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[Published by the Office for Protection
from Research Risks (now the Office of Human Research Protections), 1993] Institutional
Review Board Guidebook * CHAPTER V * |
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A. Introduction B. Drug Trials Applicable Laws and Regulations Applicable Laws and Regulations Applicable Law and Regulations E. Use of Radioactive Materials and X-Rays Applicable Laws and Regulations Clinical Trials of HIV-Related
Therapies Informing
Subjects of Their HIV Serostatus Availability of Drugs and Other Therapeutic Agents G. Transplants Applicable Laws and Regulations Identifying and Deciphering Genes Applicable Laws and Regulations Applicable Laws and Regulations Suggestions for Further Reading Most of the research reviewed by
IRBs falls within the broad categories of biomedical or behavioral research.
IRBs should be sensitive to specific aspects of biomedical and behavioral
research in their review of protocols. Biomedical research includes both
studies designed primarily to increase the scientific base of information
about normal or abnormal physiology and development and studies primarily
intended to evaluate the safety, effectiveness or usefulness of a medical
product, procedure, or intervention. The terms "behavioral
research" or "the behavioral sciences" may be used to refer
either to studies of the behavior of individuals, or to studies of the
behavior of aggregates such as groups, organizations, or societies. The broad
objective of the behavioral and social sciences is similar to that of the
biomedical sciences: to establish a body of demonstrable, replicable facts
and theory that contributes to knowledge and to the amelioration of human
problems. It is neither possible nor
necessary to draw a clean line between biomedical and behavioral research.
Some biomedical research pertains to behavior (e.g., in psychiatry, neurology,
or epidemiology), and many of the methods used in behavioral research, such
as observation and the questioning of subjects, are also used in biomedical
research. Research may be designed to evaluate the behavioral changes that
result from a biomedical intervention (e.g., lessening of depression
after taking a particular medication or changes in psychiatric disorders
following hemodialysis) or to examine physiological responses to behavioral
interventions (e.g., lowering of blood pressure through biofeedback or
weight loss through hypnosis). Some studies involve functions that are not
easily defined as either behavioral or physiological (e.g., sleep, exercise,
or diet). Thus, although it is sometimes useful to refer to biomedical or
behavioral and social research as if they involve distinct activities, there
is considerable overlap among the three areas. (While the use of such terms
as "behavioral and social research" may imply that social research
is distinct from behavioral research, this distinction generally has little
utility for the work of IRBs and is not applied here.) The questions that are
of concern to IRBs stem not from the label attached to the research but from
the nature of the interventions and the characteristics of the subjects in any
given study. It is for this reason that institutions and federal agencies are
concerned that IRB members be knowledgeable about the various types of
research reviewed by that IRB. Biomedical research employs many
methods and research designs. Studies designed to evaluate the safety,
effectiveness, or usefulness of an intervention include research on therapies
(e.g., drugs, diet, exercise, surgical interventions, or medical
devices), diagnostic procedures (e.g., CAT scans or prenatal diagnosis
through amniocentesis, chorionic villi testing, and fetoscopy), and
preventive measures (e.g., vaccines, diet, or fluoridated toothpaste).
Research on normal human functioning and development can include studies of
the human body while exercising, fasting, feeding, sleeping, or learning, or
responding to such things as stress or sensory stimulation. Some studies
compare the functioning of a particular physiological system at different
stages of development (e.g., infancy, childhood, adolescence,
adulthood, or old age). Others are directed at defining normal childhood
development so that deviations from normal can be identified. Sometimes
research, particularly records research, is used to develop and refine
hypotheses. Research on specific disease processes is often needed before
improved methods of prevention, diagnoses, and treatment can be developed (e.g.,
research on the biochemical changes associated with AIDS or schizophrenia, or
the neurological changes associated with senile dementia of the Alzheimer
type). Research on the human genome and genetic markers is expected to create
new avenues for understanding disease processes and their eventual control. Subjects of some biomedical
studies engage in ordinary tasks (e.g., exercise, learn a series of
words, or respond to various sensory stimuli) while measurements of
physiological and bodily functions are made. Although many procedures used in
biomedical research are similar to those used in routine physical
examinations, at times more invasive procedures (e.g., "spinal
taps," skin or muscle biopsies, or X-rays used in conjunction with
contrast dyes) must be used if a desired measurement is to be made. Although
research designed to generate information about normal physiology or a
disease process is not concerned with evaluating a medical intervention, it
may still require the use of invasive procedures. When the research deals
with subjects whose condition is not normal, the research can have either therapeutic
or nontherapeutic purposes. Other biomedical studies do not
involve human subjects or are exempt from the human subjects regulations,
and, therefore, do not require IRB review. This category includes research
with animals and research on preexisting samples of materials (tissue, blood,
or urine) collected for other purposes, where the information is recorded by
the investigator in such a manner that subjects cannot be identified,
directly or through identifiers linked to the subjects [Federal Policy §___.101(b)(4)]. It also
includes research based on records, when the data are recorded in such a
manner that the individuals to whom the records pertain cannot be identified,
either directly or through identifiers linked to them [Federal Policy §___.101(b)(4)]. [See
Guidebook Chapter 4,
"Considerations of Research Design."] Some biomedical studies,
particularly those conducted to evaluate new therapies or treatments, use
such rigorous experimental methods as random assignment to treatment
and control groups. Other studies, such as those directed at establishing the
normal range of some element in the blood, may involve no experimental
intervention and no assignment of subjects to groups. [See Guidebook Chapter 4, "Considerations of
Research Design."] The fact that much biomedical
research is conducted for the purpose of evaluating new therapies or
treatments leads to two problems for IRBs. The first is to some degree a
problem of IRB jurisdiction; the second is a problem of risk/benefit
assessment. The distinction between research and treatment can become blurred
in patient care settings, as well as in some educational and training
settings. This distinction raises questions of IRB jurisdiction over the
research: Is the proposed activity one that requires IRB review (pursuant
either to federal regulations or institutional policy)? A discussion of this
issue appears in the Guidebook in Chapter 1, Section A, "Jurisdiction
of the Institutional Review Board." The second distinction between research
and therapies that may pose a problem for IRBs concerns risk/benefit
assessments in research on therapies. Often, the risks of a study may seem
justified by a therapy provided as part of the study. IRBs should determine,
however, whether the anticipated therapeutic benefits would be available to
persons who are not participating in a study that presents additional risks.
As is discussed in the Guidebook Section on risk/benefit analysis [Chapter 3, Section A], such
benefits should not be used to justify risks presented by the research. The IRB's general responsibilities
in reviewing biomedical research are discussed in other chapters of the
Guidebook. [See Chapter 3,
"Basic IRB Review," and Chapter
4, "Considerations of Research Design."] Special concerns
arising in the conduct of certain types of biomedical research are discussed
in the following Sections of this chapter on "Drug
Trials," "Vaccine Trials," "Medical Devices," "Use of
Radioactive Materials and X-Rays," "HIV-Related
Research," "Transplants," "Human Genetic Research," and "Alcohol
and Drug Research." The additional IRB responsibilities that arise
when the subjects of biomedical research are other than healthy, normal
adults are set forth in Chapter 6, "Special Classes of Subjects." The scope and diversity of
research areas in the behavioral and social sciences is quite broad. Some
research is readily applicable to human affairs; other studies may broaden
understanding without any apparent or immediate application. Some research is
designed to test hypotheses derived from theory; other research is primarily
descriptive. Still other research may be directed at evaluating an
intervention or social program. Theories and methods vary both
across and within disciplines; the same problems may be approached by
researchers trained in different disciplines. For example, some research
psychologists work in laboratories studying the neurology, anatomy, and
physiology that underlies perception, learning, instinctual behavior, and
emotional responses. Other psychologists may perform survey research,
observational studies, or small group experiments that differ little from
work done by some sociologists. Within anthropology, physical anthropology
overlaps with paleontology, anatomy, and genetics, while the social or
cultural anthropologist studies the organization, institutions, and belief
and value systems of societies or groups of people. Behavioral research involving
human subjects generates data by means of questionnaires, observation,
studies of existing records, and experimental designs involving exposure to
some type of stimulus or intervention. Many variations of these four basic
methods are used. Questions may be asked in person, over the telephone, or by
means of a questionnaire. Observation may or may not be covert, and the
observer may or may not be a participant in the activity being studied.
Records studied in research may be public (e.g., vital statistics,
motor vehicle registrations, or court records) or non-public and sensitive (e.g.,
medical or educational records in which the subjects are identified).
Experimental studies may be conducted in public places, in private settings (e.g.,
a clinic or therapist's office), or in laboratories. Interventions in such
studies range from the innocuous, such as varying the package design of
commercial products, to the potentially significant, such as varying behavior
modification techniques in studying the treatment of alcoholism. Not all
behavioral research involves human subjects. Studies of human migration are
often undertaken using anonymous U.S. Census data, and much research in
behavioral psychology is done with animals. In addition, many categories of
behavioral research that do involve human subjects are exempt from the
federal regulations for protection of human subjects. [See Federal Policy §___.101.] This exemption does
not imply that investigators have no ethical responsibilities to subjects in
such research; it means only that IRB review and approval of the research is
not required by federal regulations. Most behavioral research involves
no physical intervention and no physical risk. However, some studies do
present a risk of social harm (e.g., harm to a subject's reputation,
which is sometimes a danger if confidentiality is not maintained) or
psychological harm, which may occur if the research involves deception or
provides subjects with unwelcome and disturbing information about themselves.
When deception is involved, the IRB needs to be satisfied that the deception
is necessary and that, when appropriate, the subjects will be debriefed.
(Debriefing may be inappropriate, for example, when the debriefing itself may
present an unreasonable risk of harm without a counterveiling benefit.) The
IRB should also make sure that the proposed subject population is suitable. [See
Guidebook Chapter 3, Section A,
"Risk/Benefit Analysis."] Some studies involve the
possibility of a moral wrong, which is what some commentators have labeled
the ethical problems posed by deception of subjects or invasions of their privacy.
Although some psychologists have overemphasized the value and necessity of
using deception, deception or incomplete disclosure may be the only
scientifically valid approach for certain research. An example of such
research would be a study designed to determine the effect of group pressure
(i.e., responses of others) on a subject's estimate of the length of a
series of lines. In some groups, pseudo-subjects would be told in advance to
give incorrect answers to questions about the length of the lines to
determine the effect of such misinformation on the real subjects' responses.
Obviously, if the subjects were told all about the research design and its
purpose in advance, it would not be possible to do the research. IRBs need to
determine whether any deception or invasion of privacy involved in a research
protocol is justified. Some social and behavioral
researchers are concerned that IRB judgments at times seem to be influenced
more by the subject matter of the study than by concerns about informed
consent or risks to subjects. Researchers cite examples of studies that
involve minimal risk and pose no consent questions, but that encounter
difficult with some IRBs, particularly IRBs in medical settings. Some
researchers believe that IRBs are more likely to object to research on the
behavior or values of the powerful (e.g., physicians, professors, or
managers) than to research using similar methods but on subjects of lower
status (e.g., patients, students, or workers). Other researchers
believe that IRBs sometimes perceive research on controversial topics, such
as deviant sexual behavior or fraud in science, as presenting ethical
problems because of the nature of the activity being studied, rather than
because of research methods, risks, or the rights of subjects. Still others
complain of a less specific prejudice against social and behavioral research
on the grounds that it is "soft" or concerned with trivial
questions. Some behavioral research involves
human subjects in studies of heredity and human behavior, genetics, race and
IQ, psychobiology, or sociobiology. Vigorous ethical debates about these
studies arise out of the fear that scientific data may be used to justify
social stratification and prejudice, or that certain groups will appear to be
genetically inferior. The possible use — or misuse — of research findings,
however, should not be a matter for IRB review, despite the importance of
this question. The incidence of such problems may
well have decreased because the regulations exempt much social research and
provide additional flexibility regarding informed consent. IRBs should resist
placing restrictions on research because of its subject matter; IRBs should
instead be concerned about research methods and the rights and welfare of
research subjects. IRBs must differentiate disapproving a research proposal
because of qualms about the subject being explored or its possible findings,
such as genetic differences in intelligence, from disapproving research
involving the performance of illegal or unethical acts. The former raises
serious issues of academic freedom; the latter is quite different and
appropriate. Whatever the propriety of institutional administrators
prohibiting research to protect the institutions from being associated with
controversial or sensitive subjects, it is generally agreed that this is not
an appropriate concern for an IRB, whose function is to protect human
subjects. Fieldwork, or ethnographic
research, involves observation of and interaction with the persons or group
being studied in the group's own environment, often for long periods of time.
Since fieldwork is a research process that gains shape and substance as the
study progresses, it is difficult, if not impossible, to specify detailed
contents and objectives in a protocol. After gaining access to the
fieldwork setting, the ongoing demands of scientifically and morally sound
research involve gaining the approval and trust of the persons being studied.
These processes, as well as the research itself, involve complex, continuing
interactions between researcher and hosts that cannot be reduced to an
informed consent form. Thus, while the idea of consent is not inapplicable in
fieldwork, IRBs and researchers need to adapt prevailing notions of
acceptable protocols and consent procedures to the realities of fieldwork.
IRBs should keep in mind the possibility of granting a waiver of informed
consent. Social policy experimentation
involves interventions in social or economic systems for use in planning
public policy. Such experimentation often involves studying the costs and
benefits of alternative ways of providing health, educational, or welfare
services at national, state, or local levels. Some of this research may be
exempt from IRB review under §___.101(b)(5)
of the Federal Policy. That section exempts research and demonstration
projects that are conducted by or subject to the approval of department or
agency heads, and that are designed to study, evaluate, or otherwise examine:
(1) public benefit or service programs; (2) procedures for obtaining benefits
or services under those programs; (3) possible changes in or alternatives to
those programs or procedures; or (4) possible changes in methods or levels of
payment for benefits or services under those programs. INTRODUCTION Drug trials provide the transition
from promising basic or laboratory research to helpful therapeutic or
diagnostic procedures for patients. New drugs that offer the hope of some beneficial
response in afflicted patients are first tested in animal models. But animal
trials do not necessarily demonstrate what the physiological,
pharmacological, or toxicological effects of a new drug will be in human
beings. Only by careful testing in human subjects can the safety and
effectiveness of a new drug be evaluated. The Food and Drug Administration
(FDA) is responsible for monitoring the testing of new drugs in humans, for
determining whether a new drug can be marketed, and for observing drugs after
marketing to be sure that they are safe, effective, and properly labeled [21 CFR 312 and 21 CFR 314]. See also Guidebook Chapter 4, Section H, "Clinical Trials,"
and Section J, "Assignment
of Subjects to Experimental and Control Groups." Clinical Trial: A controlled study involving human
subjects, designed to evaluate prospectively the safety and effectiveness of
new drugs or devices or of behavioral interventions. Drug: Any chemical compound that may be used on
or administered to humans as an aid in the diagnosis, treatment, cure,
mitigation, or prevention of disease or other abnormal conditions. Investigational New Drug or
Device: A drug or device
permitted by FDA to be tested in humans, but not yet determined to be safe
and effective for a particular use in the general population, and not yet
licensed for marketing. Investigator: In clinical trials, an individual who
actually conducts an investigation [21 CFR
312.3]. Any interventions (e.g., drugs) involved in the study are
administered to subjects under the immediate direction of the investigator. (See
also: Principal Investigator.) Phase 1, 2, 3, 4 Drug Trials: Different stages of testing drugs in
human, from first application in humans (Phase 1) through limited and broad
clinical tests (Phase 3), to postmarketing studies (Phase 4). Phase 1 Drug Trial:
Phase 1 trials include the initial introduction of an investigational new
drug into humans. These studies are typically conducted with healthy
volunteers; sometimes, where the drug is intended for use in patients with a
particular disease, however, such patients may participate as subjects. Phase
1 trials are designed to determine the metabolic and pharmacological actions
of the drug in humans, the side effects associated with increasing doses (to
establish a safe dose range), and, if possible, to gain early evidence of
effectiveness; they are typically closely monitored. The ultimate goal of
Phase 1 trials is to obtain sufficient information about the drug's
pharmacokinetics and pharmacological effects to permit the design of
well-controlled, sufficiently valid Phase 2 studies. Other examples of Phase
1 studies include studies of drug metabolism, structure-activity
relationships, and mechanisms of actions in humans, as well as studies in
which investigational drugs are used as research tools to explore biological
phenomena or disease processes. The total number of subjects involved in
Phase 1 investigations is generally in the range of 20-80. Phase 2 Drug Trial:
Phase 2 trials include controlled clinical studies conducted to evaluate the
drug's effectiveness for a particular indication in patients with the disease
or condition under study, and to determine the common short-term side effects
and risks associated with the drug. These studies are typically
well-controlled, closely monitored, and conducted with a relatively small
number of patients, usually involving no more than several hundred subjects. Phase 3 Drug Trial:
Phase 3 trials involve the administration of a new drug to a larger number of
patients in different clinical settings to determine its safety,
effectiveness, and appropriate dosage. They are performed after preliminary
evidence of effectiveness has been obtained, and are intended to gather
necessary additional information about effectiveness and safety for
evaluating the overall benefit-risk relationship of the drug, and to provide
an adequate basis for physician labeling. In Phase 3 studies, the drug is
used the way it would be administered when marketed. When these studies are
completed and the sponsor believes that the drug is safe and effective under
specific conditions, the sponsor applies to FDA for approval to market the
drug. Phase 3 trials usually involve several hundred to several thousand
patient-subjects. Phase 4 Drug Trial:
Concurrent with marketing approval, FDA may seek agreement from the sponsor
to conduct certain postmarketing (Phase 4) studies to delineate additional
information about the drug's risks, benefits, and optimal use. These studies
could include, but would not be limited to, studying different doses or schedules
of administration than were used in Phase 2 studies, use of the drug in other
patient populations or other stages of the disease, or use of the drug over a
longer period of time [21 CFR §312.85]. Principal Investigator: The scientist or scholar with primary
responsibility for the design and conduct of a research project. (See also:
Investigator.) Sponsor: A person or entity that initiates a
clinical investigation of a drug — usually the drug manufacturer or research
institution that developed the drug. The sponsor does not actually conduct
the investigation but rather distributes the new drug to investigators and
physicians for clinical trials. The drug is administered to subjects under
the immediate direction of an investigator who is not also a sponsor. A
clinical investigator may, however, serve as a sponsor-investigator. The
sponsor assumes responsibility for investigating the new drug, including
responsibility for compliance with applicable laws and regulations. The
sponsor, for example, is responsible for obtaining FDA approval to conduct a
trial and for reporting the results of the trial to the FDA. Sponsor-Investigator: An individual who both initiates and
actually conducts, alone or with others, a clinical investigation.
Corporations, agencies or other institutions do not qualify as
sponsor-investigators. Once a chemical (drug) is
identified as having a potential effect on a disease state, it is subjected
to testing in animals. Initial animal tests are designed to see whether the
chemical has any desired drug effects, what dosage levels are poisonous, what
the safe dosage range might be in humans, and whether there is a reason to
test the chemical in humans. Additional animal tests may be required as human
tests progress. If initial animal tests indicate that the drug can be safely
tested in humans and that the chemical may be therapeutically useful, the
drug sponsor will submit an Investigational New Drug Application (IND) to the
FDA. In the IND, the sponsor must describe the complete composition of
the drug, its source, and how it is made. In addition, the sponsor must
submit the results of all animal studies that support the drug's potential
usefulness in humans and that define its toxicity in animals. The data should
indicate that no human subject will be exposed to an unreasonable risk.
The IND must also include a protocol describing the plan for testing
in humans. To permit the FDA to review the materials and make sure subjects
will not be exposed to unreasonable risks, the sponsor may not begin clinical
tests for 30 days after submitting the IND. At the end of that period, the
sponsor may begin the proposed clinical trial unless the FDA has asked for a
delay because of a potential safety problem involving use of the drug. Clinical trials are conducted by clinical investigators
(usually physicians) who have entered into an agreement with a sponsor to
conduct the study. All physicians administering an investigational drug
agree to conditions regarding the conduct of the study outlined by FDA
regulations. Clinical investigators agree to these conditions by signing an
FDA form that certifies that the investigator has obtained IRB review and
approval prior to conducting the study. Investigational new drugs may be
available outside of a clinical trial, through a treatment protocol, to
patients with life-threatening or other serious diseases for which no
satisfactory alternative drug or other therapy exists. Established by the FDA
in 1987, the Treatment Investigational New Drug exemption (Treatment IND) is
a treatment protocol that is added to an existing IND. The Treatment IND
allows physicians to treat qualifying patients according to the protocol.
Treatment INDs are discussed in greater detail in Guidebook Chapter 2, Section B, "Food and Drug
Administration Regulations and Policies." For further information concerning
human subjects research to which FDA regulations apply, contact: Mr. Richard M. Klein In reviewing proposed drug
research, IRBs must first consider whether the protocol is scientifically
sound. Since this decision is not the IRB's primary concern, however, an IRB
may rely on the FDA, institutions, scientific review committees, funding
agencies (e.g., NIH), or others for this determination. [See
the Introduction to Guidebook Chapter
4, "Considerations of Research Design" for a discussion of this
question.] Evaluating the risks and benefits of drug trials requires IRBs to
consider many aspects of the study design, paying special attention to the study
population, the trial phase, and mechanisms for data analysis and
surveillance. Risk/benefit analysis and review of the procedure for obtaining
informed consent must be performed in all IRB reviews. [See
Guidebook Chapter 3, Section A,
"Risk/Benefit Analysis," and Chapter 3, Section B, "Informed
Consent."] In addition, subjects participating in studies involving
investigational drugs must be told that the FDA may have access to their
medical records as they pertain to the study. The obligation of IRBs and
investigators to assure that subjects understand the purposes, methods, and
possible hazards of the research is more difficult to fulfill when
prospective subjects are seriously ill and in need of therapy. The consent
process may require additional efforts and attention for research involving
particularly vulnerable subjects such as the seriously ill. [See Chapter 6,
Section G, "Terminally Ill Patients."] Phase 1 trials are historically safest because they
usually involve administering a single dose to healthy volunteers. However,
Phase 1 trials may pose the highest level of unknown risk because they
involve the drug's first administration to humans. (With highly toxic drugs
such as cancer chemotherapies, Phase 1 trials are usually conducted with
cancer patients as subjects.) Insofar as possible, risks should be identified
from previous laboratory experiments and animal trials. The FDA, which reviews
Phase 1 trials submitted in the initial IND application, may have valuable
information and recommendations on particular protocols. Subjects in Phase 2 trials
are usually patients with the condition that the new drug is intended to
detect or treat. IRBs should recognize that although Phase 2 testing is
preceded by earlier clinical trials, the physiological responses of healthy
volunteers to a therapeutic drug may not be reliable indicators of how safe
the drug is for persons who are ill, taking other medication, or have
immunodeficiencies. Since the primary purpose of a Phase 2 trial is to test
the drug's effectiveness in achieving its purpose, the responses of subjects
receiving the drug are usually compared with those of subjects who are not
receiving the drug (control subjects). Whether control subjects
receive some existing therapy or a placebo is a research design issue
with serious ethical implications. Where an alternate safe and effective drug
is available for a serious condition being studied, it should generally be
given to the control subjects; however, existing therapies may be inadequate
because they are of limited effectiveness against the disease, they have
relatively high levels of toxicity, or because they are inconvenient to
administer. When determining the acceptability of a proposed research design,
IRBs must examine the risks and effectiveness of existing therapies, as well
as the risks associated with providing no therapy (or a placebo). [See
Chapter 4, "Considerations of
Research Design."] While most drug trials involve
agents that the FDA has not yet approved for marketing, some drugs may be the
subject of further testing concurrent with or following FDA approval.
Post-marketing investigations, also called Phase 4 trials, are
conducted to develop further information about the article's safety or
effectiveness. Such studies might, for example, seek to establish the safety
or effectiveness of using the drug for a new indication, with a new dosage
level or a new route of administration [21
CFR §312.85]. Phase 4 studies should be
distinguished from use of a marketed product by a physician for an indication
not in the approved labeling as part of the "practice of medicine."
Investigational use of a marketed product differs from such uses by
physicians in that the principal intent of the investigational use of a test
article is to develop information about its safety or efficacy; the
submission of an IND or IDE may therefore be required. The
criteria for submission of an IND or IDE for investigational use of a
marketed product is described in the FDA's IRB Information Sheet
entitled, "Investigational Use of Marketed Products," (1989, pp.
70-71). Throughout drug trials, the
distinction between therapy and research must be maintained. A physician who
participates in research by administering a new drug to consenting patients
must ensure that the patients understand and remember that the drug is
experimental, and that its benefits for the condition under study are
unproven. Furthermore, whereas the principal investigator's primary
allegiance is to the protocol, the physician's allegiance is to the patient.
Where an individual is both an investigator and the subject's treating
physician, these two allegiances may conflict. The subject must recognize
that the person with whom he or she is dealing may have such conflicting
interests. The IRB should be aware of the need to inform the patient of the
potential conflict. If the trial is to collect
accurate and timely data concerning the drug's safety and effectiveness,
procedures for identifying positive and negative responses to the drug should
be in place, and all participating physicians should be well integrated into
a reporting system. The principal investigator is responsible for keeping all
subjects informed of material changes in the design and conduct of the
research, and must communicate new information that might affect their
willingness to continue as subjects [Federal
Policy §___.116]. The IRB may assist the investigator in deciding when
information from accumulating data should be disclosed to participating or
prospective subjects. The disclosure of information gained during the conduct
of the trial is especially important with patients entering a study when it
is nearing completion. As part of their determination of
the appropriate methods for conducting continuing reviews of ongoing studies,
IRBs should be aware of the arrangements made for monitoring the study
results. In FDA-regulated clinical investigations, arrangements for data
monitoring are the sponsor's responsibility. The sponsor may designate an
independent person or group (often called a data and safety monitoring
board) to assume this responsibility. An IRB may function in such a
capacity; however, most IRBs do not have the necessary expertise. Independent
monitoring is most appropriate when the study is double-masked (i.e.,
neither the subjects nor the investigators know which drug a subject is
receiving) or if the trial is multicentered. Ongoing monitoring of drug
trials includes review of data on therapeutic effects, side effects and the
effects of any changes in the study design. [See also Guidebook
Chapter 3, Section E,
"Monitoring and Observation."] Sponsors must notify the FDA and
all participating investigators of any adverse experiences associated with the
use of an investigational new drug that is both serious and unexpected [21 CFR 312.32]. Occasionally, hazards are
discovered after a trial is concluded. If the drug has since been marketed,
the FDA and the drug manufacturer are usually responsible for notifying users
and physicians. 1. Is the proposed research
scientifically sound? 2. Has sufficient information been
obtained from the literature, experimental and animal studies, and the FDA to
define, as far as possible, the potential risks of and the precise need for
studies involving human subjects? 3. Does the principal investigator
have the appropriate qualifications, experience, and facilities to ensure
that all aspects of the trial and follow-up will be conducted rigorously and
with due regard for the safety and well-being of the subjects? 4. Have appropriate measures been
adopted to ensure that subjects understand the objectives and consequences,
particularly the risks, of their participation? 5. Are sufficient safeguards
provided to ensure the confidentiality of data generated during
research? 6. Are adequate procedures
provided for the ongoing surveillance of the drug's effectiveness and safety,
and for notifying subjects and physicians of significant risks? 7. Has appropriate FDA review and
clearance been obtained? APPLICABLE LAWS AND REGULATIONS Federal Policy for the protection
of human subjects 21 CFR 50 [FDA: Informed
consent] INTRODUCTION Vaccines are used to prevent
infectious diseases. Successful vaccine trials have resulted in the
development of safe and effective vaccines for polio, measles, rubella, hepatitis
B, pneumococcal pneumonia, and other serious diseases. Currently, vaccines
are being evaluated to prevent infectious diseases such as AIDS (or
transmission of HIV), malaria, tuberculosis, trachoma, cytomegalovirus,
herpes simplex, and influenza. Vaccines must undergo clinical testing prior
to approval and licensure by the FDA. The regulations governing the
conduct of clinical trials on investigational vaccines are the same as those
governing the conduct of investigational new drug research [see
Guidebook Chapter 5, Section B, "Drug Trials"];
however, the risks and benefits associated with vaccine trials
may differ from those of drug trials. A vaccine is a biologic; its use
in trials involving human subjects is similar to the use of any drug.
Vaccines do, however, differ from therapeutic drugs in two important ways. As
used here, they are not designed to diagnose or cure disease in afflicted
individuals; their purpose is to prevent a particular disease in healthy
human beings. Vaccines are also used to protect people with a high
statistical risk for contracting a particular disease or for suffering
especially serious consequences from a disease. Vaccines trigger the body's
normal immune response, producing antibodies that protect against future
infection. Some vaccines (e.g., those containing active microorganisms
or live-attenuated vaccines) have a small but real disease-producing
capacity. Thus, one rare risk of a new vaccine is the possibility of
infecting a healthy subject with the very disease researchers are seeking to
prevent. More often, however, subjects involved in vaccine trials temporarily
suffer from some of the symptoms and effects of the disease (e.g.,
polio, German measles) as they acquire immunity.
The development of vaccines is of
considerable benefit to society, especially in the case of devastating or
highly infectious diseases. The direct benefit to the individual subject
receiving a new vaccine is the possibility of immunity (i.e.,
protection against future disease). The benefits of such immunity will vary
depending on: (1) the severity of the disease to be avoided; (2) the
likelihood that the subject will be exposed to the infectious disease; and
(3) in the case of certain diseases, the likelihood that the subject would
suffer adverse consequences should he or she contract the disease. Some
populations will be at greater risk of contracting an infectious disease than
others, either because they are more likely to be exposed to the disease or
because they have an increased susceptibility to it. Among those who contract
an infectious disease, there may be some sub-groups that are particularly
vulnerable to adverse consequences (e.g., children, persons of
advanced age, or persons suffering from other illnesses). For most diseases, participation
in vaccine trials carries the generally small risk of contracting the
disease. [In some vaccine trials (e.g., HIV) there is no such risk. In
the case of HIV vaccine research, the lack of risk is due to the manner in
which the vaccine is derived.] The risks of participating in a vaccine trial
also include adverse effects unrelated to the disease in question (e.g.,
slight fever, headache, muscle soreness, or muscle aches). Such side effects
are usually short-lived, tolerable, and not life-threatening. Again, the
degree of risk associated with participating in a vaccine trial varies
depending on the subjects' vulnerability to the adverse side effects of the
vaccine. Some subjects may have an allergic or anaphylactic (i.e., a
decrease rather than an increase in immunity) reaction to the vaccine.
Anaphylactic reactions to vaccines cause the recipient to be hypersusceptible
to the disease. Such reactions are generally unpredictable, and may be
serious or potentially life-threatening. The IRB should be aware of other
risks associated with vaccine trials, including the possibility that vaccines
produced synthetically or using recombinant DNA techniques may present risks
as yet unknown, that groups often most likely to benefit from receiving a
vaccine are often the most vulnerable to coercion (e.g.,
institutionalized persons or children), and that subjects in control groups
may erroneously assume that they have been immunized. When determining whether the risks
are reasonable in relation to the benefits, IRBs should consider the severity
of the disease, the risk of contracting the disease, and any special
vulnerability of the subject population to the potential adverse effects of
the vaccine. The most difficult cases are those in which the subjects most
likely to benefit from participating in the vaccine trial are also the
subjects at the greatest risk of suffering from the vaccine's potential
adverse effects. Some of the risks inherent in
vaccine trials can be minimized. Before a vaccine is approved for testing
with human subjects, IRBs should receive satisfactory evidence that animal
trials and laboratory tests have, to the extent possible, demonstrated its
safety. Since the sponsor must submit such information to the FDA as part of
its investigational new drug application (IND), IRBs can readily obtain
evidence of safety as well. Mechanisms for protecting human
subjects from some risks can be built into the vaccine study design. For
example, with careful screening, investigators can avoid enrolling persons
who may be susceptible to certain adverse reactions. Furthermore, trials can
be designed to involve subjects who are most likely to be exposed to the
infectious agent and who stand to benefit most from the protection afforded
by the vaccine. Selecting subjects in this way avoids exposing those who may
not be in need of its protective benefits to the risks of the vaccine. In
many situations, however, Phase 1 trials should be designed to
evaluate low risk subjects. For example, an effective hepatitis B vaccine
already exists. It would therefore be appropriate to determine that an
investigational vaccine for hepatitis B is immunogenic in humans prior to use
in high risk subjects. Vaccine trials require careful
monitoring of human subjects for both immune status and adverse reactions.
The monitoring reflects the dual goals of any trial to determine both the
effectiveness and the safety of the investigational substance or device.
Although subjects in vaccine trials should be advised beforehand of known or
anticipated side effects, rare or unknown reactions may occur. FDA
regulations require that subjects be provided with written instructions about
whom to contact in the event of serious adverse reactions or research-related
injury. IRBs should also be aware that
large-scale field trials of a vaccine may involve many thousands of subjects,
making monitoring difficult. The IRB should make sure that the sponsor has
made provisions for monitoring the progress of the research, the immune
status of participants, and side effects reported. Maintaining careful
records is important both for monitoring the safety and effectiveness of the
vaccine and for locating subjects for follow-up. If a vaccine either does not
immunize the subject or does so for too limited a time, subjects may
erroneously assume they are protected and fail to seek necessary medical
attention. In addition, members of a control group may (incorrectly)
assume they are immune from the disease because they believe they have
received an effective vaccine (which they have not). IRBs sometimes require
that control group subjects be given the first opportunity to receive the
vaccine once its safety and effectiveness have been established. If such
arrangements are not part of the research design, at the end of the trial
control subjects should be informed of both their status vis a vis the
vaccine, and the outcome of the trial: e.g., that the vaccine was
shown to be safe and effective, but that they either did not receive the
vaccine or did not receive an effective dose of the vaccine. For a discussion of ethical issues
related to the clinical testing of AIDS vaccines, see Guidebook Chapter 5, Section F, "AIDS/HIV-Related Research." 1. Has appropriate FDA clearance
and an approved IND been obtained? 2. Is there evidence that the
vaccine has been adequately tested in animal trials and in the laboratory? 3. Where appropriate, are subjects
clearly told in the consent process that they might receive a placebo or
ineffective dose of the vaccine, and thus may not be protected against the
disease? 4. Does the protocol provide
adequate plans to monitor all subjects for immune status and adverse
reactions, respond to problems, and disseminate results? 5. Will subjects be informed about
what to do and whom to contact in case of a serious adverse reaction or
research-related injury? APPLICABLE LAWS AND REGULATIONS Federal Policy for the protection
of human subjects 21 CFR 50 [FDA: Informed
consent] Comprehensive federal regulations
governing investigations involving medical devices are comparatively new.
In addition to their other duties, IRBs reviewing certain device
investigations must also determine whether a device study presents a
significant or nonsignificant risk to the human subjects participating in the
study. When making determinations of significant versus nonsignificant risk,
IRBs must consider not only the risks associated with use of the device
itself, but also the risks associated with the investigational device study
as a whole. 510(k) Device: A
medical device that is considered substantially equivalent to a device that
was or is being legally marketed. A sponsor planning to market such a device
must submit notification to the FDA 90 days in advance of placing the device
on the market. If the FDA concurs with the sponsor, the device may then be
marketed. 510(k) is the section of the Food, Drug and Cosmetic Act that
describes premarket notification; hence the designation "510(k)
device." General Controls:
Certain FDA statutory provisions designed to control the safety of /marketed
drugs and devices. The general controls include provisions on adulteration,
misbranding, banned devices, good manufacturing practices, notification and
record keeping, and other sections of the Medical Device Amendments to the
Food, Drug and Cosmetic Act [21 U.S. Code §360(c) (Food, Drug and Cosmetic
Act §513)]. Investigational Device Exemptions (IDE): Exemptions from certain regulations found
in the Medical Device Amendments that allow shipment of unapproved devices
for use in clinical investigations. Medical Device: A
diagnostic or therapeutic article that does not achieve any of its principal
intended purposes through chemical action within or on the body. Such devices
include diagnostic test kits, crutches, electrodes, pacemakers, arterial
grafts, intraocular lenses, and orthopedic pins or other orthopedic
equipment. Nonsignificant Risk Device: An investigational medical device that does not present significant
risk to the patient. (See also: Significant Risk Device.) Postamendments Devices: Medical devices marketed after enactment of the 1976 Medical Device
Amendments. Preamendments Devices:
Medical devices marketed before the enactment of the 1976 Medical Device
Amendments. Predicate Devices:
Currently legally marketed devices to which new devices may be found
substantially equivalent under the 510(k) process. Premarket Approval:
Process of scientific and regulatory review by the FDA to ensure the safety
and effectiveness of Class III devices. Significant Risk Device: An investigational medical device that presents a potential for
serious risk to the health, safety, or welfare of the subject. Such a device
is: • intended for use as an implant and presents a potential for serious
risk to the health, safety, or welfare of the subject; or The 1976 Medical Device Amendments
(the Amendments) to the Federal Food, Drug and Cosmetic Act (the Act) were
passed to give the FDA additional authority to assure safety and
effectiveness in devices intended for human use. New medical devices must be
cleared by the FDA prior to being placed on the market. As part of the
clearance process, all medical devices are classified into one of three
categories by the FDA based on the extent of control necessary to ensure the
safety and effectiveness of each device [21 U.S. Code §360(c) (Food, Drug and
Cosmetic Act §513)]. Medical devices are classified as
Class I, Class II, or Class III devices depending on several criteria.
Devices are classified as Class I medical devices if their safety and
effectiveness can be assured by the general controls of the Amendments. The
general controls include the provisions of the Act pertaining to
adulteration, misbranding, banned devices, notification, repair, replacement
or refund, records and reports, and restricted devices. In addition, general
controls require device manufacturers or other designated persons, unless
specifically exempted, to register their establishment, list their device,
submit a premarket notification application, and be in compliance with the good
manufacturing practices (GMPs). If a device cannot be classified as a Class I
device because the general controls are insufficient to provide reasonable
assurance of the safety and effectiveness of the device, the device may
qualify for Class II classification. A Class II device must comply with
general controls, and, in addition, the sponsor must provide sufficient
information about the device to establish special controls that are
sufficient to provide such assurance. Examples of special controls include
the promulgation of performance standards, postmarket surveillance, the
establishment of patient registries, and the development and dissemination of
guidelines. Devices are classified as Class
III devices when: (1) their safety and effectiveness cannot be reasonably
assured through either general or special controls; and (2) they are
life-sustaining, life-supporting, implanted in the body, or of substantial
importance in preventing impairment to health. A new device that a manufacturer
claims is substantially equivalent to a currently legally marketed device may
be marketed after the FDA is notified of the intent to market, and the agency
concurs with the manufacturer's claim of equivalence to other marketed
devices. If the FDA determines that the new device is not substantially
equivalent to a predicate device, the new device is automatically
placed in Class III, and the manufacturer must obtain premarket approval
from the FDA. Alternatively, the sponsor (or others) may petition the FDA to
reclassify the device into Class I or II. Investigational devices are
medical devices that are the object of clinical research to determine their
safety or effectiveness. Clinical investigations are necessary to support a
request for premarket approval. Studies involving human subjects that are
undertaken to develop safety and effectiveness data for medical devices must
be conducted according to the requirements of the Investigational Device
Exemption regulations [21 CFR 812] or
Investigational Exemptions for Intraocular Lenses [21 CFR 813]. An approved
IDE exempts a device from certain sections of the Act (e.g.,
misbranding under §502; registration, listing, and premarket notification
under §510; special controls under §513; premarket approval under §515;
banned devices under §516; records and reports under §519; restricted devices
under §520(e); good manufacturing practices under §520(f); and color additive
requirements under §706). The IDE regulation describes two
types of device investigations: significant risk device studies and nonsignificant
risk device studies. Clinical trials involving significant risk devices
require both FDA and IRB approval; sponsors must meet the full IDE
requirements, including obtaining an FDA-approved IDE. Approval of studies
involving nonsignificant risk devices require only IRB approval; no IDE is
required to be formally submitted to the FDA. However, the sponsor must
comply with the abbreviated regulatory requirements for such devices [21 CFR 812.2(b)]. The FDA may overturn
IRB determinations that a device presents no significant risk. In reviewing studies involving
medical devices, IRBs should recognize that they must make two determinations:
(1) whether a device study presents significant or nonsignificant risk; and
(2) whether the study should be approved. These questions should be
considered separately because the issues involved in making these decisions
are quite different. Determining whether a device study poses a significant
risk is based solely on considerations of risk to subjects, while IRB
approval of the study is based on many factors. The discussion in this
Section first considers IRB determinations of significant risk. The FDA reviews and approves IDEs
for significant risk device studies; it exercises less regulatory control
over nonsignificant risk device studies. The initial responsibility for
making the nonsignificant risk assessment for studies lies with the sponsor.
If the sponsor believes that a particular device study presents a
nonsignificant risk, the sponsor should provide the IRB with the study
proposal, an explanation of why the device study presents a nonsignificant
risk, and any other supporting information, such as reports of prior
investigations. The sponsor should also tell the IRB whether the FDA or any
other IRB has made a risk assessment and what the results of those
assessments were. The IRB reviews the information, and may or may not agree
with the sponsor's determination. If the IRB finds that the device study
presents a nonsignificant risk, the investigation may begin without
submission of an IDE application to the FDA. If the IRB disagrees with the
sponsor's determination that a device study presents nonsignificant risk to
human subjects, the sponsor must so notify the FDA, whether or not the
sponsor ultimately conducts the study at that institution. If the study comes to the
attention of the FDA, the agency's Office of Device Evaluation may reach a
different conclusion on the risk presented by a device study than that
reached by the IRB. If the FDA overrules an IRB's decision that a device
study presents nonsignificant risk, the sponsor must then submit an IDE
application to the FDA. The IRB must then review the investigation as a
significant risk device study, and the investigator will be subject to more
stringent recordkeeping and reporting requirements. In determining whether a device
study presents a significant or a nonsignificant risk, both the risks of the
device and the risks associated with the procedure for using the device (e.g.,
surgery for installing an implant) must be considered. The comparison of
risks is the basis for the other decision the IRB must make: whether to
approve the research. The clinical investigator should
provide the IRB with adequate information about a device's regulatory status
and the results of any risk assessment the FDA may have made. The IRB may
also ask the sponsor whether other IRBs have reviewed the study and what
determinations were made. IRBs may also request the sponsor or clinical
investigator to provide documentation of appropriate FDA clearances, and may
consult the FDA for its opinion on risk. In the past, clinical
investigations of intraocular lenses (IOLs) differed from other medical
device studies in that there were few restrictions on the total number of
subjects in an IOL investigation. Unlimited "adjunct" studies were
phased out when enough approved IOLs became commercially available. IOL
studies are now limited in enrollment size, as are other medical device
studies. Clinical investigations involving
IOLs that commenced before July 27, 1981, are exempt from investigational
device requirements [21 CFR 812],
since they are subject to specific regulations on intraocular lenses [21 CFR
813], which specify procedures for IRB review and informed consent. The IRB's second responsibility is
to decide whether to approve the proposed research. In general, full IRB
review is required for both significant and nonsignificant risk studies.
However, some studies involving nonsignificant risk devices may also be
considered minimal risk studies, and thus may be reviewed through the
expedited review procedure established by the IRB. IRBs need to keep in mind the
difference between the risk/benefit evaluation made in the context of
approving the research and the IRB's assessment of whether use of the device
poses significant or nonsignificant risk. The latter decision categorizes the
degree of risk of harm based upon the seriousness of the harm that may result
from the use of the device; the former is a balancing of those risks (plus
the risks of the research process) against the potential benefits to be
gained from conducting the research. The criteria for deciding whether
a medical device study should be approved are the same as those used to
evaluate research involving any FDA-regulated product. The IRB should
determine that risks to subjects are minimized and are reasonable in relation
to anticipated benefits and knowledge to be gained, that subject selection is
equitable, informed consent procedures and documentation are adequate, and
that provisions for monitoring the study and protecting subjects' privacy and
confidentiality of data are acceptable. As in other clinical investigations,
an IRB's decision to approve the research must take into account the risks
and benefits of the investigational device as compared with the other
available therapies. However, the IRB should not simply consider the increase
in risk over standard treatment, but rather the risk of the procedure as a
whole. For further information and
guidance on studies involving medical devices, contact: Dr. Michael J. Blackwell Mr. Richard M. Klein 1. What risks are presented by the
device? Are they significant or nonsignificant? 2. Have other IRBs reviewed and
made decisions regarding this device? (Such information should be available
from the sponsor or clinical investigator.) 3. What is the status of the
device with the FDA? Has the device been approved for marketing? Is the
device approved for other indications? Is it now being studied for a different
indication? Is an IDE needed for this device? If so, has it been approved? APPLICABLE LAW AND REGULATIONS Federal
Policy for the protection of human subjects The Food, Drug and Cosmetic Act,
as amended [codified at U.S. Code, Title 21] The Medical Device Amendments of
1976 [P.L. 94-295, 90 Stat. 539 (May 28, 1976)] The Safe Medical Devices Act of
1990 [P.L. 101-629] 21 CFR 50 [FDA: Informed consent] E. USE OF RADIOACTIVE MATERIALS AND
X-RAYS INTRODUCTION Radiopharmaceuticals and X-rays
are widely used in medicine today for both diagnostic and therapeutic
purposes. Certain aspects of human physiology can only be studied through exposure
to radiation, or can be studied more safely by radiation than by alternative
methods. The types of radiation used most
frequently in medical investigations and treatments are X-rays, gamma rays,
and beta radiation. In addition to passing X-rays through the body to produce
an image, some procedures use contrast agents to outline or define the shape
of internal structures, or to image metabolic processes. Nuclear medicine
uses procedures in which radioactive materials (i.e.,
radiopharmaceuticals) are injected, ingested, or inhaled into the body. Most
medical institutions have a radiation safety committee responsible for
evaluating the risks of medical projects involving radiation and limiting the
radiation exposure of employees and patients. Nevertheless, IRBs should have
an understanding of radiation and its biological effects so they can evaluate
the relative risks and benefits of research proposals utilizing radioactive
materials or X-rays. Radioactive Drug:
Any substance defined as a drug in §201(b)(1) of the Federal Food, Drug and
Cosmetic Act that exhibits spontaneous disintegration of unstable nuclei with
the emission of nuclear particles or photons [21 CFR 310.3(n)]. Included are
any nonradioactive reagent kit or nuclide generator that is intended to be
used in the preparation of a radioactive drug and "radioactive
biological products," as defined in 21 CFR 600.3(ee). Drugs such as
carbon-containing compounds or potassium-containing salts containing trace
quantities of naturally occurring radionuclides are not considered
radioactive drugs. Radioactive Drug Research Committee (RDRC): An FDA-approved institutional committee
responsible for the use of radioactive drugs in human subjects for certain
research purposes [21 CFR 361.1]. Research
involving human subjects that proposes to use radioactive drugs must be
approved by the RDRC and must meet various FDA requirements, including
limitations on the pharmacological dose and the radiation dose. The research
must be basic research, not intended for diagnosis or treatment of a disease.
Furthermore, the exposure to radiation must be justified by the quality of
the study and the importance of the information it seeks to obtain. The
committee is also responsible for continuing review of the drug use to ensure
that the research continues to comply with FDA requirements, including
reporting obligations. The committee must include experts in nuclear medicine
as well as other medical and scientific members. Radiopaque Contrast Agents: Materials that stop or attenuate radiation that is passed through
the body, creating an outline on film of the organ(s) being examined.
Contrast agents, sometimes called "dyes," do not contain
radioisotopes. When such agents are used, exposure to radiation results only
from the X-ray equipment used in the examination. The chemical structure of
radiopaque contrast agents can produce a variety of adverse reactions, some
of which may be severe — and possibly life-threatening — in certain individuals. Radiopharmaceuticals:
Radioactive drugs that are labeled or tagged with a radioisotope. These
materials are largely physiological or subpharmacological in action, and, in
many cases, function much like materials found in the body. The principal
risk associated with these materials is the consequent radiation exposure to
the body or to specific organ systems when they are introduced into the body. REM: Acronym for
Roentgen Equivalent in Man; the unit of measurement for a dose of an ionizing
radiation that produces the same biological effect as a unit of absorbed dose
(1 rad) of ordinary X-rays. One millirem is equal to 1/1000 of a rem. The quantity of natural background
radiation to which we are exposed varies considerably (e.g., radiation
exposures are much lower at sea level than they are at higher altitudes). The
average annual natural background radiation from all sources in the United
States is approximately 100 to 125 millirems (mrem) per year, while some
individual exposures may be more than 400 mrem per year. Diagnostic medical
procedures are the most likely source of additional radiation exposure.
Estimates suggest that medical procedures increase the total exposure by 50
to 70 mrem per person per year. Experts disagree, however, over the
fundamental concepts that affect how radiation risks from medical procedures
and other sources are estimated. The disagreements include debate about the
existence of a theoretical threshold level below which no harmful effects
occur. The National Council for Radiation Protection and Measurement (NCRPM)
takes the position that there is no absolutely safe radiation dose.
Generally, only approximations of risk from exposure are available; they are
based on extrapolations from known exposures to high levels of radiation. The
NCRPM has recommended dose standards; the Nuclear Regulatory Commission (NRC)
has established occupational dose limits. The occupational dose limits vary
according to the part of the body exposed to radiation. The NRC is responsible for those
radioactive materials considered to be "source material,"
"byproduct material," or "special nuclear material" [10
CFR Parts 30, 40, and 70]. The NRC directly regulates these materials in 21
states; the other 29 states, known as "Agreement States," have
entered into an agreement with the NRC to regulate uses within their states
of byproduct material, source material, or special nuclear material involving
less than certain quantities. Agreement States may have unique policies or
standards concerning the use of radioactive materials in research that could,
in some cases, be more restrictive than those of the NRC. Naturally-occurring
or accelerator-produced radioactive materials (NARM), such as Thallium-201,
are not covered by the Atomic Energy Act; therefore they are not regulated by
the NRC. Those radioactive materials (NARM) may be dealt with under specific
state regulations (in both Agreement States as well as non-Agreement States)
governing the use of radioactive materials. The FDA requires investigators to
submit an Investigational New Drug Application (IND) for radioactive drugs,
kits, or generators that are to be used for investigational diagnostic or
therapeutic purposes (including testing to establish their safety and
effectiveness). An exception is made for radioactive drugs to be used in
certain research designed to study the metabolism of the drug or to gather
information about human physiology, pathophysiology, or biochemistry, but not
intended for immediate therapeutic, diagnostic, or similar purposes [21 CFR 361.1]. If the radiation dose will not
exceed the limits set forth in these regulations, the study design meets
other research criteria, and the protocol is approved by a Radioactive Drug
Research Committee (RDRC), the investigator does not need to submit an IND.
Current radiation limits for the use of such drugs in research (including
radiation doses from X-ray procedures that would not have occurred but for
the study) are as follows [21 CFR 361.1]: • For an adult research subject, radiation to the whole body, active
blood-forming organs, the lens of the eye, or the gonads may not exceed a
single dose of 3 rems or an annual cumulative dose of 5 rems. [See also 21 CFR 312.2(b), providing certain
exemptions from IND application requirements.] In addition to the RDRC, most
medical institutions also have an Institutional Radiation Safety Committee,
which assesses the risks that may be associated with exposure to radiation,
both for research subjects and employees. In some states or institutions,
review by the Radiation Safety Committee is mandated by law or policy; in
others, the committee's review is offered as an opinion to the IRB to help it
assess the risks and benefits of a given study involving radiation exposure. An IRB should distinguish between
radiation exposure resulting from routine medical management of a patient and
radiation exposure that is part of research, including a clinical
investigation. Although the occupational dose limits may not necessarily be
appropriate when applied in a research setting, they do provide some guidance
when exposure to radiation for research purposes is contemplated. The likelihood of adverse effects
associated with radiation exposure is generally considered to be low, but
adverse effects can be serious when they do occur. Some effects rarely present
themselves until many years after the subject has been exposed to radiation.
The two adverse effects most commonly associated with radiation exposure are
certain types of cancer and genetic damage. The increased risk of genetic
damage is of particular concern because exposure to radiation may involve
substantial risk to the subject's unborn offspring. When the proposed
research poses risk of genetic damage, an IRB should pay particular attention
to the subject selection criteria. The human embryo is known to be
particularly susceptible to damage from exposure to radiation; research
involving pregnant or possibly pregnant women has therefore been of
particular concern. Pregnancy tests could be required where doubt exists as
to the presence of pregnancy, or the subject might be asked to use an
effective contraceptive method during the course of the research. [See
Guidebook Chapter 3, Section C,
"Selection of Subjects," and Chapter 6, Section B, "Women."]
Recent studies have suggested that male sperm cells are also adversely
affected by radiation. Thus, no radiation dose should be considered risk-free
if it is directed toward, or absorbed by, the reproductive organs. Research involving radiation may
also pose risks to lab personnel, nursing staff, and family members. This
increased risk usually results from exposure to nuclear sources of radiation
used in a medical device or nuclear medicine or radiotherapy. For example,
when nuclear-powered artificial heart implants were under consideration, a
federal panel expressed concern over the possible exposure and resultant risk
to the patient's spouse. Additional risk may be associated
with the intravascular administration of contrast agents used in X-ray
procedures (e.g., intravenous pylograms (IVP), venograms, and cardiac
catheterizations). The risks vary depending on the dose of the contrast
agents, the chemical nature of the contrast agent used, and the age and
disease state of the subject. Conditions such as advanced age, renal disease,
diabetes, cardiac, or cerebrovascular disease, asthma, or chronic obstructive
pulmonary disease may greatly increase the risk associated with the proposed
study. Unsuspected anaphylactic reactions may also, although rarely, occur. Radiopharmaceuticals present relatively low risks of adverse
reactions unrelated to their radioactivity. The principal risks associated
with radiopharmaceuticals are posed by the radioisotope's energy, its
half-life, the radiosensitivity of the organ system being studied, and the
radiation dose to the target organ, adjacent organs, and the whole body.
Other factors are, however, also relevant. For example, the dose of a labeled
brain receptor agent or the status of a subject's brain receptors must be
considered. In addition to determining the
level of risk associated with exposure to radiation, IRBs must be concerned
with informed consent. Specifically, IRBs must determine what subjects should
be told: how properly to communicate the uncertainty about the risk of harm
posed by exposure to the level of radiation involved in the study. Since
subjects must be given sufficient information on which to decide whether to
participate, consent should be based on information that the subjects may
reasonably be expected to want to know. The question for the IRB is how much
risk must there be before a "reasonable volunteer" would want to
know about it. Given the sensitivity of our society to the uncertainty surrounding
the risks associated with radiation exposure, IRBs should require that
subjects be told that participation in the research involves exposure to
radiation. Several ways of explaining the
risks associated with exposure to radioactive materials to potential subjects
have been suggested, but none are totally satisfactory. One method used is
comparing the risk of death from radiation exposure to that of more familiar
activities such as air travel or cigarette smoking. A second method compares
the incidence of death per year from radiation exposure with the mortality
rates of various occupations. Comparisons may also be made between the
proposed research exposure and the dose received from cosmic and background
radiation to which a subject is naturally exposed. The proposed research
exposure may also be compared with the annual maximum permissible exposures
suggested by the NCRPM for occupational workers. Finally, the research
exposure can be compared with exposures from more familiar medical
procedures, such as chest X-rays. The major problem with expressing
risks in comparative terms is that the actual risk from low levels of
exposure is not known. This uncertainty should be communicated to research
subjects. Even in cases where the risks from exposure are considered to be
minimal and not reasonably foreseeable, the IRB may determine that the
information concerning exposure and its possible effects is something that
research subjects might reasonably want to know. The IRB should ensure that the
risks of radiation exposure are minimized. In an attempt to minimize
radiation exposure, experts have developed a principle known as ALARA: As
Low As Reasonably Achievable. IRBs should ensure
that the ALARA principle is observed. [See also 21 CFR 361.1(b)(3) (limit on radiation
dose).] 1. Can the information to be
gained from the research project be gathered using methods that do not expose
subjects to more radiation than that to which they would naturally be
exposed? 2. Could the research be performed
on patients undergoing the procedures for diagnostic or therapeutic purposes? 3. Will the smallest exposure
(dose) possible be used in the study? 4. Have investigators taken steps
to avoid re-exposure? Are procedures in place to ensure that investigators
will use a minimum number of re-exposures in the event that the study needs
to be repeated? 5. Are adequate radiation safety
measures being taken to protect research subjects and others who may be
exposed to radiation? 6. Have the investigators taken
adequate precautions to screen subjects and exclude those not essential to
the research project and those at increased risk from exposure to radiation
or contrast agents? 7. Will both men and women be
informed of the risks to future offspring due to possible genetic damage? 8. Will women of childbearing
potential be adequately informed of the risks to an embryo associated with
radiation exposure in early pregnancy, and of the importance of disclosing a
possible pregnancy to the investigator? Does the protocol make adequate
provisions for detecting pregnancies? APPLICABLE
LAWS AND REGULATIONS Federal Policy for the protection
of human subjects 10 CFR 19 [NRC: Notices, instructions, and reports to workers;
inspections] State
laws regarding radioactive materials licensure INTRODUCTION The human
immunodeficiency virus (HIV) is a pathogenic retrovirus that causes acquired immunodeficiency
syndrome (AIDS) and its related diseases in humans. Because of its high rate
of mortality, AIDS has become the center of worldwide attention; research
into the development of safe and effective therapies, as well as methods of
prevention of this fatal disease, is currently a national public health
priority. HIV-related
research centers on both biomedical and behavioral questions. Biomedical
research has been characterized as falling into five major scientific
categories: "(1) the study of the distribution of HIV infection and AIDS
in the population (epidemiology) and the pattern of disease progression
(natural history); (2) the identification and characterization of the virus
that causes AIDS (etiologic agent); (3) delineation of the mechanisms by
which the virus destroys the immune system and produces disease
(pathogenesis); (4) the development and testing of potential therapies for
HIV infection and its complications; and (5) the development and evaluation
of potential AIDS vaccines" [Hamburg and Fauci (1989), p. 22]. Behavioral
research on HIV focuses on: (1) identifying the social, psychological, and
behavioral conditions of disease transmission and prevention; (2) the effects
of psychological state on immunosuppression; and (3) the role of psychology
in alleviating the distress experienced by persons affected by HIV infection
(including families, friends, and persons at risk). Research
designed to answer the many biomedical and behavioral questions presented by
HIV poses numerous ethical concerns. Primary among them are considerations of
privacy, confidentiality, and justice (fairness in the
distribution of the benefits and risks of research). The subjects involved in
HIV-related research, HIV-infected individuals, and persons at risk of HIV
infection, are particularly vulnerable, both because of their disease status,
and because the disease disproportionately affects certain populations: male
homosexuals and bisexuals, intravenous drug users, minorities, and,
increasingly, women and children. [See Guidebook Chapter 6, "Special Classes of
Subjects."] An overriding concern in HIV
research is confidentiality. Subjects included in HIV-related studies are
understandably concerned about the confidentiality of the data, since
breaches in confidentiality could have severe adverse consequences such as
loss of employment or insurance coverage, or criminal charges. OPRR guidance
on HIV studies states that: where identifiers are not required by the design of the study, they
are not to be recorded. If identifiers are recorded, they should be
separated, if possible, from data and stored securely, with linkage restored
only when necessary to conduct the research. No lists should be retained identifying
those who elected not to participate. Participants must be given a fair,
clear explanation of how information about them will be handled. As a general principle, information is not to be disclosed without
the subject's consent. The protocol must clearly state who is entitled to see
records with identifiers, both within and outside the project. This statement
must take account of the possibility of review of records by the funding
agency.... [OPRR Reports, Dear Colleague Letter (December 26, 1984), p.3.] IRBs should also consider whether
and how information from HIV-related studies will be recorded in subjects'
medical records, and may decide to impose limits on the recording of such
data. Before agreeing to participate in an HIV study, subjects should be
informed of exactly what information will be recorded, and whether any state
laws require the reporting of HIV infection or other disclosures of
information. The research protocol should also deal with the possibility of
attempts under compulsory legal process to force disclosure of records, how
such attempts will be responded to, and whether individuals will be notified
of such attempts. [See also the Guidebook Chapter 3, Section D, "Privacy and Confidentiality,"
which deals with certificates of confidentiality and subpoenas.] The protocol
should specifically set forth how to respond to requests by third parties who
have authorizations for disclosure of information signed by subjects. An
extensive set of guidelines for confidentiality in research on HIV has been
developed by a group of prominent scholars, practitioners, and community
members, and may be helpful to IRBs considering HIV-related protocols. [See
Bayer, Levine, and Murray (1984).] The PHS has an established policy
on the issuance of certificates of confidentiality to projects that are
subject to the reporting of communicable diseases to state and local health
departments. The policy applies to projects that intend routinely to
determine whether its subjects have communicable diseases, and that are
required to report them under state law. Certificates will be issued: (1)
where the referring treating physicians assure the project that they have
complied with reporting requirements; (2) the investigator has reached an
agreement with the health department about how he or she will cooperate with
the department to help serve the purposes of the reporting requirements
(unless the investigator can show why such cooperation is precluded); and (3)
only where disclosures of identifiable information about subjects comply with
regulations on subject protection, and are explained clearly to subjects
prior to their participation [Mason (August 9, 1991)]. [See also
Guidebook Chapter 3, Section D,
"Privacy and Confidentiality."] The giving of voluntary consent,
axiomatic to all research involving human subjects, applies equally in
HIV-related research. Complicating the consent issue, however, is that HIV-related
illness, particularly in its later stages, can cause dementia, thus affecting
the ability of subjects to give consent or continue to consent to ongoing
research. Research protocols should deal with this possibility; IRBs should
ensure that subjects in this particularly vulnerable condition are adequately
protected. [See also Guidebook Chapter 6, Section D,
"Cognitively Impaired."] Research on vaccines and
treatments poses some of the most difficult questions, including the level of
acceptable risk to subjects when the disease is fatal and no effective
therapy is available; whether HIV-infected patients can be used as a placebo
group that is not given experimental treatments; how subjects should be
selected to receive experimental therapies; whether and under what
circumstances healthy and at-risk but not-yet-HIV-infected persons can
ethically be asked to participate in vaccine trials. Clinical
Trials of HIV-Related Therapies. Randomized clinical trials (RCTs) and the ethical problems
surrounding their use is discussed in Guidebook Chapter 4, Section H and related
Guidebook Sections. This Section will focus on questions of particular
concern for research involving HIV-infected individuals. Randomized, controlled clinical
trials are considered the research design most likely to yield valid
scientific results for the evaluation of the safety and effectiveness of
experimental therapies. Ethical use of RCTs depends on the existence of both
the ability to state a null hypothesis (also called "theoretical
equipoise") and that there be no other therapy known to be more
effective than the one being studied in the RCT. A report produced by a
working group on clinical HIV research convened by the American Foundation
for AIDS Research argues, however, that when no known effective alternative
therapy exists, as is presently the case with HIV, it may be justified to
consider the use of other forms of controls such as historical controls (that
is, to compare the effects of the therapy in the trial population with the
treatment experiences of patients with the same disease before use of the
experimental therapy) [Levine, Dubler, and Levine (1991), pp. 3, 6]. The justification
for this position is that the conditions of "clinical equipoise" (a
situation in which there is a "current or likely dispute among expert
members of the clinical community as to which of two or more therapies is
superior in all relevant respects," and which is also necessary for an
RCT to be ethical) are not satisfied [id.]. The working group issued a
document that included 57 recommendations on the conduct of clinical research
on HIV, which IRBs may wish to consult [id.]. The use of placebo controls is
particularly problematic. As a general matter, where the disease is lethal or
seriously debilitating, as in the case of HIV, the use of placebo controls in
place of an active control is difficult to justify ethically, despite the
possibility that the experimental therapy is harmful (e.g., toxic)
rather than therapeutic. In the language of the Belmont Report,
the question of the use of control groups in this situation is one of beneficence:
Are potential benefits maximized in all arms of the trial? The fatal nature
of the disease leaves patients in a desperate position in which many seek any
promising treatment. It has been suggested that the question may be resolved
in favor of placebo controls only under two conditions: (1) when there is
either no known effective therapy that can be used as an active control, or
subjects are persons who cannot tolerate a known effective therapy; and (2)
the trial therapy is "so scarce that only a limited number of patients
can receive it" [Levine, Dubler, and Levine (1991), p. 8]. A fair way to
then assign subjects to the active and control arm(s) is through a lottery
[id.] [See also Macklin and Friedland (1986), pp. 277-79, and
Guidebook Chapter 4, Section H,
"Clinical Trials," and related Guidebook Sections.] Once there is sufficient evidence
of either a beneficial therapeutic effect, unacceptable side effects, or
indication that there is a very low probability of establishing statistically
significant research results, the trial should be stopped or the protocol
should be modified [Macklin and Friedland (1986), pp. 177-78]. Where an
experimental therapy is shown to have a beneficial therapeutic effect, the
control group should be offered access to the experimental therapy.
Prospective subjects should be informed of the probability of being assigned
to the control group, the risks associated with being assigned to either the
treatment or control group, the criteria that will be used for determining a
beneficial effect sufficient to discontinue the control arm of the trial, and
the consequences of discontinuing the control arm (e.g., will control
subjects be added to the experimental group, will they be given the
experimental therapy on a treatment basis, will they be offered the
experimental therapy only if they pay for its cost, or will they be dropped
from the study without access to the experimental therapy). It should be made
clear to prospective subjects that the likelihood of the experimental therapy
having harmful effects may well be as great as the likelihood of its having
beneficial effects. The selection and recruitment of
subjects is also of concern. Subjects for clinical trials are often recruited
on the recommendation of treating physicians. Unable or unwilling to obtain
medical care, many individuals have been excluded from participation in
trials. Others, not aware of the existence of trials, are also left out. Care
should be taken to ensure the appropriate inclusion of women, children and
adolescents, and minority groups in HIV-related clinical trials. Note also
that IRBs must follow the additional protections provided in the DHHS
regulations wherever applicable. [See Subpart B (fetuses, pregnant women, and
human in vitro fertilization), Subpart C (prisoners),
and Subpart D (children).] When reviewing protocols involving
HIV-infected or at-risk individuals or persons, IRBs should consider
including (as consultants, if they are not already members) persons
knowledgeable about and experienced in working with such subjects [Federal Policy §___.107]. Some investigatory
groups have used "community advisory committees" as a means both of
better understanding the concerns of the subject population and of educating
the HIV-infected community about clinical research. Vaccines. The testing of AIDS/HIV vaccines in human subjects
raises substantial ethical issues. First and foremost is the question of
risks and benefits. Limited availability of animal data means that many of
the risks that might be associated with an AIDS/HIV vaccine (e.g.,
vaccine-induced immunotoxicity) are unknown. Nonetheless, the importance of
developing an AIDS/HIV vaccine is felt to outweigh these uncertainties. From
the standpoint of protecting the welfare of human subjects, however, the lack
of knowledge about risk and the potential for the existence of serious risk
must be clearly communicated and consented to by prospective subjects. While all viral vaccines pose
risks, HIV vaccines may, in addition, increase the risk of acquiring the
disease when subsequently exposed to HIV. Also, because of potential immune
tolerance, subjects may not be able to be vaccinated with a different
AIDS/HIV vaccine if the experimental one proves ineffective. Persons with
whom the subject is in close contact may also be at risk of transmission of
recombinant viruses (through the injection site). IRBs should consider the
degree to which investigators have minimized these risks, and ensure that
subjects are adequately informed of and consent to these and other potential
physical risks. Another issue about which subjects
must be informed is the effect of participation in the trial on their HIV
serostatus and the potential social ramifications of changes in HIV
serostatus. Just as persons infected with HIV through more usual means of
transmission (e.g., sexual activity, the use of intravenous drugs, or
blood transfusions) will test positive on antibody screening tests, so too
will persons immunized with experimental AIDS/HIV vaccines. There may be
limited access to diagnostic methods for distinguishing between persons who
are HIV-infected and persons who have received HIV vaccinations. One way to
help alleviate this problem is for trial sponsors to follow the lead of the
National Institute of Allergy and Infectious Diseases (NIAID), and provide
subjects with documentation certifying participation in the vaccine trial.
Nonetheless, participation in AIDS/HIV vaccine trials in itself may carry a
social stigma. Informing
Subjects of Their HIV Serostatus. Some research protocols involve screening blood samples for HIV
seroprevalence or other procedures through which subjects' HIV serostatus
will be discovered. In addition to ensuring that the confidentiality of this
information and all research data is scrupulously provided for, and that
subjects will be informed that they will be tested and of the risks and
benefits involved, IRBs will need to consider the circumstances under which
subjects should or must be told of their HIV serostatus. PHS policy requires
that where HIV testing is conducted or supported by the PHS, individuals whose
test results are associated with personal identifiers must be informed of
their own test results and provided the opportunity to receive appropriate
counseling unless the situation calls for an exception under the special
circumstances set forth in the policy. Under the PHS policy, individuals may
not be given the option "not to know" their test results, either at
the time of consenting to be tested or thereafter. The acceptable
"special circumstances" include such compelling and immediate
reasons as an indication that a given individual would attempt suicide if
informed that he or she was HIV seropositive; that extremely valuable
knowledge might be gained from research involving subjects who would be
expected to refuse to learn their HIV antibody results; or research
activities conducted at foreign sites where cultural norms, the health
resource capabilities, and official health policies of the host country
preclude informing subjects of their HIV serostatus. Subjects should also be
informed early in the consent process of any plans to notify subjects' sexual
or needle-sharing partners. [See OPRR Reports ("Dear
Colleague" letters dated December 26, 1984 and June 10, 1988).] Several
commentators have taken issue with the position that subjects should be told of
their serostatus regardless of their wishes. [See, e.g., Novick (1986)
and Dubler (1986); compare Landesman (1986).] While this issue may be
controversial, opportunities for early intervention weigh in favor of
policies that require informing subjects of their HIV serostatus. Counseling. Whenever subjects will be informed of
their HIV serostatus, appropriate pretest and post test counseling must be
provided. Counselors should be qualified to provide HIV test counseling and
partner notification services. IRBs should ensure that such provisions are
made. [See OPRR Reports ("Dear Colleague" letters dated
December 26, 1984 and June 10, 1988)] See also Guidebook Chapter 2, Section B, "Food and Drug
Administration Regulations and Policies" (discussing expanded
availability of investigational agents), and Chapter 4, "Considerations of
Research Design." Behavioral Research. Research on behavioral questions related to HIV often centers on
what behavioral factors contribute to disease transmission and dissemination,
as well as other psychosocial factors related to HIV (e.g., the
relationship of stress to immunosuppression). The American Psychological
Association has expressed concerns for subjects' privacy, protections against
the intrusive nature of behavioral research (because research on risk factors
and modes of disease transmission often probes intimate details of subjects'
lives such as sexual practices and past history of illicit drug use),
confidentiality, and the need to carefully debrief subjects. Vulnerability
of Subjects. In
addition to the ethical issues raised by the conduct of HIV-related research
itself, the involvement of HIV-infected subjects presents special concerns to
which IRBs should be sensitive. As noted above, homosexual and bisexual men,
intravenous drug users, minorities, and, increasingly, women and children
constitute the bulk of the HIV-infected population. Their vulnerability as
subjects arises primarily because their HIV status presents special concerns
of confidentiality and privacy. Knowledge of a person's HIV status can lead
to discriminatory practices on the part of employers, landlords, insurance
companies, and others. That HIV disproportionately affects certain
populations heightens the threat of inappropriate disclosure of HIV-related
data. In addition, characteristics of the progression of AIDS, which can
include both physical incapacity and loss of mental capacity, can impinge on
subjects' ability to exercise their right to autonomy in the course of the
research. IRBs can ensure that AIDS patients and other HIV-infected subjects
are adequately protected by viewing each subject first and foremost as an
individual. Researchers working with HIV-infected persons must be capable of
dealing with social, emotional, and psychological, as well as physical
factors. Taking such a multifaceted approach to working with this subject
population is a means of incorporating the various necessary cultural and
filial influences into the research relationship. Researchers should seek the
advice and consultation of experts in these and other relevant fields as
necessary. Another factor that heightens the
vulnerability of HIV-infected individuals is the lack of available treatment
alternatives. At present, HIV infection is believed uniformly to progress to
AIDS; no available treatment cures AIDS, although some therapies postpone the
onset and severity of opportunistic infection. Prospective subjects in HIV-related
studies may, therefore, agree to participate in research out of a hope for a
cure, which may or may not be realistic. But while IRBs should protect
subjects against exposure to excessive risk, they must also guard against
paternalism. Despite the fatal nature of the disease, there may be risks to
which individuals should not be asked to subject themselves; despite their
vulnerability, however, prospective subjects should be given the opportunity
to participate and obtain whatever benefits may be available. IRBs should
consider protocols and make their evaluation of the requisite factors (i.e.,
the level of risk involved, a positive risk/benefit ratio, equitable
selection of subjects, informed consent, and protection of privacy and
confidentiality) with this concern in mind. The additional protection that
IRBs can provide is to ensure that the protocol, its goals, and the research
benefits and risks are clearly and simply delineated and communicated to the
subject. It is important that participation in the research not engender
either false hopes or a sense of hopelessness. Furthermore, IRBs should try
to ensure that access to health care does not serve as a lure for
participation. IRBs need to review participant
eligibility requirements closely and extensively monitor the data collection
and analysis process. The consent process should also be carefully
considered, with special attention to provisions for determining mental
capacity to consent and alternative means for obtaining consent, where necessary.
[See Guidebook Chapter 6,
Section D, "Cognitively Impaired."] The duration of any health
care to be rendered through participation, including counseling, should be
thoroughly reviewed with subjects. As noted above, subjects must be clearly
and explicitly informed of any applicable law or policy that requires either
partner notification or notification to health authorities of subjects' HIV
serostatus or disease status. Finally, many HIV-infected persons
are economically and/or educationally disadvantaged, and may need adjunct
services or other help to be able to participate in research. To ensure that
all affected groups have an adequate opportunity to participate, IRBs should
give some thought to how investigators might meet these needs, thereby
encouraging a broader distribution of the risks and benefits of HIV-related
research. Availability
of Drugs and Other Therapeutic Agents for AIDS and HIV-Related Conditions. The availability of experimental drugs
and other therapeutic agents for the treatment of AIDS and other HIV-related
conditions has been highly controversial. Two mechanisms, Treatment INDs, and
a subset of Treatment INDs, Parallel Track programs, have been developed by
the FDA to meet this concern. They are discussed in the Guidebook in Chapter
2, Section B, "Food and Drug
Administration Regulations and Policies." POINTS TO CONSIDER 1. Pre-screening clinical study
participants for HIV antibody status: See the list of questions
provided in OPRR Reports, "Points to Consider for Institutional
Review Boards (IRBs) Regarding the Screening of Volunteers for HIV Antibody
Status," (circa August, 1989). 2. Is the composition of the IRB
membership appropriate for an adequate review of the protocol? Should the IRB
seek consultation with laypersons, persons with AIDS or who are HIV-infected,
or members of the HIV-affected community? 3. Are subjects' privacy and
confidentiality adequately protected? Are certificates of confidentiality
appropriate? 4. Does the consent process
provide adequately for the special needs of subjects participating in
HIV-related research, including subjects with impaired mental capacities and
the difficulties of communicating the risks presented by drug and vaccine
trials? 5. Will the informed consent
process clearly inform the subject of all pertinent information (e.g.,
the circumstances under which the investigator may terminate the subject's
participation without the subject's consent; the circumstances under which
the subject may withdraw from participation and the costs associated with
withdrawal; the financial costs of participation; how medical care will be
handled in the event of injury or onset of opportunistic illness; whether
partner notification and/or disease status reporting to health authorities
will occur)? 6. Is there a mechanism for
dealing with changes in mental capacity and continuing consent? Who will give
consent in the event of diminished mental capacity or lack of majority (in
the case of children)? Is it necessary to obtain subjects' assent? 7. Are protections against
coercion in place? 8. If the protocol involves a
clinical trial, have appropriate FDA clearances and an approved IND been
obtained? 9. Does the protocol provide for
adequate monitoring of all subjects for adverse reactions? Are provisions
made for early termination? 10. Will subjects be informed
about what to do and whom to contact in case of a serious adverse reaction or
research-related injury? 11. Will subjects involved in
behavioral research be adequately debriefed? Are intrusions into subjects'
privacy minimized? APPLICABLE LAWS AND REGULATIONS Federal Policy for the protection
of human subjects 21 CFR 50 [FDA: Informed
consent] Federal Register 57 (April 15, 1992): 13250-13259 [FDA: Parallel
track policy] State and local laws concerning
the reporting of HIV-related information Public Health Service policies
related to AIDS research: U.S. Public Health Service. National Institutes of Health.
"Guidance for Institutional Review Boards for AIDS Studies" [Dear
Colleague Letter]. OPRR Reports (December 26, 1984). U.S. Public Health Service. National Institutes of Health.
"Policy on Informing Those Tested About HIV Serostatus" [Dear
Colleague Letter]. OPRR Reports (June 10, 1988). U.S. Public Health Service. National Institutes of Health.
"Points to Consider for Institutional Review Boards (IRBs) Regarding the
Screening of Volunteers for HIV Antibody Status" [Dear Colleague Letter]
OPRR Reports [circa August, 1989]. James O. Mason [Assistant Secretary for Health]. "Certificates
of Confidentiality — Disease Reporting" [Memorandum]. (August 9, 1991.) INTRODUCTION Numerous ethical issues confront
IRBs considering research that involves the transplantation of organs or
tissues into human subjects. Transplanted organs may be either natural or
artificial; natural organs or tissue may be of either human or animal origin.
Ethical issues include the physical and psychological risks to the donor and
recipient, informed consent, coercion, and the selection of
recipient-subjects (i.e., the distribution of organs or tissue to
needy recipients). The ethical considerations
surrounding the transplantation of organs concern two basic problems: the scientific
basis of the procedure (i.e., risk to the recipient-subject) and the
procurement of organs for transplantation. The first problem raises issues
with which IRBs are familiar: determining whether the proposed research poses
an acceptable risk; balancing that risk with the potential benefits; ensuring
that the patient-subject and the donor give their informed consent; and
ensuring that the decision to participate is free from coercion and undue
influence. The second problem has several facets, including the appropriate
selection of recipient-subjects and the obtaining of organs. Equitable
subject selection for research on transplantation raises unique questions
because of the involvement of the donor in the process and because of the
scarcity of appropriate materials (e.g., organs, tissue, or bone
marrow) for the transplant procedure. The use of fetal tissue in
transplantation is dealt with in Guidebook Chapter 6, Section A, "Fetuses
and Human In Vitro Fertilization." Experimental transplants are
performed using a number of techniques: An organ or tissue can be obtained
from a living relative, a living nonrelative, or a deceased person (usually a
nonrelative). Transplants can also be performed using organs or tissue from
animals (called xenografts); portions of organs have also been
transplanted from living relatives into patient-subjects. The use of
artificial implants is another method of replacing diseased organs that has
been pursued. The transplant procedure requires
the matching of various factors between donor and recipient (e.g.,
blood and tissue types). To increase the likelihood of a match (i.e.,
to decrease the likelihood that the organ or tissue will be rejected by the
recipient's system), living relatives are a preferred source of organs or
tissue. For some organs, such as a heart, such an arrangement is obviously
impossible. Furthermore, the subject may not have a living relative who
provides an appropriate match or who is willing to donate the organ or
tissue. Candidates for experimental
transplant procedures are usually under threat of imminent death;
experimental transplant procedures are a last hope for survival. The highly
vulnerable status of potential subjects makes stringent review of proposed
transplant research essential. Transplant investigations involving children
as subjects are governed by Subpart D of the DHHS regulations [45 CFR 46.401-409]. [See Guidebook Chapter 6, Section C, "Children
and Minors."] The first issue with which IRBs
must concern themselves is whether the risk of the transplant procedure is
outweighed by the potential benefits of the research. [See Guidebook
Chapter 3, Section A,
"Risk/Benefit Analysis."] The benefits take two forms: intended
therapeutic benefit for the individual subject and the benefit to society
from the knowledge gained from the research. An important factor when
considering the benefit to individual subjects is the availability and
quality of therapeutic alternatives for potential subjects. The subjects'
prospects for survival and quality of life, with or without the transplant,
will be particularly relevant to the IRB's decision. Transplants involving living
donors present a second level of risk that must be evaluated: the risk of
obtaining the organ from the donor. That risk entails the risk of the removal
procedure itself, plus the long-term risks of living without the donated
organ or tissue. When balancing those risks against the potential benefits,
one can see that the relationship of the donor to the recipient may be
relevant. The donor will not therapeutically benefit from the donation; quite
the contrary. The benefit comes, rather from the direct good the donor gives
the recipient. In this regard, the living related donor will benefit more
directly than will the living nonrelated donor: He or she is increasing the
likelihood that the relative (about whom he or she presumably cares more than
would a nonrelated donor) will live longer. As with any research involving
human subjects, IRBs need to ensure that subjects give informed consent
that is free from coercion or undue influence. Potential subjects for studies
involving experimental transplants must be clearly informed of the highly
experimental nature of the procedure, including the state of knowledge about
the prospects for long-term viability of the organ or tissue. Complicating the question of
consent when the research involves transplants is the involvement of a donor.
Where the donor is living, his or her consent must be obtained; the
regulations concerning research subjects apply fully to the donor as well as
to the recipient. Where the donor is deceased, his or her next of kin must be
consulted: State and federal Required Request Laws mandate that the treating
physician ask if the family wishes to donate organs from the patient upon his
or her death; the deceased may also have indicated a desire to donate his or
her organs in the event of death by, for instance, signing an organ donation
card. Technological innovations that
allow for the preservation of cadavers and organs has led to concerns about
treating brain dead persons as research objects. Some question exists whether
deceased donors come within the jurisdiction of IRBs because the federal
regulations define subjects as "living individual[s]" [Federal Policy §___.102(f)]. Nevertheless, the President's
Commission [(1983), p. 41] suggested that IRBs consider requiring review
of research on brain dead persons "to determine whether...it is
consistent with 'commonly held convictions about respect for the dead.'"
[See also Levine (1986), p. 78.] Considerable controversy surrounds
the use of anencephalic infants as a source of organs for donation, with most
commentators arguing against their use. The involvement of living related
donors also raises concerns of coercion and undue influence. The pressure on
relatives to donate needed organs or tissues is unquestionably great; IRBs
must carefully scrutinize the proposed consent process. Some investigators
have provided for both medical and psychiatric evaluations and counseling as
part of the donor consent process, as well as a waiting period (if feasible)
before the transplantation, during which the donor may withdraw consent. Some
investigators have also provided for a consent advocate for the donor who is
not directly involved in the donor's operation. [See, e.g., Singer,
et. al. (1989).] A further complication to the
consent process for organ donors is the minor who is a potential donor for a
relative — a sibling, for instance. Where the donor is a minor, the
regulations concerning children and minors as research subjects apply [45 CFR 46.401-46.409]. Organ donations from
minors raise concerns about the ability of the minor to comprehend the risks
of donation, as well as the possibility of coercion or undue influence. [See
Guidebook Chapter 6, Section C,
"Children and Minors."] IRBs may want to consider requesting
the guidance of a court of law before allowing a given donation to be made. Experimental xenografts have been
particularly controversial. The celebrated Baby Fae case, in which an infant
received the transplanted heart of a baboon, raised serious questions about IRB
review of research involving human subjects. Any research involving
transplants should be carefully reviewed by an IRB regardless of the source
of funding. The extremely risky nature of the procedure and the special
vulnerability of the subjects demand that their welfare be scrupulously
protected. Subjects must be clearly informed of the state of knowledge about
the long-term viability of the transplant, of alternatives to the procedure,
and of all possible physical and psychological effects that may result from
the transplant and any other procedures that will be undertaken as a part of
the transplant. Consent to the transplant must be carefully documented. [See
Caplan (1985), p. 3343]. 1. Does the consent process
adequately protect both the donor and the recipient? Is sufficient
information provided regarding the risks of all procedures involved? Is
adequate provision made for incompetent subjects by providing for trustworthy
proxy decision makers? 2. Have both donors and recipients
been adequately protected against coercion and undue influence? 3. Are special regulatory
provisions applicable, e.g., Subpart D governing children as subjects? APPLICABLE LAWS AND REGULATIONS Federal Policy §___.111(a)(3) [Criteria for IRB approval of research: equitable selection of subjects] Omnibus Budget Reconciliation Act of 1986 (Pub. L. 99-509) enacted sec. 1138, Social Security Act (Required Request Law) The Uniform Anatomical Gift Act The Uniform Definition of Death Act State and local laws pertaining to organ donation INTRODUCTION Human genetic research involves
the study of inherited human traits. Much of this research is aimed at
identifying DNA mutations that can help cause specific health problems,
developing methods of identifying those mutations in patients, and improving
the interventions available to help patients address those problems. The
identification of genetic mutations enables clinicians to predict the
likelihood that persons will develop a given health problem in the future or
pass on a health risk to their children. For many disorders, however, there
will be a considerable time lag between the ability to determine the
likelihood of disease and the ability to treat the disease. Efforts to isolate DNA mutations
involved in disease in order to understand the origins of the
pathophysiological process are becoming increasingly common across the broad
sweep of biomedical research, from cardiology to oncology to psychiatry. IRBs
should expect to see more of these kinds of studies in the future. The U.S.
Human Genome Project (part of the worldwide research effort known as the Human
Genome Initiative) is one of the genetic tool making efforts that is
facilitating this growth, through the production of better genetic maps and
sequencing technology. The ethical issues raised by this
scientific trend primarily concern the management of psychosocially potent
personal genetic information. For researchers and IRBs, the major challenge
in addressing these issues is the fact that genetic studies typically involve
families; the research subjects involved in genetic studies are usually related
to each other. As a result, research findings about individual subjects can
have direct implications for other subjects, information flow between
subjects is increased, and participation decisions are not made entirely
independently. A second set of ethical issues emerge in cases in which the
results of these studies are used to develop therapeutic interventions at the
genetic level. Such concerns involve the special safety precautions and
subject selection considerations required for gene therapy research. Some of the areas described in
this Section present issues for which no clear guidance can be given at this
point, either because not enough is known about the risks presented by the
research, or because no consensus on the appropriate resolution of the
problem yet exists. IRBs
need to become familiar with the issues and be prepared to address them in
the context in which they arise in their particular research setting. Because
of the uncertainties involved in genetic research, IRBs may not, for some time,
be able to set clear standards for investigators. What IRBs can do, however,
is ensure that investigators have thought through the factors that may affect
the rights and welfare of human subjects (e.g., risks to privacy,
psychological risks, employment and insurance risks). IRBs should require
investigators to explain their thoughts on these problems, how they plan to
handle them, and how they plan to communicate them to subjects. IRBs would do well to work
together with investigators, so that investigators see the IRB, as they
should, as a partner in developing research protocols that adequately protect
the participants. For example, IRBs may want to sponsor workshops within
their institutions to help inform investigators of what the IRB will be
looking for, or invite investigators to consult with the IRB prior to
developing genetic research protocols. Voluntary organizations involved
in supporting research on various genetic disorders (e.g., genetic
disease support groups and voluntary health associations) can also be useful
sources of information for IRBs. Through consultation with voluntary
organizations, IRBs can obtain useful information on the human subjects
concerns of prospective research participants. These groups can also help act
as intermediaries for subject recruitment, which may be particularly helpful
for family studies, and can help provide counseling and support services. Not
only can they help IRBs (e.g., in subject recruitment), but both IRBs
and voluntary organizations benefit when their constituent publics are
well-informed about what IRBs do (and do not do). The issues raised in this Section
of the Guidebook are addressed with particular reference to genetic research.
General discussion of these issues (e.g., risk/benefit analysis, informed
consent, privacy and confidentiality, and vulnerable populations) will also
be useful to IRBs, and are found in other chapters of the Guidebook
(primarily Chapter 3, "Basic IRB
Review," Chapter 4,
"Considerations of Research Design," and Chapter 6, "Special Classes of
Subjects"). Lod Score: An expression
of the probability that a gene and a marker are linked. Genotype: The
genetic constitution of an individual. Phenotype: The
physical manifestation of a gene function. Proband: The person
whose case serves as the stimulus for the study of other members of the
family to identify the possible genetic factors involved in a given disease,
condition, or characteristic. It may be useful to think of
genetic research as being carried out on a continuum comprising four stages:
(1) pedigree studies (to discover the pattern of inheritance of a disease and
to catalog the range of symptoms involved); (2) positional cloning studies
(to localize and identify specific genes); (3) DNA diagnostic studies (to
develop techniques for determining the presence of specific DNA mutations);
and (4) gene therapy research (to develop treatments for genetic disease at
the DNA level). Unlike the risks presented by many
biomedical research protocols considered by IRBs, the primary risks involved
in the first three types of genetic research are risks of social and
psychological harm, rather than risks of physical injury. Genetic studies
that generate information about subjects' personal health risks can provoke
anxiety and confusion, damage familial relationships, and compromise the
subjects' insurability and employment opportunities. For many genetic
research protocols, these psychosocial risks can be significant enough to
warrant careful IRB review and discussion. The fact that genetic studies are
often limited to the collection of family history information and blood
drawing should not, therefore, automatically classify them as "minimal
risk" studies qualifying for expedited IRB review. When investigators attempt to
document and study the natural history of an inherited disease, condition, or
characteristic, they do so by identifying individual members of families
presenting the disease, condition, or characteristic and obtaining information
about them and the other members of their family. The result is a pedigree
analysis, which, in addition to tracing the natural history of a disease and
documenting the range of symptoms involved, may also reveal information about
family members that individual members may not have known about previously (e.g.,
the existence of previously unknown relatives or the presence of stigmatizing
diseases, such as mental illness). It may also reveal information about the
likelihood that individual members of the family either are carriers of
genetic defects or will be affected by the disease. Subject Recruitment and
Retention. The
familial nature of the research cohorts involved in pedigree studies can pose
challenges for ensuring that recruitment procedures are free of elements that
unduly influence decisions to participate. The very nature of the research
exerts pressure on family members to take part, because the more complete the
pedigree, the more reliable the resulting information will be. For example, revealing
who else in the family has agreed to participate may act as an undue
influence on an individual's decision, as may recruiting individuals in the
presence of other family members. (Both would also constitute a breach of
confidentiality. The problem of confidentiality will be dealt with later in
this Section.) Recruitment plans, some of which
are described here, can attempt to address these problems; each approach has
its own strengths and weaknesses. One strategy is to use the proband
as the point of contact for recruiting. This approach insulates families from
pressure by the investigator, but presents the risk that the proband may be
personally interested in the research findings and exert undue pressure on
relatives to enroll in the study. Furthermore, the proband may not want to
act as a recruiter for fear that other family members will then know that he
or she is affected by the disease. Another approach is direct recruitment by
the investigator through letters or telephone calls to individuals whose
identity is supplied by the proband. Direct recruitment by the investigator
may, however, be seen as an invasion of privacy by family members. (Similar
issues arise in epidemiologic research. See Guidebook Chapter 4, Section E.) A third
approach is to recruit participants through support groups or lay
organizations. Adopting this strategy requires investigator and IRB
confidence that these organizations will be as scrupulous in their own
efforts to protect subjects as the investigator would be. A fourth
possibility is to contact individuals through their personal physicians.
Prospective subjects contacted by their physician may, however, feel that
their health care will be compromised if they do not agree to participate. In
the end, the IRB must ensure that the recruitment plan minimizes the
possibility of coercion or undue influence [Federal
Policy §___.116]. In contrast to inappropriate
pressure placed on prospective participants to join the study is the
possibility that a subject may agree to participate out of a misguided effort
to obtain therapy. The purposes of the research and how subjects will or will
not benefit by participation must be clearly explained. (See
discussion below on informed consent). Investigators and IRBs need to
consider each of these concerns in arriving at a recruitment strategy that
protects these various interests. Defining Risks and Benefits. Potential risks and benefits
should be discussed thoroughly with prospective subjects. In genetic
research, the primary risks, outside of gene therapy, are psychological and
social (referred to generally as "psychosocial") rather than
physical. IRBs should review genetic research with such risks in mind. Psychological risk includes the
risk of harm from learning genetic information about oneself (e.g.,
that one is affected by a genetic disorder that has not yet manifested
itself). Complicating the communication of genetic information is that often
the information is limited to probabilities. Furthermore, the development of
genetic data carries with it a margin of error; some information communicated
to subjects will, in the end, prove to be wrong. In either event,
participants are subjected to the stress of receiving such information. For
example, researchers involved in developing presymptomatic tests for
Huntington Disease (HD) have been concerned that the emotional impact of
learning the results may lead some subjects to attempt suicide. They have therefore
asked whether prospective participants should be screened for emotional
stability prior to acceptance into a research protocol. Note that these same disclosures
of information can also be beneficial. One of the primary benefits of
participation in genetic research is that the receipt of genetic information,
however imperfect, can reduce uncertainty about whether participants will
likely develop a disease that runs in their family (and possibly whether they
have passed the gene along to their children). Where subjects learn that they
will likely develop or pass along the disease, they might better plan for the
future. To minimize the psychological
harms presented by pedigree research, IRBs should make sure that
investigators will provide for adequate counseling to subjects on the meaning
of the genetic information they receive. Genetic counseling is not a simple
matter and must be done by persons qualified and experienced in communicating
the meaning of genetic information to persons participating in genetic
research or persons who seek genetic testing. Social risks include
stigmatization, discrimination, labelling, and potential loss of or
difficulty in obtaining employment or insurance. Changes in familial
relationships are also social ramifications of genetic research. For example,
an employer who knew that an employee had an 80 percent chance of developing
HD in her 40s might deny her promotion opportunities on the calculation that
their investment in training would be better spent on someone without this
known likelihood. Of course, the company may be acting irrationally (the
other candidate might be hit by a car the next day, or have some totally
unknown predisposition to debilitating disease), but the risk for our subject
of developing HD is real, nonetheless. One problem with allowing
third-parties access to genetic information is the likelihood that
information, poorly understood, will be misused. Likewise, an insurer with
access to genetic information may be likely to deny coverage to applicants
when risk of disease is in an unfavorable balance. Insuring against uncertain
risks is what insurance companies do; when the likelihood of disease becomes
more certain, they may refuse to accept the applicant's "bet." Debate about the social policy
implications of genetic information is vitally important and is occurring on
a national and international level, but is not literally a concern for IRBs.
The IRB's concern is, first, to ensure that these risks will be disclosed to
subjects, and, second, to protect subjects against unwarranted disclosures of
information. See also Guidebook Chapter 3, Section A, "Risk/Benefit
Analysis," and Chapter 3, Section B, "Informed
Consent," for further discussion of these issues. Privacy and Confidentiality
Protections. Special
privacy and confidentiality concerns arise in genetic family studies because
of the special relationship between the participants. IRBs should keep in
mind that within families, each person is an individual who deserves to have
information about him- or herself kept confidential. Family members are not
entitled to each other's diagnoses. Before revealing medical or personal
information about individuals to other family members, investigators must
obtain the consent of the individual. Another problem that arises in
genetic family studies that is also common in other areas of research
involving interviews with subjects is the provision by a subject of
information about another person. In pedigree studies, for example, the
proband or other family member is usually asked to provide information about
other members of the family. The ethical question presented by this practice
is whether that information can become part of the study without the consent
of the person about whom the data pertains. While no consensus on this issue
has yet been reached, IRBs may consider collection of data in this manner
acceptable, depending on the nature of the risks and sensitivities involved.
It may be helpful, for example, to draw a distinction between information
about others provided by a subject that is also available to the investigator
through public sources (e.g., family names and addresses) and other
personal information that is not available through public sources (e.g.,
information about medical conditions or adoptions). IRBs should require investigators
to establish ahead of time what information will be revealed to whom and
under what circumstances, and to communicate these conditions to subjects in
clear language. For example, if the pedigree is revealed to the study
participants, family members will learn not only about themselves but about
each other. The possibility that family members who did not participate might
also learn of the pedigree data should not be overlooked. Subjects should
know and agree ahead of time to what they might learn (and what they will not
learn), both about themselves and others, and what others might learn about
them. One approach would be never to reveal the pedigree to participating
subjects. Many investigators record their pedigrees using code numbers rather
than names. IRBs should note, however, that when a study involves a rare
disease or a "known" family, the substitution of numbers for names
does not eliminate the problem. Even where the protocol calls for
providing certain information to subjects, participants in genetic studies
should be given the option of not receiving genetic information about
themselves or others that they do not wish to receive. In genetic research,
the potential for psychosocial harm accruing to persons who express a desire
not to receive information gained through the study and the uncertainties
surrounding the disease-predictive value of the early phases of contemporary
genetic research is felt to outweigh benefits of required disclosure. (A
possible exception involving circumstances where early treatment of
genetically-linked disease improves prognoses is discussed in the section on
identifying and deciphering genes, below.) Data must be stored in such a
manner that does not directly identify individuals. In general, except where
directly authorized by individual subjects, data may not be released to
anyone other than the subject. An exception to requiring explicit
authorization for the release of data may be secondary research use of the
data, where the data are not especially sensitive and where confidentiality
can be assured. IRBs should exercise their discretion in reviewing protocols
that call for the secondary use of genetic data. Furthermore, when reviewing
a consent documents, IRBs should note agreements made by investigators not to
release information without the express consent of subjects. Subsequent
requests for access to the data are subject to agreements made in the consent
process. For studies involving socially sensitive traits or conditions,
investigators might also consider requesting a certificate of
confidentiality. [See Guidebook Chapter 3, Section D, "Privacy and
Confidentiality."] Informed Consent. The information presented to subjects in
the informed consent process should be as specific as possible. Subjects
should be told both the known risks, as well as the uncertainty surrounding
the risks of participation. Among the uncertainties is the likelihood that
useful information will result from the study (it may not). Prospective
participants often come into genetic studies with unrealistic expectations of
how they will benefit from the study, and without an appreciation of
low-probability risks that are not well-understood by anyone. To the extent
possible, unrealistic expectations should be dispelled in the informed
consent process. The provision of relevant
information should take place as a thoughtful discussion with prospective
subjects. Through this process, subjects should be informed: • about the kind of information they will be provided (e.g.,
that they will receive only information the investigator feels is significant
and reliable, or that no genetic information will be provided) and at what
point in the study they will receive that information; Information should be given to subjects
in clear language, suitable to their age, cultural background, and physical
and mental capabilities. Accommodations should be made for persons with
learning disabilities (as distinguished from persons who suffer diminished
mental capacity). The consent process should take place in the subject's
native language, through an interpreter, if necessary; consent documents
should be translated into the subject's native language. The IRB should
satisfy itself that great care will be taken by the investigator to ensure
that prospective subjects fully understand the risks and benefits involved in
participation. Disposition of DNA Samples. When tissue samples are to be collected
for later DNA analysis, numerous issues must be addressed by investigators
and IRBs. Primary among them are through what mechanism samples should be
collected, who can have access to the samples and for what purposes, who owns
the DNA, and how incorrect genetic information (due, for example, to faulty
laboratory analysis) can be corrected. The American Society of Human
Genetics' Ad Hoc Committee on DNA Technology has published a set of Points to
Consider on DNA banking and DNA analysis (1987), with which IRBs may wish to
acquaint themselves. While not all of the Society's recommendations may be
directly applicable to the IRB's concerns, it is worth noting the importance
the Society places on appropriate counseling and limited access to familial
genotypes. The genetic information (and
tissue samples, where applicable) collected under a research protocol are of
continuing importance to the families involved in the research. An important
question for IRBs to consider is what will happen to the data (and samples)
when funding for the research ends. Particular attention should be paid to
protecting the confidentiality of the data and obtaining consent from the
participants for any use of the data (and samples) that is not strictly
within the original uses to which the participants agreed. Withdrawal from
Participation.
Attention should be paid to subjects' rights when they decide to withdraw
from participation in the study. The federal regulations clearly require that
subjects be free to withdraw from participation without penalty or loss of
benefits to which they are otherwise entitled [Federal
Policy §___.116(a)(8)]. What the regulations do not address, however, is
how to treat data or tissue samples obtained from subjects who subsequently
withdraw from the study. A similar question was addressed by the California
Supreme Court in the Moore case [John Moore v. The Regents of the
University of California (1990)]. While Moore constitutes binding
legal authority only in California and has not, as of this writing, been adopted
in other jurisdictions, the court's findings may be helpful for exploring
possible approaches to handling the treatment of data and tissue samples when
a subject withdraws from a genetic study. In Moore, the California
Supreme Court held that cell lines established from a donated sample are not
the property of the person who donated the sample. Extrapolating to the
broader context of genetic research generally, the underlying principle would
be that withdrawal releases the subject from providing further information or
tissue samples, and perhaps requires the removal of the subject's identity
from all research records, but does not require the investigator to eliminate
the resulting data from the study or to destroy the cell line. In pedigree studies, for example,
investigators may respond to a request to withdraw by removing all
information about that person and his or her spouse and children from the
pedigree, but it is not clear that removal of the information is required by
the human subjects regulations or any other legal principle. Secondary Use of Tissue
Samples. Where a new
study proposes to use samples collected for a previously conducted study,
IRBs should consider whether the consent given for the earlier study also
applies to the new study. Where the purposes of the new study diverge
significantly from the purposes of the original protocol, and where the new
study depends on the familial identifiability of the samples, new consent
should be obtained. Vulnerable Populations. IRBs should ensure that the investigator
conduct the research with sensitivity to the specific mental and physical
manifestations of the particular disorders being investigated. Depending on
the disease, and, therefore, the likely presenting population, investigators
should be prepared to communicate effectively and with sensitivity with
persons who have physical limitations (e.g., deafness or blindness),
learning disabilities, cognitive impairments, or any other life circumstance
that may affect their participation (e.g., severe pain). The nature of genetic research
raises some special concerns when the research will involve children,
physically or cognitively impaired persons, older persons, or any subject
population likely to have special needs. Not only must the IRB ensure that
their participation is fully voluntary and informed, IRBs must also be sure
to evaluate the risks and benefits of the research as they apply to these
special populations. The risk of participation for an adult differs from that
of children; persons who suffer from diminished mental capacities may be
subject to different risks than persons who do not. If children will be
involved in the research, IRBs should seriously consider consulting with
experts in child development and others knowledgeable about risks to children
and families. Similarly, if physically or cognitively impaired persons will
be involved in the research, IRBs should consider consulting with experts who
can advise them on the special concerns their participation raises. Where
applicable, 45 CFR 46 Subparts B, C, and D
(pertaining to women, fetuses, prisoners, and children) must be followed. [See
also Guidebook Chapter 6, Section
C, "Children and Minors," Section D, "Cognitively Impaired
Persons," Section G,
"Terminally Ill Patients," Section H, "Elderly/Aged
Persons," and Section
I, "Minorities."]The involvement of children in genetic research
raises many concerns, including pressure brought by family members on the
child to participate and the potential for harm that may result from
disclosure of genetic or incidental information. Even seemingly harmless
research may actually present serious risks of harm to children. For example,
interviewing children for genetic research on psychological disorders, such
as schizophrenia or depression, or on alcoholism may inadvertently convey
information about family members (the child may well wonder why he or she is
being asked about alcoholism in the family) or cause self-doubt or
stigmatization on the part of the child. Furthermore, disclosures of data to
third-parties may result in children being labelled or stigmatized as, for
example, potential alcohol abusers. IRBs must look carefully at both the
questions that will be asked of children and the information that will be
directly conveyed to them to determine whether the research involves more
than minimal risk. The advisability of including children in studies of
untreatable, fatal disorders such as HD has been strongly questioned [MacKay
(1984), p. 3]. IRBs should also consider the
mental capacities of participants in genetic research. In some diseases, such
as Alzheimer Disease, patients will suffer loss of mental capacity over a
period of time. In addition, it is possible that a family member might be
comatose or legally incompetent for reasons unrelated to the disease under
study. Special attention should be paid to methods of ensuring voluntary consent
by the subject or the subject's legally authorized representative [Federal Policy §§___.102(c), ___.116]. Under the regulations, a "legally
authorized representative" is defined as "an individual or judicial
or other body authorized under applicable law to consent on behalf of a
prospective subject to the subject's participation in the procedure(s)
involved in the research" [Federal Policy
§§___.102(c)] IRBs should pay particular attention to state and local
laws relating to persons authorized to give permission for participation in
research on behalf of prospective subjects, noting that such
"proxy" consent to participation in research that does not involve
a direct medical benefit may differ from consent to receive medical
treatment. Where possible, the subject's assent should be sought; his or her
dissent should be honored. [See also Guidebook Chapter 6, Section D,
"Cognitively Impaired."] In appropriate circumstances the
IRB might consider granting waivers of consent or alteration of the consent
process. [See MacKay (1984), pp. 3-4, and Levine (1986).] The federal
regulations allow for waivers or alterations in the consent process where the
IRB finds that: (1) the research involves no more than minimal risk; (2) the
waiver or alteration will not adversely affect the rights and welfare of the
subject; (3) the research could not practicably be carried out without the
waiver or alteration; and (4) whenever appropriate, the subjects will be
provided with additional pertinent information after participation [Federal Policy §___.116(d)]. Again, IRBs should
carefully consider whether the research qualifies as "minimal
risk." Publication Practices. One final issue involving consent is the
publication of research data. The publication of pedigrees can easily result
in the identification of study participants. Where a risk of identification
exists, participants must consent, in writing, to the release of personal
information. Various authors have noted the problem of obtaining consent for
the publication of identifying data, and have recommended that consent to the
publication be obtained immediately prior to the publication, rather than as
part of the consent to treatment or participation in research. [See, e.g.,
Rost and Cohen (1976) and Murray and Pagon (1984).] It is worth noting,
however, that to address this concern, IRBs must also resolve the following
questions: Who determines the risk of identification, and on what grounds?
Who are defined as participants (is it everyone listed in the pedigree, some
of whom have been contacted by investigators, some of whom have had
information about them provided by a family member)? While IRBs must be careful to
avoid inappropriate restrictions on investigators' research publications,
some evaluation of publication plans is important as part of the IRB's
overall interest in preserving the confidentiality of research subjects. One
approach for investigators to use in evaluating their publication plans might
be to work in a step-wise fashion: First, is publication of the pedigree
essential? If publication of the pedigree or other identifying data (e.g.,
case histories, photographs, or radiographs) is essential, can some
identifying data be omitted without changing the scientific message? (The
practice of altering data — such as changing the birth order and gender — is controversial,
and no clear professional consensus yet exists as to whether this is an
appropriate practice.) Finally, if the pedigree must be published, and if
identifying data cannot be omitted in an appropriate manner without changing
the scientific message, subjects must give their permission for publication
of data that may reveal their identity. Another concern about publication
is the potential for publicity of the research results, and the exposure of
participants to such publicity. Consent by individuals to such publicity does
not resolve the question. Because genetic research involves families, the
agreement of one subject to participate in releases of information to the
media (including interviews and the like) has significant implications for other
members of the family, particularly where the research is of a sensitive
nature. IRBs should ensure that the investigator has addressed this
possibility. Expedited Review and
Exemption from Review.
The expedited review process is available for minimal risk research where the
research activity is limited to one of a specified category (as published in
the Federal Register), including the provision of blood samples [Federal Policy §___.110; Federal Register
46 (January 26, 1981): 8392]. In genetic studies that involve a blood draw,
the additional psychosocial risks are likely to raise the risk beyond the
"minimal risk" level allowable for expedited review. When an
expedited review is requested, IRBs should review the question of minimal
risk carefully. With respect to exemption from
review, the development of a pedigree through interviews with family members
is likely to create identifying information, even where individuals will not
be identified. Such research would not, therefore, qualify for exemption from
review under the federal regulations [Federal
Policy §___.101(b)(2)]. Identifying
and Deciphering Genes Research focusing on identifying
the specific genetic component of a particular disease, condition, or
characteristic relies upon DNA analysis of tissue samples taken from the
members of families in which the condition appears. Many issues raised by
pedigree analysis are relevant to this stage of research as well: pressure or
coercion in recruiting subjects; informing prospective subjects of the
possible harms; minimizing psychological harm through counseling and
education; protection of confidentiality (which is particularly problematic
when family members constitute the subject population); control over the use
of DNA tissue samples; and protecting particularly vulnerable persons, all of
which were discussed in the previous section. Additional issues include:
determining when the data constitute "information;" additional risks
presented by this stage of research (e.g., the possibility of
incidental findings); and possible conflicts between subjects' rights and
investigators' duties with respect to revealing the results of the study to
subjects [i.e., telling subjects whether they (or their relatives)
carry the defect, and the meaning of their status with respect to the
likelihood of suffering from the disease or passing it along to their
children]. Access to Data: Interim
Findings. An issue
that must be resolved prior to beginning any genetic study is who will have
access to the data and the stage in the research at which they will have
access. The issue of information transfer is vitally important in all genetic
research, but particularly in the first three stages of investigation. A
crucial question investigators and IRBs must address is whether (and which)
interim findings will be communicated to subjects. Experts disagree about whether
interim or inconclusive findings should be communicated to subjects, although
most agree that they should not (that only confirmed, reliable findings
constitute "information"). Persons who oppose revealing interim
findings argue that the harms that could result from revealing preliminary
data whose interpretation changes when more precise or reliable data become
available are serious, including anxiety or irrational — and possibly harmful
— medical interventions. They argue that such harms are avoidable by
controlling the flow of information to subjects and limiting communications
to those that constitute reliable information. MacKay (1984), writing about
the development of genetic tests, argues against revealing interim findings,
contending that preliminary results do not yet constitute
"information" since "until an initial finding is confirmed,
there is no reliable information" to communicate to subjects, and that
"even...confirmed findings may have some unforseen limitations" [p.
3]. He argues that subjects should not be given information about their
individual test results until the findings have been confirmed through the
"development of a reliable, accurate, safe and valid presymptomatic
test" [pp. 2-3; see also Fost and Farrell (1990)]. Others have
argued that all interim results should be shared with subjects, based on the
principle of autonomy — that subjects have a right to know what has been
learned about them. These arguments are equally
relevant at any of the first three stages of genetic research. IRBs should
consider these arguments, weighing the possible harms and benefits. Investigators
should determine, prior to initiation of the study, the point at which the
data will be considered solid enough to be constitute information that should
be provided to subjects. Investigators should further consider coding the
data and separating the research records from individuals' medical records,
so that neither the investigators nor the subjects may gain access to them
[MacKay (1984), p. 3]. Reilly (1980) suggests that IRBs
develop general policies governing the disclosure of information to subjects,
to help make these determinations. He suggests that at least the following
three factors be considered: "(1) the magnitude of the threat posed to
the subject, (2) the accuracy with which the data predict that the threat
will be realized, and (3) the possibility that action can be taken to avoid
or ameliorate the potential injury" [p. 5]. IRBs should ask
investigators to define three categories of disclosure: (1) "findings
that are of such potential importance to the subject that they must be
disclosed immediately;" (2) "data that are of importance to
subjects..., but about which [the investigator] should exercise judgment
about the decision to disclose....[i]n effect, these are data that trigger a
duty to consider the question of disclosure;" and (3) "data that do
not require special disclosure" [pp. 5, 12]. IRBs should consider whether the
investigator's approach appropriately balances the risks and benefits
involved in providing access to the data. Subjects should be told, as part of
the consent process, whether, when, and what information they will receive.
Any disclosures of genetic information should be accompanied by appropriate
counseling by trained genetic counselors. However the IRB resolves this
question, investigators should explain to prospective subjects the basis
according to which they will decide which data will be disclosed to whom, and
when those disclosures will be made. Access to Data: The
Subjects' "Right Not to Know." Subjects generally retain the right not to
receive information about the results of a study that reveals their genetic
status. A possible exception involves circumstances where early treatment of
genetically-linked disease could improve the subject's prognosis. In such
circumstances, investigators may have a duty to inform the subject about the
existence of the genetic defect and to advise him or her to seek medical
advice. [See, e.g., Andrews (1991).] (As of this writing, a legal duty
of investigators to inform subjects about the existence of genetic defects
has not been firmly established.) Furthermore, the existence of a
genetic defect that is linked to disease may have important implications for
family members; can or should the confidentiality of subjects' data be
compromised to allow other family members to be warned? The President's
Commission (1983), addressed this question with respect to information
generated from genetic screening. The Commission's discussion may also be
relevant to information obtained as the result of genetic research, at stages
that precede genetic screening. The Commission concluded that: [the] ethical duty of [providing confidentiality] can be overridden
only if several conditions are satisfied: (1) reasonable efforts to elicit
voluntary consent to disclosure have failed; (2) there is a high probability
both that harm will occur if the information is withheld and that the
disclosed information will actually be used to avert harm; (3) the harm that
identifiable individuals would suffer would be serious; and (4) appropriate
precautions are taken to ensure that only the genetic information needed for
diagnosis and/or treatment of the disease in question is disclosed [p. 44]. The Commission further advised
that, to the extent possible, persons undergoing genetic screening should be asked
to consent in advance to the disclosure of genetic information to relatives
in the event that such useful information is discovered [pp. 43-44]. Whether
a legal duty exists to warn relatives of possible genetic defects has not yet
been established. [See Robertson (1992), pp. 92-94.] Access to Data: Incidental
Findings. IRBs should
also ensure that investigators adequately deal with how they will handle
incidental findings; that is, what will be done with genetic information that
is learned during the course of the study that does not directly relate to
the research. For example, in intergenerational pedigree analyses, questions
of paternity or parentage can come up. DNA analysis will reveal information
indicating that an individual's biological parents are not who he or she
thought they were; blood typing may reveal similar information. DNA analysis
may also reveal information about diseases or conditions other than the
disease or condition under study. Prospective subjects should be informed
during the consent process that the discovery of such information is
possible. Appropriate counseling should be provided to educate subjects about
the meaning of the genetic information they have received, and to assist them
in coping with any psychosocial effects of participation. Access to Data: Secondary
Use. Investigators
should also address secondary use of research data (e.g., by other
investigators, or by themselves for different research purposes). Where
secondary uses can be foreseen, consent to the use should be sought. Express
consent to access to data for secondary uses should be obtained for sensitive
data and for circumstances under which confidentiality cannot be assured. Testing individuals to determine
the presence of genetic defects falls into four basic categories:
·
Testing
for carrier status to
identify individuals whose genetic makeup includes a gene or a chromosome
abnormality that might have serious health implications for their children.
Carrier testing is usually requested by adults who have some indication that
they may be carriers of a genetically-linked disorder (e.g., because
they are members of an ethnic group known to have a high incidence of the
disorder, because a relative has a genetic disease, or because a spouse knows
that he or she is a carrier). Testing will provide such persons information
about the risks of being a carrier and of passing on either the disease or
abnormal genes to their children. For recessive diseases, for example, a
carrier will pass on the disease to their children only if the other
biological parent is also a carrier of the same defective gene. ·
Prenatal
testing is aimed at
detecting the presence of genetic or chromosomal abnormalities in fetuses.
Examination of the genetic makeup of the fetus is done through amniocentesis,
chorionic villi sampling, blood sampling from the umbilical cord and blood
samples from the mother. ·
Risk
assessment testing
(sometimes referred to as "presymptomatic testing") determines the
probability that a person will develop a genetically-linked disease at some
point in the future. The degree of certainty with which risk assessment tests
can predict the likelihood of disease differs depending on the disease. For
some diseases the actual gene has been located, making tests more accurate
than for diseases for which only a marker has been found. Further, some
markers are more closely linked to the gene than are others, thereby having a
more predictive quality than others. Protocols involving genetic
testing raise somewhat different issues, depending on whether the tests are
under development or are already established as reliable. IRBs are concerned
with research aimed at developing genetic tests. The ethical issues raised by the
various kinds of genetic testing largely concern the concept of autonomy
or self-determination. Before consenting to undergo genetic tests, whether
new tests that are being developed, or already-established genetic tests,
subjects should fully understand what it is they are going to learn about
themselves, what they are not going to learn about themselves, and how
reliable the information will be. Subjects must have information on which to
base their decisions whether or not to go ahead with the testing. When the
research involves the development of a genetic test, however, the
uncertainties involved make the consent process problematic: How does one
adequately alert subjects to the psychosocial risks of testing when the point
of the study is to try to help define those risks? Research on pre-test
education in effect experiments with the informed consent process. Can
subjects consent to research knowing that one of the risks is that they may
not be adequately informed about what they are agreeing to? The federal
regulations allow IRBs to approve consent procedures that do not include or
that alter some or all of the elements of informed consent; one of the
requirements is that the research must involve no more than minimal risk [Federal Policy §___.116(d)]. Research that
involves deliberate withholding of information or deception is reviewed
pursuant to those provisions. Even where it is permitted, purposeful
nondisclosure of pertinent information is allowed only to the extent
necessary to conduct the study (e.g., when disclosure of the
information would affect the outcome of the study). Furthermore, subjects
must consent to the nondisclosure; that is, they must be told that there is
some relevant information about the study that they will not be told prior to
consenting to participate. [See Levine (1986, p. 117) and discussion
in Guidebook Chapter 3, Section
B, "Informed Consent."] In genetic testing research, however,
the nondisclosure is not purposeful; rather, the nature and extent of the
psychosocial risks involved is simply unknown. IRBs must look carefully at
such studies to ensure that subjects are adequately protected. Investigators
should provide the IRB their assessment of unknown risks. Subjects should be
informed, in clear, understandable language, of the possibility of
undisclosed risks, including any information the investigator has about their
possible nature and extent. Research results should be
communicated to the subject by someone who possesses the appropriate medical
and counseling expertise with which to explain the meaning of the test
results. That person should ensure that the subject comprehends the
information that has been provided to him or her, regardless of the time that
may be involved. Furthermore, it may be appropriate to provide counseling not
just for the subjects themselves, but also for their families. Consent to
involve family members, should the need arise, should be sought as part of
the consent to be tested. Smurl and Weaver (1987) have
developed a set of proposed ethical guidelines for the clinical testing of
risk assessment tests for HD. IRBs reviewing investigations of risk
assessment genetic tests should find their recommendations helpful. Many of
their recommendations follow the arguments set forth in the discussions in
the Guidebook on pedigree analysis and identifying and deciphering genes. The misuse of genetic information
due to misunderstanding its meaning is a risk faced by all participants in
genetic research. Investigators can minimize this risk by working to educate
not only subjects, but also the medical profession and the public about
genetic testing. The term "diagnostic" is often used, but the term
does not really apply. Genetic tests identify risks rather than
"diagnose" the presence of disease. Discrimination in employment or
in obtaining insurance are two areas that are of major concern, particularly
where the genetic trait is one that is thought to indicate a predisposition
to diseases or conditions caused by exposure to environmental agents.
Significant damage has been done by, for example, misperceptions about what
it means to be a carrier of sickle cell trait. Persons who carry the sickle
cell trait have been denied jobs or have been otherwise discriminated
against. Education, together with protecting subjects against disclosure of
genetic information, can help minimize the risk of discrimination. Gene therapy attempts to treat
genetic disease by altering an individual's cells. Gene therapy can involve
treatment of either somatic (nonreproductive) cells or germline
(reproductive) cells. Genetic changes made to somatic cells affect only the
individual who has received treatment; genetic changes made to germline cells
may be passed on to the patient's descendants. A distinction must be made
between gene therapy designed to treat or eliminate disease or serious
medical, psychological, or behavioral conditions (e.g., cystic
fibrosis), and the "improvement" of human characteristics (e.g.,
height). Gene therapy techniques involving
somatic cells are aimed at curing genetic disease in individuals by inserting
properly functioning genes into the individual's somatic cells [Walters
(1989), pp. 220-221]. The approach for making genetic changes to germ line
cells is to add new DNA to early embryos in an attempt to change the genes
not only in the individual, but also the genes passed on to his or her
progeny. Walters (1989) has described the process as follows: In studies involving mice, for example, genes have been added to
one-cell mouse embryos after the sperm had penetrated the egg but before the
genetic material from the sperm and egg are joined within the same nucleus.
If the experiment is successful, these added genes are then adopted by the
embryo. As the embryo grows and the number of embryonic cells increases, the
added genes become part of every new embryonic cell. Later, when the sperm or
egg cells of the mouse develop, the added genes are included in approximately
half of these reproductive cells. Thus, when the mouse reproduces, some of
its progeny receive the added genes, and so on through the generations [p.
221]. After being reviewed and approved
by the IRB and the local institutional biosafety committee, gene therapy
protocols for research conducted at or sponsored by an institution that
receives any support for recombinant DNA research from NIH must be reviewed
by the Recombinant DNA Advisory Committee (RAC) at NIH. At present, the RAC
will consider human somatic cell gene therapy protocols, but not germline
cell gene therapy protocols. The process of review is as follows: The Human
Gene Therapy Subcommittee conducts a public review of the protocol, then
submits its recommendation to the RAC; if the RAC approves the protocol, it
is forwarded to the director of NIH for final approval. The RAC, through a Points to
Consider Subcommittee, has established "Points to Consider in the Design
and Submission of Protocols for the Transfer of Recombinant DNA into Human
Subjects." Among the ethical concerns that investigators must address
are subject selection, informed consent, and privacy and confidentiality.
Investigators must also justify the use of recombinant DNA techniques against
alternative methodologies and delineate the risks and benefits of the
research. A summary of the Points to Consider follows; IRBs would be
well-served to follow a similar line of inquiry when reviewing protocols that
involve the transfer of recombinant DNA into human subjects. The RAC Points to Consider. The following points should be addressed
by all protocols involving somatic cell gene therapy: A. The proposed research should be
fully described. 1. Where recombinant DNA will be used for therapeutic purposes: a. Why is the disease a good candidate for gene therapy? b. After reviewing the natural history and range of expression of the
disease (including the available objective and/or quantifiable measures of
disease activity), are the usual effects of the disease predictable enough to
allow for meaningful assessment of gene therapy? c. What is the therapeutic goal of the research: to prevent all
manifestations of the disease, to halt the progression of the disease after
symptoms have begun to appear, or to reverse manifestations of the disease in
seriously ill persons? d. What alternative therapies exist? In what groups of patients are these
therapies effective? What are their relative advantages and disadvantages as
compared with the proposed gene therapy? 2. When recombinant DNA will be transferred for nontherapeutic
purposes: a. Into what cells will the recombinant DNA be transferred? Why is
the transfer of recombinant DNA necessary for the proposed research? What
questions can be answered by using recombinant DNA? b. What alternative methodologies exist? What are their relative
advantages and disadvantages as compared to the use of recombinant DNA? B. The research design and
anticipated risks and benefits should be described. 1. A full description of the methods and reagents to be employed for
gene delivery and the rationale for their use should be provided to the IRB
(a list of specific points to be addressed is provided in the Points to
Consider). 2. Previous pre-clinical studies, including risk-assessment studies,
that support the investigator claims about safety and effectiveness should be
described. The investigator should explain why the model chosen is the most
appropriate (a list of specific issues to be addressed is provided in the
Points to Consider). 3. The treatment to be administered to patients and the diagnostic
methods that will be used to monitor the success or failure of the treatment
should be described, including any relevant previous clinical studies using
similar methods that have been performed (specific issues to be addressed are
provided in the Points to Consider). 4. Any potential benefits and hazards to persons other than the
patients should be described. 5. The qualifications of the investigator(s) and the adequacy of the
clinical facilities should be given. C. Methods for patient selection
should be described, including the numbers of patients, the recruitment procedures
that will be used, the eligibility criteria that will be used (both exclusion
and inclusion criteria), and how the investigator will select among eligible
patients if it is not possible to include all who desire to participate. D. Methods for obtaining informed
consent should be described. Where the study involves pediatric or mentally
handicapped patients, investigators should describe the procedures for
seeking the permission of parents or guardians, and, where applicable, the
assent of each patient (in keeping with the requirements of 45 CFR 46). In particular, investigators should
address: 1. How the major points covered in A-C will be disclosed to potential
participants in understandable language; 2. How the innovative character and the possible (including
theoretically possible) adverse effects of the experiments will be discussed
with patients; how the potential adverse effects will be compared with the
consequences of the disease; and what will be said to convey that some of
these adverse effects, if they occur, could be irreversible; 3. How the financial costs to the subject of the experiment and any
available alternatives will be explained to the patients; 4. How patients will be informed that they may be subjected to media
attention as a result of participating; and 5. How patients will be informed about the irreversible consequences
of some of the procedures; about any adverse medical consequences that might
occur if they withdraw from the study once it has begun; and about any
preconditions to participation, such as their willingness to cooperate in
long-term follow-up and autopsy in the event of a patient's death following
gene transfer. E. Measures that will be taken to
protect the privacy of patients and their families and for maintaining the
confidentiality of research data should be described. IRB Considerations. The potential risks associated with gene
therapy may weigh against the involvement of human subjects in gene therapy
trials. As Walters (1989) has described it: There are clearly some risks and some unknowns associated with even
this simplest type of gene therapy [somatic cell gene therapy]. For example,
it is not presently possible to control where the retroviral vectors will
"touch down" when they reach the nuclei of the patient's...cells.
In other words, currently-available vectors are unguided missiles. There is
some concern among researchers that the vectors may disrupt
properly-functioning genes and therefore kill some cells or, more seriously,
that the vectors may activate some previously dormant cancer-causing genes.
It is also possible that the domesticated retroviral vectors will recombine
with other DNA or other viruses and so recapture their native capacity to
produce more retroviruses and to infect large number of cells [p. 222]. IRBs need to consider the risks
and benefits of gene therapy carefully, and, if a protocol is approved,
ensure that subjects will be thoroughly informed of the risks and benefits
involved in the procedure. It must be made clear to subjects that the
investigation has both a therapeutic intent and the goal of acquiring
scientific knowledge. Investigators should be careful not to raise
unrealistically the hopes of the subjects and their families [Fletcher (1985)
p. 298]. Protocols involving children are
subject to the special provisions of 45 CFR 46 Subpart D. IRBs should pay particular
attention to protecting children, including obtaining assent from child-participants,
wherever possible. IRBs may want to consider using a consultant, an IRB
member, or a "group consent auditor" to oversee the consent
process, ensuring that the child's best interests have been carefully
considered [Fletcher (1985), pp. 298-99]. Fletcher argues that IRBs should
refrain from allowing the hopeless situation of subjects to overshadow the
consideration of acceptable risk. He concludes that "even if the degree
of risk does not approach the level of 'dangerous'...[d]esperation about [a]
child's condition is not a sound premise for experimental gene therapy.
Children in imminent danger of death should not be selected as subjects for
the first trials" [p. 297]. [See also Guidebook Chapter 6, Section C, "Children
and Minors."] Special attention should also be
paid to the possibility of mental impairment. [See Guidebook Chapter 6, Section D,
"Cognitively Impaired."] 1. Does the proposed study
population comprise family members? Has the appropriateness of various
strategies for recruiting subjects (e.g., recruiting by the proband or
other family members, by the investigator, through support groups, or through
prospective subjects' personal physicians) been considered? Does the proposed
strategy for recruiting subjects sufficiently protect prospective subjects
from the possibility of coercion or undue influence? 2. Does the investigator plan to
use the proband or the proband's clinical medical records as a source of
research data about other persons (e.g., other family members)? If so,
must their consent be obtained before their data can be included, or is the
permission of the person providing the information sufficient? 3. Has the investigator
established clear guidelines for disclosure of information, including interim
or inconclusive research results, to the subjects? Will subjects be informed,
in clear language, about what information they are entitled to receive at
what point in the research? Will subjects receive an explanation of the
meaning of the information they receive? 4. Will family members be
protected against disclosures of medical or other personal information about
themselves to other family members? Will they be given the option not to
receive information about themselves? Will limits on such protections be
clearly communicated to subjects, including obtaining advance consent to such
disclosures (e.g., when family members will be warned about health risks)? 5. Will the possible psychological
and social risks of genetic research be adequately considered in the consent
process? Will appropriate counseling be provided, both as part of the consent
process and when communicating test or other research results to subjects? 6. Will subjects be informed about
the possibility that incidental findings may be made (e.g., paternity,
diseases, or conditions other than the one(s) under study)? 7. Will the data be protected from
disclosure to third parties, such as employers and insurance companies? Will
the data be stored in a secure manner? Will the data be coded so as to
protect the identity of subjects? Is a request for a certificate of
confidentiality appropriate? 8. Does the investigator plan to
disclose research findings to subjects' physicians for clinical use? Are such
plans appropriate? Will the possibility of such disclosures be discussed with
and consented to by prospective subjects? 9. Will vulnerable populations (e.g.,
children, persons with impaired mental capacities) be adequately protected?
Under what circumstances can a research subject serve to grant permission to
involve a minor child or an incapacitated adult in a study? 10. Have adequate provisions been
made for protecting against misuse of tissue samples (e.g.,
confidentiality, obtaining consent for any use not within the original
purpose for which the samples were collected)? What agreements with subjects
are necessary to use stored materials for new studies or for clinical
diagnoses? 11. Have adequate provisions been
made for the treatment of data and tissue samples in the event of subject
withdrawal from the study? 12. Do the investigator's
publication plans threaten the privacy or confidentiality of subjects? Has
adequate consideration been given to ways in which subjects' privacy and
confidentiality can be protected (e.g., providing for consent to
publication of identifying information)? 13. Have the RAC's Points to
Consider for gene therapy protocols been considered? Some of the questions arising from
the conduct of large pedigree studies were addressed at an NIH workshop
jointly sponsored by the National Center for Human Genome Research (NCHGR)
and the Office for Protection from Research Risks (OPRR) in October of 1992.
For further information on the availability of the papers presented at the
workshop (listed in "Suggestions for Further Reading," below),
contact: Dr Eric T. Juengst Dr. Joan P. Porter APPLICABLE LAWS AND REGULATIONS Federal Policy for the protection
of human subjects Federal Policy §___.116 [Informed
consent] 45 CFR 46 Subpart D [DHHS:
Additional protections for children involved as subjects in research] Federal, state, and local laws or
regulations governing confidentiality of information Federal, state, and local laws or
regulations pertaining to insurance There are currently no laws or
regulations specifically governing the involvement of human subjects in genetic
research, but the following guidelines may be useful: U.S. Department of Health and Human Services. Public Health Service.
National Institutes of Health. "Federal Guidelines for Recombinant DNA
Molecule Research." 51 Federal Register (May 7, 1986): 16958. U.S. Department of Health and Human Services. Public Health Service.
National Institutes of Health. "Recombinant DNA Molecule Research,
Proposed Actions under Guidelines; Notice." 50 Federal Register
(August 19, 1985): 33462-33467. U.S. Department of Health and Human Services. Public Health Service.
National Institutes of Health. Recombinant DNA Advisory Committee. Points to
Consider Subcommittee. "Points to Consider in the Design and Submission
of Protocols for the Transfer of Recombinant DNA into Human Subjects." Recombinant
DNA Technical Bulletin 12 (No. 3, September 1989): 151-170. Alcohol and drug research focuses
on use, abuse, and dependence on abuse-liable substances, and may or may not
involve the administration of an abusable substance. It may seek to
investigate physiological responses to alcohol or drugs, or may be aimed at
the treatment of alcohol or drug abuse. Treatment protocols may be behavioral
or biomedical, including the administration of medications. Abuse-liable: Pharmacological substances that have the
potential for creating abusive dependency. Abuse-liable substances can
include both illicit drugs (e.g., heroin) and licit drugs (e.g.,
methamphetamines). Research on alcohol or drug use
raises special concerns for IRBs because the research often involves the
administration of abuse-liable substances. Further, subjects' capacity
to provide informed consent is often compromised. Institutionalization may
also have an impact on the prospective subject's ability to choose freely to
participate in research. Other issues IRBs need to consider
are the selection of subjects and confidentiality. With respect to
confidentiality, federal, state, and local laws regarding criminal behavior
must be considered, because legal requirements may impinge on the ability of
the researcher to guarantee confidentiality. Finally, researchers may face
ethical problems with the study design, such as the morality of giving
alcohol to alcoholics, or the problems associated with studies that include
placebo arms. The National Advisory Council on
Alcohol Abuse and Alcoholism (the Council) has issued guidelines entitled Recommended
Council Guidelines on Ethyl Alcohol Administration in Human Experimentation
(1989). Many of the recommendations apply equally well to studies involving
abuse-liable drugs. The Council's recommendations contain a series of
questions and answers about research involving alcohol administration to
human subjects, and should be consulted by IRBs reviewing protocols involving
alcohol- or drug-related research. Risk/Benefit. A number of issues raised by alcohol and
drug research focus on considerations of risk and benefit. Where alcohol or
drugs will be administered to subjects, IRBs should consider, for example,
whether the subjects are drug or alcohol abusers, and whether participation
of the proposed populations is likely to expose the subjects to harm [see the
Recommended Council Guidelines (1989), pp. 5-6]. Investigators must
adequately assess the potential for toxicity, and make provisions for
clinical care of subjects where it will likely be needed. Further, the need
for access to medical backup services (i.e., the presence of a nurse
or physician during conduct of the research, or the availability of a
physician "on call") should be considered. Other risks presented by some drug
or alcohol research are those inherent in self-administration of abuse-liable
substances. IRBs should consider such risks, including the possibility that
subjects may self-administer an increasing amount of the drug to levels
higher than those to which they are accustomed, and the possible harms that
might result. Where the study has a placebo arm,
investigators need to consider the various effects the use of placebos might
have and provide mechanisms for dealing with them so that subjects are
adequately protected. For example, in a study in which subjects are told that
the investigational agent blocks the effect of an abuse-liable drug, a
subject, believing herself not to be in the placebo arm, might
self-administer sufficiently large doses of the drug to fatally overdose.
Investigators should be prepared to address this issue (e.g., through
informed consent, monitoring, use of an in-patient subject population, or
other means). Adequate provisions must be made
to eliminate the risk of drug or alcohol impairment before the subject leaves
the research site. The Council Guidelines describe
investigators' obligations to facilitate the entry of alcoholics who are
current, active drinkers into treatment programs [p. 6]. The Guidelines go on
to point out that where potential subjects "have completed the initial
phase of treatment and progressed into rehabilitation or recovery,"
their involvement in research in which alcohol will be administered requires
"extremely strong scientific justification and risk/benefit
assessment" [p. 6]. Further, Council policy holds that "it is
considered inappropriate to administer alcohol to any recovering alcoholic
who is abstinent and living a sober life in the community" [p. 6]. In addition to the risk/benefit
questions discussed here, the Council Guidelines also consider such issues as
the age of subjects, the involvement of alcohol-naïve subjects, deception or
incomplete disclosure, medical and psychological evaluation of subjects prior
to participation, and follow-up of subjects. Incentives
for Participation. IRBs should consider whether any remuneration offered to
subjects for their participation is appropriate. Any remuneration (e.g.,
money, food, lodging, or medical care) should be commensurate with the burden
of participation, and should not be such that it constitutes an undue
inducement or is coercive. The possible involvement of drug
or alcohol abusers in drug and alcohol research has led some investigators
not to offer any remuneration to their subjects for fear of unfairly inducing
their participation. Many potential participants are unemployed or otherwise
economically disadvantaged, so that concern over this issue is appropriate.
Nonetheless, to assume that any remuneration given to alcohol and drug
abusing constitutes an undue influence is also unfair. IRBs should consider
this issue carefully. Informed
Consent. In drug and alcohol research, concerns about the consent process
focus on determining the competence of subjects to consent to the research
and effectively communicating the information necessary to obtain informed
consent. With respect to competence, IRBs should ensure that competence is
assessed rather than assumed. Because there are no generally accepted
standards for determining competence to consent to research, the IRB plays an
important role in assessing the researcher's proposed procedures. IRBs should
take an active part in helping researchers formulate appropriate criteria and
procedures, taking into consideration the degree of risk presented. The same
or similar considerations as those discussed Guidebook Chapter 6, Section D,
"Cognitively Impaired," would apply, noting, however, that the
capacity to consent to research may fluctuate, depending on the subject's
state of inebriation. The Council recommendations on competency to consent state that: due consideration should be given to the cognitive, physiologic and
motivational states of the individuals in terms of their ability to fully
understand the context of the informed consent. Individuals who are severely
intoxicated or in a confusional withdrawal state are unable to give true
informed consent. Alternatively, a blood alcohol concentration (BAC) of zero
for the potential subject may not be a required prerequisite, depending upon
cognitive capabilities of the individual at that time. If there is a question
of a potential subject's ability to give meaningful informed consent, an
independent clinician, ethical consultant, or uninvolved third party with
appropriate qualifications may be asked to evaluate this ability [p. 4]. In drug research, the lack of
physical measures for levels of drugs means that investigators must rely (as
must alcohol researchers, in many instances) on clinical judgments based on
other indications of mental competence (e.g., through evaluating the
prospective subject's ability to converse or observing his or her motor
skills). The consent document must use
language that is understandable to the subject population, including ethnic
sensitivities. Further, the Council states its belief that "it [is] appropriate
that every informed consent form should indicate that the drug, alcohol, is a
toxin and a reinforcing agent which may cause changes in behavior, including
repetitive or excessive consumption. Such a statement would appropriately
acknowledge that alcohol is not an innocuous substance, and that everyone who
drinks alcohol is at some risk" [p.4]. Investigators should be aware of
federal, state, and local laws regarding criminal behavior, and any possible
reporting requirements, whether they relate to criminal activity or other
issues, such as HIV serostatus (see Guidebook Chapter 5, Section F, "AIDS/HIV-Related Research" ). They
should give the IRB evidence that they have considered these requirements and
provide a means of dealing with them. The IRB should seek legal advice if
necessary. The consent document should explain any limits on the
investigator's ability to provide confidentiality of the data, including any
required reporting to law enforcement or health authorities. [See also
discussion of certificates of confidentiality below and in Guidebook Chapter
3, Section D, "Privacy and
Confidentiality."] Subject
Selection. The
question of subject selection also requires IRB attention. Drug- or
alcohol-dependent individuals should not be taken advantage of. As the
Council states, researchers must "avoid using subjects merely because of
their easy availability, low social or economic status, or limited capacity to
understand the nature of the research." Furthermore, IRBs should ensure
that the proposed subject population is appropriate in terms of "age,
sex, familial or genetic background, prior alcohol use, other drug use, and
general medical and psychological condition, including, if appropriate,
alcoholism recovery status." IRBs should consult the Council's
recommendations, which describe these issues in greater detail. IRBs must take into consideration
the fact that the subject population of alcohol abusers and users of illicit
drugs might include a significant number of adolescents. The protocol must
address this issue. If subjects who are not adults participate, the
additional protections for of 45 CFR 46 Subpart
D apply. [See Guidebook Chapter
6, Section C, "Children and Minors."] Privacy
and Confidentiality.
Records indicating alcohol abuse or illicit drug use are of an obviously
sensitive nature, and must be provided appropriate confidentiality. Methods
for assuring adequate protection of the privacy of subjects and the
confidentiality of the information gathered about them (including the fact of
participation in a drug or alcohol treatment program) should also be described
by the investigator. Individually identifiable information that is
"sensitive" should be safeguarded; requests for the release of such
information to others, for research or auditing, should be allowed only when
continued confidentiality is guaranteed. To protect data against compelled
disclosure, investigators may request a certificate of confidentiality from
an appropriate federal official [42 CFR 2 and 2A]. For example, the directors
of the National Institute of Mental Health, the National Institute on Alcohol
Abuse and Alcoholism and the National Institute on Drug Abuse are authorized
to grant such protection for research on mental disorders or the use and
effects of alcohol and other psychoactive drugs. IRBs and investigators should
note, however, that certificates of confidentiality protect research data
from compelled disclosure; they do not cover voluntary disclosures (e.g.,
reporting of communicable diseases or suspected child abuse). The consent
document should not, therefore, promise that "no information will ever
be released," but should clearly spell out what can and cannot be
released. For information on certificates of
confidentiality, contact: National Institute on Alcohol Abuse and Alcoholism Dr. Fulton Caldwell National Institute on Drug Abuse Ms. Jacqueline R. Porter Cmdr. Lura S. Oravec National Institute of Mental Health Dr. Anthony Pollitt Other health research Mr. John P. Fanning For further discussion of
certificates of confidentiality, see Guidebook Chapter 3, Section D, "Privacy and
Confidentiality." IRB
Membership. IRBs that regularly review research involving vulnerable subjects are
required by DHHS and FDA regulations to consider including among their
members one or more individuals who are knowledgeable about and experienced
in working with those subjects [45 CFR 46.107;
21 CFR 56.107]. In addition, the IRB
must be sure that additional safeguards are in place to protect the rights
and welfare of these subjects [45 CFR 46.111(b); 21 CFR
56.111(b)]. For Further Information. Investigators and IRB members wishing to discuss
drug research involving human subjects should contact: Cmdr. Lura S. Oravec 1. Does the IRB's membership include
sufficient expertise for reviewing the protocol? 2. Will the subject's drug or
alcohol dependency create a deficient mental status which will preclude the
subject's continuing ability to consent to participation in research? Will
prospective subjects be in either a state of intoxication or withdrawal when
approached to consent to participation? What mechanisms are proposed for
evaluating subjects' competence to consent? Are they adequate? 3. Have additional safeguards been
implemented to minimize risks (e.g., pregnancy tests or procedures for
ensuring that subjects cannot leave the research site while intoxicated)? 4. Are there federal, state, or
local laws regarding criminal behavior or reporting requirements that must be
considered? How will they be dealt with? Will prospective subjects be
informed of any reporting requirements? 5. Have the investigators provided
for maintaining subjects' privacy and confidentiality? Should the
investigators obtain a certificate of confidentiality to protect against
compelled disclosure of their data? 6. Are adolescents potential
participants? Have the additional requirements of 45 CFR 46 Subpart D been met? [See Guidebook
Chapter 6, Section C,
"Children and Minors."] APPLICABLE LAWS AND REGULATIONS Federal Policy for the protection
of human subjects Federal Policy §___.116 [Informed
consent] 21 CFR 50.20 and 50.25 [FDA: Informed consent] 45 CFR 46 Subpart D [DHHS:
Additional protections for children involved as subjects in research] Federal, state, and local laws
governing disclosure or reporting of criminal behavior (e.g., use of
illicit drugs) Federal, state, and local laws
governing confidentiality of information SUGGESTIONS FOR FURTHER READING A. Introduction
B. Drug Trials
C. Vaccine Trials
D. Medical Devices
E. Use of Radioactive Materials and X-Rays
F. AIDS/HIV-Related Research
G. Transplants
H. Human Genetic Research
Botkin, Jeffrey.
"Disclosure of Interim Results to Research Subjects."
I. Alcohol and Drug Research
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