Clinical Research
The conduct of clinical research introduces a unique set of ethical issues that stem from using humans as research subjects.1 An ethical maxim of human dignity famously emphasized by Immanuel Kant is that humans always should be treated as an end in themselves and never as a means of achieving another end.2 The essential ethical problem in using humans as research subjects is that it violates Kant’s ethical axiom because they are employed as the means to the end of answering a scientific question. Justifying the violation of Kant’s maxim imparts a series of ethical obligations on the clinical investigator to maximally protect the interests and welfare of the human research subject. Investigators must obtain the subject’s voluntary consent and protect the subject from exploitation, unnecessary suffering, and other harms. Directly or indirectly, all the ethical issues I discuss in this chapter result from the use of the human subject as a means to the end of conducting clinical research.
Clinical investigators using human subjects in research develop a relationship with them that shares some features of the patient-physician relationship. The investigator-subject relationship imparts ethical duties to the investigator because the investigator intervenes in subjects’ lives and creates potential harms to them. These ethical duties comprise a responsibility to protect and guard the subjects’ welfare throughout the trial. Some ethicists have argued that medical researchers owe human subjects the same level of care that physicians owe patients, a quantity exceeding that which is stipulated in the research protocol.3 Other scholars hold that the ethical requirements of physicians providing medical care cannot translate fully to investigators conducting clinical research4 and investigators therefore lack the fiduciary duty to research subjects that physicians have to patients.5
Clinical research is a systematic investigation designed to create generalizable knowledge to advance science and ultimately to benefit mankind. Without the potential good that may result from clinical research, no risk of harm to the human subject could be justified. The use of humans as research subjects can be conceptualized as permitting an acceptable risk of harm to one person with consent in exchange for greater benefits to others in the future (and possibly for the subject now). A person’s decision to serve as a research subject may be an act of altruism or an attempt to improve his or her health by receiving the latest treatment. At a minimum, the human subject’s participation should be voluntary and undertaken only after a full disclosure of the attendant risks and possible benefits. The disclosure-consent ethical requirement is the research equivalent of the clinical doctrine of informed consent.
To fully understand the concept of clinical research, it is useful to distinguish it from related endeavors.6 These distinctions are important because related endeavors that are not research may not require the degree of regulation and informed consent required for the ethical conduct of research. Therapeutic innovation is related to research but is intended to benefit an individual patient, not necessarily to develop generalizable knowledge.7 Therapeutic
innovation, unlike research, may not be intended for publication. The distinction between research and quality improvement is subtle with much overlap. Although the intent of quality improvement initiatives originally was local, now they are being viewed more as research because their results are being generalized into practice standards.8
innovation, unlike research, may not be intended for publication. The distinction between research and quality improvement is subtle with much overlap. Although the intent of quality improvement initiatives originally was local, now they are being viewed more as research because their results are being generalized into practice standards.8
One element of an ethical analysis of clinical research is the ratio of scientific knowledge gained to harms risked by the human subject. The design and execution of a clinical trial may be considered an ethical matter because a poorly designed or executed trial will generate invalid results and thus render as unjustifiable even trivial risks to the study subjects. Professional conduct issues are also important. To maintain scientific integrity, the investigators must not have conflicts of interest or must adequately disclose those than cannot be eliminated.
Ezekiel Emanuel and his colleagues epitomized the seven requirements that make clinical research ethical: (1) value—the research must yield enhancements of health or knowledge; (2) scientific validity—methodological rigor is required to make the results valid; (3) fair subject selection—subject selection should be based upon scientific objectives and should not unfairly exploit vulnerability or award privilege; (4) favorable risk-benefit ratio—the totality of benefits to the individual and society should outweigh the risks to the study subject; (5) independent review—a body of responsible reviewers should scrutinize the study and approve it only if it meets stringent scientific and ethical criteria; (6) informed consent—the free, informed, and voluntary consent of the research subject is essential; and (7) respect for enrolled subjects—the investigators are responsible for protecting the welfare of the subject throughout the study and subjects may withdraw from the study at any time without repercussion.9 Because of the risks and time devoted to participating in the study, human subjects also have a right to know the aggregate conclusions of the research.10
In a survey of over 300 physicians and nurses involved in clinical investigation at the National Institutes of Health, Gordon DuVal and colleagues studied the incidence and types of ethical dilemmas encountered in clinical research. They found that 95% of investigators could identify their most difficult type of ethical problem and 76% could recall a recent ethical dilemma. Nearly half the surveyed clinical investigators reported requesting an ethics consultation to help resolve an intractable ethical problem. They scored the value of the consultation at a mean of 8 out of 10. The extent of their training and experience in ethics predicted the likelihood that they would request an ethics consultation but was not predictive of their satisfaction with the consultation. The investigators acknowledged that most hospital ethics consultation services do not provide research ethics consultations.11
HISTORY AND DEVELOPMENT OF CODES OF RESEARCH ETHICS
The history of research ethics begins with shameful examples of investigators’ unethical behavior and ends with the development of an international consensus on the ethical standards of human subjects research design and conduct as embodied in established codes of research ethics. In the United States, a number of clinical trials and other experiments were performed on patients in the 19th and early 20th centuries without their consent.12 In a controversial article in 1966, Henry K. Beecher, a Harvard anesthesiology professor and pioneer in American research ethics, chronicled 22 examples of unethical research performed in American institutions during the 20th century.13
The most widely publicized examples of unethical clinical research in the UnitedStates were the Tuskegee syphilis study, the Willowbrook hepatitis experiment, and the Jewish Chronic Disease Hospital cancer study, probably because they took place in the second half of the 20th century, after international codes of clinical research had been accepted. The Tuskegee syphilis study was begun in 1932 by the United States Public Health Service (USPHS) to examine the natural history of untreated (or undertreated14) syphilis in a group of 399 poor black male sharecroppers from Macon County, Georgia.
Following World War II when penicillin became widely available, the men remained untreated and some remained unaware that a treatment existed that might help them. Amazingly, the study continued until 1972 when Peter Buxton, a USPHS official who was frustrated at having his ethical concerns about the study ignored by more senior USPHS officials, alerted reporters who subsequently published exposés of the study in the New York Times and the Washington Star. Public outrage generated by these articles prompted the USPHS to terminate the study in 1972. In 2000, on behalf of the United States government, President Clinton formally apologized to the few Tuskegee research subjects remaining alive.15
Following World War II when penicillin became widely available, the men remained untreated and some remained unaware that a treatment existed that might help them. Amazingly, the study continued until 1972 when Peter Buxton, a USPHS official who was frustrated at having his ethical concerns about the study ignored by more senior USPHS officials, alerted reporters who subsequently published exposés of the study in the New York Times and the Washington Star. Public outrage generated by these articles prompted the USPHS to terminate the study in 1972. In 2000, on behalf of the United States government, President Clinton formally apologized to the few Tuskegee research subjects remaining alive.15
The Willowbrook State School hepatitis study involved the purposeful induction of hepatitis A virus (and other enteric pathogens) in institutionalized mentally retarded children. The goal of the study was to understand the spread of enteric pathogens within institutions and thereby reduce the risk of hepatitis spread through institutionalized patients, a serious medical problem in all such institutions. Although Saul Krugman, one of the principal investigators, later explained that parental consent for the study had been obtained, the extent to which the children’s parents were informed of risks or alternatives was a point of criticism and remains unclear.16
The Jewish Chronic Disease Hospital of Brooklyn cancer study, spearheaded in 1964 by Chester Southam, a noted Memorial Sloan-Kettering Cancer Center investigator, involved the injection of live cancer cells into 22 hospitalized patients without their knowledge to study the immunology of cancer. Patients were told that they would receive injections of a “cell suspension” but the word “cancer” was omitted because Southam believed that the chance that these cells actually would produce a cancer was minimal and he feared that the word “cancer” would frighten patients unnecessarily. Some staff physicians refused to participate because they believed it was wrong. When a member of the hospital board of directors learned of the research, he sued to have it stopped. The cessation of the research was accomplished through the resulting publicity.17
Without comparison, the medical experiments provoking the greatest worldwide public outrage were the infamous human experiments conducted during the Third Reich. These sadistic medical studies were carried out by German physicians on victims of Nazi death camps, with no attempt to obtain consent and, remarkably, with no reluctance on the part of the physicians.18 Worldwide horror and disgust provoked by public reporting of these experiments and the unspeakable suffering of their victims led to the development of codes of research ethics, beginning with the Nuremberg Code of 1947.
In Nuremberg, Germany, in 1947, following the trials of Nazi physicians who had conducted the despicable human experiments, American jurists formulated the Nuremberg Code. Its authors are believed to have been Judge Harold Sebring and Drs. Leo Alexander and Andrew Ivy. The Nuremberg Code stated axiomatically that no research should be conducted on human subjects without their full and voluntary consent. The Code stipulated further that all clinical experiments should be designed to minimize unnecessary suffering and excessive risk. Human research subjects should be protected at all times and free to terminate participation in the study at will.19
In 1964, the World Medical Association meeting in Helsinki formulated an international code of research ethics called the Declaration of Helsinki and amended it in six subsequent revisions through 2004. The Declaration of Helsinki provides 32 ethical principles to guide physicians in all biomedical research that involves human subjects. The Declaration reasserts the principles of the Nuremberg Code and places additional ethical duties on the investigator to insure the welfare of the human research subject at all times during the study.20
Commissions in the United States drafted reports stipulating additional standards of ethical conduct of research involving human subjects. The most noteworthy of these are the Belmont Report and Protecting Human Subjects. The Belmont Report was published in 1978 by the United States National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. The unique feature
of the Belmont Report was its emphasis on the ethical principles of respect for persons, beneficence, and justice in the realm of human experimentation, and its explanation of how the rules for protecting human research subjects were derived from ethical principles.21
of the Belmont Report was its emphasis on the ethical principles of respect for persons, beneficence, and justice in the realm of human experimentation, and its explanation of how the rules for protecting human research subjects were derived from ethical principles.21
In 1981, the United States President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research published Protecting Human Subjects. This report reiterated the principles embodied in the Nuremberg Code and the Belmont Report. It further required a favorable assessment of risks and benefits of the research and stipulated fair procedures in the selection of subjects.22 It suggested a heightened role for the institutional review board (IRB), which had been mandated in American law by the National Research Act of 1974, to better oversee and protect human research subjects. IRB approval now is mandatory. In a study of clinical trials published in major medical journals, investigators reported subjects’ consent or IRB approval in 91% of trials.23
IRBs exist because of the general acknowledgement that neither the full protection of human research subjects nor the responsibility for determining whether research fulfills ethical standards should be left solely to the investigator. The functions of the IRB are stipulated in federal regulations.24 Approval by the local IRB is a federally mandated prerequisite for any research involving human subjects under the “common rule,” so named because the regulations have been adopted by all agencies that conduct or fund human subjects research.25 The IRB has three principal roles: (1) to certify and document that the patient’s full and free informed consent has been obtained; (2) to demonstrate that the risks to the research subject are outweighed by the totality of potential benefits to the subject and future patients; and (3) to protect the privacy, confidentiality, dignity, and welfare of the human research subject.26
The functioning of the contemporary IRB is governed by both federal regulations and local practices. Variation in IRB daily operations among institutions is permissible. In many academic medical centers, the IRB agenda and personnel are overwhelmed with the volume of experimental protocols to review. The constant pressure to expedite approval of protocols at times may make review less careful than is optimal. Multicenter trials are another stress on IRBs. Some IRBs provide only a casual review if the study has been approved previously by another institution’s IRB.27 In a comprehensive analysis from the Consortium to Examine Clinical Research Ethics, Ezekiel Emanuel and colleagues identified these among 15 systemic problems of contemporary IRB structure, function, and oversight, and proposed recommendations for improvements.28 (See further discussion in chapter 5.)
Additional national and international agencies have propounded research guidelines.29 In 1993, the Council for International Organi-zations of Medical Sciences and the World Health Organization published International Ethical Guidelines for Biomedical Research Involving Human Subjects.30 In the United States, the National Institutes of Health (NIH) Office for Human Research Protection (OHRP, formerly known as the Office for the Protection from Research Risks or OPRR) publishes and updates guidelines on protecting human subjects that govern all research projects receiving federal funding.31 The United States National Bioethics Advisory Commission proposed recommendations for heightening consent and competency requirements when investigators perform clinical trials on vulnerable research subjects.32 The Association of American Medical Colleges formulated a guide to scientific societies for developing codes of ethics in research.33 The American Association for the Advancement of Science now publishes a newsletter with guidelines on ethical conduct for scientists.34 Franklin Miller and Alan Wertheimer recently pointed out that the paternalism inherent in research ethics guidelines is fully justified and does not conflict with the primacy of obtaining subjects’ informed consent.35
VALID CONSENT
Since the drafting of the Nuremberg Code 60 years ago, the necessity of obtaining the full, free and informed consent of the research
subject has been elevated to an axiom of clinical research. Implicit in the doctrine of consent is the right of the research subject to refuse entrance into the study or to withdraw from the study at any time. As is true in the doctrine of informed consent for clinical treatment, a subject’s consent for research becomes valid only after there has been complete disclosure of the risks and benefits of the various treatment arms and their alternatives. The subject must have the cognitive capacity to accept or refuse, and there must be no coercion by individuals or agencies. The formalization of the consent process by the subject’s signing of a written document is essential. Patients volunteering as research subjects must be provided a written summary of the proposed research containing an accurate account of the consequences of their participation drafted in clear, understandable language, and including contact information for any questions or problems.36
subject has been elevated to an axiom of clinical research. Implicit in the doctrine of consent is the right of the research subject to refuse entrance into the study or to withdraw from the study at any time. As is true in the doctrine of informed consent for clinical treatment, a subject’s consent for research becomes valid only after there has been complete disclosure of the risks and benefits of the various treatment arms and their alternatives. The subject must have the cognitive capacity to accept or refuse, and there must be no coercion by individuals or agencies. The formalization of the consent process by the subject’s signing of a written document is essential. Patients volunteering as research subjects must be provided a written summary of the proposed research containing an accurate account of the consequences of their participation drafted in clear, understandable language, and including contact information for any questions or problems.36
Valid consent for serving as a subject in a clinical trial is an ideal that often is not realized in practice.37 Busy investigators often spend insufficient time on the process of education of the patient in the details of their participation in the clinical trial. Even when much time has been spent, there is evidence that many research subjects simply fail to understand the information in consent forms,38 misunderstand the concept of randomization,39 fail to appreciate the difference between a clinical trial and ordinary therapy, or cannot comprehend the language of the consent form.40 Some subjects summarily decide to enroll and do not pay attention to the wealth of information presented to them and contained in the consent form.
A research subject’s failure to understand that participation in a clinical trial is primarily for the purpose of research and not therapy is an intractable problem in research ethics that Paul Applebaum and colleagues called the “therapeutic misconception.”41 Many patients consent to participate in a clinical trial because they believe that the trial represents their best chance to receive the latest and best treatment.42 Despite the investigator’s efforts to explain the research nature of the clinical trial, the patient continues to conceptualize participation as an opportunity to receive therapy. Some patients erroneously assume that the newest experimental treatment is necessarily the best treatment and therefore simply wish to have access to it. The therapeutic framing of most clinical trials of pharmaceuticals further aggravates the therapeutic misconception43 as does the circumstance of dual agency in which the clinical investigator also is the patient’s physician.44
Volunteering as a subject in a phase I oncology trial raises several ethical concerns. Subjects should not be coerced into consenting for clinical trials because coercion violates the freedom criterion for valid consent. However, some patients with widespread cancer for whom no known therapy is effective conceptualize their choice as either enrolling in a phase I oncology trial or dying. They automatically conclude that they have no real choice and therefore must enroll. As a result, during the consent process, they neither seek to learn nor attend to the described details of treatment side effects or other adverse consequences. Some scholars have called this circumstance “implicit coercion of desperate volunteers” and believe that it raises doubts about whether such a subject’s consent ever can be truly voluntary.45 A study from the National Institutes of Health showed that as patients became sicker, they understood less of the consent document and more frequently misunderstood the experimental purpose of the clinical trial. The authors pointed out that “research patients with life-threatening illnesses continue to view themselves primarily as patients seeking treatments.”46
In the consent process, investigators (particularly in phase I oncology trials) have a heightened duty to be unambiguously clear about the research basis of the clinical trial and its true benefits to patient-subjects and society.47 Interventional attempts to improve subjects’ understanding and enhance voluntariness have had mixed results.48 The actual magnitude of the ethical problem of desperate volunteers may be overstated because the benefit to patients from participating in phase I oncology trials is greater than that formerly assumed and usually is sufficient to satisfy the ethical requirement of a favorable risk-benefit ratio.49
Moreover, investigators make offers of participation to prospective research subjects, not threats; therefore overt coercion usually is not practiced.50 The ethical problems of phase I oncology trials are further mitigated because consent forms almost never promise benefit and usually communicate serious risks.51 Another problem faced by patients who volunteer for a phase I study is that current Medicare regulations deny hospice benefits to any terminally ill patient enrolled in a phase I oncology trial. This perverse disincentive should be eliminated.52
Moreover, investigators make offers of participation to prospective research subjects, not threats; therefore overt coercion usually is not practiced.50 The ethical problems of phase I oncology trials are further mitigated because consent forms almost never promise benefit and usually communicate serious risks.51 Another problem faced by patients who volunteer for a phase I study is that current Medicare regulations deny hospice benefits to any terminally ill patient enrolled in a phase I oncology trial. This perverse disincentive should be eliminated.52
In a recent study of subjects offered participation in a phase I gene transfer therapy trial for Parkinson’s disease, Scott Kim and colleagues examined the differences between equal groups of prospective subjects who volunteered and who refused. They found that those subjects willing to participate tended to perceive a lower probability of risk, were tolerant of greater risk, were more optimistic about the benefits of the research to society, and were more decisive and action-oriented.53
Some patients prefer to defer the decision to enroll in a clinical trial to their physicians whom they trust implicitly. When the clinical investigator also serves as the patient’s physician, this double agency further compounds the confusion in the patient’s mind between research and therapy and also creates a conflict of interest.54 In some cases, patients consent to participate in a clinical trial out of gratitude to their physicians because their participation may be the most demonstrable way patients can express their gratitude. Although there is nothing wrong with expressing gratitude, some patients may fear retaliation from their physician if they refuse to participate, a condition that raises the question of true voluntary consent. In a recent article, the physician-attorney-ethicist David Orentlicher boldly suggested that when the preferred course of treatment for a particular condition is unknown, patients’ treatment should be conditional on their willingness to participate as a research subject in a clinical trial to fulfill the societal goal of learning the best treatment.55
A practicing physician may conduct research consisting of an experimental or innovative therapy on a single patient, an “n-of-1” experiment, that is not part of an IRB-approved study.56 Physicians conducting ad hoc experimental therapy should assure themselves that a scientific basis exists for the experiment and that the patient has provided full valid consent with an understanding that the therapy is experimental. In those instances in which the experimental therapy poses a significant risk to the patient, before beginning the physi-cian should discuss the advisability of proceeding with the experiment with knowledgeable colleagues.57
Whether to pay research subjects remains controversial. Some scholars have worried that subjects enrolling in a clinical trial may be subjected to “undue inducement” if payments were offered. The same fear has been raised in research in developing countries (see below) in which participating in the research may be the only means for impoverished citizens to obtain a particular therapy.58 Although a few scholars have argued that paying research subjects is inherently unethical because it may motivate a patient to take risks that he or she otherwise never would take,59 most commentators agree that it is acceptable in some cases if it is regulated by careful attention to the intersection of ethical considerations and market forces.60 Federal regulations leave the matter of payments to IRBs to decide, but the “common rule” regulation prohibits “undue inducement.”61 In a survey of 32 research organizations, Neal Dickert and colleagues found that most organizations paid research subjects for their time (87%), inconvenience (84%), travel (68%), as an incentive (58%), or for risks incurred (32%), but only 37% had written policies governing payments.62 Ezekiel Emanuel pointed out that inducements are a normal part of life and human motivation and are not inherently unethical. He believes that proper informed consent and IRB oversight of the risk-benefit ratio can prevent inducements from becoming undue.63
Robert Truog and colleagues provocatively argued that subjects’ informed consent is not always necessary for their participation in clinical trials. The authors pointed out that physicians are authorized to treat individual patients with experimental therapies in a clinical context
with general consent and require specific consent for the same therapy only when it is part of a clinical trial. They offered criteria exempting informed consent in clinical trials, the first of which is that all treatments in the trial must be available outside the trial with-out specific informed consent.64 But here they confounded the ethical and legal requirements for consent. If an experimental therapy is proposed, ethically it should require the same degree of consent, irrespective of whether it is in a clinical trial. However, they were correct in asserting that there is a marked difference between the ideal and real consent-obtaining behaviors of physicians in the two circumstances.
with general consent and require specific consent for the same therapy only when it is part of a clinical trial. They offered criteria exempting informed consent in clinical trials, the first of which is that all treatments in the trial must be available outside the trial with-out specific informed consent.64 But here they confounded the ethical and legal requirements for consent. If an experimental therapy is proposed, ethically it should require the same degree of consent, irrespective of whether it is in a clinical trial. However, they were correct in asserting that there is a marked difference between the ideal and real consent-obtaining behaviors of physicians in the two circumstances.
Whether institutions have an ethical responsibility to provide compensation or medical care to subjects who sustain research injuries remains controversial. Some scholars assert that institutions have an ethical duty to provide care or compensation regardless of blame and whether the subjects have been paid or not. Other scholars disagree, claiming that compensation or care for research injuries is not ethically required because the subjects were made aware of the risks and accepted them during the informed consent process.65 Academic medical centers have varying policies on providing compensation and care of subjects who sustain research injuries, with slightly more than half not providing free care.66 Irrespective of a particular institution’s policy on payment, each research protocol should clearly stipulate the plan for handling research-related injuries, so that during the consent process, the subject is aware of and concurs with how this contingency will be handled.
Consent for Vulnerable Subjects
The principal remaining controversies in obtaining consent for research surround obtaining the consent of a “vulnerable subject.” Subjects are classified as vulnerable when they reasonably cannot be expected to provide independent valid consent, as a conse-quence of treatment urgency or of physical or cognitive incapacity, and thus they require surrogates to provide consent on their behalf. Vulnerable subjects deserve special procedural protections because they have been the victims of past research abuses resulting from deficient or absent surrogate consent. But neither should they be overprotected to the point that research cannot be done at all because research on their conditions is desirable. Thus, reasonable guidelines should be formulated for conducting research on vulnerable subjects that adequately protect but do not overprotect them. The major categories of vulnerable subjects are those with emergency conditions, children, and patients with cognitive impairments. Carol Levine and colleagues decried the recent tendency to expand the class of vulnerable patients to include people residing in economically disadvantaged countries, members of lower socioeconomic groups, and other large groups because the concept loses meaning and force when applied to too many people.67
Emergency Research.
Often it is impossible to obtain valid consent for a clinical trial to study an emergency treatment. The problem is how a clinical trial ever can be administered in a setting in which it may not feasible to obtain consent because of the obvious time constraints of emergency treatment and the frequent unavailability of surrogates. Some scholars have advocated that the doctrine of implied (waived) consent could be applied in this circumstance, arguing by analogy that the emergency treatment doctrine permitting physicians to provide standard emergency therapy without consent also should pertain to conducting emergency research. However, given that the standard for obtaining consent for serving as a research subject is more stringent than consent for clinical care, and that many patients refuse to enter clinical trials, it is not clear that consent for an emergency clinical trial can be merely presumed.68
Unless the consent issue can be handled successfully, no ethically acceptable clinical trials can be conducted for studying emergency treatments.69 The Coalition Conference of Acute Resuscitation and Critical Care Researchers pointed out that patients with emergency conditions not only are vulnerable to being victimized by their incapacity but also are vulnerable
to being denied potentially life-saving treatments if those treatments cannot be studied adequately. They urged the development of federal guidelines to permit and regulate such studies.70
to being denied potentially life-saving treatments if those treatments cannot be studied adequately. They urged the development of federal guidelines to permit and regulate such studies.70
Federal regulations propounded by the United States Food and Drug Administration (FDA) and the United States Department of Health and Human Services (DHHS) address the situation of informed consent in emergency research.71 The regulations stipulate those emergency circumstances in which it is acceptable for a clinical trial to be performed without the consent of the research subject. The FDA criteria72 permit the use of an investigational drug in an emergency instance if: (1) the human subject is confronted by a life-threatening situation necessitating the use of the test article; (2) informed consent cannot be obtained from the subject because of an inability to communicate; (3) time is insufficient to obtain consent from the subject’s legal representative; and (4) there is no available alternative method of approved or generally recognized therapy that provides an equal or greater likelihood of saving the life of the subject.73
Similarly, the DHSS regulations to waive informed consent74 require that: (1) the research involves no more than minimal risk to the subject; (2) the waiver will not adversely affect the rights and welfare of subjects; (3) the research could not be practicably carried out without the waiver; and (4) whenever appropriate, the subjects will be provided with additional pertinent information after participation.75 Alison Wichman and Alan Sandler tabulated the specific FDA and DHHS criteria for designing an acceptable clinical trial using the consent waiver.76
These federal regulations were written because of the shared belief that individuals and society would be best served if emergency research took place. Authority has been vested in the IRB to guarantee that the approved clinical trials are justified by their scientific validity, safety, and proper patient protections. Members of the public mandated to serve on IRBs have a responsibility to define normative risks. They and the other IRB members have the additional difficult task of determining whether the proposed research falls within the definition of “minimal risk.”77 Minimal risk usually refers to a probability and magnitude of harm not greater than that ordinarily encountered in daily life.78 David Wendler criticized this definition as flawed because many people choose to undergo significant risks in their daily lives.79 Two respected research ethics scholars, Robert Levine and Jay Katz, wondered whether IRB members will be able to adequately interpret and apply these criteria to successfully approve randomized clinical trials of emergency medications.80
Children.
The participation of a minor in a clinical trial raises vexing questions that attempt to balance the opposing goals of paternalistic protection of vulnerable minors against their appropriate access to clinical trials to establish efficacy and safety of therapy.81 A minor’s participation requires consent of the minor’s surrogate decision maker (usually the parent) and the assent of the minor, provided the minor is capable of understanding the proposed clinical trial.82 “Assent” is the term referring to the child’s permission to proceed with treatment or experimental therapy. Although assent does not replace the legal duty of parental or other surrogate consent, it is an ethical prerequisite for treatment of children, especially for experimental purposes. The Committee on Bioethics of the American Academy of Pediatrics issued recommendations for obtaining assent in children of various ages.83 Nancy Ondrusek and colleagues determined that children under the age of nine years lacked the capacity to understand the fundamental characteristics of a research study. They proposed that the concept of assent for research in children should be implemented only once children are at least nine years old.84
Federal regulations from the DHSS and FDA and overseen by the NIH Office of Human Research Protection (OHRP) permit certain research in children and other vulnerable human subject populations for whom there is no prospect of direct benefit only if the research involves no greater than minimal risk.85 Federal regulations define minimal risk as the risk for which “…the probability and
magnitude of the harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests.”86 However, this seemingly straightforward concept implying a very low absolute risk has been subject to varying interpretations and considerable disagreement. Charles Weijer, a leader in research ethics, has provided a comprehensive analysis of the ethical and legal concepts of risk in clinical trials.87
magnitude of the harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests.”86 However, this seemingly straightforward concept implying a very low absolute risk has been subject to varying interpretations and considerable disagreement. Charles Weijer, a leader in research ethics, has provided a comprehensive analysis of the ethical and legal concepts of risk in clinical trials.87
For example, applying the concept to research on children, Benjamin Freedman and colleagues pointed out that children and teenagers frequently conduct highly risky behaviors in the course of their normal daily lives, such as riding bicycles without helmets, driving automobiles recklessly and without using seatbelts, and engaging in unprotected sexual intercourse.88 Thus, they ponder, is the concept of minimal risk meant to entail a magnitude of risks such as these simply because they are encountered in daily life? Because what counts as minimal risk is subject to such varying interpretations, it is no surprise that IRBs have struggled with the task of assessing whether the risks of a clinical trial for which they are considering approval are or are not greater than minimal risk and applying the regulations consistently and correctly.89
David Wendler and colleagues quantified risks that children experience in everyday life. They found that the risk of injury or death from automobile trips and participation in sports were greater than that produced by experimental therapeutic agents that many IRBs dismissed on the grounds of posing risks greater than those encountered in ordinary life.90 Loretta Kopelman advocated a plausible sliding scale analysis to more reasonably interpret the federal regulations.91 Because of the intractable ambiguity of the language of federal regulations and their inconsistent application, some scholars have called for the creation of a national consensus on the interpretation of the regulations.92
Researchers wishing to seek IRB approval of a clinical trial have a great incentive to seek minimal risk status to comply with the statute even when the risks arguably are greater than minimal. Indeed, the OHRP catalogued a series of risk misstatements or misjudgments in funded protocols. In its first year of operation, the OHRP restricted or suspended research activities at eight institutions because of failure to accurately assess risks in consent forms or provide safeguards for vulnerable subjects.93
Patients with Cognitive Impairment.
Research on patients with cognitive impairment is discussed in chapter 15.
Privacy and the HIPAA Regulations
The United States Congress enacted the Health Insurance Portability and Accountability Act (HIPAA) in 1996 to protect citizens’ health information. In December 2000, the Depart-ment of Health and Human Services issued the Privacy Rule establishing standards for protecting health information. Staff members of hospitals, physicians’ offices, and other health sites have been instructed in how to comply with the lengthy and cumbersome new privacy and confidentiality regulations that took effect in April 2003 (see chapter 3). Although the Privacy Rule was intended primarily to protect clinical information, its broad application to “covered entities” encompassed medical information collected in the context of human subjects research.94
The Privacy Rule concerns all “individually identifiable” health information created or maintained by a covered entity including a research enterprise. The HIPAA regulations heighten the requirements for obtaining infor-med consent from research subjects over those already required by the United States federal research consent requirements. The prolixity and complexity of the regulatory language has spawned an industry of consultants to interpret the regulations and of compliance officers to assure that they are followed correctly. IRBs have struggled to understand the precise requirements of the new law, particularly as it applies to research involving data registries, and in defining those situations in which waivers or exemptions may be permissible.95
Commentators have opined that the regulations have hampered research because of the logistical hurdles they impose, the added
expense of compliance, the fear and intimidation that IRB members and investigators have experienced over their own liability for possibly violating a regulation, and the fact that alternative means of protecting research subjects’ privacy could be accomplished without the problems caused by HIPAA. IRB members have required that investigators add complex and lengthy text to research consent forms to comply fully with HIPAA regulations. This additional text is likely to confuse research subjects and is unlikely to improve their understanding of the study.96 Clearly, the HIPAA regulations, intended to improve privacy protection of confidential medical information, have had a perverse effect of impeding clinical research while providing no obvious benefit.
expense of compliance, the fear and intimidation that IRB members and investigators have experienced over their own liability for possibly violating a regulation, and the fact that alternative means of protecting research subjects’ privacy could be accomplished without the problems caused by HIPAA. IRB members have required that investigators add complex and lengthy text to research consent forms to comply fully with HIPAA regulations. This additional text is likely to confuse research subjects and is unlikely to improve their understanding of the study.96 Clearly, the HIPAA regulations, intended to improve privacy protection of confidential medical information, have had a perverse effect of impeding clinical research while providing no obvious benefit.
THE RANDOMIZED CLINICAL TRIAL
The randomized clinical trial (RCT) is the ultimate scientifically rigorous clinical investigation.97 The RCT is an experiment testing a hypothesis in which the investigator randomly assigns patients to groups experiencing different exposures to interventions. By carefully controlling the intervention arms to assure that the groups are otherwise identical in composition and treatment, the investigator can reasonably conclude that any measured difference in the outcomes of the groups resulted from the difference in exposures because that was the only difference among them.98
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