Mr. Chairman and Members of the Subcommittees:
I am Tom Puglisi, Director of the Division of Human Subject Protections, Office for
Protection from Research Risks (OPRR), Office of Extramural Research, National Institutes
of Health (NIH). I am accompanied by Gary B. Ellis, OPRR's
Director. We are pleased to appear before the Subcommittees to report on OPRR's oversight of protection of the rights and welfare
of human research subjects at the Veterans Affairs (VA) Greater Los Angeles Healthcare
System.
In 1995, I headed a site visit to the VA West Los Angeles, which led to the events
giving us cause to meet this morning. Dr. Ellis chairs the Interagency Committee on
Protecting Human Research Subjects (known formally as the Subcommittee on Human Subjects
Research, Committee on Science, National Science and Technology Council), of which the VA
is an active member.
This Spring marks the 25th anniversary of the promulgation in 1974 of the Department of
Health and Human Services (DHHS) regulations for Protection of Human Subjects in research
(Title 45, Code of Federal Regulations, Part 46; May 30, 1974) and the enactment of the
National Research Act (Public Law 93-348; July 12, 1974). At their core (Subpart A), the
DHHS regulations contain requirements for assuring compliance by research institutions;
requirements for researchers obtaining and documenting informed consent; and requirements
for Institutional Review Board (IRB) membership, function, operations, review of research,
and record keeping. The DHHS regulations also contain additional protections for certain
vulnerable research subjects--pregnant women (Subpart B), prisoners (Subpart C), and
children (Subpart D).
The "Common Rule"
In 1991, the core DHHS regulations (45 CFR Part 46, Subpart A) were formally adopted by
more than a dozen other Departments and Agencies that conduct or fund research involving
human subjects as the Federal Policy for the Protection of Human Subjects, or "Common Rule."
In 1991, the Department of Veterans Affairs promulgated this rule at 38 CFR Part 16.
Today, the 1991 Federal Policy is shared by 17 Departments and Agencies, representing
most, but not all, of the federal Departments and Agencies sponsoring human-subjects
research.
In addition, certain federally sponsored and much privately sponsored research is
subject to the regulations of the Food and Drug Administration (FDA) at 21 CFR Parts 50
and 56. FDA regulations confer protections on human subjects in research when a drug,
device, biologic, food additive, color additive, electronic product, or other test article
subject to FDA regulation is involved. FDA regulations and the provisions of the Common
Rule are largely congruent, although some significant differences exist.
The Common Rule defines "research"as "a
systematic investigation, including research development, testing, and evaluation,
designed to develop or contribute to generalizable knowledge."Activities which meet this definition constitute
research for purposes of the Common Rule, whether or not they are conducted or supported
under a program which is considered research for other purposes. Some demonstration and
service programs, for example, may include research activities.
The Common Rule defines "human subject"as "a
living individual about whom an investigator (whether professional or student) conducting
research obtains (1) data through intervention or interaction with the individual, or (2)
identifiable private information."
Institutional Review Boards
The cornerstone of our system of protection of human research subjects is the local
Institutional Review Board at the research site. The IRB is, by federal regulation, to
consist of a minimum of five people, including at least one scientist, one nonscientist,
and one person not otherwise affiliated with that institution. The nonscientist must be
present to achieve a quorum. The members must have varying backgrounds to promote complete
and adequate review of research activities commonly conducted by the institution.
The IRB must be sufficiently qualified through the experience, expertise, and diversity
of its members to promote respect for its advice and counsel in safeguarding the rights
and welfare of human subjects. In addition to possessing the professional competence
necessary to review specific research activities, the IRB must be able to ascertain the
acceptability of proposed research in terms of institutional commitments and regulations,
applicable law, and standards of professional conduct and practice. The IRB must therefore
include persons knowledgeable in these areas.
Under the Common Rule, 17 federal Departments and Agencies cannot provide funds for
human subjects research unless an IRB approves the protocols for such studies. No
human-subjects research supported by a Common Rule Department or Agency may be initiated,
and no ongoing research may continue, in the absence of an IRB approval.
Let me turn briefly to the specific responsibilities of the Institutional Review Board.
IRB review assures that:
risks to subjects are minimized;
risks to subjects are reasonable in relation to
anticipated benefits, if any, to subjects, and the importance of the knowledge that may
reasonably be expected to result;
selection of subjects is equitable;
there is proper informed consent and
documentation of informed consent;
when appropriate, the research plan makes
adequate provision for monitoring the data collected to ensure the safety of subjects;
when appropriate, there are adequate provisions
to protect the privacy of subjects and to maintain the confidentiality of data; and
additional safeguards have been included in the
study to protect the rights and welfare of any subjects likely to be vulnerable to
coercion or undue influence
Once research is initiated, IRBs have continuing responsibilities. These include:
The conduct of continuing review at intervals
appropriate to the degree of risk, and in any event, not less than once per year.
Authority to observe or have a third party
observe the consent process and the research.
Receipt of prompt reports from investigators of
any unanticipated problems involving risks to subjects or others, or any serious or
continuing noncompliance with the IRB's
requirements or determination, or with the regulations.
Authority to suspend or terminate IRB approval of
research that is not being conducted in accord with the IRB=s requirements or that has been associated with
unexpected serious harm to subjects.
Informed Consent
All present today know how integral--how crucial--the process of informed consent is.
Many have a general picture of informed consent, and it is useful to add higher resolution
to that picture. Federal regulations specify 14 elements of informed consent, 8 of which
are required:
(1) A statement that the study involves research, an explanation of the purposes of the
research and the expected duration of the subject's participation, a description of the
procedures to be followed, and identification of any procedures which are experimental.
(2) A description of any reasonably foreseeable risks or discomforts to the subject.
(3) A description of any benefits to the subject or to others which may reasonably be
expected from the research.
(4) A disclosure of appropriate alternative procedures or courses of treatment, if any,
that might be advantageous to the subject.
(5) A statement describing the extent, if any, to which confidentiality of records
identifying the subject will be maintained.
(6) For research involving more than minimal risk, an explanation as to whether any
compensation and an explanation as to whether any medical treatments are available if
injury occurs and, if so, what they consist of, or where further information may be
obtained.
(7) An explanation of whom to contact for answers to pertinent questions about the
research and research subjects' rights, and whom to contact in the event of a
research-related injury to the subject.
(8) A statement that participation is voluntary, refusal to participate will involve no
penalty or loss of benefits to which the subject is otherwise entitled, and the subject
may discontinue participation at any time without penalty or loss of benefits to which the
subject is otherwise entitled.
A researcher who seeks to recruit an individual for research without conveying all of
these elements of information in language understandable to the potential subject is not
obtaining informed consent.
Assurance of Compliance
Within DHHS, OPRR oversees implementation of the human-subject regulations in all DHHS
facilities as well as domestic and foreign institutions or sites receiving DHHS funds. In
keeping with the provisions of the Common Rule, OPRR requires that each DHHS agency and
extramural research institution that conducts research involving human subjects sets forth
the procedures it will use to protect human subjects in a policy statement called an
"Assurance" of compliance. Under the Common Rule, OPRR has authority for
approving an Assurance at DHHS-funded institutions for federal-wide use.
An Assurance with OPRR is a formal, written commitment to: (1) widely held ethical
principles; (2) the DHHS Regulations for Protection of Human Subjects; and (3)
institutional procedures adequate to safeguard the rights and welfare of human subjects.
The terms of the institution's Assurance are negotiated with OPRR. The detailed, written
Assurance statement becomes the instrument that OPRR uses to gauge an institution's
compliance with human subject protections if there is a problem. Where noncompliance has
occurred, OPRR has the authority to require corrective actions under the Assurance or to
withdraw its approval of the Assurance.
At OPRR's discretion, institutions with a large volume of research and demonstrated
expertise in human subjects protection may be granted a Multiple Project Assurance (MPA).
A Multiple Project Assurance, as the term implies, is an institution's pledge of full
human subject protections for multiple projects at the institution.
At present, OPRR holds some 430 Multiple Project Assurances that cover some 730
research institutions in the United States
and Canada. Most of these Multiple Project
Assurances, at the voluntary election of the research institution, commit all activities
at the institution--irrespective of funding source--to the DHHS regulations for Protection
of Human Subjects. OPRR appreciates the willingness of many institutions to choose this
voluntary option.
From 1987 to 1998, the VA West Los Angeles held Multiple Project Assurance #M-1097, and
the VA Sepulveda held Multiple Project Assurance #M-1292. [First approved in 1982, MPA
#M-1097 initially covered only the Wadsworth facility. The Sepulveda MPA #M-1292 was first
approved in 1983.] Coincident with an administrative merger and at the request of these
institutions, a new Multiple Project Assurance, #M-1087, was approved in 1998 for the VA
Greater Los Angeles Healthcare System.
On March 22, 1999, OPRR deactivated Multiple Project Assurance #M1087 for reasons I
will describe in a moment. First, I will describe the history of OPRR's interaction with the VA West Los Angeles.
OPRR's oversight of compliance by the VA West
Los Angeles with DHHS human-subject rules
In 1993, as OPRR was investigating informed consent in schizophrenia research at the
University of California Los Angeles, OPRR received an allegation that informed consent
procedures for schizophrenia research at the VA West Los Angeles also failed to meet
regulatory standards. Upon investigation, OPRR found that numerous informed consent
documents lacked basic, required information such as a complete description of (i) the
procedures for manipulation and withdrawal of medications; (ii) reasonably
foreseeable research risks; and (iii) potentially advantageous alternatives to research
participation.
OPRR required correction of these deficiencies in July 1994. OPRR also required that
the VA West Los Angeles implement four additional protections for subjects of
psychiatric research; specifically, (i) that the IRB include, at every meeting where such
research is reviewed, a special representative who could give voice to the perspective of
potential subjects in safeguarding their rights and welfare; (ii) that informed consent
documents disclose when medication is determined by the research protocol rather than by
clinical need; (iii) that informed consent documents disclose when the treating
clinicians are also the research investigators; and (iv) that a special Data and Safety
Monitoring Board (DSMB) be established to monitor such research (i.e., where the treating
clinicians are also the research investigators). The VA West Los Angeles agreed to
implement these corrective actions, and its Multiple Project Assurance was restricted to
require quarterly progress reports to OPRR documenting implementation.
In January 1995, I led an OPRR site visit to the VA West Los Angeles. The site visit
revealed a number of deficiencies in the Institutional Review Board's operating procedures and record-keeping practices
that undermined the effectiveness of systemic protections for human subjects. These
deficiencies included (i) inadequate monitoring of changes required by the IRB; (ii)
inappropriate designation of exemptions; (iii) inappropriate use of expedited review
procedures; (iv) inadequate continuing review procedures; and (v) inadequate
procedures for reporting unanticipated problems involving risks to subjects or others. The
site visit also revealed the need for (i) a comprehensive education program for IRB
members and investigators; and (ii) increased support staff for the IRBs.
These findings were communicated to VA West Los Angeles officials orally at
the conclusion of the site visit, and in writing on February 14, 1995. The facility's Multiple Project Assurance remained restricted, and
quarterly progress reports documenting appropriate corrective actions were required.
OPRR continued to receive progress reports from the VA West Los Angeles in 1996, but no
progress reports were received in 1997. OPRR requested additional information in
April 1998, because it was still not clear that all required actions had been
successfully implemented. The VA West Los Angeles provided reports to OPRR in June and
November 1998.
Review of this information by OPRR revealed continuing, serious deficiencies in human
subject protection procedures at the West Los Angeles facility. In specific, OPRR reviewed
the minutes of 9 IRB meetings conducted in May, June, and July 1998. OPRR found that in 7
of those 9 meetings, the IRB conducted business (i.e., approved human subjects research)
without a valid quorum, either because a majority of members failed to appear or because
there was no nonscientist member present, as the regulations require. Two of those
meetings lacked both a numerical quorum and a nonscientist member.
In addition, you will recall that in 1994 OPRR required that the IRB include a special
subject representative when reviewing psychiatric research. In OPRR's 1998 review of 9 IRB meetings, 1 of the 3 meetings
at which psychiatric research was approved failed to include such a representative.
Moreover, OPRR found that the VA West Los Angeles failed to document implementation of
the 1994 requirement for a Data and Safety Monitoring Board to oversee psychiatric
research. In fact, the VA West Los Angeles Policy and Procedure Manual for Human Subjects
Research, provided to OPRR in November 1998, states that "DSMB monitoring procedures have not been finalized
yet" (page 22), 4 years after OPRR imposed
the requirement.
In addition, OPRR was concerned that individual IRB members did not appear to be
receiving and reviewing sufficient written information to ensure substantive continuing
review of research, as the DHHS human subjects regulations require. In specific, the VA
West Los Angeles Policy and Procedure Manual for Human Subjects Research states that such
information need only be reviewed by one member (page 23). OPRR further found that the IRB
minutes failed to document any discussion of research protocols during continuing review.
OPRR also determined that expedited review procedures, which are permitted only for
certain specified categories of minimal risk research, were still being used
inappropriately, 4 years after OPRR had brought this issue to the attention of the VA West
Los Angeles IRBs.
OPRR's action of March 22, 1999
In view of the extended history of concerns and as a result of these latest findings,
OPRR concluded that more stringent oversight was needed of DHHS-supported human subjects
research involving the VA Greater Los Angeles Healthcare System. Therefore, OPRR
deactivated the VA Greater Los Angeles Healthcare System Multiple Project Assurance
(#M-1087). This action, effective March 22, 1999, removed the Assurance required for
conduct of federally supported human subjects research.
OPRR directed the VA Greater Los Angeles Healthcare System to suspend enrollment of new
subjects in all DHHS-supported research, except in extraordinary cases verified by OPRR to
be in the best interests of an individual subject. Research activities involving
previously enrolled subjects were allowed to continue where continuation is in the best
interests of individual subjects.
DHHS-supported human subjects research may resume at the VA Greater Los Angeles
Healthcare System only under new Assurance mechanisms that entail either (i) OPRR review
of individual protocols and informed consent documents (i.e., the Single Project Assurance
mechanism); or (ii) oversight by a collaborating institution's IRB under the approval of OPRR (i.e., the
Interinstitutional Assurance mechanism).
Enrollment of subjects in DHHS-supported research may not resume until acceptable
Assurance mechanisms have been approved by OPRR. However, OPRR stands ready to proceed
under such mechanisms as soon as the VA Greater Los Angeles Healthcare System certifies
valid IRB review and approval of each of its DHHS-supported human subjects projects. OPRR
notes that on April 6, the VA requested, and OPRR granted, a 3-month extension of OPRR's deadline for VA conduct of these reviews.
OPRR oversight of other human-subject protections at other VA facilities
As I indicated previously, OPRR has authority under the Common Rule for approving an
Assurance at DHHS-funded institutions for federal-wide use. When an Assurance approved for
federal-wide use is on file with OPRR, other Department and Agency heads, including the
Department of Veterans Affairs, rely on that Assurance of an institution's compliance with the Common Rule.
At present, 41 VA facilities hold Multiple Project Assurances that are approved by OPRR
for federal-wide use. Some 50 VA facilities are covered under other Assurance mechanisms
that are limited to specific categories of DHHS-supported research.
OPRR is currently conducting 3 compliance oversight investigations that involve VA
facilities; specifically, (i) the James A. Haley VA Hospital, in association with the
University of South Florida in Tampa; (ii) the Philadelphia VA Medical Center; and
(iii) the Cincinnati VA Medical Center, in association with the University of Cincinnati.
The Tampa research involves nephrology experiments on salt regulation; the Philadelphia
research involves cardiology research; and the Cincinnati research involves psychiatric
research.
I am not able to comment further on these ongoing investigations because OPRR has not
yet reached any determinations of fact in these cases. OPRR will be happy to inform the
Subcommittees as soon as such determinations have been made.
OPRR recently completed a complex investigation of several DHHS-supported psychiatric
research projects at the VA Medical Center in the Bronx, New York. DHHS-supported research
at the Bronx VA is covered under the Mount Sinai School of Medicine Multiple Project
Assurance. OPRR determined that the informed consent documents for these projects failed
to provide adequate descriptions of the research purpose; the research procedures; the
reasonably foreseeable risks and discomforts of the research; and the potentially
advantageous alternatives to research participation. Subjects in one of these projects,
conducted in the mid-1980s, suffered at least some short-term harm or discomfort in the
form of an exacerbation of psychiatric symptoms.
OPRR determined that appropriate corrective actions have been implemented by Mount
Sinai Medical Center and the Bronx VA to ensure compliance with DHHS regulations in
current and future research. Among these actions are the adoption of specific guidelines
for research involving medication withdrawal or washout, including requirements that (i)
an independent health professional must assess each prospective subject's capacity to consent prior to enrollment; (ii) an
independent physician must monitor each subject's
participation in the research; and (iii) the risks of drug withdrawal, placebo
administration, and experimental drugs must be included.
Conclusion
Our enduring and vigorous system of protection of human research subjects is designed
to prevent physical injury, psychological injury, and harm to the dignity of research
subjects, as biomedical and behavioral scientists pursue new knowledge for the common
good. We are always interested in improving the system to make research as safe as it can
possibly be.
Of special interest today are the rights and welfare of human subjects under the
auspices of the Department of Veterans Affairs. OPRR does not have either an immediate or
an historical basis for distinguishing compliance of those VA medical centers under its
purview, as a class, from other biomedical and behavioral research institutions.
It is abundantly clear, however, that VA medical centers have a profound obligation to
ensure that our nation's veterans are afforded
the highest possible levels of protection when they become subjects of research. To the
extent that any research conducted at VA facilities involves any veteran-subject who may
be vulnerable to coercion or undue influence for any reason, the VA has a special
responsibility to provide particularly stringent protections. In formal, Common Rule
language, such vulnerability requires that "additional
safeguards have been included in the study to protect the rights and welfare of these
subjects." Clearly, the VA must set its aim well
beyond minimal compliance with regulatory standards.
In the final analysis, Mr. Chairman and Members of the Subcommittees, research
investigators, institutions, and we are stewards of a trust agreement with the people who
volunteer to be research subjects. We have a system in place that strives, to the greatest
degree possible, to (i) minimize the potential for harm; (ii) enable and protect
individual, autonomous choice; and (iii) promote the pursuit of new knowledge. By doing
so, we protect the rights and welfare of our many citizens who make a remarkable
contribution to the common good by electing to volunteer for research studies. We owe them
our best effort.
Thank you, Mr. Chairman. We are pleased to answer any questions about our system for
safeguarding the rights and welfare of human research subjects.
____________________
For additional information about protection of human research subjects, see:
www.nih.gov/grants/oprr/oprr.htm
