United States General Accounting Office

GAO Testimony

Before the Committee on Governmental Affairs

U.S. Senate

For Release on Delivery

Expected at 9:00 a.m.

Tuesday, March 12, 1996

SCIENTIFIC RESEARCH

Continued Vigilance Critical

to Protecting Human

Subjects

Statement of Sarah F. Jaggar, Director

Health Financing and Public Health Issues

Health, Education, and Human Services Division

G O A

years

1921 - 1996

GAO/T-HEHS-96-102

Mr. Chairman and Members of the Committee:

I am pleased to be here today to testify on our report to the Committee on

efforts to protect human research subjects.1

 Concerns have been raised

about the effectiveness of today’s safeguards in light of the recent

disclosures of unethical Cold War-era radiation experiments and reports of

infringements on subjects’ rights, such as in a contemporary study of

breast cancer.

Over the past 3 decades, the Department of Health and Human Services

(HHS)—the primary federal sponsor of biomedical and behavioral

research—has established procedures to minimize risks experienced by

patients and healthy volunteers who participate in research that it

supports or regulates. We reviewed HHS’ human subject protection

system, concentrating on the prevention, monitoring, and enforcement

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

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

(FDA). Within FDA, we examined the human subject protection activities

of the Center for Drug Evaluation and Research because drug research is

the largest segment of biomedical research.2

 We interviewed federal and

research institution officials; medical and behavioral researchers;

representatives of the drug industry; and experts in bioethics, law, and

social science. We also reviewed HHS and FDA regulations, guidelines,

and records and human subject protection procedures and records at

research institutions.

I would like to highlight three key findings from our report. First, HHS’

oversight of tens of thousands of studies appears to have reduced the

likelihood that serious abuses of human subjects, comparable to past

tragic events, will occur. Second, no practical level of oversight can

guarantee that each researcher will protect subjects with complete

integrity. The detection of recent instances of potential or actual harm to

subjects both demonstrates that abuses can occur and also suggests that

the current oversight activities are working. Finally, various time,

resource, and other pressures have reduced or threaten to reduce the

effectiveness of such oversight.

1

Scientific Research: Continued Vigilance Critical to Protecting Human Subjects (GAO/HEHS-96-72,

Mar. 8, 1996).

2

FDA’s Center for Biologics Evaluation and Research and Center for Devices and Radiological Health

also carry out activities to protect human subjects of product testing. These activities were not

included in the scope of our review.

Page 1 GAO/T-HEHS-96-102
Background Since the 1960s, there have been significant advances in protecting the

rights and welfare of human subjects in biomedical and behavioral

research. The federal presence has grown in this area, establishing and

enforcing regulations for protecting human subjects in federally funded

and federally regulated research. HHS’ regulation of biomedical and

behavioral research consists of two principal tiers of review: one at the

federal level and one at the research institution level. Both tiers are

responsible for ensuring that individual researchers and their research

institutions comply with federal laws and regulations for protecting human

subjects. When the core of HHS’ human protection regulations was

adopted by 15 other federal departments and agencies in 1991, it became

known as the Common Rule.3

Within the HHS oversight system there are several entities overseeing

compliance with human protection regulations. At the federal level are the

NIH’s OPRR and the FDA. At the local level, institutional review boards

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

university or other research institution—are responsible for implementing

federal human subject protection requirements for research conducted at

or supported by their institutions. In general, IRB members are scientists

and nonscientists who volunteer to review proposed studies.

The Common Rule requires research institutions receiving federal support

and federal agencies conducting research to establish IRBs 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. 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.

3

Currently, these regulations have been adopted by 17 federal departments and agencies: the

Departments of Agriculture, Energy, Commerce, Health and Human Services, Housing and Urban

Development, Justice, Defense, Education, Veterans Affairs, and Transportation; the National

Aeronautics and Space Administration; the Social Security Administration; the Consumer Product

Safety Commission; the Agency for International Development; the Environmental Protection Agency;

the National Science Foundation; and the Central Intelligence Agency.

Page 2 GAO/T-HEHS-96-102
Preventive Efforts

Have Been Important

in Reducing

Likelihood of Abuses

Preventing harm to human subjects’ rights and welfare is the overarching

goal of HHS’ protection system. The organizational components of the

system—OPRR, FDA, and local IRBs—have heightened the compliance of

the research community with human protection guidelines through a

variety of activities.

Oprr Requires a Formal

Commitment to Federal

Regulations

OPRR’s chief preventive measure is its assurance process. Assurances are

contract-like agreements made by research institutions to comply with

federal human subject protection requirements. Assurances include the

following: a statement of ethical conduct principles, a guarantee that an

IRB has been designated to approve and periodically review the

institution’s studies, and the specifics of the IRB’s membership,

responsibilities, and process for reviewing and approving proposals. An

institution must have an assurance approved by OPRR before the

institution can receive HHS research funding.

Depending on an institution’s willingness and expertise, as well as the

requirements of specific research studies, OPRR can negotiate several

different types of assurances. Through a multiple project assurance, for

example, OPRR can delegate broad authority to an institution, allowing it

to approve a wide array of research studies. Or, through a single project

assurance, OPRR can retain the authority to approve studies one by one.

As of November 1995, OPRR had 451 active multiple project assurances

and over 3,000 active single project assurances. OPRR also had over 1,300

active cooperative project assurances, which pertain to multiple-site

research projects.

Fda Reviews Subject

Protections Before

Permitting Drug Studies

FDA 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 IRB that

will examine their study. FDA can request modifications to proposals or

reject proposals deemed to present unacceptable risk.

Page 3 GAO/T-HEHS-96-102
Irbs Examine Researchers’

Plans to Protect Subjects’

Rights and Welfare

IRBs play a major role in the protection of patients and healthy volunteers,

according to federal officials and members of the research community

alike. For each study conducted using human subjects, researchers must

first get IRB approval.4

 In fact, HHS will neither fund new human subject

research nor authorize ongoing research to continue without IRB

approval. The IRB’s basic role when deciding whether to approve new

research is to determine if the rights and welfare of subjects will be

safeguarded. IRB members ensure that a study’s procedures are consistent

with sound research design and that the consent document conforms to

federal rules for adequate informed consent. IRB reviews, however,

generally do not involve direct observation of the research study or the

process in which a subject’s consent is obtained.

IRB members are 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

community values.

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

boards can decide whether the study should continue.

Federal Monitoring

and Enforcement

Identify and Address

Human Subject

Protection Violations

No system of prevention is foolproof. Therefore, FDA’s and OPRR’s

monitoring and enforcement efforts include review of results of IRB

operations, clinical trials, and allegations of researcher misconduct.

4

Six 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 (that is, 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 recording and collection of nail clippings, for example, are

considered minimal risk research. The IRB chairman or a chairman-appointed IRB member, rather

than the full board, conducts expedited reviews.

Page 4 GAO/T-HEHS-96-102
Fda’s Monitoring of Irbs

and Drug Researchers

Identifies Violations

FDA’s primary tool for monitoring human subject protection is its on-site

inspections of the IRBs that oversee drug research. FDA’s inspections of

IRBs demonstrate that, at some institutions, compliance with federal

oversight rules is uneven. 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. Among the

more serious violations cited were the following: participation of

researchers as IRB members in reviewing their own studies, absence of a

process for tracking ongoing studies, and failure to ensure that required

elements of informed consent were contained in consent documents. The

FDA Warning Letters terminated the IRBs’ authority to approve new

studies or to recruit new subjects into ongoing studies until FDA received

adequate assurance of corrective action. From October 1993 to

November 1995, FDA found less serious deficiencies involving about 200

other IRBs, such as failure to document the names of IRB members and

failure of IRB minutes to identify controversial issues discussed.

In addition to monitoring IRBs, FDA must be satisfied that manufacturers

have complied with human subject protection regulations during clinical

trials. To this end, FDA conducts on-site inspections of individual drug

studies. When examining how a trial was conducted, FDA determines, for

example, if subject selection criteria were followed, if subjects’ consent

was documented, and if adverse events were reported. FDA’s principal

focus in these efforts, however, is to verify the accuracy and completeness

of study data as well as the researcher’s adherence to the approved

protocol.

Most of the drug study violations FDA identifies are relatively minor. From

1977 to 1995, about one-half of the violations related to the adequacy of

the informed consent forms. FDA also identifies more serious violations.

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

regarding their conduct of drug research with human subjects. It cited

such instances of serious misconduct as failure to obtain informed

consent; forgery of subjects’ signatures on informed consent forms; failure

to inform patients that a drug was experimental; and failure to report

subjects’ adverse reactions to drugs under study, including a subject’s

death.

Fda Can Impose Penalties

for Serious Violations

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

Page 5 GAO/T-HEHS-96-102
investigational drugs, (3) disqualifying a researcher from the use of

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

Oprr Investigates

Allegations of

Noncompliance

OPRR also responds to inquiries and investigates allegations of potential

harm to human subjects. These inquiries and investigations are largely

handled by telephone and correspondence; few investigations result in site

visits. Over the past 5 years, OPRR has investigated numerous allegations

of 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 HIV-positive

subjects in Zaire. Among cases currently under investigation are

allegations that researchers at a university-based fertility clinic transferred

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

donors.

Oprr Can Restrict

Research Until Violations

Are Corrected

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.

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’ system for protecting

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

reduce the effectiveness of IRBs, OPRR, and FDA.

First, pressure from heavy workloads and competing priorities can

weaken IRB oversight.

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

only 1 or 2 minutes of review per study.

Page 6 GAO/T-HEHS-96-102
• Some IRBs allow administrative staff with no scientific expertise—not

board members themselves—to review continuing review forms, ensuring

only that the information has been provided.

• The independence of IRB reviews can be compromised in cases in which

IRB members have close collegial ties with researchers at their

institutions, when there are pressures from institution officials to attract

and retain funding, when IRB members have financial ties to the study,

and when IRB members are reluctant to criticize studies led by leading

scientists.

• The increasing complexity of research makes it difficult for some IRBs to

adequately assess human subject protection issues when members are not

conversant with the technical aspects of a proposed study, or when

studies raise ethical questions that have not been satisfactorily resolved

within the research community.

• Given the growing number of large-scale trials, if most involved IRBs have

approved a proposed study, then IRBs at other institutions may feel

pressured to mute their concerns about the study.

• Pressures to recruit subjects can lead some researchers and IRBs to

overlook informed consent deficiencies.

Second, various factors may hamper OPRR oversight.

• OPRR staff make no site visits during assurance negotiations; instead, they

review an institution’s written application and conduct written or oral

follow-up. In contrast, on the basis of experience gained from on-site

investigations for compliance purposes, OPRR staff told us that their

ability to evaluate an institution’s human protection system is greatly

enhanced by direct observation and personal interaction with IRB staff,

IRB members, and researchers. In the future, OPRR expects to conduct

from 12 to 24 technical assistance visits annually to institutions holding

OPRR assurances.

• NIH’s organizational structure may hamper the independence of OPRR

with respect to its oversight of studies conducted by NIH’s Office of

Intramural Research. From a broad organizational perspective, a potential

weakness exists because NIH is both the regulator of human subject

protections as well as an agency conducting its own research programs.

The NIH Director, therefore, has responsibility for both the success of

NIH’s intramural research programs and the enforcement of human

subject protection regulations by OPRR.

Third, FDA’s inspections of drug research may permit violations to go

undetected.

Page 7 GAO/T-HEHS-96-102
• FDA’s inspection program is geared more toward protecting the eventual

consumer of the drug than the subjects on whom the drug was tested. FDA

does not inspect all drug studies but concentrates its efforts on

commercial products likely to be approved for consumer use.

Furthermore, FDA’s routine on-site inspections of drug studies are

conducted only after clinical trials have concluded and subjects have

completed their participation.

• Gaps also exist in FDA’s inspection of IRBs. FDA’s Center for Drug

Evaluation and Research 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—one

that contains several major research centers conducting studies with

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

Furthermore, FDA is 3 to 5 years behind in its scheduled reinspection of

some IRBs with which it had noted problems.

• FDA officials told us that some of its 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.

Fourth, additional pressures make it difficult to guarantee the protection

of human subjects.

• When seriously ill individuals, such as some HIV patients, equate

experimental and proven therapies, some question the need for

protections that appear only to restrict their access to therapy.

• When physician-researchers 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.

• When physicians use an innovative but unproven technique to treat

patients, they may not consider the procedure to be research. Such

treatments, however, could constitute unregulated research, placing

people at risk of harm from unproven techniques.

Conclusions Our work suggests that over the last 3 decades federal regulators and

members of the research community have improved the protection of

human research participants. However, holes inevitably exist in the

regulatory net because no oversight system can guarantee complete

protection for each individual. The goals remain to encourage researchers’

ethical behavior without hobbling scientific research and to refine

Page 8 GAO/T-HEHS-96-102
regulations and oversight activities to further improve subject protections.

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.

Mr. Chairman, this concludes my prepared statement. I will be happy to

answer any questions you or the other Members may have.

For more information about this testimony, please call Bruce D. Layton, Assistant

Director, at (202) 512-7119. Other major contributors included Frederick K. Caison,

Linda S. Lootens, and Hannah F. Fein.

(108268) Page 9 GAO/T-HEHS-96-102
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