphasized scientific aspects of studies, and IRB's 

were composed principally of physicians and othei health scientists; but 

these professionals, from the beginning, considered the ethical implications of research. Increasingly, officers 

of institutions found that sensitivity 

to community standards of ethics, as 

wen as involvement of nonscientists, 

was Important in considering planned studies; as a result, lawyers, the clergy, 

ethicists, and other nonscientists from 

outside the institution were added to 

IRB's. The original concept remained, 

however, that the board was to advise 

the officers of the institution on the 

acceptability of the proposed study 

within the institution; this advice naturally involved, but was not limited to, 

the obligations of the institution to its _ patients and subjects. 

In the 1960's, the National Institutes 

of Health of HEW began requiring 

IRB reView as part of the process of 

providing grants and contracts for re­

___ .J 

FEDERAL REGISTER, VOL 43, NO 153-TUESDAY, AUGUST 8, 1978 
35188 PROPOSED RULES 

search involving human subjects. The 

purposes were several: First, such requirement would provide HEW with 

an assurance that community standards-would be considered in determining the acceptability of a proposed investigation, a goal difficult to attain 

with centralized review at the level of 

the Federal Government. Second, it 

would provide patients and subjects 

additional protection. Specifically, an 

IRB is generally capable of making a· 

better informed judgment about the 

potential risks and benefits of the pro­ posed study than an individual subject; thus, IRB review supplements the 

use of informed consent as a safeguard of the rights and safety of the subject. 

Third, IRB review would relieve HEW 

of the burden of reviewing an applica­ tion that would subsequently be unacceptable within the institution in 

which the investigation is proposed to 

be conducted. In addition, the process of IRB review and approval of a study; providing a review anticipating, in 

·part, HEW's review, could substantially improve the quality of a research 

protocol. To assure a certain degree of 

Independence of· the IRB's in reviewing proposed investigations, HEW required outside membership on each 

IRB <i.e., at least one or more members cannot be associated with the institution other than by virtue of par­ ticipation on the board) and stated 

that no application for a research 

grant or contract would be approved 

unless it had IRB approval <i.e., the 

officers of the institution could not 

overrule a negative decision by a 

board). In taking these steps, HEW effectively created a new relationship between the IRB's and the government, altered to some degree the relationship between the IRB's and the 

parent institutions, and implied a special duty on the part of an IRB to protect subjects, in addition to its duties 

to the institution and to HEW. 

These various roles of IRB's have, as 

noted earlier, become widely accepted 

among research scientists throughout the world. Such review is- now performed for clinical investigations that 

do not involve institutionalized pa­ tients or subjects. Thus, it may no 

longer be strictly appropriate to call 

the process "institutional review." · Indeed, in many situations other 

names are used, such as "human experimentation committee" and "clinical investigations review board"; FDA 

itself conducts review of all human 

studies funded by the agency through 

its "Research Involving Human Subjects" or "RIHS" Committee. Committee and boards to review clinical investigations may be created and appointed under the auspices of a local or 

State gove.rnment health agency, a 

community hospital, a private or 

public medical school, a county or 

State medical society, the State medical licensing board, or an independent 

nonprofit group such as a foundation 

or society interested in a particular 

health concern, e.g., kidney disease or 

family planning, or an organization involved in intergroup communications, 

e.g., the American Arbitration Association. Because of the lack of any consistent terminology in this area, and in 

view of the widespread current use of 

the phase "institutional review," the 

Commissioner has elected to adopt that phrase in this proposal. However, 

the Commissioner advises readers not 

to interpret this usage as limiting the 

intent of this proposal to research involving institutionalized subjects or 

conducted by an institution; likewise, 

the term "institution," as used in this 

notice, is not limited to hospitals and 

other health-care establishments. The 

Commissioner welcomes comments 

suggesting more understandable and 

comprehensive terminology for use in 

subsequent notices and orders. 

In addition to the generally accepted 

purposes for IRB review of clinical investigations involving humans, the 

Commissioner seeks two new goals in 

this proposal. First, local 'IRB review 

can provide ongoing review of an investigation to assess, for example, conformity with the approved protocol, including any approved amendments. 

Ongoing review enhances protection of subjects by assuring that any 

changes in protocol are reviewed and 

approved in advance. Essential to the 

decision to authorize exposure of 

humans to risk is a conclusion on the 

potential benefits to the subjects and/ 

or to scientific knowledge. Any action 

or failure to act during the investiga­ tion that adversely affects the ability 

of the investigation to yield _these 

benefits may, as a consequence, destroy the justification for the risk. 

Further exposure of humans may no 

loriger be warranted, even though no 

change in the actual risks has occurred. Thus, ongoing review includes 

more than evaluating reports of new 

safety concerns; it may cover other aspects of the conduct of the clinical investigation. 

Second, apart from subject protec­ tion, continuing review of an ongoing 

clinical investigation by an IRB can 

provide FDA with greater confidence 

in the quality and integrity of the data 

submitted at the conclusion of the investigation. As noted earlier, and discussed in detail in the preamble to the 

good laboratory practices proposal, 

FDA, the Congress, and others have 

recently become quite concerned 

about the validity and reliability of 

scientific data on the safety and effectiveness of products regulated by FDA. 

Although much of the concern has focused on long-term toxicology testing· 

in animals, the substantial increases in 

FDA's budget and operating' resources 

included a mandate that the aeency 

assure the quality and inteerity of 

data generated by studies in humans 

as well. It immediately appeared, from 

past experience with IRB's and from 

the lack of other available local independent processes to examine oneoing 

research, that IRB's could assist FDA 

in carrying out this mandate. The 

Commissioner does not intend, howev· 

er. that IRB's undertake major new 

responsibilities to assure data validity, Rather, the agency contemplates that 

the present activities or IRB's in ascer· 

taining adherence to approved proto· 

cols, reviewing proposed modifications 

in protocols, and considering the capo.. 

bility of individual investigators and of 

supporting facilities to carry out protocols, will serve as an important ad· 

junct to other programs that FDA Is 

undertaking to increase its assurance 

of the reliability of clinical scientific 

data. These programs include develop. 

ment of regulations governing the con· 

duct of clinical investigators and the 

-obligations of sponsors and monitors 

of clinical investigations proposed in 

the FEDERAL REGISTER of September 

27, 1977 <42 FR 49612>, more extensive 

FDA oversight of ongoing clinical In· 

vestigations, and more frequent In· 

depth audits of data presented to the 

agency. 

UNIFORr.I FDA STANDARDS FOR 

l:N'STITUTIONAL REVIEW BOARDS 

For the reasons described earlier, 

the Commissioner has elected to pro·

pose a single set of standards applica· 

ble to all IRB's involved In the Initial 

review, approval, and continuing 

review of clinical investigations involV· 

ing human subjects that require prior 

FDA review or that are subsequently submitted to FDA in support of an np· 

plication for a research or marketinrr 

permit. This regulation, if adopted, 

:may not eliminate the need ·in the 

future to propose additional require• 

ment.'3 relevant to the particular art!· 

cle under study, but it will reduce the 

potential for duplicative and inconsist· 

ent regulations or interpretations of 

policy. The Commissioner recognizes 

that a single IRB may, at any one 

time, be reviewing investigations on a 

variety of products that are regulated 

by several of the separate bureaus of 

FDA, e.g., Bureau of Drugs, Bureau of 

Biologics, and Bureau of Medical De· 

vices. In addition, the IRB may also be 

revie·wing the same or other investiga· tions subject to institutional review re· 

quirements of HEW or other Federal 

departments or agencies. A uniform 

standard will thus ease the burdens on 

these boards in complying with the aP· 

plicable regulations. 

To achieve this objective, the Com· 

missioner proposes to add a new Part 

56 to Title 21 of the Code of Federal 

FEDERAL REGISTER, VOL 43, NO 153-TUESDAY, AUGUST 8, 1978 
Regulations to oe entitled "Institutional Review Boards." -This proposed 

new part will be codified in "Subchapter A-General Provisions" of 

FDA's regulations, thereby applying 

to all regulated products that are involved in human experimentation. 

-This proposal revises and extends current FDA standards 'On mB review to 

most investigations involving human · subjects when such investigations are 

regulated by or submitted to FDA, 

lists dermitions applicable to the part, 

-presents the requirements for the or­

-ganization and· operation of an mB, 

and establishes standards and procedures for taking appropriate regulatory actions in the event of noncompliance with these regulations. Additionally, this proposal contains specific 

amendments needed for conformance 

to existingFDA regulations. 

To assure uniform standards, any 'Clinical investigation required to have 

mB review would be within the scope

of the }lart, whether the investigation 

required the prior review of any of the 

bureaus 'OI FDA, e.g;, Drugs, Biologics, 

or Medical Devices, or whether the investigation did not Ieceive prior FDA 

review but was subsequently submitted, :or held for FDA inspection, in 

-support of an application to one of 

those· bureaus, or to the Bureau of 

Foods or the ·Bureau of·Radiological 

Health. This statement of scope is set· 

forth in proposed§ 56.1. · The particular requirements in proposed part 56 are based upon: (1) The 

current regulations regarding institutional review for investigational studies on new drugs.(set forth in 21 CFR 

312.1Ca1C2), form FD-1571, item lO.c.; 

21 CFR 312.1Ca1C12), form FD-1572, 

item 3.; and 21 CFR 312.1Ca>C13), form 

FD-1573, item.2a.) (the 4 'IND regulations"), .(2) the experience of. the 

Bureau of Drugs and the Bureau of 

Biologics in admi:Distering these regulations, (3) the proposed regulations 

regarding institutional review for investigational studies on certain medical devices for human use published in 

the IDE proposal, (4) comments reeeived on the IDE proposal, and (5) 

regulations regarding institutional · review for clinical studies funded or 

supported by HEW (45 CFR Part 46, 

Subpart A).. 

CmCUMSTANCES :tN WmCH.AN mB Is 

oR Is NoT REQUIRED 

Under the. IND regulations, ffiB 

review is required whenever the 

human subjects involved in the clinical investigation are institutionalized 

-or whenever the investigation is conducted by an individual affiliated with 

an institution that assumes responsi­ bility for the investigation. The IDE 

proposal followed tbese two principles 

and aaded a third: m.B review is required whenever tbe investigation is 

PROPOSED RULES . 

conducted in an institution that hns 

an mB meeting FDA standards (proposed § 812.60(a)C3)). 

The Commissioner believes the purposes and processes of mB review are 

now so widely accepted, and its value 

so generally recognized, thn.t all cllnical investigations should undergo sqch 

review unless circumstances clearly 

'Inake it unnecessary, or infeasible, or 

contrary to the patient's interest. 

Therefore, the Commissioner Is proposing in § 56.2Ca) to make mB re\iew 

and approval a general precondition to 

an application for a permit to conduct 

a clinical investigation that is subject 

to requirements under section 505(1), 

507Cd), or 520Cg) of the net for prior 

submissJon to FDA for review, and in 

some cases approval, before the investigation may be commenced. The Commissioner further proposes in § 56.2Cb> 

that FDA generally will not consider 

any data or information that has been 

derived from a clinical investigation in 

support of an application for a research or marketing permit llilless the 

investigation was conducted under an 

mB. This rule would not mean that 

the results of the investigation need 

not be subniltted to FDA. The usual 

rule that all data and information relevant to a particular article, e.g., a pro­

}losed or marketed product, must be 

submitted remains in effect. Finding 

that the investigation ls not ncceptable in support of an application for a 

research or marketing permit means 

that the agency will not authorize further testing or ruther marketing if the 

claim for safety or effectiveness of the 

product is based upon thn.t investigation. This approach reflects current 

agency policy: even in situations where 

the scientific validity of an investigational drug study ls not In question, 

FDA may receive' data but not use 

them in support of a decision to approve testing or commercial distribution .of a drug because of ethical improprieties in the conduct of the 

study. C21 CFR 312.20.) 

The Commissioner recognizes that 

there may be situations in which the 

mB requirement may be unnecessary, 

redundant, or contrary to the interests 

of a subJect. For example, a late 

"phase 3" drug study will frequently 

involve several investigators trcntlng 

nonlnstitutlonalized Individuals in sep. 

arate areas under the same protocol; 

multiple review ls extremely burdensome and, by this- time, the drug will 

usually have been studied In severn.l 

settings employing mB's. Or, for another example, in an emergency FDA 

may be asked to add an investigator to 

a particular investigation to pro\ide 

the test article to a single patient only; 

prior mB review would delay administration of the article and might jeopardize the subject's health. The Commissioner therefore proposes in 

35189 

§ 56.2Cc> to waive the mB requirement 

in certain specified situations and to 

accept an application for waiver in 

other situations upon a showing that 

the requirement ls not necessary 

either !or J)rotecting the subjects .involved or !or assuring the validity or 

rellabllity of the scientific data. The 

section provides, however, that the requirement will not be waived in three 

.situations; (1) When the clinical investigation involves institutionalized 

human subjects; (2) When the clinical 

Jnvestlgation ls conducted on the 

premises of. or utilizes personnel orresources of, an institution having an 

mB meeting FDA's standards; and <3> 

When the Conunlssioner finds that 

the risks to the subjects in the investigation justify utilizing an mB review. 

The Conunlssioner is also proposi..ng 

to waive the requirements for mB 

revlf!w for all studies that were commenced prior to, and that are to be 

completed \lt1thin 1 year following, the 

effective date of these proposed regulations and were not otherwise required under FDA regulations to have 

such review. This "grandfather

clause" will avoid rejection of studies 

that would result from .a. retroactive 

application of the IRB requirements. 

In addition to expanding the types

of clinical investigations covered, the 

Conunlssioner emphasizes that the 

major change in this proposal from existing investigational new-4Jrug <IND> 

regulations ls to require institutional 

review prior to submission of a proposed study that is subject to IND or 

investigational device - exemption 

<IDE> requirements. The current lND 

requirements merely require an assur­

'31lce that mB review will be obtained 

prior to actual commencement of the 

investigation. The change is proposed 

to enable FDA to rely on mB's to 

screen out studies that would not be 

performed even if FDA reviewed them 

favorably, and to provide FDA with 

better information on the mB's being 

utilized by sponsors and investigators 

undermD's and IDE's. 

DEPINmoNs 

Section 56.3 contains proposed definitions for all of the special terms 

used in part 56. Many technical terms 

can be variably or imprecisely interpreted by persons affected by the proposed regulations; these terms are defined to provide a common basis of understanding for the agency. clinical 

investigators, the regulated manufacturers and other sponsors of clinical 

studies. and the general J>Ublic. In addition. other definitions have been · proposed for more precisely describing 

the extent and applicability of the 

J)roposed regulations. 

In proposed § 56.3Ca>. the term "act'" 

is llm1ted to the Federal Food, Drug.

and Cosmetic Act. as amended. This is 

FEDERAl REGISTER, VOL 43, NO 153-TUESDAY. AUGUST 8, 1978 
35190 PROPOSED RULES 

consistent with definitions appearing 

elsewhere in FDA's regulations. Other 

statutes, when discussed, will be mentioned by name, e.g., the Public 

Health Service Act. 

A new definition required by the decision to make these proposed regulations agencywide in scope is the term 

"application for research or marketing 

permit" in § 56.3(b). This definition includes all of the various requirements 

for submission of scientific data and 

information to the agency under its 

regulatory jurisdiction, even though in 

certain cases no permission is technically required from FDA for the conduct of a proposed activity with a particular product, i.e., carrying out research or continuing to market a product. The term is intended solely as a 

shorthand way of referring to at least 

22 separate categories of data and information that are now, or in the-near 

future will become, subject to requirements for submission to the agency. 

To facilitate further the applicabil­ ity of a single set of regulations to all 

studies involving products or articles 

coming within the agency's purview, the Commissioner is proposing in 

§ 56.3Cc) to describe each such study as 

a "clinical investigation," which is defined as any experiment involving a 

test article <defined below> which experiment involves human subjects and 

either: (1) Is subject to requirements under sections 505(1), 507(d), or 520(g) 

of the act for prior submission to FDA 

for review, and in some cases_ approval, 

before it can be commenced, or <2> is 

not subject to requirements for prior 

submission but the results of which 

are intended to be later submitted to, 

or held for inspection bY, FDA as part of an application for a research or 

marketing permit. Within the category of clinical research, the definition 

excludes studies that do not utilize 

any test articles, or do not utilize them 

in a manner that requires prior FDA 

approval or subsequent FDA review 

because the studies are not regulated by or intended to be submitted to 

FDA. The definition also excludes 

studies that do not involve human subjects. 

The terms "institution," "institutional review board," and "institutionalized subject" are defined for the first 

time in proposed § 56.3 (d), <e>, and (f). · 

Although since 1971 FDA has had a 

requirement that clinical drug investigations involving institutionalized subjects be reviewed and monitored by an 

institutional review · committee or 

board, no guidelines defining the outer 

limits of these concepts have . been 

issued. 

The Commissioner proposes that the 

definition of "institution" include any 

corporation, scientific or academic establishment, or government agency 

that engages in the conduct of research on human subjects or in the delivery of medical services to individuals; this. definition would therefore 

include: a university _that performs research with students, a retirement 

home that primarily provides housing 

and personal care to the elderly but 

also cares for health needs of .residents, and a manufacturer that uses 

its employees as subjects in the course 

of product development. 

The term "institutional review 

·board" is defined as any board, committee, or other formally organized 

group created to review research involving human subjects, approve the 

initiation of such research, monitor its 

conduct, and when necessary suspend 

or terminate the research. The Commissioner notes that the use of the 

word "board" reflects terminology of 

the National Research Act of 1975 

<Pub. L. 93-348), HEW regulations (45 

CFR Part 46), and discussions of the 

National Commission on the Protection of Human Subjects in Biomedical 

and Behavioral Research. However, 

the Commissioner also recognizes that 

existing FDA regulations, e.g., 21 CFR 

312.1, use the term "committee" as 

does section 520(g) of the act. The 

Commissioner believes there is no 

practical difference between the two 

words and has elected to follow Departmental terminology. 

An "institutionalized subject," as defined, includes two categories: First, 

any individual who is voluntarily e'enfined on the premises of, and in the 

care of, an institution for more than 1 

day; outpatients are excluded from the 

definition in keeping with existing FDA policy. Second, any individual involuntarily confined for any period of 

time in an institution such as a penal facility or a hospital by civil commitment. Because of the involuntary 

nature ·of the confinement and the 

general absence of any therapeutic 

need for an experimental article, the 

Commissioner believes the ffiB protec­ tion should apply in every such situation. Thus, these proposed regulations 

will continue to require institutional 

review of all clinical investigations involving an institutionalized subject. Proposed § 56.3(k) defines "subject" 

as any individual who is or becomes a 

participant in a clinical investigation, 

either as the recipient of the test article or as a control. The term also includes both healthy or normal individuals and patients to wliom the test ar- . ticle might offer a therapeutic benefit. 

This definition is in accord with past 

FDA policy. The term is limited to 

human beings: 

Other proposed definitions include 

terms to describe those who initiate 

and carry out clinical investigations: "sponsor," "investigator," and "sponsor-investigator." The word "sponsor" is currently defined 21 CFR 310.3(j) 

and 510.3<k>, but the Commissioner 

believes this definition is unsatisfnc· 

tory in that it fails to distinguish the 

other commonly used word "invcstlga. 

tor," which is not defined. While thene 

"terms are widely understood, their 

precise meanings are difficult to ex· 

press. The key distinctions seem to lie 

bE·tween one who initiates the project 

<the sponsor> and one who actually conducts the study <the investigator>. 

These distinctions have been incorpo· rated in the proposed definitions, In 

proposed § 56.3 (g), (h), and (i), togeth· 

er with a further distinction: investir:a· 

tors must be individuals, while sponsors are defined as "persons," which 

term includes an individual, partner· ship, corporation, association, sclentif· 

ic or academic establishment, government agency or organizational unit 

thereof, and any other legal entity, 

The Commissioner believes that these 

distinctions will clarify the participants' respective roles and duties. 

Many studies, approximately 45 per· 

cent of IND's in the Bureau of Drugs, for example, are initiated and actually 

conducted by the same individual; this 

investigator may personally carry out 

the study or may do so with other investigators responsible to him or her. 

The Commissioner believes it impor· 

tant to identify the hybrid role of the 

"sponsor-investigator" and, where al)· 

propriate in FDA's regulations reeard· 

ing clinical investigations, to allow spc· 

cial provisions for that role. Thus, pro· posed § 56.3(j) defines this term. 

Unlike the term "sponsor," the term 

"sponsor-investigator" is limited to in· 

dividuals. For purposes of this propou· al, the sponsor-investigator has the ob· 

ligations of both a sponsor and an In· 

vestigator. 

In § 56.3(1) the Commissioner pro· 

poses to define the term "test article" 

to describe those Items being studied 

that are subject to FDA's jurisdiction 

and to these regUlations. The term in· 

cludes those new drugs, biologics for 

human use, and medical devices for 

human use, studies of which require 

prior review by FDA under an IND or 

IDE. In addition, the term includes 

food additives, color additives, cosmetics, drug products and biological prod· 

ucts for human use, electronic prod· 

ucts, and medical devices for human 

use. The broad definition of "test artl· 

cle" is··intended to include substances 

for which clinical investigations are 

submitted to FDA in support of an ap­ plication for permission to market a 

product, but which investigations need 

not be conducted under an IND or 

IDE, e.g., studies on food additives or 

cosmetics, certain drug bloavaUabiUty 

studies described in 21 CFR 320.31, 

and studies on medical devices for 

human use not required to be submit· 

ted to FDA for prior review under proposed 21 CFR part 812. As noted earll· 

FEDERAL REGISTER, VOL 43, NO 153-TUESDAY, AUGUST 8, 1978 
PROPOSED ~ULES 35191 

er, however, a test article is covered by sional group, or of only one sex. In ad­ co~dered to violate the.section anala.­

these regulations only if it is usedln. a dition, diversity in the raclal and cul­ go us to proposed § 56.26Ca>. ~The Comclinical investigation involving human tural composition of the IRB is re­ missioner believes that reimbursement 

subjects. quired. Ideally, the membership would for, IRB expenses probably should be 

reflect both general competence in scl­ permitted. Extension of an IRB con-. REVIEW BY INSTITUTION .entific matters and sensitivity to ethi­ cept to areas where it has not been 

The agency has consistently held 

that reView and approval of a proposed clinical .investigation by an IRB 

does not preclude a :subsequent decision by the institution itself to reject 

the -investigation. The Commissioner 

recognizes that factors in :addition to 

scientific -validity -and ethical acceptability must be taken into account by 

officials of the ln.stitution in deciding 

whether to authorize a particular investigation. At the .same time, agency 

policy haS been t~t a <:linical investigation rejected by- an IRB cannot be 

-.authorized J.ater by the institution 

unless the IRB itself rescinds the re­ jection. In the absence ofsuch.a prohi­

-bition. the board would become purely . advisory ,and its. responsibilities eliminated. These principles are restated in 

proposed § 56.8. Comments received on the IDE proposalsuggested that an.institution be allowed to1:reate .a "superffi.B" or .an "appellate IRB" which 

could reverse or overrule rlecislons of more particularized IRE's, i.e., those 

decisions dealing with . a particular 

type of test article. The Commissioner 

advises that the agency has no objection to an arrangement !or a full com­ mittee and .specialized subcommittees 

if both the parent ffi.B and the par­

.ticularized "sub-IRB'.s" meet the re­ quirements of part 56. Appeals of adverse IRB determinations to other institutional bodiesthat do notmeetthe 

requirements 'of . part 56, · however, 

-would not be allowed under the proposed regulation. (See also the discus­

'Sion of -proposed § 56.34 below.) ·The 

National Commission for the Protection of Human Subjects in Biomedical 

and Behavioral Research, created by 

mandate·of theNational Research Act 

'Of 1975, has received many comments 

relating to an mB appeal mechanism. 

'The Commissioner advises that FDA 

will carefully review the recommenda­

.:tlons of the National Commiss1o:il in 

this area once they are publisbed and 

propose any appropriate cbanges in 

FDA regulations. · 

ORGANIZATION AND PERsoNNEL 

Proposed subpart B e5tablishes general req~ements for tbe organization 

and composition of an lRB. Most of 

·these proposed' requirements follow 

-existing FDA ~d BEW requirements. The board must be· romposed of. at 

least five· -persons with varying back­

·grounds. To '3SSUre 'SUfficient .diversity · to evauiate the llFoposed clinical investigation in terms of :science, law, professional ethics, and community .a.tti­ .tudes, :no .IRB shall. be .composed -en­ tirely nf .members· of .a s1ngle profescal concerns. Proposed § 56.21Ca) describes the types of individuals who 

would contribute to this goal: Physicians, lawyers, clergy ethicists, con­ sumers, social scientists, other scientists and nonscientists. This listing 

should not, however, be int~rpreted as 

requiring one individual from each cat~gory. The IDE proposal referred 

to. scientific expertise to evalunt~ each 

particular proposed investigation. 

Comments ·objected that this would 

necessitate a large number of medical or other scientific speclnllsts as .mem­ bers to assure such exQertise. The 

Commissioner has revised this language to follow more closely current 

HEW regulations, so that.the section 

requires "professional competence nec­ essary to comprehend the scientific . nature of the investigation:'' This revision should alleviate many of the con­ cerns expressed by the comments. 

Proposed § 56.21Cb) requires that the 

records of an IRB identify each 

member by name. earned degrees, oc­ ·cupation and title, and other informa- . tion sufficient to describe each mem­ ber's chief anticipated contribution to 

the board's deliberations. 

Proposed §§ 56.25 and 56.26 adopt 

from existing HEW regulations two 

types of requirements to protect the 

'independence and objectivity of an IRB. Section 56:25 that a board may 

not consist entirely of officlnls ~r employees of the institution in which the 

clinical investigation is to be performed. Section 56.26 excludes any 

member of the board who is mvolved 

in the investigation itseU !tom.partlci­ . pating in the IRB's deliberations, 

except to respond to requests for in­ . formation. In addition, no investigator :or .sponsor shall participate in the se­ lection of members for an IRB to 

review the sponsor's or sponsor-inves­ tigator's proposed investigations, 

unless expressly permitted by FDA 

upon a ·shoWing that. such participation is essential. Other conflicting interests are also forbidden, and responsibility is left to the lRB t~ determine 

·whether a member has a conflicting 

.interest. Both sections provide that 

the records of. an IRB identify any relationships between members and institutions, .sponsors, and Investigators 

and the extent to which a. member 

participated in reviewing an. investlga. 

tion in which he or she :had.a conflicting interest. 

Comments on the IDE ' proposal 

.questioned whether compensation by a·.sponsor for the ndminlstrative ex­ ]lenses ~f an lRB and/or the services 

·of the .members of :an IRB :would be 

primarily used will necessitate more IRB activity and consequently more · administrative expenses for document­

,lng activities, recordkeeping, liability 

insurance, and slmDar overhead ex­ penditures. It is not reasonable to 

e....-pect that these new costs will 

.always be borne ·bY the institutions or bodies that create and operate the 

IRB's. The Commissioner is more con­ cerned about payment by a sponsor. 

dlrecUy or indlrecUy, for the services 

·of IRB memb-ers. The difficulties oflocating indl\iduals willing to serve on IRB's, especially persons not affiliated 

with the institution, may be increased 

by requiring more clinical investigations to be reviewed by IRB's. At the same time, the potential problems of 

allowing reasonable compensation 

appear serious. The Commissioner 

does not propose, in this notice. any 

specific resolution of ~ither the question of administrative expenses or the 

matter of member compensation; com­ ments are especially invited to address 

these points, describing whether a need exists for financial assistance for 

sponsors and, if a need exists. ways to 

permit it while minimizing any con­ !llcts o! interests. 

The Commissioner recognizes that an IRB may not be large enough or .adequately composed to consider the 

scientific and safety issues of every 

complex and specialized clinical investigation. In such cases, the committee 

may wish to use a subcommittee or consultants to assist its review, provided the memb-ers o! the subcommittee or the consultants also do not have 

any confilct of interest. The Commissioner intends to allow !or such fle.'dblllty, and proposed § 56.34 eJo.-pliciUy 

authorizes use of nonvoting consultants. 

PROCEDURES FOR REvn:w OF CLINICAL 


IlNESTIGATIONS BY AN lRB 


Subpart E sets forth the general and 

speclfJe procedures to be followed by an IRB in its review of. proposed and 

ongoing clinical investigations. Maximum flexibllity in the operations of 

the board isintended. Thus, the board 

may have its own procedures for con­ ducting reviews and for reporting -ac­ -tlons to the investigator, to the parent institution, and, where appropriate, to 

the sponsor. Most of the proposed re­ .quirements Teflect existing FDA or HEW regulations, or only modest ex­ tensions ofthese guidelines. · The first requirement. contained ln. 

proposed § 56.80, stateS the obligation 

of the board to put its ]lrocedures ln. 

writing, and to follow those proceFEDERAL I.EGlSTEl, VOL 43, N0.153-TUESDAY, AUGUSTS. 1978 
35192 PROPOSED RULES 

dures. Comments on the IDE proposal As described in proposed §56.85, the 

suggested that discretion be left to the mB shall base its evaluation of a cliniinstitution to decide whether it, or its cal investigation upon a review of the 

IRB, should promulgate the board's investigational plan or protocol agreed 

procedures. The Commissioner has upon by the investigator and the span­ adopted this suggestion. sor, reports of pertinent past investigaProposed § 56.82 describes require- tions involving the test article, the maments for a quorum by which an IRB terials to be used in obtaining consent 

is to do business. First, all significant of subjects, and any other information 

business, such as approval or suspen- that the board considers necessary to 

sion of an inves!igation, must be done a thorough evaluation of the investiby a quorum, as described in the regu- gation. Upon receipt of a submission, 

lations. Second, a quorum must consist the IRB shall notify the investigator of a majority of the members, unless or sponsor, as appropriate, of the date 

the board has 20 or more members, in of receipt and shall inform him or her 

which case 10 members shall consti- ·that the investigation may not begin 

tute a quorum. Third, at least one li- · until the board has approved it and 

censed physician, one scientist, and until the investigation otherwise 

one nonscientist, e.g., lawyer, clergy, meets FDA requirements, e.g., an IND 

or consumer, must be present for a or IDE has been filed and no objecquorum. Finally, a quorum shall be de- tions has been received from FDA. 

termined by the members present at a The board may ask for additional inmeeting; proxy votes, telephone con- formation and may recommend modiferences, and votes by mail are not ac- fications or conditions to the investiceptable methods of carrying out im- gator before deciding to approve or 

portant IRB activities. ResponSes to reject the investigation. 

similar sections in the IDE proposal The mB should review the protocol expressed concern that requiring cer- and supporting information and 

tain types of individuals to be present decide, as soon as possible after receipt for a quorum could produce a veto of the information, whether to appower on behalf of one person. Often prove or disapprove a proposed clinical 

cited was the lay representative, who, · investigation. The IRB shall notify, in 

by staying away, could prevent IRB writing, the investigator, the instituaction. No specific examples of such' tion, and, if appropriate, the sponsor 

incidents were pmvided. The Comniis- of the board's decisions. If the board 

sioner doubts that board members disapproves the investigation, its writwould be that irresponsible and be- ten notification shall include a statelieves that any patterri of such con- ment of the reasons therefor, as product might justify remoyal of the of- vided in proposed § 56.85<e>. 

fending member from the board. The A current requirement, reiterated in 

Commissioner therefore concludes § 56.87<a> of this proposal, mandates 

that the presumed problem can be the IRB to review each ongoing clinidealt with and that the general goal of cal investigation at intervals appropribalanced participation in IRB deci- ate to the degree of risk, but in no case 

sions justifies the quorum require- less often than once a year. The board 

ment. Other comments on the IDE may, as part of its continuing review 

proposal expressed concern that the of approv~d investigations, decide-that 

quorum requirement could prevent its approval of a particular investigaIRB action in emergency situations, tion should .be withdrawn and the inbecause of the possible unavailability vestigation be suspended or terminator members who are not employed by ed; this is provided for in proposed 

the institution, e.g., lay members. The § 56.87(b). This decision may be made 

Commissioner does not believe that at any time during the investigation this problem is great. If· -unexpected and should occur as soon as possible 

toxicity appears with use of the test after discovery of the grounds for such 

substance, emergency action to sus- action. If an IRB decides to suspend or 

pend the study to-protect subjects can terminate an investigation, it shall 

be taken by officials of an institution, notify in writing the investigator reupon advice of the available IRB mem- sponsible for the conduct of the invesbers, without formal IRB action. tigation and the institution' of its deciEmergency action to deviate from a sion, including a statement of the reaportocol in order to reduce or elimi- sons for withdrawing its approval. It 

nate ·a risk to subjects will not require may also, if appropriate, notify the 

prior IRB review and formal board sponsor of the investigation. 

action under FDA regulations govern­ ing IND's; these regulations (21 CFR CRITERIA FOR REVIEW . 312.1(a)(2) FD-1571 item 10.c) appear An institutional review board must 

to provide sufficient flexibility to deal evaluate a clinical investigation not 

with emergencies. The Commissioner only in terms of its scientific validity believes other actions should be taken and medical soundness, but also in 

by a balance "'quorum. Further com­ terms of institutional commitments 

ments are invited on these issues, how­ and regulations, applicable law, standever. ards of professional conduct and practice, and community attitudes. Be· 

cause of the many factors a boax·d 

must consider in determining to approve or disapprove a study, FDA hns 

not in the past attempted to provide 

criteria for IRB approval or disapproval of investigations. The enactment of 

the Medical Device Amendments of 

1976, however, established a new role 

for IRB's in the regulatory scheme 

and specifically provided that FDA rc· 

quire prior submission of IDE studiN~ 

to a board unless "the process of 

review by [an IRBJ is inadequate • • •" 

<section 520(g)(3)(A}(ii}(II) of tho not 

(21 U.S.C. 360j(g)(3)(A)(ii}(II))). It hns 

therefore become necessary for FDA 

to provide some guidance in defining 

what an IRB review must consist of to 

be adequate under this section of the 

act. This was originally contained in 

§ 812.66 <e> and <f> of the IDE proposo.I and was the subject of many comments. The Commissioner believes 

that it is appropriate to extend IRB 

review standards, as modified, based 

on the comments, to all IRB's partici­ pating in clinical investigations subject 

to proposed part 56. Proposed § 56.90 

does not attempt to include all the 

grounds on which a. board might base 

such decisions; proposed § 56.90(a) au· 

thorizes an IRB to disapprove a study 

on any ·of the grounds within the 

scope of review conferred on the board 

by the institution that created it. The 

Commissioner recognizes that situations may arise where matters that 

would be of great concern to an IRB 

might be insufficient for action by 

FDA, e.g., where the study is at odds 

with local ethical and moral standards 

or where the board's responsib111ty ex· 

tends into areas such as allocating fl. 

nancial or other resources amonfl' rc· 

search programs in the institution. 

In contrast, proposed § 56.90Cb> outlines those factors that mandate disap­ proval in every situation, because they 

directly affect the validity of the clinl· 

cal investigation or the rights and 

safety of the subjects. The Commis· 

stoner proposes to set forth the folloW· 

ing criteria as specific grounds necessi· 

tating disapproval of a proposed cllnl· 

cal investigation by the board: 

A board shall disapprove, and may 

suspend or terminate, a clinical inves· 

tigation if it finds that: 

(1) The information on the basis of 

which the board is evaluating tho 

study is found to contain any untrue 

statement or omission of a fact mater!· 

al to the board's evaluation. Clearly, IL 

reliable determination of the safety of 

the test article for purposes of inltlnt· 

ing human studies cannot be mnde If 

the data on which such determina.tlon 

is to be made are either false or incom· 

plete. 

<2> The reports of prior investlga· 

tions with the test article are found in· 

FEDERAL REGISTER, VOL 43, NO 153-TUESDAY, AUGUST 8, 1978 
- adequate to support a conclusion that 

clinical trials are reasonably safe. 

<35 The investigator responsible for 

the conduct of the investigation does 

not possess the scientific training and 

experience needed to conduct an investigation of the safety, an_d, whex:e appropriate, effectiveness of the test 

article. · · (4) The available clinict.llaboratory 

facilities are inadequate.to ·assure that 

the investigation will be conducted 

properly and in conformity with the 

protocol.

(5) The clinical investigation exposes 

the human subjects to undue risks. In 

assessing whether the risks to the subjects are undue, the board shall consider, among other factors, whether 

the sum of the benefits to the subjects 

and the importance of the knowledge 

to be gained justify allowing the subjects to participate, whether the subjects will be adequately protected, 

whether informed consent will be obtained; and whether the investigation 

will be subjected to continuing review 

by the IRB. This provision parallels 

HEW regulations in 45 CFR 46.102Cb). 

(6) The investigation does not conform to, or is not being conducted in 

accordance with, the understandings of the-l:Joa.rd and the requirements of 

FDA <e.g., IND and IDE regulations 

and informed consent standards). . 	 The Commissioner recognizes that, 

in certain cases, the facts which would 

require tlie IRB to disapprove an investigation might not rome to the 

board's .attention until after it had already approved the. investigation. In 

these cases; proposed § 56.90(b) provides that the board may suspend or 

terminate approval of that investigation, but does not mandate such action 

because of the complexities relating to 

the ongoing care of subjects, particularly patients, in the study. The decision to suspend or terminate an investigation involves additional factors 

such as risks to subjects from the 

action, the need for availability of continuing medical care fm;- subjects in 

the event of suspension or termination, and the ·right of subjects to participate in the decision. The board is 

directed in proposed § 56.92 to consider 

these matters in determining whether 

to suspend or terminate a clinical investigation and what should be done 

regarding continuing observation of 

subjects. 

RECORDS AND REPORTS 

An IRB is required to prepare and 

maintain records on its activities with 

regard to individual clinical investigations. This obligation, which is current 

FDA policy, is proposed to be set forth 

in § 56.185. Among the records that · must be kept are the materials submitted to the board by the investigator or 

sponsor, the information regarding 

PROPOSED RULES 

board members required by subpart B 

of proposed part 56, minutes and other 

records of meetings, including a wrltteq summary of every discussion and 

decision on a substantive issue, recommendations and actions of the board. 

and dated reports of successive reviews. 

Current FDA regulations require that IRB records be retained 3 years 

after the completion or discontinuance 

of an IND study. This is not consistent 

with the record retention requirements applicable to the IND investigators. The Commissioner proposes in 

§ 56.195 to eliminate this discrepancy, 

and to clarify other minor ambiguities in the existing regulations. As proposed, all data and information required by these IRB regulations shall 

be retained for one or the following 

three alternative periods, whichever is 

shortest: 

<1> A period of at lenst 2 years following the date on which an applica­ tion for a research or marketing 

permit, in suppo.rt of which the results 

of the cllnlcal investigation were submitted, is approved by FDA; 

<2> A period of at least 5 years following the date on which the results 

of the clinical investigation are submitted to FDA in support of an application for a research or marketing 

permit; or 

<3> In other situations <e.g., where 

the cllnlcal investigation does not 

result in the submission of data. in sup. 

port of an application for a research 

or marketing permit), a period of at 

least 2 years following the date. on 

which the study is completed, terminated, or discontinued. 

COMPLIANCE AND ENFoRCEMENT 

Defining the role that IRB's play in 

reviewing proposalS for and the performance of studies !1}volving human 

subjects, to protect the rights and 

safety of subjects and to help assure 

that the data produced are valid and 

useful for the scientific and regulatory 

decisions made by FDA, constitutes a 

major clarification of FDA policy. It 

does, however, raise the question of 

how to assure that IRB's fulfill the 

standards found to be necessary or desirable by FDA, and what to do if a 

board falls to meet these standards. 

Several options are ava.llable, and each 

has an appropriate. place in FDA's 

compliance program. The regulatory 

sanctions available for use in cases of 

noncompliance include: 

<1> Notifying the IRB of deficiencies 

observed during an inspection. It will 

be the practice of an FDA investigator 

to do this before leaving the premises 

upon concluding an inspection. . (2) issuing more formal warnings 

that important discrepancies between 

the conditions observed and regulatory standards must be corrected for 

35193 

the IRB to avoid more serious regulatory action. This step generally will be 

accomplished through formal regulatory corresPondence. 

C3) Determining that data from one 

or more specific clinlcal investigations 

will not be considered by FDA in support of an appllcation·for a research 

or marketing pe.rmlt. This determination would not mean that the data 

from completed studies need not be 

submitted to FDA. The usual rule that 

all data and information relevant to a 

particular article, e.g., a proposed or 

marketed product, must be submitted 

remains in effect. A finding that a 

clinlcal investigation is not acceptable in support of an application for a research or marketing permit means 

that the agency will not authorize further research or future marketing if 

the claim of safety or effectiveness of 

the product, or other condition necessary for such research or marketing, is 

based upon that investigation. Rejec­ tion or a particular investigation from 

consideration in support of an application is provided for by statute in the 

procedures and. criteria for determining whether the application is approvable under the act or the Pnblic 

Health Service Act. For example. a dete.rmlnation that a faulty study precludes a finding that a new drug is 

safe would be made in accordance with 

the procedures set forth in section 

505Cd> of the act and 21 CFR Part 314. 

Accordingly, no speclal procedures 

need be prescribed. The standards for 

IRB organization and operation thus 

represent amplification of the legal requirements regarding evidence of 

safety and, where applicable, effectiveness, necessary to approve an application for a research or marketing 

pe.rmlt.

(4) Disqualifying an IRB as an acceptable reviewer of clinlcal investiga­ tions. Disqualiflcation which the Commissioner believes should be uncommon, would mean that no new clinical 

investigation subject to prior submission to FDA, ie., via an IND or IDE. 

would be authorized if it were to be 

conducted under review of the board. 

Further, it would mean that similar 

ongoing investigations under its review 

could be terminated or SUSRended 

until transferred to another board for . review. It would also mean that data 

and information from any clinical· -investigation reviewed by ·the board 

mlght not be considered in support of 

an application for a research or marketing pe.rmlt. In this case, the determination that data generated under 

the review of the board are not accept­ able in support of an application is not 

llmlted to a particular study but may 

extend to all Investigations reviewed 

by the board that may have been affected by the substandard acts or 

omissions. This sanction would be utiFEDERAL REGISTER, VOL 43, NO 153-TUESDAY, AUGUST 8, 1978 
35194 PROPOSED RULES 

lized when the deficiencies found with 

an mB are of such a widespread or 

fundamental nature that the rights 

and safety of subjects in, or the qual­ ity and integrity-of, a number of investigations reviewed by the board have 

probably been compromised, or when 

the ffiB has failed to- comply with 

FDA's standards after previous warnings from FDA. 

A similar concept on the sanctions 

available to deal with noncomplying 

ffiB's in the IDE proposal evoked 

probably more comment, and more intense objection, than any other aspect 

of that proposal. The Commissioner 

believes that this was due, at least in 

part, to an inadequate explanation of 

the agency's need for such a sanction 

and to a misapprehension of the frequency with which disqualification 

might be used. The Commissioner believes disqualification is an important alternative to rejection of specific investigations and legal prosecution (discussed below> because it can reduce by consolidation the number of FDA investigations and administrative pro­ ceedings that might be required if 

FDA acted only on a study-by-study 

basis. This mechanism also can permit the agency to accept the results of an 

investigation that it might otherwise 

have to reject for lack of any alternat,ive sanctions; this would result in repetition of the study with an unnecessary risk to human subjects. Disquali­ fication obviates using judicial proceedings except for the most deliberate or flagrant offenses. Unlike rejection of a specific investigation and 

legal prosecution, disqualification is 

not explicitly provided for by statute, 

although it is implicit in section 520(g) 

of the act with respect to ffiB review 

of device investigations. This necessitates promulgation of regulations describing the procedures for and consequences of imposing this sanction; 

much of the remainder of this preamble is devoted to this matter. This extensive discussion should not, however, -be read as implying that disqualification is the exclusive or even the primary administrative action for noncompliance with these regulations. 

Disqualification will be used only 

when the Commissioner concludes 

that lesser sanctions have not been or 

probably will not be effective in 

achieving compliance. (5) Obtaining a court injunction 

against further violations of the act 

and implementing regulations. This 

form of judicial action has not previ­ ously been utilized by FDA to enforce 

the regulations regarding clinical investigations such as standards regarding IRB's, but may be considered in 

the future if appropriate. (6) Recommending prosecution of a 

board, its institution, the investigator 

and/or the sponsor of a clinical investigation for violations of Federal 

criminal laws, including violations of 

the act and/or the United States 

Criminal Code <e.g., 18 U.S.C. 1001). 

Because in most instances the board is 

not pnder a direct statutory obligation 

to FDA, the circumstances in which 

this sanction might be utilized are few 

in number and extraordinary in 

nature. 

The Commissioner is aware of the 

wide range of severity in these sanctions. He has directed the preparation of a compliance program identifying 

the administrative and legal sanctions 

which FDA may invoke upon findings 

of various types of noncompliance. These sanctions and the internal pro­ cedures by which they will be applied 

will be contained in an FDA compliance program guide to be made publicly available upon its completion, now 

projected for late this year. An understanding of this document should assuage fears that boards not in compliance with the mB standards will be 

subject to unreasonable penalties. 

DISQUALIFICATION OF AN ffiB 

Food and Drug Administration expe­ rience in enforcing regulations pertaining to the conduct of persons carrying out clinical investigations subject to the agency's jurisdiction has indicated a need for administrative sanctions in addition to court enforcement 

proceedings and rejection of data on a 

study-by-study basis. Criminal prosecutions are serious, demand significant resources, and may be unappropriate when the noncompliance does 

not reflect criminal intent, bad faith, 

or gross negligence. Study-by-study audits and proceedings to reject~data 

also cost much in time and resources; 

they may be redunpant if the violations are pervasive, or inappropriate if 

the data are scientifically valid. For 

these reasons, FDA has in the past used another sanction, termed the 

"disqualification process," to obtain 

compliance with the requirements regarding clinical investigators <see 21 

CFR 312.1<c) and 511.l<c)). 

Disqualification, in the case of clinical investigators, has simply meant 

that an investigator is no longer eligible to receive investigational drugs 

under the investigator's own or someone else's IND. It imposes no fine; it 

attaches no financial liability, except 

to the extent that an investigator may 

be unable to fulfill a research contract; it does not revoke a medical license or institutional privileges. The 

disqualification of an investigator is 

intended to achieve two objectives: First, it precludes a disqualified investigator from access to any test article 

until the investigator can demonstrate 

his or her ability and willingness to 

conform to the standards for conducting clinical• investigations essential to 

assure scientifically sound and ethical 

research; second, disqualification pro· 

vides a mechanism for refusing to 

accept data prepared by the investign· 

tor in support of an application for a 

research or marketing permit. Dls· 

qualification has not been used with 

great frequency by FDA. 

After reassessing FDA's experience with disqualification, evaluating the 

available alternatives for enforcement 

of these regulations, reviewing and the 

comments received on the IDE propos• 

al, and considering the factors just dis· 

cussed, the Commissioner has tenta· 

tively decided that the disqualification 

inechanisin should continue to be usrd 

by FDA in all areas of clinical invesU· 

gation and for all involved parties, in· 

eluding ffiB's. In addition to these fac• 

tors cited in favor of this sanction, 

many participants in the development and marketing of products regulated 

by FDA, including sponsors, investiglt· 

tors, and agency officials, are famllinr 

with this process because of its use in 

the IND process; as IRB's gain expert· 

ence with FDA, the Commissioner elt• 

pects that they will better understand 

the disqualification mechanism and be 

less anxious that it ma.y be used ca.prl· ciously. 

'.rhe proposed regulations governing 

disqualification of IRB's are ser forth 

in subpart K of part 56. Proposed 

§ 56.200 codifies the purposes of dl!l· 

qualification to state clearly the meo.n· 

intr of this administration action. 

Comments received on the IDE pro· posed disqualification regulations, and 

statements made at a public hearlnC' 

before the Commissioner on the pro· 

posed disqualification regulations rc• 

garding noncllnical testing faclllties as 

part of the good laboratory practice 

rulemaking initiated in the FEDERAL 

REGISTER of November 19, 1976 <41 FR 

51206), objected to the way in which 

the grounds for disqualification were 

set forth in these documents. Comments and statements are on dlspla!l in the office of the Hearing Clerk, 

Food and Drug Administration, as 

part of the records of those proceed· ings (docket No. 76N-0324 and 76N.. 0400, respectively). The Commissioner 

concurs that, as drafted, those propos· als implied that disqualification could 

occur as the result of insignificant de. 

ficiencies in meeting regulatory stand· 

ards, and suggested that FDA might in 

the future invoke this sanction fal' 

more frequently than indicated in the 

preambles to those proposals. 

To clarify FDA's intent in proposing 

the disqualification mechanism and to 

minimize the possible abuse of this 

sanction in the future, the Commls· 

sioner proposes, in § 56.202, a more rc· 

strictive statement of the grounds for 

disqualification of an .mB. An ffiB 

may be disqualified only if the Com· 

missioner finds all three of the follow· 

FEDERAL REGISTER, VOL 43, NO 153-TUESDAY, AUGUST 8, 1978 
PROPOSED RULES 	 35195 

ing: . (1) That the board failed to CFR part 16, the procedural regula- for his decision to terminate the pro­ comply with one or more of the stand­ tions for regulatory hearings before ceeding. 

ards set·forth in part 56 or in any FDA. (3) The notice shall state the · Once a final order has been issued, 

other FDA regulations -regarding time within which a hearing may be the Commissioner shall so notify the 

standards for mB's, e.g., any supple­ requested, which shall not be less than IRB and the institution that estabmental requirements in the IND or 3 working days from the receipt of the llshed ft. If the board Is disqualified, 

IDE regulations; <2> that the noncom­ notice; except In cases where safety o! • the Commissioner will also· notify, to 

pliance adversely affected the validity subjects requires Immediate action, the extent possible, the sponsor of 

of the data produced in the investiga­ ample time would be allowed the every cllnlcal Investigation subject to 

tion, and/or the rights and/or safety board to prepare !or and appear at the an IND or IDE that the IRB reviewed. 

of the human subjects; and (3) that hearing. <4> The notice shall contain Because FDA does not usually receive · other lesser regulatory actions, such as the name, address, and t~lephone Information about other clinical inveswarnings or rejection of data from. in­ number of the FDA o!flclal who has tigations before they are completed dividual clinical· investigations, have been designated by the Commissioner and submitted' to the agency, it will 

not been or probably will not be ade­ is presiding officer for the regulatory not generally be possible to notify 

quate to achieve compliance by the hearing and to whom any request may sponsors of uncompleted studies. Comboard. These requirements assure that be filed by registered man, telegram, ments orr this provision in the IDE 

the sanction will not be used in trivial telex personal delivery• or any other proposal requested that the sponsors situations but only when the violation mod~ of written comm~catlon. and/or the investigators of cllnlcal incompromised the integrity of the in­ In the past under the disquallflca- vestlgations under review by a board 

vestigation or the interests of the sub­ tion regulations pertaining to cllnlcal be notified at the commencem~t. jects. The proposed regulation further Investigators, the Bureau of Drugs has rather than the completion, of ~­ requires the Commissioner to consider provided an "informal" conference qualification proceedings. The}~~­ the availability, and past or probable with the officer who Issued the notice cation offered was that these mdiVIdeffectiveness, of lesser sanctions as al­ before the "formal" disqualification uals might wish to protect their inte!­

-ternatives to disqualification. It would hearing <see 21 CFR a12 l(c)(l)) est in continuing an investigation or m 

not, however, preclude disqualification 	 • • knowing that the results of the inveswithout aprior warning or other regu­ These conferences frequently had 	 tlrition would be accepted by FDA

many formal trappings, such as st~no- later. The Commissioner Is concerned latory action where the mB's activities evidence a deliberate violation of 	 graphic transcripts, and were often that such notifJcation might lead to 

FDA standards or a flagrant disregard followed by the contemplated hearing. exresslvely complicated multiparty

of This process doubled the tlme and ex-	 proceedings that are unnecessary. As the mB's obligations. · The Commissioner proposes, in pense of all parties Involved without discussed below, after the decision to 

§ 56.204, to establish a uniform proce­ discernable bene!Jt. The Commissioner disqualify is made, questions regarding 

dure :Qas therefore decided not to provide the status of ongoing investigations to be followed by the several 

FDA bureaus regulating or ·reviewing for such an informal conference in and the acceptability of data will be 

. clinical· investigatioiiS on articles sub­ these regulations. The procedures pro- considered and any interests affected 

. ject to FDA jurisdiction. Each bureau posed should provide adequate flex!- will be heard. The commissioner is 

will be initially responsible for admin­ bllty and fairness to all parties. not convinced that every potentially 

istering the mB regulations for the Comments on the disqualification p.!fected sponsor and investigator 

products and substances under its pur­ procedures contained in the IDE pro- should be notified every time disqualiview, as part of processing applications posal objected that the regulatory flcatlon of an IRB is proposed, but he 

for research and marketing permits hearing process denied an adversary invites further comment on this 

submitted to that bureau. In t}lose hearing, a rJght to counsel, transcripts, matter. The Commissioner does becases where the bureau believes that cross-examination, and an . appeal lleve, however. that other HEW agenrejection of specific investigations and mechanfsm. The Commissioner advises cles dealing with IRB's should be notiother remedies is inadequate to that regulatory hearings under part 16 !Jed of problems promptly. Therefore, 

achieve compliance, the Commissioner provide all of those safeguards as well proposed § 56.213<c> requires the Commay elect to begm the disqualification as others essential to due process. In- missioner to provide other components 

proceedings by providing a notice of terested persons are referred to those of HEW with such information simulthe proposed action to the board; reguiatlons for a complete description taneously with a proposal to disqualify 

there would be an opportunity for a -of the procedures proposed to be ap. the board. 

regulatory hearing before the Com­ plicable to disqualification proceedings Once an institutional review board 

missioner or a person designated by and may comment on the adequacy has been disqualified, no new clinical 

him; and final action on the proposed and appropriateness of these proce- investigation requiring prior review by 

disqualification would be taken only dures for purposes of disqualification FDA, as well as Institutional review, 

by the Commissioner or a person to of mB's. will be authorized by FDA if it is to be 

whom this authority had been official­ If, after the regulatory hearing or conducted under the review of the disly delegated. after the time for requesting a. hearing qualified board; this rule is proposed 

The written notice provided to the expires without a request being made, in § 56.210Ca>. Because the agency has 

mB upon commencement of a dis­ the Commissioner upon an evaluation no statutory authority to suspend or 

qualification proceeding shall contain of the administrative record, makes terminate cllnlcal investigations not 

the following items of information, in the findings required for disquallflca- done under an IND or IDE, it will not 

accordance with 21 CFR 16.22(a). (1) tion, he shall prepare and issue a. final be possible to deny permission to conThe notice shall specify the facts that . order disqualifying the mB. Proposed duct these investigations when they 

are believed to justify disqualification. § 56.206 provides that the final order involve a disqualified IRB. 

(2) The notice shall state that the shall Include a statement of the basis In fssulrlg an order disqualifying an 

board has an opportunity for a regula­ for the disqualification. If, on the IRB, the Commissioner must consider 

tory hearing on the proposed disquali­ other hand, the Commissioner deter- what, if anything, should be done refication before the Commissioner, or a mlnes not to make these findings, he carding ongoing investigations that inperson designated by him, and that shall issue a final order t~rmlnating volve the board. Several options are 

such hearing will be conducted in ac- . the disqualification proceeding and available: allowing the lnvestgations to 

cordance with the provisions of 21 shall Include a statement of the basis proceed for a perJod of time to permit 

FEDERAL REGISTER, VOL 43, NO 153-TUESDAY, AUGUST 8, 1978 
35196 PROPOSED RULES 

completion or to permit corrective act!ons; limiting the continuation of the 

investigations to subjects who are already participating; requiring tranfer 

of responsibility for the further review 

of the investigation to an mB that is 

in compliance with FDA standards; or 

terminating the investigation completely. A special concern- is the subject who cannot be safely withdrawn 

from the investigation because, for example, the subject has an implanted 

investigational device that must be 

surgically removed, or because abrupt 

withdrawal of the investigational drug

may create a life-threatening problem. 

Clearly, some provision must be made 

for such cases if ongoing investigations 

are to be suspended upon disqualification of an IRB. The Commissioner 

does not believe it possible, much less 

advisable, to require that any particu­ lar option be used for ongoing investigations. This choice must be made, on 

a study-by-study basis, considering the 

nature of the investigation, the 

number of subjects involved, the risks 

to them from suspension of the study, and the need for further review by an 

acceptable mB. Section § 56.210(b) of 

the proposed regulations authorizes, 

but does not require, the actions that 

might be taken. The Commissioner 

specially invites comments on these 

proposals and suggestions for other 

ways to address this sensitive problem. Proposed § 54.210Cc) provides that 

each application for a research or marketing permit, approved or not, that 

contains or relies upon a clinical investigation conducted under the review of 

a disqualified mB may be examined to 

determine whether the study was, or 

would be, essential to FDA's decision 

to approve the application. This authority is also discretionary, and 

would depend on the types of prob­ lems that led to disqualification and 

the nature of the investigation invalved. If it is determined that, without the results of the investigation in 

question, further clinical trials would 

not have been allowed or a product license would not have been approved, 

FDA will then determine whether 

data from the investigation are acceptable, notwithstanding disqualification. 

To avoid FDA's having to audit 

every such investigation, any study reviewed by an mB prior to or after disqualification but before reinstatement 

may be presumed to be unacce~table, 

and the person relying on the data resuiting from the investigation may be 

required to establish that the data 

were not affected by the circumstances which led to disqualification. The sponsor or applicant may be required to submit validating information. If FDA determines that the clinical investigation was or would be essential, and is not acceptable, it will be 

eliminated from the consideration of 

the application for a research or marketing permit. Elimination of such 

data may serve as "new information" 

justifying termination of an IND or 

IDE, initiation of the withdrawal of 

approval of a product license, or the 

.revocation of a product monograph or 

standard. , Under proposed § 56.210Cd), the FDA 

will hot consider, in support of any application for a research or marketing permit, any clinical investigation 

begun under the review of an mB 

after it has been disqualified. This 

rule does not, however, relieve the ap­ plicant from any requirement under 

any other applicable statute or regulation that all daj;a and information regarding clinical experience with the 

article in question be submitted to the 

agency. 

The Commissioner advises that it is 

not necessary that an mB be disqualified for the agency to reject consideration of a particular clinical investigation in support of an application for a 

research or marketing permit. The crlteria set forth in the statute and regu­ lations applicable to each type of ap­ plication, together with the regulations regarding the conduct of clinical 

investigations, will still be used to 

evaluate the scientific validity and 

meaning of the results of each investigation. T:P,e agency may apply these 

regulations to a particular investiga­ tion and determine that it is so inadequate in terms of science or ethics 

that it will not or should not support a 

claim of ·safety or effectiveness for a · product. If the sponsor of the product 

wishes to contest this finding, the op­ portunity to do so will be provided in 

the procedures for denying or withdrawing the. approval of the application. 

The Commissioner believes that it is 

contrary to the public interest to provide a two-step process whereby a par­ ticular investigation would be disqualified under procedures similar to those 

proposed in· subpart K of part 56, and 

then the application itself would be 

denied under procedures set forth in 

other regulations. Efficiency and fairness suggest that these issues be resolved at the same time in one pro­ ceeding, if that is required. It may be 

that, although a particular investiga. 

tion is not acceptable, other data and 

information in the application will 

support a product's safety or effectiveness, and therefore no proceeding is 

necessary to rule on the acceptability 

of the particular investigation. Likewise, the agency may choose to reject 

individual investigations without disqualifying an mB when, for example, 

the investigation was performed 

during a period when the mB was not 

in compliance with FDA standards, 

but the mB has since come into compliance. 

The Commissioner further advises 

that it is likely that the usual formal 

regulatory action taken for noncompli· 

ance will be rejection of individual in· 

vestigations and that disqualification 

of an IRB will be reserved for tho rare 

cases where the rejection of a parUcU• 

lar investigation is an inadequate regu· 

latory response. 

The agency believes that it should 

affirmatively provide information re· 

garding the disqualification of an mn 

to entities having professional deal· 

ings with that board, suc}.l as other 

Federal, State or local governmen~ 

agencies supporting research studies. 

Many objections were received to this 

aspect of disqualification in the IDE 

proposal. The Commissioner believes, 

however, that because a number of 

Federal agencies have adopted very similar standards regarding IRB's in 

conjunction with human experimenta• tion supported, by grant or' contract, 

with the taxpayers' dollars, a Federal 

agency that finds an IRB out of com• 

pliance with those standards has n 

duty to notify its sister agencies.

Moreover, the Commissioner believe~! 

that providing such information is 

within the purpose of section 705 of 

the act (21 U.S.C. 375). 

Because the Commissioner rccog• ndzes. that the consequences of such 

notice could have a serious adverse 

effect on the board and its members, 

he believes that the board and its 

members must be aware that such 

notice is one of the results of disquall· fication. C/. Wisconsin v. Constantin· 

eau, 400 U.S. 433 <1971). Proposed 

§ 56.213Ca> expressly authorizes FDA 

to notify other entities when the Com· 

missioner believes that such disclosure 

would further the public interest or 

would promote compliance with the 

applicable FDA standards. This deter· 

mination is within the discretion of 

the Commissioner upon consideration 

of the circumstances justifying the 

disqualification, any mitigatine condi· 

tions, and the degree to which other 

agencies or persons are involved with 

the ongoing activities of the board. If 

he gives any notice, the Commissioner 

shall provide a copy of the final dis· 

qualification order, indicate its leeal 

meaning, and state that FDA is not 

advising or recommending that the 

person notified take any action upon 

the matter. A copy of each notifica• 

tion shall be given to the board. 

Both the determination that an IRB 

has been disqualified and the admlnls· 

trative record regarding such determi· 

nation are disclosable to the publlc under the Freedom of Information Act 

(5 U.S.C. 552) and under the FDA 

public information regulations (21 

CFR part 20) as records relating to an 

administrative enforcement action 

that has been completed. This is 

stated in proposed§ 56.213Cb). 

FEDERAL REGISTER, VOL 43, NO 153-TUESDAY, AUGUST 8, 1978 
PROPOSED RULES 35197 

Because disqualification of an IRB 

may be neither a sufficient nor an ap­ -propriate sanction in every case, the 

Commissioner believes that disqualification must be mdependent of. and 

neither in lieu of nor a precondition 

to, other proceedings or actions authorized by law. Proposed § 56.215 

makes clear, therefore, that FDA may 

at any time recommend institution of 

any appropriate judicial proceedings, 

civil or criminal, and any other appro­ priate regulatory action,.in addition to 

or iii lieu of, and prior to, simultaneously with, or subsequent to, disqualification. This would, of course, include refusing to consider a particular investigation in support of a particular 

application, the regulatory action that 

probably will be most commonly used 

in cases of significant noncompliance 

with the mB standards. The agency 

may also refer the matter to another 

Federal, State, or local governmental 

agency for such action as that agency determines to be appropriate. 

Disqualification is principally a remedial action to prevent future violations, to assure that the rights and 

safety of subjects are appropriately 

protected and that data in support of 

applications are produced under circumstances that increase the likelihood of their scientific validity. Thus, 

the Commissioner concludes that disqualification should continue indefinitely until the agency finds that the 

IRE can and will fulfill the requirements imposed under these proposed standards. 

Proposed § 56.219 authorizes the 

Commissioner to reinstate an mB, i.e.• 

to determine that it may again review 

investigations under an IND or IDE, 

and that data from investigations 

under its review may once again be 

considered in support of applications 

for research or marketing permits, if 

he finds that the board can provide adequate assurances that it will operate_in compliance witii. FDA standards. 

An mB that wishes to be reinstated 

shall explain to the Commissioner 

why it believes reinstatement is warranted, and shall provide a detailed description of the corrective actions the 

board has taken or intends to take to 

assure that the acts or omissions that 

led to its disqualification will not 

recur. The Commissioner may condition reinstatement upon the board's 

passing a subsequent FDA inspection. 

In fairness to the mB, all persons or 

organizations notified under proposed 

§ 56.213(a) of the board's previous disqualification must be notified when it 

is later reinstated; proposed § 56.219 so 

provides. Once reinstated, an mB may 

thereafter review additional new clinical investigations. A determination 

that an mB has been reinstated is 

also disclosable to the public under 

the Freedom of Information Act and 

under 21 CFR Part 20 as records relating to completed admlnlstratlve enforcement actions. 

LEGAL AUTHORITY 

The resul~ of literally hundreds or 

clinical investigations are submitted to 

FDA each year by persons seeking regulatory action by the agency. To 

obtain a marketing license, clinical research data are oUered to support the 

safety and effectiveness or functlonn· 

lity of a product, e.g., a food or color 

additive, or a. drug, biologic or medical 

device for human use. Even where a 11· 

cense is not required or already bas 

issued, such data may be relied upon 

to demonstrate the bioavallablllty of a 

marketed drug, the general recognition of safety or a product, or the absence of any need for premarket approval or a product standard for a 

device. In evaluating the enormous 

volume of clinical investigations filed 

with FDA, many types of sclenU!Ic 

and regulatory review must be devoted 

to these studies apart from determin· 

ing their ethical and scientific accept­ ability and their basic validity, e.g., to 

interpret the results and to evaluate 

the status of the arrected products in 

light of the results. Given the llm1ted 

resources within the agency, the Commissioner believes that FDA must 

have standards to screen out those 

clinical .investigations that are likely 

to be unacceptable and thus should 

not be authorized by FDA or that warrant little further evaluation in support of a product application. Promul· 

gating these standards provides one 

process for making this judgment. 

While compliance with the requirements for mB review does not guarantee the ethical or scienU!Ic acceptabUity of, or the validity of data from, a 

clinical investigation, failure to 

comply increases substantially the 

probability that the results will not be 

useful to FDA. Moreover, as noted 

elsewhere in this preamble, the regula­ tions reflect principles recognized by 

the scientific community as essential 

to sound research involving human 

subjects. Thus, these standards will 

assist FDA in identifying those investigations that cannot be permitted to be 

carried out or considered in support of 

an application for a. research or marketing permit. 

Under section '701Ca.> of the Act, the 

Commissioner is empowered to promulgate reguia.tlons for the elliclent 

enforcement of the Act. Previously, the Commissioner bas issued regula­ tions <21 CFR 314.111Ca.)(5)) for determining whether a clinical investigation of a drug intended for human use, 

among other things, was scientifically 

reliable and valid, in the words of the 

Act: "adequate and well-controlled," to 

support approval of a new drug. These 

regulations were issued under section 

'701Ca> of the Act and bave_been 

upheld by the Supreme Court Csee 

Weinberger v. H117lSon. WestcoU & 

Dunning, Inc., 412 U.S. 609 <19'73}; see 

also Upjohn· Co. v. Finch. 422 F.2d 944 

(6th Cir. 1970) and Phannaceutical. 

ManuJa.t!lurers ~ssociation v. Richardson. 318 F. Supp. 301 CD. Del.l970)). 

Furthermore. sections 505<i>. 507Cdl. 

and 520(g) of the Act regarding clinical investigations that require prior 

FDA authorization, direct the Commissioner to promulgate regulations to 

protect the public health in the course 

of those investigations. For the reasons discussed at the outset of this 

notice, the Commissioner finds that 

mB's are an essential element to safeguard the right and safety of human 

subjects in virtually all studies conducted under those sections of the 

Act. Section 520Cg> of the Act further 

necessitates the establishment of regu­ lations regarding the functioning of 

local institutional review committees 

to review proposed clinical testing of 

certain medical devices. These proposed regulations are intended to fulfill these mandates. 

The Commissioner bas therefore 

concluded that legal authority to pro­ mulgate these regul~tions regarding 

clinical investigators exists under sections 505(1), 507Cd>. 520Cg>. and 701Ca> 

or the Act, as essential to protection of 

the public health and safety and to enforcement of the agency's responsibilities under sections 406, 408. 409, 502. 

505, 506; 507. 510, 513. 514. 515. 516, 

518, 519, 520, 601, 706. and 801 of the 

Act. as well as the responsibilities of 

FDA under sections 351 and 354 to 

360F of the Public Health Service Act. 

!NSPECIIONS OF lNsn:roTIONAL REVIEW 

BOARDS 

It follovJS from the authority to promulgate these regulations that FDA 

also bas authority to presence the 

terms on which it will accept data generated in a. clinical investigation reviewed by an mB. 

Therefore, the agency will not consider data from a. clinical investigation in support o! an application for a. research or marketing permit unless the 

board that reviewed the investigation 

consents to insPection by FDA. This 

rule is set forth in proposed § 56.15Cb>~ 

The Commissioner believes that this 

requirement does not infringe on any 

right or obligations of an mB or its institution that may, at any time. refuse 

to consent to insPection or withdraw 

its consent. In this event, however. 

FDA will not consider the results of 

the study in support of an application and may consider disqualifying the 

b.oard. This action may adversely 

aUect the status of an application submitted by a third person. e.g.. the 

gponsor of a study under a grant or 

contract; but this is strictly a. matter 

' FEDERAL REGISTER, VOL 43, NO 153-TUESDAY, AUGUST 8, 1978 
i15198 

between those parties. The Commissioner advises all persons who sponsor, 

under grant or contract, clinical investigations that may be submitted to 

FDA to consider including provisions 

regarding FDA ins~ections in the 

grant or contract. Such a provision is 

especially important if the board is 

not otherwise aware that the results 

of the investigation may be submitted 

to FDA. 

Inspections of many IRB's will' not 

necessarily be conditioned upon consent. Under section 704Ca> of the 'act, 

FDA may inSpect establishments, including consulting laboratories, in 

which certain drugS" and devices are 

processed or held, and may examine 

research data that would be subject to 

reporting and inspection pursuant to 

section 505 CD or Cj}, 507 Cd} or (g), 5i9, 

or 520(g} of the act. (See in this regard 

21 CFR 200.10.} Thus, most sponsors 

and many investigators under IND's 

and IDE's, and those institutions in 

which such studies are conducted, 

would be subject to FDA inspection 

whether or not they consented. 

The Commissioner wishes to point 

out that since 1971 FDA has exercised 

authority to inspect IRB's. Between 

1971 and 1976,""for example,- approxi-· 

mately 75 IRB inspections were completed by the Bureau of Drugs. Language in the current regulations regarding FDA's authority has, however, 

been interpreted by some, e.g., the 

GAO in its recent. report, to mandate 

periodic inspections. The agency intends to inspect IRB's on both a 

random basis and in response to particular problems. The number of IRB's 

inspected and the depth to which they 

' will be audited remain a function of 

available ;FDA resources. Therefore, 

the Commissioner proposes in § 56.15 

to restate FDA's authority and at the 

same time to eliminate any possible interpretation that FDA will inspect IRB's at any preestablished frequency. 

The current FDA policies regarding 

inspection of records of clinical investigations require clarification. During 

FDA inspections of clinical investigators and institutions in which studies 

were conducted, agency officials were 

occasionally refused access to records 

containing the names of human subJects, on grounds of the confidentiality of the physician-patient relationship 

and the subject's right to privacy. Numerous questions and objections were 

also submitted regarding statements 

about FDA inspections of records regarding clinical investigations made in 

the IDE proposal. Therefore, the 

Commissioner finds it necessary to 

state clearly a~d publicly when FDA 

will request access to such records, and 

if such access is requested, how the 

agency will safeguard the privacy of 

subjects. 

PROPOSED RULES 

First, the agency does not need to inspect medical history records routinely. The scientific evluation of case 

report forms, and of summary tables 

proposed from the data in these 

forms, is the basic mechanism by _whic_!}.-FDA assesses the study data. 

However, the agency's inspections 

have uncovered a significant number 

of errors of omission and commission 

in information submitted to the 

agency. For this reason FDA has initiated an inspectional program that includes the onsite audit of certain data 

submitted to the agency. During this 

audit, access to the subject's identification is incidental to the review of 

such records. When such records are 

reviewed, as described in current regulations, "the names of the subjects 

need not be divulged unless the records of the particular subjects require 

a more detailed study of the cases, or 

unless there is a reason to believe that 

the records do not represent actual 

studies or do not represent actual results obtained" Csee § 312.1(a} C21 CFR 

312.1Ca>5>. To assure the privacy of iildividually identifiable medical records, 

FDA has implemented clear and extraordinarily exacting guidelines for 

FDA personnel who conduct inspections of medical records containing the 

names of individual research subjects. Before an inspection, FDA personnel 

will generally notify the IRB of FDA's 

intent to inspect the IRB's records, 

with a view to arranging a mutually 

convenient inspection time. Agency personnel must invite a representative 

of the IRB- to be present with them 

throughout GDA's records review, and 

they must inform the representative 

that he or she may see the records 

which they may wish to copy and may 

review any records tliat are copied. Agency personnel may not copy medical records containing the names of research subjects, and the representative is to be given the right to delete any 

information that could identify an individual subject, except when: (1} The 

agency has reason to believe that the 

consent of human subjects was not obtained; or (2} there is reason to believe 

that the records do not represent 

actual studies, or do not represent 

actual results obtained. The excep­ tions to the prohibition against the 

copying of individually identifiable 

medical records by FDA personnel rest 

primarily on the need to determine 

whether a given research subject in 

fact exists and whether the research 

subject. in fact participated in the investigation. Where an individually 

identifiable medical record is copied ·and reviewed by the agency, the 

record is properly safeguarded within 

FDA and is used or disseminated 

under conditions that protect the privacy of the individual to the fullest 

possible extent consistent with laws 

relating to public disclosure of infor· 

mation (Freedom of Information and 

Privacy Act regulations> and the lnw 

enforcement responsibllltfes of the 

agency. 

The. Commissioner proposes in 

§ 56.15Ca> that an IRB permit author· 

ized FDA personnel, at reasonable 

times and in a reasonable manner, and 

only for purposes of verification of the 

data and information submitted to 

FDA: Ca> To inspect all records re· 

quired by these regulations, (b) to 

copy such records that do not identify 

the names of human subjects or from 

which the identifying information has 

been deleted, and (c) to copy such rec· 

ords that identify the names of human 

subjects, without deletion of the iden· 

tifying information, upon notice that 

FDA has reason to believe that tho 

consent of human subjects was not ob· 

tained, that the reports submitted by 

the investigator to the sponsor, or to 

the IRB, do not represent actual case~1 

or actual results obtained, or that such 

reports or other required records 

appear to be otherwise false or mis· 

leading. 

The Commissioner recognizes the 

highly sensitive nature of this provl· 

sion, as reflected in the many com· 

ments already received by FDA on the 

IDE proposal. The Commissioner wei· 

comes reasoned discussions of the 

issues involved and specific proposals 

under which patient confidentiality 

could be further protected without 

compromising the ablllty of FDA to 

verify clinical data submitted in SUP· 

port of applications for research or 

marketing permits. 

CONFORMING AMENDMENTS 

The Commissioner Is proposing to 

amend the procedural regulations (21 

CFR 16.1> regarding regulatory hear· 

ings before the FDA to add a. cross-ref· 

erence to the procedures proposed in 

this notice regarding disquallfication 

ofaniRB. 

The current definitions of the term 

"sponsor" found in 21 CFR 310.3(j) 

and 510.3Ck> are to be superseded by 

the proposed definition in § 56.3(!} dis· 

cussed above. Therefore, the Commls· 

sioner is proposing to eliminate the 

current definitions. 

Because of the clarifications of the 

standards regarding IRB's, the Com· 

missioner proposes to revise the IND 

regulations in 21 CFR 312.Ha.>, forms 

FD-1571, FD-1572, and FD-1573, to ~orrespond with the proposed part 56. 

Rather than repeat these provisions in 

the forms in this proposal, which 

might confuse readers and lead to dU· 

plicative comments, the Commissioner 

gives notice that the forms will be re· 

vised in the final order to reiterate the 

standards proposed here, as modified 

in light of the comments received. 

FEDERAL REGISTER, VOL 43, NO 153-TUESDAY, AUGUST 8, 1978 
PROPOSED RULES 	 35199 

The Commissioner also proposes to 

add or revise provisions in regulations 

regarding food and color additives, new drug applications, bioavailability, 

and bioequivalence testing requirements, OTC drug products, radioactive 

drugs, antibiotic drugs, bio1ogica1 

product licenses, cosmetics, and electronic products, to incorporate appropriate imp1ementing provisions for, 

and cross-references to, part 56. 

The Food and Drug Administration 

has determined that this document 

does not contain an agency action cov­ ered by 21 CFR 25.1(b) and consideration by the agency of the need for preparing an environmental impact statement is not/required. 

Therefore, u,nder the Federal Food, 

Drug, and Cosmetic Act <sees. 406, 408, 

409, 502, 503, 505, 506, 507, 510, 513­

516, 518-520, 601, 701(a), 706, and 801, 

52 Stat. 1049-1054 as amended, 1055, 

1058 as amended, 55 Stat. 851 as amended, 59 Stat. 463 as amended, 68 

Stat. 511-518 'as amended, 72 Stat. 

1785-1788 as -.amended, 74 Stat. 399­

407 as amended, 76 Stat. 794-795 as . amended, 90 Stat. 540-546, 560, 562­

574 (21 u.s.c. 346, 346a, 348, 352, 353, 

355, 356, 357,. 360, 360c-360f, 360h360j, 361, 371(a), 376, and 381)) and 

the Public Health Service Act <sees. 

215, 351, 354-360F, 58 Stat. 690, 702 as amended,.82 Stat.ll73-1186 as amended <42 U.S.C. 216, 262, 263b-263n)) and 

under authority delegated to him <21 

CFR 5.1), the Commissioner proposes 

that ~apter I of title 21 of the Code 

of Federal Regulations be amended as follows: 

SUBCHAPTER A-GENERAL 


PART 16-REGULATORY HEARING BEFORE 


THE FOOD AND DRUG ADMINISTRATION 


1. In § 16.1, by adding new paragraph 

(b)(27) to read as follows: 

§ 16.1 Scope. 

* * * * * 

(b)* * * 

(27> Section 56.204Cbl, relating to 

disqualifyirig an institutional review 

board. 

2. By adding new part 56 to·read as follows: · 

PART 56-INSTITUTIONAL REVIEW BOARDS 

Subpart :A-General Provisions 

Sec. 

56.1 Scope. 

56.2 	 Circumstances in which an institution· 

al review board is required; exemptions. 

56.3 De!mitions: 

56.8 Review by institution. 

56.15 	 Inspection of an institutional review 

board. · 

Subpart B-Organization ani! Personnel 

56.21 	 Diversity of membership of an instl· 

tutional review board. 

Sec. 

56.25 	 Relationship between members and 

institution. 

56.26 	 Relationship between members and 

sponsor, lnvestlcntor, or Investigation. 

56.34 Consultants. 

Subparts C and D-[Reserved] 

Subpart E-Boa~ Operations 

56.80 	 Written procedures !or review of 

cllnicallnvesUcntlons by an institutional 

review board. 

56.82 Quorum requirements. 

56.85 	 Procedures for lnltlal review or a cllnlcalinvestlcntlon. 

56.87 	 Procedures for continuing re\iew and 

suspension or termination o! a clinical 

investfcntlon. 

56.90 	 Criteria for dls:lppro\'al. suspension. or termination of a clinical lnvestlcntlon. 

56.92 	 Order to suspend or terminate a 

cllnicallnvestlcntion. 

Subparh Fthrough !-(Reserved} 

Subpart J-Records and Reports 

56.185 Records of an institutional review 

board. 

.56.195 Retention of records. 

Subpart K-Disquallflcollon of an lnsiiMionall.evlew 

Board 

56.200 Purpose. 

56.202 Grounds for disqualification. 

56.204 	 Notice of and opportunity for a 

hearing on proposed dlsqualUicaUon. 56.206 Final order on disqualUicatlon. .,. 

56.210 Actions on dlsquall!icatlon. 

56.213 	 Public disclosure of ln!ormaUon rc­ gnrdlng disquallDcatlon. 

56.215 	 Alternative or additional actions to 

disciuallficatlon. 

56.219 	 Reinstatement or a disqualified institutional review board. 

AUTHORITY Sees. 406, 408, 409, 502, 503, 

505, 506, 507, 510, 513-516, 518-520, 601, 

701(a), 706, and 801, Pub. L. 717, 52 Stat. 

1049-1054 as amended, 1055, 1058 as amend· 

ed, 55 Stat. 851 as amended, 59 Stat. 463 as amended, 68 Stat. 511-518 as amended, 72 

Stat. 1785-1788 as amended. 74 Stat. 399­

407 as amended, 76 Stat. 794-795 as amend· 

ed, 90 Stat. 540-5411, 560, 562-574 (21 U.S.C. 

346, 346a., 348, 352, 353, 355, 356, 357, 360, 

360c-360!, 360h..;i60J, 361, 371(a), 376, and 

381>, sees. 215 351, 354-360F, Pub. L. 410, 58 

Stat. 690, 702 as amended, 82 Stat. ll73­

1186,as amended (42 U.S.C. 216, 262, 263b263n>. 

Subpart A-General Provisions, 

§ 56.1 Scope. 

This part contains the general standards for the composition, operation, 

and responsibility of an institutional 

review board that reviews cllnlcal investigations regulated by the Food and 

Drug Administration under sections 

505(1), 507Cd), and 520Cg) of the act, as 

well as clinlcalinvestlgatlons that support applications for research or mar­ keting permlts for products regulated 

by the Food and Drug AdmlnJstrnUon, 

including food and color additives, cos­ metics, drugs· for human use, medical 

devices for human use, biological products for human use, and electronic 

products. Additional specific standards 

for the composition, operation, and re­ sponsibility of an institutional :review 

board that reviews clinical investigations invol\ing particular test articles 

and products may be found in other 

parts, e.g., parts 312 and 812, of this 

chapter. Compliance with these parts 

is intended to protect the rights and 

safety of human subjects involved in 

such Investigations and to help assure the quality and integrity of the data 

!lied pursuant to sections 406, 408, 409, 

502, 503, 505, 506, 507, 510, 513-516, 

518-520, 601, 706, and 801 of the act 

and sections 351 and 354-360F of the~ 

Public Health Service Act. 

§ 56.2 Circumstances in which an institutional redew board is required; exemptions. 

Ca) Except as provided in paragraph 

Cc> of this section, the Food and Drug 

Administration will not accept.any aPplication for a research permit for a clinical investigation Cas required in 

parts 312 and 812 of this chapter> 

unless that investigation has been re­ viewed and approved by, and remains 

subject to continuing review by, an institutional review board meeting the 

requirements of this part. 

Cb> Except as provided in paragraph 

Cc> of this section, the Food and Drug 

Administration will not consider in 

support of an application for a re­ search or marketing permit any data or Information that has been derived 

from a clinlcal investigation unless 

that Investigation had been approved 

by, and was subject to initial and con­ tinuing :review by, an institutional 

review board meeting the requirements of this part. The determination 

that a clinlcal investigation may not 

be considered in support of an application for a research or marketing 

permit does not, however, relieve the 

applicant for such a permit of any obligation under any other applicable 

regulation to submit the results of the 

investigation to the Food and Drug 

Administration. 

<c> (1) The Food and Drug Administration will waive the requirement for 

institutional review board re\iew 

whenever the investigation com­ menced prior to and was completed 

·within 1 year following Cinsert effective date of this section> and was not 

otherwise subject to requirements for 

institutional review under Food and 

Drug Administration :regulations prior 

to that date. 

C2) Except as provided in this paragraph (c)C2>, the Food and Drug Administration will waive the requirement on request of an applicant. ifthe 

Commlssloner determines that the re­ quirement Js not necessary either for 

protecting the subjects invo1ved or for 

assuring the validity or reliability of 

the scientific data Ce.g., in a phase 3 

FEDERAL REGISTER, VOL 43, NO 153-TUESDAY, AUGUST 8, 1978 
35200 PROPOSED RULES 

investigational drug study <see 

§ 312.l(a)(2), form FD-1571, item 10, of 

this chapter> on outpatient subjects). Any applicant for a research or marketing permit may include a request 

for waiver, with supporting information, in the application. In the case of 

applications for a research peJ:lllit 

granted on an emergency basis, such 

request for waiver may be made over 

the telephone and be granted orally 

by the Food and Drug Administration 

at the same time the emergency application is approved on an oral basis, 

and may be conditioned upon subse· 

quent review by an institutional 

review board. Written confirmation of 

any oral request for and grant of a 

waiver shall be included in the official 

application submitted subsequent to 

the emergency authorization of such 

application. The requirement will not 

be waived in any of the following situations: 

(i) When the clinical investigation 

involves institutionalized human subjects. 

(ii) When the clinical investigation is 

conducted on the premises of an institution that has an institutional review 

board meeting the requirements of 

t.his part. <iii> When the Food and Drug Ad· 

ministration determines that the risks 

to the subjects justify such review. 

§ 56.3 Definitions. 

As used in this part: 

<a> "Act" means the Federal Food, 

Drug, and Cosmetic Act, as amended 

(sees. 201-902, 52 Stat. 1040 et seq., as 

amended (21 U.S.C. 321-392)). 

(b) "Application for research or marketing permit" includes: 

<1> A color additive petition, described in part 71 of this chapter. (2) Data and information regarding 

a substance submitted as part of the 

procedures for establishing that a substance is generally recognized as safe 

for a use which results or may reasonably be expected to result, directly or 

indirectly, in its becoming a component or otherwise affecting the characteristics of any food, described in 

§§ 170.35 and 570.35 of this chapter. (3) A food additive petition, described in part 171 of this chapter. (4) Data and information regarding 

a food additive submitted as part of 

the procedures regarding food addi· 

tives permitted to be used on an inter· 

1m basis pending additional study, de· 

scribed in § 180.1 of this chapter. (5) Data and information regarding 

<7> A new drug application, described 

in part 314 of this cl].apter. , (8) Data and information regarding 

the bioavailability or bioequivalence of 

drugs for human use submitted as part 

of the procedures for issuing, amending, or repealing a bioequivalence requirement, desctibed in part 320 of 

this cliapter. (9) Data and information regarding 

an over-the-counter drug for human 

use submitted as part of the proce­ dures for classifying such drugs as 

generally recognized as safe and effective and not misbranded, described in 

part 330 of this chapter. (10) Data and information regarding 

a prescription drug for human use submitted as part of the procedures for 

classifying such drugs as generally recognized as safe and effective and not 

misbranded, to be described in this 

-chapter. (11) Data and information regarding 

an antibiotic drug submitted as part of 

the procedures for issuing, amending, 

or repealing regulations for such 

drugs, described in part 430 of this , chapter. ­ <12> An application for a biological product license, described in part 601 

of this chapter. ~ 

<13> Data and information regarding 

.,_a biological product submitted as part 

of the procedures for determining that ~ licensed biological products are safe 

and effective and not misbranded, described in part 601 of this chapter. 

<14> An "Application for an Investigational Device Exemption," described 

in part 812 of this chapter. 

<15> Data and information regarding 

a-- medical device for human use submitted as part of the procedures for 

classifying such devices, described in 

section 513 of the act. 

<16> Data and information regarding 

a medical device for human use submitted as part of the procedures for 

establishing, amending, or repealing a 

standard for such device, described in 

section 514 of the act. 

<17) An application for premarket 

approval of a medical device for 

human use, described in section 515 of 

the act. 

<18) A product development protocol 

for a medical device for human use, 

described in section 515 of the act. 

<19) Data and information regarding 

an electronic product submitted as 

part of the procedures for establishing, amending, or repealing a standard 

for such products, described in section 

358 of the Public Health Service Act. 

a substance submitted as part of the - <20) Data and information regarding 

procedures for establishing a tolerance - an electronic product submitted as 

for unavoidable contaminants in food 

and food-packaging materials, de· 

scribed in section 406 of the act. 

(6) A "Notice of Claimed Investiga­ tional Exemption for a New Drug," de· 

scribed in part 312 of this chapter. 

part of the procedures for obtaining a 

variance from-any electronic product performance standard, as described in 

§ 1010.4 of this chapter. (21) Data and information regarding 

an electronic product submitted as 

part of the procedures for grantint~. 

amending, or extending an exemption 

from a radiation safety performance 

standard, as described in § 1010.5 of 

this chapter. (22) Data and information regarding 

an electronic product submitted as 

part of the procedures for obtaining 

an exemption from notification of a 

radiation safety defect or failure of 

compliance with a radiation safety 

performance standard, described in 

subpart D of part 1003 of this chapter. 

<c> "Clinical investigation" means 

any experiment that involves a test ar· 

ticle and one or more human subjects 

and that either is subject to require· 

ments for prior submission to the 

Food and Drug Administration under 

section 505(i), 507(d), or 520(g) of tho 

act, or is not subject to requirements 

for prior submission to the Food and 

Drug Administration under these sec· 

tions of the act, but the results of 

which are intended to be later submit· 

ted to, or held for inspection by, th(l 

Food and Drug Administration as part. 

of an application for a research or 

marketing permit. The term does noL 

include experiments that are subject. 

to the provisions of part 58 of this 

chapter, regarding nonclinlcal Inborn· 

tory studies. 

(cl) "Institution" means a person 

<other than an individual) who en· 

gages in the conduct of research on 

subjects or in the delivery of medical 

services to individuals, as a primary ac· 

tiVity or as an adjunct to providing 

residential or custodial care to 

humans. The term includes, for exam· 

ple, a hospital, retirement home, 

prison, academic establishment, and 

pharmaceutical or device manufactur· 

er. Tbe word "facility" as used in sec• 

tion 520(g) of the act is deemed to be 

synonomous with the term "institu· 

tion" for purposes of this part. 

<e> "Institutional review board" 

means any board, committee, or other 

group formally designated by an instl· 

tution for the purposes of reviewing 

clinical investigations or pther types of 

biomedical research involving humans 

as subjects, approving the initiation of 

such investigations or research, over· 

seeing the conduct of such investlga· 

tions or research, and/or terminating 

or suspending such investigations or 

research when necessary for the pro· 

tection of the subjects. The term has 

the same meaning as the phrase "lnsti· 

tutinal review committee" as used in 

section 520(g) of the act. 

(f) "Institutionalized · subject" 

means: 

<1> A subject who Is voluntarily con· 

fined for a period of more than 24 con· 

tinuous hours on the premises of, and 

in the care of, and institution (e.g., a 

hospital inpatient or a retirement 

home resident>, whether or not that 

.· 

FEDERAL REGISTER, VOL 43, NO 153-TUESDAY, AUGUST 8, 1978 
PROPOSED RULES 	 35201 

institution is a sponsor of the clinical 

investigation; and . <·2> A subject who is involuntarily 

cenfined for any .period of tune in a 

penal institution <e.g., jail, workhouse, 

house of detention, or prison), or another institution <e.g., a hospital> by virtue of a sentence, order, decree, or 

judgment under a criminal or civil 

statute, or awaiting arraignment, commitment, trial, or sentencing under 

such a statute, or by virtue of statutes 

or commitment procedures which provide alternatives to criminal prosecution o:~: incarceration in a penal facility. 

(g) "Investigator" means an individual who actually conducts a clinical investigation <Le., under whose immediate direction the test article is administered or dispensed to, or used involving a subject>. 

<h> "Person" includes any individual, 

partnership, corporation, association, 

'scientific or academic establishment, 

Government· agency or organizational 

unit of a Government agency, and any 

other legal entity. 

(i) "Sponsor" means a person who 

initiates a clinical investigation, but 

who does not actually conduct the investigatlon, i.e., the test article is administered or dispensed to, or used involving, a subject under the immediate 

direction of another individual. A 

person other than an individual <e.g., 

corporation or agency> that uses. one 

or more of its own employees to conduct an investigation that it has initiated is considered to be a sponsor <not 

a sponsor-investigator), and the employees are considered to be investigators. 

(j) "Sponsor-investigator" means an 

individual who both initiates and actually conducts, alone or with others, a 

clinical investigation, i.e., under whose 

immediate direction the test article is . administered or dispensed to, or used 

involving, a subject. The term does not 

include any person other than an individual, e.g., it does not include a corporation or agency. The obligations of a 

sponsor-investigator under this part 

include both those of a sponsor ·and . those of an investigator. 

<k> "Subject" means a human who is 

or becomes a participant in a clinical 

investigation, either as a recipient of 

the test article or as a control. A subject may be either a person in normal 

health or a patient to whom the test 

article might offer a therapeutic benefit or provide diagnostic information 

or a better understanding of a disease 

or metabolic process. m "l'est article" means any drug for 

human use, biological product for 

human use, medical device for human 

use, human food additive, color additive, cosmetic, electronic product, or 

any other article subject to regulation 

unde:r; the Act or under sections 351 or 

354-360F of the Public Health Service 

Act. 

56.8 	 Review by institution. 

Approval by an institutional revievr 

board of a clinical investigation may 

be subject to further appropriate 

review and approval, disapproval, suspension, or termination by officials or 

the institution. Disapproval, suspension, or termination of such an investigation by ,an institutional revievt 

board, however, may not be overruled 

by such officials. 

56.15 	 Inspection or nn instltutionnl re\"iew 

bonrd. 

'<a> An institutional review board 

shall permit an authorized employee 

of the Food and Drug Administration, 

at reasonable times and in a reasonable manner, !or purposes of verification of case reports and other information prepared as part or the data and 

information to be submitted by the 

sponsor to the Food and Drug Administration and of assessment of compliance with the requirements set forth 

in this and other parts, e.g., parts 312 

and 812 of this chapter: 

(1) To inspect records required to be 

made or kept by· the institutional 

reivew board as part of, or relevant to, 

its activities relating to clinical investigations; 

<2> To copy such records which do 

not identify the names o! human subjects or from which the identifying information has been deleted; and 

(3) To copy such records that Identify the human subjects, without deletion of the identifying information, 

but only upon notice that the Food 

and Drug Administration has reason 

to believe that the consent of human 

subjects was not obtained, that the reports submitted by the investigator to 

the sponsor Cor to the institutional 

review board) do not represent actual 

cases or actual results obtained, or 

that such reports or other required 

records apprear to be otherwise false 

or misleading. 

(b) The Food and Drug Administration may refuse to consider a clinical 

investigation in support of an application for a research or marketing 

permit if the institutional review 

board that reviewed the investigation 

refuses to allow an inspection under 

this section. The determination that a 

clinical investigation may not be considered in support of an· application 

for a research or marketing permit 

does not, however, relieve the applicant for such a permit o! any obligation under any other applicable statute or regulation to submit the results 

of the investigation to the Food and 

Drug Administration. 

Subpart B-Organil:atian and Personnel. 

56.21 	 m~·ersity or membership or an institutional review board. 

Ca> An institutional review board 

shall be composed of not fewer than 

five individuals with vahing cultural 

backgrounds to assure complete and 

adequate review of the clinical investigation. The board shall be sufficiently qualified through the maturity, experience, and expertise of its members 

and diversity of its membership to 

insure respect for its advice and counsel for safeguarding the rights and 

safety or subjects. In ~ddition to possessing the profeSsional competence 

necessary to comprehend the scientific 

nature of the investigation. the board 

must be able to ascertain the accept­ ability or a study in terms of institutional commitments and regulations <where appropriate), applicable law, 

standards of professional conduct and 

practice, and community attitudes. 

Such board shall include at least one 

licensed physician, as well as individ- · uals whose primary concerns are in 

nonscientific areas <e.g., lawyers, 

clergy, ethicists, consumers, and social 

scientists>. No board shall consist entirely_ or members of only one sex, 

race, or professional group. 

(b) The records of a board shall 

identify each member by name, earned 

degrees if any, occupation and title, 

and other pertinent indications of experience Csuch as board certification 

or licenses> sufficient to descn'be each 

member's chief anticipated contn'butlons to such board's deliberations. 

56.25 	 Relationship between members and 

Institution. 

<a> The institutional review board 

shall not consist entirely of individuals 

who are officers, employees, or agents 

of, or are otherwise associated with, 

the institution, apart from their membership on the institutional review 

board. 

(b) The records of a board shall 

Identify the employment or other relationship between each member and 

the institution, including the membership on the board <e.g., full-time employee, part-time employee, a member 

of governing panel or board, paict consultant, or unpaid consultant>. 

§ 56.26 Relationship between memberS 

nnd sponsor, investigator, or investigation. 

Ca> No member of an institutional 

review board shall participate in the 

board's initial or continuing re1..iew of 

any clinical investigation in which the 

member has a conflicting interest, or 

of any investigation involving an investigator or sponsor who participated in 

his or her selection for the board, 

except to provide information request­ ed by the board. The board is responsiFEDERAL REGISTER, VOL 43, NO 153-TUESDAY, AUGUST 8, 1978 
35202 PROPOSED RULES 

ble for determining whether a member 

has a conflicting interest. No investigator or sponsor shall participate in 

the selection of members for a board 

that will review his or her investiga­ tion. The Food and Drug Administration may waive the requirements of 

this section upon a request contained 

in the relevant application for a research or marketing permit; the request shall ·contain information describing the reasons why it is necessary for the investigator or sponsor to 

participate in the selection of board 

members. ., (b) The records of a board shall 

identify the employment or other relationship between each member and 

the investigator or sponsor of any 

clinical investigation reviewed by the 

board (e.g., full-time employee, parttime employee, member of the governing board or panel, paid consultant, or 

unpaid consultant>. If any such relationship exists, the records shall describe the extent to which the member 

participated in the initial or continuing review of the investigation. 

§ 56.34 Consultants. 

An institutional review board may, 

at its discretion, invite persons with 

competence in special areas to assist in 

the review of complex issues which require expertise beyond or in addition 

to that available on the board. Such 

persons may not vote with the board. 

Subparts C and D [Reserved] 

Subpart E-Board Operations 

§ 56.80 Written procedures for review of 

clinical investigations by an institutional review board. 

.An institutional review board shall 

follow written procedures for conducting its initial and continuing review 

and. monitoring of clinical investigations and for reporting its findings and 

actions to the investigator, the institution, and, where appropriate, the sponsor. Such procedures may be promulgated by the institution or by the 

board. 

§ 56.82 Quorum requirements; 

<a> An institutional review board 

shall conduct all significant business 

(e.g., approval, disapproval, suspension, or termination of a clinical investigation, or approval of a consent 

form> by a quorum of its members 

present at a meeting. The quorum· 

shall be defined in the written procedures of the board, consistent with the 

requirements of this section. 

(b) The number of members to constitute a quorum may not be less than 

a majority of the members of the 

board, unless the board has 20 or more 

members, in which case 10 members 

shall constitute a quorum. 

(C) A quorum shall consist of a least 

one licensed physician, one scientist, 

and one nonscientist <e.g., lawyer or 

clergy), 

.<d> A quorum shall be determined 

only by members present at a meeting. 

Proxy votes, telephone conferences, 

and votes by mail shall not constitute 

a meeting or presence at a meeting. 

§ 56.85 Proce'dures for initial review of a clinical investigati~n. 

<a> An institutional review board 

shall not approve a proposed clinical 

investigation until it has received in 

writing and reviewed the investigational plan or protocol, reports of pertinent prior animal and human studies 

conducted with the test article, and 

the materials to be used in obtaining 

consent of subjects. 

(b) Upon receipt of a proposed investigation, the board shall inform in 

'writing the investigator or sponsor, as 

appropriate, of the date of such receipt and that the investigation may 

not begin until th~ board notifies the 

investigator or sponsor, as appropriate, that it has approved the investigation and until the sponsor has complied with any other preinvestigation 

requirements of the Food and Drug 

Administration. 

<c> If the board has any question regarding the proposed investigation, or 

desires any further information, it 

may request the investigator or sponsor to provide the necessary information or materials as written amendments to the submission. The board 

may advise the investigator or sponsor, as appropriate, on modifications, 

conditions, or other amendments to 

the investigational plan or protocol 

and/or the material to be used to 

obtain consent of subjects, which 

might improve the acceptability of the 

proposed investigation to the board. 

Any modifications, conditions, or 

other amendments to the investigational plan or protocol shall be made 

in writing as amendl:ilents to the submission. 

(d) The board should review and approve or disapprove a proposed investigation as soon as possible after receipt 

of the submission and any amendments in response to requests or 

advice from the board. 

<e> The board shall notify in writing 

the investigator or the sponsor, as appropriate, and the institution, of its 

decision to .approve or disapprove the 

proposed investigation. If the board 

decides to disapprove an investigation, 

it shall include in its written notification a statement of the reasons for its 

decision. 

§ 56.87 Procedures for continuing review 

and suspension or termination of u clinical investigation. 

CeJ An institutional review board 

shall continue to review a clinical in· 

vestigation that it has approved until 

the investigation is concluded or is dis· 

continued. Such continuing review 

shall be undertaken at intervals appro· 

priate to the degree of risk, but not ex· 

ceeding 1 year, to assure that the in· 

vestigation is being conducted in com• 

pliance with the requirements, under· 

standings, and recommendations of 

the board and with the requirements 

of the act and implementing regula· 

tions <e.g., parts 312 and 81:f of this 

chapter). 

(b) A board may, at any time, sus• 

pend or terminate a previously ap· 

proved clinical investigation. · The 

board shall notify in writing the investigator or the sponsor, as appropriate, 

and the institution of its decision to 

take such action, including a state· 

ment of the reasons for its decision. 

§ 56.90 Criteria for disapproval, auspcn· 

sion, or termination of a clinical htvcs• 

tigation. 

<a> An institutional review board 

may disapprove, suspend, or terminate 

a clinical investigation for any of the 

reasons within the scope of review 

conferred upon the board by the insti• • 

tutil)n that created it. It shall state its 

reasons in writing. A board may·recon· 

sider its action, with or without sub· 

mission of additional information, and 

the decision of a board of any one in· 

stitution regarding a proposed clinical 

investigation shall not preclude a dif· 

ferent decision by the board of an• 

other institution that might consider 

the same investigation . (b) A board shall disapprove, and 

may suspend or terminate, a clinical 

investigation if it finds that: 

(1) The information submitted to 

the board contains an untrue state· 

ment of fact material to the board or 

omits material information required 

by the board to review and evaluate 

the clinical investigation. (2) The report of prior investigations 

with the test article Is inadequate to 

support a conclusion that it is reason· 

ably safe to initiate or continue the 

clinical investigation. 

<3> The investigator does not possess 

the scientific training and experience appropriate to qualify the investigator 

as a suitable expert to Investlgo.te the 

safety and, where appropriate, effec· 

tiveness of the test article. 

(4) The available clinical laboratory 

facilities and medical support are inadequate to assure that the clinical in· 

vestigation will be conducted properly 

and in conformity with the protocol. 

<5> The clinical investigation exposes 

or will expose subjects to undue risks. 

FEDERAL REGISTER, VOL 43, NO 153-TUESDAY, AUGUST 8, 1978 
In assessing risks, the board shall consider, among other factors: 

(i) Whether the risks to the subject 

are so outweighed by the sum of the 

benefits to the subject and the importance of the knowledge to be gained as 

to warrant a decision to allow the subject to accept these risks; 

(ii) Whether the rights and safety of 

subjects will be adequately protected; 

(iii) Whether legally effective informed consent will be obtained by 

adequate and appropriate methods in 

accordance with the requirements of 

§310.102 or subpart F of part 812 of 

this chapter; and 

(iv) Whether the conduct of the 

clinical investigation will be or is being 

reviewed by the sponsor and by the 

lioard at intervals appropriate to the 

degree of perceive.!! risk. . (6) The clinical investigation does 

not conform to, or iS not being conducted iii accordance with, the submission to the board and the requirements of the Act and implementing

regulations (e.g., parts 3l2 and 812 of 

this chapter>. 

§56.92 Order to suspend or terminate a clinical investigation. 

" If an institutional review board decides to order the suspension or termi­ ,nation of a clinical investigation, it 

shall include in its order provisions regarding any subject who·has previously been allowed to participate in the 

investigation and who either.would <if 

the investigation were not suspended 

or terminated> continue to receive the .test -article or have it used involving 

him or her, or who would not continue 

to receive it or have it used involving 

him or her but who remains under the 

supervision of·the investigator. Such 

provisions shall take into account, 

among other factors, the risks to the 

subject from the withdrawal of the 

test article or from its continued administration by another physician,.the 

.need for further medical supervision, 

the availability of qualified medical 

personnel, and the rights of the subject, including the right to participate 

in the decision as to future care. 

Subparts FThrough I (Reserved] 

Subpart J-Records and Reports 

§ 56.185 Records of an institutional review 

board. 

An institutional review board shall 

prepare and maintain adequate docu­ . mentation of, its activities regarding 

each clinical investigation, including 

the following: 

<a> Records of information submitted to the board by an investigator 

and/orthesponsor;­

<b> Information on board members 

required under subpart B of this part; 

<c> Attendance at and minutes of 

board meetings, including a written 

summary of the discussion of any substantive issues and their resolution;· 

PROPOSED RULES 

(d) Board recommendations and actions, with a record of the number of 

members voting in favor or and 

against the decision; and 

<e> Dated reports of successive reviews as they are performed. 

§ 56.195 Retention or records. 

An institutional review board shall 

retain the records required by this 

part regarding a particular clinical Investigation for whichever of the following periods Is shortest: 

<a> A period of 2 years following the 

date on which the test article Is ap. proved by the Food and Drug Administration !or marketing !or the purposes which were the subject of the investigation; 

(b) A period of 5 years following the 

date on which the results of the Investigation are submitted to the Food and 

Drug Administration In support of or 

as"part or an application !or a research 

or marketing permit !or the test article for the PurPOSes that were the subject of the Investigation; or 

<c> In other situations <e.g., where 

the investigation does not result In the 

submission of the data !rom the investigation in support of an application 

for a research or marketing permit>, a 

period of 2 years following the date on 

which the entire clinical investigation 

<not merely the investigator's portion 

of an investigation involving more 

than one investigator> is completed, 

terminated, or discontlnued, or the exemption under which the investigation 

is being conducted is terminated or 

withdrawn by the Food and Drug Administration. 

Subpart K-Dlsquallflcatlon of an Institutional 

Revlaw Board . § 56.200 Purpose. 

The purposes or'disqualification of 

an institutional review board that falls 

to comply with the standards set forth 

in this part- <or other regulations regarding such boarps in this chapter) 

may be one or both of the following: 

<a> To preclude it !rom reviewing clinical investigations subject to requirements for prior submissin to the 

Food and Drug Administration under 

section 505(1), 507(d), or 520(g) of the 

Act until such time as it becomes 

likely that it will abide by such regulations of- that such violations will not 

recur. This will assure that all such 

clinical investigations are under the 

review of a board that compiles with 

appropriate Federal standards. The 

determination to disqualify an institutional review board does not necessarily constitute a finding or recommendation that the board or any of its 

members should be subject to other 

sanctions by the institution that created it or by sponsors of clinic;alinvestigatlons under Its review. 

<b> To preclude the consideration of 

any clinical investigations in support 

35203 

of applications for a research or marketing permit !rom the Food and Drug 

Administration, which investigations

have been conducted under the review 

of the board until such time as the investigations are subject to review by 

an institutional review board that 

complies with the applicable standards, or that it can be adeqUately demonstrated that such violations did not 

occur during, or affect the validity or 

acceptability of, a particular investigation or investigations. The determination that a cl1nlcal investigation may 

not be considered in support of an ap. 

plication for a research or marketing

permit does not, however, relieve the 

applicant for such a permit of any obligation under any other applicable 

statute or regulation to submit the results of the investigation to the Food 

and Drug Administration. 

§ 56.202 Grounds for disqualification. 

The Commissioner may disqualify 

an institutional review board upon

finding all of the following: 

<a> The institutional review board 

faDed to comply with any of the regulations set forth in this part or other 

regulations regarding such boards in 

this chapter; 

(b) The noncompliance adversely affected the validity of the clinical investigation or the rights or the safety of 

the subjects; and 

(c) Other lesser regulatory actions 

(e.g., warnings or rejection of data 

!rom individual investigations> have 

not been or will probably not be adequate to assure that the board will 

comply vlith such regulations in the 

future. 

§ 56.20-1 Notice or an opportunity for a 

hearing on proposed disqualification. 

<a> Whenever the Commissioner has 

information indicating that grounds 

exist under § 56.202 which in the Commissioners's opinion may justify dis-_ 

qualification of an institutionat.review 

board, the Commissioner may issue to 

the board a written notice proposing 

that the board be disqualified. 

<b> A hearing on the disqualification 

of an institutional review board shall 

be conducted in accordance with the 

requirements for a regulatory hearing 

setforth in part 16 of this chapter. 

§ 56.206 Final order on disqualification. 

<a> If the Commissioner, after the 

regulatory hearing or after the time 

!or requesting a hearing expires without a request being made, upon an 

evaluation of the administrative 

record of the disqualification proceeding, makes the finding required in 

§ 56.202, the Commissioner shall issue 

a final order disqualifying the institutional review board. Such order shall 

include a statement of the basis for 

.. 


FEDERAL REGISTER, VOL 43, NO 153-TUESDAY, AUGUST 8, 1978 
3520=i 

that determination and shall prescribe 

any actions (set forth in § 56.210(b)}..j;<i be taken with regard to ongoing cWffi;__ cal investigations being conduc~d • 

under the review of the board. UpO:ii issuing a final order, the Commissioner shall notify {with a copy of the 

order> the board of the action, as. well as the institution that established the 

board, the sponsor of each clinical investigation subject to requirements for 

prior submission to the Food and Drug 

Administration which was under the 

review of the board, and the investigators of such investigations who were 

under the review of the board. 

(b) If the Commissioner, after a regulatory hearing or after the time for 

requesting a hearing expires without a 

request being made, upon an evaluation of the administrative record of 

the disqualification proceeding, deter- . mines not to make the findings required in § 56.202, the Commissioner 

shall issue a final order terminating the disqualification proceeding. Such 

order shall include a statement of the 

basis for that determination. Upon issuing a final order, the Commissioner 

shall notify the board and provide a 

copy of the order. 

§ 56.210 Actions on disqualification. 

(a) No clinical investigation subject 

to requirements for prior submission 

to the Food and Drug Administration · and to requirements for institutional 

review board review under § 56.2 will 

be authorized by the Commissioner if 

such investigation is to be conducted 

under the review of a disqualified 

board. 

(b) The Commissioner, after considering the nature. of each ongoing clini· 

cal investigation subject to requirements for prior submission to the 

Food and Drug Administration which 

is being conducted under the review of 

the board, the number of subjects involved, the risks to them from suspension of the investigation, and the need 

for involvement of an acceptable institutional review board, may direct, in 

the final order disqualifying a board 

under § 56.206(a), that one or more of 

the following actions be taken with 

regard to each such investigation: <1> The investigation may be terminated or suspended in its entirety 

until the board is reinstated under 

§ 56.219 or another board accepts responsibility for review of the investigation. 

(2) No new subject shall be allowed 

to participate, or be requested to participate, in the investigation until the 

board is reinstated under § 56.219 or 

another board accepts responsibility 

for review of the investigation. (3) Any subject who has previously 

been allowed to participate in the investigation and who remains under 

the supervision of an investigator, but 

PROPOSED RULES . 

who is no longer receiviilg the test article or having it used involving him or 

her Ci.e., one having followup monitoring by the investigation or one acting as a control) should continue to be 

monitored by the investigator but 

shall not again receive the test article, 

or have it used involving him or her, 

until the board is reinstated under 

§ 56.219 or another board accepts re-· sponsibility for review of the investigation. 

<4> Any subject who has been allowed to participate in the investigation· and who, but for suspension of 

the investigation, would continue to 

receive the test article or have it used 

involving him or her, shall not receive 

it or have it used until either: 

(i) Another board accepts resonsibility for review of the investigation, or 

(ii) The clinical investigator determines in writing that it is contrary to 

the health of the subject to defer further use of the test article until another board can assume responsibility for review of the investigation. In such 

a case, the Commissioner may impose 

any further conditions that the Commissioner deems appropriate to protect the rights and safety of the subject. 

<c> Once an institutional review 

·board 	has been disqualified, each ap­ plication for a research or marketing 

permit, whether approved or not, containing or relying upon any clinical investigation conducted under the 

review of the board may be examined 

to determine whether the investigation was or would be essential to a reg­ ulatory decision regarding the application. If it is determined that the investigation was or would be essential, the 

Commissioner shall also determine 

whether the investigation is acceptable, notwithstanding the disqualification of the board. Any investigation 

reviewed by a board before or after its 

disqualification may be presumed to 

be unacceptable, and the person relying on the investigation may be required to establish that the investigation was not affected by. the circumstances which led to disqualification of 

the board, e.g., by submitting validating information. If the investigation is 

determined to be Unacceptable, such 

investigation shall be eliminated from 

consideration in support of the application, and such elimination may serve as new information justifying the termination or withdrawal of approval of 

the application. 

<d> No clinical investigation begun under the review of an institutional 

review board after the date of its disqualification shall be considered in 

support of any application for a research or marketing permit, unless the 

board has been reinstated under 

§ 56.219. "'The determination that a 

clinical investigation may not be considered in support of· an application 

for a research or marketing permit 

does not, however, relieve the appll· 

cant for such a permit of any oblfeo.· 

tion under any other applicable stat· 

ute or regulation to submit the results 

of the investigation to the Food and 

Drug Administration. 

§ 56.213 Public disclosure of lnformntlon 

regarding disqualification. 

<a> Upon issuance of a final order 

disqualifying an institutional review 

board, the Commissioner may notify 

all or any interested persons. Such 

notice may be given in the discretion 

of the Commissioner whenever the 

Commissioner believes that such dis· 

closure would further the public inter· 

est or would promote compliance with 

the regulations set forth in this part. Such notice, if given, shall include a 

copy of the final order issued under 

§ 56.206(a) and shall state that the dis· 

qualification constitutes a determina· 

tion by the Commissioner that the bo~rd is not eligible to review cllnico.l 

investigations subject to requirements 

for prior submission to the Food and 

Drug Administration and that the re· 

suits of any clinical investigations con• 

ducted under the review of tho board 

may not be considered by the Food 

and Drug Administration in support of 

any application for a research or mar· 

keting permit. The notice shall fur· 

ther state that it is given because of 

the professional relations between the 

board and the person notified and 

that the Food and Drug Adminlstro.· 

tion is not advising or recommending 

that any action be. taken by the person 

notified. 

(b) A determination that an institutional review board has been disquall· fied and the administrative record re· 

garding such determination are dlsclo· 

sable to the public under part 20 of 

this chapter. 

<c> Whenever the Commissioner has 

reason to believe that an institutiono.l 

revievr. board may be subject to dis· 

qualification, the Commissioner shall 

so notify other agencies in the Depart· 

ment of Health, Education, and Wei· 

fare that support research involving 

human subjects at the time of or after 

proposing disqualification of the board 

under § 56.204(a). 

§ 56.215 Alternative or nddltlonal actions 

to disqualification. 

Disqualification of an institutiono.l 

review board under this subpart is in· 

dependent of, and neither in lieu or 

nor a precondition to, other proceed· 

ings or actions authorized by tho act. 

The Commissioner may, o.t any time, 

through the Department of Justice in· 

stitute any appropriate judicio.l pro· ceedings (civil or crimino.D and any other appropriate regulatory action, in 

addition to or in lieu of, and before, o.t 

• 

FEDERAL REGISTER, VOL 43, NO 153-TUESDAY, AUGUST 8, 1978 
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PROPOSED RULES 	 35205• 

the time of, or after, disqualification. The Commissioner may also refer pertinent matters to another Federal, 

State, or local government agency for 

such action as that agency determines 

to be appropriate. · 

§ 56.219 Reinstatement of a disqualified 

institutional review board. 

<a> An institutional review board 

that has been disqualified may be reinstated as eligible to review clinical investigations subje~t to requirements 

for prior submission to the Food and 

Drug Administration, or as acceptable 

to be the reviewer of clinical investigations to be submitted to the food and 

Drug Administration, if the Commissioner determines, upon an evaluation 

of a written submission from the 

board, that the board can adequately 

assure that it will operate in compliance with the standards set fortli in 

this part and other applicable regula­ tions in this chapter, e.g., parts 312 or 

812. 

<b> A disqualified board that wishes 

to be so reinstated shall present in 

writing to the Commissioner reasons 

why it believes it should be reinstated 

and a detailed description of the corrective actions it has taken or intends 

to take to assure that the acts or omissions that led to disqualification will 

not recur. The Commissioner may condition reinstatement upon the board's · being 	found in compliance with the 

applicable regulations upon an inspection. 

<c> If a board is reinstated, the Commissioner shall so notify the board 

and all persons who . were notified 

under § 56.213 of the disqualification of the board. A determination that a 

board has been reinstated is disclosable to the public under part 20 of this 

chapter. 

PART 71-COLOR ADDITIVE PETITIONS 

3. By amending part 71: 

a. In § 71.1 by adding new paragraph 

(i) to read as follows: 

§ 71.1 Petitions. 

<D If clinical investigations involving human subjects are involved, petitions 

filed with the Commissioner under 

section 706<b> of the act shall include 

statements ~egarding each such clinical investigation contained in the petition that it either was conducted in 

compliance with the requirements for 

institutional review set forth in part 

56 of t~ chapter or was not subject 

to such requirements in accordance 

with § 56.22<c> of this chapter. b. In § 71.6 by adding a new sentence 

at the end of paragraph <b> to read as 

follows: 

§ 71.6 Extension or time for studying petitions; substantl\'C amendments; withdrawal or petitions without prejudice. 

<b> • • • If clinical investigations involving human subjects are Involved. 

additional Information or data submitted in support or filed petitions shall 

include statements regarding each 

such clinical Investigation from which 

the Information or data are derived, 

that it either was conducted in compllance with the requirements for institutional review set forth In part 56 of 

this chapter or was not subject to such 

requirements In accordance with 

§ 56.2Cc> of this chapter. .. 

SUBCHAPTER a-FOOD FOlt HUMAN CONSUMPTION 

PART 171-FOOD ADDffiVE PETmONS 

4. By amending part 171: 

a. 1n § 171.1 by adding new paragraph <m> to read as follows: 

§ 171.1 Petitions. 

<m> If clinical investigations Involving human subjects are Involved, petitions filed with the Commissioner 

under section 409Cb) of the aot shall 

include statements regarding each 

such clinical Investigation relied upon 

in the petition that It either was conducted in compliance with the requirements for institutional review set 

forth In part 56 or this chapter or was 

not subject to such requtJ-ements In accordance with § 56.2Cc> or this chapter. 

b. In § 171.6 by adQing a new sentence at the end or the paragraph to 

read as follows: 

§ 171.6 Amendment or petition. 

• • • If ·clinical Investigations in· 

volving human subjects are involved, 

additional Information and data submitted In support of filed petitions 

shall include statements regarding 

each such clinical Investigation !rom 

which the information or data are derived that it either was conducted In 

compliance with the requirements !or 

institutional review set forth In part 

56 or this chapter or was not subJect 

to such requirements In accordance 

with § 56.2Cc) of this chapter. 

PART 180-FOOD ADDinVES PERMITTED IN 

FOOD ON AN INTERIM BASIS OR IN CON· 

TACT WITH FOOD PENDING ADDffiONAL 

Part 180 is amended In § 180.1 by 

adding a new paragraph Cc>CG> to read 

as follows: 

§ 180.1 GeneraL 

(C) * • • 

(6) I! clinical Investigations Involving 

human subjects are Involved, such investigations filed with the Commissioner shall Include, with respect to 

each Investigation, either a statement 

that the Investigation has been or 'will 

be conducted In compliance with the 

requirements for Institutional review 

set forth In part 56 of.this chapter; or 

a statement that the Investigation is 

not subject to such requirements in accordance with § 56.2(c) of this chapter. 

SUBCHAPTU D-Dli.UGS FOlt HUMAN USE 

PART 310-NEW DlUGS 

§ 310.3 [Amended] 

5. Part 310 is amended in § 310.3 

Deftnftfons ancl interpretations. by deleting and reserving paragraph (j). 

PART 312-NEW DlUGS FOR 


INVESTIGAnONAL USE 


6. Part 312 is amended In § 312.1 by redesignating paragraph (d)Cll> gg 

(d)(12) and addfug a new paragraph 

(d)(ll). 

§ 312.1 Conditions for exemption or new drugs for investigational use. 

(d) ••• 

<11> The clinical investigations are 

not being conducted in compliance with the requirements regarding institutional review set forth in this part 

or part 56 of this chapter; or 

PART 314-NEW DlUG APPUCAnONS 

7. Part 314 is amended: 

a. In § 314.1 by adding a new item 16 

to form FD-356H in paragraph CcJ<2> 

and by redesignating paragraph <D<7> 

as <DCS> and adding a new paragraph (f)(7) to read as follows: 

§ 314.1 Applications. 

(C) • * • 

(2) ••• 

Foim FD-356H-Rev.l974: 

16. Conduct of clinical inrestigaliO'nSStatements regarding each clinical investicatfon invohing human subjects contained 

in the appUcaUon that it either was con­ ducted in compliance ·with the requirements !or lnstftutfonal review set !orth in Part 56 

FEDERAL REGISTER, VOL 43, NO 1.53-TUESDAY, AUGUST 8, 1978 
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35206 

_,. 

of this chapter or was not subject to such 

requirements In accordance with § 56.2Cc> of 

this chapter. 

(f) • *. 

(7) Statements regarding each clinical investigation involving human subjects contained in the application that 

it either was conducted in compliance 

with the requiremenU: the institutional review set forth in part 56 of this 

chapter or was not subject to such requirements in accordance with 

§ 56.2(c) of this chapter. 

b. In § 314.8 by adding a new paragraph <n> to read as follows: 

§ 314.8 Supplemental applications. 

• • * • • 

<n> A supplemental application that 

contains clinical investigations involving human subjects shall include statements by the applicant regarding. each 

such investigation that it either was 

conducted in compliance with the requirements for institutional review set 

forth in Part 56 of this chapter or was 

not subject to such requirements in accordance with § 56.2(c) of this chapter. 

c. In §314.9 by adding new· paragraph <e> to read as follows: 

§ 314.9 Insufficient information in application. · 

. . 

<e> The information contained in an 

application shall be considered insufficient to determine whether a drug is 

safe and effective for use unless the 

application includes statements regarding each clinical investigation involvings human subjects contained in 

the application that it either was conducted in compliance with the requirements for institutional review set 

forth in Part 56 of this chapter or was 

not subject to such requirements in accordance with § 56.2(c) of this chapter. 

d. In § 314.12 by adding new paragraph <e> to read as follows: 

§ 314.12 Untrue statements in application. 

<e> Any clinical investigation involving human subjects contained in the 

application subject to the requirements for institutional review set 

forth in part 56 of this chapter was 

not conducted in compliance with such 

requirements. 

e. In § 314.110 by adding new paragraph <a><ll> to read as follows: 

PROPOSED RULES 

§ 314.110 Reasons for refusing to file applications. 

<a> • • • · <11> The applicant fails to include in 

the application statements regarding 

each clinical investigation involving 

human subjects contained in the application that it either was conducted 

in compliance with the requirements 

for institutional review set forth in 

part 56 of this chapter or was not subject to such requirements in accordance with § 56.2(c) of this chapter. 

.. f. In § 314.111 by adding paragraph 

<a><11> to read as follows: 4 

§ 314.111 Refusal to approve the application. 

<a> • • • 

<11> Any clinical investigation involving human subjects contained in the 

application sUbject to the requirements for institutional review set 

forth in Part 56 of this chapter was 

not conducted in compliance with such 

requirements. 

g. In § 314.115 by adding new paragraph <c><7> to read as follows: 

§ 314.115 Withdrawal of approval of an application. 

(C)*** 

<7> That any clinical investigation involving human subjects contained in 

the application subject to the require: 

ments for institutional review set 

forth in Part 51> of this chapter was 

not conducted in cop1pliance with such 

requirements. 

PART 320-BIOAVAILABILITY AND 


BIOEQUIVALENCE REQUIREMENTS 


8. Part 320 is amended: 

a. In § 320.31 by adding a new para­ grapla (f) to read as follows: 

§ 320.31 Applicability of requirements. re· garding a "Notice of Claimed Investiga· 

tiona( Exemption for a New Drug." 

<f) An in vivo bioavailability study in 

humans shall be conducted in compli· 

ance with the requirements for institu· 

tional review set forth in part 56 of 

this chapter, regardless of whether 

the study is conducted under a "Notice 

of Claimed Investigational Exemption for a New Drug." 

b. in § 320.57 by adding a new para­ graph <e> to read as follows: ­

§ 320.57 Requirements of the conduct of 

in vivo bioequivalence tcstlnrr In 

humans. 

<e> If a bioequivalence requirement 

provides for in vivo testing in humo.ns, 

any person conducting such testing 

shall comply with the requirements of 

§ 320.31. 

PAIIT 330-0VER-THI:-COUNTER (OTC) 

HillMAN DRUGS WHICH ARE GENERALLY 

RECOGNIZED AS SAFE AND EFFECTIVE: AND 

NOT MISBRANDED 

9. Part 330 is amended in § 330.10 by 

adding new paragraph (e) to read as 

follows: 

§ 330.10 Procedures for clnsslfylng o·rc 

drugs us generally recognized as snfc 

and effective and not mlsbrandl!d, nnd 

for establishing monographs. 

<e> Institutional review. Information 

and data submitted under this section 

after <insert effective date of this 

paragraph) shall include statements 

regarding each clinical investigation 

involving human subjects, from which 

the information and data are derived, 

that it either was conducted in compli·. 

ance with the requirements for Jnstitu· 

tional review set forth in part 56 of 

this chapter or was not subject to such 

requirements in accordance with 

§ 56.2(c) of this chapter. 

PARi 361-PRESCRIPTION DRUGS FOR 

HUMAN USE GENERALLY RECOGNIZED AS 

SAFE AND EFFECTIVE AND NOT MISBRAND· 

ED: DRUGS USED IN RESEARCH 

10. Part 361 is amended in §361.1 by 

revising paragraph (d)(9) to read as 

follows: 

§ 361.1 Radioactive drugs for certuln re• 11earch uses. 

(d) ••• 

(9) Anproval by an institutional 

review board. The investigator shall 

obtain the review and approval of an 

institutional review board that con· 

forms to the requirements of part 56 

of this chapter. 

PART 430-ANTIBIOTIC DRUGS; GENERAL 

11. Part 430 is amended in §430.20 

by adding new paragraph (g) to read 

as follows: 

FEDERAL REGISTER, VOL 43, NO 153-TUESDAY, AUGUST 8, 1978 
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• • • • • 

PROPOSED RULES .35207 f 

§430.20 Procedure for the issuance, product to be sold, bartered, or e.xamendment. or repeal ofregulations. changed · or offered, sent, carried or 

brought for sale, barter or exchange; -· *· summaries of results of tests per­ * * * * formed on the lot
 represented by (g) No regulation providing for the the submitted sample
: and speci­ certification of an antibiotic drug for mens of the label, enclosures and con­ human use shall be issued or amended tainers proposed to be used for the unless each clinical investigation in­ product. An appllcatl9n for license volving human subjects on which the shall not be considered a.s filed until issuance or amendment or the regula­ all pertinent Information and data are tion is based was conducted in compli­ received from the manufacturer by ance with the requirements for institu­ the Bureau of Biologics. The applicant tional review set forth in part 56 of shall also include an environmental · this chapter or was not subject to such Impact analysis report analyzing the requirements in accordance with environmental impact of the manufac­ § 56.2Cc) of this chapter. turing process and the ultimate use or 

consumption of the biological product 

pursuant to § 25.1 of this chapter. In PART 431-CERTIFICATION OF ANTIBIOTIC lieu of the procedures described in this DRUGS paragraph, applications for radioactive 

12. Part 431 is amended in § 431.1'1 biological products shall be handled a.s 

by adding a new paragraph <I> to read set forth in paragraph <b> of this secas follows: · tion. 

§ 431.17 New antibiotic and antibiotic-con­ * • • • • taining products. b. In § 601.25 by revising paragraph 

<h><I> and adding a new paragraph <1> * * * * to read a.s follows: 

(1) Statements regarding each clinical investigation involving human sub­ § 601.25 Review procedures to determine 

jects contained in the request that it that licensed biological products nrc 

either was conducted in compliance safe, effecU\'e, nnd not misbranded 

with the requirements for institution­ under prescribed, recommended, or 
 al review set forth in part 56 of' this suggested conditions of use. 
 chapter or was not subject to such re- · 
 quirements in · accordance with 
 * • • • • 

§ 56.2Cc) of this chapter. <h> Additional studies. <1> Within 30 

days following publication of the !lnal 

order, each licensee for a biological SUBCHAPTER F-BIOLOGICS product designated a.s requiring furPART 601-LICENSING ther study to justify continued mar­ - . . . . ~ketlng on an interim basis, pursuant to 

13. Part 601IS amen~e?: paragraph (f)(3) of this section, shall 

.a. In § 601.2 by reVISmg paragraph satisfy the Commissioner of Food and 

<a> to read as follows: Drugs in writing that studies adequate 

and appropriate to resolve the ques­ § 601.2 Applications for establishment and 

product licenses; procedures for filing. tions raised about the product have. 

been undertaken, or the Federal Gov­ . (a) General. To obtain a license for ernment may undertake tb,_ese studies. 

any establishment or product, the Any study involving a clinical investi­ manufacturer shall make application gation that involves human subjects to the Director, Bureau of Biologics, shall be conducted in compliance with

on forms prescribed for such purpose, the requirements for institutional and in the case of an application for a review set forth in part 56 or this product license, shall submit data de­ chapter, unless it is not subject to rived from laboratory and clinical such requirements In accordance with studies which demonstrate that the § 5S.2(c) of this chapter. The Commis­ manufactured product meets pre­ sioner may extend this 30-day period scribed standards of safety, purity, if necessary, either to review and net and- potency; statements regarding on proposed protocols or upon indica­ each clinical investigation involving tion from the licensee that the studies human subjects contained in the ap­ will commence at a speclfied reason­ plication that it either was conducted able time. If no such commitment is in compliance with the requirements made, or adequate and appropriate for institutional review set forth in . studies are not undertaken, the prod­ part 56 of this chapter or was not sub­ uct licenses shall be revoked. ject to such requirements in accordance with § 56.2Cc) of this chapter, a 

full description of manufacturing * * 

methods; data establishing stability of m Institutional review. Information 

the product through the dating and data submitted under this section 

period; sample
 representative of the after (insert effective date of this 

paragraph) shall include statements 

regarding each clinical investigation involving human subjects that it 

either was conducted in compliance ~ith the requirements for fustitutional review set forth in·part 56 of this 

chapter or was not subject to such requirements in accordance with 

§ 56.2<c> of this chapter. 

c.By revising § 601.30 to read as follows: 

§ 601.30 Licenses required; products for 

controlled investigation only. 

Any biological or trivalent organic arsenical manufactured in any foreign 

country and intended for sale, barter. 

or exchange shall be refused entry by 

collectors of custoDIS unless manufactured in an establishment holding an 

unsupended and unrevoked establishment and product license. Unlicensed 

products which are not imported for 

sale, barter, or exchange and which 

are intended solely for purposes . of 

controlled investigation involving human subjects are admissible only if 

the investigation is conducted in accordance with section 505 of the Federal Food, Drug, and Cosmetic Act, as 

amended, and, if subject to them, in 

compliance with the requirements for 

institutional review set forth in part 56 of this chapter. 

PART 630--ADDmONAL STANDARDS FOR 

VIRAL VACCINES 

14. Part 630 is amended: 

By revising the first sentence of 

§ 630.11 to read as follows: 

§ 630.11 Clinical trials to qualify for license. 

To qualify for license, the antigenicity of the vaccine shall have been d_etermlned by clinical trials of adequate 

statistical design conducted in compliance with part 56 of this chapter. 

unless exempted under§ 56.2. * * • 

b. By revising the first sentence of 

§ 630.31 to read a.s follows: 

§ 630.31 Clinical trials to qualify for li­ cense. 

To qualliy for license, the antigenicity of the vaccine shall have been determined by clinical trials of adequate statistical design conducted in compliance ~ith part 56 of this chapter. unless exempted under § 56.2 of this 

chapter, by subcutaneous administration of the product. • * * 

c. By revising § 630.51 to read as follows: 

§ 630.51 Clinical trials to qualify for li­ cense. 

To qualify for license, the antigenicity of Mumps Virus Vaccine. Live, 

FEDERAL REGISTER, VOL 43, NO 153-TUESDAY, AUGUST 8, 1978 
• • • • • 

35208 PROPOSED RULES 

shall be determined by clinical trials 

conducted in compliance with part 56 

of this chapter, unless § 56.2 of this 

chapter, that follow the procedures 

prescribed in exempted under §630.31 

except that the immunogenic effect 

shall be demonstrated by establishing 

that a protective antibody response 

has occurred in at least 90 percent of 

each of the five groups of mumps-sus­ ceptible individuals, each having received the parenteral adniinistration 

of a virus vaccine dose which is not 

greater than that which was demonstrated to be safe in field studies 

<§ 630.50(b)) when used -under comparable conditions. 

d. By revising § 630.61 to read as follows: 

§ 630.61 Clinical trials to qualify for license. 

To qualify for license, the antigeni­ city of Rubella Virus Vaccine, Live, 

shall be determined by clinical trials 

conducted in compliance with part 56 

of this chapter, unless exempted under §56.2 of this chapter, that 

follow the procedures prescribed in 

§630.31 except that the immunogenic effect shall be demonstrated by establishing that a protective antibody response has occurred in at least 90 percent of each of the five groups of rubella susceptible individuals, each 

having received the parenteral administration of a virus vaccine dose which 

is not greater than that which was 

demonstrated to be safe in field studies when used under comparable conditions. 

e. By revising the first sentence of 

§630.81 to read as follows: 

§ 630.81 Clinical trials to qualify for li­ cense. 

In addition to demonstrating that 

the measles component meets the requirements of § 630.31, the measles 

and smallpox antigenicity of the final 

product shall be determined by clinical 

trials of adequate statistical design conducted in compliance with part 56 

of this chapter, unless exempted under § 56.2 of this chapter, and_with 

three consecutive lots of final vaccine 

manufactured by the sanie methods 

and administered as recommended by 

the manufacturer. • * * 

PART 1003-NOTIFICATION OF DEFECTS OR 


FAILURE TO COMPLY 


15. In § 1003.31 by revising para­ graph (b) to rea·d a.S follows: 

§ 1003.31 Granting the exemption. 

(b) Such views and evidence shall be 

confined to matters relevant to whether the defect in the product or its failure to comply with an applicable Federal standard is such as to create a sig­ nificant risk of injury, including genetic injury, to any person and shall be 

presented in writing unless the Secretary determines that an oral presenta­ tion is desirable. Where such evidence 

includes clinical investigations involving human subjects, the data submitted shall include, with respect to each 

clinical investigation, either a statement that each investigation was conducted in compliance with the requirements set forth in part 56 of this chapter; or a statement that the investigation is not subject to such requirements in accordance with § 56.2<c> of 

this chapter. 

SUBCHAPTER I-RADIOLOGICAL HEALTH 

PART 1010-PERFORMANCE STANDARDS FOR 

ELECTRONIC PRODUCTS: GENERAL 

16. Part 1010 is amended: 

a. By amending § 1010.4 by adding 

paragraph <b><1><xi> to read as follows: 

1010.4 Variances. 

• * * * * 

(b) • * * 

(1) * *. 

<xi> If the electronic product is used 

in a clinical investigation involving human subjects and subject to the requirements for institutional review set 

forth in part 56 of this chapter, the investigation shall be conducted in compliance with such requirements. 

• • * • • 

b. In § 1010.5 by revising paragraph 

<c><l2) to read as follows: 

§ 1010.5 Exemptions for products Intended 

for United States Government use. 

* • • • 

(C)*** 

(12> Such other information required by regulation or by the Direc· 

tor, Bureau of Radiological Health, to 

evaluate and act on the appltcatlon. Where such information includes clini· 

cal investigations involving human 

subjects, the information shall in· 

elude, with respect to each clinical in· 

vestigation, either a statement that 

each investigation was conducted in 

compliance with the requirements set 

forth in part 56 of this chapter: or a 

statement that the investigation is not 

subject to such requirements in ac· 

cordance with § 56.2(c) of this chapter. 

Interested persons may, on or before 

December 6, 1978, submit to the Hear· 

ing Clerk (HFA-305), Food and Drug 

Administration, Room 4-65, 5600 Fish· 

ers Lane, Rockville, Md. 20857, written 

comments regarding this proposal. 

Four copies of all comments shall be 

submitted, except that individuals 

may submit single copies of comments, 

and shall be identified with the Hear· 

ing Clerk docket number found in the 

heading of this document. Recevied 

comments may be seen in the above 

office between the hours of 9 a.m. and 

4 p.m., Monday through Friday. 

NoTE.-The Food and Drug Admlnlstra· 

tlon has determined that this document 

does not contain a major proposal requiring preparation of an economic Impact statl"• 

ment under Executive Order 11821 (M 

amended by Executive Order 11049) and 

OMB Circular A-107. A copy of the econom· ic impact assessment Is on file with tlie 

Hearing Clerk, Food and Drug Admlnlstra• 

tion. 

Dated: August 1, 1978. 

DONALD KENNEDY, 

Commissioner ofFood and Drugs. 

[F'R Doc. 78-21780 Filed 8-7-78: 8:45 aml 

FEDERAL REGISTER, VOL 43, NO 153-TUESDAY, AUGUST 8, 1978