United States General Accounting Office

GAO Report to the Ranking Minority Member,

Committee on Governmental Affairs,

U.S. Senate

March 1996 SCIENTIFIC

RESEARCH

Continued Vigilance

Critical to Protecting

Human Subjects

G O A

years

1921 - 1996

GAO/HEHS-96-72

GAO United States

General Accounting Office

Washington, D.C. 20548

Health, Education, and

Human Services Division

B-259279 

March 8, 1996

The Honorable John Glenn

Ranking Minority Member

Committee on Governmental Affairs

United States Senate

Dear Senator Glenn:

The 40-year Tuskegee study in which treatment was withheld from black

men with syphilis, the injection of live cancer cells into elderly patients in

the 1960s, and the recent disclosure of unethical Cold War-era radiation

experiments1

 have demonstrated breakdowns in the protection of human

subjects in scientific experiments sponsored by the federal government

and others. Much of the concern focuses on whether participants in these

experiments knew and understood what they would be subjected to and

had an adequate opportunity to decline to participate. These and other

issues related to protecting human research subjects were recently

addressed by the President’s Advisory Committee on Human Radiation

Experiments.2

Since the 1960s, significant advances in protecting the rights and interests

of human subjects in biomedical and behavioral research have occurred.

The federal presence has grown in this area, establishing and reinforcing

ethical practices for protecting human subjects in federally funded and

federally regulated research. The Department of Health and Human

Services (HHS) is the primary federal department sponsoring biomedical

and behavioral research. Its regulatory apparatus for overseeing such

research, which has evolved over the past three decades, consists of two

principal tiers of review: one at the research institution level and the other

at the federal level. Both tiers are responsible for ensuring that individual

researchers and their research institutions comply with federal laws and

regulations for protecting human subjects.

Despite the presence of institutional and federal oversight, abuses still

occur, as evidenced by the recent infringement of patients’ rights in breast

cancer research. Concerned about the adequacy of current oversight, you

asked us to determine (1) whether federal oversight procedures have

1

We have testified previously on this issue: see Human Experimentation: An Overview on Cold War Era

Programs (GAO/T-NSIAD-94-266, Sept. 28, 1994) and Health and Safety: Status of Federal Efforts to

Disclose Cold War Radiation Experiments Involving Humans (GAO/T-RCED-95-40, Dec. 1, 1994).

2

Advisory Committee on Human Radiation Experiments, Final Report, Washington, D.C.: Oct. 1995.

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reduced the likelihood of abuses of human subjects and (2) whether

weaknesses exist that could limit the effectiveness of the current oversight

apparatus.

Because of HHS’ annual $5 billion investment through about 16,000 awards

involving human subjects and its lead role in setting, monitoring, and

enforcing subject protections, we reviewed HHS’ oversight system. Within

HHS, we concentrated our review on the Office for Protection from

Research Risks (OPRR) and the Food and Drug Administration’s (FDA)

Center for Drug Evaluation and Research (CDER). We interviewed federal

and research institution officials; reviewed HHS and FDA regulations,

procedures, and records; examined institutional procedures, guidelines,

and records; and interviewed scientific researchers, as well as experts in

human subject protection, from universities, medical centers, and

subjects’ rights groups. These researchers and experts included

representatives drawn from the fields of bioethics, law, medicine, and

social science. We also interviewed representatives of the drug industry.

We performed our work from September 1994 to December 1995 in

accordance with generally accepted government auditing standards. See

appendix I for a detailed discussion of our scope and methodology.

Results in Brief Today’s oversight of tens of thousands of HHS-funded research and

FDA-regulated drug studies appears to have reduced the likelihood that

serious abuses of human subjects, comparable to past tragic events, will

occur. The conspicuous activity of local institutional review boards and

human subject protection efforts by federal agencies have heightened the

research community’s awareness of ethical conduct standards, increased

compliance with federal regulations, and served as deterrents to abuse of

subjects’ rights and welfare. However, little data exist that directly

measure the effectiveness of human subject protection regulations.

No practical level of oversight can guarantee that each researcher will

protect subjects with complete integrity. The detection of instances of

potential or actual harm to subjects both demonstrates that abuses can

occur and suggests that the current oversight activities are working. The

government and the research community, whose ultimate goal is the

advancement of scientific knowledge, struggle to balance two sometimes

competing objectives—the need to protect research subjects from

avoidable harm and the desire to minimize regulatory burden on research

institutions and their individual scientists. Various time, resource, and

other pressures, however, have reduced or threaten to reduce the

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effectiveness of local review board and federal agency oversight. In this

context, the need for continued vigilance over human subject research

should remain a priority for the research community and agencies charged

with oversight.

Background From 1962 through 1991, HHS’ system for protecting human research

subjects was created, piece by piece, largely in response to disclosures of

dangerous or controversial biomedical and behavioral research. (See app.

II for more historical information.) The tragic consequences of

thalidomide use in the United States3

 and revelation of the Tuskegee

syphilis study shocked the public and convinced national policymakers

that unregulated biomedical research represented a clear threat to

research subjects. Two expressions of this concern were the passage of

the National Research Act and the promulgation of human subject

protection regulations by the Department of Health, Education, and

Welfare (HEW)4

 in 1974. The act also established the National Commission

for the Protection of Human Subjects of Biomedical and Behavioral

Research to guide federal human subject protection policy.5

 When the core

of the human subject protection regulations was adopted by 15 other

departments and agencies in 1991, it became known as the Common Rule.6

3

Thalidomide is a sedative that was approved for use in Europe in the late 1950s and was widely used

by pregnant women at risk of premature delivery and miscarriage. Although not dangerous to the

mother, the drug caused severe birth defects. Although FDA had not approved the drug for use in the

United States, the manufacturer supplied the drug to U.S. physicians to establish its safety, as was the

common practice of that time. By 1962 it had become evident in Europe that thalidomide was harmful,

and the investigational studies were stopped in this country. In that same year, it was also revealed

that many of the patients participating in the U.S. clinical trials had not been informed that they were

part of an investigational study nor had many given their consent.

4

Now the Department of Health and Human Services.

5

Between 1974 and 1995, six blue-ribbon panels were established to address ethical issues in

biomedical and behavioral research: the National Commission for the Protection of Human Subjects of

Biomedical and Behavioral Research (1974-78), the HEW Ethics Advisory Board (1978-80), the

President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral

Research (1980-83), the Biomedical Ethics Advisory Committee (1985-89), and the Advisory Committee

on Human Radiation Experiments (1994-95). In addition, in October 1995, the President established the

National Bioethics Advisory Commission with a mandate to report on current human subject

protections.

6

Currently, 17 departments and agencies that conduct or support biomedical and behavioral research

involving human subjects have adopted regulations for protecting human research subjects. The first

15 to adopt the Common Rule, based on the core of HHS’ regulations, were the Departments of

Agriculture, Energy, Commerce, Housing and Urban Development, Justice, Defense, Education,

Veterans Affairs, and Transportation; the National Aeronautics and Space Administration; the

Consumer Product Safety Commission; the Agency for International Development; the Environmental

Protection Agency; the National Science Foundation; and the Central Intelligence Agency. In addition,

when the Social Security Administration became an independent agency in 1995, its enabling statute

bound it to follow HHS’ regulations.

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The Common Rule requires research institutions receiving federal support

and federal agencies conducting research to establish committees to

review research proposals for risk of harm to human subjects and to

perform other duties to protect human research subjects. It also stipulates

requirements related to informed consent—how researchers must inform

potential subjects of the risks to which they, as study participants, agree to

be exposed. (See fig. 1 for Basic Elements of Informed Consent.) HHS

regulations contain additional protections not included in the Common

Rule for research involving vulnerable populations—namely, pregnant

women, fetuses, subjects of in vitro fertilization research, prisoners, and

children. In the late 1970s and early 1980s, HHS considered but did not

adopt recommendations by two national commissions for specific

regulations to protect institutionalized mentally disabled subjects.

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Figure 1: Basic Elements of Informed

Consent

A statement stipulating that research is involved, what the

purpose of the research is, what the duration of the subject's

involvement will be, and what procedures the subject will

undergo.

A description of foreseeable risks or discomforts to the subject.

A description of expected benefits, if any, to the subject and

others.

The disclosure of alternative procedures or courses of

treatment.

A statement describing the extent to which confidentiality of

records identifying the subject will be maintained.

For research that poses more than minimal risk to subjects, an

explanation of the availability and nature of any compensation

or medical treatment if injury occurs.

Names of people to contact for further information about the

research, the subjects’ rights, and notification of researchrelated injury.

A statement stipulating that participation is voluntary and no

penalties will be imposed for refusal to participate in research;

subject can choose to discontinue participation at any time.

Within the HHS oversight system, OPRR and FDA are the key federal entities

overseeing compliance with informed consent and other human subject

protection regulations.7

 Both entities carry out oversight functions central

to the operation of the human subject protection system, including policy

setting, prevention, monitoring, and enforcement. Institutional review

boards (IRB)—that is, review panels that are usually associated with a

particular university or other research institution—are responsible for

7

FDA’s regulations covering human subject research are nearly identical to HHS’ human subject

protection regulations. One difference concerns the requirement for informed consent from patients

involved in emergency medical care research. FDA and OPRR are working to harmonize these rules.

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implementing federal human subject protection requirements for research

conducted at or supported by their institutions.

OPRR is located within the National Institutes of Health (NIH), the principal

federal agency responsible for supporting biomedical and behavioral

research. About one-half of OPRR’s 28 full-time employees are responsible

for overseeing protections in the approximately 16,000 HHS awards

involving human subjects. The other half are devoted to ensuring the

humane care and use of laboratory animals. Three physician volunteers

augment OPRR’s human subject protection staff. OPRR has an annual budget

of $1.9 million, about one-half of which is targeted to human subject

protection activities.

FDA is responsible for protecting the rights of human subjects enrolled in

research with products it regulates—drugs, medical devices, biologics,

foods, and cosmetics. Our review focused on oversight activities of FDA’s

Center for Drug Evaluation and Research, which carries out most of FDA’s

human subject protection activities.8

 At CDER, responsibility for human

subject protection activities is shared between the Office of Drug

Evaluation and the Division of Scientific Investigations. The Office of Drug

Evaluation reviews manufacturers’ and researchers’ requests to conduct

drug studies on human subjects. The Division of Scientific Investigations

reviews FDA’s field inspection reports on IRBs and investigators and makes

final determinations regarding compliance violations. Routine and

for-cause on-site inspections are conducted by field staff, who are also

responsible for examining the integrity of research data, assessing

compliance with good manufacturing practices, and examining other

issues related to FDA’s oversight of all its regulated products.

Within research institutions, oversight is done primarily by IRBs

responsible for examining research proposals and ongoing studies.9

 No

data exist on the exact number of IRBs in the country but estimates range

from 3,000 to 5,000. Most are found at universities, hospitals, and private

research facilities; a few are free standing. Human subject research

8

FDA’s Center for Biologics Evaluation and Research (CBER) and Center for Devices and Radiological

Health (CDRH) also carry out activities to protect human subjects of product testing. These activities

were not included in the scope of our review.

9

Additional reviews occur at local institutions. At some institutions, researchers are required to obtain

approval from departmental officials, and if necessary, from such issue-specific groups as the radiation

safety committee or the cancer research group. In addition, data and safety committees monitor

ongoing research for data indicating safety and efficacy. They can recommend modification to the

informed consent form or clinical trials. In addition, they can recommend stopping the study if

problems arise or if the therapeutic effect has been demonstrated. Private companies also audit drug

research that they sponsor.

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conducted by NIH itself, for example, is governed by the 14 IRBs of the NIH

Intramural Research Program.10 In general, IRBs are composed chiefly of

scientists at their respective institutions. They are required to have a

minimum of five members, at least one of whom is a scientist, one a

nonscientist, and one a person not otherwise affiliated with the research

institution. They are also required to have a diverse membership; in

determining membership, consideration must be given to race, gender, and

cultural background.

Preventive Efforts

Have Been Important

in Reducing

Likelihood of Abuses

The presence of local review bodies and federal oversight agencies

appears to have heightened the awareness and sensitivity of the research

community to the importance of respecting subjects’ rights and welfare.

Written commitments, which bind research institutions to comply with

human subject protection requirements, are an important element of the

protection system. By requiring individual researchers and IRBs to uphold

their institution’s commitments, the system works to prevent harm to

participants in most experimental studies. However, the effectiveness of

the HHS human subject protection regulations in ensuring compliance by

institutions and individual researchers has not been systematically

studied.

Assurances Commit

Institutions to Uphold

Human Subject Protection

Requirements

Research institutions must commit to uphold human subject protection

requirements before engaging in research with human subjects conducted

or funded by any of the departments or agencies that adopted the

Common Rule. To be eligible to receive such funding, an institution must

enter into a contract-like agreement, called an assurance. This is the

written promise of an institution housing research studies to comply with

federal ethical conduct standards. OPRR, the federal office within NIH that

approves assurances for research funded by HHS, requires assurances to

(1) include a statement of ethical conduct principles, (2) stipulate that a

review board has been designated to approve and periodically review the

institution’s studies, and (3) specify the review board’s membership,

responsibilities, and process for reviewing and approving proposals.

Assurances serve as one of the system’s chief preventive measures.

10In addition to IRB review, NIH requires panels of in-house experts and nongovernment scientists to

review research proposals’ protections for human subjects and scientific merit before funding

intramural and extramural research grant applications. The NIH Office of Intramural Research

supports research in NIH’s own laboratories, whereas the Office of Extramural Research supports

research of nonfederal scientists in universities, medical hospitals, and research institutions

throughout the United States and abroad.

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OPRR’s authority to require assurances derives from the 1974 National

Research Act, which formalized the practice of obtaining from institutions

receiving HHS funding written assurances of their commitment to the

ethical conduct of research. When the legislation was enacted, NIH had

already developed assurance-type documents with many universities,

which OPRR reviewed. Approving an assurance involves no site visits by

OPRR to the institution; rather, negotiations are handled through

correspondence and telephone calls with institution officials.

OPRR assurances are of several types. Multiple project assurances are

approved for universities and other major research centers that conduct a

substantial number of studies and have demonstrated a willingness and

the expertise to comply with human subject protection requirements.

Through a multiple project assurance, an institution does not need to

reapply through OPRR for eligibility to receive HHS funds for each new study

approved by its IRB. An assurance covers the institution’s human subject

studies for 3 years, at which time the institution must renew its

assurance.11 Renewals are for a 5-year period. As a practical matter,

multiple project assurances allow institutions to conduct research with no

further OPRR involvement until the assurance is up for renewal. As of

November 1995, 451 active OPRR multiple project assurances covered more

than 500 research institutions. These institutions receive most of HHS’

funding for research with human subjects. Primary responsibility for

negotiating all multiple project assurances in OPRR rests with a retired

physician who used to be employed for this purpose by OPRR. Since

retiring, she has continued this work on an unpaid, part-time basis.

Currently, the assurance branch chief is responsible for approving all

multiple project assurances OPRR negotiates.

At institutions without a multiple project assurance, an assurance

agreement must be negotiated with OPRR for each individual study. These

are called single project assurances and require OPRR to review, for each

study, documentation similar to that required for a multiple project

assurance. In addition, OPRR reviews the study’s informed consent form

before approving a single project assurance. As of November 1995, OPRR

had 3,063 active single project assurances. Primary oversight of these

assurances rests with three full-time staff in OPRR’s assurance branch.

A third type of assurance—the cooperative project assurance—recognizes

that research is frequently conducted at multiple sites under joint

11Almost all institutions holding multiple project assurances commit themselves to apply the terms of

the assurance to all their human subject studies, not just those funded by HHS.

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institutional sponsorship. One example is the National Surgical Adjuvant

Project for Breast and Bowel Cancers, sponsored by the National Cancer

Institute and conducted at over 300 sites. OPRR requires each participating

institution to have a cooperative project assurance for all its joint

research, regardless of other assurances held by the institution. For

projects conducted under cooperative project assurances, OPRR designates

reviewers to approve each research protocol and a prototype informed

consent form. IRBs at the participating institutions must also approve the

protocol and the informed consent document. IRBs can require additional

explanations to be included in the informed consent document. However,

they cannot modify the core elements of the protocol, which is to be

consistent across all sites. Nor can they delete or substantially modify the

discussion of risks and alternative treatments in the prototype consent

document without notice and justification. As of November 1995, OPRR had

1,333 active cooperative project assurances. Assurance branch staff

responsible for single project assurances also review cooperative

assurances with additional support provided by other OPRR staff and

others.

FDA Requires

Commitment to Human

Subject Protection

Standards

FDA also works to prevent the occurrence of human subject protection

violations in the drug research it regulates. Before permitting drug

research with human subjects, FDA requires researchers to submit a brief

statement that they will uphold ethical standards and identify the

institutional review board that will examine the study. Sponsors are

required to provide the results of chemical and animal studies with the

new drug, submit the proposed study procedures for using human

subjects, and commit to ensuring that a properly constituted IRB will

review the proposed study. FDA reviews this information to ensure the

study poses no unacceptable risks to subjects, is ethically sound, and is

likely to achieve the study objectives. FDA can request modifications to or

reject proposals deemed to present unacceptable risk. FDA’s prevention

efforts overlap OPRR’s if the drug study is supported by HHS funds.

Federal Entities’ Education

of Research Community Is

Another Preventive

Measure

Both OPRR and FDA educate the research community on issues related to

protecting human research subjects. Both respond directly to questions

from individual researchers, IRBs, and institutional officials. They

cosponsor about four human subject protection workshops annually

across the country that are attended on a voluntary basis by IRB members,

research institution officials, and researchers. OPRR also issues written

guidance that defines terms and clarifies ambiguities in human subject

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protection requirements. OPRR may provide additional information to

individual institutions during its negotiation of assurances. FDA also

provides guidelines on informed consent, research proposal review, and

recordkeeping to IRBs, research sponsors, and researchers.

IRBs Serve as Gatekeepers

in Approving Research

Federal officials and the research community alike commonly cite IRBs as

a key line of defense protecting patients and healthy volunteers

participating in research. Federal regulations authorize IRBs to approve,

approve with modification, or withhold approval from new research

projects. Researchers must get approval from the appropriate IRB

associated with their institution before beginning research with human

subjects.12 IRBs are required to review ongoing projects annually or more

often depending on the level of risk. HHS will not fund new human subject

research or authorize ongoing research to continue without the local IRB’s

approval.

Specifically, IRBs are required to ensure that, for each project reviewed,

risks are minimized and reasonable in relation to anticipated benefits,

subjects are properly informed and give consent to participate, and the

rights and welfare of subjects are maintained in other ways as well. IRBs

are required to include scientists and nonscientists as members. IRBs must

also consider gender, racial, and ethnic diversity in their membership

selection in order to be sensitive to a broad range of social as well as

scientific issues. IRB members are also expected to recognize that certain

research subjects—such as children, prisoners, the mentally disabled, and

individuals who are economically or educationally disadvantaged—are

likely to be vulnerable to coercion or undue influence. The local nature of

most IRBs enables members to be familiar with the research institution’s

resources and commitments, the investigators’ capabilities and

reputations, and the prevailing values and ethics of the community and

subject population.

In deciding whether to approve new research, IRBs are required to

determine that a study’s procedures are consistent with sound research

design and do not unnecessarily expose subjects to risk. In addition, IRBs

are required to examine the study investigators’ efforts to obtain subjects’

12Six categories of research are exempt from IRB review, such as many types of studies that evaluate

educational techniques. Federal regulations also allow for expedited review of research that presents

only minimal risk to subjects (i.e., no greater harm than encountered in daily life). The Secretary of

Health and Human Services has approved 10 categories of research that may be reviewed using

expedited review procedures. Voice recordings and collection of nail clippings, for example, are

considered minimal risk research. The IRB chair or a chair-appointed IRB member, rather than the full

board, conducts expedited reviews.

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consent, including examining the informed consent document when

applicable.13 They do this to ensure that the document specifies the

procedures the subject will undergo in language and terminology the

subject can understand, the risks to the subject, and alternative treatments

available and that the document makes explicit, among other things, the

right of individuals to decline to participate in the study or to withdraw at

any time.

IRB members told us that they spend most of their time reviewing the

informed consent document associated with a study. IRB reviews generally

do not involve direct observation of the research study or of the process in

which a subject’s consent is obtained, however. As a result, IRBs must rely

on investigators’ and consent monitors’ assessments of subjects’ reading

skills, fluency in English, and mental capacity. An IRB can authorize the use

of a consent monitor to observe the delivery of informed consent, for

example, when potential subjects might not have the mental capacity to

understand all aspects of the consent process.

IRBs are also required to review previously approved research periodically.

The purpose of these continuing reviews is for IRBs to keep abreast of a

study’s potential for harm and benefit to subjects so that IRBs can decide

whether the study should continue. Principal investigators must therefore

report the presence of adverse effects on study subjects, which allows the

IRB to assess whether the seriousness of risk has changed. IRBs should also

consider whether advances in knowledge or technology have occurred

that would require reconsidering the appropriateness of the study’s

purpose or protocol. In addition, they should review such details as

whether the number of subjects in the study corresponds to the number

initially approved.

Federal Monitoring

and Enforcement

Identify and Address

Human Subject

Protection Violations

No system of prevention is foolproof—indeed, FDA’s and OPRR’s monitoring

identifies abuses and other evidence of noncompliance. Federal

monitoring efforts for human subject protection violations include reviews

of study documentation, IRB operations, and allegations of misconduct.

Federal enforcement activities serve to stem further adverse

consequences. In fact, FDA officials, researchers, and drug industry

representatives we interviewed told us that the FDA’s oversight of drug

13IRBs may waive documentation of informed consent under certain circumstances. For example,

under HHS regulations, informed consent can be waived when the only record linking the subject and

the research would be the consent document and the principal risk would be potential harm resulting

from a breach of confidentiality. Informed consent can also be waived under HHS and FDA regulations

when the research presents no more than minimal risk of harm to subjects and involves no procedures

for which written consent is normally required outside of the research context.

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research motivates researchers and IRBs to follow proper human subject

protection procedures.

FDA Has a Variety of

Monitoring Activities and

Enforcement Options

FDA monitors drug research for compliance with human subject

protections. By conducting on-site inspections of IRBs, reviewing progress

reports from researchers and sponsoring drug companies, and making

on-site inspections of clinical studies and investigators, FDA becomes

aware of noncompliance with federal regulations. FDA officials told us that

most institutions and researchers respond quickly and positively to

inspection findings, and the presence of an FDA inspection process deters

human subject protection violations.

FDA’s inspection of IRBs is its primary monitoring tool for human subject

protection. FDA inspects IRBs to determine their adherence to federal

human subject protection requirements.14 FDA inspections of IRBs consist

primarily of an on-site examination of the IRBs’ minutes, written operating

procedures, and other documentation that substantiates initial and

continuing review and proper IRB membership. During these inspections,

FDA interviews the chair or the administrator of the IRB to learn details

about the IRB’s operation. FDA also determines whether consent forms

contain all required elements and are signed by subjects.

FDA has three levels of priority for inspecting the roughly 1,200 IRBs that

oversee drug research. FDA gives top priority to the reinspection of IRBs for

which it found serious deficiencies in the IRBs’ review of studies. FDA’s next

priority is examining IRBs that were unknown to FDA until identified by

researchers in their applications to begin drug studies with human

subjects. FDA’s lowest priority is the routine reinspection of IRBs. Between

fiscal years 1990 and 1995, CDER issued each year, on average, the results

of 158 inspections of IRBs overseeing drug research.15

14Because of the commonalities among IRB inspections performed for CDER, CBER, and CDRH, an

inspection conducted for one of FDA’s centers—for example, CDER—can serve to protect subjects in

studies regulated by CBER or CDRH. Furthermore, FDA’s IRB inspections enable it to monitor human

subject protection aspects of some of the ongoing and completed studies that were reviewed by the

IRB.

15In fiscal year 1995, FDA allocated about 13 full-time-equivalent positions in its field offices for the

on-site inspection of IRBs reviewing research on drugs, medical devices, and biologic products. At

CDER, FDA allocated about 6 full-time-equivalent positions to the Division of Scientific Investigations

for its oversight of IRB inspections. These positions are also responsible for inspections of Radioactive

Drug Research Committees, which are located at certain research institutions. FDA conducts about

five such inspections each year.

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Between January 1993 and November 1995, FDA issued 31 Warning Letters

to institutions regarding significant deficiencies in the performance of

their IRBs’ oversight of drug research.16 These Warning Letters imposed

sanctions—until CDER received adequate assurance that the IRB had taken

corrective action—on the IRBs’ ability to approve new studies, allow entry

of new subjects into ongoing studies, or both. Among the more serious

violations cited were the following: researchers participated as IRB

members in the review of their own studies; institutional officials falsely

claimed no trials had been conducted that would have required IRB review;

IRBs had no process to track ongoing studies; IRBs used expedited rather

than full review to approve major study changes; IRBs failed to correct

deficiencies noted during a previous FDA inspection; IRBs failed to ensure

that required elements of informed consent were contained in consent

documents; and IRBs allowed their members to vote by telephone instead

of convening the board.

FDA officials told us that FDA has never had to invoke its ultimate

sanction—disqualification—for seriously deficient IRBs. On about 60

occasions, institutions disbanded their IRBs upon FDA’s findings of serious

noncompliance. In most of these instances, the research projects approved

by the IRBs had already been completed.

FDA’s examination of individual drug studies is another component of its

human subject protection monitoring. Before a manufacturer can receive

FDA approval to market a drug, it must satisfy FDA that it has complied with

FDA’s human subject protection regulations during clinical trials. The

monitoring includes reviews of progress reports and on-site inspections.

Although FDA examines documentation on protection matters, its principal

focus in these efforts is to verify the accuracy and completeness of study

data as well as the researcher’s adherence to the approved protocol.

When researchers begin clinical trials, FDA’s Office of Drug Evaluation

requires them, through their sponsors, to submit annual progress reports

and also to report within 10 working days any serious and unexpected

adverse incidents involving subjects as well as major changes to the study

protocol. If these reports indicate potential or actual harm to subjects, FDA

can suspend or terminate the study.

16In January 1993, FDA instituted a new system with two categories of IRB noncompliance findings. In

the first category, FDA issues Warning Letters for the most serious problems. The second

category—voluntary action indicated—applies to less serious findings of IRB noncompliance. From

October 1993 to November 1995, FDA requested voluntary actions from about 200 IRBs for a variety of

reasons, such as failure to identify IRB members, failure of IRB minutes to identify controversial issues

discussed, and too little time spent reviewing studies.

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FDA’s on-site inspections of drug studies generally occur after clinical trials

have concluded. There are two types of inspections: routine and for-cause.

Routine inspections are conducted after a manufacturer has completed its

clinical trials and submits a new drug application (NDA) to FDA for approval

to market the product. During fiscal years 1990 through 1995, FDA issued

each year, on average, the results of about 265 routine inspections of drug

studies.17 The sites visited are typically university-based research facilities,

independent testing laboratories, and the offices of physicians

participating in drug trials.

Inspections of drug studies also include an assessment of how well

subjects were protected during the study: whether the consent document,

study protocol, and required revisions to them were reviewed and

approved by an IRB before enrolling subjects; whether signed consent

forms were obtained from each enrolled subject;18 whether adverse

incident and status reports were submitted to the IRB once research began;

and whether subjects were recruited properly. FDA inspectors look for

evidence that researchers reported all safety-related information to the

sponsor, reasons why subjects dropped out of the study, and other matters

related to the integrity of study data. In addition, FDA often interviews

researchers and sometimes interviews subjects.

While routine inspections generally occur after completion of clinical

trials, for-cause inspections can occur at any time during the course of

drug testing with humans. FDA conducts for-cause inspections when its

review of status reports submitted by researchers indicates possible

misconduct, or when it receives allegations of serious misconduct. FDA

conducts about a dozen for-cause inspections annually.

Most of the violations FDA identifies through its routine inspections of

individual drug studies are relatively minor. From 1977 to 1995, about

one-half of the violations related to the adequacy of the informed consent

forms. For example, FDA frequently found violations of the requirement to

specify in the informed consent document whom subjects can contact if

they have concerns about research, subjects’ rights, or research-related

injury.

17In fiscal year 1995, FDA allocated about 45 full-time-equivalent positions to its field staff for

inspecting studies of drugs, medical devices, and biologic products. In addition, FDA allocated about 9

full-time-equivalent positions to CDER’s Division of Scientific Investigations for inspecting drug

studies and investigators.

18Because FDA has had problems verifying that informed consent was obtained from a research

subject before participation in a study, it published a proposed rule in December 1995 that would

require dating the written consent form at the time consent was obtained.

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FDA also identified more serious violations in its routine and for-cause

inspections. We reviewed 69 of the 84 letters describing deficiencies that

FDA issued to drug researchers between April 1980 and November 1995.

These letters cited instances of serious misconduct, including failure to

obtain informed consent; forgery of subjects’ signatures on informed

consent forms; failure to inform patients that a drug was experimental;

fabrication of data to make subjects eligible for study; submission of false

electrocardiograms, X rays, and lab test results to the company

underwriting the research; failure to report subjects’ adverse reactions to

drugs under study, including a subject’s death; failure to obtain informed

consent and an IRB’s approval for a study touting a human growth hormone

as a cure for Alzheimer’s disease; proceeding with a cancer study after FDA

had suspended it for protocol deficiencies; and failure to inform patients

that a drug sold to them was experimental and contained a steroid.

Since 1980, FDA has taken 99 actions against 84 clinical investigators

regarding their conduct of drug research with human subjects. FDA has

used four types of actions to enforce its regulations: (1) obtaining a

promise from a researcher to abide by FDA requirements for conducting

drug research; (2) invoking a range of restrictions on a researcher’s use of

investigational drugs; (3) disqualifying a researcher from using

investigational drugs; and (4) criminally prosecuting a researcher.

OPRR Investigates

Allegations of

Noncompliance and

Requires Corrective Action

OPRR also responds to inquiries and investigates allegations, but few

investigations result in site visits; inquiries and investigations are largely

handled by telephone and correspondence. OPRR receives complaints

about human subject protection issues from a variety of sources, including

NIH inspection teams, FDA, subjects and their families, staff from research

institutions, news media, and the Congress. The majority of

noncompliance reports come from the institutions themselves, which are

required to report unanticipated problems, such as injuries and serious or

continuing noncompliance, to OPRR as part of the assurance agreement.

The number of compliance cases investigated by OPRR grew from 32 open

cases in January 1993 to 107 cases under investigation in June 1995. OPRR

officials and others attribute the increase to a heightened awareness of

human subject protection issues and more extensive media coverage of

untoward research events rather than to an increase in the actual

occurrence of noncompliance.

Over the past 5 years, OPRR’s compliance staff of four full-time employees

and two volunteers have investigated several studies for allegations

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involving serious human subject protection violations. One such example

was OPRR’s investigation of whether informed consent procedures clearly

identified the risk of death to volunteers in the tamoxifen breast cancer

prevention trial. OPRR found that informed consent documents at some

sites failed to identify some of tamoxifen’s potentially fatal risks, such as

uterine cancer, liver cancer, and embolism. In another instance, OPRR

compliance investigators found deficiencies in informed consent and in IRB

review procedures in a joint NIH-French study of subjects who had tested

positive for the human immunodeficiency virus (HIV) in Zaire. In a third

case, OPRR compliance staff investigated a study of schizophrenia at a

major university because of complaints from families of two subjects

associated with the study. In that investigation, OPRR found that the

informed consent documents failed to adequately describe the research

procedures, research risks, and alternative courses of treatment. In

addition, OPRR found that the researchers inappropriately obtained the

subjects’ oral consent rather than written consent as required by HHS

regulations. Among cases currently under investigation, OPRR is reviewing

allegations that researchers at a university-based fertility clinic transferred

eggs from unsuspecting donors to other women without the consent of the

donors.

Our review of OPRR files showed that OPRR found such deficiencies as the

failure of an IRB to give full review of projects at a convened meeting or to

adequately review ongoing research. OPRR also found IRB approval of

informed consent documents that did not clearly state the study’s purpose,

did not identify the study’s risks of the research, and did not present

information that would be understandable to the subjects.

In many cases, OPRR has required institutions to take corrective action. In

some instances, OPRR has suspended an institution’s authority to conduct

further research in a particular area until problems with its IRBs were

fixed. From 1990 to mid-1995, there were 17 instances in which OPRR

imposed some type of restriction on an institution’s authority to conduct

human subject research. For example, in some cases, OPRR suspended the

enrollment of new subjects; in others, OPRR excluded certain types of

research from coverage by multiple project assurances, thereby requiring

single project assurances and the direct involvement of OPRR in reviewing

each study’s informed consent forms and other documents. To document

corrective actions, institutions are generally required to submit quarterly

reports to OPRR. OPRR lifts a restriction when it is satisfied that the

institution has taken appropriate corrective actions—in most cases, after

receiving quarterly reports for about a year to 18 months.

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Multiple Factors

Weaken Institutional

and Federal Human

Subject Protection

Efforts

Oversight systems are by nature limited to minimizing, rather than fully

eliminating, the potential for mishap, and HHS’s system for protecting

human subjects is no exception. Various factors reduce or threaten to

reduce the system’s effectiveness. IRBs face the pressure of heavy

workloads and competing professional demands. OPRR is often remote

from the institutions it oversees. FDA’s processes, while including on-site

inspections, may permit human subject protection violations to go

undetected. Moreover, the complexity and volume of research under

review and the difficulty of ensuring that individuals truly understand the

risks they may experience as research subjects can weaken the

effectiveness of human subject protections.

Workload and Other

Demands Impair IRB

Oversight

Federal officials, experts, and research community members we

interviewed consistently mentioned several concerns about the operations

of IRBs. First, IRB reviews are labor intensive and time consuming, forcing

boards to balance the need to make reviews thorough against the need to

get them done. IRB members are usually physicians, scientists, university

professors, and hospital department heads who are not paid for their IRB

service. Board members themselves told us they face a heavy workload,

and others in the research community have raised concerns that heavy

workload impairs IRB review.

In some cases, the sheer number of studies necessitates that IRBs spend

only 1 or 2 minutes of review per study. FDA found one IRB that had

reviewed as many as 200 proposals and ongoing studies at a meeting.

Several experts told us of other instances in which IRBs had reviewed 100

to 150 studies in one meeting. In many such cases, one, two, or several

individuals—known as “primary reviewers”—may be assigned to examine

a study comprehensively in advance of the IRB meeting, often held

monthly. In these cases the other IRB members rely on the conclusions

drawn by the primary reviewers and may be less prepared to identify and

discuss potential problems with proposals. In addition, IRB members and

researchers told us that, given the time constraints, a good portion of the

meetings is devoted to assessing the adequacy of the consent forms at the

expense of reviewing research designs.

Second, federal officials and experts in IRB issues have been particularly

concerned with IRBs’ conduct of continuing reviews. They assert that these

reviews are typically either superficial or not done at all. According to

OPRR officials, IRBs have not always understood the requirements for

continuing review, and, in other cases, IRB workload demands have

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reduced the quality of this review.19 In some cases, IRB administrative staff

with no scientific expertise—not IRB members themselves—review

continuing review forms, ensuring only that the information has been

provided. Heavy workload also necessitates that IRBs rely largely on

investigators’ self-assessments in conducting continuing reviews. That is,

IRBs review statements completed by the study’s investigators and, with

rare exceptions, do not verify the accuracy of the reported information.

Although experts disagree on the desired level of IRB verification, its value

was demonstrated recently in a report by HHS’ Office of Inspector

General.20 The report cited one instance in which nine researchers failed

to notify their IRBs, as required, of major deviations from a study protocol.

In another instance, a surgeon reported to the IRB the implantation of an

experimental device in 37 subjects. The HHS review team found that this

surgeon and his coinvestigators had actually implanted the device in 258

subjects, thus far exceeding the limit of 75 subjects specified in the

research protocol and approved by the IRB. In cases such as these, the

possibility exists that a researcher could selectively report favorable

results.

Third, experts we interviewed raised concerns about the independence of

IRB reviews. For example, they told us that close collegial ties with

researchers at their institutions, pressures from institution officials to

attract and retain government or corporate research funding,21 financial

ties to the research study, and reluctance to criticize studies led by leading

scientists can compromise the independence of IRB reviews. Although

most experts we interviewed agreed that instances of these problems

occur, they did not have enough evidence to determine the frequency or

the extent of the problem.

Finally, some IRBs are viewed by their institutions and by researchers as a

low-priority administrative hurdle. As a result, these IRBs have difficulty

securing the administrative and computer support they require. For

example, OPRR has found instances of IRB staff working in office space

insufficient to conduct review board business effectively, manual filing

19The January 1995 issue of OPRR Reports addressed the subject of continuing review of

research—institutional and IRB responsibilities. OPRR periodically distributes OPRR Reports to about

5,500 institutions, IRB members, and others in the research community.

20Department of Health and Human Services, Office of Inspector General, Investigational Devices:

Four Case Studies (OEI-05-94-00100) (Washington, D.C.: HHS, Apr. 1995).

21IRB “shopping” has been cited as a threat to human subject protection. In several instances,

corporate sponsors shifted projects away from institutions where local reviewers raised concerns

about the sponsor’s study. See Sherertz, Robert J., and Stephen A. Streed, “Medical Devices: Significant

Risk vs. Nonsignificant Risk,” Journal of the American Medical Association, Vol. 272, No. 12, Sept. 28,

1994, pp. 955-956.

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systems too primitive to ensure that continuing reviews were conducted at

the required times, and lack of privacy for IRB staff to take the sensitive

telephone calls of subjects who may want to register complaints. At such

institutions, researchers may not always follow IRB requirements, such as

revising informed consent forms or reporting adverse events.

Various Factors May

Hamper OPRR Oversight

OPRR’s reliance on the assurance process for preventing the violation of

human subject protections requires that OPRR have sufficient basis for

judging an institution’s ability to satisfy human subject protection

requirements. At times, however, OPRR’s assurance negotiation process

falls short of that goal. OPRR staff are rarely direct observers of the

institutions they oversee. They make no site visits during assurance

negotiations, but instead review solely an institution’s written application

and conduct written or oral follow-up. Usually, document review does not

include an examination of the manuals that detail the human subject

protection procedures that the institution requires its IRBs and researchers

to follow. Similarly, almost all of OPRR’s compliance investigations—

reviews in response to allegations of misconduct—are carried out through

correspondence. In the 5 years preceding April 1995, OPRR made 15 site

visits as part of the 202 compliance investigations it completed.

What OPRR has found in its site visits made in the course of investigating

allegations of violations illustrates the value of such visits. For example,

when we accompanied OPRR on a compliance site visit to a major research

university, OPRR learned details about the institution’s IRB operations and

reporting chain idiosyncrasies that it was previously unaware of despite

having reviewed the institution’s assurance documents. This visit resulted

in the temporary suspension of the human subject research under the

surveillance of one of the university’s two IRBs.

OPRR officials told us that they lack the time and funds for more site visits

for assurance negotiations or compliance. They acknowledged, however,

that when they did make site visits, their investigations were significantly

enhanced by communicating face-to-face with officials, researchers, and

the administrative staff assigned to the institution’s IRB. On-site

investigations have also been more thorough and expeditious because

OPRR had ready access to study files and IRB records and could quickly

follow leads. Site visits also provided OPRR the opportunity to educate

institutional staff about ethical conduct practices by enabling OPRR staff to

be immediately available to discuss and answer questions about human

subject protection issues. Through these exchanges, OPRR staff learned

Page 19 GAO/HEHS-96-72 Protecting Human Research Subjects
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about problems, such as those with continuing review, that other

institutions could be experiencing. Experts we interviewed also said that

OPRR’s prevention efforts would be more effective if it were to make site

visits to institutions in the process of approving and renewing assurances.

In addition, NIH’s organizational structure may hamper OPRR’s independent

oversight and enforcement of human subject protection regulations,

although we found no specific instance in which this occurred. Although

OPRR is located within the Office of Extramural Research, OPRR is

responsible for enforcing compliance with human subject protection

regulations for research conducted or supported by both the Office of

Intramural Research and the Office of Extramural Research. Under this

structure, the OPRR Director reports to the Deputy Director for Extramural

Research, who, in turn, reports to the Director of NIH. Because the Deputy

Director for Intramural Research also reports to the Director of NIH, OPRR

has no direct authority over the research conducted by the intramural

program. As a result, when OPRR cited NIH’s Office of Intramural Research

in 1991 for compliance violations, for example, OPRR had to depend on that

office’s good will and professional conduct to implement the corrective

action plan proposed by OPRR, since OPRR did not have direct authority to

require NIH to correct violations. According to OPRR, NIH will complete

implementation of the plan by April 1996, 5 years after the problems were

noted.

From a broader organizational perspective, a potential weakness exists

because NIH is both the regulator of human subject protection issues as

well as an institution conducting its own human subject research. The

Director of NIH, therefore, has responsibility for both the success of NIH’s

intramural research program and for the enforcement of human subject

protection regulations by OPRR.

FDA Oversight Has Certain

Limitations

In some instances, FDA’s oversight efforts may permit violations of human

subject protections to go undetected. For example, researchers who use

human subjects in drug research are required to submit to their sponsor

periodic progress reports during the course of the trials. These reports

include adverse events, project status, and changes to the research

protocol. The sponsor, in turn, reports adverse events to FDA. The

reporting process, however, is a passive one in which FDA relies on

researchers and their sponsors to report potential or actual adverse

medical events during clinical trials. Violations of subjects’ rights, such as

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inadequate informed consent or IRB review, however, are not required to

be reported.

Two gaps in FDA’s inspection of drug studies have implications for human

subject protections. First, FDA only conducts routine on-site inspections

after clinical trials have concluded and subjects have completed their

participation. Second, FDA officials told us that because of resource

limitations, FDA does not inspect all studies; instead, it concentrates its

efforts on those products that both are likely to be approved for consumer

use and could pose high risk to consumers.22 FDA officials told us that the

primary reason for these inspections is to review the integrity of the

study’s data before initiating a review of the drug’s safety and

effectiveness. In essence, then, FDA’s inspection program is geared more

toward protecting the eventual consumer of the drug than the subjects on

whom the drug was tested.23

Gaps also exist in FDA’s inspection of IRBs. CDER annually issues the results

of about 158 inspections of the approximately 1,200 IRBs reviewing drug

studies, although its goal has been to complete and issue reports on about

250 inspections each year. We found that in one of FDA’s 21 districts—a

district that contains several major research centers conducting studies

with human subjects—12 IRBs had not been inspected for 10 or more years

on behalf of CDER, CBER, or CDRH. Furthermore, although FDA’s policy is to

accelerate the timetable for reinspecting IRBs found to have significant

problems, we noted instances in which FDA conducted its reinspection 3 to

5 years later. FDA officials told us that, because of resource constraints, IRB

inspections receive lower priority than inspections of FDA-regulated

products or manufacturing practices.

Finally, experts we interviewed raised concerns about the unevenness of

FDA inspectors’ expertise, which they believe could enable human subject

protection violations to go undetected. FDA officials acknowledge that

some inspectors may be inadequately prepared to understand the human

subject protection implications of drug studies and to ask meaningful

follow-up questions on the research protocols they review. FDA officials

22Studies for certain products, such as vitamins, antimicrobial handwashes, and saline solutions, are

not inspected by FDA because they pose low risk for consumers.

23FDA calls drug studies that are sponsored by pharmaceutical companies and are intended to lead to a

marketable product “commercial” studies. Commercial studies can involve thousands of subjects. In

contrast, “research” studies are typically sponsored by individual researchers, do not result in

commercial products, and usually involve a small number of subjects. FDA does not routinely inspect

research studies. FDA officials told us, however, that FDA inspects studies that are important to the

approval of all NDAs containing clinical data.

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also noted that some inspectors lack practical experience in reviewing

drug studies because they work in districts with few bioresearch sites and

therefore usually inspect other types of regulated products.

Other Pressures in the

Research Environment

May Weaken Oversight

Effectiveness

Several additional pressures make guaranteeing the protection of human

subjects difficult. Many of the experts we interviewed raised concerns

about the growing complexity of science, the increasing number of

multicenter trials, and the vulnerability of certain subject populations. The

extent of these problems, however, has not been studied.

First, the increasing complexity of research makes it difficult for IRBs to

assess human subject protection issues when members are not conversant

with the technical aspects of a proposed study. In such cases, the IRB’s

ability to assess the risks or benefits posed to subjects and the adequacy of

language found in the consent document is questionable. In addition,

cutting edge science can present new ethical dilemmas for IRBs to

confront. Experimental human reproductive techniques and ownership of

genetic material, for example, have raised ethical questions that thus far

have not been satisfactorily resolved.

Second, the growing number of large-scale trials carried out at multiple

research sites presents other problems for IRBs, both at initial and

continuing review. Proposals for multicenter trials are reviewed by an IRB

associated with each local research site. If most involved IRBs have

approved a proposed study—that is, determined that the study is safe,

ethical, and appropriately described in consent forms—then remaining

IRBs at other institutions may feel pressured to mute their concerns about

the study. Furthermore, during the course of a multicenter trial, each

participating IRB receives numerous reports of adverse events from other

research sites. Because of the volume of reports, IRB members may have

difficulty discerning which adverse events are both relevant and serious

enough to warrant their taking note of them.

Third, IRBs and researchers may not always be sensitive to subjects who

have a stake in believing that research is at worst benign and at best

beneficial. For many seriously ill individuals—such as HIV patients, for

example—experimental therapies represent the best source of hope. Such

subjects often equate experimental and proven therapies, leading some of

them to question the need for protections that appear only to restrict their

access to therapy. The Advisory Committee on Human Radiation

Experiments notes that

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“...patient-subjects who have serious illnesses may have unrealistic expectations both

about the possibility that they will personally benefit by being a research subject and about

the discomforts and hardships that sometimes accompany research.”24

Volunteers who want to be included in biomedical or behavioral studies

because they believe in the advancement of science or because

researchers offer financial incentives are another group whose personal

stake in the research may go unnoticed by IRBs and researchers, thereby

weakening oversight.

Fourth, an inherent conflict of interest exists when physician-researchers

include their patients in research protocols. If the physicians do not

clearly distinguish between research and treatment in their attempt to

inform subjects, the possible benefits of a study can be overemphasized

and the risks minimized.

Fifth, pressures to recruit subjects can lead researchers and IRBs to

overlook deficiencies in efforts to inform subjects of potential risks. This

problem has been exacerbated, a consultant to IRBs told us, by NIH and FDA

guidelines that now require that subjects selected for the studies over

which the agencies have jurisdiction reflect the gender and racial

composition of potentially affected populations. These guidelines are in

place for the purpose of generalizing research results to the widest

possible range of population groups.

Finally, the line between research and medical treatment is not always

clear to clinicians. Controversy exists regarding whether certain medical

procedures should be categorized as research. For example, in some cases

physicians may use an innovative but unproven technique to treat patients

without considering the procedure to be research. From the standpoint of

the physicians, they are providing treatment to individual patients rather

than conducting a clinical trial. Given this view, they do not seek IRB

approval. From the standpoint of experts we interviewed, however, such

treatments could constitute unregulated research and place people at risk

of harm from unproven techniques.

Conclusions With the issuance of federal regulations covering much human subject

research and the maturation of the HHS oversight system, researchers have

become more aware of ethical conduct standards and more often comply

with them. Because no oversight system can be designed to guarantee

24Advisory Committee on Human Radiation Experiments, Final Report, p. 798.

Page 23 GAO/HEHS-96-72 Protecting Human Research Subjects
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complete protection for each individual, holes inevitably exist in the

regulatory net. Federal and IRB reviewers rarely observe the interaction

between researchers and subjects during the informed consent process or

throughout the course of the study. Whether research institutions are

examined by OPRR for eligibility to receive HHS funding, research studies

are assessed by IRBs for their compliance with HHS regulations, or

applications to conduct drug trials are reviewed by FDA, oversight is

present, but at a distance.

There is consensus among experts and regulators about the benefits of

first-hand review, but continuous on-site inspections of every research

institution and its studies are neither feasible nor desirable because of the

regulatory burden this would impose on both the research community and

regulators. Finding the balance, however, between that extreme and a

process that relies almost exclusively on paper reviews is the fundamental

challenge facing regulators and IRBs in the current HHS oversight system.

Individuals participating in biomedical and behavioral research are

essential to the advancement of science and medicine. Federal regulators

and research institutions, therefore, continually strive to improve the

protection of human participants without imposing an unwieldy,

burdensome regulatory apparatus. To continue to prevent the occurrence

of human subject protection violations and to identify and correct

violations that do occur remain essential objectives of the system. Given

the many pressures that can weaken the effectiveness of the protection

system, continued vigilance is critical to ensuring that subjects are

protected from harm.

Agency Comments NIH and FDA reviewed a draft of this report and provided comments, which

are reproduced in appendixes III and IV. NIH and FDA found the report to be

generally accurate and suggested revisions to clarify specific aspects of

our discussion of the human subject protection system. We incorporated

these as appropriate, basing the changes in some instances on further

discussions with officials from each agency.

In its comments, NIH recognized the importance of on-site visits to

research institutions by OPRR staff and noted that the number of technical

assistance visits would be increased to 12 to 24 per year. This action

should help strengthen human subject protection efforts by institutions

and investigators as well as improve OPRR’s assurance, monitoring, and

enforcement efforts.

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In its comments, NIH also stated that OPRR’s independent oversight and

authority to enforce human subject protection regulations within NIH are

not compromised by OPRR’s location within the NIH organizational

structure. NIH said that the lines of authority of the NIH Deputy Director for

Intramural Research and the OPRR Director do not cross within NIH and,

therefore, that OPRR’s authority is not compromised. We disagree with NIH’s

conclusion and believe that a potential weakness exists in OPRR’s ability to

enforce human subject protection regulations within NIH. This weakness

results from the chain of command within NIH and the NIH Director’s dual

responsibilities for the success of the intramural research program and

OPRR’s enforcement of human subject protection regulations. We have

amplified our discussion of these issues in the report.

In its comments on our draft report, FDA raised concerns that our work

understates FDA’s accomplishments and the efforts to protect human

subjects of product testing by the industries regulated by FDA. Because

human subject protection activities in drug research account for most of

FDA’s efforts in this area, we limited the scope of our work to an

examination of CDER’s oversight. We have modified the report to

acknowledge the human subject protection activities of the Center for

Biologics Evaluation and Research and the Center for Devices and

Radiological Health. Furthermore, we have clarified that the inspection

reports and actions to enforce regulations we discuss are for CDER’s

oversight of IRBs and drug studies, and we have included additional

information FDA provided on fiscal year 1995 activities.

FDA also focused on our presentation of aspects of its IRB inspection

programs. FDA commented that (1) the IRB inspection program is the

principal way in which FDA addresses the issue of human subject

protection, (2) IRB inspections can enhance protection for subjects in

specific studies, and (3) an IRB inspection conducted for one center—for

example, CDER—can serve to protect subjects in studies regulated by CBER

and CDRH. We have modified the report to address these points.

As agreed with your office, unless you publicly announce its contents

earlier, we plan no further distribution of this report until 7 days from the

date of this letter. At that time, we will send copies of this report to the

Secretary of HHS, the Director of NIH, the Commissioner of FDA, and other

interested parties.

Page 25 GAO/HEHS-96-72 Protecting Human Research Subjects
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This report was prepared under the direction of Mark V. Nadel, Associate

Director for National and Public Health Issues. If you or your staff have

any questions, please call me at (202) 512-7119 or Bruce D. Layton,

Assistant Director, at (202) 512-6837. Other major contributors to this

report include Frederick K. Caison, Linda S. Lootens, and Hannah F. Fein.

Sincerely yours,

Sarah F. Jaggar

Director, Health Financing and

 Public Health Issues

Page 26 GAO/HEHS-96-72 Protecting Human Research Subjects
Page 27 GAO/HEHS-96-72 Protecting Human Research Subjects
Contents

Letter 1

Appendix I 

Scope and

Methodology

30

Appendix II 

Landmark Events

Affecting the

Development of HHS’

Human Subject

Protection System

32

Appendix III 

Comments From the

National Institutes of

Health

33

Appendix IV 

Comments From the

Food and Drug

Administration

39

Figure Figure 1: Basic Elements of Informed Consent 5

Page 28 GAO/HEHS-96-72 Protecting Human Research Subjects
Contents

Abbreviations

CBER Center for Biologics Evaluation and Research

CDER Center for Drug Evaluation and Research

CDRH Center for Devices and Radiological Health

FDA Food and Drug Administration

HEW Department of Health, Education, and Welfare

HIV human immunodeficiency virus

HHS Department of Health and Human Services

IRB institutional review board

NDA new drug application

NIH National Institutes of Health

OPRR Office for Protection from Research Risks

Page 29 GAO/HEHS-96-72 Protecting Human Research Subjects
Appendix I 

Scope and Methodology

We focused our work on the Department of Health and Human Services

(HHS)—the federal department sponsoring biomedical and behavioral

research with the largest human subject research budget, over $5 billion in

fiscal year 1995. Within HHS, we examined the policy and oversight roles of

the two entities with primary responsibility for protecting human research

subjects: the National Institutes of Health’s (NIH) Office for Protection

from Research Risks (OPRR) and the Food and Drug Administration (FDA).

OPRR is responsible for enforcing compliance with HHS human subject

protection regulations when human subject research is conducted or

supported by HHS. FDA is responsible for protecting the rights of human

subjects enrolled in research with products it regulates—drugs, medical

devices, and biologics. We limited our review to FDA’s Center for Drug

Evaluation and Research (CDER) because drug research is the largest

segment of biomedical research. Because of this volume, FDA conducts

more oversight activities in the drug products area than it does for medical

devices and biological products, with CDER carrying out most of FDA’s

human subject protection activities. Although FDA’s Center for Biologics

Evaluation and Research and Center for Devices and Radiological Health

also have programs to protect human subjects, these Centers were not

included in our review.

To gather information about the federal role in protecting human subjects,

we interviewed NIH, OPRR, and FDA officials and reviewed regulations,

policies, procedures, guidelines, and educational materials the entities

provide to institutional review boards (IRB) and researchers. To learn

about the nature of OPRR findings and corrective actions, we reviewed 40

of the 166 compliance case files handled by OPRR from 1988 through March

1995, including 30 files we randomly selected and 10 files OPRR officials

selected as representing the most serious violations. We accompanied

OPRR staff on a compliance site visit to a major research institution and

reviewed OPRR site visit reports from compliance visits conducted from

September 1990 through December 1994. We also reviewed examples of

inspection files, 69 of the 84 letters describing deficiencies that FDA issued

to drug researchers from April 1980 through November 1995, and all 31

Warning Letters issued to IRBs regarding their oversight of drug research

between January 1993 and November 1995. In addition, we reviewed

correspondence between FDA and institutions in cases where FDA

inspections found that IRBs did not comply with human subject protection

regulations.

To examine how local level protections work, we reviewed the

professional literature, including the reports of presidential and

Page 30 GAO/HEHS-96-72 Protecting Human Research Subjects
Appendix I 

Scope and Methodology

congressional commissions; interviewed research institution officials, IRB

members, and researchers; and reviewed research documents, such as

institutional guidelines for IRBs and researchers, IRB minutes, and informed

consent forms. We attended an IRB meeting to observe an IRB review of

proposed research. We interviewed numerous experts from across the

nation with experience in bioethics, medicine, social science, law, and

human subject protection issues. These experts included university and

hospital researchers, subjects’ rights advocates, IRB members, human

subject protection consultants, and representatives from the drug industry.

We performed our field work from September 1994 to December 1995 in

accordance with generally accepted government auditing standards.

Page 31 GAO/HEHS-96-72 Protecting Human Research Subjects
Appendix II 

Landmark Events Affecting the

Development of HHS’ Human Subject

Protection System

HHS and FDA human subject

protection regulations made

substantially identical.

HHS adopts regulations for

research involving children.

HHS adopts

regulations for

research

involving

fetuses,

pregnant

women,

human in vitro

fertilization,

and prisoners.

1961

1962

1963

1964

1965

1966

1967

1968

1969

1970

1971

1972

1973

1974

1975

1976

1977

1978

1979

1980

1981

1982

1983

1984

1985

1986

1987

1988

1989

1990

1991

1992

1993

1994

1995

In reaction to

thalidomide tragedy, the

Drug Amendments of

1962 (P.L.87-781) are

enacted—first federal

statute that requires

consent of research

subjects.

Congress enacts National

Research Act (P.L. 93-348)

requiring written assurances

from research institutions and

IRB review.

National Commission

established by Congress to

make recommendations on

bioethical issues.

HEW issues first federal human

subject protection regulations.

Fifteen other federal

agencies adopt regulations

based on the core of the

HHS regulations, known as

the Common Rule.

Presidential Advisory Committee on

Human Radiation Experiments

formed to investigate Cold War

radiation experiments.

President orders creation of National

Bioethics Advisory Commission.

Previously classified Cold Warera human radiation

experiments revealed.

Advisory Committee on Human Radiation

Experiments reports deficiencies in current

human protection system and recommends

specific improvements.

NIH institutes require

awardees to provide

statement of

responsibilities for

conduct of hazardous

research.

Surgeon General issues

subject protection policy

for all Public Health

Service-supported

research.

Unsuspecting patients given investigational drug

thalidomide, causing severe birth defects in children.

Study commissioned by NIH finds that few research

institutions have effective subject protections.

Publication of social

psychological study of

obedience to authority in

which subjects believed

they were administering

electric shocks to others

raises questions about

deception and consent in

behavioral research.

Injection of live

cancer cells into

elderly patients at

Jewish Chronic

Disease Hospital

revealed.

Human radiation experiments at

University of Cincinnati in which

adequacy of informed consent

is questioned.

Public Health Service concedes

that in a 40-year study in

Tuskegee, Alabama, treatment

was withheld from black men

with syphilis.

EVENT FEDERAL ACTION

Page 32 GAO/HEHS-96-72 Protecting Human Research Subjects
Appendix III 

Comments From the National Institutes of

Health

Page 33 GAO/HEHS-96-72 Protecting Human Research Subjects
Appendix III 

Comments From the National Institutes of

Health

Page 34 GAO/HEHS-96-72 Protecting Human Research Subjects
Appendix III 

Comments From the National Institutes of

Health

Now on p. 2.

Now on p. 2.

Now on p. 3.

Now on p. 3.

Now on p. 3.

Now on p. 3, footnote 5.

Now on p. 3, footnote 5.

Now on p. 4.

Now on p. 6.

Now on p. 5, footnote 7.

Page 35 GAO/HEHS-96-72 Protecting Human Research Subjects
Appendix III 

Comments From the National Institutes of

Health

Now on p. 5, footnote 7.

Now on pp. 6-7.

Now on p. 7.

Now on p. 8.

Now on p. 8.

Page 36 GAO/HEHS-96-72 Protecting Human Research Subjects
Appendix III 

Comments From the National Institutes of

Health

Now on p. 8.

Now on p. 8, footnote 11.

Now on p. 9.

Now on p. 9.

Now on p. 10, footnote 12.

Now on p. 10, footnote 12.

Now on p. 10, footnote 12.

Now on p. 11.

Now on p. 11.

Now on p. 11.

Now on p. 11.

Now on p. 11.

Page 37 GAO/HEHS-96-72 Protecting Human Research Subjects
Appendix III 

Comments From the National Institutes of

Health

Now on p. 15.

Now on p. 15.

Now on p. 17.

Now on p. 19.

Now on p. 30.

Now on p. 30.

Now on p. 3, footnote 6.

Now on p. 3, footnote 6.

Now on p. 3, footnote 6.

Now on p. 32.

Now on p. 32.

Now on p. 32.

Now on p. 32.

Now on p. 32.

Page 38 GAO/HEHS-96-72 Protecting Human Research Subjects
Appendix IV 

Comments From the Food and Drug

Administration

Page 39 GAO/HEHS-96-72 Protecting Human Research Subjects
Appendix IV 

Comments From the Food and Drug

Administration

Page 40 GAO/HEHS-96-72 Protecting Human Research Subjects
Appendix IV 

Comments From the Food and Drug

Administration

Throughout the report.

Now on p. 1.

Now on p. 5.

Now on p. 5.

Page 41 GAO/HEHS-96-72 Protecting Human Research Subjects
Appendix IV 

Comments From the Food and Drug

Administration

Now on p. 5, footnote 7.

Page 42 GAO/HEHS-96-72 Protecting Human Research Subjects
Appendix IV 

Comments From the Food and Drug

Administration

Now on p. 6.

Now on p. 9.

Now on p. 11, footnote 13.

Now on p. 12.

Page 43 GAO/HEHS-96-72 Protecting Human Research Subjects
Appendix IV 

Comments From the Food and Drug

Administration

Now on p. 14, footnote 18.

Now on p. 12.

Now on p. 13.

Page 44 GAO/HEHS-96-72 Protecting Human Research Subjects
Appendix IV 

Comments From the Food and Drug

Administration

Now on p. 13.

Now on p. 15.

Page 45 GAO/HEHS-96-72 Protecting Human Research Subjects
Appendix IV 

Comments From the Food and Drug

Administration

Now on p. 20.

Now on p. 21, footnote 23.

Now on p. 30.

(108207) Page 46 GAO/HEHS-96-72 Protecting Human Research Subjects
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