Mr. Chairman and Members of the Committee:
I am Gary Ellis, Director of the Office for Protection from
Research Risks (OPRR). The Office for Protection from Research
Risks, housed administratively and physically at the National
Institutes of Health (NIH), is charged with implementing
regulations regarding the Protection of Human Subjects (45 CFR
Part 46) that have been promulgated by the Department of Health
and Human Services (HHS). In doing so, OPRR oversees a
welldeveloped, yet ever-evolving, system of protection of human
research subjects. The Food and Drug Administration (FDA) also
has human subject protection regulations that apply to research
involving products such as drugs, biologics, and medical devices.
The FDA has provided a written statement for the record that
includes its comments on today's report from the General
Accounting Office (GAO). Mary Pendergast, FDA Deputy
Commissioner and Senior Adviser to the Commissioner, is present
to answer any questions you may have regarding FDA's process.
My testimony, today describes the interests of the Department
in protecting human subjects in research--a responsibility of
enormous weight.
In response to Executive Order 12975 (October 3, 1995), OPRR
conducted a February 1996 review of the protections of the rights
and welfare of human research subjects that are afforded by
existing policies and procedures for research conducted or
supported by HHS.
OPRR's review documents an ever-evolving, dynamic system of
protection of human research subjects based on multiple layers of
review by expert and lay people exercising their best judgment.
As such, this system of protection is highly sensitive to, and
readily influenced by, educational efforts. OPRR and the HHS
components that conduct and support research are well-invested in
education and have specific plans,to enhance that commitment even
further. The Department has accepted lead-agency responsibility
for support of the new National Bioethics Advisory Commission
(NBAC). Taken together, current and planned activities sum to
HHS' retaining as a priority continued vigilance over human
subjects protection. The recent call by Secretary Shalala to
make bioethics "as sophisticated as our science" embraces the
intent of Executive Order 12975 and reemphasizes OPRR's charge.
HHS Regulations for Protection of Human Subjects
At Title 45, Code of Federal Regulations, Part 46 (45 CFR
Part 46), the Department has codified its regulations for
Protection of Human Subjects. There are four subparts:
Subpart A (last revised June 18, 1991) is the Basic DHHS
Policy for Protection of Human Research Subjects. Sixteen other
Federal departments and agencies are also formally bound to
identical text by statute, regulation, or Executive Order. OPRR
chairs and staffs the interagency body responsible for fostering
uniform implementation of this common rule --the Human Subjects
Research Subcommittee. Committee on Health, Safety, and Food,
National Science and Technology Council.
Subpart B (last revised November 3, 1978) identifies
Additional DHHS Protections Pertaining to Research, Development,
and Related Activities Involving Fetuses, Pregnant Women, and
Human In Vitro Fertilization. Subpart B is currently undergoing
review in the Department.
Subpart C (last revised November 16, 1978) identifies
Additional DHHS Protections Pertaining to Biomedical and
Behavioral Research Involving Prisoners as Subjects.
Subpart D (last revised March 8, 1983) identifies Additional
DHHS Protections for Children Involved as Subjects in Research.
The local Institutional Review Board (IRB) at the research
site is the cornerstone of this svstem of protection of human
subjects. No human subjects research may be initiated, and no
ongoing research may continue, in the absence of IRB approval.
HHS cannot provide funds for, or conduct, human subjects research
unless one or more IRBs approves the protocol for such studies.
An IRB is established at the local level and, by regulation,
has a minimum of five people, including at least one scientist,
one nonscientist, and one person not otherwise affiliated with
that institution.
IRB review is a prospective as well as continuing review of
research by a group of individuals A,ith no formal interest in
the research. In reviewing research, IRBs must be knowledgeable
about the research site; the resources of the institution; the
capabilities and reputations of the investigators and staff; and
the prevailing values and ethics of the community and, most
important, the likely subject population.
In order to approve research, the IRB must determine that all
of the following requirements are satisfied:
- Risks to human subjects are minimized.
- Risks to human subjects are reasonable in relation to
anticipated benefits, if any, to human subjects, and the
importance of the knowledge that may reasonably be expected to
result.
- Selection of human subjects is equitable.
- human subject or the human subjects legally authorized
representative, in accordance with, and to the extent required by
45 CFR Part 46.
- Informed consent will be appropriately documented in
accordance with and to the extent required by 45 CFR Part 46.
- When appropriate, the research plan makes adequate
provision for monitoring the data collected to ensure the safety
of human subjects.
- When appropriate, there are adequate, provisions to
protect the privacy of human subjects and to maintain the
confidentiality of data.
In addition, when some or all of the human subjects are
likely to be vulnerable to coercion or undue influence,
additional safeguards have been included in the study to protect
the rights and welfare of these human subjects.
Once research is underway, the IRB must conduct continuing
review of the research, at intervals appropriate to the degree of
risk--in any event, at least once per year.
Continuing review is substantive and meaningful. In
approving the continuation of ongoing research, an IRB attests to
its satisfaction that the research continues to be conducted in
accord with all relevant provisions of the regulations.
I mentioned that IRBs oversee the informed consent process.
The regulations specifN, eight required elements of informed
consent:
- A statement that the studv 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.
- A description of anv reasonably foreseeable risks or
discomforts to the subject.
- A description of anv benefits to the subject or to others
which may reasonably be expected from the research.
- A disclosure of appropriate alternative procedures or
courses of treatment, if any, that might be advantageous to the
subject.
- A statement describing the extent, if any, to which
confidentiality of records identifying the subject will be
maintained.
- 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 then, consist of, or where further information
may be obtained.
- 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.
- 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.
OPRR implements these regulations by: (i) negotiating formal,
written assurances of compliance with institutions engaged in
research covered by 45 CFR Part 46; (ii) investigation and
oversight of institutional compliance; and (iii) professional and
public education.
Assurance of Compliance with 45 CFR Part 46
Each institution engaged in research (i) covered by 45 CFR
Part 46 and (ii) conducted or supported by HHS must provide
assurance satisfactory to OPRR that it will comply with 45 CFR
Part 46. OPRR employs several types of assurance instruments.
Institutions with a track record in human subjects protection
satisfactory to OPRR are selected for the Multiple Project
Assurance (MPA). At present, 448 institutions hold an active
MPA. Of these institutions, 98 percent have voluntarily elected
to extend the protections of 45 CFR Part 46 to non-HHS-supported
research.
In seeking assurances for their respective research
portfolios, the 16 other Federal Departments and Agencies that
have embraced Subpart A of 45 CFR Part 46 (also known as the
"Federal Policy for the Protection of Human Subjects" and the
"Common Rule") are often linked to OPRR. In lieu of requiring
institutional assurances for work they conduct or support, they
are required to accept assurances, appropriate for the research
in question, on file with OPRR and approved for Federal-wide use
by OPRR.
OPRR also negotiates Single Project Assurances (3,133
currently active) and Cooperative Project Assurances (1,345
currently active) to meet the varying circumstances of
HHS-supported research at other- than-MPA-assured institutions.
The recommendations of the Advisory Committee on Human
Radiation Experiments (ACHRE) identify three problems in consent
forms reviewed by ACHRE: (i) overly optimistic portrayal of the
likely benefits of research; (ii) inadequate explanation of the
impact of research procedures on quality of life and personal
finances; and (iii) incomprehensibility, to lav people. OPRR
staff were provided with this ACHRE analysis immediately upon the
October 3, 1995 release of the ACHRE report, so that OPRR staff
could incorporate this information into OPRR review of IRB
handling of informed consent documents prior to approving
assurances to comply with 45 CFR Part 46. Additionally, this
ACHRE analysis is being featured in professional and public
educational activities described below.
Investigation and Oversipht of Institutional Compliance
Under 45 CFR Part 46, there are multiple administrative
actions that can be taken for violation of the regulations. OPRR
may restrict or suspend its approval of an institution's
assurance. Affected research projects cannot be supported by HHS
until the terms of the restriction have been satisfied. Examples
of such restrictions include, but are not limited to:
- suspending the assurance's applicability relative to some or
all research projects until specified protections have been
implemented;
- requiring prior OPRR review of some or all research projects
to be conducted under the assurance;
- requiring that some or all investigators conducting research
under the assurance receive appropriate human subject education;
- requiring special reporting to OPRR.
OPRR may withdraw its approval of an institution's assurance.
Affected research projects cannot be conducted or supported by
any HHS component until approval of an appropriate assurance is
reinstated bv OPRR.
OPRR may recommend to appropriate HHS officials or Public
Health Service (PHS) agency heads:
- that an institution, a component of an institution (e.g.,
department or an investigator) be temporarily suspended or
permanently removed from participation in specific projects,
- that HHS peer review groups be notified of an institution's
or an investigator's past noncompliance prior to review of new
projects; or
- that institutions or investigators be declared ineligible to
participate in HHS-supported research (i.e., debarment or
suspension). If OPRR makes this recommendation, the debarment or
suspension process may be initiated in accordance with the
procedures specified at 45 CFR Part 76. Debarment or suspension
of a participant in a program by one agency has government-wide
effect.
OPRR currently has 81 open compliance oversight
investigations. One-quarter of these derive from non-HHS-funded
research, owing to institutions' voluntary commitment of all
research to HHS rules. Since January 1, 1990, OPRR has initiated
321 human subject compliance oversight investigations, of which
240 were completed as of January 31, 1996. During this period,
OPRR conducted 18 "for-cause" site visits (i.e., in the course of
compliance investigations) and 10 "not- for-cause" site visits
(i.e., for technical assistance).
Corrective actions based on compliance oversight evaluations
are intended to remedy identified noncompliance with 45 CFR Part
46 and to prevent reoccurrence. Because each compliance
investigation is different, OPRR tailors its corrective actions
to the nature of the violation and to the improvements needed in
the affected institution's system of protections. The large
majority of the 227 investigations completed from 1990 through
1995 involved some corrective action on the part of the
institution. Such actions include institutional sanction or
increased monitoring of individual investigators, modification of
informed consent documents for specific studies, changes in IRB
policies and procedures, and revision of the institutional system
of protection for human subjects.
The following are examples of additional oversight mechanisms
within HHS:
- Initial scientific and technical review groups must take into
consideration the risks to subjects of proposed research, the
adequacy of protection against these risks, the potential
benefits of the research, and the importance of the knowledge to
be gained. This second level of independent review of research
involving human subjects, which requires detailed documentation
of the consent process and any additional human subjects
concerns, follows local IRB review. OPRR is informed when NIH
peer review groups identify concerns about human subject
protections, and these concerns must be resolved before an award
may be made.
- Cooperative Oncology Group research supported by the National
Cancer Institute is monitored through a program of on-site audits
which include an evaluation of human subject protections.
- Many NIH-supported, multi-center, clinical trials include
provision for monitoring by an independent Data and Safety
Monitoring Board, which periodically evaluates emerging data to
ensure subject safety as the trials progress.
- HHS benefits from the continuing and detailed inspection of
IRBs conducted by FDA field staff. The findings of such
inspections are shared with OPRR, when an applicable
OPRR-approved assurance exists. In turn, OPRR provides the
results of its compliance oversight site visits to FDA.
Professional and Public Education
OPRR responds on a day-to-day and long-term basis to requests
for clarification and guidance with respect to ethical issues
raised in connection with biomedical or behavioral research
involving human subjects, as required by Section 491(b)(1) of the
Public Health Service Act. In addition, OPRR promulgates
interpretation of 45 CFR Part 46 by means of periodic "Dear
Colleague" letters; sponsorship with FDA of 4 to 6 national
workshops each year, serving an annual total of approximately
1,000 attendees; free distribution of three instructional
videotapes; production of the comprehensive Institutional Review
Board Guidebook; and technical assistance site visits. OPRR
fulfills hundreds of requests for educational materials each
month via a voice mailbox and FAX-on-demand service. Fulltext
OPRR materials will soon be electronically retrievable.
In light of the focus of ACHRE recommendations on IRBS, the
cornerstone of the HHS response to the ACHRE report is enhanced
education directed toward the conununity of IRB members, IRB
administrators, institutional officials, researchers, and
potential human subjects. OPRR collaborates closely with Public
Responsibility in Medicine and Research (PRIM&R), a Boston-based
private, nonprofit organization, to stage an annual public
meeting for individuals interested in the governance of human
subjects research. More than 600 people attended the October
1995 PRIM&R meeting, at which the ACHRE recommendations were
presented for the first time to the IRB community.
OPRR has scheduled presentations and discussions of the ACHRE
recommendations at upcoming national human subjects protection
workshops in Atlanta (April 11-12, 1996), Oklahoma City (June
3-5, 1996), Honolulu (July 26-27, 1996), Peoria IL (September
26-27, 1996). and Houston (November 1-2, 1996). The November
11-12, 1996 PRIM&R annual conference (San Diego) is expected to
address IRB implementation of the ACHRE recommendations.
One ACHRE recommendation to IRBs is that they appropriately
allocate their time so that the), can adequately review studies
that pose more than minimal risk to human subjects. Anticipating
this recommendation, OPRR issued a May 5, 1995 "Dear Colleague"
letter with guidance on this point. OPRR reminded institutions
of the procedures described at 45 CFR 46.110 that permit
expedited review of activities that involve no more than minimal
risk and are identified on a list of 10 research categories
promulgated by the Secretary of HHS in 1981. In its letter, OPRR
also reminded institutions of the six categories of research at
45 CFR 46.101(b)(1)-(6) that are exempt from IRB review.
The ACHRE demonstrated the utility of first-hand, external
examination of institutional oversight of human subjects
research, and there is a consensus among experts and regulators
about the benefits of such review. Accordingly, OPRR expects to
enhance its educational efforts to include a program of technical
assistance site visits. Such visits, to number from 12 to 24 per
year, are of mutual educational benefit - strengthening both the
institutions program of human subject protections and ensuring
the fidelity of OPRR's assurance negotiations and documents.
The ACHRE identified the urgent need for better understanding
and implementation of the informed consent transaction between
researcher and subject. The specificity of the language about
informed consent in 45 CFR Part 46, its endurance through many
years, and the enthusiasm with which all parties adhere to it all
belie the fact that little empirical work exists to document the
degree of understanding achieved by research participants. There
is a paucitv of data that bear upon, for example, (i) a research
subject's comprehension of a study's methods and procedures; (ii)
subject's understanding of relative risks and benefits of
participation; (iii) subject's understanding of confidentiality
and any exceptions to confidentiality; (iv) subject's
understanding of the implications of withdrawal from a study; and
(v) subject's ability to distinguish between the roles of
clinician and investigator--and the consequences of failure to
make that distinction. Such data are needed to aid in designing
informed consent procedures that are readily comprehended by
prospective participants and, at the same time, impart all
critical information.
In July 1995, the National Institute of Mental Health (NIMH)
announced an important program that will make available NIMH
research funds for investigations into the informed consent
process in research involving individuals with mental disorders.
NIMH has thus taken the lead in stimulating investigations into
the informed consent process in research, and OPRR hopes that
this is an indication of an increasing investment by supporters
of research in the development of new knowledge related to
informed consent. In addition to the NIMH activity, in November
1995, the NIH Office of Extramural Research convened an
interagency group to begin pursuit of a broad research agenda in
informed consent.
Taken together, these efforts -- undertaken on a national
scale to ensure the centrality of ethics in human subjects
research -- maintain and reinforce the trajectory of HHS on the
path of preventing misadventures in contemporary human subjects
research.
National Bioethics Advisory Commission
There exists a void in our multi-tiered system of human
subjects protection, that of a national body that can deliberate
and advise on difficult issues in bioethics as they arise. In
the past. the Nation has had a demonstrated need for a national,
deliberative body of private citizens to offer the Federal
Government analysis of the bioethical dimensions of ongoing and
ne,,N, activities and problems. From 1974 to 1978, the National
Commission for the Protection of Human Subjects of Biomedical and
Behavioral Research was highly productive, laying out much of the
philosophical basis for our current regulatory system. Following
the National Commission, an Ethics Advisory Board was active in
the Department of Health, Education, and Welfare. Then, in the
early 1980s, the President's Commission for the Study of Ethical
Problems in Medicine and Biomedical and Behavioral Research
served an important role.
The need for such a body is arguably greater today than ever
before. The ACHRE report recommended establishment of a
mechanism to provide for the continuing interpretation and
application of ethics rules and principles for the conduct of
human subject research in an open and public forum. The ACHRE
identified at least three unresolved ethical issues in need of
such deliberation:
- clarification of the meaning of minimal risk in research with
healthy children;
- development of regulations to govem the conduct of research
with institutionalized children; and
- development of guidelines for research involving adults of
questionable competence, particularly for research in which
subjects are placed at more than minimal risk but are offered no
prospect of direct medical benefit.
On October 3, 1995, Executive Order 12975 created the
National Bioethics Advisory Commission, to be appointed by the
President. OPRR has since been coordinating the initial efforts
of administration of the NBAC, so that the NBAC can begin
operations and begin to address the recommendations of the ACHRE
at an early date.
General Accounting Office Analysis
Today, we are pleased to receive from the GAO its independent
analysis of HHS oversight of human subjects protection.
The GAO's "Scientific Research: Continued Vigilance Critical
to Protecting Human Subjects" accurately describes the overall
functions related to human research subjects of OPRR. including
education by means of guidance and workshops; prevention in the
form of negotiating written assurances; and oversight through
inquiries and investigations.
In particular, the GAO report acknowledges that current
oversight activities are working. GAO review of 40 OPRR
compliance case files, accompaniment of OPRR staff on a
compliance site visit to a major research institution, and
interviews found that OPRR effectively identifies noncompliance,
requires institutions to take corrective actions, and, in most
cases, achieves satisfactory resolution of institutional
noncompliance within 12 to 18 months.
The GAO Report identifies a consensus among experts and
regulators about the benefits of first-hand review of
institutional oversight of human subject research. Accordingly,
OPRR expects to enhance its activities to include a program of
technical assistance site visits, as I described a moment ago.
OPRR expects to continue its program of for-cause and
not-for-cause compliance site visits.
The GAO report notes that primary responsibility for OPRR's
negotiating Multiple Project Assurances of compilance covering
the 450 to 500 institutions that receive most of HHS' funding for
human subjects research rests with one individual. The NIH
Director honored this part-time, unpaid physician in June 1995
with the NIH Director's Award for her extraordinary service, and
OPRR is proceeding to recruit for a health scientist
administrator to join her in negotiating Multiple Project
Assurances.
NIH is described by the GAO Report as "in the position of
regulating itself" and OPRR as in a position of "potential
weakness," when OPRR oversees human subjects research conducted
by NIH (i.e., by the NIH intramural Research Program.) in fact,
OPRR oversees and interacts with NIH just as with any extramural
research institution. NIH holds a Multiple Project Assurance
approved by OPRR. The NIH institutional official and Multiple
Project Assurance signatory is the NIH Deputy Director for
Intramural Research, who heads the NIH Intramural Research
Program. OPRR's independent oversight and authority are not
compromised, as the lines of authority of the NIH Deputy Director
for Intramural Research and the OPRR Director do not cross within
NIH. The NIH Intramural Research Program's need for 5 years to
implement corrective actions after being cited by OPRR in 1991
for compliance violations is best viewed as an index of the
complexity of fully implementing the corrective actions rather
than a function of weakness in OPRR's ability to enforce human
protection regulations within the NIH organizational structure.
In the final analysis, research investigators and
institutions are stewards of a trust agreement with the people
who volunteer to be research subjects. We have a system in place
that to the greatest degree possible (i) minimizes the potential
for harm, (ii) enables and protects individual, autonomous
choice, and (iii) promotes the pursuit of new knowledge. By
doing so, we protect the rights and welfare of our fellow
citizens who make a remark able contribution to the common good
by electing to volunteer for research studies. We owe them our
best effort.
Thank you, Mr. Chairman. I am pleased to answer any
questions about our system for safeguarding the rights and
welfare of human research subjects.
