GAO

United States General Accounting Office

Report to Congressional Requesters

September 2000 VA RESEARCH

Protections for Human

Subjects Need to Be

Strengthened

GAO/HEHS-00-155

Page 1 GAO/HEHS-00-155 VA Protections for Human Subjects

Contents

Letter 3

Appendixes Appendix I: Scope and Methodology 46

Appendix II: Comments From the Department of Veterans Affairs 50

Appendix III: GAO Contact and Staff Acknowledgments 55

Related GAO Products 56

Tables Table 1: Characteristics of Sampled VA Medical Centers 47

Figures Figure 1: Human Research Project Review and Approval Process

at VA Medical Centers 11

Figure 2: Noncompliance With VA Regulations at Eight Sites 12

Figure 3: Elements of Informed Consent Required by VA

Regulations 14

Figure 4: VA’s Regulatory Criteria for IRB Approval of Research

Projects 20

Abbreviations

FDA Food and Drug Administration

HHS Department of Health and Human Services

IRB institutional review board

NIH National Institutes of Health

OHRP Office for Human Research Protections

OPRR Office for Protection from Research Risks

ORCA Office of Research Compliance and Assurance

ORD Office of Research and Development

VA Department of Veterans Affairs
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United States General Accounting Office

Washington, D.C. 20548

Health, Education, and

Human Services Division

B-283287 Letr

September 28, 2000

The Honorable Terry Everett

Chairman

The Honorable Corrine Brown

Ranking Democratic Member

Subcommittee on Oversight and Investigations

Committee on Veterans’ Affairs

House of Representatives

The Honorable Cliff Stearns

Chairman

The Honorable Luis V. Gutierrez

Ranking Democratic Member

Subcommittee on Health

Committee on Veterans’ Affairs

House of Representatives

Every year thousands of veterans volunteer to participate in biomedical or

behavioral research projects under the auspices of the Department of

Veterans Affairs (VA). They do so for different reasons, including to

improve the medical conditions of themselves and others, advance science,

and serve their country. But research is not without risks. VA studies, like

other federally funded research programs, are governed by regulations

designed to minimize risks and protect the rights and welfare of research

participants. VA must ensure that veterans who agree to become subjects

in VA research are given accurate and understandable information about

procedures, risks, and benefits so that they can make informed decisions

about volunteering. However, veterans who rely on VA for their health care

often do so because they are unable to afford private health care and may

fear jeopardizing their care if they do not agree to participate in research.

VA has a special responsibility, therefore, to ensure that veterans are not

unduly influenced in their decision to participate in research projects and

that their rights and welfare are protected if they volunteer to participate.

Concerns about VA’s protection of its human research subjects came to

national attention in March 1999. At that time, all human research was

suspended at the West Los Angeles VA Medical Center after officials there

failed to correct long-standing problems with its system for protecting

human subjects. Concerns about human subject protections have not been
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limited to VA. Public attention has recently been focused on concerns

about the safety of research subjects in other public and private research

institutions. Department of Health and Human Services (HHS)

investigations of violations of human subject protections have led to the

suspension of research activities at several universities and hospitals.

Furthermore, the HHS Office of Inspector General has raised concerns

about the adequacy of current human subject protections nationwide in a

series of reports. These reports note that protections for research subjects

are threatened by recent changes in the research environment that have

included a heightened industry role in sponsoring research, proliferation of

multicenter trials, increased number and complexity of research proposals,

increased demand by patients to participate in clinical trials, and changes

in health care delivery systems affecting research programs.

Since the suspension of human research at the West Los Angeles VA

Medical Center in March 1999, four additional VA medical centers have

been affected by sanctions applied by regulatory agencies against their

affiliated universities. Concerned about the rights and welfare of veterans

who volunteer to participate in research at VA and the effectiveness of its

human subject protection system, you asked us to (1) assess VA’s

implementation of human subject protections, (2) identify whether

weaknesses exist in VA’s system for protecting human subjects, and (3)

assess VA’s actions to improve human subject protections at those sites

affected by sanctions applied by regulatory agencies and throughout VA’s

health care system.

To address these objectives, we reviewed VA regulations and guidance and

interviewed headquarters officials responsible for human subject research

activities. We visited eight VA medical centers to review their policies,

procedures, and practices for protecting human subjects. We selected these

medical centers to reflect major differences in VA research programs,

including the number of studies they conduct with human subjects and the

institutions responsible for operating the local institutional review board

(IRB), the committee tasked with reviewing a research study’s protections

for human subjects. At these medical centers, we examined IRB activities

to determine whether appropriate protections for human subjects were in

place. We also visited three other VA medical centers affected by recent

restrictions of their human research programs and reviewed the changes

implemented there in response to HHS regulators. We talked with senior

research officials at two additional VA medical centers similarly affected by

sanctions applied by regulatory agencies. Because research programs at

five of the VA facilities we visited involved university affiliates, we also
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reviewed documents and interviewed officials responsible for human

subject protection issues at those institutions. We performed our work

from June 1999 through August 2000 in accordance with generally accepted

government auditing standards. See app. I for a detailed discussion of our

scope and methodology.

Results in Brief VA has adopted a system of protections for human research subjects, but

we found substantial problems with its implementation of these

protections. Medical centers we visited did not comply with all regulations

to protect the rights and welfare of research participants. Among the

problems we observed were failures to provide adequate information to

subjects before they participated in research, inadequate reviews of

proposed and ongoing research, insufficient staff and space for review

boards, and incomplete documentation of review board activities. We

found relatively few problems at some sites that had stronger systems to

protect human subjects, but we observed multiple problems at other sites.

Although the results of our visits to medical centers cannot be projected to

VA as a whole, the extent of the problems we found strongly indicates that

human subject protections at VA need to be strengthened.

Three specific weaknesses have compromised VA’s ability to protect human

subjects in research. First, VA headquarters has not provided medical

center research staff with adequate guidance about human subject

protections and thus has not ensured that research staff have all the

information they need to protect the rights and welfare of human subjects.

Second, insufficient monitoring and oversight of local human subject

protections have permitted noncompliance with regulations to go

undetected and uncorrected. Third, VA has not ensured that funds needed

for human subject protections are allocated for that purpose at the medical

centers, with officials at some medical centers reporting that they did not

have sufficient resources to accomplish their mandated responsibilities.

To VA’s credit, substantial corrective actions have been implemented at

three medical centers in response to sanctions by regulatory agencies

taken against their human research programs, but VA’s systemwide efforts

at improving protections have been slow to develop. Medical centers

affected by sanctions have taken numerous steps to improve human

subject protections, for example, by hiring and training IRB staff and

developing written procedures for their IRB operations. Despite some

difficulties, these medical centers have made progress, and each has

resumed human research activities. VA has, however, been slow to take
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action to identify any systemwide deficiencies and obtain necessary

information about the human subject protection systems at its medical

centers. VA has made promising steps, for example, by establishing the

Office of Research Compliance and Assurance to monitor human subject

protections at individual medical centers and across the system and

developing a system to use an external organization to accredit IRBs.

However, it is too soon to determine whether they will fulfill their

objectives.

In light of these problems, we make recommendations to the Acting

Secretary of Veterans Affairs to strengthen VA’s protections of the rights

and welfare of human subjects by providing staff training and resources

and taking other steps to ensure that medical centers and their IRBs

comply with all applicable human subject protection regulations. VA

concurred with our recommendations.

Background Conducting research is one of VA’s core missions. VA researchers have been

involved in a variety of important advances in medical research, including

development of the cardiac pacemaker, kidney transplant technology,

prosthetic devices, and drug treatments for high blood pressure and

schizophrenia. For fiscal year 2000, Congress appropriated $321 million for

VA’s research programs, which support a wide range of human, animal, and

basic science studies. VA uses a competitive funding process in which its

Office of Research and Development (ORD) allocates about $296 million of

these funds to VA researchers, with awards based on scientific merit and

potential contribution to knowledge of issues of particular concern to VA.

VA allocates most of the remainder to indirect costs of research, which

includes support for the human subjects protection system.
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Besides the appropriation for research, VA allocates funds from its medical

care appropriation to support the research infrastructure at medical

centers such as laboratory facilities and investigator salaries. In fiscal year

2000, this allocation amounted to $343 million. VA researchers receive

additional grants and contracts from other federal agencies such as the

National Institutes of Health (NIH), research foundations, and private

industry sponsors, including pharmaceutical companies. In fiscal year

1999, these additional funds amounted to approximately $481 million.

Nonprofit research foundations linked to VA medical centers control some

of these non-VA research funds.1 In fiscal year 2000, biomedical or

behavioral research involving human subjects is being conducted at about

70 percent of VA medical centers.

VA is responsible for ensuring that all human research it conducts or

supports meets the requirements of VA regulations, regardless of whether

that research is funded by VA, the subjects are veterans, or the studies are

conducted on VA grounds. Responsibility for administration and oversight

of the research program has rested primarily with ORD. Recently, VA

created the Office of Research Compliance and Assurance (ORCA), which

has been charged with advising the Under Secretary for Health on all

matters affecting the integrity of research protections for humans and

animals, promoting the ethical conduct of research, and investigating

allegations of research improprieties.

1

The Veterans’ Benefits and Services Act of 1988 authorized VA to establish nonprofit

research corporations at its medical centers to broaden VA’s ability to accept and manage

private and non-VA public funds to support research programs. In 1998, there were 87

nonprofit research corporations associated with VA medical centers with total revenues of

almost $122 million.
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Some VA research is also subject to oversight by two HHS components.

The Food and Drug Administration (FDA) is responsible for protecting the

rights of human subjects enrolled in research with products it regulates—

drugs, medical devices, biologics, foods, and cosmetics. Research that

involves human subjects and is funded by HHS is subject to oversight by its

Office for Human Research Protections (OHRP).2 HHS requires institutions

conducting human research with HHS funds to file a document with OHRP

that indicates a commitment to comply with federal regulations. This

document, called an assurance, may cover a single study (a single project

assurance), or it may allow the institution to conduct multiple studies (a

multiple project assurance).3 When an institution files a multiple project

assurance with OHRP, all federally funded research involving human

subjects at that institution must comply with HHS regulations. Both FDA

and OHRP have the authority to monitor those studies conducted under

their jurisdiction, and each can take action against investigators, IRBs, or

institutions that fail to comply with applicable regulations.

Regulations Establish a

System to Protect Human

Subjects

Research with human subjects conducted at VA facilities is governed by

regulations designed to protect their rights and welfare. These regulations

establish minimum standards for the conduct and review of research to

ensure that research involving human subjects is conducted in accordance

with the three ethical principles outlined by the National Commission for

the Protection of Human Subjects of Biomedical and Behavioral Research.4

First, the principle of respect for persons requires acknowledgement of

individual autonomy, and conversely, the need to protect those with

diminished autonomy. In practice, this principle requires that subjects give

informed consent to participate in research; that is, they must be given

sufficient information about a studyincluding its purpose, procedures,

2

The Office for Human Research Protections (OHRP) is in the Office of the Assistant

Secretary for Health. HHS established OHRP in June 2000 to assume the human subject

protection functions of the former Office for Protection from Research Risks (OPRR),

which was part of NIH. In this report, we refer to both organizations as OHRP. Actions taken

before June 18, 2000, were taken by OPRR.

3

FDA does not have a comparable system of assurances.

4

National Commission for the Protection of Human Subjects of Biomedical and Behavioral

Research, The Belmont Report: Ethical Principles and Guidelines for the Protection of

Human Subjects of Research, Apr. 18, 1979. The commission was established by the

National Research Act of 1974. Federal regulations for the protection of human subjects

reflect the recommendations of the Belmont Report.
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risks, and benefitsto decide whether to participate. They must also

understand this information, and their consent must be voluntary. Second,

the principle of beneficence requires that the expected benefits of research

to the individual or to society outweigh its anticipated risks. Third, the

principle of justice requires fair subject selection procedures, so that both

the benefits and the burdens of research are distributed across a number of

individuals in a just manner.

In 1981, in response to the National Commission, both HHS and FDA

promulgated revised regulations for the protection of human subjects.

Seventeen federal departments and agencies, including HHS and VA, have

adopted the core of HHS regulations.5 FDA’s regulations are slightly

different from those adopted by HHS and VA.

To safeguard the rights of subjects and promote ethical research, these

federal regulations create a system in which the responsibility for the

protection of human subjects is assigned to three groups.

• Investigators are responsible for conducting their research in

accordance with applicable federal regulations and for ensuring that

legally effective consent is obtained from each subject or his or her

legally authorized representative.

• Institutions are responsible for establishing oversight mechanisms for

research including establishing local committees known as institutional

review boards (IRB), which are responsible for reviewing research

proposals before studies are initiated and after they are under way to

help ensure that research is conducted in accordance with the three

principles described above.

• Agencies, including VA, are responsible for ensuring that their IRBs

comply with applicable federal regulations and that they have sufficient

space and staff to accomplish their obligations.

5

VA and HHS regulations share a common core, but HHS regulations include additional

requirements for research involving fetuses, pregnant women, human in vitro fertilization,

prisoners, and children. VA research funded by other federal agencies having human

subjects regulations, such as the Department of Defense, is also subject to oversight

authority by those agencies. In most cases, the applicable federal regulations are essentially

the same as those for VA.
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VA Human Subject

Protection System

VA requires each of its medical centers that engages in research with

human subjects to establish its own IRB6 or secure the services of an IRB at

an affiliated university. As of August 2000, approximately 40 percent of the

medical centers conducting research with human subjects relied on an IRB

at an affiliated university. The IRB sends its recommendations to the VA

medical center’s research and development committee, which is

responsible for maintaining standards of scientific quality, laboratory

safety, and the safety of human and animal subjects. The research and

development committee is charged with reviewing each study’s budget;

assessing the availability of needed space, personnel, equipment, and

supplies; and determining the effect of the planned research on the

investigator’s other responsibilities, including the provision of clinical

services. The committee can disapprove a study; however, VA regulations

prevent the research and development committee (or any other

institutional official or body) from overturning an IRB decision to

disapprove a study.

A VA investigator who wants to conduct research with human subjects

must develop a research plan (called a protocol), supporting documents,

and a consent form. The consent form is designed to provide potential

subjects with sufficient information about the study, including its

procedures, risks, and benefits, to allow the subject to make an informed

decision about whether to participate in the study (see fig. 1). The

investigator then submits these materials for review. The study is not to be

initiated until both the IRB and the research and development committee

have approved it, and these committees may insist on changes to the

protocol or consent form. Once approval has been given, VA regulations

prohibit any unapproved changes to the study’s procedures, unless doing

so is absolutely necessary to ensure the safety of a subject. If an

investigator wants to alter some aspect of the study, then the IRB must

review and approve an amendment or modification to the protocol. In a

process known as continuing review, each study is to be re-reviewed at

least once per year, and more frequently if the degree of risk warrants it.

6

Within VA, the IRB is a subcommittee of a medical center’s research and development

committee and is often called the Subcommittee on Human Studies.
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Figure 1: Human Research Project Review and Approval Process at VA Medical Centers

Implementation Of

Human Subject

Protections Uneven

We found variation across medical centers and their affiliated universities

in the implementation of VA regulations and policies involving protections

for human subjects. At the eight sites we visited, we found noncompliance

with VA regulations in four areas: (1) informed consent; (2) IRB review; (3)

IRB membership, staff, and space; and (4) IRB documentation. The

problems we identified are similar to problems that OHRP noted in letters

to universities and hospitals it has found to be out of compliance with

federal regulations. As shown in fig. 2, some sites we visited had more

problems than did others.
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Figure 2: Noncompliance With VA Regulations at Eight Sites

a

We reviewed from 14 to 20 IRB-approved consent forms at each site. We reviewed a total of 138

forms.

b

We compared consent forms signed by subjects to IRB-approved consent forms for 17 to 20 studies

at each of four sites. We compared forms for a total of 73 studies.

Of the sites we visited, those with the most extensive violations of VA

regulations relied on VA-run IRBs. We identified fewer problems at the
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IRBs in our sample that were run by universities. In particular, we observed

fewer problems with IRB membership, staff, space, and documentation at

university-run IRBs than at VA-run IRBs. University-run IRBs were also

more likely to conduct thorough and timely continuing reviews than VA-run

IRBs. University-run IRBs we visited were not without problems, however.

We found that some IRB-approved consent forms at each site omitted

required information and some investigators used nonapproved consent

forms.

Informed Consent We found problems with the content or use of informed consent forms at

all of the medical centers we visited. We found that some informed consent

documents that had been approved for use by IRBs provided incomplete or

unclear information. In addition, we found some studies in which the

investigators used nonapproved consent forms when enrolling subjects. We

also found one instance in which research was conducted without consent.

Informed consent is a primary ethical requirement of research with human

subjects and reflects the principle of respect for persons. The ability of

competent subjects to make informed decisions about whether to

participate in research and the ability of legally authorized representatives

to protect those who are unable to provide consent because they are

incapacitated are undermined when IRBs fail to ensure that all required

information is included in consent forms or when investigators fail to

obtain consent using approved procedures.

Information in IRB-Approved

Consent Forms

We found that 60 percent of the 138 IRB-approved consent forms that we

randomly sampled from lists of active projects provided incomplete or

unclear information about required elements of informed consent. (Fig. 3

lists the elements of informed consent required by VA regulations.) Each

IRB we visited approved some consent forms that contained incomplete

information. For example, IRB-approved consent forms did not

• indicate that blood would be drawn in a study on the effects of exposure

to Agent Orange,

• mention possible risks of a biopsy in a study designed to test a treatment

for esophageal cancer,

• describe alternative treatment options in a study comparing two drug

treatments for schizophrenia, and

• indicate who would have access to data obtained during a study on

treatment for cirrhosis of the liver.
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Figure 3: Elements of Informed Consent Required by VA Regulations

Source: VA Regulations (38 C.F.R. section 16.116).

Of the 84 IRB-approved consent forms we identified that omitted required

elements or provided incomplete information, almost half did so for two or

more required elements. For example, the consent form for a study of

treatments to reduce the recurrence of melanoma did not provide clear

information about the duration of the study, nor did it state whom to

contact for information about research subjects’ rights. Participants were

also told that data would continue to be obtained from their medical

records even if they withdrew from the study. Thus, the consent document
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for this study provided incomplete information about two required

elements and appeared to negate the subject’s right to withdraw from the

study at any time. Moreover, this consent form might have created undue

influence because it inappropriately suggested that the subjects’ own

physician endorsed the potential benefits to the subject of participating in

this study. Because the participants in this study are randomly assigned to

receive either an unproven treatment or no treatment, the physician would

have no way of knowing whether participation would benefit the subject.

VA regulations allow an IRB to approve a consent procedure that alters or

omits one or more of the required elements of consent if it finds and

documents certain conditions. We were unable to find such documentation

in the cases we reviewed. Moreover, 37 of the IRB-approved consent forms

that omitted or provided incomplete information about a required element

were for studies that involved investigational drugs or devices. Thus, both

VA and FDA regulations had to be met, and when informed consent is

required, FDA regulations do not permit IRBs to alter or omit any required

elements of informed consent.

The information that was omitted most frequently—in about 15 percent of

formswas the person to whom subjects should direct questions about

their rights as research subjects. This information, which is required by

regulations, is not included in the standard template for informed consent

that VA policy requires investigators to use.

Sites varied in the number of IRB-approved forms that provided incomplete

information and the number of incomplete or absent elements in approved

forms. The percent of approved consent forms with incomplete

information ranged from 78 to 100 percent of our sample at the four sites

with the greatest number of these problems. Moreover, forms from these

four sites often provided incomplete descriptions of two or more required

elements of informed consent. As many as four elements of informed

consent were missing or incomplete in IRB-approved forms at these sites.

At the two sites where we found the fewest problems, about three-fourths

of our sample of approved consent forms were problem-free, and multiple

problems in the same form were rare.
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In addition to information required by VA regulations, VA policy also

requires that informed consent forms indicate that VA will provide free

medical treatment for research-related injuries.7 We found that about 30

percent of the IRB-approved consent documents we reviewed did not

include this statement. The absence of this statement varied by site. (These

data are not included in fig. 2, which presents noncompliance with VA

regulations.) The majority of forms we sampled at two university-run IRBs

did not include this information, and one VA-run IRB included it only about

half the time. In contrast, the forms at the other university-run IRBs and at

the four other VA-run IRBs almost always included it.

The requirement for informed consent was waived for eight of the projects

we reviewed, and in each case, our review indicated that the study qualified

for the waiver. According to VA regulations, certain categories of

researchfor example, studies of existing data that cannot be linked,

directly or indirectly, to specific individualsdo not require informed

consent or IRB approval. VA regulations also allow for a waiver of informed

consent in some research that is not eligible for an exemption from IRB

review, provided that the IRB determines that certain conditions apply.

Investigator Noncompliance

With Consent Requirements

Although all the consent forms we obtained from investigators indicated

that consent to participate in research had been obtained, we found that

investigators did not always obtain consent appropriately. In this review of

consent forms, we found 18 studies in which the investigators used

nonapproved consent forms when enrolling subjects. We also separately

identified one instance in which research was conducted without consent.

We asked investigators at each site to show us signed consent forms from a

randomly selected sample of their subjects. We examined 540 such consent

forms, all of which had the signature of a subject or a surrogate. In addition

to determining that investigators were able to produce these signed

consent forms, at four sites we also compared these signed forms with

consent forms that IRBs had approved for use in these studies. We found

that investigators had used nonapproved consent forms with one or more

subjects in 18 of the 73 studies we examined. A total of 33 of 292 subjects

had signed nonapproved consent forms. The extent of this problem varied

by site. We found that one or more subjects had signed a nonapproved form

7

VA regulations specify two exceptions to the requirement that VA treat research-related

injuries: (a) the injury results from the subject’s own noncompliance with study procedures

or (b) the research is done by VA contractors (38 C.F.R. section 17.85).
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in 12 to 33 percent of the studies we examined at these four sites. Some of

the nonapproved forms that were signed by subjects omitted key

information that had been included in the IRB-approved version of the

consent form. For example, the nonapproved form that had been signed by

all four subjects enrolled in a study on treatments for lymphoma did not

mention that the study would involve multiple bone marrow biopsies, the

possible risks of those biopsies, or possible side effects of two drugs used

in the studyinformation that was included in the IRB-approved consent

form.

We identified one instance in which research procedures were performed

without consent in the projects in our sample. In this instance, a patient

who had not given consent was subjected to an esophageal biopsy for

research purposes. This biopsy, which was not reported to the IRB,

occurred in conjunction with a biopsy performed for diagnostic purposes

in November 1997.

We also found that investigators or their staff had not fully complied with

requirements for obtaining consent in three other studies in our sample. In

each of these, subjects had consented and steps were implemented to

address the problem.

• In October 1998, an investigator learned that a subject with

schizophrenia did not understand his right to withdraw from research at

any time. Upon discovering this, the investigator fired the person who

had obtained the subject’s consent, withdrew the subject from the study,

and reported the incident to the IRB.

• In May 1997, FDA discovered that the consent form signed by subjects in

a study of an investigational device to facilitate walking among

paraplegics had not included all the necessary information about their

participation. The problem was reported to the IRB, the consent form

was rewritten, and three previously enrolled subjects were given a

revised form and a chance to withdraw from participation.

• In July 1997, an investigator realized that he did not have IRB approval

for the protocol and consent form that had been used for 73

subjectsincluding schizophrenics, their family members, and health

care providerswho had completed a questionnaire to assess decisionmaking. The investigator reported the situation to the IRB, which

required that subjects be given a revised approved consent form.
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We found one other problem in subject enrollment procedures used by an

investigator, although in this case VA regulations were not involved. One

subject who was incapacitated as a result of dementia was

enrolledcontrary to VA policyin a noninvasive study of abdominal

aneurysms. Although the subject’s surrogate had provided consent,8 VA

policy establishes protections for incapacitated subjects by prohibiting

their enrollment in research that can be conducted with competent

subjects. We encountered eight other cases in which surrogates enrolled

incapacitated subjects in research, but we were unable to determine

whether these cases were in accordance with VA’s policy.

IRB Review of Research We found that five of the sites we visited did not implement certain

required procedures for IRB review of research. For example, we found

that studies at two sites were not reviewed by all necessary IRB members

and four IRBs did not ensure timely or thorough continuing review of

ongoing research.

Initial IRB Review—

Required Approval During

Convened IRB Meetings

We found that two IRBs did not comply with VA regulations that research

must be approved during properly convened meetings, either because

meetings were held without a quorum or because the IRB chair improperly

approved a high-risk study outside an IRB meeting. With the exception of

certain categories of research involving minimal risk to subjects, VA

regulations require IRBs to review research at convened meetings attended

by a quorum, defined as a majority of members that includes at least one

member whose primary concerns are in nonscientific areas. These

regulations establish criteria for IRB meeting quorums to ensure that

decisions about the protection of human participants in research reflect the

consideration of diverse perspectives on research, including the views of

scientists and nonscientists with a range of experience and expertise.

These protections are undermined when initial review is not conducted in

accordance with these requirements.

Four of seven meetings held by one VA-run IRB between January 1998 and

August 1999 were held without a quorum. As a result, 17 studies were

initiated without legitimate IRB approval, including studies on new drug

treatments for unstable coronary symptoms and pneumonia. We examined

8

VA regulations allow legally authorized representatives to provide consent to participate in

research for incapacitated subjects.
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four to six sets of minutes from IRB meetings held at the other seven IRBs

we visited and found that a quorum was present at each.

We found one other instance in which requirements for approval of

research at convened IRB meetings were violated. A university-run IRB

considered a high-risk drug study for cardiac patients and determined that

re-review would be necessary after the investigator addressed several

concerns. IRB minutes stated that because the drug company sponsoring

the research would have rejected their site if a time deadline were not met,

the IRB chair approved the study before the IRB reconsidered it. Although

there are circumstances under which an IRB chair can approve a study, in

all such cases the research must have been found to pose only minimal risk

to subjects. In this instance, the IRB had determined that the study posed a

high degree of risk.

On the other hand, our sample also included 16 other studies that met

criteria for approval outside a convened IRB meeting. VA regulations allow

such a procedure (called expedited review) for studies that pose only

minimal risk to subjects and that fall into one of several categories of

research. Under expedited review procedures, the IRB chair, or one or

more experienced IRB members designated by the chair, are authorized to

approve research. For example, IRB approval was expedited for a study on

the effects of a weight loss program in which subjects would attend

informational sessions about diet and weight loss and have their weight

and health monitored using routine, minimal-risk procedures.

Initial ReviewSufficiency of

Written Information From

Investigators

We found that the IRBs we visited differed in the sufficiency of the written

information they asked investigators to provide about human subject

protections prior to review. VA regulations identify eight criteria that IRBs

must assess before approving research (see fig. 4). Although VA regulations

do not specify the information IRBs must review to assess these criteria

upon initial review, much of the information can only be provided by

investigators. Because offsite study sponsors often prepare the consent

forms and protocols used in multisite studies, IRBs must have sufficient

information to assess whether the local investigator can properly

implement human subject protections.

We found that information in IRB files did not always address all the

criteria that must be satisfied for an IRB to approve a study. Of the sites we

visited, only one university-run IRB routinely requested detailed

information from local investigators about each criterion in its application
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forms. For example, two IRBs did not routinely ask local investigators any

questions about risks or about plans for monitoring the safety of subjects.

Figure 4: VA’s Regulatory Criteria for IRB Approval of Research Projects

Source: VA Regulations (38 C.F.R. section 16.111).

Similarly, IRBs differed in the information they had from investigators

about special protections for subjects who are likely to be vulnerable to

coercion or undue influence. VA regulations require that IRBs ensure that

additional safeguards are in place to protect the rights and welfare of such

subjects; however, the regulations do not specify the nature of such

safeguards. We analyzed project files for 27 studies designed to address
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issues involving psychiatric conditions that can be associated with a

diminished capacity for decision-makingpsychoses, mood disorders, and

organic mental disorders such as dementia. We found that the investigator

had included information about additional safeguards in applications for

IRB approval in only about half of these studies. For example, we reviewed

from two to six files for projects involving potentially vulnerable subjects

at each site and found references to additional protections in most of the

relevant project files we sampled at four sites. In contrast, at two other

locations no such documentation was evident in any of the IRB files we

reviewed for projects involving subjects with psychiatric disorders that

could affect decision-making.

Some sites have implemented procedures that afford special protections

for some such subjects. Examples follow.

• Subjects at one medical center who are recruited for psychiatric

research and whose mental illness can affect decision-making are

typically tested for their comprehension of central consent issues before

enrollment in a study.

• At another medical center, seriously mentally ill subjects who

participate in studies involving a risk that their symptoms might worsen

are monitored by a physician who is independent of the research and

who is assigned responsibility for deciding whether the subject should

remain in the study or be withdrawn.

• Alzheimer’s researchers at a third site have established research

registries for potential subjects, who were still able to give consent, and

their caregivers. By enrolling, subjects agree to allow medical

information to be entered into a data bank and to be contacted about

future studies. By agreeing to be contacted, however, potential subjects

have not consented to participate in future studies. Because these

potential subjects are recruited for future studies through registries, the

risk of undue influence that occurs when physicians recruit their

patients is minimized. Moreover, rules for these registries limit the

number of researchers who may contact each person, ensure that

potential subjects are recruited only for studies for which they are in

fact eligible, and allow registry managers to conduct follow-up surveys

to ensure that members of the registries are satisfied with the way

researchers treat them.
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Continuing Review We found that three VA-run IRBs did not meet VA’s regulatory requirement

that each study must be re-reviewed at intervals not to exceed 1 year.9

Regular re-review of a project and associated reports of problems allows an

IRB to assess the ratio of risks to benefits on the basis of data obtained

since the study began and to ensure that subjects are appropriately

informed of those risks and benefits. We examined the dates of continuing

review for 73 projects at 6 sites that had received initial approval more than

1 year before our visit. Of these projects, 54 (74 percent) had been reviewed

on time within the past year. The median delay for the 19 projects that were

not re-reviewed on time was about 1 month. At one VA-run site, only one of

the nine projects we reviewed that were more than 1 year old had been rereviewed on time. At another VA-run site, about half of the necessary

continuing reviews from our sample were conducted within 1 year, but

delays of up to 14 months occurred in the other half. The three universityrun IRBs we visited achieved high rates of timely continuing review.

Four VA-run IRBs we visited reviewed insufficient information when

conducting continuing review. OHRP has stated that compliance with

regulatory requirements for continuing review entails, at a minimum, IRB

review of

• the study protocol and any amendments;

• the current consent form;

• the number of subjects who have been enrolled; and

• information relevant to risks, including adverse events, unanticipated

problems involving risks to the subject or others, withdrawal of subjects

from the study, complaints about the study, and a summary of any recent

information relevant to risk assessment.

Only half of the IRBs we visited required the investigator to submit the

most recent version of the consent document or asked about subjects who

have withdrawn (or been withdrawn) from the study. All eight IRBs

required reports of the number of subjects who had participated and

adverse events.

9

Two university-run IRBs we visited re-review studies they have classified as posing a high

degree of risk every 6 months.
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IRB staff told us that reports of adverse events are difficult for IRBs to

handle. Regulations require investigators to report to the IRB unanticipated

problems involving risks to subjects, and IRBs must review adverse events

reported by all sites where the study is being conducted. The concerns we

heard on our site visits were similar to those described in several recent

reports on difficulties that IRBs nationwide face when handling large

numbers of adverse event reports in the absence of key information

necessary for their interpretation.10 For example, reports of adverse events

from drug studies do not indicate whether the subject who experienced the

adverse event had received an experimental drug or a different treatment,

such as a placebo. Regulatory bodies such as FDA and OHRP and research

sponsors such as the National Cancer Institute have recently argued that

adverse event reports from studies involving many subjects are often best

handled by special committees called data and safety monitoring boards.

These boards are typically established by research sponsors and include

statisticians and other scientists who analyze data collected during the

course of a clinical trial to detect risks to subjects. A few of the IRBs we

visited were attempting to develop systems to track adverse events.

Even when a data and safety monitoring board has been established to

analyze adverse event reports associated with a study, it is not required to

report its findings to IRBs. In VA these boards, referred to as data

monitoring boards, analyze only those adverse events reported in

multicenter studies funded by VA through a program called Cooperative

Studies. If results indicate that a study protocol or consent form must be

modified, reports are released by the coordinating center for that

cooperative study. It sends such reports to investigators and to the

associate chiefs of staff for research and development at participating

medical centers, with instructions to share the information with IRBs.

Reports are not submitted to IRBs directly. Similarly, VA’s policy manual

does not require that reports from data and safety monitoring boards

associated with non-VA-funded research be submitted to its IRBs or

medical centers. VA’s policy manual also does not require investigators or

IRBs to ascertain whether a data and safety monitoring board has been

established for studies in which its investigators participate.

10See, for example, HHS Office of Inspector General, Institutional Review Boards: A Time for

Reform, OEI-01-97-00193 (Washington, D.C.: HHS, June 1998).
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IRB Membership, Staff, and

Space

IRBs at the eight facilities we visited met certain membership

requirements, but two did not ensure that their members had no potential

conflicts of interest. We also found problems involving the number of IRB

staff or IRB space at five facilities. VA regulations require that IRBs have

sufficient administrative staff and space to review research and preserve

the confidentiality of files.

VA regulations for IRB membership include requirements that IRBs have at

least five members and must include a scientist, a nonscientist, and at least

one person who is not otherwise affiliated with the institution. (Individual

members may fulfill more than one criterion.) We checked IRB

membership rosters from the eight facilities we visited and found that all

met these requirements. In addition, VA regulations state that if the IRB

regularly reviews research involving a vulnerable category of subjects, then

consideration should be given to including at least one member who has

experience working with that group. Each of the eight IRBs we visited

included someone from the institution’s psychiatry, psychology, or other

mental health department, allowing access to specialized expertise with

regard to the potential vulnerabilities of mentally ill subjects.

We also found that each of the university-run IRBs we visited had members

who were on staff at the affiliated VA medical center. Inclusion of VA staff

helps fulfill VA’s regulatory requirement that IRBs have knowledge of the

local research institution, including the scope of research activities, types

of subjects likely to be involved, and the size and complexity of the

institution. Officials at the medical centers we visited that relied on the

IRBs of university affiliates reported that the larger academic community

of the university offered advantages for IRB membership, including a

broader range of expertise and reduced potential for conflicts of interest

because IRB members would be less likely to be research colleagues of

investigators. In addition, because all VA investigators at these three

medical centers also held faculty appointments at the university,

investigators did not need to apply for IRB approval from both the

university and VA. Officials at some of the medical centers that operated

their own IRBs reported that the advantages of doing so included

maintaining greater control over the research review process and the

increased likelihood that the IRB would know particular investigators and

veteran subjects.

We found that two VA-run IRBs did not ensure that their members had no

potential conflicts of interest. VA regulations state that no IRB may have a

member participate in an IRB initial or continuing review of any project in
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which that member has a conflict of interest. Although we found that

investigators who were IRB members appropriately abstained or recused

themselves from voting on their projects, two IRBs had, as a voting

member, the associate chief of staff for research and development for their

medical centers. The duties of a VA medical center’s associate chief of staff

for research and development include helping local investigators obtain

intramural or extramural research funds. As noted by OHRP, such

institutional officials thus have a potential conflict of interest in conducting

IRB reviews. These two officials told us, however, that they believed their

objectivity as IRB members was not compromised by their other

responsibilities.

Officials at four of the VA-run IRBs told us that they did not have adequate

staff to support IRB operations, as required by VA regulations. IRB

administrative staff provide crucial services such as reviewing applications

for completeness, corresponding with investigators, and maintaining IRB

records. In addition, some administrative staff serve on IRBs as experts on

regulatory issues. The VA-run IRBs we visited typically had one or two IRB

staff members who often had other responsibilities. For example, at one of

these sites, where a single staff person worked part-time for an IRB that

reviews 200 to 300 projects annually, the IRB chair reported that IRB

activities, such as suggesting revisions to consent forms, were curtailed

due to insufficient staff support. In May 2000, VA headquarters distributed

preliminary estimates for the number of administrative IRB staff that a

medical center should have. This guidance noted that staffing levels would

vary with the breadth and complexity of the research program. ORD

officials acknowledged that these benchmarks are a first approximation in

an effort to identify appropriate staffing levels.

In addition to staff, IRBs must have secure, private areas for the review and

discussion of confidential materials. IRBs also need office space for the

IRB chair and administrative staff, secure file storage, and computer

support. We found that IRB administrative staff at three sites—two of them

VA-run IRBslacked sufficient space to conduct their work or store all IRB

documents. For example, we observed IRB file folders stacked loosely on

top of file cabinets and on floors at one of these sites.

Documentation of IRB

Activities, Findings, and

Procedures

Six of the eight IRBs we visited did not maintain all the records required by

VA regulations. Inadequate documentation does not, in itself, place

subjects at risk. However, records of actions, deliberations, and procedures
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can help identify problems and corrective actions. Thus, documentary

failures prevent appropriate monitoring and oversight activities.

We found inadequate documentation in IRB files for about 9 percent of the

ongoing projects we reviewed. For example, some files failed to include

copies of all correspondence regarding IRB actions between the IRB and

investigators, or copies of all approved consent forms. VA regulations

require IRBs to retain these documents for at least 3 years after a study is

terminated. Required documents were missing from one or more IRB files

at five of the eight sites we visited.

VA regulations require each facility to maintain written procedures that it

will follow for conducting initial and continuing review, reporting IRB

findings and actions to investigators and appropriate officials, and

determining when special steps are necessary to monitor ongoing projects.

Our review indicated wide differences between facilities in the adequacy of

these documents. One VA-run facility has written procedures regarding

criteria for exemption from IRB review and for use of expedited review

procedures that are not in accordance with VA regulations. In addition, one

medical center had been cited by the FDA for failure to have adequate

written procedures in June 1999. The center agreed to have them in place

by August 1999 but did not do so until December 1999. The written

procedures available from three other VA-run IRBs did not include required

descriptions of procedures for conducting project review, determining

when additional monitoring of projects is necessary, or responding to

investigator noncompliance. In contrast, the written procedures of the

three university-run IRBs included all required procedures.

We found one instance in which failure to have required written policies

resulted in a further violation of VA regulations. Specifically, the previously

discussed esophageal biopsy, which was conducted without consent, was

not reported to the IRB or OHRP as required. VA regulations require

institutions to ensure that “serious or continuing noncompliance”11 by

investigators is reported to the IRB. A similar report must be filed with

OHRP if the institution has an HHS-approved assurance, as did the medical

center involved. The Associate Chief of Staff for Research and

Development told us that he did not report the event to the IRB or OHRP

because he followed the procedures for handling scientific misconduct

outlined in VA’s policy manual. Nothing in the IRB’s project files for that

11VA regulations, 38 C.F.R. section 16.103(b)(5).
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investigator indicated a finding or report of noncompliance, imposition of

any special restrictions or conditions for future research, or suspension or

termination of research.

We found that some IRB minutes did not comply with VA regulations,

which require the minutes to include a record of actions, the basis for

requiring changes in or disapproving research, and a written summary of

discussions of controverted issues and their resolution. At each site, we

reviewed from four to seven sets of minutes from IRB meetings held from

December 1997 through October 1999. IRB actions were almost always

clearly recorded in the minutes we examined at each site. Minutes from six

facilities routinely included written summaries of discussions and reasons

for actions. Two VA-run IRBs, however, rarely included substantive

discussions of these matters in their minutes.12

Facilities also varied in their compliance with VA regulations about

recording votes by IRB members during project review. The regulations

state that minutes of IRB meetings must indicate the number of members

voting for and against and the number of those abstaining. Two VA-run

IRBs typically recorded votes as unanimous, and minutes from one other

VA-run IRB recorded some votes as “approved,” without specifying vote

totals. Without exact numbers, the presence of a majority of IRB members

required during each vote cannot be confirmed. The voting records in

minutes from the remaining IRBs we visited were generally in compliance

with regulations. However, in one set of minutes from one site, we found

that the total number of votes cast for each decision consistently exceeded

the number of members listed in attendance.

12The absence of documentation does not necessarily indicate an IRB’s failure to ensure

appropriate additional safeguards. For example, one study discussed at an IRB meeting we

attended addressed mania, a psychiatric condition that could interfere with subjects’

capacity to provide informed consent. Because the investigator’s application to the IRB had

not addressed this issue, an IRB member had contacted the investigator and confirmed that

plans for the study included a series of steps to ensure that only competent subjects would

be recruited. These plans were reported to the IRB in detail before it voted to approve the

study, but nothing was recorded in the minutes about these recruitment procedures.
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Specific Weaknesses

Compromise VA’s

Protection of Human

Subjects

We identified three specific weaknesses in VA’s system for protecting

human subjects: not ensuring that research staff have appropriate

guidance, insufficient monitoring and oversight activity, and not ensuring

that the necessary funds for human subject protections are provided. These

weaknesses indicate that human subject protection issues have not

historically received adequate attention from VA headquarters.

Headquarters Has Not

Provided Adequate

Guidance

VA headquarters has not provided the guidance necessary to ensure that its

medical center staff are adequately informed about requirements for the

protection of human research subjects. We found that VA did not develop a

systemwide educational program, ensure that each of its facilities had an

appropriate training program in place, or provide guidance about training

to its facilities. We also found problems with the guidance VA provides

about procedures for handling informed consent records. Efforts to protect

the rights and welfare of human subjects are undermined when research

staff have not been given clear, comprehensive guidance about human

subject protections.

VA headquarters officials told us that VA did not have a systemwide

educational program devoted to human subject protection issues and that

more training is needed. We found that three of the medical centers we

visited had no educational program for IRB members, IRB staff, or

investigators. From its October 1999 survey of VA field management, VA

headquarters research officials learned that 12 of 22 Veterans Integrated

Service Networks13 did not have an adequate plan for the ongoing

education of IRB members, IRB administrative staff, or investigators about

the regulatory requirements for protecting human subjects. In particular,

medical centers with small research programs identified difficulties in

establishing educational programs. Those facilities that had programs often

reported that their university affiliates ran the training programs. A need

for increased educational guidance from headquarters was one of the most

commonly identified issues regarding human subject protections in the

survey. OHRP and HHS’s Office of Inspector General have stressed that

educational programs are critical to ensuring that IRBs comply with

regulations and are able to assess the acceptability of research proposals in

13In 1995, VA created 22 Veterans Integrated Service Networks, a new management structure

to coordinate the activities of and allocate funds to VA hospitals, outpatient clinics, nursing

homes, and other facilities in each region.
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light of those regulations and to ensuring that investigators understand

their responsibilities to protect human subjects.

On the other hand, two VA-run IRBs and the three university-run IRBs we

visited have implemented their own educational programs for both

investigators and IRB members and staff, generally without guidance from

headquarters. These programs included training new IRB members,

devoting a portion of IRB meetings to discussion of issues involving the

protection of human subjects, having some IRB members and staff attend

national conferences about IRB operations, and instituting a certification

program for investigators. Although we did not evaluate the adequacy of

these programs, one of these sites, a university affiliate, developed an

educational program that has been cited by HHS’s Office of Inspector

General as a best practice for training in human subject protection issues.

In addition to finding that VA did not have a systemwide educational

program, we found problems with VA guidance for documenting consent to

participate in research. VA’s policy manual includes two requirements that

go beyond its regulations for the protection of human subjects: (1) the

original signed consent form is to be placed in the subject’s medical record

and (2) investigators are to use a standard template developed by VA to

obtain consent.

A VA official in ORD told us that the purpose of requiring the placement of

signed research consent forms in medical records is to ensure that treating

professionals are aware of relevant medical information. He

acknowledged, however, that consent forms in medical records are not

always readily accessible to treatment staff because they may be housed in

old volumes of medical records maintained in storage areas. He also noted

that medical records personnel at some VA medical centers have discarded

consent forms rather than filing them. Our findings confirmed this. We

were unable to locate consent forms in 20 percent of 187 medical records

we reviewed at 7 of the 8 medical centers we visited. The remaining

medical center we visited recently developed a system for scanning signed

consent documents into its electronic medical records. However, these

consent forms were not located in a part of the electronic record that

would be routinely accessed by treating personnel.

Some medical center research staff suggested that placing a synopsis of

each study in a prominent place within subjects’ medical records would

ensure that treating professionals know about relevant research

participation, thus minimizing risks to subjects. We observed such a
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strategy at the Denver VA Medical Center, where a special flag in each

subject’s electronic medical record links the reader to a brief summary of

the study and to any investigational drugs involved. VA has not

implemented a systemwide procedure for indicating research involvement

in electronic medical records.

Another area of concern is VA’s standard template for informed consent.

This template includes space for investigators to enter study-specific

information and exact language for requirements common to all consent

forms. VA’s policy manual requires all VA investigators to use this form. We

identified several problems with this template.

• The template does not reflect the regulatory requirement that a contact

be provided for subjects to call with questions about their rights as

research participants.

• For studies conducted at both VA and non-VA locations, use of the VA

template created problems. In these cases, adherence to VA’s policy

requires development and IRB approval of two consent forms—one

based on VA’s template and one for the other location. Failure to use an

appropriate IRB-approved consent form in these dual-form studies was

the reason subjects signed nonapproved forms in 10 of the 33 cases

previously discussed.

• VA has not provided clear guidance about the role of a witness to the

consent process. Under VA regulations, a witness signature is needed

only when the elements of informed consent have been presented orally.

We found only 1 study in our sample of 146 in which consent was

obtained orally. However, we found that 405 of the 540 signed consent

forms we examined had been signed by a witness. OHRP guidance

indicates that a witness to a subject’s consent to participate in research

may be appropriate when aspects of the study create concerns about the

enrollment process. In such cases, an independent witness can provide

a valuable check on the consent process to certify, for example, that key

information was properly conveyed and that subjects were not unduly

coerced into participation. On the other hand, such a witness can

represent an unnecessary intrusion into a potential subject’s privacy.

VA’s consent template includes a line for the signature of a witness,

without specifying who may serve as a witness, what the witness is

attesting to, or the circumstances under which the witness is needed.

Similarly, VA’s policy manual lacks guidance about who should serve as a

witness or what that person’s role is.
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VA Has Not Exercised

Sufficient Oversight

We found that VA did not have an effective system for monitoring

protections of human subjects. Several instances follow.

• VA headquarters and affected medical centers were generally unaware

of regulatory investigations and impending actions by OHRP or FDA

against university-run IRBs until after the regulatory sanctions were

applied. VA was unable to ensure that FDA could notify VA of planned

inspections and provide copies of post-inspection correspondence

because VA was unable to provide FDA with a list of its university-run

IRBs until July 2000. VA did not have a complete list of those medical

centers that used their own IRBs, relied on a university-run IRB, or were

covered by an OHRP assurance until July 2000.

• Until OHRP’s regulatory action against the West Los Angeles VA Medical

Center, VA was unaware that each of its facilities was required to

provide a written assurance that it will comply with all federal

regulations regarding the protection of human subjects. Written

assurances facilitate proper oversight by ensuring documentation of

core agreements between VA headquarters and IRBs. They also can

provide evidence of knowledge of the regulations governing human

subject protections and demonstrate an institution’s commitment to

those protections. When VA subsequently obtained these assurances, it

did not require medical centers to submit local written procedures for

implementing human subject protections, as the regulations required.

Review of written procedures can indicate gaps or errors in required

local policies and procedures.

• VA headquarters has not provided medical centers with guidance in

ensuring access to minutes or other key information when they arrange

for the services of a university-run IRB. As a result, one medical center

we visited did not have access to the minutes of its university-run IRB,

and two medical centers affected by regulatory sanctions against their

affiliated universities had not monitored IRB minutes to assess

compliance with regulations.

Furthermore, we found that VA headquarters and medical centers we

visited did not effectively monitor investigators and their studies.

Specifically, only one of the eight medical centers we visited checked

whether investigators provided subjects with the correct IRB-approved

consent form. That medical center recently began checking one signed

consent form from each study as part of its continuing review. In addition,

the files of one university-run IRB we visited did not correctly identify

which researchers at the VA medical center were responsible for the

studies the IRB had approved because the medical center required that
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department chairs rather than researchers be listed as principal

investigators.

VA Has Not Ensured

Necessary Funding for

Human Subject Protections

Responsibility for funding human subject protections at medical centers is

diffused across several decisionmakers, each of whom may also have

competing priorities for the same funds. As a result, no one official is

responsible for ensuring that medical center research programs have the

resources necessary to support IRB operations and provide training in

human subject protections. Although VA has not determined the funding

amounts needed for human subject protection activities at the medical

centers, research officials at five of the eight medical centers we visited

told us that they had insufficient funds to ensure adequate operation of

their human subject protection systems.

We found that medical centers typically relied on several sources of funds

to support the indirect costs of research, which include human subject

protection activities. These sources included VA’s research appropriation,

VA’s medical care appropriation, and non-VA research sponsors such as

NIH or pharmaceutical companies. Different decisionmakers control the

funds potentially available to a medical center from these sources.

• The medical center’s associate chief of staff for research and

development controls the portion of the research appropriation targeted

for the indirect costs of research.

• The medical center’s director controls the portion of the medical care

appropriation allocated for indirect costs of research.

• Funds from non-VA research sponsors are generally held by a medical

center’s nonprofit research foundation and are controlled by its board of

directors, which has discretion over their use.

As a result, responsibility for ensuring that human subject protections are

adequately funded at each medical center is diffused across several

decisionmakers. In addition, the decisionmakers at some of the medical

centers we visited told us that they did not allocate additional funds for

human subject protection activities because they had to consider those

needs against the competing priorities of research support and medical

care delivery. Headquarters research officials confirmed that these

organizational tensions have created a situation in which there is no clear

focus of responsibility for funding human subject protection activities at

medical centers.
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One of the indirect costs of operating an IRB is the time spent by IRB chairs

and members meeting their IRB responsibilities. Headquarters research

officials told us that providing release time for IRB chairs and members has

been a long-standing problem. VA staff at the medical centers we visited

conduct their IRB activity as a collateral duty. We were told that the time

commitment for members, and particularly for IRB chairs, is significant.

Chairs and members spend time reviewing protocols before meetings,

corresponding with investigators, attending IRB meetings, and preparing

and reviewing documentation. We were told that the lack of release time

made it difficult to recruit and retain IRB chairs and members. We found

one instance in which a university paid VA to subsidize the costs of

covering the emergency room duties of a VA physician who chaired an IRB

that VA used. In another instance, a research official at one medical center

told us that IRB meetings are held in the evening and that the nonprofit

foundation pays IRB members. This arrangement allows members to fulfill

their primary VA obligations during the day without the collateral

responsibility of serving on the IRB.

Research officials at five of the eight medical centers we visited reported

that they had insufficient funds to ensure adequate operation of their

human subject protection systems. Of particular concern, officials told us,

was that lack of funds prevented hiring and training staff. Officials from

some medical centers also told us that their nonprofit research foundations

recognized that the level of VA funding for IRB operations was inadequate,

and therefore contributed varying amounts of funds for specific local

needs, such as training investigators in human subject protections or hiring

IRB staff. For example, one nonprofit contributed $25,000 in fiscal year

2000 to support investigator training in human subject protections. Some

VA nonprofit foundations and universities are charging private industry

sponsors a fee for IRB review of their projects to help support IRB

operations. However, headquarters research officials told us that VA has

not determined the funding amounts needed for human subject protection

activities at the medical centers. They said that such a determination is

necessary for planning funding levels and ensuring that human subject

protection activities are appropriately funded.
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Local Actions Address

Problems Identified by

Regulators But

Systemwide Focus

Slow to Develop

Substantial corrective actions have been implemented at three medical

centers in response to sanctions by regulatory agencies against their

human research programs. These steps represent progress in meeting the

requirements imposed by regulators and VA management, and each of the

facilities, despite some difficulties, has resumed human research activities.

VA has, however, been slow to identify systemwide deficiencies and to

obtain information needed to step up oversight of human subject

protection systems at its medical centers. Nonetheless, VA’s recent

responses, such as establishment of the Office of Research Compliance and

Assurance (ORCA) to monitor human subject protections at individual

medical centers and across the system, are promising.

Substantial Local Actions

Taken to Correct

Noncompliance

The three medical centers and their affiliated universities we visited that

had actions taken against them by regulators—West Los Angeles, Chicago

Westside, and Denver—have made progress in implementing substantial

changes to their human subject protection systems. Their written

procedures appear to be in compliance with regulations, and their staffing

levels seem reasonable for the workload.

These medical centers and their affiliated universities, along with two

others, had been affected by serious regulatory sanctions. Regulators found

numerous problems at these institutions, including failure to obtain

informed consent, failure to conduct adequate and timely continuing

review of research, and failure to have adequate written IRB policies and

procedures. OHRP deactivated West Los Angeles VA Medical Center’s

multiple project assurance with HHS on March 22, 1999. It restricted the

assurance held by the University of Illinois at Chicago, which served as the

IRB of record for Chicago Westside VA Medical Center on August 27, 1999.

On September 13, 1999, FDA suspended certain research projects at a

consortium of six Colorado research institutions, including the Denver VA

Medical Center. The University of Colorado, the location of the

consortium’s IRB, suspended research with human subjects at all six sites

in response to a letter from OHRP dated September 22, 1999, which raised

concerns about IRB noncompliance with regulations. On December 17,

1999, OHRP restricted the multiple project assurance with Virginia

Commonwealth University, which had been the IRB of record for the

Richmond VA Medical Center. FDA had issued a warning letter to the

university several months earlier about the IRB operations. On January 19,

2000, OHRP restricted the multiple project assurance with the University of
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Alabama at Birmingham, which was the IRB of record for the Birmingham

VA Medical Center.

There were three immediate responses in West Los Angeles, Chicago, and

Denver to the sanctions imposed by regulatory agencies: a suspension of

enrollment of new subjects in almost all research projects; an assessment

of the appropriateness of the continued participation of previously enrolled

subjects; and a determination by VA headquarters and affiliated universities

of actions needed to improve human subject protection programs at each

site. Each medical center or affiliated university that we visited then made

extensive changes to its human subject protection system. These changes

involved reconstituting IRBs; increasing the number of IRB administrative

staff; training IRB members, staff, and investigators in the principles and

procedures of human subject protection; creating or extensively revising

IRB procedures; increasing working space for IRB operations; creating new

databases for tracking protocols through the review process; re-reviewing

projects; and resuming research activities. As of February 2000, all projects

at the West Los Angeles VA Medical Center had been re-reviewed by an

IRB. As of June 2000, all projects for the Chicago Westside VA Medical

Center had been submitted to university-run IRBs for re-review, and as of

July 2000, all projects had been re-reviewed for the Denver VA Medical

Center. The Denver VA Medical Center’s IRB has been informed by OHRP

and FDA that as of June 2000, its corrective actions are appropriate. On

July 18, 2000, OHRP removed the restriction on the University of Illinois at

Chicago stating that the university has developed and implemented an

improved system for the protection of human subjects in research and has

adequately completed all required actions.

Responses varied across sites, however, because of differing

responsibilities for IRB operations and site-specific problems that needed

to be addressed. For example, at the West Los Angeles VA Medical Center,

which operated its own IRB, VA headquarters and medical center officials

made extensive changes in research personnel responsible for human

subject protections. From April 1999 to the time of our visit in March 2000,

about 50 employees had been rotated through the program with a few

assigned full-time to support research and development and IRB

operations. The university affiliated with the Chicago Westside VA Medical

Center hired a nationally known expert in human subject protections to

lead a comprehensive restructuring of its IRB operations.

We identified two issues of concern at the West Los Angeles VA Medical

Center. First, VA’s authorization of a resumption of IRB operations at West
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Los Angeles on April 19, 1999—less than 1 month after OHRP’s deactivation

of its multiple project assurance—was premature. At that time, the medical

center still lacked approved, written procedures for operation. Such

procedures are required by regulations. It also was relying on untrained

administrative staff to assist the newly formed IRBs. Furthermore, VA’s

investigators had not been trained in human subject protection issues.

Our second issue of concern is that officials at the West Los Angeles VA

Medical Center were particularly slow to respond to OHRP’s requirements.

In its 1999 letter deactivating the medical center’s multiple project

assurance, OHRP noted the medical center’s continued lack of

responsiveness to issues raised by OHRP over a 5-year period. For

example, in 1994, OHRP required that the medical center establish a data

and safety monitoring board to oversee studies involving subjects with

severe psychiatric disorders. It took until February 2000 for medical center

officials to approve standard operating procedures for the data and safety

monitoring board and to hire its staff.14 In another instance, OHRP cited the

medical center in 1995 for a lack of adequate written procedures for human

subject protections. However, it took the medical center until February

2000 to develop and approve these procedures. Similarly, in 1995, OHRP

strongly recommended that medical center officials develop an ongoing

training program for investigators. Medical center officials told us they plan

to begin such training in September 2000.

At the Chicago Westside VA Medical Center, we found that, in permitting

the continued participation of previously enrolled subjects in some

projects, VA and the university-run IRBs did not ensure that continuing

review requirements were met for these projects. When we raised this issue

with officials during our February 2000 visit, they acknowledged this lack

of oversight. They have since required investigators for these projects to

submit materials for continuing review.

We found that the Chicago Westside VA Medical Center did not play an

active role in assisting its university-run IRBs to improve its human subject

protection system. The medical center organizational chart for research

and development did not show any linkage with the three university IRBs.

The medical center had only one representative among the 18 members of

14The medical center established such a board in 1995, but it met only briefly. Although an

interim board met several times in 1999 after OHRP’s regulatory action, its minutes state

that it was unable to function due to a lack of staff.
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the biomedical IRB and one on the 17-member combined biomedicalbehavioral IRB. There were no VA representatives on the third IRB, an IRB

that reviewed behavioral studies because, as officials told us, VA conducted

few such studies. At the time of our visit to the medical center—over 5

months after the OHRP action—the medical center had done little to

improve its communication with the IRBs despite the recommendation to

do so made by the VA headquarters site visit team in September 1999.

Although one local VA research official participated on a university

committee charged with prioritizing studies for re-review and made

suggestions to modify the IRB form used by investigators to submit

protocols for review, the medical center had not established a mechanism

for routine contact with and monitoring of the IRBs. In addition, the

medical center was unaware of VA protocols being submitted for IRB

review, IRB actions to approve or disapprove continuation of studies, and

serious adverse events that could affect veterans who were subjects of

research. At the time of our visit, the medical center was unable to provide

us with reliable data on which investigators had been trained by the

university in human subject protection regulations and issues.

Furthermore, as of July 2000, the medical center had not responded to a

May 2000 request from the university for comments on their new IRB

procedures manual.

In contrast, the Denver VA Medical Center established mechanisms to

enhance communication between the research and development program

and its three university-run IRBs by having regular meetings and increasing

the number of VA personnel on the IRBs. As of June 2000, the chair of one

of the university-run IRBs and the co-chair of another were VA employees.

Five other VA employees served as members of the IRBs. Medical center

personnel were working closely with their counterparts in the university to

design a database that would allow VA research officials access to VA

project information at the university-run IRBs.

When the IRBs at their affiliated universities faced sanctions by regulatory

agencies, officials at the Richmond and Birmingham medical centers chose

to establish their own IRBs. They told us they did so to increase their

control over the research review process. These officials told us they each

created an IRB, developed written procedures, trained IRB members, and

resumed their research programs after re-reviewing their projects. In

addition, the Birmingham VA Medical Center has trained investigators and

IRB staff, and the Richmond VA Medical Center has trained research staff.
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Systemwide Approach Slow

to Develop

VA has been slow to recognize and address systemwide deficiencies in its

human subject protection activities. Although OHRP identified problems

with human subject protections at the West Los Angeles VA Medical Center

in 1994, VA did not have a plan to address systemwide concerns involving

research until July 1998. VA did not begin to implement systemwide

changes until after OHRP took regulatory action against the medical center

in March 1999. VA’s initial responses to regulators’ actions affecting the

West Los Angeles VA Medical Center and other medical centers were crisisdriven and site-specific. Specifically, headquarters formed teams that

conducted site visits to determine actions needed at the affected medical

centers. Headquarters monitored corrective actions at the medical centers

primarily through an exchange of reports and correspondence.

In July 1998, VA developed a plan to reorganize its field research

operations. This plan addressed a variety of research concerns including

the involvement of human subjects and the ethical conduct of studies. Only

recently, however, has VA headquarters begun to implement systemwide

changes to improve its human subject protections. Its steps have included

providing information to investigators and research staff, obtaining

information about medical centers’ research programs, and making

organizational changes to enhance monitoring and oversight of research

involving human subjects. These steps have been slowly implemented, but

they provide a promising foundation for improvements to protections for

human subjects in VA research.

Providing Information to

Investigators and Local Research

Staff

VA headquarters officials have taken several steps to provide information

to VA investigators and local research staff about human subject

protections. The initial information provided by ORD described issues at

affected medical centers. It was not until October 1999 that ORD provided

medical centers with specific actions that could be helpful in strengthening

their human subject research programs.

Starting with its May 1999 bimonthly conference call with associate chiefs

of staff for research and development, ORD began discussing human

subject protection issues in light of the March 1999 OHRP action against

the West Los Angeles VA Medical Center. Also in May 1999, they began to

plan a series of educational programs for investigators, IRB members,

research administrators, and medical center directors focused on human

subject protection issues. In October 1999, ORD held a nationwide

videoconference in which OHRP and VA research officials discussed

human subject protection issues and answered questions from VA staff.
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Also in October 1999, ORD began to list on its Web site human subject

protection information available through OHRP and other organizations

and distributed a summary of lessons learned from institutions that had

been affected by recent sanctions by regulatory agencies. ORD officials

told us they expect to complete a draft of a revised policy manual for VA

research by September 2000.

ORCA officials have also implemented initiatives. For example, it began

bimonthly teleconference calls in February 2000 with IRB and research

officials at medical centers to share information and obtain input on human

protection issues. In March 2000, ORCA issued its first newsletter to local

research officials. This educational newsletter, planned as a twice a month

series, will address informed consent and human subject protection issues.

In April 2000, ORCA convened a group of VA research staff and outside

experts in human subject protections to identify training courses

developed elsewhere that VA could use. The group also plans to develop

guidance and strategies for VA to use to train IRB staff, members, and

investigators. Beginning in May 2000, ORCA sent the first of three notices

to local research programs alerting them of current human subject

protection concerns. In June 2000, it began issuing a monthly set of news

clippings on human subject protection issues.

In 1999, VA’s National Center for Ethics sponsored a conference on ethics in

research and issued related reports including a discussion of principles for

researchers’ consideration on the principles guiding the ethical conduct of

research involving participants with impaired capacity to consent. VA is

participating in national efforts to develop policies and procedures for

protecting these participants.15

Obtaining Information About

Local Research Programs

VA headquarters officials have acknowledged that they lacked key

information about research programs at medical centers. To obtain more

15See VHA National Center for Ethics, Challenges and Change: Reports From the Veterans

Health Administration (VHA) Bioethics Committee (Veterans Health Administration, Office

of the Under Secretary, Washington, D.C.: 1999). VA’s policy manual addresses a narrow set

of circumstances related to questions of capacity to consent, namely, cases in which a

person has been found to be incompetent. VA plans to develop guidance regarding consent

when ability to consent is in question such as when decision-making capacity fluctuates or

is declining. The National Bioethics Advisory Commission (NBAC) has also addressed these

complicated issues in Research Involving Persons With Mental Disorders That May Affect

Decisionmaking Capacity (NBAC, Rockville, Md.: December 1998). VA is participating with

the National Science and Technology Council to consider how to implement NBAC

recommendations.
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accurate and complete information, they have taken several steps.

Examples follow.

• In October 1998, VA research officials began to develop a new

computerized data system to improve the comprehensiveness and

accuracy of data about studies involving human subjects at VA medical

centers. As of June 2000, development was still under way.

• In April 1999, VA asked its medical centers whether they operated their

own IRB or relied on the IRB of an affiliated university. VA also asked

whether assurances with OHRP were involved. ORCA finished verifying

this information in July 2000.

• In October 1999, ORD sent a questionnaire to the director of each

Veterans Integrated Service Network to assess the adequacy of staffing

and support for human subject protections at the medical centers in

each network. A lack of adequate resources was one of the three most

common problems identified. Sixteen of the 22 networks reported

inadequate IRB support, including staff, space, and equipment. Fourteen

networks identified education as a priority issue and cited the need for

educational opportunities and guidance documents. In May 2000,

headquarters sent information to the networks on educational

opportunities and made suggestions for the level of administrative

staffing of IRBs.

• By February 2000, VA had accepted an assurance from each medical

center conducting human research that it would comply with

regulations for the protection of human subjects.

• In April 2000, VA’s Chief Financial Officer reported that VA would

implement a system to allow for the explicit accounting of funds from

the medical care appropriation that are used by medical centers to

support the indirect costs of research.

These steps are necessary to obtain key information about human subject

research programs at medical centers. This information will allow

headquarters officials to determine the additional steps that may be needed

locally or systemwide to ensure compliance with regulations and the

protection of human subjects.

Implementing Organizational

Changes to Enhance Monitoring

and Oversight

VA is implementing two organizational changes to enhance its monitoring

and oversight of human research programs. The Under Secretary for Health

announced these changes in April 1999, but as of August 2000, they had not

been fully implemented. They are designed to allow routine onsite

monitoring of research programs, thereby helping medical centers identify

weaknesses and develop strategies to improve compliance with regulations
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and the protection of human subjects. Although promising in concept, it is

too soon to determine whether the initiatives described below will fulfill

their objectives.

• In April 1999, VA announced the creation of ORCA. VA did not begin

staffing this office until it appointed the chief officer in December 1999.

VA plans that ORCA will have eight headquarters staff by September 30,

2000, and four regional offices with four staff each by December 31,

2000. As of July 2000, VA had not completed its staffing of the

headquarters component and had not filled any regional office positions.

Although ORCA’s specific plans for monitoring medical center research

activities were still under development in summer 2000, officials told us

that they planned to conduct a site visit on a rotating basis to each

medical center conducting human research. As of July 2000, ORCA

officials told us they had not developed a specific schedule for

conducting these visits, but they expect to do so when the regional

offices are staffed. ORCA’s headquarters has a budget of $600,000 for

fiscal year 2000 and $1.5 million for fiscal year 2001. The regional offices

have a budget of $1.9 million for fiscal year 2000 and $2.3 million for

fiscal year 2001.

• In August 2000, VA awarded a $5.8 million, 5-year contract for external

accreditation of its IRBs. This contract requires the contractor to

conduct a site visit every 3 years to each medical center conducting

human research. The contractor is expected to review IRB performance

and to assess its compliance with regulations. VA officials told us that

VA expects that the university-run IRBs it uses will grant access to the

accreditation team. VA is the first research organization to have an

external accreditation of its human research programs.

Conclusions VA has not ensured that its medical centers have fully implemented

required procedures for the protection of human subjects. Primary

responsibility for implementation of these protections lies with local

institutionsmedical centers and their IRBs. Although we cannot

generalize from our sample to the universe of VA research institutions, we

found sufficient evidence of noncompliance with applicable federal

regulations to be concerned. We also found that incomplete access to

information about adverse events experienced by research participants

made it difficult for IRBs to fulfill their mandate. We found widespread

weaknesses in the management of human subject protections that VA had

not identified because of its low level of monitoring. VA’s past failure to

ensure that its research facilities had the resources, including staff,
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training, and guidance, needed to accomplish their obligations suggests

that headquarters has not given attention or sufficient priority to the

protection of human subjects.

Despite a 5-year record of problems at the West Los Angeles VA Medical

Center, VA did not begin to implement systemwide improvements until

OHRP took regulatory action against the medical center. VA’s initial actions

were primarily crisis-driven and site-specific. Generally, appropriate

corrective actions have now been implemented at each of the three medical

centers we visited that were affected by regulatory sanctions. However,

VA’s progress on systemwide improvements to its human subject protection

system has been slow. VA only recently began to obtain the information it

needs—such as identifying which medical centers use their own IRBs and

which rely on university-run IRBsto plan necessary systemwide

improvements.

Some facilities we visited and projects we reviewed appeared to have

reasonably strong protections for the rights and welfare of participants.

VA’s recent efforts to improve its human subject protections systemwide

and its commitment to developing an effective oversight and monitoring

system are important steps toward ensuring that all VA facilities meet

requirements, but it is too soon to determine how well these initiatives will

fulfill their objectives.

VA has a long history of important contributions to medical research, and it

could set important precedents in improving human research protections.

For example, VA is the first federal agency to take action to externally

accredit its IRBs. Whether VA medical centers establish their own IRBs or

work with university-run IRBs, VA needs to ensure that the IRBs have

adequate resources, and VA must exercise its oversight authority if it is to

know what guidance, preventive efforts, or corrective actions are needed.

Recommendations To strengthen VA’s protections for human subjects, we recommend that the

Acting Secretary of Veterans Affairs direct the Under Secretary for Health

to take immediate steps to ensure that VA medical centers, their IRBs—

whether operated by VA or not—and VA investigators comply with all

applicable regulations for the protection of human subjects by

• providing research staff with current, comprehensive, and clear

guidance regarding protections for the rights and welfare of human

research subjects;
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• providing periodic training to investigators, IRB members, and IRB staff

about research ethics and standards for protecting human subjects;

• developing a mechanism for handling adverse event reports to ensure

that IRBs have the information they need to safeguard the rights and

welfare of human research participants;

• expediting development of information needed to monitor local

protection systems, investigators, and studies and to ensure that

oversight activities are implemented; and

• determining the funding levels needed to support human subject

protection activities at medical centers and ensuring an appropriate

allocation of funds to support these activities.

Agency Comments In written comments (see app. II) on a draft of this report, VA agreed with

our findings and recommendations. VA said that initiatives it has already

planned and implemented will provide a foundation for a national

prototype in effective human subject protections.

Although VA agreed that its implementation of a systematic approach to

human subject protections has been slow to develop, it provided

clarification regarding statements in the draft report that VA had not

focused attention on systemwide weaknesses until after the March 1999

regulatory action at the West Los Angeles VA Medical Center. VA stated that

planning for the establishment of regional offices for risk management and

research compliance had begun almost 1 year earlier. We have modified the

report accordingly.

In concurring with our recommendations to provide research staff with

current, comprehensive, and clear guidance and training about human

subject protections, VA identified initiatives planned or under way to

improve its guidance, disseminate the guidance, and train research staff in

its use. These initiatives represent promising efforts. Whether VA’s plans for

guidance and training are effective will depend upon implementation

details. VA must ensure that its research staff have access to and receive

current guidance and training to enable them to meet their obligations to

protect the rights and welfare of human research subjects.

VA agreed with our recommendation to improve adverse event reporting

and said it has expanded the distribution of reports from its data

monitoring boards to include all appropriate IRBs. VA has also indicated its

intention to participate in governmentwide efforts to address this matter.

These are important first steps in ensuring that IRBs have the information
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they need to safeguard the rights and welfare of human subjects. However,

because the VA monitoring boards analyze only those adverse events

reported in VA’s multicenter Cooperative Studies program, further efforts to

address reports of adverse events from other studies are necessary.

VA also concurred with our recommendation to improve monitoring and

oversight of human subject protection activities and identified several

activities it has planned or implemented, such as external accreditation of

IRBs and establishment of performance measures related to human subject

protections for medical center research officials. Oversight and monitoring

are essential if VA is to know whether the procedures at its medical centers

and affiliated universities comply with human subject protection

regulations. Whether the actions VA plans to take in this area will be

sufficient depends on how effectively they are implemented.

Finally, VA concurred with our recommendation to determine the funding

levels needed to support human subject protection activities at medical

centers and then ensure an appropriate allocation of funds to support these

activities. VA’s response notes that it has begun to account for medical

center expenditures associated with research support—an important first

step toward determining necessary funding levels. However, VA did not

discuss how it would ensure that funds are appropriately allocated to

human subject protection activities. As we noted, organizational tensions

within VA have created a situation in which there is no clear focus of

responsibility for funding such activities at medical centers. Until this is

addressed, we are concerned that VA cannot ensure that human subject

protections will be appropriately funded.

VA officials also provided technical comments, which we incorporated

where appropriate.

We are sending this report to the Honorable Hershel W. Gober, Acting

Secretary of Veterans Affairs, appropriate congressional committees, and

other interested parties. We will also make copies available to others upon

request.
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Please contact me at (202) 512-7101 if you or your staff have any questions.

An additional GAO contact and the names of other staff who made major

contributions to this report are listed in app. III.

Cynthia A. Bascetta

Associate Director, Veterans’ Affairs and

Military Health Care Issues
Page 46 GAO/HEHS-00-155 VA Protections for Human Subjects

Appendix I

Scope and Methodology ApApenednxidexiIs

Our objectives were to (1) assess the Department of Veterans Affairs’ (VA)

implementation of human subject protections, (2) identify whether

weaknesses exist in VA’s system for protecting human subjects, and (3)

assess VA’s actions to improve human subject protections at those sites

affected by sanctions imposed by regulatory agencies and throughout VA’s

health care system.

To achieve these objectives, we reviewed VA, Food and Drug

Administration (FDA), and Department of Health and Human Services

(HHS) regulations and VA policies for the protection of human subjects;

interviewed VA research officials; visited selected VA medical centers to

assess local implementation of these standards; and visited VA medical

centers affected by research restrictions. We also interviewed officials

from the Office for Human Research Protections (OHRP) and reviewed

HHS guidance. We reviewed records of congressional hearings; reports on

human subject protections, including those issued by the HHS Office of

Inspector General, the Institute of Medicine, and the National Bioethics

Advisory Commission; and the literature on the history of human subject

protections.

To assess VA’s implementation of human subject protections, we conducted

site visits at eight VA medical centers: Atlanta, Ga.; Baltimore, Md.;

Cleveland, Ohio; Dallas, Tex.; Louisville, Ky.; Providence, R.I.; Seattle,

Wash.; and Washington, D.C. We selected sites to reflect major differences

in VA research programs (see table 1). First, we selected medical centers

that differed in the number of studies they conduct with human subjects.

Second, we selected medical centers that differed in the institutions

responsible for operating the committee tasked with reviewing each study

to assess its protections for human subjectsthe institutional review

board (IRB). Third, we selected facilities that differed in the assurance

arrangements they had with OHRP. Some institutions had filed a legally

binding commitment to comply with federal regulations called a multiple

project assurance with OHRP; other institutions had not. Our results from

these eight medical centers cannot be generalized to other sites.
Appendix I

Scope and Methodology

Page 47 GAO/HEHS-00-155 VA Protections for Human Subjects

Table 1: Characteristics of Sampled VA Medical Centers

a

These data, obtained from VA’s Research and Development Information System, were the most

recent data regarding the number of studies involving human subjects available at the time we selected

our sites.

b

The Atlanta VA Medical Center’s IRB-of-record is that of Emory University. At the time of our visit,

Emory had two IRBs that together review about 2,000 projects each year.

c

The Baltimore VA Medical Center’s IRB-of-record is that of the University of Maryland, Baltimore. Its

two IRBs together review about 1,200 projects each year.

d

Consent forms in Baltimore were in electronic rather than paper medical records.

e

The Cleveland VA Medical Center is one of four cosignatories to a multiple project assurance; the

others are Case Western Reserve University, the University Hospitals of Cleveland, and the

MetroHealth System. Each of these four institutions has its own IRB. Representatives of each IRB

serve on a single IRB advisory committee designed to promote discussion of concerns and continuing

improvement of the IRB system.

f

The Seattle VA Medical Center’s IRB-of-record is that of the University of Washington, which also

serves the Boise VA Medical Center in Idaho. The University of Washington has three IRBs, two

restricted to medical research and one restricted to behavioral research; together they review about

3,000 projects per year. The University of Washington has agreements with several other institutions

for specific IRB reviews. For example, in recognition of the specialized expertise required for cancer

research, the IRBs of Swedish Hospital or the Fred Hutchinson Cancer Research Center review all

such protocols, including VA cancer studies. We obtained IRB records for one project from each of

those sites.

At each site, we interviewed local research personnel, including the

associate chief of staff for research and development, the IRB chair, and

staff responsible for providing administrative support to the IRB. We

attended an IRB meeting at six sites (Atlanta, Cleveland, Dallas,

Providence, Seattle, and Washington, D.C). We also reviewed written

procedures describing how the IRB and institution implement human

VA medical

center

Institution

responsible for

operating IRB

Multiple

project

assurance

filed with

OHRP

Number of VA

human research

studies reported

in fiscal year

1998a

Number

of

studies

in our

sample

Number of

signed

consent

forms sought

from

investigators

Number of

signed

consent

forms

sought in

medical

records

Number

of IRB

minutes

in our

sample

Atlanta Universityb Yes 217 20 59 30 6

Baltimore Universityc Yes 356 17 87 15d 5

Cleveland VA and

Affiliatese

Yes 67 15 59 20 4

Dallas VA Yes 235 20 92 32 5

Louisville VA No 102 15 57 23 7

Providence VA No 90 20 74 36 5

Seattle Universityf Yes 354 22 72 29 5

Washington, D.C. VA Yes 320 17 40 17 5
Appendix I

Scope and Methodology

Page 48 GAO/HEHS-00-155 VA Protections for Human Subjects

subject protections and a sample of four to seven sets of IRB minutes from

the last 2 years (December 1997 through October 1999) at each site.

We randomly selected a sample of 15 to 22 projects at each site for detailed

analysis. To ensure that our selection included research on potentially

vulnerable participants, we oversampled studies designed to provide

information about psychiatric conditions that can affect decision-making

capacity, such as dementia, schizophrenia, and depression. Up to onefourth of the studies we sampled at any one site were in this category. We

examined IRB records for each project in our sample (146 in all, including

27 psychiatric studies). For the subset of 138 studies that required written

consent, we reviewed the most recently approved consent form.1 To

determine whether subjects had signed appropriate consent forms

indicating willingness to participate in research and whether those forms

were available as required, we examined about 5 signed consent forms

maintained in investigators’ files from each of 125 studies. We also tried to

obtain about two signed consent forms from each project in paper medical

records. This sample included 98 projects. Some medical records could

not be made readily available to us. For example, some medical records

were at a different location during our visit.

To assess corrective actions at VA medical centers in response to

restrictions on their human research programs, we conducted 2-day visits

to three facilities where human research was suspendedChicago

Westside, Ill.; Denver, Co.; and West Los Angeles, Ca.2 Our site visit team

included an expert in human subject protections under contract to us. For

each of these sites, we examined the OHRP and FDA reports associated

with the restriction of human research, action plans for resolving identified

problems, documents regarding current human subject operations, and the

status of the research program and human subject protections at the time

of our visits (February 2000 and March 2000). We discussed these matters

with medical center officials and officials from IRBs at affiliated

universities when they were involved. In addition, we reviewed documents

and interviewed officials from two other medical centersBirmingham,

Ala., and Richmond, Va. These facilities were also affected when the IRBs

1

Eight projects in our sample did not require written informed consent because they were

exempt from IRB review (five studies) or because informed consent procedures were

appropriately waived for all subjects (three studies).

2

The West Los Angeles VA Medical Center is now part of the VA Greater Los Angeles

Healthcare System.
Appendix I

Scope and Methodology

Page 49 GAO/HEHS-00-155 VA Protections for Human Subjects

of their affiliated universities were cited for noncompliance with federal

regulations. Both have now established their own IRBs.

We conducted our work between June 1999 and August 2000 in accordance

with generally accepted government auditing standards.
Page 50 GAO/HEHS-00-155 VA Protections for Human Subjects

Appendix II

Comments From the Department of Veterans

Affairs ApendxiI
Appendix II

Comments From the Department of Veterans

Affairs

Page 51 GAO/HEHS-00-155 VA Protections for Human Subjects
Appendix II

Comments From the Department of Veterans

Affairs

Page 52 GAO/HEHS-00-155 VA Protections for Human Subjects
Appendix II

Comments From the Department of Veterans

Affairs

Page 53 GAO/HEHS-00-155 VA Protections for Human Subjects
Appendix II

Comments From the Department of Veterans

Affairs

Page 54 GAO/HEHS-00-155 VA Protections for Human Subjects
Page 55 GAO/HEHS-00-155 VA Protections for Human Subjects

Appendix III

GAO Contact and Staff Acknowledgments ApendxiI

GAO Contact Bruce D. Layton, (202) 512-6837

Staff

Acknowledgments

Cheryl Brand, Kristen Joan Anderson, Jacquelyn Clinton, Patricia Jones,

and Janice Raynor also made key contributions to this report. In addition,

Barry Bedrick and Julian Klazkin provided advice on legal issues, and

Deborah Edwards provided advice on methodological issues.
Page 56 GAO/HEHS-00-155 VA Protections for Human Subjects

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Oversight of Privacy Protections Is Limited (GAO/HEHS-99-55).

Medical Records Privacy: Uses and Oversight of Patient Information in

Research (GAO/T-HEHS-99-70).

Scientific Research: Continued Vigilance Critical to Protecting Human

Subjects (GAO/T-HEHS-96-102).

Scientific Research: Continued Vigilance Critical to Protecting Human

Subjects (GAO/HEHS-96-72).

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