Scientific Research: Continued Vigilance Critical to Protecting Human
Subjects (Testimony, 03/12/96, GAO/T-HEHS-96-102).

GAO discussed the Department of Health and Human Services' (HHS) efforts
to protect human research subjects, focusing on the prevention,
monitoring, and enforcement activities of the National Institutes of
Health's Office for Protection from Research Risks (OPRR) and the Food
and Drug Administration (FDA). GAO noted that: (1) to ensure the
protection of human research subjects, the agencies require researchers
to make assurance agreements that they will comply with federal human
subject protection requirements and uphold ethical standards; (2) the
agencies also use institutional review boards (IRB), local review panels
that review research plans to ensure that human subjects are protected;
(3) both FDA and OPRR conduct on-site visits and inspections, clinical
trials, investigations of allegations of researcher misconduct, and IRB
reviews to identify violations of protection requirements; (4) to
enforce the regulations, FDA and OPRR have requested modifications to
research plans, restricted researchers' use of drugs, disqualified,
suspended, or criminally prosecuted researchers; and (5) oversight
effectiveness is hampered by heavy IRB workloads and competing
priorities, organizational conflicts-of-interest, limited site visits
and inspections, and pressures resulting from differing perceptions on
the need for research versus treatment.

--------------------------- Indexing Terms -----------------------------

 REPORTNUM:  T-HEHS-96-102
     TITLE:  Scientific Research: Continued Vigilance Critical to 
             Protecting Human Subjects
      DATE:  03/12/96
   SUBJECT:  Ethical conduct
             Biological research
             Behavioral sciences research
             Informed consent (medical law)
             Safety regulation
             Research program management
             Safety standards
             Pharmacological research
             Conflict of interest

             
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Cover
================================================================ COVER


Before the Committee on Governmental Affairs
U.S.  Senate

For Release on Delivery
Expected at 9:00 a.m.
Tuesday, March 12, 1996

SCIENTIFIC RESEARCH
- CONTINUED VIGILANCE CRITICAL
TO PROTECTING HUMAN SUBJECTS

Statement of Sarah F.  Jaggar, Director
Health Financing and Public Health Issues
Health, Education, and Human Services Division

GAO/T-HEHS-96-102

GAO/HEHS-96-102T


(108268)


Abbreviations
=============================================================== ABBREV


============================================================ Chapter 0

Mr.  Chairman and Members of the Committee: 

I am pleased to be here today to testify on our report to the
Committee on efforts to protect human research subjects.\1 Concerns
have been raised about the effectiveness of today's safeguards in
light of the recent disclosures of unethical Cold War-era radiation
experiments and reports of infringements on subjects' rights, such as
in a contemporary study of breast cancer. 

Over the past 3 decades, the Department of Health and Human Services
(HHS)--the primary federal sponsor of biomedical and behavioral
research--has established procedures to minimize risks experienced by
patients and healthy volunteers who participate in research that it
supports or regulates.  We reviewed HHS' human subject protection
system, concentrating on the prevention, monitoring, and enforcement
activities of the National Institutes of Health's (NIH) Office for
Protection from Research Risks (OPRR) and the Food and Drug
Administration (FDA).  Within FDA, we examined the human subject
protection activities of the Center for Drug Evaluation and Research
because drug research is the largest segment of biomedical
research.\2 We interviewed federal and research institution
officials; medical and behavioral researchers; representatives of the
drug industry; and experts in bioethics, law, and social science.  We
also reviewed HHS and FDA regulations, guidelines, and records and
human subject protection procedures and records at research
institutions. 

I would like to highlight three key findings from our report.  First,
HHS' oversight of tens of thousands of studies appears to have
reduced the likelihood that serious abuses of human subjects,
comparable to past tragic events, will occur.  Second, no practical
level of oversight can guarantee that each researcher will protect
subjects with complete integrity.  The detection of recent instances
of potential or actual harm to subjects both demonstrates that abuses
can occur and also suggests that the current oversight activities are
working.  Finally, various time, resource, and other pressures have
reduced or threaten to reduce the effectiveness of such oversight. 


--------------------
\1 Scientific Research:  Continued Vigilance Critical to Protecting
Human Subjects (GAO/HEHS-96-72, Mar.  8, 1996). 

\2 FDA's Center for Biologics Evaluation and Research and Center for
Devices and Radiological Health also carry out activities to protect
human subjects of product testing.  These activities were not
included in the scope of our review. 


   BACKGROUND
---------------------------------------------------------- Chapter 0:1

Since the 1960s, there have been significant advances in protecting
the rights and welfare of human subjects in biomedical and behavioral
research.  The federal presence has grown in this area, establishing
and enforcing regulations for protecting human subjects in federally
funded and federally regulated research.  HHS' regulation of
biomedical and behavioral research consists of two principal tiers of
review:  one at the federal level and one at the research institution
level.  Both tiers are responsible for ensuring that individual
researchers and their research institutions comply with federal laws
and regulations for protecting human subjects.  When the core of HHS'
human protection regulations was adopted by 15 other federal
departments and agencies in 1991, it became known as the Common
Rule.\3

Within the HHS oversight system there are several entities overseeing
compliance with human protection regulations.  At the federal level
are the NIH's OPRR and the FDA.  At the local level, institutional
review boards (IRB)--that is, review panels that are usually
associated with a particular university or other research
institution--are responsible for implementing federal human subject
protection requirements for research conducted at or supported by
their institutions.  In general, IRB members are scientists and
nonscientists who volunteer to review proposed studies. 

The Common Rule requires research institutions receiving federal
support and federal agencies conducting research to establish IRBs to
review research proposals for risk of harm to human subjects and to
perform other duties to protect human research subjects.  It also
stipulates requirements related to informed consent--how researchers
must inform potential subjects of the risks to which they, as study
participants, agree to be exposed.  HHS regulations contain
additional protections not included in the Common Rule for research
involving vulnerable populations--namely, pregnant women, fetuses,
subjects of in vitro fertilization research, prisoners, and children. 


--------------------
\3 Currently, these regulations have been adopted by 17 federal
departments and agencies:  the Departments of Agriculture, Energy,
Commerce, Health and Human Services, Housing and Urban Development,
Justice, Defense, Education, Veterans Affairs, and Transportation;
the National Aeronautics and Space Administration; the Social
Security Administration; the Consumer Product Safety Commission; the
Agency for International Development; the Environmental Protection
Agency; the National Science Foundation; and the Central Intelligence
Agency. 


   PREVENTIVE EFFORTS HAVE BEEN
   IMPORTANT IN REDUCING
   LIKELIHOOD OF ABUSES
---------------------------------------------------------- Chapter 0:2

Preventing harm to human subjects' rights and welfare is the
overarching goal of HHS' protection system.  The organizational
components of the system--OPRR, FDA, and local IRBs--have heightened
the compliance of the research community with human protection
guidelines through a variety of activities. 


      OPRR REQUIRES A FORMAL
      COMMITMENT TO FEDERAL
      REGULATIONS
-------------------------------------------------------- Chapter 0:2.1

OPRR's chief preventive measure is its assurance process.  Assurances
are contract-like agreements made by research institutions to comply
with federal human subject protection requirements.  Assurances
include the following:  a statement of ethical conduct principles, a
guarantee that an IRB has been designated to approve and periodically
review the institution's studies, and the specifics of the IRB's
membership, responsibilities, and process for reviewing and approving
proposals.  An institution must have an assurance approved by OPRR
before the institution can receive HHS research funding. 

Depending on an institution's willingness and expertise, as well as
the requirements of specific research studies, OPRR can negotiate
several different types of assurances.  Through a multiple project
assurance, for example, OPRR can delegate broad authority to an
institution, allowing it to approve a wide array of research studies. 
Or, through a single project assurance, OPRR can retain the authority
to approve studies one by one.  As of November 1995, OPRR had 451
active multiple project assurances and over 3,000 active single
project assurances.  OPRR also had over 1,300 active cooperative
project assurances, which pertain to multiple- site research
projects. 


      FDA REVIEWS SUBJECT
      PROTECTIONS BEFORE
      PERMITTING DRUG STUDIES
-------------------------------------------------------- Chapter 0:2.2

FDA works to prevent the occurrence of human subject protection
violations in the drug research it regulates.  Before permitting drug
research with human subjects, FDA requires researchers to submit a
brief statement that they will uphold ethical standards and identify
the IRB that will examine their study.  FDA can request modifications
to proposals or reject proposals deemed to present unacceptable risk. 


      IRBS EXAMINE RESEARCHERS'
      PLANS TO PROTECT SUBJECTS'
      RIGHTS AND WELFARE
-------------------------------------------------------- Chapter 0:2.3

IRBs play a major role in the protection of patients and healthy
volunteers, according to federal officials and members of the
research community alike.  For each study conducted using human
subjects, researchers must first get IRB approval.\4 In fact, HHS
will neither fund new human subject research nor authorize ongoing
research to continue without IRB approval.  The IRB's basic role when
deciding whether to approve new research is to determine if the
rights and welfare of subjects will be safeguarded.  IRB members
ensure that a study's procedures are consistent with sound research
design and that the consent document conforms to federal rules for
adequate informed consent.  IRB reviews, however, generally do not
involve direct observation of the research study or the process in
which a subject's consent is obtained. 

IRB members are expected to recognize that certain research
subjects--such as children, prisoners, the mentally disabled, and
individuals who are economically or educationally disadvantaged--are
likely to be vulnerable to coercion or undue influence.  The local
nature of most IRBs enables members to be familiar with the research
institution's resources and commitments, the investigators'
capabilities, and community values. 

IRBs are also required to review previously approved research
periodically.  The purpose of these continuing reviews is for IRBs to
keep abreast of a study's potential for harm and benefit to subjects
so that boards can decide whether the study should continue. 


--------------------
\4 Six categories of research are exempt from IRB review, such as
many types of studies that evaluate educational techniques.  Federal
regulations also allow for expedited review of research that presents
only minimal risk to subjects (that is, no greater harm than
encountered in daily life).  The Secretary of Health and Human
Services has approved 10 categories of research that may be reviewed
using expedited review procedures.  Voice recording and collection of
nail clippings, for example, are considered minimal risk research. 
The IRB chairman or a chairman-appointed IRB member, rather than the
full board, conducts expedited reviews. 


   FEDERAL MONITORING AND
   ENFORCEMENT IDENTIFY AND
   ADDRESS HUMAN SUBJECT
   PROTECTION VIOLATIONS
---------------------------------------------------------- Chapter 0:3

No system of prevention is foolproof.  Therefore, FDA's and OPRR's
monitoring and enforcement efforts include review of results of IRB
operations, clinical trials, and allegations of researcher
misconduct. 


      FDA'S MONITORING OF IRBS AND
      DRUG RESEARCHERS IDENTIFIES
      VIOLATIONS
-------------------------------------------------------- Chapter 0:3.1

FDA's primary tool for monitoring human subject protection is its
on-site inspections of the IRBs that oversee drug research.  FDA's
inspections of IRBs demonstrate that, at some institutions,
compliance with federal oversight rules is uneven.  Between January
1993 and November 1995, FDA issued 31 Warning Letters to institutions
regarding significant deficiencies in the performance of their IRBs'
oversight of drug research.  Among the more serious violations cited
were the following:  participation of researchers as IRB members in
reviewing their own studies, absence of a process for tracking
ongoing studies, and failure to ensure that required elements of
informed consent were contained in consent documents.  The FDA
Warning Letters terminated the IRBs' authority to approve new studies
or to recruit new subjects into ongoing studies until FDA received
adequate assurance of corrective action.  From October 1993 to
November 1995, FDA found less serious deficiencies involving about
200 other IRBs, such as failure to document the names of IRB members
and failure of IRB minutes to identify controversial issues
discussed. 

In addition to monitoring IRBs, FDA must be satisfied that
manufacturers have complied with human subject protection regulations
during clinical trials.  To this end, FDA conducts on-site
inspections of individual drug studies.  When examining how a trial
was conducted, FDA determines, for example, if subject selection
criteria were followed, if subjects' consent was documented, and if
adverse events were reported.  FDA's principal focus in these
efforts, however, is to verify the accuracy and completeness of study
data as well as the researcher's adherence to the approved protocol. 

Most of the drug study violations FDA identifies are relatively
minor.  From 1977 to 1995, about one-half of the violations related
to the adequacy of the informed consent forms.  FDA also identifies
more serious violations.  Since 1980, FDA has taken 99 actions
against 84 clinical investigators regarding their conduct of drug
research with human subjects.  It cited such instances of serious
misconduct as failure to obtain informed consent; forgery of
subjects' signatures on informed consent forms; failure to inform
patients that a drug was experimental; and failure to report
subjects' adverse reactions to drugs under study, including a
subject's death. 


      FDA CAN IMPOSE PENALTIES FOR
      SERIOUS VIOLATIONS
-------------------------------------------------------- Chapter 0:3.2

FDA has used four types of actions to enforce its regulations:  (1)
obtaining a promise from a researcher to abide by FDA requirements
for conducting drug research, (2) invoking a range of restrictions on
a researcher's use of investigational drugs, (3) disqualifying a
researcher from the use of investigational drugs, and (4) criminally
prosecuting a researcher. 


      OPRR INVESTIGATES
      ALLEGATIONS OF NONCOMPLIANCE
-------------------------------------------------------- Chapter 0:3.3

OPRR also responds to inquiries and investigates allegations of
potential harm to human subjects.  These inquiries and investigations
are largely handled by telephone and correspondence; few
investigations result in site visits.  Over the past 5 years, OPRR
has investigated numerous allegations of serious human subject
protection violations.  One such example was OPRR's investigation of
whether informed consent procedures clearly identified the risk of
death to volunteers in the tamoxifen breast cancer prevention trial. 
OPRR found that informed consent documents at some sites failed to
identify some of tamoxifen's potentially fatal risks, such as uterine
cancer, liver cancer, and embolism.  In another instance, OPRR
compliance investigators found deficiencies in informed consent and
in IRB review procedures in a joint NIH-French study of HIV-positive
subjects in Zaire.  Among cases currently under investigation are
allegations that researchers at a university-based fertility clinic
transferred eggs from unsuspecting donors to other women, without
consent of the donors. 


      OPRR CAN RESTRICT RESEARCH
      UNTIL VIOLATIONS ARE
      CORRECTED
-------------------------------------------------------- Chapter 0:3.4

In many cases, OPRR has required institutions to take corrective
action.  In some instances, OPRR has suspended an institution's
authority to conduct further research in a particular area until
problems with its IRBs were fixed.  From 1990 to mid-1995, there were
17 instances in which OPRR imposed some type of restriction on an
institution's authority to conduct human subject research. 


   MULTIPLE FACTORS WEAKEN
   INSTITUTIONAL AND FEDERAL HUMAN
   SUBJECT PROTECTION EFFORTS
---------------------------------------------------------- Chapter 0:4

Oversight systems are by nature limited to minimizing, rather than
fully eliminating, the potential for mishap, and HHS' system for
protecting human subjects is no exception.  Various factors reduce or
threaten to reduce the effectiveness of IRBs, OPRR, and FDA. 

First, pressure from heavy workloads and competing priorities can
weaken IRB oversight. 

  In some cases, the sheer number of studies necessitates that IRBs
     spend only 1 or 2 minutes of review per study. 

  Some IRBs allow administrative staff with no scientific
     expertise--not board members themselves--to review continuing
     review forms, ensuring only that the information has been
     provided. 

  The independence of IRB reviews can be compromised in cases in
     which IRB members have close collegial ties with researchers at
     their institutions, when there are pressures from institution
     officials to attract and retain funding, when IRB members have
     financial ties to the study, and when IRB members are reluctant
     to criticize studies led by leading scientists. 

  The increasing complexity of research makes it difficult for some
     IRBs to adequately assess human subject protection issues when
     members are not conversant with the technical aspects of a
     proposed study, or when studies raise ethical questions that
     have not been satisfactorily resolved within the research
     community. 

  Given the growing number of large-scale trials, if most involved
     IRBs have approved a proposed study, then IRBs at other
     institutions may feel pressured to mute their concerns about the
     study. 

  Pressures to recruit subjects can lead some researchers and IRBs to
     overlook informed consent deficiencies. 

Second, various factors may hamper OPRR oversight. 

  OPRR staff make no site visits during assurance negotiations;
     instead, they review an institution's written application and
     conduct written or oral follow-up.  In contrast, on the basis of
     experience gained from on-site investigations for compliance
     purposes, OPRR staff told us that their ability to evaluate an
     institution's human protection system is greatly enhanced by
     direct observation and personal interaction with IRB staff, IRB
     members, and researchers.  In the future, OPRR expects to
     conduct from 12 to 24 technical assistance visits annually to
     institutions holding OPRR assurances. 

  NIH's organizational structure may hamper the independence of OPRR
     with respect to its oversight of studies conducted by NIH's
     Office of Intramural Research.  From a broad organizational
     perspective, a potential weakness exists because NIH is both the
     regulator of human subject protections as well as an agency
     conducting its own research programs.  The NIH Director,
     therefore, has responsibility for both the success of NIH's
     intramural research programs and the enforcement of human
     subject protection regulations by OPRR. 

Third, FDA's inspections of drug research may permit violations to go
undetected. 

  FDA's inspection program is geared more toward protecting the
     eventual consumer of the drug than the subjects on whom the drug
     was tested.  FDA does not inspect all drug studies but
     concentrates its efforts on commercial products likely to be
     approved for consumer use.  Furthermore, FDA's routine on-site
     inspections of drug studies are conducted only after clinical
     trials have concluded and subjects have completed their
     participation. 

  Gaps also exist in FDA's inspection of IRBs.  FDA's Center for Drug
     Evaluation and Research annually issues the results of about 158
     inspections of the approximately 1,200 IRBs reviewing drug
     studies, although its goal has been to complete and issue
     reports on about 250 inspections each year.  We found that in
     one of FDA's 21 districts--one that contains several major
     research centers conducting studies with human subjects--12 IRBs
     had not been inspected for 10 or more years.  Furthermore, FDA
     is 3 to 5 years behind in its scheduled reinspection of some
     IRBs with which it had noted problems. 

  FDA officials told us that some of its inspectors may be
     inadequately prepared to understand the human subject protection
     implications of drug studies and to ask meaningful follow-up
     questions on the research protocols they review. 

Fourth, additional pressures make it difficult to guarantee the
protection of human subjects. 

  When seriously ill individuals, such as some HIV patients, equate
     experimental and proven therapies, some question the need for
     protections that appear only to restrict their access to
     therapy. 

  When physician-researchers do not clearly distinguish between
     research and treatment in their attempt to inform subjects, the
     possible benefits of a study can be overemphasized and the risks
     minimized. 

  When physicians use an innovative but unproven technique to treat
     patients, they may not consider the procedure to be research. 
     Such treatments, however, could constitute unregulated research,
     placing people at risk of harm from unproven techniques. 


   CONCLUSIONS
---------------------------------------------------------- Chapter 0:5

Our work suggests that over the last 3 decades federal regulators and
members of the research community have improved the protection of
human research participants.  However, holes inevitably exist in the
regulatory net because no oversight system can guarantee complete
protection for each individual.  The goals remain to encourage
researchers' ethical behavior without hobbling scientific research
and to refine regulations and oversight activities to further improve
subject protections.  Given the many pressures that can weaken the
effectiveness of the protection system, continued vigilance is
critical to ensuring that subjects are protected from harm. 


-------------------------------------------------------- Chapter 0:5.1

Mr.  Chairman, this concludes my prepared statement.  I will be happy
to answer any questions you or the other Members may have.




















For more information about this testimony, please call Bruce D.
Layton, Assistant Director, at (202) 512-7119. Other major
contributors included Frederick K. Caison, Linda S. Lootens, and
Hannah F. Fein.
----------------------------------------------------------------------
----------------------------------------------------------------------

*** End of document. ***