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Institutional Review
Board * CHAPTER V
* 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." DEFINITIONS
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 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. OVERVIEW
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:
IRB CONSIDERATIONS
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. POINTS TO CONSIDER
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
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. DEFINITIONS
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."
POINTS TO CONSIDER
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 INTRODUCTION
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. DEFINITIONS
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:
OVERVIEW 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. IRB CONSIDERATIONS 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:
Mr. Richard M. Klein POINTS TO CONSIDER 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] 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. DEFINITIONS 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. OVERVIEW 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]: [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. IRB CONSIDERATIONS 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).] POINTS TO CONSIDER 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
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). IRB CONSIDERATIONS
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:
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
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. "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." OVERVIEW
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. IRB CONSIDERATIONS
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]. POINTS TO CONSIDER 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
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
Guidebook
BIOMEDICAL AND BEHAVIORAL RESEARCH:
AN
OVERVIEW
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.
Mr. Richard M. Klein
Office of Health Affairs
(HFY-20)
Food and Drug Administration
5600 Fishers Lane
Rockville,
MD 20857
Tel: (301) 443-1382
21 CFR 50 [FDA: Informed consent]
21 CFR 56 [FDA: IRB review
and approval]
21 CFR 312 [FDA: Investigational new drugs]
21 CFR 52
[FDA: Sponsor and monitor (proposed)]
21 CFR 54 [FDA: Clinical
investigators (proposed)]
IRB CONSIDERATIONS
21 CFR 50 [FDA: Informed consent]
21 CFR 56 [FDA: IRB review
and approval]
21 CFR 312 [FDA: Investigational new drug research]
21 CFR
600-800 [FDA: Standards for biological products]
21 CFR 630 [FDA: Standards
for viral vaccines]
• intended for use as an implant and presents a potential for
serious risk to the health, safety, or welfare of the subject; or
•
purported or represented to be of use in supporting or sustaining human life
and presents a potential for serious risk to the health, safety, or welfare
of the subject; or
• intended for a use that is of substantial importance
in diagnosing, curing, mitigating, or treating disease, or otherwise
preventing impairment of human health, and presents a potential for serious
risk to the health, safety, or welfare of the subject; or
• otherwise
presents a potential for serious risk to the health, safety, or welfare of a
subject.
Dr. Michael J. Blackwell
Chief, IDE Section
(HFZ-403)
Office of Device Evaluation
Center for Devices and
Radiological Health
Food and Drug Administration
1390 Piccard
Drive
Rockville, MD 20850
Tel: (301) 427-1190
Health Assessment Policy Staff
Office of
Health Affairs (HFY-20)
Food and Drug Administration
Room 11-44, 5600
Fishers Lane
Rockville, MD 20857
Tel: (301)
443-1382
21 CFR 50 [FDA: Informed consent]
21 CFR 56 [FDA: IRB review
and approval]
21 CFR 812 [FDA: Investigational device exemptions]
21 CFR
813 [FDA: Investigational exemptions for intraocular lenses]
• 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.
•
The amount of radiation to other organs may not exceed a single dose of 5
rems or an annual cumulative dose of 15 rems.
• Permissible doses for
children (persons under age 18) are 10 percent of those for adults. The FDA
must approve studies involving children before the study
begins.
10 CFR 19 [NRC: Notices, instructions, and reports to workers;
inspections]
10 CFR 20 [NRC: Standards for protection against
radiation]
10 CFR 35 [NRC: Medical use of byproduct material]
21 CFR 50
[FDA: Informed consent]
21 CFR 56 [FDA: IRB review and approval]
21 CFR
361.1 [FDA: Radioactive drugs for certain research uses]
21 CFR 312 [FDA:
Investigational new drug application]
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.
21 CFR 50 [FDA: Informed consent]
21 CFR 56 [FDA: IRB review
and approval]
21 CFR 312 [FDA: New drugs for investigational use]
45 CFR
46, Subparts B-D [DHHS: Protection of human subjects]
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).
Federal Policy §___.111(a)(3) [Criteria for IRB approval of
research: equitable selection of subjects]