An Examination of Federal Oversight of Human Subject Research (Research Involving Human Participants V1)
Author(s):
C.K. Gunsalus
Executive
Summary
The National Bioethics Advisory Commission (NBAC) seeks to
determine whether to improve the federal regulatory system for
the protection of human subjects, and if needed, in what ways.
This paper was commissioned to examine whether NBAC should
recommend unifying federal oversight of federal and private
human subjects research under a single government office such
as the Office for Protection from Research Risks (OPRR).
The question posed by NBAC encompasses two related but
distinct groups of issues: 1) those pertaining to unification
of federal human subject protection oversight in a single
agency or office and 2) those raised by expansion of the scope
of federal oversight to cover not just federally funded, but
also privately conducted human subjects research.
NBAC seeks to protect all human subjects of research against
abuse or exploitation. But to get to that goal, NBAC must
grapple with several fundamental questions: should citizenship
or residency in the United States ensure a minimum level of
protection against the risks inherent in research involving
human subjects? If so, how is that level of protection defined?
Is it possible to provide that level of protection efficiently,
cost-effectively, and without burdening research that presents
little or no risk to human subjects?
Our current system for protecting human subjects of research
has many acknowledged strengths, and it balances effectively
the competing interests always present in a regulatory system.
It has served remarkably well for decades, and achieved many of
the goals it was originally designed to meet. On the other
hand, aspects of the system have known deficiencies that
require correction and improvement. The recommendations in this
paper are not designed to detract from the strengths of a good
system, but to improve upon it in ways that will be beneficial
without undue regulatory burden.
This paper recommends four elements for an improved
regulatory system:
- Correcting structural/organizational deficiencies in the
present regulatory system,
- Unifying federal oversight of human subject research in
one federal office or agency, but leaving in place the
current jurisdiction of FDA over the approval of drugs,
medical devices, and biologics,
- Using existing federal offices as structural models for
unified oversight of human subjects research, and
- Expanding the scope of regulation incrementally rather
than globally. This recommendation envisions an expansion of
federal jurisdiction only to identified categories of
research that meet the criterion of presenting known
risks to human subjects of research.
Correcting Deficiencies. A series of
studies over recent years, culminating in the June 1998
Department of Health and Human Services (DHHS) Office of the
Inspector General (OIG) report on Institutional Review Boards
(IRBs) and the NBAC-commissioned papers by Drs. John C.
Fletcher and Charles R. McCarthy, have identified deficiencies
in our present system for protecting human subjects. These must
be corrected in tandem with any expansion of federal oversight.
Of particular concern are the conflicts of interest inherent in
OPRR's location within an agency for which it has a
monitoring responsibility. Other key issues include the
inadequate (and evidently declining) governmental resources
allocated for the protection of human subjects; inconsistency
of human subject protection across the government; and
minimizing bureaucratic procedures in favor of educational
efforts and true accountability.
Unification of Oversight Responsibilities.
Responsibility for oversight of federally conducted or
sponsored research should be consolidated into one federal
agency or office. Responsibility for drug, device, and biologic
approvals should remain with FDA, but the two agencies should
develop a memorandum of understanding to codify their
cooperation and coordination. Information is presented on
existing governmental agencies that might serve as models for a
reorganized and strengthened human subject protection
office.
Recommended Strategy for Expanding Regulatory
Scope. This paper proposes adopting a strategy of
including all research posing "known risks" to
human subjects of research under federal jurisdiction
regardless of the source of funding or nature of the
organization conducting the research. This approach is
sensitive to current societal concerns about unchecked
governmental regulation and should fare well under cost/benefit
analyses. If NBAC adopts this proposed strategy, further work
will be necessary, first to devise a mechanism for defining
known risks, and then to develop a procedure for bringing
relevant categories of research under federal jurisdiction.
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I. Introduction
NBAC unanimously adopted a resolution on May 17, 1997, that
"No person in the United States should be enrolled in
research without the twin protections of informed consent by an
authorized person and independent review of the risks and
benefits of the research."1 This position was reinforced when
President Clinton asserted in a commencement address that same
month that "[w]e must never allow our citizens to be
unwitting guinea pigs in scientific experiments that put them
at risk without their consent and full
knowledge."2 While the NBAC resolution and presidential
declaration seem to be straightforward expressions of
fundamental American beliefs about human rights and dignity,
translating them into practice will be far from
straightforward.
First, whether or not it is immediately apparent, these
statements imply a sweeping expansion of federal regulation of
research involving human subjects. Paradoxically, cats, dogs,
rabbits, hamsters, guinea pigs, and nonhuman primates have more
federal protection from the risks of participation in research
than do humans.3 The federal government has regulated all research on
these animals,regardless of the source of
funding,since the Animal Welfare Act was first enacted
in 1966. In contrast, the only research involving human
subjects that is regulated by our government is that which a)
is funded by one of seventeen federal agencies, b) is conducted
without federal funds at an institution voluntarily extending
federal oversight to the research, or c) involves drugs,
devices, or biologics falling within the jurisdiction of the
FDA. Absent these conditions, individuals with concerns or
complaints about their treatment have no recourse except
through civil litigation or criminal statutes. Thus at present,
the minimum protections NBAC and the President seek are not
even provided in all research conducted or paid for by the
federal government, let alone that performed in the private
sector.
While we cannot know how much unregulated research on human
subjects takes place in the United States,precisely
because it is not regulated,indications are that it is
significant. Information about problematic practices in such
research surfaces with sufficient regularity that expanded
government oversight must be seriously considered.
Second, our system for the protection of human subjects of
research is more than 30 years old, and, while the basic system
is sound, we know that it has shortcomings. Beyond our
knowledge of the existence of problematic unregulated research,
we know that even regulated research may be exposing human
subjects of research to inappropriate risks. Some of the
deficiencies in the current regulatory structure and
implementation are described in the Report of the DHHS
Inspector General, Institutional Review Boards: A Time for
Reform (June 1998), the Report of the Human Radiation
Interagency Working Group (March 1997), the General Accounting
Office (GAO) Report, Scientific Research: Continued Vigilance
Critical to Protecting Human Subjects (1996), and the findings
of the Advisory Committee on Human Radiation Experiments
(ACHRE) (October 1995).4 To implement fully the NBAC resolution and give
meaning to the President's declaration, some of the
identified problems in the current system must be
corrected.
A pivotal issue is how federal oversight in our purposefully
decentralized system of oversight for human subjects is
fractionated, with 17 separate federal agencies holding
responsibility. The decision to place primary responsibility
for human subject protections with local IRBs at institutions
conducting research is well suited in many respects to our
thriving research system. But federal oversight and protections
are unevenly implemented and variably enforced, leading to
serious gaps in human subject protections.
Another issue that NBAC must confront directly is the
federal commitment to human subject protection as revealed
through the resources devoted to the task. There is evidence
that funding in this area has declined despite significant
increases in research.5 Unless accompanied by adequate resources, neither
reforms of our existing system nor expansion of federal
protection will produce meaningful or long-lasting change.
Any proposal for change should be grounded in a clear
statement of principles and goals: What is to be accomplished?
The NBAC resolution already contains two goals: informed
consent and independent ethical review for all persons
"enrolled in research." But the resolution does
not define the "research" it intends to encompass
or the level of risk at which these twin protections should
attach.
Comprehensive application of the present federal definition
of research,purposefully designed to be broad in its
application and reach,could sweep myriad low-risk
activities into a regulatory structure with unknown costs and
implications. Activities that have never before been labeled as
"research" could become subject to regulation,
commanding resources for their review and oversight, ultimately
to the detriment of human subjects in higher risk
situations.
Many of this nation's 3,000-plus6 IRBs are already overloaded
by their current workloads. As the GAO report observes:
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 not paid for their
IRB service. Board members themselves face a heavy
workload and others in the research community have raised
concerns that heavy workload impairs IRB review.7
Research institutions would complain,and with some
merit,if their workload is increased by a broad
expansion of types of research requiring IRB review. One result
could be a dramatic increase in the number of for-profit IRBs,
or an incentive for IRBs to provide superficial reviews, or
both. Careful design and implementation will be required to
avoid a system that substitutes mechanical review for
substantive ethical considerations.
Expanding federal jurisdiction to assure that "no
person" is enrolled in research without the twin
protections specified by NBAC requires care and
focus,and will require changes in federal law and the
commitment of additional federal resources to assure compliance
with that law. To explore the issues raised by a unification of
oversight into one federal agency and by a proposed expansion
of federal oversight of research involving human subjects, we
must examine 1) the present structure of federal regulatory
protection, including its functioning, shortcomings, and the
gaps in its coverage and 2) practical problems inherent in
expanding the scope of federal oversight. These two issues are
intertwined to a considerable degree.
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II. The
Present Federal System for Human Subject Protection
Government regulation frequently arises as a reaction to
revelations that disturb the public conscience. The federal
oversight of research involving human subjects is no exception.
As recounted in David J. Rothman's
Strangers at the Bedside: A History of How Law and
Bioethics Transformed Medical Decision-Making,8 the entry of the
federal government into this realm was driven by a combination
of dramatic scientific/medical advances and scandals concerning
abuses of human subjects of research. Medical advances in
genetic engineering and heart transplantation gave rise to
questions about the beginning, end, and quality of life. At the
same time, disclosure of the now infamous Tuskegee experiment
in 1972 and the abuses of human subjects detailed in Dr. Henry
Beecher's 1966 paper in the New England Journal of
Medicine drew attention from the media and
Congress.9
These in turn opened new areas of ethical debate including
whether certain procedures should be governed outside the
physician-patient relationship. More sophisticated versions of
these questions are still with us today.
The reaction of the biomedical research establishment to
these questions and to the prospect of government intrusion
into the historical preserve of physicians and researchers was
negative and strong,but not sufficient to convince
Congress that patients and human subjects of research would be
adequately protected without government intervention.
Nonetheless, the strength of the reaction helped to shape the
system of protection that resulted; similarly strong reactions
can be expected to new proposals for change.
A. Background and Overview
Before moving to expand federal protections to subjects of
currently unregulated research, we should examine the present
system, which has grown incrementally over a period of years.
The first federal policies covering research funded by the
Department of Health, Education and Welfare (now DHHS) were
issued in 1966. The first congressionally mandated commission,
the National Commission for the Protection of Human Subjects of
Biomedical and Behavioral Research (National Commission),
started its work in 1974.10 It produced ten reports over four years
that provide the ethical foundation for the system of
protections in place today. Even so, it took until 1991 for a
subset of federal agencies to agree upon the Federal Policy for
the Protection of Human Subjects11 as the core regulation governing
research conducted by or under the auspices of the government.
This policy is often referred to as "the Common
Rule." The Common Rule is not followed by all federal
agencies, and it is unevenly enforced by those that do.
In 1994, Dr. Robyn Y. Nishimi of the Office of Technology
Assessment (OTA), testified before Congress that:
No statute governs the general oversight of research
involving Americans. Moreover, the current system, while
changing incrementally, has fallen short of implementing, or
did not implement at all, recommendations made between 1973 and
1982 by an ad hoc committee of DHEW, a congressional report and
two congressionally mandated commissions.12
Research involving human subjects may be regulated by the
federal government through three separate mechanisms: a)
because it is sponsored by a federal office or agency
subscribing to the Common Rule; b) because an institution
conducting research not sponsored by the federal government has
voluntarily granted jurisdiction over the research to OPRR
through a negotiated assurance; or c) because the research
involves regulated drugs or medical devices over which the FDA
has jurisdiction. An unknown quantity of research is not
regulated either because the sponsoring/conducting agency does
not subscribe to the Common Rule or has not negotiated an
assurance extending federal jurisdiction or because the
research is privately sponsored/conducted and not subject to
FDA approval.
1. The Common Rule
Summary of Common Rule Provisions. The
approach of the Common Rule to regulation of human subject
research is decentralized, involving negotiation of assurances
by the institutions where research is conducted with federal
agencies certifying that certain procedural and substantive
protections will be provided. While these assurances are
received and overseen by the various federal agencies, review
of specific proposed experimental protocols and informed
consent forms occurs at the local level through IRBs. Federal
requirements govern the composition and activities of IRBs, but
as we shall see, true oversight and accountability for the
rigor and consistency of IRBs has not been attained.
Six categories of research are exempt from full IRB review
under the Common Rule.13 These review procedures permit research meeting
specific, narrow criteria to proceed without any formal review.
The six exemption categories, developed with public comment and
through negotiation and policy formulation involving an
interagency committee over a period of ten years, offer
important insight into one mechanism that might be employed to
address the practical problems that could arise from broadening
the scope of federal regulation. (See below.) There are
additional categories of research for which IRBs may use
expedited review procedures, on the theory that the types of
research involved, like voice recordings or collection of
fingernail clippings, are less intrusive and pose a low level
of risk to the subject.14
Application of the Common Rule. Seventeen
federal agencies that fund or conduct research subscribe to the
Common Rule and thus use an approach similar to that of DHHS,
the lead federal agency in this area, with the important
exception that most do not have an active program for assuring
compliance with applicable regulations. While there is no
definitive assessment of how many federal agencies conduct or
fund research on human subjects, the 1981 report of the
President's Commission for the Study of Ethical Problems
in Medicine and Biomedical and Behavioral Research,
Protecting Human Subjects, documented that 23 federal
entities funded research involving human subjects.15 Dr. Nishimi of
OTA testified to Congress in 1994 that:
a definitive picture of current federal implementation
and oversight of existing regulations to protect human research
subjects is not available .Currently, information from all
agencies on the total number of all research grants or
contracts, total funding for research and grants involving
human subjects, and number of full time equivalent personnel
devoted to assurance and compliance has not been collected in a
coordinated or centralized fashion.
For some agencies, information even limited to the number
of, funding levels for, and types of research involved for
current grants or contracts using human subjects could not be
reported as recently as March 1994, although the common rule
has been effective since June 1991. Without such information,
ensuring that proper institutional assurances are in place and
then overseeing compliance would appear to be
problematic.16
Within DHHS, OPRR assumes oversight responsibility for both
human and animal subjects of research. The FDA also has
responsibility for protecting the rights and welfare of human
subjects of research, in the context of its required approvals
for drugs and medical devices. While both OPRR and FDA have
mechanisms for reviewing cases of alleged noncompliance with
federal regulations and responding to them,17 most other agencies do
not. As Dr. Nishimi noted in 1994:
agencies will not be aware of violations of existing
regulations unless a rigorous system is in place to monitor
compliance. Put another way, those Departments and agencies
that are not looking for problems will not find any
problems.18
The ACHRE inventoried federal experiments on human subjects
and found that:
In most federal agencies, current mechanisms of oversight of
research involving human subjects are limited to audits for
cause and a review of paperwork requirements. These strategies
do not provide a sufficient basis for assuring that the present
system is working properly.19
2. OPRR Oversight System
OPRR relies heavily upon the assurances it negotiates with
institutions conducting research. These assurances contain the
institutions' provisions for protecting the welfare of
human subjects and generally follow common patterns. In
addition to the promises institutions provide in their
negotiated assurances, OPRR provides educational support and
information to IRBs and queries institutions about reports of
noncompliance. OPRR conducts a number of record reviews through
paper correspondence and a much smaller number of on-site,
for-cause reviews of IRB effectiveness. Both the GAO and the
DHHS OIG compliment the effectiveness of OPRR's
compliance reviews, but both also comment upon the
extraordinarily limited extent of on-site visits, due to
staffing and budgetary constraints.
Currently, OPRR negotiates an assurance with each
institution that receives research support from DHHS.20 Each assurance
requires significant amounts of time and review by OPRR.
According to the GAO, in 1996 OPRR had about 14 full-time
equivalent staff devoted to human subject protection, with a
budget for those activities of under $1 million. OPRR augments
its professional staff with three physician
volunteers.21 Most major institutions accepting federal research
funding negotiate Multiple Project Assurances (MPAs) with OPRR
through which they agree to provide the same protections to all
subjects of research conducted at the institution that they do
for research funded by DHHS. There are almost 450 MPAs covering
more than 750 entities operating around 700 IRBs; they are
virtually all in the United States.22 Two to four times as many
institutions negotiate only Single Project Assurances (SPAs)
for each individual project funded in whole or in part by DHHS
(covering around 3,000 IRBs), or Cooperative Project Assurances
(for multisite clinical trials), with another 1,250 associated
IRBs.
There are about 3,000 active SPAs,locations where we
know that some DHHS-regulated research is conducted but no MPA
is in place to cover other research that may be performed at
that institution.23 At these institutions, other research involving
human subjects may occur without any governmentally provided
protections for the subjects of that research. This does not
necessarily mean that the research is not reviewed by an IRB,
as institutions may choose voluntarily to extend those
protections to all subjects of research,or they may not.
It does mean that there is no federal jurisdiction to
investigate if a subject of research files a complaint.
OPRR reports that negotiation of assurances for SPAs
requires more time than other negotiations, because they
usually involve OPRR scrutiny of protocols and informed consent
documents from institutions with little or no history of review
of research involving human subjects. Because DHHS funds
research in 80 countries around the world, institutions
negotiating SPAs are not all in the United States.
These and other recent reviews of the IRB system emphasize
the changes that time and resource constraints have brought to
their oversight by OPRR. While all contribute to a conclusion
that OPRR does a good job of protecting human subjects of
research, they also illustrate that its resources are
inadequate for its present responsibilities and indicate areas
where changes could strengthen its performance.24 The assurance
negotiation process, for example, has by most accounts become
routinized.25 The NBAC-commissioned paper by Dr. McCarthy
provides background on the educational nature of the assurance
negotiation process in its early phases: He implies that these
negotiations were usually conducted on-site at institutions and
describes how mutually beneficial these exchanges were, both
for institutions with little background in these issues and for
OPRR officials in gaining insight into the institution's
culture. By now, the negotiation process has lost much of this
educational flavor; perhaps its time has just passed.
The McCarthy paper also describes an OPRR that was able to
sustain a much larger educational program than is now the case.
As an ongoing constant educational program is essential if
consistency is to be achieved in a decentralized system, this
is a serious matter. It is not an overstatement to suggest
that, in a large distributed oversight system, high-quality
educational programs are the cornerstone of true
accountability. The report of the ACHRE went so far as to
recommend that:
efforts be undertaken on a national scale to ensure
the centrality of ethics in the conduct of scientists whose
research involves human subjects. The necessary changes
are unlikely to occur solely through the strengthening of
federal rules and regulations or the development of harsher
penalties. The federal government must work in concert
with the biomedical research community to exert leadership that
alters the way in which research with human subjects is
conceived and conducted so that no one in the scientific
community should be able to say "I didn't
know" or "nobody told me" about the
substance or importance of research ethics.26
Much of OPRR's ability to conduct such programs has
since been curtailed by budgetary reductions and limitations,
although an ongoing set of programs is offered annually through
co-sponsorship arrangements. Dr. McCarthy raises cautions
against the conflicts of interest that can arise when regulated
institutions are assuming responsibility for part of the cost
of educational programs in this way.
OPRR's reliance upon a paper-based and time-intensive
assurance negotiation system is no longer desirable. OPRR
agrees with the calls from external observers that it is time
to make changes in the negotiation of assurances.27 Replacing the
assurance system with a streamlined registration system seems a
sound alternative. If change of this nature were adopted
expeditiously, it would free some resources for activities more
conducive to true accountability. OPRR should be able to make
this change without regulatory modification, but should be
encouraged to do so by NBAC.
Other recommendations of the OIG,several of which
mirror changes OPRR staff have indicated they would like to
adopt,will require more resources than are presently
available to OPRR. This is a central issue with which NBAC must
grapple as it formulates it recommendations.
3. FDA Oversight System
The FDA is responsible for the safety and effectiveness of
medicines and medical devices. As part of its regulatory
responsibilities, FDA requires that studies involving
investigational new drugs, devices, and biologics receive
review and approval by an approved IRB and that researchers
submit statements that they will uphold ethical standards. FDA
has "concurred" with the Common Rule, but has not
adopted it in its entirety; while its regulations are largely
congruent with those that OPRR enforces, there are differences
in its IRB and informed consent regulations.
A major difference is that FDA does not require or negotiate
assurances with institutions. It oversees IRBs through an
inspection program, in which it routinely performs on-site
procedural reviews of IRBs to determine whether they are in
compliance with their own procedures and with applicable FDA
regulations. The GAO reported that FDA employed about 13
full-time equivalent staff members devoted to IRB inspections
in fiscal year 1995.28 FDA also has monitoring activities for individual
drug studies and for clinical trials. Each involves reviewing
compliance with consent requirements and other human subject
protection protocols.
The GAO reviews concluded that while the FDA program is
rigorous and that it detects (and corrects) problems in human
subject research, "FDA's inspection program is
geared more toward protecting the eventual consumer of the drug
than the subjects on whom the drug was tested."29 If NBAC wishes
to assure protection for human research subjects, this
observation should trigger serious examination and
consideration.
4. Nonsubscribing Federal Agencies
Subjects of research conducted or funded by federal agencies
that do not subscribe to the Common Rule do not receive its
core protections. There are indications that research is funded
or conducted by the Nuclear Regulatory Commission, the National
Endowment for the Humanities, and the Department of
Labor.30
In 1995, the ACHRE found that the magnitude of research
conducted by federal agencies not in compliance with the Common
Rule is a significant concern and recommended that there be an
assessment of the level of that research. It further
recommended action to "ensure that all subjects are
afforded the protections it offers."31 Anticipating the ACHRE
findings, President Clinton issued an Executive Memorandum in
1994 intended to address gaps in government coverage;
specifically, he ordered that all federal agencies and
departments should come into compliance with the Common Rule
and to suspend noncompliant experiments immediately.32 There is no
evidence that any department or agency suspended a single
activity following the President's instruction. The
staff of NBAC is researching the issue of federal agency
compliance with the Common Rule and this Executive
Memorandum.
5. A Caveat,Not All Unregulated Research Goes
Without Review
It is important to note that federal regulation is neither
the only mechanism through which research is independently
reviewed nor is it the only way participants in research are
offered the protection of informed consent. It may not be
appropriate to assume that expanding the scope of federal
regulation is the only way to achieve the twin goals of
assuring informed consent by subjects and objective review of
protocols. Many universities extend to nonfederally funded
research the same oversight required by federal regulation,
mandating that all research conducted at the institution is
subject to review by an IRB. Of course, in virtually all cases
this voluntary extension lacks independent compliance
oversight, so NBAC must confront the degree to which it
considers compliance oversight to be essential to a federal
protection system.
B. Documented Shortcomings of the Present System
Two recent reviews, one by the GAO in 1996 and one by the
OIG of DHHS in 1998, document serious shortcomings in the
functioning of IRBs across the country.33 Because our decentralized
system depends upon local IRBs for review of research
protocols, IRBs are the lynchpin of our human subject
protection system. The two most recent reports build upon the
earlier findings of the ACHRE.
These reports follow a string of earlier reports examining
shortcomings in our systems of protections, and containing
recommendations that have not been fully implemented. Recall
Nishimi's 1994 congressional testimony noting how many
recommendations delivered over the decades have not been
implemented. In that same testimony, she characterized national
responses to problems as fitting a "crisis
management" model, in which publicity leads to a
commission, but few actual changes. A footnote to her testimony
records that the President's Commission made a follow-up
report to Congress two years after its first report and called
the progress in the interim "disappointing."
Nishimi, in 1994, stated that: "The Commission
identified numerous deficiencies in agencies' mechanisms
to protect human subjects. It made a series of recommendations
to improve Federal oversight, but to date virtually none has
been implemented."34 The ACHRE found in its 1995 report that
"in comparison with the practices and policies of the
1940s and 1950s, there have been significant advances in the
protection of the rights and interests of human subjects of
biomedical research. However, we also find that there is
evidence of serious deficiencies in some parts of the current
system ." Their review found evidence of
"substantial variation in the performance of
institutional review boards" as well as in review of
research proposal documents and in informed consent documents.
Most importantly for NBAC, the committee found "evidence
of confusion over the distinction between research and
therapy."35 It is worth remembering that the original National
Commission spent a great deal of time in the early
1970s,and commissioned several analyses to assist its
deliberations,examining the distinction between research
and therapy as it set about devising a recommended definition
of "research" to be regulated. ACHRE also
articulated concerns about "adult subjects with
questionable capacity" and research involving
institutionalized children. NBAC is already addressing the
concerns ACHRE identified about adult subjects with
questionable capacity; the issue of the distinction (if any)
between research and therapy will continue to be central to all
discussions of appropriate regulatory scope.
Consistent with the comments of other observers, ACHRE
recommended that IRBs give more attention to activities that
pose more than minimal risk to subjects and that they seek to
reduce paperwork and procedural requirements for activities
posing less than minimal risk. In other words, focus resources
on areas of greatest risk and concern to subjects.
GAO, in its 1996 review of human subject protections, found
that "[t]he detection of recent instances of potential
or actual harm to subjects both demonstrates that abuses can
occur and also suggests that current oversight activities are
working [but] various time, resource and other pressures
have reduced or threaten to reduce the effectiveness of such
oversight."36 GAO found that the heavy workload of IRBs can
weaken their oversight; that OPRR's restricted site
visit schedule and its location within the National Institutes
of Health (NIH) hamper the effectiveness of its oversight of
IRBs; and that changes in the nature of research and pressures
for availability of unproven medical treatments make it
difficult to protect human subjects.37 GAO also commented upon the
organizational weakness in the location of OPRR within NIH that
is examined in the NBAC-commissioned papers by Drs. Fletcher
and McCarthy.38 This is a topic NBAC must address in its final
recommendations.
The OIG reports find that "the effectiveness of IRBs
is in jeopardy"39 with six major findings:
- IRBs face major changes in the research environment,
including those stemming from the expansion of managed care,
increased commercialization of research, proliferation of
multisite trials, new types of research, increased number of
research proposals, and the rise of patient consumerism;
- IRBs review too much, too quickly, with too little
expertise;
- IRBs conduct minimal continuing review of approved
research;
- IRBs face conflicts that threaten their
independence;
- IRBs provide too little training for investigators and
board members; and
- Neither IRBs nor HHS devote much attention to evaluating
the effectiveness of IRBs.40
While the OIG report found that OPRR's on-site visits
provide a better basis for assessment of an IRB's
performance than either its assurance process or the FDA
inspection process, it also noted that OPRR's resource
constraints prevented it from making more than one for-cause
site visit in the calendar year between April 1997 and May
1998. The OIG report stressed that it is a cardinal failing of
our present system that neither OPRR nor FDA have a primary
focus on assuring the effectiveness of IRBs. While the OIG
report does not document any widespread abuses, the fact that
we have no effective mechanism for assuring the accountability
of IRBs is cause for grave concern.
The OIG report recommends "reengineering" the
federal oversight process, with specific suggestions for
revamping both the OPRR assurance process and the FDA
inspection process for IRBs. Several recommendations focus on
modifying procedural requirements in order to focus more
effectively upon fundamental protections for human subjects of
research. This is a theme that NBAC should embrace in all of
its recommendations for change.
These findings only reinforce the sense that our existing
system requires reform. While these reforms should be
included in any recommendations made by NBAC, they should
accompany, not supersede, additional changes to address
identified risks to human subjects in presently unregulated
research.
Recommendation 1: Correct Identified Deficiencies in
Existing Federal Human Subjects Protection System
Before recommending that the federal government assume
expanded responsibility for protection of human subjects
involved in research, we should assure that it can fulfill its
present obligations appropriately. We know our present review
system has defects. Of those issues, the following seem most
relevant to the expansion and unification questions posed by
NBAC.
Recommendation 1A: Streamline the Assurance
System
A number of informed observers,including some within
OPRR itself,have come to believe that the existing
assurance negotiation process has lost much of its original
utility and has instead become unduly bureaucratic and
cumbersome. While the process had important educational
components in the early years of federal regulation, now that
research institutions have become more sophisticated in this
area, its time may have passed. Dr. Gary Ellis, testifying
before the Subcommittee on Human Resources of the Committee on
Government Reform and Oversight of the United States House of
Representatives, acknowledged as much.41
The most consistently proposed change that is
relatively easily implemented (i.e., without any regulatory
modification) involves transforming the assurance system into a
simplified registration system.
Streamlining the present assurance system would allow
precious resources to be redirected to higher priority
activities, including education and a more rigorous IRB
performance-monitoring system. (Redirection of existing
resources alone is unlikely to be sufficient to meet the full
need but would be a good first step.) For example, if a
registration model is adopted, instead of negotiating each
assurance, OPRR would require each regulated entity to register
with OPRR, providing the minimal amount of information required
by the regulations.42 This approach would preserve the essential tether
of the government to the system of institutional protections
for the purposes of education and, when necessary, compliance
oversight.
Recommendation 1B: Achieve Consistency Across the
Government,Require Full Adherence to the Common
Rule
Across the federal government the uneven application of
existing regulations requires improvement: Even after President
Clinton's 1994 directive, not all federal agencies
subscribe formally to the Common Rule, and among those that do
the level of adherence is mixed. NBAC staff are studying
current levels of compliance among federal agencies.
Any recommendations formulated by NBAC should
explicitly require,at a minimum,government-wide
compliance with human subject protection
regulations.
Recommendation 1C: Achieve Consistency Across the
Government,Unify Government Oversight
In addition to requiring all government agencies to
adhere to the Common Rule, NBAC should recommend unification of
government oversight of human subjects in one federal agency or
office. Given the uniform positive reviews from a variety of
observers for OPRR's expertise and effectiveness, this
function should be assigned to OPRR, although the structure
will require modification both to address the independence of
the monitoring function. (See Recommendation 1D
below.) Separate FDA jurisdiction over drugs, medical devices,
and biologics should be retained, but FDA and the OPRR
successor should enter into a Memorandum of Understanding to
coordinate their functions and reduce the burden on multiply
regulated entities. See further detail on this topic below.
Recommendation 1D: Assure Independence of the
Government's Monitoring Function
As noted by multiple observers from GAO to DHHS OIG to Drs.
Fletcher and McCarthy, OPRR's placement within DHHS
presents serious structural problems that must not be
perpetuated. A supplemental statement issued by GAO in response
to congressional questions following the presentation of the
GAO report noted: " 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
protections by OPRR."43 An approach for resolving these
structural conflicts of interest must be incorporated into any
proposed federal oversight mechanisms. The most obvious
mechanism is to move OPRR (or any successor office/agency) out
of NIH and place it elsewhere within the executive
branch. Any successor office/agency should have the
weight of authority necessary to carry out its mission, as well
as the necessary resources. See Section IV below.
Recommendation 1E: Provide Adequate
Resources
The current OPRR does not have enough staff or a large
enough budget to meet its current mandate adequately, let alone
to execute expanded responsibilities. It should be of serious
concern that the financial commitment of DHHS to human subject
protection, measured in financial terms, has been declining
over time, even while research funding is increasing.44 While it is
likely that additional resources are required to meet existing
compliance oversight responsibilities, it seems without
question that current resources for educational programs are
inadequate. The consistency and quality of any decentralized
system is necessarily dependent upon careful and continuing
education of participants across sites. Documented
deficiencies in the operation of IRBs call for more educational
efforts and performance assessments; these tasks cannot be
undertaken for research under OPRR's current purview
without additional resources. These costs should be
assessed and addressed in addition to the projected costs for
any new responsibilities. Mechanisms for addressing these
shortcomings must be incorporated into any NBAC
recommendations.
Reviews of the performance of OPRR in protecting subjects
repeatedly show that it has the ability to address these
shortcomings, but does not have sufficient resources for doing
so. OPRR comes up short in any measure of educational
activities, site visits, and timely resolution of allegations
of noncompliance,to the detriment of current human
research subjects.
Assuming identified deficiencies in the existing oversight
system are corrected, then NBAC can move to considering
expansion of federal jurisdiction in its effort to improve the
federal regulatory system for the protection of human subjects.
Rather than expanding regulation globally, however, and then
finding mechanisms for removing low- or no-risk research from
its purview, this paper recommends a different approach.
Back to Top
III. Issues
Involved in the Expansion of Federal Oversight
Beyond the responsibility of the federal government to
address known deficiencies in our system, we also know that
there are human research subjects who are not receiving basic
federal protections and who should be. How to provide those
protections effectively,identifying the core protections
to be provided around which societal consensus exists, focusing
upon serious risks and with a reasonable cost/benefit
ratio,is the challenge. NBAC must fully understand the
gaps in current protection and practical problems that must be
solved before recommending an expansion of federal oversight to
encompass privately conducted research.
A. Gaps in Federal Protection
The OIG report on IRBs and the ACHRE report illustrate
places where even research that is covered by federal
regulation may not be receiving meaningful or accountable
oversight. Beyond that, current federal regulations for
protection of human subjects do not reach: research conducted
or funded by federal agencies not subscribing to the Common
Rule; research that is not federally funded conducted at
institutions with SPAs and not covered by that
institution's assurance; and privately conducted
research that is not subject to FDA jurisdiction. In none of
these areas can it be assured that NBAC "twin
protections" of informed consent and independent review
are provided.
Dr. Gary Ellis, Director of OPRR, and others have offered
examples where potentially harmful research has been reported,
but where the subjects are not protected by federal
regulation.45 Recent news reports about Viagra, the "male
potency pill" contain references to clinics beginning
their own research on its effects on women.46 (See Attachment A.) Are
the participants in those efforts likely to receive the twin
protections of informed consent and independent review of the
risks? Do we, as a society, believe they should?
And what about the students and families about whom
information would be stored in the database described in a
January 1997 report in the Washington Post? (See
Attachment B.) That report described a school district
implementing a student database that would let schools compile
medical and dental histories and records of behavioral
problems, learning disabilities, and family income. The
newspaper report indicated that the new database would allow
"administrators to monitor whether students of a
particular ethnic background or sex were doing better or worse
than others in English, algebra or any other course .a
broader database would help administrators examine demographic,
academic and extracurricular information in an effort to
pinpoint causes and solutions."47 Such databases could also
provide a rich resource for researchers, but research uses are
not currently regulated.
Other examples abound. They include research conducted at or
by:
- Some in vitro fertilization clinics:
Example: women who had experienced multiple
miscarriages alleged that they were misled about the
substantial financial cost of participating in research to
pregnancy.48 (See Attachment C1: OPRR had no jurisdiction
to review these complaints because this research was not
subject to any assurance.)
- Some weight loss or diet clinics:
Example: OPRR received a complaint about a
coercive structure of payment for participation in weight
loss research that made it extremely unlikely that the
subjects would discontinue participation prior to the
completion of research.49 (See Attachment C2: OPRR had no
jurisdiction to review these complaints because they
occurred at unregulated entities.)
- Some physicians' offices:
Example: a woman who had been treated for
breast cancer alleged that identifiable private information
from her medical record had been placed in a registry and
made available to research investigators without her
consent.50 (See Attachment C3: OPRR had no jurisdiction
to review these complaints because treatment was not
provided under any research protocol, and the assurance of
the hospital maintaining the registry covered only
DHHS-supported research. DHHS did not provide any support
for the development or maintenance of the registry.)
and: a December 1996 publication in a
professional journal for reconstructive surgeons describing
a prospective study comparing lateral and standard face
lifts; there is no indication that patients were aware of
or consented to their inclusion in the study.51 (See
Attachment C4.)
- Some dentists' offices:
Example: a 1995 university news release
describes private-foundation funding of a dentist's
study of removal and replacement of mercury amalgam dental
fillings from approximately 30 patients.52 (See Attachment
C5.)
- Some psychotherapists' offices:
Example: OPRR has received complaints from
patients subjected to "experimental"
psychotherapy techniques, but had no authority to
investigate the complaints, because their practitioners
were not affiliated with any regulated entity.53 (See
Attachment C6.)
- Some corporate and industrial health safety and fitness
programs:
Example: attempts to enhance the physical
fitness of loss prevention officers involved collection of
data (e.g., activity monitoring) that would likely reveal
unsatisfactory job performance.
and: "team management" research in
which unsuspecting individuals were subjected to a sham
robbery, resulting in significant stress, fear, and
anxiety54 (see Attachment C7); another complainant to
OPRR described "fright response" research in
which participants were subjected to unexpected and
disturbing visual stimuli.
- Some developers of genetic tests:
Example: the Task Force on Genetic Testing of
the National Institutes of Health/Department of Energy
Working Group in Ethical, Legal, and Social Implications of
Human Genome Research reported in May 1997 that a
substantial number of genetic tests are being developed
without the oversight of IRBs. Twenty-six percent of 140
not-for-profit organizations developing genetic tests had
not submitted any protocol for review; 41 percent of 54
biotechnology companies had not submitted any protocol for
review.55
- Colleges and universities not receiving federal research
funds:
Example: research presented in 1997 at a
national conference of English professors in which the
researchers displayed notes taken by psychotherapist during
work with a real client including name and other
identifying information on that client, revealing a history
of sexual abuse and suicidal tendencies. Given the content
of federal regulations and the conventions observed by
reputable IRBs, it seems most unlikely that this research
was ever reviewed (or approved) by an independent review
body.56 (See Attachment C8.)
- Some federal research conducted under the auspices of
agencies not subscribing to the Common Rule:
Example: The National Endowment for the Humanities
does not subscribe to the Common Rule. As a result, unless
the home institutions of the researchers have negotiated MPAs
with OPRR, the research announced in an April 1998 report in
the Chronicle of Higher Education might,or might not
have,received IRB review at the home institutions. The
research projects announced include projects on topics such
as "Children's Developing Knowledge of How to
Create Words: A Study in Linguistics," "West
African Infant Care Practices," and
"Bilingualism in an Immigrant Community."
Without further information, it is hard to tell whether
issues of confidentiality were fully addressed before this
research was initiated or whether any independent body
reviewed the effects of participation on the children.
- Research by unregulated entities:
Example: Nishimi's 1994 congressional
testimony referenced research funded by a pharmaceutical
company in which private physicians were given grants to
identify children of short stature.57 (See Attachment C9; OPRR
had no jurisdiction over the research because no regulated
entities were involved.)
Other research-related activities that could, and in some
cases information exists to suggest they already have, present
risks to human subjects include health services research and
internal evaluation research. Health services research is
increasingly common as managed care becomes more pervasive and
typically involves efforts to measure efficacy and
cost-effectiveness of various treatments in managed care
organizations. Internal evaluation research involves
comparisons of management techniques, labor practices, and
other corporate research into how employees like or perceive
their work environment. It will be a challenge to find the
lines between benign surveys of employee satisfaction and more
intrusive and/or coercive research that could compromise
employee privacy. But while some of these examples are more
egregious violations than others, none of them are currently
regulated unless the research is funded by one of the Common
Rule agencies.
B. Practical Problems in Expanding Federal Oversight
What might be the consequences of expanding the current
definition of research and applying it globally to all research
involving human subjects? More particularly, what is the
wisdom, practicality, and cost-effectiveness of bringing a
potentially broad range of activities under the scope of
federal regulation?
1. What Should Be the Definition of
"Research"?
Global applicability of the
current definition of research could encompass many activities
that impose very little or even no risk to subjects of that
research. While the scope of federal protection is narrow, the
current definition of research used for regulated activities is
very broad:
'Research' means a systematic investigation
designed to develop or contribute to generalizable
knowledge.58
Many forms of polling, much market research, and arguably
some forms of journalism could be considered "systematic
investigation designed to develop or to contribute to
generalizable knowledge" that is obtained "through
intervention or interaction" with individuals or that
involves "identifiable private information" about
those individuals. Differentiating between activities that
should be covered and those for which expanded federal
regulation might be burdensome could consume significant
resources and time on the part of many individuals and could
prove divisive and distracting from the goal of protecting
Americans from risk of serious harm through participation in
research.
Should the current definition be used as is, or could it be
modified to avoid such a result? The current definition was
purposefully designed to be assure that subjects of research
would be protected,whatever the research might be.
Appendix Two of the Belmont Report (the report of the National
Commission) contains a number of commissioned papers, at least
four of which address the boundaries between research and
therapy.59
These papers were commissioned as part of the National
Commission's formulation of its recommendations,
including the definition of research in its final report.
When that definition was published in the Federal Register,
only 21 comments addressed the proposed definition of research
in the rulemaking process.60 The commentary accompanying the final
regulation in January 1981 characterized those comments as
follows: "While a few commentators favored the proposed
definition because it offered flexibility to the IRB, a
majority of the twenty-one opposed or raised questions about
the definition. Several commentators felt that the definition
is too broad and should be restricted to biomedical
research. " The DHHS Response to the comments
observed that:
HHS believes that public concerns that the definitions are
too broad will in most cases be met by the exemptions from the
regulation. The National Commission, although not identifying
specific fields of research, clearly intended to include
behavioral studies in the recommended definition of
'research.' HHS agrees with this conclusion and
does not believe that the definition of 'research'
violates the rights of investigators given that the regulations
exempt research which offers little or no risk to the rights
and welfare of human research subjects.61
While one approach to the problem of sweeping low-risk
research into an expanded federal regulatory scheme is to
narrow the definition of research, the continuing progress of
scientific advances applicable to human treatment suggests this
is not a sound approach. No better definition of research than
that currently used has attracted consensus support in the
almost 30 years this definition has been in place. In the
absence of a tested alternative, altering the definition itself
seems unwise.
If the present definition is perpetuated rather than
modified, it is likely that development of new exemptions
should be considered to obviate unintended consequences of
expanded regulatory scope and to focus government protections
upon areas posing the greatest medical and ethical risks. It
should be possible to craft appropriate exemptions for very
low-risk "research." In approaching such a task,
the risk of harm must be balanced with the burden of
regulation. On the other hand, given the extended and somewhat
tortuous process required to develop and refine the current
definitions and exemptions, some caution seems warranted.
Before NBAC makes recommendations that might require the
development of new exemption categories, alternatives should be
carefully considered.
For example, not only would it be necessary to develop
consensus across a broad spectrum of constituencies about new
exemptions, but regulatory language would need to be carefully
crafted and tested. Based on experience, this might well take a
period of years. Would the entire process of expanding the twin
protections of informed consent and IRB review be delayed in
the meantime, or would we go through a period in which
potentially harmless or very low-risk activities would undergo
unnecessary review? If the latter, what long-term effects might
that have for a system that by many accounts is already
overburdened and near the breaking point?
2. Who Decides an Activity Is Exempt? Conflict of Interest
Questions
After the development of appropriate exemptions and
embodying regulatory language, still another practical problem
arises: Who will determine the applicability of the exemptions?
It is fundamental that a person performing research has a
conflict of interest in deciding that his or her research is
exempt from review. This implies independent review, which
raises a raft of troubling questions: Who will perform these
reviews? How much paperwork will it require? For researchers
not affiliated with universities, where will they find an
appropriate IRB? Will this intensify existing incentives for a
proliferation of for-profit IRBs? Might core ethical
examinations be diluted by expanding the workload of IRBs along
with the requirements for paperwork and review of low-risk
research? At what cost might this occur?
The prospect that expansion might divert valuable resources
and energy from projects needing thoughtful ethical review is
troubling. It is not difficult to envision the creation of an
extensive and burdensome, possibly profit-driven,
rubber-stamping review system that dilutes attention to the
serious ethical issues that research involving human subjects
can imply. This is an outcome no one seeks. Further, the costs
are potentially very large.
3. Costs
The costs involved in globally extending the current system
could be significant. One indicator of the possible costs is
that each (single-site) protocol review by Independent Review
Consulting, Inc., (a reputable for-profit IRB that provides IRB
services for unaffiliated investigators) costs $1,200.62 This does not,
of course, include the costs involved in preparing materials to
be reviewed by the IRB. Assuming that the direct costs of
non-institutional review boards are comparable to those of
academic IRBs, very large sums of money (representing the costs
of creation, review, and maintenance of required information)
could be at stake in a dramatically expanded system of human
subject protections, especially those involving low-risk
activities. The cost/benefit ratio for such an approach does
not seem advantageous, especially in today's political
environment.
Recommendation 2: Expand Regulation Incrementally,
Not Globally (at Least at First)
This recommendation proposes an alternative to expanding the
scope of federal regulation very broadly and then crafting
appropriate exemptions. It suggests adding targeted areas to
the scope of federal oversight areas of research. Two possible
mechanisms are proposed for NBAC's consideration.
Recommendation 2A: Expand Jurisdiction Incrementally
as "Known Risks" are Identified
As a starting place, NBAC might focus upon the goals
articulated by the President of protecting subjects from
unwitting participation and undue risk by focusing upon
targeted areas. Given the estimate of the ACHRE that "40
to 50 percent of human subjects research poses no more than
minimal risk of harm to subjects,"63 it is all the more critical
to focus any new regulatory energy on activities that put human
subjects at risk. While we cannot know if ACHRE's
estimate will extrapolate to presently unregulated activities,
it is a reasonable starting point for thinking about these
issues.
The goal should be to define areas of national concern by
focusing on documented instances where human subjects have been
exposed to:
- unwarranted risks,
- where they have been induced to participate in research
without full understanding of those risks (or of the
remoteness of personal benefit to them from the
participation); and
- where the protocols have not been subject to independent
review for compliance with generally accepted standards of
research involving human subjects.
The targeted areas would focus on categories of
"known risks",research that we know puts
human beings at risk, whether conducted privately or with
federal support. An incremental approach seems more
consistent with current trends in public policy, while still
providing appropriate protections to residents of this country
who participate in risky research activities. This approach
would be more amenable to a documented cost/benefit analysis,
and thus might be more persuasive to the public and to
lawmakers.
Adopting this recommendation implies the development of
categories requiring protection and procedures for invoking
that protection. At first glance, likely candidate categories
include:
- all unapproved, invasive procedures (e.g., work performed
at in vitro fertilization clinics) that involve genetic
tests;
- research conducted at institutions with a research
mission (primarily universities) receiving federal funds, but
that is not directly federally supported (see below);
and
- other research posing documented risks to participants as
gleaned from reports of problems.
Another, more controversial, category requiring serious
examination is research that involves dignitary damage or
breaches of confidentiality leaving the subject at risk.
An effort to identify and document known risks implies
significant work, but this effort will likely be more
productively expended,and generate greater
support,than that required to extend the present
regulatory system to cover "all" research.
Recommendation 2B: Explore Expanding OPRR's
Jurisdiction Without Statutory Change
Historically, OPRR has taken the position that the language
of the Public Health Service Act64 requires mandatory compliance with
its provisions only for research that is actually funded in
whole or in part by DHHS. Thus, institutions filing an MPA
voluntarily agree to apply federal regulations for human
subject protections to non-DHHS research. Institutions that
file SPAs have no obligation to ensure IRB review or informed
consent for any other research involving human subjects. This
may well be a more conservative interpretation of the Act than
it requires.
NBAC should seek assistance and advice from the DHHS
Office of the General Counsel to determine whether a broader
reading of this statute is permissible. Specifically,
"research" is not qualified in Sections 491(a) and
(b)1 and refers to any biomedical or behavioral research
involving human subjects. Can the Act be read to refer
to all research at any institution supported by DHHS funds, not
just research that is directly supported by DHHS?
Further advice and legal review will be necessary to explore
this possibility. Such an expansion of OPRR's
jurisdiction will require a considerable addition of resources
to OPRR. While seeking such advice may seem burdensome, the
possible gains for regulated entities and for governmental
efficiency warrant the effort.
Back to Top
IV. Possible Structures for Unified Federal
Oversight
Whether NBAC decides to expand federal jurisdiction to
encompass areas of known risks or to pursue more global federal
jurisdiction, a different federal structure will be needed than
is now in place. Deficiencies of the existing system that
should be addressed in any proposed reforms should include more
consistency and coordination across the government, as well as
in the government's interactions with regulated
entities. Given the size of the federal government and the vast
array of research sites across the country, NBAC should seek a
structure that will provide a single office that works in a
distributed style. Some existing agencies or offices that
currently function in this way provide models that have much to
offer as exemplars. These include the Office of Governmental
Ethics (OGE), the Office of Special Counsel (OSC), and the
Nuclear Regulatory Commission (NRC). Although different in size
and mission, each has educational and compliance-monitoring
responsibilities, and each operates in a decentralized,
distributed fashion.
Before considering the placement of the human subject
protection monitoring system, one most important issue must be
addressed,namely, in a unified federal oversight system,
what should happen to the current functions represented in OPRR
and FDA?
A. Unify OPRR and FDA?
Although it is always simpler from the perspective of a
regulated entity to have only one federal oversight office, the
missions of OPRR and FDA are sufficiently distinct that a
strong case can be made that their independent functions should
be maintained. Further, this is clearly the most pragmatic
solution, since they currently operate under two distinct
statutory authorizations, and the political ramifications of
attempting a unification seem more complex and difficult than
the gain would warrant. FDA and OPRR currently work in a
coordinated fashion and have significant overlap in their
approaches to regulated entities.
Thus, NBAC should recommend that these separate
functions,drug and medical device approval and research
oversight,should remain the primary province of FDA and
the OPRR successor, respectively. The OPRR successor should be
responsible for all regulated research involving human
subjects, both government wide, and whatever private research
is added to the regulatory structure.
To enhance coordination and cooperation, the two agencies
should enter into a Memorandum of Understanding that addresses
interagency cooperation and jurisdiction and establishes a
formal coordinating function. This should include new
agreements covering IRB oversight to assure that the protection
of human subjects is addressed in a reasonable, cost-effective
way, especially in light of the GAO's cautions about the
substance of FDA IRB reviews and of concerns voiced by
regulated entities about the sometimes burdensome nature of
joint (and uncoordinated) jurisdiction by two federal agencies
over the same IRBs.
NBAC or the successor agency may need to commission an
examination of other special-purpose agency IRB regulations
(for example, those at the Centers for Disease Control and
perhaps the Department of Energy and/or those in classified
settings) to determine whether other accommodations or
Memoranda of Understanding might facilitate appropriate
regulatory oversight.
B. Possible Models
The following existing governmental offices offer insights
into possible models for an OPRR successor office that would
oversee all human subject research.
1. OGE
The mandate of the OGE is to prevent ethical misconduct
within the executive branch; it has responsibility for the
prevention of conflicts of interest and for resolving those
conflicts of interest that do arise. There are five applicable
federal statutes for which it has enforcement responsibility.
The Office of Public Integrity in the Department of Justice
reviews OGE ethics opinions because it has enforcement
authority for the underlying criminal statutes.
Created in the aftermath of the Watergate scandal, OGE was
originally located within the Office of Personnel Management.
During the Reagan administration, OGE became an independent
agency. The Director is appointed by the President, with the
advice and consent of the Senate, but that is the only
politically appointed position in the agency. The remainder of
the staff, about 80 people, are civil service employees. In
contrast, OPRR has around 17 full-time staff members devoted to
human subject protection (out of 28 total staff members).
OPRR's FY 1995 budget was $2.25 million. Its FY 1996
budget was $2.13 million, and its FY 1997 budget was $2.10
million, a little more than half of which was spent on human
subject protection activities.
OGE promulgates standards of conduct based on 14 fundamental
principles. Its advisory opinions and ethical guidance are
widely disseminated in the federal ethics community to assist
in keeping officials informed and up to date. OGE oversees a
broadly decentralized program in which each federal agency
names a Designated Agency Ethics Official (DAEO); these 144
officials report jointly to the head of the agency and to OGE.
This model seems particularly relevant when considering a
government-wide human subject protection function.
OGE supports the DAEOs by developing educational materials
and conducting training workshops for them and the other staff
in each agency with responsibility for ethics compliance, who
together comprise what is known as the federal "ethics
community." There are close to 12,000 part-time members
of the federal ethics community, with about 400 of them serving
on a full-time basis. While OGE audits their performance on a
regular basis, the DAEOs hold significant responsibility within
their agencies for educational programs and for compliance with
congressional and presidential directives. This model of
distributed responsibility dovetails nicely with the local
control philosophy of federal oversight for research involving
human subjects.
Although OGE focuses its efforts on education and providing
positive guidance in response to questions, it also maintains a
significant audit program, with 27 full-time auditors. These
auditors review advice provided by DAEOs, the content of agency
ethics training programs, and required financial disclosure
forms. When violations of the standards of conduct are
substantiated, they can lead to administrative sanctions
(including reprimands, time off without pay, and/or demotion).
Violations of the five applicable statutes carry higher
penalties. OGE has 77 full-time employees and an annual budget
of $7.6 million. See Attachment D for further information on
OGE.
OGE's independence from other government agencies
presents an example that would cure the structural deficiencies
found in OPRR's placement within an agency that it must
also monitor for compliance, as cited by GAO and Drs. Fletcher
and McCarthy. At the same time, the joint reporting status of
the DAEOs presents an interesting model that balances working
within each agency's individual culture while achieving
consistent policy interpretation. Further, its independent
standing emphasizes the importance of the issue it monitors and
insulates it from political pressures. Finally, the distributed
model could prove equally strong in the setting of regulated
institutions.
On the other hand, OGE's independent status and
relatively small size may also reduce its leverage in budgetary
processes, as it may not always have a seat at the table when
budgetary compromises are reached. Embedded within a larger
federal agency, budgetary negotiations have a different
complexion. It is difficult to predict the quality and
consistency of top-level attention to issues of human subject
protection if those responsibilities are placed in an
independent agency or department, especially in periods lacking
in public focus on these issues.
2. OSC
The OSC was originally part of the U.S. Merit Systems
Protection Board, but became "an independent federal
investigative and prosecutorial agency" in July 1989. The
principal responsibilities of the OSC are three-fold: 1)
investigating allegations of prohibited personnel practice; 2)
interpreting and enforcing the Hatch Act (political activities
of federal employees); and 3) operating a whistleblower
disclosure hotline to receive information "about
wrongdoing in government." The OSC's role was
expanded in 1994 to include investigation and prosecution of
cases involving the denial of federal employment rights to
veterans.
The President appoints the head of the agency, the Special
Counsel. The remainder of the staff, about 95 civil service
employees, report to the Special Counsel to carry out
OSC's responsibilities. OSC's 1998 budget was
$8.4 million.
Although OSC's responsibilities are primarily
executed within the executive branch, it serves as a useful
model for NBAC because of its ability to work in a distributed,
decentralized way across the full range of federal agencies.
For example, OSC has jurisdiction to investigate allegations of
prohibited personnel practices within any executive branch
agency. These investigations are frequently conducted in
conjunction with other government agencies. This model is
particularly useful when thinking about oversight of
intragovernment activities. See Attachment E for further
information on OSC.
3. NRC
Holding wide regulatory and compliance responsibilities, the
NRC operates on a completely different,and much
larger,scale than the previously discussed offices.
Established as an independent agency in 1974 by the Energy
Reorganization Act, the purpose of the NRC is to "ensure
adequate protection of the public health and safety, the common
defense and security, and the environment in the use of nuclear
materials in the United States." The NRC's
responsibilities include regulation of commercial nuclear power
reactors; medical, academic, and industrial uses of nuclear
materials; and the transport, storage, and disposal of nuclear
materials and waste. The NRC adheres to five Principles of Good
Regulation that encourage ethical performance, openness to the
public, efficient management and administration, clear
regulations, and reliability.
Five commissioners are appointed by the President and
confirmed by the Senate for five-year terms. One of the
appointed commissioners is designated by the President to
function as the chairman. A civil service staff reports to an
executive director, who executes the directives of the
commission. The overall structure and organization of the NRC
provide NBAC with another established model of an independent
agency that works in a distributed way within federal agencies
and at diverse academic and private sites throughout the
country. Further, it provides a model to examine when
considering suggestions, such as Dr. Fletcher's, that
OPRR (or its successor) needs a citizen advisory panel.
Divided into divisions with specific responsibilities, the
NRC has educational and compliance responsibilities similar to
those of the OPRR, albeit on a much larger scale. Among its
multiple divisions are one with responsibility for regulatory
programs and another with responsibility for oversight and
investigations. An Office of State Programs coordinates NRC
activities with state and local governments as well as with
other federal agencies and the sovereign Indian nations. NRC
has 3,000 employees and an annual budget of $468 million. See
Attachment F for further information on NRC.
Given the magnitude of NRC, it is somewhat difficult to make
relevant comparisons to how this model might operate if
translated into the human subject protection area. One
possibility is that NBAC, or some similarly constituted
commission, could serve as the policymaking body, with OPRR and
FDA staffs carrying out their present roles. In such a
configuration, perhaps the OPRR (research-oversight) function
would fall under the NBAC successor function while the FDA
staff would remain in that agency but have dual policy
guidance.
If NBAC or a successor commission were to serve as the
policymaking or advisory body for an OPRR successor, two issues
must be addressed: 1) NBAC's present expiration date
(authority for human subject protection cannot be allowed to
expire) and 2) the need for a revised charter to provide formal
regulatory authority.
Recommendation 3: Explore Existing Models of Federal
Offices/Agencies with Both Educational and Compliance
Responsibilities,Design NBAC's Recommendations
Based Upon Those Models
Devising an improved governmental structure for a unified
human subjects protection system will take expertise beyond the
scope of this paper. Aside from explorations of the policy and
political implications of its recommendations, NBAC will need
to commission legal analyses of what enabling legislation or
regulation will be necessary to effect any structure it
suggests. NBAC must also address,perhaps through
additional commissioned papers or through advice from
established governmental mechanisms,reasonable resource
allocations for the expanded functions it envisions.
Because this problem has been so intractable for so long, I
encourage NBAC to provide specific instruction and draft
legislation as part of its final report to the executive and
legislative branches. Otherwise, its recommendations could well
become just one more report sitting on a shelf.
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V.
Conclusion
In its June 1998 report, the OIG of DHHS found significant
cause for concern in the current operation of our human subject
protection system. While the OIG found no "widespread
abuses of human research subjects," its report identified
aspects of our current system in pressing need of reform. This
report does not stand alone: The observations of the OIG echo
and reinforce those of multiple other observers of the current
system, including many inside the government who hold
responsibilities for protecting human subjects of research.
The challenge for NBAC is to devise recommendations for
assuring substantive ethical consideration of the serious
issues present in human subject research that can be enacted in
the current political environment. This means addressing
identified deficiencies in our current regulatory scheme,
filling in some of the known gaps representing areas of real
risk to residents of this country who participate in research,
and assuring true accountability for this regulatory system in
a cost-effective manner.
Responding to these challenges requires retooling the
existing federal structure to provide cleaner lines of
authority, uniform implementation of existing rules across the
government, and streamlined links between the government and
local IRBs.
Research subjects,particularly those who are not told
they are participating in experimental activities or those
participating in research that has not received prior
independent ethical review,are among the most vulnerable
of our population. In permitting their rights, welfare, and
dignity to be compromised, we compromise our own.
It is time to finish the job of protecting human subjects
that began more than three decades ago.
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Acknowledgments
I am very grateful for the kind and generous help accorded
to me by many people during the course of this process. Ada Sue
Selwitz (University of Kentucky), Joan Rachlin (PRIM&R),
Paula Knudson (University of Texas Health Science Center at
Houston), Eric Meslin (NBAC), Gary Ellis (OPRR), and Michael
Walker (University of Illinois) reviewed drafts of this paper
in progress and provided many helpful comments; any errors that
remain are my own.
A number of people gave graciously of their time and
expertise in response to requests, including Stuart Gilman of
the Office of Government Ethics, Victor Baird of the Senate
Ethics Committee, Michelle Russell-Einhorn and Tom Puglisi of
the Office for Protection from Research Risks, Allan Shipp of
the American Association of Medical Colleges, Sal Giorgiani of
Pfizer Pharmaceuticals, Mark Frankel and Al Teich of the
American Association for the Advancement of Science, Erica
Heath of Independent Review Consulting, Inc., and Robert Levine
of Yale University.
Melanie Marino provided research support and editorial
assistance throughout the development of this paper. Debra
Kincaid was her usual cheerful self in helping to make room for
this project amongst many others.
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Attachments
A: Kolata, G. "Doctors Debate Use of Drug to Help
Women's Sex Lives." New York Times National. April
25, 1998.
B: Robberson, T. "Plan for Student Database Stirs
Opposition in Fairfax." Washington Post. January 9,
1997.
C1: OPRR Compliance Oversight Log. Letter to Dr. Melody Lin,
Compliance Oversight, NIH, received June 18, 1993. Obtained
from the OPRR under the Freedom of Information Act.
C2: OPRR Compliance Oversight Log. Regarding the Newark Beth
Israel Medical Center, received September 28, 1994. Obtained
from the OPRR under the Freedom of Information Act.
C3: OPRR Compliance Oversight Log. Regarding the St. Vincent
Hospital Medical Center, Portland, Oregon, received April 13,
1995. Obtained from the OPRR under the Freedom of Information
Act.
C4: Ivy, E.J., Lorenc, Z., and Aston, S.J. "Is there
a Difference? A Prospective Study Comparing Lateral and
Standard SMAS Face Lifts with Extended SMAS and Composite
Rhytidectomies." Plastic and Reconstructive Surgery.
December 1996.
C5: "Adolf Coors Foundation Grants $240,000 to UCCS
to Study Effects of Mercury Fillings." University of
Colorado at Colorado Springs, Office of Public Relations.
November 9, 1995. Obtained from the OPRR under the Freedom of
Information Act request by C.K. Gunsalus, 1998.
C6: OPRR Compliance Oversight Log. Received January 29,
1993. Obtained from the OPRR under the Freedom of Information
Act request by C.K. Gunsalus, 1998.
C7: Romano, L. "A Night at the Office Became a
Nightmare." Washington Post. January 29, 1997.
C8: Letter from Dr. Gary Ellis to Dr. Curt Tompkins with
attachments, April 28, 1997. Letter from Dr. Gary Ellis to Sung
M. Lee, July 21, 1997. Obtained from the OPRR under the Freedom
of Information Act request by C.K. Gunsalus, 1998.
C9: Kolata, G. "Selling Growth Drug for Children: The
Legal and Ethical Questions." New York Times National.
August 15, 1997.
D: U.S. Office of Government Ethics. www.usoge.gov. Accessed
June 11, 1998.
E: U.S. Office of Special Counsel. www.access.gpo.gov/osc.
Accessed June 11, 1998.
F: U.S. Nuclear Regulatory Commission. www.nrc.gov. Accessed
June 11, 1998.
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Footnotes