Scientific Research: Continued Vigilance Critical to Protecting Human
Subjects (Letter Report, 03/08/96, GAO/HEHS-96-72).

Pursuant to a congressional request, GAO reviewed the federal oversight
systems for protecting human subjects in federally sponsored scientific
experiments, focusing on whether the oversight procedures: (1) have
reduced the likelihood of abuses of human subjects; and (2) have
weaknesses that could limit their effectiveness.

GAO found that: (1) federal efforts to prevent the abuse of human
research subjects include establishing institutional review boards,
educating the research community, and requiring written commitments from
researchers to comply with standards for the protection of human
subjects; (2) although these efforts work to prevent harm to
participants in most experimental studies, the effectiveness of those
standards in ensuring compliance has not been systematically studied;
(3) federal monitoring activities for the protection of human research
subjects include on-site inspections and reviews of study documentation,
institutional review board operations, and allegations of misconduct;
(4) actions to enforce the human research subject protection
requirements include research restrictions, researcher disqualification,
criminal prosecution, and suspensions from conducting further research;
and (5) the oversight procedures are impaired by institutional review
boards' heavy workloads and competing demands, limited funds for on-site
inspections, the complexity and volume of research under review, and
reliance on researchers' self-assurances that they are complying with
requirements.

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

 REPORTNUM:  HEHS-96-72
     TITLE:  Scientific Research: Continued Vigilance Critical to 
             Protecting Human Subjects
      DATE:  03/08/96
   SUBJECT:  Ethical conduct
             Biological research
             Behavioral sciences research
             Pharmacological research
             Safety regulation
             Research program management
             Safety standards
             Informed consent (medical law)

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


Report to the Ranking Minority Member, Committee on Governmental
Affairs, U.S.  Senate

March 1996

SCIENTIFIC RESEARCH - CONTINUED
VIGILANCE CRITICAL TO PROTECTING
HUMAN SUBJECTS

GAO/HEHS-96-72

Protecting Human Research Subjects

(108207)


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

  CBER - Center for Biologics Evaluation and Research
  CDER - Center for Drug Evaluation and Research
  CDRH - Center for Devices and Radiological Health
  FDA - Food and Drug Administration
  HEW - Department of Health, Education, and Welfare
  HIV - human immunodeficiency virus
  HHS - Department of Health and Human Services
  IRB - institutional review board
  NDA - new drug application
  NIH - National Institutes of Health
  OPRR - Office for Protection from Research Risks

Letter
=============================================================== LETTER


B-259279

March 8, 1996

The Honorable John Glenn
Ranking Minority Member
Committee on Governmental Affairs
United States Senate

Dear Senator Glenn: 

The 40-year Tuskegee study in which treatment was withheld from black
men with syphilis, the injection of live cancer cells into elderly
patients in the 1960s, and the recent disclosure of unethical Cold
War-era radiation experiments\1

have demonstrated breakdowns in the protection of human subjects in
scientific experiments sponsored by the federal government and
others.  Much of the concern focuses on whether participants in these
experiments knew and understood what they would be subjected to and
had an adequate opportunity to decline to participate.  These and
other issues related to protecting human research subjects were
recently addressed by the President's Advisory Committee on Human
Radiation Experiments.\2

Since the 1960s, significant advances in protecting the rights and
interests of human subjects in biomedical and behavioral research
have occurred.  The federal presence has grown in this area,
establishing and reinforcing ethical practices for protecting human
subjects in federally funded and federally regulated research.  The
Department of Health and Human Services (HHS) is the primary federal
department sponsoring biomedical and behavioral research.  Its
regulatory apparatus for overseeing such research, which has evolved
over the past three decades, consists of two principal tiers of
review:  one at the research institution level and the other at the
federal level.  Both tiers are responsible for ensuring that
individual researchers and their research institutions comply with
federal laws and regulations for protecting human subjects. 

Despite the presence of institutional and federal oversight, abuses
still occur, as evidenced by the recent infringement of patients'
rights in breast cancer research.  Concerned about the adequacy of
current oversight, you asked us to determine (1) whether federal
oversight procedures have reduced the likelihood of abuses of human
subjects and (2) whether weaknesses exist that could limit the
effectiveness of the current oversight apparatus. 

Because of HHS' annual $5 billion investment through about 16,000
awards involving human subjects and its lead role in setting,
monitoring, and enforcing subject protections, we reviewed HHS'
oversight system.  Within HHS, we concentrated our review on the
Office for Protection from Research Risks (OPRR) and the Food and
Drug Administration's (FDA) Center for Drug Evaluation and Research
(CDER).  We interviewed federal and research institution officials;
reviewed HHS and FDA regulations, procedures, and records; examined
institutional procedures, guidelines, and records; and interviewed
scientific researchers, as well as experts in human subject
protection, from universities, medical centers, and subjects' rights
groups.  These researchers and experts included representatives drawn
from the fields of bioethics, law, medicine, and social science.  We
also interviewed representatives of the drug industry.  We performed
our work from September 1994 to December 1995 in accordance with
generally accepted government auditing standards.  See appendix I for
a detailed discussion of our scope and methodology. 


--------------------
\1 We have testified previously on this issue:  see Human
Experimentation:  An Overview on Cold War Era Programs
(GAO/T-NSIAD-94-266, Sept.  28, 1994) and Health and Safety:  Status
of Federal Efforts to Disclose Cold War Radiation Experiments
Involving Humans (GAO/T-RCED-95-40, Dec.  1, 1994). 

\2 Advisory Committee on Human Radiation Experiments, Final Report,
Washington, D.C.:  Oct.  1995. 


   RESULTS IN BRIEF
------------------------------------------------------------ Letter :1

Today's oversight of tens of thousands of HHS-funded research and
FDA-regulated drug studies appears to have reduced the likelihood
that serious abuses of human subjects, comparable to past tragic
events, will occur.  The conspicuous activity of local institutional
review boards and human subject protection efforts by federal
agencies have heightened the research community's awareness of
ethical conduct standards, increased compliance with federal
regulations, and served as deterrents to abuse of subjects' rights
and welfare.  However, little data exist that directly measure the
effectiveness of human subject protection regulations. 

No practical level of oversight can guarantee that each researcher
will protect subjects with complete integrity.  The detection of
instances of potential or actual harm to subjects both demonstrates
that abuses can occur and suggests that the current oversight
activities are working.  The government and the research community,
whose ultimate goal is the advancement of scientific knowledge,
struggle to balance two sometimes competing objectives--the need to
protect research subjects from avoidable harm and the desire to
minimize regulatory burden on research institutions and their
individual scientists.  Various time, resource, and other pressures,
however, have reduced or threaten to reduce the effectiveness of
local review board and federal agency oversight.  In this context,
the need for continued vigilance over human subject research should
remain a priority for the research community and agencies charged
with oversight. 


   BACKGROUND
------------------------------------------------------------ Letter :2

From 1962 through 1991, HHS' system for protecting human research
subjects was created, piece by piece, largely in response to
disclosures of dangerous or controversial biomedical and behavioral
research.  (See app.  II for more historical information.) The tragic
consequences of thalidomide use in the United States\3 and revelation
of the Tuskegee syphilis study shocked the public and convinced
national policymakers that unregulated biomedical research
represented a clear threat to research subjects.  Two expressions of
this concern were the passage of the National Research Act and the
promulgation of human subject protection regulations by the
Department of Health, Education, and Welfare (HEW)\4 in 1974.  The
act also established the National Commission for the Protection of
Human Subjects of Biomedical and Behavioral Research to guide federal
human subject protection policy.\5 When the core of the human subject
protection regulations was adopted by 15 other departments and
agencies in 1991, it became known as the Common Rule.\6

The Common Rule requires research institutions receiving federal
support and federal agencies conducting research to establish
committees to review research proposals for risk of harm to human
subjects and to perform other duties to protect human research
subjects.  It also stipulates requirements related to informed
consent--how researchers must inform potential subjects of the risks
to which they, as study participants, agree to be exposed.  (See fig. 
1 for Basic Elements of Informed Consent.) HHS regulations contain
additional protections not included in the Common Rule for research
involving vulnerable populations--namely, pregnant women, fetuses,
subjects of in vitro fertilization research, prisoners, and children. 
In the late 1970s and early 1980s, HHS considered but did not adopt
recommendations by two national commissions for specific regulations
to protect institutionalized mentally disabled subjects. 

   Figure 1:  Basic Elements of
   Informed Consent

   (See figure in printed
   edition.)

Within the HHS oversight system, OPRR and FDA are the key federal
entities overseeing compliance with informed consent and other human
subject protection regulations.\7

Both entities carry out oversight functions central to the operation
of the human subject protection system, including policy setting,
prevention, monitoring, and enforcement.  Institutional review boards
(IRB)--that is, review panels that are usually associated with a
particular university or other research institution--are responsible
for implementing federal human subject protection requirements for
research conducted at or supported by their institutions. 

OPRR is located within the National Institutes of Health (NIH), the
principal federal agency responsible for supporting biomedical and
behavioral research.  About one-half of OPRR's 28 full-time employees
are responsible for overseeing protections in the approximately
16,000 HHS awards involving human subjects.  The other half are
devoted to ensuring the humane care and use of laboratory animals. 
Three physician volunteers augment OPRR's human subject protection
staff.  OPRR has an annual budget of $1.9 million, about one-half of
which is targeted to human subject protection activities. 

FDA is responsible for protecting the rights of human subjects
enrolled in research with products it regulates--drugs, medical
devices, biologics, foods, and cosmetics.  Our review focused on
oversight activities of FDA's Center for Drug Evaluation and
Research, which carries out most of FDA's human subject protection
activities.\8 At CDER, responsibility for human subject protection
activities is shared between the Office of Drug Evaluation and the
Division of Scientific Investigations.  The Office of Drug Evaluation
reviews manufacturers' and researchers' requests to conduct drug
studies on human subjects.  The Division of Scientific Investigations
reviews FDA's field inspection reports on IRBs and investigators and
makes final determinations regarding compliance violations.  Routine
and for-cause on-site inspections are conducted by field staff, who
are also responsible for examining the integrity of research data,
assessing compliance with good manufacturing practices, and examining
other issues related to FDA's oversight of all its regulated
products. 

Within research institutions, oversight is done primarily by IRBs
responsible for examining research proposals and ongoing studies.\9
No data exist on the exact number of IRBs in the country but
estimates range from 3,000 to 5,000.  Most are found at universities,
hospitals, and private research facilities; a few are free standing. 
Human subject research conducted by NIH itself, for example, is
governed by the 14 IRBs of the NIH Intramural Research Program.\10 In
general, IRBs are composed chiefly of scientists at their respective
institutions.  They are required to have a minimum of five members,
at least one of whom is a scientist, one a nonscientist, and one a
person not otherwise affiliated with the research institution.  They
are also required to have a diverse membership; in determining
membership, consideration must be given to race, gender, and cultural
background. 


--------------------
\3 Thalidomide is a sedative that was approved for use in Europe in
the late 1950s and was widely used by pregnant women at risk of
premature delivery and miscarriage.  Although not dangerous to the
mother, the drug caused severe birth defects.  Although FDA had not
approved the drug for use in the United States, the manufacturer
supplied the drug to U.S.  physicians to establish its safety, as was
the common practice of that time.  By 1962 it had become evident in
Europe that thalidomide was harmful, and the investigational studies
were stopped in this country.  In that same year, it was also
revealed that many of the patients participating in the U.S. 
clinical trials had not been informed that they were part of an
investigational study nor had many given their consent. 

\4 Now the Department of Health and Human Services. 

\5 Between 1974 and 1995, six blue-ribbon panels were established to
address ethical issues in biomedical and behavioral research:  the
National Commission for the Protection of Human Subjects of
Biomedical and Behavioral Research (1974-78), the HEW Ethics Advisory
Board (1978-80), the President's Commission for the Study of Ethical
Problems in Medicine and Biomedical and Behavioral Research
(1980-83), the Biomedical Ethics Advisory Committee (1985-89), and
the Advisory Committee on Human Radiation Experiments (1994-95).  In
addition, in October 1995, the President established the National
Bioethics Advisory Commission with a mandate to report on current
human subject protections. 

\6 Currently, 17 departments and agencies that conduct or support
biomedical and behavioral research involving human subjects have
adopted regulations for protecting human research subjects.  The
first 15 to adopt the Common Rule, based on the core of HHS'
regulations, were the Departments of Agriculture, Energy, Commerce,
Housing and Urban Development, Justice, Defense, Education, Veterans
Affairs, and Transportation; the National Aeronautics and Space
Administration; the Consumer Product Safety Commission; the Agency
for International Development; the Environmental Protection Agency;
the National Science Foundation; and the Central Intelligence Agency. 
In addition, when the Social Security Administration became an
independent agency in 1995, its enabling statute bound it to follow
HHS' regulations. 

\7 FDA's regulations covering human subject research are nearly
identical to HHS' human subject protection regulations.  One
difference concerns the requirement for informed consent from
patients involved in emergency medical care research.  FDA and OPRR
are working to harmonize these rules. 

\8 FDA's Center for Biologics Evaluation and Research (CBER) and
Center for Devices and Radiological Health (CDRH) also carry out
activities to protect human subjects of product testing.  These
activities were not included in the scope of our review. 

\9 Additional reviews occur at local institutions.  At some
institutions, researchers are required to obtain approval from
departmental officials, and if necessary, from such issue-specific
groups as the radiation safety committee or the cancer research
group.  In addition, data and safety committees monitor ongoing
research for data indicating safety and efficacy.  They can recommend
modification to the informed consent form or clinical trials.  In
addition, they can recommend stopping the study if problems arise or
if the therapeutic effect has been demonstrated.  Private companies
also audit drug research that they sponsor. 

\10 In addition to IRB review, NIH requires panels of in-house
experts and nongovernment scientists to review research proposals'
protections for human subjects and scientific merit before funding
intramural and extramural research grant applications.  The NIH
Office of Intramural Research supports research in NIH's own
laboratories, whereas the Office of Extramural Research supports
research of nonfederal scientists in universities, medical hospitals,
and research institutions throughout the United States and abroad. 


   PREVENTIVE EFFORTS HAVE BEEN
   IMPORTANT IN REDUCING
   LIKELIHOOD OF ABUSES
------------------------------------------------------------ Letter :3

The presence of local review bodies and federal oversight agencies
appears to have heightened the awareness and sensitivity of the
research community to the importance of respecting subjects' rights
and welfare.  Written commitments, which bind research institutions
to comply with human subject protection requirements, are an
important element of the protection system.  By requiring individual
researchers and IRBs to uphold their institution's commitments, the
system works to prevent harm to participants in most experimental
studies.  However, the effectiveness of the HHS human subject
protection regulations in ensuring compliance by institutions and
individual researchers has not been systematically studied. 


      ASSURANCES COMMIT
      INSTITUTIONS TO UPHOLD HUMAN
      SUBJECT PROTECTION
      REQUIREMENTS
---------------------------------------------------------- Letter :3.1

Research institutions must commit to uphold human subject protection
requirements before engaging in research with human subjects
conducted or funded by any of the departments or agencies that
adopted the Common Rule.  To be eligible to receive such funding, an
institution must enter into a contract-like agreement, called an
assurance.  This is the written promise of an institution housing
research studies to comply with federal ethical conduct standards. 
OPRR, the federal office within NIH that approves assurances for
research funded by HHS, requires assurances to (1) include a
statement of ethical conduct principles, (2) stipulate that a review
board has been designated to approve and periodically review the
institution's studies, and (3) specify the review board's membership,
responsibilities, and process for reviewing and approving proposals. 
Assurances serve as one of the system's chief preventive measures. 

OPRR's authority to require assurances derives from the 1974 National
Research Act, which formalized the practice of obtaining from
institutions receiving HHS funding written assurances of their
commitment to the ethical conduct of research.  When the legislation
was enacted, NIH had already developed assurance-type documents with
many universities, which OPRR reviewed.  Approving an assurance
involves no site visits by OPRR to the institution; rather,
negotiations are handled through correspondence and telephone calls
with institution officials. 

OPRR assurances are of several types.  Multiple project assurances
are approved for universities and other major research centers that
conduct a substantial number of studies and have demonstrated a
willingness and the expertise to comply with human subject protection
requirements.  Through a multiple project assurance, an institution
does not need to reapply through OPRR for eligibility to receive HHS
funds for each new study approved by its IRB.  An assurance covers
the institution's human subject studies for 3 years, at which time
the institution must renew its assurance.\11 Renewals are for a
5-year period.  As a practical matter, multiple project assurances
allow institutions to conduct research with no further OPRR
involvement until the assurance is up for renewal.  As of November
1995, 451 active OPRR multiple project assurances covered more than
500 research institutions.  These institutions receive most of HHS'
funding for research with human subjects.  Primary responsibility for
negotiating all multiple project assurances in OPRR rests with a
retired physician who used to be employed for this purpose by OPRR. 
Since retiring, she has continued this work on an unpaid, part-time
basis.  Currently, the assurance branch chief is responsible for
approving all multiple project assurances OPRR negotiates. 

At institutions without a multiple project assurance, an assurance
agreement must be negotiated with OPRR for each individual study. 
These are called single project assurances and require OPRR to
review, for each study, documentation similar to that required for a
multiple project assurance.  In addition, OPRR reviews the study's
informed consent form before approving a single project assurance. 
As of November 1995, OPRR had 3,063 active single project assurances. 
Primary oversight of these assurances rests with three full-time
staff in OPRR's assurance branch. 

A third type of assurance--the cooperative project
assurance--recognizes that research is frequently conducted at
multiple sites under joint institutional sponsorship.  One example is
the National Surgical Adjuvant Project for Breast and Bowel Cancers,
sponsored by the National Cancer Institute and conducted at over 300
sites.  OPRR requires each participating institution to have a
cooperative project assurance for all its joint research, regardless
of other assurances held by the institution.  For projects conducted
under cooperative project assurances, OPRR designates reviewers to
approve each research protocol and a prototype informed consent form. 
IRBs at the participating institutions must also approve the protocol
and the informed consent document.  IRBs can require additional
explanations to be included in the informed consent document. 
However, they cannot modify the core elements of the protocol, which
is to be consistent across all sites.  Nor can they delete or
substantially modify the discussion of risks and alternative
treatments in the prototype consent document without notice and
justification.  As of November 1995, OPRR had 1,333 active
cooperative project assurances.  Assurance branch staff responsible
for single project assurances also review cooperative assurances with
additional support provided by other OPRR staff and others. 


--------------------
\11 Almost all institutions holding multiple project assurances
commit themselves to apply the terms of the assurance to all their
human subject studies, not just those funded by HHS. 


      FDA REQUIRES COMMITMENT TO
      HUMAN SUBJECT PROTECTION
      STANDARDS
---------------------------------------------------------- Letter :3.2

FDA also works to prevent the occurrence of human subject protection
violations in the drug research it regulates.  Before permitting drug
research with human subjects, FDA requires researchers to submit a
brief statement that they will uphold ethical standards and identify
the institutional review board that will examine the study.  Sponsors
are required to provide the results of chemical and animal studies
with the new drug, submit the proposed study procedures for using
human subjects, and commit to ensuring that a properly constituted
IRB will review the proposed study.  FDA reviews this information to
ensure the study poses no unacceptable risks to subjects, is
ethically sound, and is likely to achieve the study objectives.  FDA
can request modifications to or reject proposals deemed to present
unacceptable risk.  FDA's prevention efforts overlap OPRR's if the
drug study is supported by HHS funds. 


      FEDERAL ENTITIES' EDUCATION
      OF RESEARCH COMMUNITY IS
      ANOTHER PREVENTIVE MEASURE
---------------------------------------------------------- Letter :3.3

Both OPRR and FDA educate the research community on issues related to
protecting human research subjects.  Both respond directly to
questions from individual researchers, IRBs, and institutional
officials.  They cosponsor about four human subject protection
workshops annually across the country that are attended on a
voluntary basis by IRB members, research institution officials, and
researchers.  OPRR also issues written guidance that defines terms
and clarifies ambiguities in human subject protection requirements. 
OPRR may provide additional information to individual institutions
during its negotiation of assurances.  FDA also provides guidelines
on informed consent, research proposal review, and recordkeeping to
IRBs, research sponsors, and researchers. 


      IRBS SERVE AS GATEKEEPERS IN
      APPROVING RESEARCH
---------------------------------------------------------- Letter :3.4

Federal officials and the research community alike commonly cite IRBs
as a key line of defense protecting patients and healthy volunteers
participating in research.  Federal regulations authorize IRBs to
approve, approve with modification, or withhold approval from new
research projects.  Researchers must get approval from the
appropriate IRB associated with their institution before beginning
research with human subjects.\12 IRBs are required to review ongoing
projects annually or more often depending on the level of risk.  HHS
will not fund new human subject research or authorize ongoing
research to continue without the local IRB's approval. 

Specifically, IRBs are required to ensure that, for each project
reviewed, risks are minimized and reasonable in relation to
anticipated benefits, subjects are properly informed and give consent
to participate, and the rights and welfare of subjects are maintained
in other ways as well.  IRBs are required to include scientists and
nonscientists as members.  IRBs must also consider gender, racial,
and ethnic diversity in their membership selection in order to be
sensitive to a broad range of social as well as scientific issues. 
IRB members are also expected to recognize that certain research
subjects--such as children, prisoners, the mentally disabled, and
individuals who are economically or educationally disadvantaged--are
likely to be vulnerable to coercion or undue influence.  The local
nature of most IRBs enables members to be familiar with the research
institution's resources and commitments, the investigators'
capabilities and reputations, and the prevailing values and ethics of
the community and subject population. 

In deciding whether to approve new research, IRBs are required to
determine that a study's procedures are consistent with sound
research design and do not unnecessarily expose subjects to risk.  In
addition, IRBs are required to examine the study investigators'
efforts to obtain subjects' consent, including examining the informed
consent document when applicable.\13 They do this to ensure that the
document specifies the procedures the subject will undergo in
language and terminology the subject can understand, the risks to the
subject, and alternative treatments available and that the document
makes explicit, among other things, the right of individuals to
decline to participate in the study or to withdraw at any time. 

IRB members told us that they spend most of their time reviewing the
informed consent document associated with a study.  IRB reviews
generally do not involve direct observation of the research study or
of the process in which a subject's consent is obtained, however.  As
a result, IRBs must rely on investigators' and consent monitors'
assessments of subjects' reading skills, fluency in English, and
mental capacity.  An IRB can authorize the use of a consent monitor
to observe the delivery of informed consent, for example, when
potential subjects might not have the mental capacity to understand
all aspects of the consent process. 

IRBs are also required to review previously approved research
periodically.  The purpose of these continuing reviews is for IRBs to
keep abreast of a study's potential for harm and benefit to subjects
so that IRBs can decide whether the study should continue.  Principal
investigators must therefore report the presence of adverse effects
on study subjects, which allows the IRB to assess whether the
seriousness of risk has changed.  IRBs should also consider whether
advances in knowledge or technology have occurred that would require
reconsidering the appropriateness of the study's purpose or protocol. 
In addition, they should review such details as whether the number of
subjects in the study corresponds to the number initially approved. 


--------------------
\12 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 (i.e., no greater harm than encountered
in daily life).  The Secretary of Health and Human Services has
approved 10 categories of research that may be reviewed using
expedited review procedures.  Voice recordings and collection of nail
clippings, for example, are considered minimal risk research.  The
IRB chair or a chair-appointed IRB member, rather than the full
board, conducts expedited reviews. 

\13 IRBs may waive documentation of informed consent under certain
circumstances.  For example, under HHS regulations, informed consent
can be waived when the only record linking the subject and the
research would be the consent document and the principal risk would
be potential harm resulting from a breach of confidentiality. 
Informed consent can also be waived under HHS and FDA regulations
when the research presents no more than minimal risk of harm to
subjects and involves no procedures for which written consent is
normally required outside of the research context. 


   FEDERAL MONITORING AND
   ENFORCEMENT IDENTIFY AND
   ADDRESS HUMAN SUBJECT
   PROTECTION VIOLATIONS
------------------------------------------------------------ Letter :4

No system of prevention is foolproof--indeed, FDA's and OPRR's
monitoring identifies abuses and other evidence of noncompliance. 
Federal monitoring efforts for human subject protection violations
include reviews of study documentation, IRB operations, and
allegations of misconduct.  Federal enforcement activities serve to
stem further adverse consequences.  In fact, FDA officials,
researchers, and drug industry representatives we interviewed told us
that the FDA's oversight of drug research motivates researchers and
IRBs to follow proper human subject protection procedures. 


      FDA HAS A VARIETY OF
      MONITORING ACTIVITIES AND
      ENFORCEMENT OPTIONS
---------------------------------------------------------- Letter :4.1

FDA monitors drug research for compliance with human subject
protections.  By conducting on-site inspections of IRBS, reviewing
progress reports from researchers and sponsoring drug companies, and
making on-site inspections of clinical studies and investigators, FDA
becomes aware of noncompliance with federal regulations.  FDA
officials told us that most institutions and researchers respond
quickly and positively to inspection findings, and the presence of an
FDA inspection process deters human subject protection violations. 

FDA's inspection of IRBs is its primary monitoring tool for human
subject protection.  FDA inspects IRBs to determine their adherence
to federal human subject protection requirements.\14 FDA inspections
of IRBs consist primarily of an on-site examination of the IRBs'
minutes, written operating procedures, and other documentation that
substantiates initial and continuing review and proper IRB
membership.  During these inspections, FDA interviews the chair or
the administrator of the IRB to learn details about the IRB's
operation.  FDA also determines whether consent forms contain all
required elements and are signed by subjects. 

FDA has three levels of priority for inspecting the roughly 1,200
IRBs that oversee drug research.  FDA gives top priority to the
reinspection of IRBs for which it found serious deficiencies in the
IRBs' review of studies.  FDA's next priority is examining IRBs that
were unknown to FDA until identified by researchers in their
applications to begin drug studies with human subjects.  FDA's lowest
priority is the routine reinspection of IRBs.  Between fiscal years
1990 and 1995, CDER issued each year, on average, the results of 158
inspections of IRBs overseeing drug research.\15

Between January 1993 and November 1995, FDA issued 31 Warning Letters
to institutions regarding significant deficiencies in the performance
of their IRBs' oversight of drug research.\16 These Warning Letters
imposed sanctions--until CDER received adequate assurance that the
IRB had taken corrective action--on the IRBs' ability to approve new
studies, allow entry of new subjects into ongoing studies, or both. 
Among the more serious violations cited were the following: 
researchers participated as IRB members in the review of their own
studies; institutional officials falsely claimed no trials had been
conducted that would have required IRB review; IRBs had no process to
track ongoing studies; IRBs used expedited rather than full review to
approve major study changes; IRBs failed to correct deficiencies
noted during a previous FDA inspection; IRBs failed to ensure that
required elements of informed consent were contained in consent
documents; and IRBs allowed their members to vote by telephone
instead of convening the board. 

FDA officials told us that FDA has never had to invoke its ultimate
sanction--disqualification--for seriously deficient IRBs.  On about
60 occasions, institutions disbanded their IRBs upon FDA's findings
of serious noncompliance.  In most of these instances, the research
projects approved by the IRBs had already been completed. 

FDA's examination of individual drug studies is another component of
its human subject protection monitoring.  Before a manufacturer can
receive FDA approval to market a drug, it must satisfy FDA that it
has complied with FDA's human subject protection regulations during
clinical trials.  The monitoring includes reviews of progress reports
and on-site inspections.  Although FDA examines documentation on
protection matters, its principal focus in these efforts is to verify
the accuracy and completeness of study data as well as the
researcher's adherence to the approved protocol. 

When researchers begin clinical trials, FDA's Office of Drug
Evaluation requires them, through their sponsors, to submit annual
progress reports and also to report within 10 working days any
serious and unexpected adverse incidents involving subjects as well
as major changes to the study protocol.  If these reports indicate
potential or actual harm to subjects, FDA can suspend or terminate
the study. 

FDA's on-site inspections of drug studies generally occur after
clinical trials have concluded.  There are two types of inspections: 
routine and for-cause.  Routine inspections are conducted after a
manufacturer has completed its clinical trials and submits a new drug
application (NDA) to FDA for approval to market the product.  During
fiscal years 1990 through 1995, FDA issued each year, on average, the
results of about 265 routine inspections of drug studies.\17 The
sites visited are typically university-based research facilities,
independent testing laboratories, and the offices of physicians
participating in drug trials. 

Inspections of drug studies also include an assessment of how well
subjects were protected during the study:  whether the consent
document, study protocol, and required revisions to them were
reviewed and approved by an IRB before enrolling subjects; whether
signed consent forms were obtained from each enrolled subject;\18
whether adverse incident and status reports were submitted to the IRB
once research began; and whether subjects were recruited properly. 
FDA inspectors look for evidence that researchers reported all
safety-related information to the sponsor, reasons why subjects
dropped out of the study, and other matters related to the integrity
of study data.  In addition, FDA often interviews researchers and
sometimes interviews subjects. 

While routine inspections generally occur after completion of
clinical trials, for-cause inspections can occur at any time during
the course of drug testing with humans.  FDA conducts for-cause
inspections when its review of status reports submitted by
researchers indicates possible misconduct, or when it receives
allegations of serious misconduct.  FDA conducts about a dozen
for-cause inspections annually. 

Most of the violations FDA identifies through its routine inspections
of individual drug studies are relatively minor.  From 1977 to 1995,
about one-half of the violations related to the adequacy of the
informed consent forms.  For example, FDA frequently found violations
of the requirement to specify in the informed consent document whom
subjects can contact if they have concerns about research, subjects'
rights, or research-related injury. 

FDA also identified more serious violations in its routine and
for-cause inspections.  We reviewed 69 of the 84 letters describing
deficiencies that FDA issued to drug researchers between April 1980
and November 1995.  These letters cited instances of serious
misconduct, including failure to obtain informed consent; forgery of
subjects' signatures on informed consent forms; failure to inform
patients that a drug was experimental; fabrication of data to make
subjects eligible for study; submission of false electrocardiograms,
X rays, and lab test results to the company underwriting the
research; failure to report subjects' adverse reactions to drugs
under study, including a subject's death; failure to obtain informed
consent and an IRB's approval for a study touting a human growth
hormone as a cure for Alzheimer's disease; proceeding with a cancer
study after FDA had suspended it for protocol deficiencies; and
failure to inform patients that a drug sold to them was experimental
and contained a steroid. 

Since 1980, FDA has taken 99 actions against 84 clinical
investigators regarding their conduct of drug research with human
subjects.  FDA has used four types of actions to enforce its
regulations:  (1) obtaining a promise from a researcher to abide by
FDA requirements for conducting drug research; (2) invoking a range
of restrictions on a researcher's use of investigational drugs; (3)
disqualifying a researcher from using investigational drugs; and (4)
criminally prosecuting a researcher. 


--------------------
\14 Because of the commonalities among IRB inspections performed for
CDER, CBER, and CDRH, an inspection conducted for one of FDA's
centers--for example, CDER--can serve to protect subjects in studies
regulated by CBER or CDRH.  Furthermore, FDA's IRB inspections enable
it to monitor human subject protection aspects of some of the ongoing
and completed studies that were reviewed by the IRB. 

\15 In fiscal year 1995, FDA allocated about 13 full-time- equivalent
positions in its field offices for the on-site inspection of IRBs
reviewing research on drugs, medical devices, and biologic products. 
At CDER, FDA allocated about 6 full-time-equivalent positions to the
Division of Scientific Investigations for its oversight of IRB
inspections.  These positions are also responsible for inspections of
Radioactive Drug Research Committees, which are located at certain
research institutions.  FDA conducts about five such inspections each
year. 

\16 In January 1993, FDA instituted a new system with two categories
of IRB noncompliance findings.  In the first category, FDA issues
Warning Letters for the most serious problems.  The second
category--voluntary action indicated--applies to less serious
findings of IRB noncompliance.  From October 1993 to November 1995,
FDA requested voluntary actions from about 200 IRBs for a variety of
reasons, such as failure to identify IRB members, failure of IRB
minutes to identify controversial issues discussed, and too little
time spent reviewing studies. 

\17 In fiscal year 1995, FDA allocated about 45 full-time- equivalent
positions to its field staff for inspecting studies of drugs, medical
devices, and biologic products.  In addition, FDA allocated about 9
full-time-equivalent positions to CDER's Division of Scientific
Investigations for inspecting drug studies and investigators. 

\18 Because FDA has had problems verifying that informed consent was
obtained from a research subject before participation in a study, it
published a proposed rule in December 1995 that would require dating
the written consent form at the time consent was obtained. 


      OPRR INVESTIGATES
      ALLEGATIONS OF NONCOMPLIANCE
      AND REQUIRES CORRECTIVE
      ACTION
---------------------------------------------------------- Letter :4.2

OPRR also responds to inquiries and investigates allegations, but few
investigations result in site visits; inquiries and investigations
are largely handled by telephone and correspondence.  OPRR receives
complaints about human subject protection issues from a variety of
sources, including NIH inspection teams, FDA, subjects and their
families, staff from research institutions, news media, and the
Congress.  The majority of noncompliance reports come from the
institutions themselves, which are required to report unanticipated
problems, such as injuries and serious or continuing noncompliance,
to OPRR as part of the assurance agreement.  The number of compliance
cases investigated by OPRR grew from 32 open cases in January 1993 to
107 cases under investigation in June 1995.  OPRR officials and
others attribute the increase to a heightened awareness of human
subject protection issues and more extensive media coverage of
untoward research events rather than to an increase in the actual
occurrence of noncompliance. 

Over the past 5 years, OPRR's compliance staff of four full-time
employees and two volunteers have investigated several studies for
allegations involving serious human subject protection violations. 
One such example was OPRR's investigation of whether informed consent
procedures clearly identified the risk of death to volunteers in the
tamoxifen breast cancer prevention trial.  OPRR found that informed
consent documents at some sites failed to identify some of
tamoxifen's potentially fatal risks, such as uterine cancer, liver
cancer, and embolism.  In another instance, OPRR compliance
investigators found deficiencies in informed consent and in IRB
review procedures in a joint NIH-French study of subjects who had
tested positive for the human immunodeficiency virus (HIV) in Zaire. 
In a third case, OPRR compliance staff investigated a study of
schizophrenia at a major university because of complaints from
families of two subjects associated with the study.  In that
investigation, OPRR found that the informed consent documents failed
to adequately describe the research procedures, research risks, and
alternative courses of treatment.  In addition, OPRR found that the
researchers inappropriately obtained the subjects' oral consent
rather than written consent as required by HHS regulations.  Among
cases currently under investigation, OPRR is reviewing allegations
that researchers at a university-based fertility clinic transferred
eggs from unsuspecting donors to other women without the consent of
the donors. 

Our review of OPRR files showed that OPRR found such deficiencies as
the failure of an IRB to give full review of projects at a convened
meeting or to adequately review ongoing research.  OPRR also found
IRB approval of informed consent documents that did not clearly state
the study's purpose, did not identify the study's risks of the
research, and did not present information that would be
understandable to the subjects. 

In many cases, OPRR has required institutions to take corrective
action.  In some instances, OPRR has suspended an institution's
authority to conduct further research in a particular area until
problems with its IRBs were fixed.  From 1990 to mid-1995, there were
17 instances in which OPRR imposed some type of restriction on an
institution's authority to conduct human subject research.  For
example, in some cases, OPRR suspended the enrollment of new
subjects; in others, OPRR excluded certain types of research from
coverage by multiple project assurances, thereby requiring single
project assurances and the direct involvement of OPRR in reviewing
each study's informed consent forms and other documents.  To document
corrective actions, institutions are generally required to submit
quarterly reports to OPRR.  OPRR lifts a restriction when it is
satisfied that the institution has taken appropriate corrective
actions--in most cases, after receiving quarterly reports for about a
year to 18 months. 


   MULTIPLE FACTORS WEAKEN
   INSTITUTIONAL AND FEDERAL HUMAN
   SUBJECT PROTECTION EFFORTS
------------------------------------------------------------ Letter :5

Oversight systems are by nature limited to minimizing, rather than
fully eliminating, the potential for mishap, and HHS's system for
protecting human subjects is no exception.  Various factors reduce or
threaten to reduce the system's effectiveness.  IRBs face the
pressure of heavy workloads and competing professional demands.  OPRR
is often remote from the institutions it oversees.  FDA's processes,
while including on-site inspections, may permit human subject
protection violations to go undetected.  Moreover, the complexity and
volume of research under review and the difficulty of ensuring that
individuals truly understand the risks they may experience as
research subjects can weaken the effectiveness of human subject
protections. 


      WORKLOAD AND OTHER DEMANDS
      IMPAIR IRB OVERSIGHT
---------------------------------------------------------- Letter :5.1

Federal officials, experts, and research community members we
interviewed consistently mentioned several concerns about the
operations of IRBs.  First, IRB reviews are labor intensive and time
consuming, forcing boards to balance the need to make reviews
thorough against the need to get them done.  IRB members are usually
physicians, scientists, university professors, and hospital
department heads who are not paid for their IRB service.  Board
members themselves told us they face a heavy workload, and others in
the research community have raised concerns that heavy workload
impairs IRB review. 

In some cases, the sheer number of studies necessitates that IRBs
spend only 1 or 2 minutes of review per study.  FDA found one IRB
that had reviewed as many as 200 proposals and ongoing studies at a
meeting.  Several experts told us of other instances in which IRBs
had reviewed 100 to 150 studies in one meeting.  In many such cases,
one, two, or several individuals--known as "primary reviewers"--may
be assigned to examine a study comprehensively in advance of the IRB
meeting, often held monthly.  In these cases the other IRB members
rely on the conclusions drawn by the primary reviewers and may be
less prepared to identify and discuss potential problems with
proposals.  In addition, IRB members and researchers told us that,
given the time constraints, a good portion of the meetings is devoted
to assessing the adequacy of the consent forms at the expense of
reviewing research designs. 

Second, federal officials and experts in IRB issues have been
particularly concerned with IRBs' conduct of continuing reviews. 
They assert that these reviews are typically either superficial or
not done at all.  According to OPRR officials, IRBs have not always
understood the requirements for continuing review, and, in other
cases, IRB workload demands have reduced the quality of this
review.\19

In some cases, IRB administrative staff with no scientific
expertise--not IRB members themselves--review continuing review
forms, ensuring only that the information has been provided.  Heavy
workload also necessitates that IRBs rely largely on investigators'
self-assessments in conducting continuing reviews.  That is, IRBs
review statements completed by the study's investigators and, with
rare exceptions, do not verify the accuracy of the reported
information.  Although experts disagree on the desired level of IRB
verification, its value was demonstrated recently in a report by HHS'
Office of Inspector General.\20

The report cited one instance in which nine researchers failed to
notify their IRBs, as required, of major deviations from a study
protocol.  In another instance, a surgeon reported to the IRB the
implantation of an experimental device in 37 subjects.  The HHS
review team found that this surgeon and his coinvestigators had
actually implanted the device in 258 subjects, thus far exceeding the
limit of 75 subjects specified in the research protocol and approved
by the IRB.  In cases such as these, the possibility exists that a
researcher could selectively report favorable results. 

Third, experts we interviewed raised concerns about the independence
of IRB reviews.  For example, they told us that close collegial ties
with researchers at their institutions, pressures from institution
officials to attract and retain government or corporate research
funding,\21 financial ties to the research study, and reluctance to
criticize studies led by leading scientists can compromise the
independence of IRB reviews.  Although most experts we interviewed
agreed that instances of these problems occur, they did not have
enough evidence to determine the frequency or the extent of the
problem. 

Finally, some IRBs are viewed by their institutions and by
researchers as a low-priority administrative hurdle.  As a result,
these IRBs have difficulty securing the administrative and computer
support they require.  For example, OPRR has found instances of IRB
staff working in office space insufficient to conduct review board
business effectively, manual filing systems too primitive to ensure
that continuing reviews were conducted at the required times, and
lack of privacy for IRB staff to take the sensitive telephone calls
of subjects who may want to register complaints.  At such
institutions, researchers may not always follow IRB requirements,
such as revising informed consent forms or reporting adverse events. 


--------------------
\19 The January 1995 issue of OPRR Reports addressed the subject of
continuing review of research--institutional and IRB
responsibilities.  OPRR periodically distributes OPRR Reports to
about 5,500 institutions, IRB members, and others in the research
community. 

\20 Department of Health and Human Services, Office of Inspector
General, Investigational Devices:  Four Case Studies
(OEI-05-94-00100) (Washington, D.C.:  HHS, Apr.  1995). 

\21 IRB "shopping" has been cited as a threat to human subject
protection.  In several instances, corporate sponsors shifted
projects away from institutions where local reviewers raised concerns
about the sponsor's study.  See Sherertz, Robert J., and Stephen A. 
Streed, "Medical Devices:  Significant Risk vs.  Nonsignificant
Risk," Journal of the American Medical Association, Vol.  272, No. 
12, Sept.  28, 1994, pp.  955-956. 


      VARIOUS FACTORS MAY HAMPER
      OPRR OVERSIGHT
---------------------------------------------------------- Letter :5.2

OPRR's reliance on the assurance process for preventing the violation
of human subject protections requires that OPRR have sufficient basis
for judging an institution's ability to satisfy human subject
protection requirements.  At times, however, OPRR's assurance
negotiation process falls short of that goal.  OPRR staff are rarely
direct observers of the institutions they oversee.  They make no site
visits during assurance negotiations, but instead review solely an
institution's written application and conduct written or oral
follow-up.  Usually, document review does not include an examination
of the manuals that detail the human subject protection procedures
that the institution requires its IRBs and researchers to follow. 
Similarly, almost all of OPRR's compliance investigations--
reviews in response to allegations of misconduct--are carried out
through correspondence.  In the 5 years preceding April 1995, OPRR
made 15 site visits as part of the 202 compliance investigations it
completed. 

What OPRR has found in its site visits made in the course of
investigating allegations of violations illustrates the value of such
visits.  For example, when we accompanied OPRR on a compliance site
visit to a major research university, OPRR learned details about the
institution's IRB operations and reporting chain idiosyncrasies that
it was previously unaware of despite having reviewed the
institution's assurance documents.  This visit resulted in the
temporary suspension of the human subject research under the
surveillance of one of the university's two IRBs. 

OPRR officials told us that they lack the time and funds for more
site visits for assurance negotiations or compliance.  They
acknowledged, however, that when they did make site visits, their
investigations were significantly enhanced by communicating
face-to-face with officials, researchers, and the administrative
staff assigned to the institution's IRB.  On-site investigations have
also been more thorough and expeditious because OPRR had ready access
to study files and IRB records and could quickly follow leads.  Site
visits also provided OPRR the opportunity to educate institutional
staff about ethical conduct practices by enabling OPRR staff to be
immediately available to discuss and answer questions about human
subject protection issues.  Through these exchanges, OPRR staff
learned about problems, such as those with continuing review, that
other institutions could be experiencing.  Experts we interviewed
also said that OPRR's prevention efforts would be more effective if
it were to make site visits to institutions in the process of
approving and renewing assurances. 

In addition, NIH's organizational structure may hamper OPRR's
independent oversight and enforcement of human subject protection
regulations, although we found no specific instance in which this
occurred.  Although OPRR is located within the Office of Extramural
Research, OPRR is responsible for enforcing compliance with human
subject protection regulations for research conducted or supported by
both the Office of Intramural Research and the Office of Extramural
Research.  Under this structure, the OPRR Director reports to the
Deputy Director for Extramural Research, who, in turn, reports to the
Director of NIH.  Because the Deputy Director for Intramural Research
also reports to the Director of NIH, OPRR has no direct authority
over the research conducted by the intramural program.  As a result,
when OPRR cited NIH's Office of Intramural Research in 1991 for
compliance violations, for example, OPRR had to depend on that
office's good will and professional conduct to implement the
corrective action plan proposed by OPRR, since OPRR did not have
direct authority to require NIH to correct violations.  According to
OPRR, NIH will complete implementation of the plan by April 1996, 5
years after the problems were noted. 

From a broader organizational perspective, a potential weakness
exists because NIH is both the regulator of human subject protection
issues as well as an institution conducting its own human subject
research.  The Director of NIH, therefore, has responsibility for
both the success of NIH's intramural research program and for the
enforcement of human subject protection regulations by OPRR. 


      FDA OVERSIGHT HAS CERTAIN
      LIMITATIONS
---------------------------------------------------------- Letter :5.3

In some instances, FDA's oversight efforts may permit violations of
human subject protections to go undetected.  For example, researchers
who use human subjects in drug research are required to submit to
their sponsor periodic progress reports during the course of the
trials.  These reports include adverse events, project status, and
changes to the research protocol.  The sponsor, in turn, reports
adverse events to FDA.  The reporting process, however, is a passive
one in which FDA relies on researchers and their sponsors to report
potential or actual adverse medical events during clinical trials. 
Violations of subjects' rights, such as inadequate informed consent
or IRB review, however, are not required to be reported. 

Two gaps in FDA's inspection of drug studies have implications for
human subject protections.  First, FDA only conducts routine on-site
inspections after clinical trials have concluded and subjects have
completed their participation.  Second, FDA officials told us that
because of resource limitations, FDA does not inspect all studies;
instead, it concentrates its efforts on those products that both are
likely to be approved for consumer use and could pose high risk to
consumers.\22 FDA officials told us that the primary reason for these
inspections is to review the integrity of the study's data before
initiating a review of the drug's safety and effectiveness.  In
essence, then, FDA's inspection program is geared more toward
protecting the eventual consumer of the drug than the subjects on
whom the drug was tested.\23

Gaps also exist in FDA's inspection of IRBs.  CDER annually issues
the results of about 158 inspections of the approximately 1,200 IRBs
reviewing drug studies, although its goal has been to complete and
issue reports on about 250 inspections each year.  We found that in
one of FDA's 21 districts--a district that contains several major
research centers conducting studies with human subjects--12 IRBS had
not been inspected for 10 or more years on behalf of CDER, CBER, or
CDRH.  Furthermore, although FDA's policy is to accelerate the
timetable for reinspecting IRBs found to have significant problems,
we noted instances in which FDA conducted its reinspection 3 to 5
years later.  FDA officials told us that, because of resource
constraints, IRB inspections receive lower priority than inspections
of FDA-regulated products or manufacturing practices. 

Finally, experts we interviewed raised concerns about the unevenness
of FDA inspectors' expertise, which they believe could enable human
subject protection violations to go undetected.  FDA officials
acknowledge that some inspectors may be inadequately prepared to
understand the human subject protection implications of drug studies
and to ask meaningful follow-up questions on the research protocols
they review.  FDA officials also noted that some inspectors lack
practical experience in reviewing drug studies because they work in
districts with few bioresearch sites and therefore usually inspect
other types of regulated products. 


--------------------
\22 Studies for certain products, such as vitamins, antimicrobial
handwashes, and saline solutions, are not inspected by FDA because
they pose low risk for consumers. 

\23 FDA calls drug studies that are sponsored by pharmaceutical
companies and are intended to lead to a marketable product
"commercial" studies.  Commercial studies can involve thousands of
subjects.  In contrast, "research" studies are typically sponsored by
individual researchers, do not result in commercial products, and
usually involve a small number of subjects.  FDA does not routinely
inspect research studies.  FDA officials told us, however, that FDA
inspects studies that are important to the approval of all NDAs
containing clinical data. 


      OTHER PRESSURES IN THE
      RESEARCH ENVIRONMENT MAY
      WEAKEN OVERSIGHT
      EFFECTIVENESS
---------------------------------------------------------- Letter :5.4

Several additional pressures make guaranteeing the protection of
human subjects difficult.  Many of the experts we interviewed raised
concerns about the growing complexity of science, the increasing
number of multicenter trials, and the vulnerability of certain
subject populations.  The extent of these problems, however, has not
been studied. 

First, the increasing complexity of research makes it difficult for
IRBs to assess human subject protection issues when members are not
conversant with the technical aspects of a proposed study.  In such
cases, the IRB's ability to assess the risks or benefits posed to
subjects and the adequacy of language found in the consent document
is questionable.  In addition, cutting edge science can present new
ethical dilemmas for IRBs to confront.  Experimental human
reproductive techniques and ownership of genetic material, for
example, have raised ethical questions that thus far have not been
satisfactorily resolved. 

Second, the growing number of large-scale trials carried out at
multiple research sites presents other problems for IRBs, both at
initial and continuing review.  Proposals for multicenter trials are
reviewed by an IRB associated with each local research site.  If most
involved IRBs have approved a proposed study--that is, determined
that the study is safe, ethical, and appropriately described in
consent forms--then remaining IRBs at other institutions may feel
pressured to mute their concerns about the study.  Furthermore,
during the course of a multicenter trial, each participating IRB
receives numerous reports of adverse events from other research
sites.  Because of the volume of reports, IRB members may have
difficulty discerning which adverse events are both relevant and
serious enough to warrant their taking note of them. 

Third, IRBs and researchers may not always be sensitive to subjects
who have a stake in believing that research is at worst benign and at
best beneficial.  For many seriously ill individuals--such as HIV
patients, for example--experimental therapies represent the best
source of hope.  Such subjects often equate experimental and proven
therapies, leading some of them to question the need for protections
that appear only to restrict their access to therapy.  The Advisory
Committee on Human Radiation Experiments notes that

     "...patient-subjects who have serious illnesses may have
     unrealistic expectations both about the possibility that they
     will personally benefit by being a research subject and about
     the discomforts and hardships that sometimes accompany
     research."\24

Volunteers who want to be included in biomedical or behavioral
studies because they believe in the advancement of science or because
researchers offer financial incentives are another group whose
personal stake in the research may go unnoticed by IRBs and
researchers, thereby weakening oversight. 

Fourth, an inherent conflict of interest exists when
physician-researchers include their patients in research protocols. 
If the physicians do not clearly distinguish between research and
treatment in their attempt to inform subjects, the possible benefits
of a study can be overemphasized and the risks minimized. 

Fifth, pressures to recruit subjects can lead researchers and IRBs to
overlook deficiencies in efforts to inform subjects of potential
risks.  This problem has been exacerbated, a consultant to IRBs told
us, by NIH and FDA guidelines that now require that subjects selected
for the studies over which the agencies have jurisdiction reflect the
gender and racial composition of potentially affected populations. 
These guidelines are in place for the purpose of generalizing
research results to the widest possible range of population groups. 

Finally, the line between research and medical treatment is not
always clear to clinicians.  Controversy exists regarding whether
certain medical procedures should be categorized as research.  For
example, in some cases physicians may use an innovative but unproven
technique to treat patients without considering the procedure to be
research.  From the standpoint of the physicians, they are providing
treatment to individual patients rather than conducting a clinical
trial.  Given this view, they do not seek IRB approval.  From the
standpoint of experts we interviewed, however, such treatments could
constitute unregulated research and place people at risk of harm from
unproven techniques. 


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


   CONCLUSIONS
------------------------------------------------------------ Letter :6

With the issuance of federal regulations covering much human subject
research and the maturation of the HHS oversight system, researchers
have become more aware of ethical conduct standards and more often
comply with them.  Because no oversight system can be designed to
guarantee complete protection for each individual, holes inevitably
exist in the regulatory net.  Federal and IRB reviewers rarely
observe the interaction between researchers and subjects during the
informed consent process or throughout the course of the study. 
Whether research institutions are examined by OPRR for eligibility to
receive HHS funding, research studies are assessed by IRBs for their
compliance with HHS regulations, or applications to conduct drug
trials are reviewed by FDA, oversight is present, but at a distance. 

There is consensus among experts and regulators about the benefits of
first-hand review, but continuous on-site inspections of every
research institution and its studies are neither feasible nor
desirable because of the regulatory burden this would impose on both
the research community and regulators.  Finding the balance, however,
between that extreme and a process that relies almost exclusively on
paper reviews is the fundamental challenge facing regulators and IRBs
in the current HHS oversight system. 

Individuals participating in biomedical and behavioral research are
essential to the advancement of science and medicine.  Federal
regulators and research institutions, therefore, continually strive
to improve the protection of human participants without imposing an
unwieldy, burdensome regulatory apparatus.  To continue to prevent
the occurrence of human subject protection violations and to identify
and correct violations that do occur remain essential objectives of
the system.  Given the many pressures that can weaken the
effectiveness of the protection system, continued vigilance is
critical to ensuring that subjects are protected from harm. 


   AGENCY COMMENTS
------------------------------------------------------------ Letter :7

NIH and FDA reviewed a draft of this report and provided comments,
which are reproduced in appendixes III and IV.  NIH and FDA found the
report to be generally accurate and suggested revisions to clarify
specific aspects of our discussion of the human subject protection
system.  We incorporated these as appropriate, basing the changes in
some instances on further discussions with officials from each
agency. 

In its comments, NIH recognized the importance of on-site visits to
research institutions by OPRR staff and noted that the number of
technical assistance visits would be increased to 12 to 24 per year. 
This action should help strengthen human subject protection efforts
by institutions and investigators as well as improve OPRR's
assurance, monitoring, and enforcement efforts. 

In its comments, NIH also stated that OPRR's independent oversight
and authority to enforce human subject protection regulations within
NIH are not compromised by OPRR's location within the NIH
organizational structure.  NIH said that the lines of authority of
the NIH Deputy Director for Intramural Research and the OPRR Director
do not cross within NIH and, therefore, that OPRR's authority is not
compromised.  We disagree with NIH's conclusion and believe that a
potential weakness exists in OPRR's ability to enforce human subject
protection regulations within NIH.  This weakness results from the
chain of command within NIH and the NIH Director's dual
responsibilities for the success of the intramural research program
and OPRR's enforcement of human subject protection regulations.  We
have amplified our discussion of these issues in the report. 

In its comments on our draft report, FDA raised concerns that our
work understates FDA's accomplishments and the efforts to protect
human subjects of product testing by the industries regulated by FDA. 
Because human subject protection activities in drug research account
for most of FDA's efforts in this area, we limited the scope of our
work to an examination of CDER's oversight.  We have modified the
report to acknowledge the human subject protection activities of the
Center for Biologics Evaluation and Research and the Center for
Devices and Radiological Health.  Furthermore, we have clarified that
the inspection reports and actions to enforce regulations we discuss
are for CDER's oversight of IRBs and drug studies, and we have
included additional information FDA provided on fiscal year 1995
activities. 

FDA also focused on our presentation of aspects of its IRB inspection
programs.  FDA commented that (1) the IRB inspection program is the
principal way in which FDA addresses the issue of human subject
protection, (2) IRB inspections can enhance protection for subjects
in specific studies, and (3) an IRB inspection conducted for one
center--for example, CDER--can serve to protect subjects in studies
regulated by CBER and CDRH.  We have modified the report to address
these points. 


---------------------------------------------------------- Letter :7.1

As agreed with your office, unless you publicly announce its contents
earlier, we plan no further distribution of this report until 7 days
from the date of this letter.  At that time, we will send copies of
this report to the Secretary of HHS, the Director of NIH, the
Commissioner of FDA, and other interested parties. 

This report was prepared under the direction of Mark V.  Nadel,
Associate Director for National and Public Health Issues.  If you or
your staff have any questions, please call me at (202) 512-7119 or
Bruce D.  Layton, Assistant Director, at (202) 512-6837.  Other major
contributors to this report include Frederick K.  Caison, Linda S. 
Lootens, and Hannah F.  Fein. 

Sincerely yours,

Sarah F.  Jaggar
Director, Health Financing and
 Public Health Issues


SCOPE AND METHODOLOGY
=========================================================== Appendix I

We focused our work on the Department of Health and Human Services
(HHS)--the federal department sponsoring biomedical and behavioral
research with the largest human subject research budget, over $5
billion in fiscal year 1995.  Within HHS, we examined the policy and
oversight roles of the two entities with primary responsibility for
protecting human research subjects:  the National Institutes of
Health's (NIH) Office for Protection from Research Risks (OPRR) and
the Food and Drug Administration (FDA).  OPRR is responsible for
enforcing compliance with HHS human subject protection regulations
when human subject research is conducted or supported by HHS.  FDA is
responsible for protecting the rights of human subjects enrolled in
research with products it regulates--drugs, medical devices, and
biologics.  We limited our review to FDA's Center for Drug Evaluation
and Research (CDER) because drug research is the largest segment of
biomedical research.  Because of this volume, FDA conducts more
oversight activities in the drug products area than it does for
medical devices and biological products, with CDER carrying out most
of FDA's human subject protection activities.  Although FDA's Center
for Biologics Evaluation and Research and Center for Devices and
Radiological Health also have programs to protect human subjects,
these Centers were not included in our review. 

To gather information about the federal role in protecting human
subjects, we interviewed NIH, OPRR, and FDA officials and reviewed
regulations, policies, procedures, guidelines, and educational
materials the entities provide to institutional review boards (IRB)
and researchers.  To learn about the nature of OPRR findings and
corrective actions, we reviewed 40 of the 166 compliance case files
handled by OPRR from 1988 through March 1995, including 30 files we
randomly selected and 10 files OPRR officials selected as
representing the most serious violations.  We accompanied OPRR staff
on a compliance site visit to a major research institution and
reviewed OPRR site visit reports from compliance visits conducted
from September 1990 through December 1994.  We also reviewed examples
of inspection files, 69 of the 84 letters describing deficiencies
that FDA issued to drug researchers from April 1980 through November
1995, and all 31 Warning Letters issued to IRBs regarding their
oversight of drug research between January 1993 and November 1995. 
In addition, we reviewed correspondence between FDA and institutions
in cases where FDA inspections found that IRBs did not comply with
human subject protection regulations. 

To examine how local level protections work, we reviewed the
professional literature, including the reports of presidential and
congressional commissions; interviewed research institution
officials, IRB members, and researchers; and reviewed research
documents, such as institutional guidelines for IRBs and researchers,
IRB minutes, and informed consent forms.  We attended an IRB meeting
to observe an IRB review of proposed research.  We interviewed
numerous experts from across the nation with experience in bioethics,
medicine, social science, law, and human subject protection issues. 
These experts included university and hospital researchers, subjects'
rights advocates, IRB members, human subject protection consultants,
and representatives from the drug industry. 

We performed our field work from September 1994 to December 1995 in
accordance with generally accepted government auditing standards. 


LANDMARK EVENTS AFFECTING THE
DEVELOPMENT OF HHS' HUMAN SUBJECT
PROTECTION SYSTEM
========================================================== Appendix II



   (See figure in printed
   edition.)




(See figure in printed edition.)APPENDIX III
COMMENTS FROM THE NATIONAL
INSTITUTES OF HEALTH
========================================================== Appendix II



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(See figure in printed edition.)APPENDIX IV
COMMENTS FROM THE FOOD AND DRUG
ADMINISTRATION
========================================================== Appendix II



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