April
2002
Volume 66 |
Number
4
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| Guinea
Pigs, Big Ideas and the Glory of Regulation: Human Subjects
Protections in 2002 |
Jeffrey
H. Silverstein, M.D.
The headlines
have been shocking: "Volunteer in Asthma Study Dies After
Inhaling Drug."1 A federal agency subsequently shut down
all patient research at Johns Hopkins Medical Center. While the
ban lasted a few days, the work necessary to get all the projects
up and running again has been enormous.2 Across the country, a
five-day newspaper exposé detailed alleged research malfeasance
at a major cancer center in the Pacific Northwest.3 A 16-year-old
volunteer made national news after dying from a gene therapy experiment.
Many have asked: Is there no protection for subjects signing up
for research studies?
Ask a researcher
involved in human studies, though, and he or she will tell you
that oversight has never been more imposing. A sea change is occurring
in the field of human subjects protections that will greatly impact
both researchers and participants. Anesthesiology is a clinical
specialty and needs quality clinical research to advance and survive.
It is a challenge for the specialty to assure that all researchers
learn the intricacies of experimenting on human subjects. This
challenge is not limited to academic centers. It is increasingly
common for anesthesiologists in private practice to be asked to
participate in clinical study sponsored by a pharmaceutical company.4
This article attempts to cover two general areas. The first is
a short list of items for the individual investigator to consider,
something of a list of the most common problems seen in this area.
The second describes three initiatives that will shape the next
few years of human research.
It is frequently
written that the "modern age" of human subjects' protections
began with the publication of the Nuremberg Code, a set of principles
that the judges conducting the Nuremberg Nazi doctors' trial set
forth as a means of evaluating human participation in research.
In subsequent years, a number of other documents have advanced
the scope and breadth of human subjects' protections.
Protections
for human subjects participating in research within the United
States are delineated in federal law. The Department of Health
and Human Services (DHHS), previously the Department of Health,
Education and Welfare, published and enforces the regulations
(45 CFR 46). Although other agencies may support research, anesthesiologists
are most likely to be subjected to these rules and to those (similar
but not identical) that emanate from the Food and Drug Administration
(FDA). Both DHHS and FDA expect research to be reviewed by local
boards known as institutional review boards (IRBs). Institutions
that conduct research file assurance agreements with DHHS that
commit the entire institution to adherence to federal statutes.
Although this may apply only to federally funded research, most
institutions agree to apply the rules to all research. For researchers
working outside of a major institution, independent IRBs may review
a project. Overview of IRBs was the province (among others) of
the Office for Protection from Research Risks. As part of the
importance placed on improving oversight of IRBs and human research,
a new office, the Office for Human Research Protections was recently
created in the office of the secretary of DHHS.
A basic assumption
of human subjects' protections is that key personnel understand
the rules and regulations governing research. For industry (FDA-regulated)
studies, all investigators sign a form (1572) committing them
to following the rules. The rules are generally referred to as
"good clinical practice" (GCP). GCP is not "what
any good physician would do" but rather the detailed regulations
of how human research is conducted for submission to regulatory
authorities. In an effort to assess compliance with federal human
subjects protection, GCPs and local IRB regulations, some institutions
have undertaken various levels of internal audit of investigators.
The following summary of common things done wrong was synthesized
from a variety of sources:
Unconscious
incompetence: (When you don't know what you don't know). Fortunately
there have been few, but nonetheless notable, cases of well-meaning
and frequently productive faculty who were basically unaware of
the regulations governing research. Remedies range from extensive
re-education and supervision to debarment from future research.
Lack of
IRB approval. You must have IRB approval for most studies,
including retrospective chart reviews. IRB approval remains for
a maximum of one year. If the approval expires, patients cannot
be enrolled. A not uncommon call to the IRB comes from authors
who seek to publish a retrospective review only to have the journal
editor ask for IRB approval. Projects cannot be approved retrospectively.
Changing
the protocol without notifying the IRB. Even minor administrative
changes must be on file with the IRB. Changes that alter risk
will be reviewed and may require changes in consent.
Improper
consent. Informed consent for research should be free of any
coercion. This can be particularly difficult in the perioperative
period. It is not appropriate to have a patient sign a consent
document for research while waiting on a stretcher immediately
outside an operating room. It may difficult to find adequate time
and facilities to permit a potential subject to legitimately consider
participation in a clinical study. Also, pay attention to details
of the consent, particularly signatures, times and dates. The
subject must sign and date the form in his or her own hand.
Failure
to report adverse events. As in many situations in clinical
research, any medical professional could probably define "adverse
events." The actual definitions, however, are ensconced in
law. Serious adverse events (SAE) include any experience that
is fatal, life-threatening or permanently disabling, requires
inpatient hospitalization or is a congenital anomaly, overdose
or cancer. Investigators should interpret these definitions literally.
SAEs must be reported within 24 hours to your IRB and the study
sponsor. You must report the SAE whether you believe it was related
to the study or not. "Unexpected adverse events" have
a specific definition and different reporting requirements.
There are
requirements for education of key personnel participating in federally
funded research, and most IRBs require education and documentation
from all researchers. The requirements are not specific and can
be found in a number of formats.5,6 These resources cover primarily
human subjects protections. An investigator must study other resources
to learn about GCP and proper conduct of a clinical research study.7
IRBs oversee
the investigators, and the level of oversight of IRBs has increased.
Three major events are looming in the future that will have more
or less impact depending on where you are located. First, a series
of proposals for accreditation of Human Subjects Protections Programs
are on the horizon. The Association for the Accreditation of Human
Research Protection Programs (AAHRPP)8 is a voluntary organization
newly opened to provide an accreditation process by a nongovernmental
agency similar to the Joint Commission on Accreditation of Healthcare
Organizations. The Veterans Administration has developed a similar
program.9 These programs should begin to standardize human subjects
review across the country. The impact of these regulations will
vary widely between institutions.
A similar
push is under way to increase oversight and management of conflicts
of interest in research. Perceived and real conflicts of interest
undermine confidence in the research process. Following a number
of high-profile cases in which conflicts of interest may have
played a role, the Association of American Medical Colleges has
released its report on individual financial interest in human
research, which seeks to ban financial conflicts of interest and
requires more disclosure than has traditionally been the case.10
Finally, the
Health Insurance Portability and Accountability Act (HIPAA) has
very strict regulations regarding access to medical data. It may
no longer be possible to review medical records without obtaining
consent from the individual whose record you seek. IRBs will be
required to assess a long list of characteristics in order to
allow access to medical records.
Clinical research
is the heart-blood of anesthesiology. Living up to the challenges
of conducting human research will require organized effort.
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Jeffrey
H. Silverstein, M.D., is Associate Dean for Research, Vice-Chair
for the Institutional Review Board, Vice-Chair for Research
and Assistant Professor of Anesthesiology, Surgery, Geriatrics
and Adult Development at Mt. Sinai School of Medicine, New
York, New York. |
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