United States General Accounting Office

GAO Report to Congressional Requesters

July 1996 NIH EXTRAMURAL

CLINICAL RESEARCH

Internal Controls Are

Key to Safeguarding

Phase III Trials Against

Misconduct

G O A

years

1921 - 1996

GAO/HEHS-96-117

GAO United States

General Accounting Office

Washington, D.C. 20548

Health, Education, and

Human Services Division

B-266107 

July 11, 1996

The Honorable William S. Cohen

The Honorable Nancy L. Kassebaum

United States Senate

The National Institutes of Health (NIH) is a major sponsor of federally

funded scientific research. In fiscal year 1995, NIH sponsored about

$9 billion in extramural research—research conducted by entities outside

of NIH. About $1.2 billion was spent on Phase III clinical trials.1

In the early 1990s, disclosure that falsified data had been used in a large

Phase III clinical trial evaluating alternative treatments for breast cancer

raised concern that the results of this multimillion dollar trial had been

compromised.2

 This case and others raised questions about the

effectiveness of internal controls in safeguarding the integrity of clinical

trial data and NIH’s oversight of federally funded research it sponsors.

Because of your concerns, you asked us to determine how NIH oversees

the clinical trials it sponsors and whether internal controls are in place to

prevent misuse of federal funds and safeguard the integrity of clinical trial

data. To respond to your request, we determined the oversight

responsibilities of NIH and identified controls used to prevent and detect

misconduct in Phase III clinical trial research. We also reviewed NIH’s

approach to monitoring performance of its institutes that sponsor clinical

trials and efforts to implement agencywide policy guidance on misconduct

in research. Our review did not include an evaluation of efforts to

investigate allegations of fiscal and scientific misconduct. The Department

of Health and Human Services’ (HHS) Office of Research Integrity (ORI)

investigates some allegations of misconduct in research and oversees

investigations conducted by extramural research institutions. In our

1

NIH defines a Phase III clinical trial as any broad-based clinical study, usually involving several

hundred human participants, that evaluates either an experimental treatment compared with a control

or a comparison of two or more existing treatments. The goal of these trials is to develop scientific

evidence as the basis for considering changes in either the standard of care or public health policy.

Generally, Phase I trials involve experimental drug treatments, determining toxicity and safe drug dose

levels. Phase II trials evaluate the effectiveness of a particular treatment and look for side effects using

a small number of trial participants.

2

The National Surgical Adjuvant Breast and Bowel Project Protocol B-06, a clinical trial sponsored by

the National Cancer Institute (NCI), included an evaluation of the value of lumpectomy and breast

irradiation for treating women in the early stages of breast cancer. Publicity generated by the

discovery that the study included fraudulent data on patients enrolled by St. Luc Hospital in Montreal

raised concern about the overall accuracy of the data and conclusions. An NCI audit, however,

concluded that the data on which the trial’s analysis and results were based were adequate. NIH is

seeking restitution of costs related to this case of scientific misconduct.

Page 1 GAO/HEHS-96-117 NIH Phase III Clinical Trials
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August 1995 report, we stated that ORI had made progress in its handling of

misconduct cases since its establishment in May 1992. However, it still

faced a substantial case backlog and lengthy delays in completing its

work.3

Our review included a nonstatistical sample of four Phase III clinical trials

that had multiple sites participating in the research and were funded

through cooperative agreements—a frequently used funding mechanism in

fiscal year 1994. We conducted our work at NIH and 2 of its 17 institutes

that sponsor research—the National Institute on Aging (NIA); National

Heart, Lung, and Blood Institute (NHLBI); and several research sites. (See

app. I for a detailed discussion of our scope and methodology.) Our work

was performed between September 1995 and May 1996 in accordance with

generally accepted government auditing standards.

Results in Brief Individual NIH institutes and the institutions receiving the funds to do the

research conduct most oversight of NIH-funded Phase III clinical trials. A

number of internal controls are in place to safeguard Phase III clinical

trials against both fiscal and scientific misconduct in extramural research.

The controls that guard against fiscal misconduct are standard procedures

that must comply with federal policies and regulations on the expenditure

of federal funds. The monitoring procedures and controls that guard

against scientific misconduct are generally consistent but vary sometimes

on the basis of the management philosophy and past experience of the NIH

institute sponsoring the trial; the trial’s size, nature, and complexity; and

the way the trial is funded.

Even though controls exist to safeguard clinical trials against misconduct,

no practical level of oversight can guarantee the complete fiscal or

scientific integrity of each clinical trial NIH sponsors. The detection of

cases of potential or actual misconduct demonstrates that abuse does

occur and suggests that oversight controls do work with some

effectiveness. The application of the controls often influences their

effectiveness. For example, in the multisite NCI-sponsored breast cancer

trial in which patient data were fabricated and falsified, an internal control

procedure discovered the data irregularities. The data problem was not

promptly reported to NIH, however, after it was detected. Instead, it was

reported to the principal investigator conducting the trial, who waited 8

months before notifying NIH. To address this problem, at least one institute

3

Health Research Misconduct: HHS’ Handling of Cases Is Appropriate, but Timeliness Remains a

Concern (GAO/HEHS-95-134, Aug. 3, 1995).

Page 2 GAO/HEHS-96-117 NIH Phase III Clinical Trials
B-266107 

provides direct funding for certain data verification functions. This

approach makes key data integrity internal control functions independent

of research investigators and creates a direct link to NIH for prompt

reporting of data concerns and possible scientific misconduct. This

approach, however, is not an agencywide policy or practice for multisite

trials.

In 1994, NIH launched a study to determine how the institutes oversee and

manage the Phase III clinical trials they sponsor. An internal working

committee on clinical trial monitoring determined that the type of trial, its

funding mechanism, and the sponsoring institute greatly influence the

implementation of certain internal control measures. The committee

recommended that NIH establish some agencywide guiding principles for

managing trials. These principles would cover such areas as quality

assurance and site monitoring, level of NIH staff monitoring, and patient

confidentiality. NIH has not adopted any of the committee’s

recommendations agencywide, although in the past it has implemented

some agencywide policies designed to discourage misconduct in scientific

research. NIH believes adopting agencywide policies such as those the

committee recommended is inappropriate because all clinical trials should

not be monitored in the same way. Some institutes have selectively

adopted some of the committee’s recommendations.

Background NIH is a Public Health Service (PHS) agency within HHS. It consists of a

director’s office and 14 staff offices that oversee the operations of 24

separate units. These units include 17 institutes, each focused on specific

health or medical issues, such as cancer or aging; six research centers; and

the National Library of Medicine. Each unit separately awards funds for

the research it sponsors. NIH’s Office of Extramural Research is

responsible for agencywide activities concerning oversight of Phase III

clinical trials, such as developing policy on the review, funding, and

management of extramural grants.

NIH’s extramural research units (generally referred to in this report as

“institutes”) used various methods to fund the 470 Phase III clinical trials

they sponsored in fiscal year 1994. As figure 1 shows, the largest number

of trials (180) were funded through cooperative agreements. Regardless of

the method used to fund the trials, the institutions that are awarded the

funds are referred to as “grantee institutions” or “grantees.”

Page 3 GAO/HEHS-96-117 NIH Phase III Clinical Trials
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Figure 1: Number of Extramural Phase

III Clinical Trials Sponsored by NIH,

Fiscal Year 1994

Cooperative Agreement

180

Grants

170

Contracts

85

Other

35

Source: NIH’s Office of Extramural Research.

Most Phase III clinical trials involving multiple sites are funded through

contracts and cooperative agreements. Trials funded through contracts are

typically planned, initiated, and controlled by the sponsoring NIH institute.

The institute details the trial’s objectives, protocols, and controls.

Under cooperative agreements, however, the grantees and principal

investigators have more flexibility in planning, managing, and conducting

the trial. Although the sponsoring institute is expected to make substantial

contributions to the trial, such as providing technical assistance,

coordinating the trial’s activities, and helping to manage the trial,

operational control of the trial rests with the grantee.

Page 4 GAO/HEHS-96-117 NIH Phase III Clinical Trials
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NIH Institutes and

Grantees Provide

Oversight of Clinical

Trials

The institutes and research centers at NIH along with the grantee

institutions directly oversee and monitor Phase III clinical trials. These

entities are to ensure that controls are in place to prevent or detect the

misuse of federal funds and the falsification of data in conducting

extramural clinical research. According to NIH, these institutes and grantee

institutions know the nature and objectives of the trials and are therefore

in the best position to develop monitoring procedures to ensure safety and

data integrity. At the sites we visited, controls that safeguard against fiscal

misconduct are consistently applied among institutes and trials. Some

controls that safeguard against scientific misconduct, however, are not

always consistently used for various reasons, including the type of trial

and the sponsoring institute’s management philosophy.

Fiscal Oversight Policies

and Controls Are

Consistent Among

Institutes and Grantees

Although each institute independently oversees the clinical trials it

sponsors, the controls established to prevent and detect fiscal misconduct

were consistent among the institutes in our review. The control

procedures must conform with federal requirements and policies on the

expenditure of federal funds. Grantee institutions are responsible for

ensuring that their research scientists and other employees comply with

all applicable federal rules, regulations, and policies on the use of federal

funds. Independent auditors review grantee compliance annually in a

required financial audit.

Most grantee institutions receive federal funds from several federal

agencies. The grantees must adhere to a uniform series of regulations laid

out by the Office of Management and Budget (OMB). Chief among these

policies are cost principles that grantees must adhere to as specified in

OMB Circulars A-21, A-87, or A-122.4 These principles provide guidance on

what expenses a grantee may incur and charge against an NIH grant award.

Grantees must also follow a uniform set of administrative requirements in

OMB Circulars A-102 or A-110, detailing how grant funds should be

managed.5

 Foremost among these requirements are standards for such

areas as fiscal reporting, accounting records, internal controls, and cash

4

The cost principles that a grantee must follow depend on the nature of the grantee institution. The

applicable circulars are OMB Circular A-21, Cost Principles for Educational Institutions; OMB Circular

A-87, Cost Principles for State and Local Governments; and OMB Circular A-122, Cost Principles for

Non-Profit Organizations, which include medical centers and hospitals.

5

The applicable circulars for administrative requirements are OMB Circular A-102, Grants and

Cooperative Agreements With State and Local Governments, and OMB Circular A-110, Uniform

Administrative Requirements for Grants and Agreements with Institutions of Higher Education,

Hospitals and Other Non-Profit Organizations.

Page 5 GAO/HEHS-96-117 NIH Phase III Clinical Trials
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management. Other administrative requirements cover procurement and

property standards.

Independent auditors annually audit grantees’ fiscal management of

federal funds as required by OMB Circulars A-128 and A-133.6

 It was such an

audit that detected the embezzlement of more than $700,000 of NIH grant

funds in the early 1990s. This case of fiscal misconduct by a manager of

grants accounting occurred at the New York Medical College—the

grantee. Because the grantee institution is responsible for ensuring that

federal grant funds are properly used, the college was required to fully

refund these funds to NIH.

At the five grantee institutions we visited, we reviewed the annual

financial audits. The audits included a review of internal controls

established by the grantees to safeguard federal funds. In each case, the

audits disclosed that grantees had complied with federal guidelines and no

material weaknesses were detected in the internal controls.

When grantee institutions fail to establish and maintain adequate internal

controls and proper accounting procedures to safeguard federal funds, NIH

can impose requirements that the grantee must comply with to continue

receiving and managing grant awards. In 1995, NIH designated the

University of Minnesota, a grantee, an “exceptional organization” because

of its failed internal controls and poor accounting procedures. This

designation enabled NIH more oversight of its funds than would be feasible

under the administrative procedures normally associated with its grant

programs. NIH increased the conditions and restrictions attached to the

University’s grant award. It also required the University to develop and

successfully implement a corrective action program to address the

deficiencies before NIH would consider removing the exceptional

organization designation.

Grants Management

Officers Monitor Fiscal

Integrity

Each institute assigns grants management officers to clinical trials to

oversee the use of federal funds awarded to grantee institutions. One

method used by the grants management officers to reduce the agency’s

risk is to limit the amount of funds readily available to the grantees. For

instance, because a cooperative agreement usually covers more than 1

year, the initial award specifies how much funding will be provided each

year for the life of the agreement. However, funding is provided on a

6

For most grantees, this annual financial audit must comply with OMB Circular A-128, Audits of State

and Local Governments, or OMB Circular A-133, Audits of Institutions of Higher Education and Other

Nonprofit Institutions.

Page 6 GAO/HEHS-96-117 NIH Phase III Clinical Trials
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year-to-year basis only. The grantee must apply each year for a

continuation award for additional funding even though the total grant

amount is committed. Institutes release funds on the basis of satisfactory

performance as detailed in the annual progress reports that principal

investigators must submit. If a grantee’s progress is not satisfactory, a

grants management officer may reserve all or some of the funding until

grantee progress improves.

Institutes awarding funds for clinical trial research issue award notices

that include a section indicating whether any of the funding is restricted

and what must be done to lift the restriction. If a grantee’s funds are

restricted, the grants management officer might release the funds but

restrict their use until the grantee has completed certain tasks. For

example, in one trial we reviewed, the officer restricted administrative

funds until the sites developed a contractual agreement indicating how

they would work together.

In addition to annual progress reports, the grantee must include a

summary of annual expenditures in its Financial Status Report to the

grants management officer. This allows the officer to compare the

reported overall expenditure totals with the original budget and progress

reports. If the officer finds any significant differences, the grantee is

expected to explain them. For Phase III clinical trials funded through

contracts or cooperative agreements, according to NIH, when grantees do

not spend funds as budgeted, grants management officers must approve all

requests to rebudget funds as well as requests to carry over funds from

one year to the next.

Program Officers and

Oversight Boards Monitor

Scientific Conduct

Institutes’ oversight monitoring of clinical trials has some consistent

safeguards against scientific misconduct and protections for the safety of

trial participants. Each institute usually requires specific monitoring

methods. For example, an NIH program officer is assigned by the

sponsoring institute to monitor each Phase III trial. Program officers are

research scientists with expertise in the area being studied. Each institute

trains and develops its own program officers in monitoring and managing

clinical trials. Therefore, program officers’ training can vary by institute.7

Also, their responsibilities often vary by the institute’s management

7

In January 1995, NIH’s Office of Extramural Research instituted an agencywide training program for

all new program officers hired by the institutes. This program was designed to provide all new

program officers basic training on their role in managing any type of NIH-sponsored research. The NIH

official in charge of this training stated that NIH is considering expanding this program to include

training specifically related to monitoring and managing clinical trials.

Page 7 GAO/HEHS-96-117 NIH Phase III Clinical Trials
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philosophy, the type of trial, and the funding method—contracts or

cooperative agreements. Typically, program officers, at a minimum, rely

on basic oversight controls in monitoring clinical trials, including annual

progress and budget reports and trial participants’ recruitment and

retention statistics.

Oversight boards also monitor trials. For example, most clinical trials that

pose a potential hazard to human trial participants must be monitored by a

Data and Safety Monitoring Board or an equivalent. This board, composed

of scientists not connected with the trial, monitors a trial’s clinical data

and progress. The board also focuses on reported adverse events—adverse

changes in the health status of a human research subject in a clinical trial.

In addition to a Data and Safety Monitoring Board, each grantee institution

must establish an Institutional Review Board to approve and monitor all

research involving human subjects. An important function of this board is

to review and approve informed consent forms, making sure they have

been signed. All prospective research subjects must sign consent forms

that explain the objectives, risks, and benefits of the proposed research

before they can participate in a trial.8

In our review of clinical records at the five sites we visited, we did not find

any cases in which a consent form had not been signed by a trial

participant. However, according to a report on the NCI-sponsored breast

cancer trial,9

 only about 71 percent of trial participants gave written

informed consent before surgery; consent forms were missing or not

available or data were insufficient for 7 percent of the participants.

Controls That Protect Trial

Data Integrity Are Not

Always Consistently

Applied

Clinical trials have controls that safeguard against scientific misconduct,

including direct data verification to ensure data integrity. Because

institutes and grantees, however, have flexibility in deciding how these

controls are used, the application of the controls often varies by institute

and type of trial.

One control designed to safeguard trials against scientific misconduct is

the use of clinical monitors to review trial data. These monitors visit

clinical trial sites to verify that the established protocols are being

8

In our report, Scientific Research: Continued Vigilance Critical to Protecting Human Subjects

(GAO/HEHS-96-72, Mar. 8, 1996), we reviewed federal oversight procedures for protecting human

subjects in scientific research.

9

Michaele C. Christian and others, “The National Cancer Institute Audit of the National Surgical

Adjuvant Breast and Bowel Project Protocol B-06,” The New England Journal of Medicine, Vol. 333,

No. 22 (1995), pp. 1469-1474.

Page 8 GAO/HEHS-96-117 NIH Phase III Clinical Trials
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followed and that the data being reported match the data in the clinical

records. In one trial sponsored by the National Eye Institute, clinical

monitors found that clinical test results were being entered on data

collection sheets and not in the patients’ medical records. Clinical

research policy states that medical records are the acceptable source

documents for clinical test results so monitors required that the site also

enter reported data in the patients’ medical records.

Because clinical monitors add both expense and time to a trial, institutes

tend to use them only in the large and more complex trials. For example,

clinical monitors are being used in NIA’s largest and most expensive

ongoing Phase III clinical trial—alternative therapies for Alzheimer’s

disease. This trial is being conducted at 35 research sites and costs

$16.9 million in NIH funds. The NIA program officer for the Alzheimer’s trial

estimated that using clinical monitors in this trial delayed data entry by 6

months. This delay is acceptable, however, because of the increased

quality assurance that clinical monitors bring to the trial, according to the

program officer.

Another internal control procedure to protect data integrity is the use of

data coordinating centers. Most Phase III clinical trials that have multiple

research sites use data coordinating centers to process patient clinical

data generated during a trial. These centers inspect the data for

inconsistencies among the sites, irregularities, and fraud.

In one NIA-sponsored trial, Continence Program for Women, the data

coordinating center detected data inconsistencies between two clinical

sites and alerted both the institute and the Data and Safety Monitoring

Board. The inconsistency was caused by a different classification of

patients by the two sites. However, the center’s detection of the data

problem allowed the problem to be corrected. In an NHLBI-sponsored trial,

the data coordinating center questioned test results from one laboratory.

Further investigation by NIH’s Office of Research Integrity revealed that a

lab technician had not conducted the tests as required and had reported

false test results. NHLBI took corrective action to minimize the damage to

the trial. The institute also recovered funds paid to the laboratory, and the

technician was sanctioned.

Benefits of Data Coordinating

Centers’ Independence

NHLBI officials believe that the independence of data coordinating centers

is an essential part of internal controls. It is a way for the institute to

create a direct link to a key data verification point and to help ensure

prompt notification of potential scientific misconduct or other data

Page 9 GAO/HEHS-96-117 NIH Phase III Clinical Trials
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irregularities. For this reason, NHLBI directly funds data coordinating

centers and requires that the heads of the centers report directly to the

institute’s program officer and the Data and Safety Monitoring Board. This

approach places data coordinating centers beyond the direct control of a

trial’s principal investigator.

Other institutes that have not provided for data coordinating centers’

independence in trials have experienced problems with researchers’

influence over the centers. For example, for the three NIA trials included in

our review, data coordinating centers were funded through a subcontract

with research centers. This arrangement allowed a lead researcher, in a

dispute with the center, to withhold the center’s operating funds. The

institute’s program officer had to intervene to resolve the situation. During

our review, NIA’s policy was to independently fund data coordinating

centers for most of its multisite clinical trials.

In the breast cancer trial, NCI permitted the trial’s principal investigator to

oversee the operations of the data coordinating center. When the center

detected suspect data, the principal investigator was notified. The

investigator took about 3 months to establish that fraud had occurred and

another 5 months before notifying NCI. The investigator’s failure to

promptly notify NCI as required delayed corrective action and jeopardized

the integrity of the trial. NCI had to spend time and resources to revalidate

the trial’s initial results.

Centralized NIH

Oversight of and

Guidance on

Managing Clinical

Trials Is Limited

NIH conducts limited centralized monitoring of Phase III clinical trials. No

agencywide registry or database exists to track progress and performance

of all clinical trials and provide NIH’s management with comprehensive

reports for oversight and decisionmaking purposes.10 Although periodic

meetings occur to discuss progress of ongoing trials, no data are

systematically collected nor used to provide centralized oversight.

Furthermore, NIH has not adopted its internal committee’s

recommendations to develop agencywide guidance on quality assurance

measures and data monitoring procedures for institutes to use in managing

clinical trials. According to NIH, some of its institutes have selectively

adopted some of the committee’s recommendations, but the agency

believes adopting these policies agencywide is inappropriate because this

10The NIH Revitalization Act of 1993 mandates that women and minorities be adequately represented

in all appropriate NIH-sponsored research, including Phase III clinical trials. To ensure compliance with

this requirement, NIH’s Office of Research on Women’s Health has developed a database that monitors

the inclusion of women and minorities in NIH-funded research. The act also required NIH to develop a

registry of clinical trials involving women’s health issues.

Page 10 GAO/HEHS-96-117 NIH Phase III Clinical Trials
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erroneously assumes that all clinical trials should be monitored in the

same manner. Nonetheless, NIH and HHS have implemented some

agencywide measures in the past designed to discourage misconduct in

federally funded research.

NIH Conducts Limited

Central Oversight and

Monitoring of Phase III

Clinical Trials

Even though NIH’s Office of Extramural Research is responsible for

centralized activities concerning oversight of extramural research, such as

developing policy on the review, funding, and management of clinical

trials, it has limited knowledge of and data on the Phase III clinical trials

NIH funds and the performance of individual institutes and grantees. The

office does review institutes’ initial requests for Phase III clinical trial

research. Once a request is reviewed and ultimately approved, however,

the awarding of the grants and most of a trial’s oversight and management

are left to individual institutes.

The Office of Extramural Research might learn of a trial’s progress from

meetings of the Extramural Program Management Committee, whose

members are staff from each institute. The committee meets regularly to

discuss, among other issues, those related to Phase III clinical trials and to

exchange ideas. However, unless an institute’s representative mentions a

problem with a trial or raises concern about fiscal or scientific

misconduct, the committee or the Office of Extramural Research would

not likely know about it.

NIH has not yet implemented a centralized database or a central trial

registry to improve its oversight of the clinical trials it funds. An

automated database of all clinical trials could track progress and

performance and generate reports that would increase management’s

knowledge about the trials and improve its ability to oversee them.

Because no active central trial registry exists, NIH would have to survey

each institute just to determine the total number of Phase III clinical trials

it funds. The NIH Revitalization Act of 1993 required NIH to develop a

registry of clinical trials involving women’s health issues. NIH, however,

decided not to limit this registry to trials involving women’s health but to

include other trials. NIH’s Office of Extramural Research is developing the

Streamlined Non-Competing Award Process (SNAP) database as a pilot

experiment. According to NIH, this database will allow it to interact with

the grantee institutions and monitor research progress. NIH expects that

when SNAP is expanded to include all clinical trials, NIH staff will be able to

monitor trial progress in areas such as recruitment.

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NIH Has Not Adopted a

Recommendation to

Develop Agencywide

Guidance on Managing

Clinical Trials

Because the NIH institutes and grantees have more flexibility in deciding

how to manage clinical trials funded through cooperative agreements, the

scientific controls used in such trials vary. Aware of this variability, NIH’s

Office of Extramural Research established the NIH Working Committee on

Clinical Trial Monitoring in June 1994 to determine how its institutes

manage clinical trials. The committee members were representatives from

the institutes and research centers and were selected for their expertise in

various aspects of clinical research.

The committee’s task was to specifically review how the institutes manage

the Phase III clinical trials they sponsor. On the basis of its review, the

committee decided in 1995 that attempting to develop standards to dictate

how these trials are managed is inadvisable given the unique

characteristics of each Phase III clinical trial and the diverse nature of the

institutes. The committee did recommend, however, that NIH consider

formulating guiding principles for all the institutes to follow in managing

the trials.

The principles the committee recommended covered such areas as quality

assurance and site monitoring, patient confidentiality, level of NIH staff

involvement, and data access. Specifically, for example, in the area of

quality assurance and site monitoring, the committee recommended that

the institutes, at a minimum, conduct regular on-site monitoring of all

clinical centers and monitor key outcome data. It also recommended that

trials involving multiple clinical centers, large study populations, or

potentially harmful interventions have the substantial involvement of and

close oversight by the sponsoring institute. NIH has decided not to adopt

any of the committee’s recommendations agencywide. According to NIH,

adopting agencywide policies such as those the committee recommended

is inappropriate because it assumes that all clinical trials should be

monitored in the same way.

At one of the data coordinating centers we visited, officials expressed

frustration because standards and procedures for data collection differ by

institute as well as among program officers at the same institute. They

believe that minimal data collection standards and procedures should be

established for all trials.

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HHS and NIH Have

Implemented Some

Agencywide Policies on

Scientific Misconduct

Prompted by legislation and on their own initiative, HHS and NIH have taken

steps to discourage misconduct in federally sponsored research, including

clinical trials. These efforts have focused mainly on establishing proper

scientific conduct and conflict-of-interest reporting requirements for

grantee institutions.

In response to the Health Research Extension Act of 1985, HHS required

each grantee institution to develop a formal process delineating the steps

to be taken to resolve allegations of scientific misconduct. In addition,

institutions are required to diligently try to protect the positions and

reputations of whistleblowers. ORI monitors compliance with this

requirement.

As required by the NIH Revitalization Act of 1993, HHS recently took action

to ensure that the design, conduct, or reporting of PHS-funded research is

not affected by researchers’ outside financial interests. This applies also to

all NIH-sponsored research. Specifically, HHS issued a regulation effective

October 1, 1995, requiring that each grantee institution develop a

conflict-of-interest policy applicable to all staff benefitting from PHS

funding. To comply with this regulation, researchers must file annual

financial disclosure forms that allow the institution to determine if a

conflict of interest exists. All applications for PHS funding must contain a

certification by the institution that no conflict of interest exists. Each of

the five grantee institutions we visited had developed and implemented

conflict-of-interest policies. Because of the newness of the policies,

however, officials said it would take time to see how these policies

operated in practice and how effective the policies would be.

Conclusions A large percentage of NIH-sponsored Phase III clinical trials are funded

through cooperative agreements so both the institutes and grantees are

involved in managing the trials and developing procedures for conducting

them, according to NIH. The trials have controls designed to safeguard

against fiscal and scientific misconduct that the institutes, grantee

institutions, and research sites can apply in overseeing the trials. However,

no practical level of oversight and controls can completely eliminate the

potential for misconduct.

Most oversight of these trials is decentralized and performed

independently by each of the different institutes that sponsor clinical

research and by the grantee institutions. Because of the large number of

diverse Phase III clinical trials NIH funds and the independent nature of its

Page 13 GAO/HEHS-96-117 NIH Phase III Clinical Trials
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institutes, NIH charged a working committee with determining how such

trials are managed. The committee recommended that NIH develop some

agencywide guidance for all institutes to follow in managing these trials.

The guidance was recommended for areas such as quality assurance, site

monitoring, and the level of NIH staff involvement. Although some

institutes have implemented some of the principles, NIH believes adopting

them agencywide is inappropriate.

In the past, NIH has done little centralized oversight and monitoring of the

trials it funds and the institutes that sponsor them, except for tracking

women’s and minorities’ participation in clinical trials. NIH is, however,

developing a database that it expects will allow for monitoring elements of

clinical trials’ progress and performance.

Agency Comments In commenting on a draft of this report, NIH agreed in general with our

conclusions and noted that the report provides a balanced discussion of

the relevant issues. (See app. II.) NIH also provided technical comments,

which we incorporated as appropriate.

We are sending copies of this report to appropriate congressional

committees, the Secretary of HHS, the Director of NIH, and other interested

parties. We also will make copies available to others on request.

If you or your staff have any questions about this report, please call me at

(202) 512-7119. Other major contributors to this report are listed in

appendix III.

Sarah F. Jaggar

Director, Health Financing

 and Public Health Issues

Page 14 GAO/HEHS-96-117 NIH Phase III Clinical Trials
Page 15 GAO/HEHS-96-117 NIH Phase III Clinical Trials
Contents

Letter 1

Appendix I 

Scope and

Methodology

18

Appendix II 

Comments From the

Department of Health

and Human Services

21

Appendix III 

Major Contributors to

This Report

22

Table Table I.1: Four Phase III Clinical Trials Reviewed 19

Figure Figure 1: Number of Extramural Phase III Clinical Trials

Sponsored by NIH, Fiscal Year 1994

4

Abbreviations

HHS Department of Health and Human Services

NCI National Cancer Institute

NHLBI National Heart, Lung, and Blood Institute

NIA National Institute on Aging

NIH National Institutes of Health

OMB Office of Management and Budget

ORI Office of Research Integrity

PHS Public Health Service

SNAP Streamlined Non-Competing Award Process

Page 16 GAO/HEHS-96-117 NIH Phase III Clinical Trials
Page 17 GAO/HEHS-96-117 NIH Phase III Clinical Trials
Appendix I 

Scope and Methodology

To determine how NIH provides oversight to protect Phase III clinical trials

from fiscal and scientific misconduct, we conducted audit work at NIH;

National Institute on Aging (NIA); and National Heart, Lung, and Blood

Institute (NHLBI). We selected NIA because it is among the institutes that

provide the smallest amount of funding for Phase III clinical trials and

NHLBI because it is among the institutes that provide the largest amount of

funding. In fiscal year 1995, NIA sponsored 7 clinical trials costing about

$9 million, and NHLBI sponsored 42 trials costing about $73 million.

Selecting these institutes for review provided some perspective on

whether oversight might be influenced by the size of an institute’s clinical

trial portfolio. Also, these two institutes offered a variety of trials from

which to select for review.

We limited the scope of our review to Phase III clinical trials funded

through cooperative agreements. Under cooperative agreements, grantee

institutions have more flexibility in planning, conducting, and managing

the trials than under contracts, the other major funding method for Phase

III clinical trials. NIH institutes that sponsor the trials are expected to

provide assistance to and oversight of the trials. Our review included a

nonstatistical sample of four multisite clinical trials that varied in nature,

size, complexity, and number of sites (see table I.1). We visited five of the

clinical research sites that participated in the trials and two data

coordinating centers that processed and monitored the clinical data. The

clinical sites we visited were either state or private institutions located in

Virginia, Connecticut, and Massachusetts. The data coordinating centers

we visited differed in how they were funded.

Page 18 GAO/HEHS-96-117 NIH Phase III Clinical Trials
Appendix I 

Scope and Methodology

Table I.1: Four Phase III Clinical Trials

Reviewed

Clinical trial

Sponsoring

institute Objective

Number of

sites

FY 95

funding

(000s)

BARIa NHLBI To compare coronary

artery bypass surgery

with angioplasty

17 $3,104

STOP/ITb NIA To compare the

effects of exercise,

calcium, vitamin D,

and hormones on

bone density

4 1,919

Continence Program

for Women

NIA To compare the

effects of exercise,

estrogen, and surgery

in treating

incontinence

3 0c

Alzheimer’s Disease

Cooperative Study

NIA To examine the

effects of various

drug therapies on

Alzheimer’s disease

35 4,116

aBypass Angioplasty Revascularization Investigation.

bSites Testing Osteoporosis Prevention/Intervention Treatment.

cNo new funds were obligated in fiscal year 1995. Activities were funded through the use of funds

carried over from previous years.

To determine the oversight roles played by NIH, the institutes, and the

institutions receiving research funds, we conducted interviews, reviewed

NIH rules and regulations, examined NIH studies and reports, and reviewed

grant documents on the chosen Phase III clinical trials. We interviewed

agency officials from NIH, NIA, and NHLBI. Within NIH, we interviewed

officials from the Office of Extramural Research and the Office of

Research on Women’s Health. At NIA and NHLBI, we interviewed senior

officials, grants management personnel, and program management

officers. We also met with staff from HHS’ Office of Research Integrity to

discuss their role in investigating allegations of misconduct and the Office

of the Inspector General, which was investigating allegations of scientific

misconduct.

We also met with the principal research investigators, key research

personnel, grants and fiscal management officials, and internal audit staff

at the research sites to get their views on oversight responsibilities and

controls that protect trials against misconduct. We reviewed grantee

institutions’ policies and procedures for preventing, detecting, and

Page 19 GAO/HEHS-96-117 NIH Phase III Clinical Trials
Appendix I 

Scope and Methodology

resolving scientific misconduct, conflicts of interest, and fiscal

mismanagement. Also, we examined research documentation, clinical

records, correspondence, and external audits of the institutions.

To determine what controls exist at the central data processing point to

help ensure clinical data integrity, we visited two data coordinating

centers. One of the centers was funded independently of the clinical sites;

the other’s funding was included in the research center’s grant award. At

the coordinating centers, we observed their operation, reviewed their

policies and procedures, and interviewed key personnel about the centers’

data collection and analysis role and responsibilities. We examined reports

generated by the centers and observed the procedures they use to ensure

consistency of each clinical site’s data collection and recording

methodology. We also established how research data are analyzed to

detect data problems and reviewed the follow-up procedures the centers

use when potential problem data are discovered.

Our work was performed between September 1995 and May 1996 in

accordance with generally accepted government auditing standards.

Page 20 GAO/HEHS-96-117 NIH Phase III Clinical Trials
Appendix II 

Comments From the Department of Health

and Human Services

Page 21 GAO/HEHS-96-117 NIH Phase III Clinical Trials
Appendix III 

Major Contributors to This Report

James O. McClyde, Assistant Director, (202) 512-7152

Frank F. Putallaz, Evaluator-in-Charge, (617) 565-7527

Thomas S. Taydus, Senior Evaluator

(108251) Page 22 GAO/HEHS-96-117 NIH Phase III Clinical Trials
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