Andrew D. McRae, MD, FRCPC
Resident, Dept. of Emergency Medicine, Queen�s University
Doctoral Candidate, Dept. of Epidemiology and Biostatistics, University of Western Ontario
Table of Contents
- Introduction: Why Research Ethics?
- Regulations and Guidelines
- Basic Principles
- Research Ethics and the Law
- Special Populations
- Research in Developing Countries
- Privacy and Confidentiality
- Research Integrity and Fraud
- Conflicts of Interest
- Innovative Therapies
- The Research Ethics Board (REB) Review Process
- Figure 1: The ethical analysis of benefits and harms in research by the REB
- Appendix 1: Practical Advice for Research Ethics Board (REB) Submissions
- Appendix 2: Informed Consent Forms — Evidence and Examples
Research involving human subjects raises ethical challenges that are distinct from those encountered in clinical medicine. These challenges stem from differences in the purposes of medical care and clinical research.
Medical therapy is intended to improve the health of an individual patient. Clinical research, although it may benefit individual subjects, serves the interest of future patients. Research poses risks associated with data-collecting interventions that do not exist in clinical practice. Because of the uncertain efficacy of experimental treatments and because of the necessity for additional data-collecting interventions, the disclosure and consent process for research is different. Investigators are responsible not only for the welfare of their subjects but also for the quality of the science. Investigators may encounter conflicts between the interests of research subjects and the interests of science or of research sponsors.1
The field of research ethics has evolved to consider potential resolutions to these issues. The ultimate goal of ethical guidelines and the ethics review process is to optimally protect research subjects while simultaneously facilitating important clinical research.
Much of the philosophical reflection on the ethics of biomedical research has been produced in response to specific abuses of research subjects by investigators.
Arguably the best-known instance of the abuse of research subjects was the experimentation on prisoners by Nazi physicians during the Second World War. Using concentration camp detainees as subjects, scientists examined the effects of various infectious diseases, ingestion and injection of toxins, extremes of heat and cold, and other harmful exposures. Individuals indicted before the war crimes tribunal at Nuremberg were charged with conducting cruel experiments on vulnerable, unwilling subjects. With few exceptions, this research has had little impact on modern medical practice. The judgment of the cases against these individuals contained rules for scientific research that have become known as the “Nuremberg Code,” one of the earliest sets of guidelines for the ethical conduct of research on human subjects.2
In his influential 1966 paper “Ethics and Clinical Research,” Boston anesthesiologist Henry Beecher outlined 22 examples of investigations that deceived subjects or exposed them to unnecessary risks without their consent.3 He chose these examples from a total of 50 suspect studies, limiting his report for the sake of brevity. Of the 22 studies, only two sought the consent of subjects. In addition to the non-consensual nature of these research studies, the studies exposed subjects to inappropriately high degrees of risk for little or no therapeutic benefit. Examples cited by Beecher include a study of the effect of thymectomy on skin graft survival in children undergoing congenital heart surgery and a study of non-therapeutic transbronchial cardiac catheterization in patients undergoing bronchoscopy for pulmonary disease.
One of the studies cited by Beecher was subject to further public exposition. At the Jewish Chronic Disease Hospital in Brooklyn, New York, both cancer patients and healthy subjects were injected with cancer cells, without disclosure of the nature of the injections. The aim of the research was to identify differences in the immune response to cancer between individuals with cancer and healthy persons. After the nature of the study was exposed, the investigators were censured by the Board of Regents of the State University of New York. Importantly, the Board concluded that non-disclosure of material risks was no different from deliberate misrepresentation and that any consent obtained after withholding information was fraudulently obtained.4
Another scandal over consent for research participation originated at the Willowbrook State School, an institution for mentally handicapped children on Staten Island, New York. In the early 1960s, mild fecally transmitted hepatitis was endemic at Willowbrook. In an effort to develop a preventive agent, researchers deliberately infected children who were newly admitted to the institution. This was done on children whose parents had given consent for the study. The investigators argued that the children would have inevitably acquired hepatitis and that inclusion in the study afforded the children the best possible care. Critics not only questioned the care provided to the children but also concluded that disclosure of the nature of the intervention and its long-term risks was inadequate. Furthermore, some parents were coerced into enrolling their children into the study as a condition of their children’s admission to Willowbrook.4
Perhaps the most infamous instance of abuse of research subjects in the United States took place in a study of the natural history of syphilis funded by the U.S. Public Health Service between the 1930s and 1970s in rural Alabama. The Tuskegee Syphilis Study, as it became known, was originally designed to compare the progression of syphilis in persons of African heritage as compared with its progression in Caucasians. The study design was changed to an observational study comparing the progression of syphilis in 400 impoverished African-American men with 200 individuals not infected with syphilis. The 400 cases were not told their diagnosis. Instead, they were merely told that they had “bad blood.” They submitted to lumbar punctures and other research interventions after being told that these non-therapeutic interventions were “free treatments” for their disease. The standard therapy at the time, mercury treatments, was withheld. After penicillin became available, this effective therapy for syphilis was withheld from the subjects to preserve the observation of the natural history of the progression of the disease. The study was finally ended in 1972 after intense media scrutiny. Victims were treated with effective treatments, and a class-action lawsuit on behalf of victims was settled out of court for $10 million US. Ultimately, 28 subjects died of syphilis, 100 died from complications, 40 of the subjects’ wives became infected and 19 of their children were born with congenital syphilis.4 President Bill Clinton officially apologized to the victims and their families in 1997.5
The Department of Health, Education and Welfare appointed an advisory panel to review the Tuskegee study and the protections for human subjects provided in the Department’s policies. The panel concluded that no government department had adequate policies for research oversight and called for the establishment of a regulatory board to oversee all federally funded research. In response to the violations of subjects’ rights at Willowbrook and Tuskegee, and in other studies, the U.S. Congress established the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research in 1974.4 The National Commission’s report, known as the “Belmont Report,” would become the fundamental articulation of the principles of research ethics (see the Basic Principles section of this primer).6
Abuses of the rights of research subjects have also occurred in Canada. Dr. Ewan Cameron’s CIA-funded experiments at the Allan Memorial Institute in Montreal involved the administration of LSD, other medications and electroconvulsive therapy to subjects with minor psychiatric disorders. Dr. Cameron’s work, conducted in the 1950s and early 1960s, was part of the CIA’s mind-control research program, Project MKULTRA. The experiments were based on Cameron’s “psychic driving” theory that a damaged psyche could be rebuilt after erasing previous memories. While there was potential therapeutic benefit, the American intelligence community was interested in Dr. Cameron’s work as a potential intelligence-gathering or brainwashing technique. The CIA chose the Allan Memorial Institute as the site for these experiments so that American citizens would not be used as research subjects. The experiments were often done without the consent of subjects and resulted in significant harm. Dr. Cameron had previously served as a psychiatry expert to the Nuremberg tribunal and, at that time, had condemned experiments that were similar to his own.7
Two instances of experimentation with incomplete disclosure of the risks to subjects led to important Canadian common law rulings about informed consent for research.
A 1965 legal judgment in Halushka v. The University of Saskatchewan has set the legal standard for disclosure of research risks in consent discussions. Walter Halushka was a student at the University of Saskatchewan who volunteered to participate in a trial of a new anesthetic drug. The researchers failed to disclose that the hazards of this drug were largely unknown. Instead, he was informed that he had no reason for concern. He was told that a catheter would be inserted in a vein in his arm, but he was not told that the catheter would be advanced through his heart into the pulmonary artery. Mr. Halushka experienced a cardiac arrest. He was successfully resuscitated, but suffered irreversible cognitive impairment. The judge ruled that researchers are bound by a higher standard of disclosure to research subjects than are physicians who obtain consent for medical treatment from patients. Justice Hall, in his ruling, states that researchers are required to disclose any and all information that a reasonable person would require to reach an informed decision about research participation.8
A 1989 case from Quebec, Weiss v. Solomon, further highlights the importance of disclosure of research risks. Julius Weiss, a 62-year-old man who had undergone cataract surgery, was recruited into a study of the ability of indomethacin eye drops to reduce retinal edema. The consent form, which was revised at the urging of the hospital’s research committee, described the three fluorescein angiograms that were part of the research protocol. The risks were described as being a small likelihood of a minor allergic reaction. Mr. Weiss, in agreeing to participate, signed the consent form. After injection of the fluorescein dye, Mr. Weiss experienced a cardiovascular collapse and died. His family successfully sued the investigators and hospital, on the grounds that his heart condition (hypertrophic cardiomyopathy) should have excluded him from the study, that the risk of cardiac arrest should have been disclosed and that the resuscitation was inadequate because the appropriate equipment was not available at the scene of angiography. The judgment found that the study should have employed stringent subject screening procedures and that consent procedures for research ought to disclose even the remotest risks.9
The reaction to public reports of abusive or harmful studies has often included the development of ethical guidelines and regulations for research involving human subjects.
The Nuremberg Code is the earliest published set of ethical guidelines for biomedical research. It was part of the 1948 judgment in the Nuremberg trial of Nazi physicians who conducted experiments on prisoners during WWII.2 The Nuremberg Code includes an absolute requirement for the informed consent of the subject for research participation. Subjects may be enrolled in a study after they are informed of “. . . all . . . hazards reasonable to be expected” and agree to participate. The Code also requires that experiments be scientifically valid and that the risks are justified by the potential benefits to society in the form of generalizable knowledge. Both the subject and the researcher should be able to terminate research participation if either suspects that the research may be causing harm to the subject.
The World Medical Association published the “Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects” in 1964. Revised on seven occasions over the next 40 years, the Declaration of Helsinki articulates basic ethical principles and guidelines for research involving human subjects.10 It draws a distinction between non-therapeutic research (basic science research presenting no benefit to the research subject) and therapeutic research (research that is integrated with patient care). Enrolment in non-therapeutic research requires the informed consent of the subject, while enrolment in therapeutic research is not required if it is not consistent with patient psychology. The Declaration’s dichotomization of therapeutic and non-therapeutic research is a false one. Even in “therapeutic research,” subjects are still exposed to risks stemming from non-therapeutic, data-collecting interventions that are an integral part of a clinical study.
Despite this shortcoming, the Declaration of Helsinki contains some important advances in the regulation of clinical research.10 It recognizes that not all potential subjects have the capacity for making decisions about research participation, so it allows the enrolment of incapacitated subjects with the consent of a legally authorized substitute decision-maker. The second revision of the Declaration of Helsinki (1975) included one of the first regulatory requirements for the review of research proposals by a research ethics board to assure a study’s compliance with basic ethical principles and guidelines.
The Council for International Organizations of Medical Sciences (CIOMS), under the umbrella of the World Health Organization (WHO) and the United Nations Educational, Scientific and Cultural Organization (UNESCO), issued the “International Ethical Guidelines for Biomedical Research Involving Human Subjects” in 1982. These were revised in 1993 and 2002,11 largely in response to the ethical concerns over clinical trials of therapies for HIV/AIDS in developing countries. Other sets of guidelines with particular relevance to research in developing countries include the WHO’s 1995 “Guidelines for Good Clinical Practice for Trials on Pharmaceutical Products,”12 and the 2000 UNAIDS (Joint United Nations Programme on HIV/AIDS) document “Ethical Considerations in HIV Preventive Vaccine Research.”13
Research supported by U.S. federal funding is governed by Department of Health and Human Services regulations. Enacted into law in 1981, these regulations were most recently revised in 1995. Known as the “Common Rule,” these regulations apply to research funded by most federal departments. The Common Rule outlines requirements for informed consent and ethics board review, as well as consequences of failure to comply with regulations. Additional sections of the Common Rule outline protections for vulnerable classes of research subjects, including children, pregnant women, fetuses and neonates, and prisoners.
Federally funded research in Canada is subject to the “Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans” (TCPS).14 The TCPS was originally adopted by the Medical Research Council of Canada, the Natural Sciences and Engineering Research Council of Canada, and the Social Sciences and Humanities Research Council of Canada in 1996. It now applies to research funded by the Canadian Institutes of Health Research.
Health Canada requires that industry-funded research is performed according to the International Conference on Harmonization (of Technical Requirements for the Registration of Pharmaceuticals for Human Use) guidelines for good clinical practice (ICH-GCP). The ICH-GCP is a quality standard for the design, conducting and reporting of clinical trials developed by the regulatory agencies of the European Union, Japan and the United States to facilitate the acceptance of clinical trial information from industry in multiple regulatory jurisdictions.15 In addition to the ICH-GCP, Health Canada’s own Research Ethics Board, which reviews research performed by or funded by Health Canada, adheres to the TCPS.16
The ethical guidelines and regulations that have been developed over the past half-century reflect a set of basic ethical principles. These principles are most concisely articulated in “The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research,” the 1979 report of the U.S. National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. The Belmont Report identifies three basic principles that guide the ethical conduct of research involving human subjects: respect for persons, beneficence and justice.6
The principle of respect for persons describes two separate moral requirements. First, capable individuals should be treated as autonomous agents. Second, those with diminished autonomy require additional protections.
Practically, this means that the choices of capable individuals must be respected. This is the source of the requirement for subjects’ informed consent for research participation (as well as for clinical procedures). Deceiving or withholding information, or ignoring an individual’s wishes is considered to be disrespectful to that individual’s autonomy. Respect for persons requires that individuals participate in research voluntarily after being provided with adequate information about the nature of the research study.
Some individuals may have diminished autonomy. This is the case for children, whose capacity for self-determination develops as they mature, and also for adults whose capacity is diminished because of illness or injury. This may also be true for such individuals as prisoners or soldiers, whose liberty is restricted. The National Commission recognized that respecting these individuals means protecting them as they remain incapacitated. The extent of necessary protections depends on the degree of subjects’ vulnerability and on the risk of harm and likelihood of benefit.
Typical protections for individuals with diminished capacity include the requirement for consent from an authorized substitute decision-maker and a limit on the degree of permissible research risk. The limit on research risk should be commensurate with the degree of a subject’s vulnerability. Vulnerability is influenced by many factors, including the severity and urgency of the subject’s medical problem, and the presence or absence of a substitute decision-maker. For example, research subjects with acute incapacitating illnesses may require more stringent protections than subjects enrolled in studies of chronic medical conditions. Subjects in emergency research who have no substitute decision-maker available may require more stringent protections than those subjects who do have a substitute decision-maker.
The principle of beneficence describes the requirement to protect, as much as possible, the well-being of research subjects. This means avoiding deliberate harm and maximizing the potential benefits while minimizing the risks.
The key step in satisfying the principle of beneficence is the diligent review of a research project’s risks and potential benefits by a research ethics board (REB). The analysis of risks and potential benefits is arguably the most important function of the REB. By ensuring that the balance of risks and potential benefits is reasonable, the REB ensures that a subject’s choice to participate in research is a reasonable one.
The thoughtful analysis of risks and potential benefits involves more than ensuring a semblance of balance. In fact, the use of the term “balance” has led to unnecessary confusion about the process of analyzing risks and potential benefits. Many ethical guidelines and regulations have drawn the distinction between therapeutic research — clinical research that may benefit the subject — and non-therapeutic research — basic science research that offers no potential benefit to the subject. By attempting to “balance” risks and potential benefits in therapeutic research, REBs could permit extraordinarily risky research interventions on critically ill individuals, provided that the research presented the possibility for direct benefit to the subject. This seems at odds with the principle of respect for persons, which requires that vulnerable subjects be protected in a way that reflects their vulnerability.
The distinction between therapeutic and non-therapeutic research is a false one. Clinical research contains both therapeutic procedures — the interventions being studied — and non-therapeutic procedures — interventions used purely to gather data and answer the scientific question of the study. Therapeutic procedures offer the possibility of direct benefit to the subject. Non-therapeutic procedures, by definition, do not offer benefit but are an integral part of a research study. The use of non-therapeutic procedures is an important distinction between clinical practice and research.17
A better approach to the analysis of risks and potential benefits is to examine the risks and potential benefits of therapeutic procedures and non-therapeutic procedures separately. This framework for the analysis of risks and potential benefit is known as “component analysis.”18
Therapeutic procedures must be consistent with competent medical care, and the risks of therapeutic procedures must be justified by the potential for direct benefit to the research subject.18 In comparative studies, such as a randomized controlled trial, therapeutic procedures must satisfy the requirement for clinical equipoise. Clinical equipoise requires that a state of honest, professional disagreement as to the preferred treatment must exist in the expert clinical community. The purpose of a trial is to disturb this state of clinical equipoise and thereby provide evidence-based reasons for changing standard clinical practice. By ensuring that equipoise exists at the start of a trial, the REB assures subjects that they will not be disadvantaged or given substandard treatment by randomization to one arm of a trial or another.19 The requirement for clinical equipoise at the outset of a randomized controlled trial is explicitly stated in the TCPS (Section 7A).14
One practical implication of these ethical requirements for therapeutic procedures is that the use of placebo controls is justifiable only if no effective treatment exists for the condition under study or if no treatment is an acceptable therapeutic option.18 This is explicitly stated in Article 7.4 of the TCPS.14
While clinical equipoise offers a moral justification for the randomization of subjects, it may not assuage the conscience of an individual clinician who has a strong preference for one particular treatment in a randomized trial or who is unsure whether it is appropriate to offer study enrolment to a particular patient.20 Physician investigators have a duty of care to their subjects. If, in a physician’s clinical judgment, study participation may be inappropriate for a patient, even if that patient meets a study’s inclusion/exclusion criteria, then that particular patient should not be offered enrolment in the study. If, however, there is no compelling medical reason to exclude a patient from a study and if clinical equipoise exists, then it is inappropriate for an individual physician to ignore the disagreement in the expert clinical community and withhold study enrolment from that patient.21
Non-therapeutic procedures are assessed separately from therapeutic procedures. First, the risks of non-therapeutic procedures must be minimized as much as is possible within a sound scientific design. For example, unused serum collected for clinical purposes may be used to measure biochemical markers rather than subjecting the subject to additional blood draws. Second, the REB must determine that the risks of non-therapeutic procedures are reasonable in relation to the importance of the scientific knowledge that is expected to be gained.
For research involving vulnerable subjects, a limit on the degree of permissible risk for non-therapeutic interventions is required. Because the risks of therapeutic procedures are justified by their potential benefits and because clinical equipoise assures no disadvantage to randomization, a risk threshold can only sensibly be applied to non-therapeutic procedures. These non-therapeutic procedures represent the incremental risk of research participation. Research that enrols subjects with diminished capacity and with the consent of a substitute decision-maker, as in pediatric research, is subject to a threshold of no more than a minor increase above minimal risk. Minimal risk refers to the risks associated with daily life, including routine physical examinations or tests.22
A study may be approved by an REB only if the therapeutic procedures and non-therapeutic procedures in a study satisfy these separate ethical requirements (see Figure 118).
Critics of component analysis have argued that this framework is unduly cumbersome and doesn’t adequately distinguish between therapeutic and non-therapeutic interventions.23 Supporters of component analysis have refuted this argument and have argued that alternative approaches to the analysis of risks and potential benefits fail to withstand rigorous intellectual scrutiny.21
The principle of justice entails a fair distribution of the burden of research risks and an assurance that the benefits of research will similarly be fairly distributed. What this means is that the class of subjects bearing the burden of research risks must ultimately benefit from the results of research. It also means that all classes of subjects who may benefit from research be allowed to participate, so that the results of research may be applied to all who may benefit.
Practically, the principle of justice forbids the use of populations of convenience for research study. Subjects who are easily accessible because they are hospitalized or institutionalized already bear significant burdens because of their medical conditions. Burdening these populations with research risks is just only if the class of subjects will benefit from the research. Basic science or physiological research that offers no benefit to these subjects is permissible only if it is related to their medical condition. Otherwise, a less vulnerable subject population, such as healthy volunteers, is more appropriate.
The principle of justice also applies to research in developing countries. Studies taking place in developing countries must evaluate only treatments that will be available in those locations after the study ends. To study treatments that will not be accessible to the population is to unjustly burden these subjects with research risks without the possibility of benefit. Research in developing countries is discussed further below.
Justice also requires that the burdens and benefits of research be fairly distributed. For both scientific and ethical reasons, clinical research must include subjects suffering from the medical condition under investigation. Conversely, the exclusion of particular types of subjects (e.g., women, children, the elderly) without scientific justification may deprive these classes of subjects with valuable evidence as to the efficacy of a particular therapy.
There is no Canadian federal legislation specifically addressing the conduct of biomedical research. Rather, research at institutions receiving federal funds is governed by the guidelines outlined in the TCPS,14 as interpreted by local REBs. Quebec has specific provincial legislation. The Quebec Civil Code contains sections pertaining to biomedical research that investigators in that province should be aware of. Specific cases, as mentioned above, have generated judicial rulings that have set out specific requirements for consent for research participation.
The judgments in Halushka v. The University of Saskatchewan and Weiss v. Solomon have explicitly stated that the standard for disclosure of pertinent information in the informed consent process is higher for research than for medical practice. In research with no intended benefit to the subject, investigators are required to provide a “full and frank” disclosure of all risks, no matter how rare. To date, there have been no cases arising from harms incurred in clinical research that contained therapeutic procedures. It is therefore unclear whether the standard of disclosure would be different for clinical research than it would be for basic science research or research with no direct benefits to the subject.8,9 The TCPS requires disclosure of all reasonably foreseeable harms, and their consequences, during consent negotiations (Article 2.4).14
There is abundant literature demonstrating that research consent forms are typically worded at a more complicated reading level than is generally accessible by the general population. The basic elements of disclosure required by the TCPS can be conveyed simply in one or two pages. However, many research consent information sheets exceed 10 pages. It is likely that these additional pages convey information that is not useful to subjects, but rather is aimed at indemnifying institutions from legal liability.
Certain types of subjects are considered more vulnerable than others, by virtue of diminished capacity or the seriousness of their medical condition. Examples include children, incapable adults and emergency patients. The principle of respect for persons requires that those with diminished capacity be extended additional protections to safeguard their welfare. The protections owed to some classes of subjects are outlined in regulations or ethical guidelines, although for some types of subjects the necessary protections have been inferred by analogy.
Early in life, children are not capable of making informed decisions about research participation. Because of this lack of capacity, children constitute a vulnerable population and are entitled to additional protections. Children are supposed to be protected by a substitute decision-maker, either a parent or legal guardian. A parent is responsible for making decisions regarding research participation that are in the child’s best interests, including consenting to research participation.
As they mature, children will develop opinions about whether or not they would like to participate in a research study. For this reason, it is necessary to also seek the assent of a child prior to enrolment in a research study. Assent refers to a child’s agreement to participate in a study after having discussed the risks and potential benefits with parents, investigators and others. The assent process allows the child to understand, as much as is possible, the purpose, potential advantages and potential consequences of study participation and gives the child an opportunity to refuse to participate. The U.S. National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research established the age of 7 as an appropriate age to involve a child in discussions about study participation and to seek their assent for participation.24 However, the capacity to assent or dissent will vary between children and should be assessed individually.
The protection of having a substitute decision-maker is but one of the additional protections required for children. U.S. federal regulations impose a risk threshold of no more than a minor increase above minimal risk. What this means is that the risks of non-therapeutic research interventions can pose only a small increase above the types of risks commonly encountered in a particular child’s daily life. The threshold of a minor increase above minimal risk is derived from the parental responsibility to protect a child from excessive risk. It is consistent with a parent’s custodial duty to allow a child to be exposed to risks that slightly exceed those risks encountered in that child’s daily life.25 This is the way in which children become exposed to new experiences. If parents only permitted their children to be exposed to the risks of their daily lives, then the child would not encounter novel life experiences. To permit a child to be exposed to risks that are slightly above those encountered in daily life is consistent with a parent’s responsibilities.
In Canada, the threshold for permissible risk in pediatric research is different. The TCPS requires that research on incompetent individuals (such as children) pose no more than minimal risk without the possibility of direct benefit (Article 2.5).14 This means that basic science, physiological or epidemiologic studies may pose no more than minimal risk. However, for studies that offer possible direct therapeutic benefits, the TCPS imposes no meaningful risk threshold: as long as great benefit is possible, subjects may be exposed to great risks. This seems at odds with the principle of respect for persons, which requires that subjects be protected in a way that reflects their vulnerability. In reviewing pediatric research, REBs are advised to use component analysis to assess the risks and potential benefits. Therapeutic procedures must be consistent with competent medical care, risks must be justified by possible therapeutic benefits and the requirement for clinical equipoise must be satisfied. The risks of non-therapeutic procedures should be minimized as much as possible within a sound scientific design, and the risks should be justified by the knowledge to be gained. The TCPS requires that an REB should enforce a threshold of minimal risk for non-therapeutic procedures in clinical research involving children.
Children with chronic illnesses face greater risks in their daily lives than do healthy children. When interpreting the threshold of no more than a minor increase above minimal risk, the risks of daily life refer to the risks of daily life of a class of subjects under study. In other words, for research on healthy children, the threshold on non-therapeutic procedures is no more than a minor increase above the risks of daily life of a healthy child. For research studies on children with chronic illnesses, the threshold is no more than a minor increase above the risks of daily life of a child afflicted with the illness under study.
Adults may lack or lose the capacity to make decisions about research participation because of injuries or acute or chronic illnesses. Incapacitated adults constitute a vulnerable population in need of protection. The protections that have historically been extended to incapacitated adults closely resemble the protections extended to children. These makes sense, since both groups of subjects lack decision-making capacity and are protected by substitute decision-makers.
The TCPS (Articles 2.5–2.7) lays out the protections that are owed to incapacitated research subjects in Canada.14 First, to ensure that these vulnerable subjects do not bear an unjust burden of research risks, incapacitated adults may be enrolled as research subjects only when the research question requires their participation. The participation of incapacitated adults must be authorized by a substitute decision-maker who is not part of the research team.
The research must pose no more than minimal risk, unless the research risks are justified by potential direct benefits. This is identical to the protections offered to pediatric research subjects. REBs should employ component analysis to ensure that therapeutic procedures and non-therapeutic procedures comply with the TCPS guidelines.
Individuals may, because of life-threatening illness or injury, lose their ability to make decisions about research participation. In the emergency or pre-hospital setting, it may be impossible or unfeasible to contact an authorized substitute decision-maker before potentially life-saving interventions are required. This creates a dilemma for emergency and resuscitation researchers. How may incapacitated subjects with life-threatening problems be enrolled in clinical trials of novel, potentially life-saving therapies? For a thorough discussion of the ethical debate over emergency research, the reader is referred to readings by Biros26 and McRae and Weijer.27
The TCPS includes a provision for a waiver of informed consent for emergency research when subjects are incapacitated and no substitute decision-maker is available (Article 2.8).14 The TCPS requires that the research cannot be practicably done without the waiver and that current treatments for the problem under study are unsatisfactory. Research risks must be “. . . not greater than [those] involved in standard efficacious care, or . . . clearly justified by the direct benefits to the subject.”
The risk threshold contained in the TCPS is problematic. It means that the sicker or more injured a subject is, the more she or he may be exposed to excessively risky non-therapeutic interventions, provided that the potential benefit of therapeutic interventions is great. This risk threshold is not adequate protection for vulnerable subjects. By applying component analysis, the risks of therapeutic procedures must be consistent with competent medical care, must be justified by their potential benefit and must satisfy the requirement for clinical equipoise. A stringent risk threshold on non-therapeutic procedures ought to be imposed. Children, who are protected by a substitute decision-maker, are also protected by a risk threshold on non-therapeutic procedures of no more than a minor increase above minimal risk. Subjects in emergency research are generally more vulnerable than children enrolled in clinical research and require the protection of a more stringent risk threshold on non-therapeutic procedures, namely, minimal risk.
A second problem with the TCPS risk threshold is the insistence on direct benefits to the subject. This effectively disallows basic science or epidemiologic studies in resuscitation or emergency settings. Basic science and epidemiologic research is required for the development of new hypotheses for potential treatments for resuscitation and emergency care. A moratorium on this type of research limits our ability to advance emergency care beyond its current state. Again, the use of component analysis appears to be the solution: basic science and epidemiologic research using a waiver of consent in resuscitation and emergency situations would be acceptable provided that the risks of the study interventions were minimal.
The use of component analysis for emergency research is consistent with the spirit of the TCPS. It protects vulnerable subjects better than do the current TCPS guidelines and allows important emergency research to proceed.
Studies performed by investigators from developed countries using subjects from developing countries with greater disease prevalence may place an unjust burden on those subjects. This problem was highlighted especially in the 1990s with HIV/AIDS treatment and prevention trials in Africa and Southeast Asia. The evaluation of drug cocktails that poorer countries could not afford placed an undue amount of risk on subjects in developing countries. Although some subjects who participated in these studies may have benefited, the results have no benefit for the population in question. The benefit would accrue only to those individuals in countries that could afford the medications under study.
In 2001, the U.S. National Bioethics Advisory Commission issued specific recommendations for U.S.-funded research in developing countries.28 CIOMS, WHO, UNESCO and UNAIDS have also issued ethical guidelines (mentioned above) for research in developing countries.11–13 Common themes in these documents include requirements for proper scientific design; for scientific and ethical review of proposed studies, with input from local authorities or ethics boards; for voluntary, informed consent from all adult participants; and the requirement to provide appropriate care to subjects during and after the trial, particularly for any harms that result from study participation.28 A study performed in a developing country can be justified only if the findings will be relevant to that country’s people. If the interventions under study are so expensive that they will not be accessible following the trial, then that trial unjustly burdens its subjects.28
Privacy refers to an individual’s right to be left alone and to keep personal information private. Confidentiality refers to a physician or researchers’ responsibility to protect a subject’s privacy.29 Participation in clinical research often requires a subject to disclose information about his or her health. It is therefore a risk of research participation that personal information may be inadvertently disclosed to unauthorized individuals. In a carefully designed clinical study, steps must be taken to assure that the privacy of subjects’ health information is protected.
Medical research, particularly epidemiologic research, often requires the review of medical records. The information contained within a patient’s record is the property of that patient. Provided that steps are taken to safeguard the privacy of medical records, including the anonymization of information retrieved from medical records, the risks to the individual subjects from examination of medical records are minimal. Consent for review of medical records is typically not required for epidemiologic research, provided that privacy safeguards are in place. If, however, the data gleaned from medical records contains identifying information or if individual patients may be identifiable through published reports of the research, then consent for the use of medical records may be required (TCPS Articles 3.2–3.3).14 A threat to privacy may result from the linkage of multiple databases for the purpose of epidemiologic research. Database linkage may result in the identifiability of individuals who were not previously identifiable. The ramifications of database linkage must be subject to the scrutiny of an REB (TCPS Article 3.6).14
Recent Canadian federal legislation, the Personal Information Protection and Electronic Documents Act (PIPEDA),30 requires stringent protections for personal health information. However, PIPEDA contains an exemption for medical and epidemiologic research, allowing access to private information provided that obtaining informed consent is impractical and the information will be used in a way that maintains confidentiality.
In academia, there is significant pressure to publish the findings of research. Career advancement and the success of grant applications are heavily influenced by the number of an investigator’s peer-reviewed publications. For these reasons, scientists may be tempted to selectively report, or falsify, the results of research studies.31
Levine categorizes incomplete data presentation as either “data trimming” or “selective presentation.”31 Data trimming refers to the exclusion of outlying data in an attempt to improve the results. Selective reporting means reporting only those data that support a study’s hypothesis. Both of these practices are dangerous, in that therapeutic choices are made based on scientific evidence. Data trimming and selective reporting result in clinical decisions being made on false or incomplete data, thereby posing unnecessary risks to patients.
Outright falsification of data has previously occurred when the data generated by a clinical study did not support the investigators’ hypotheses. Levine calls scientific fraud the “capital offence of science.”31 This egregious practice puts patients at risk and demeans the contributions of research subjects. Like data trimming and selective reporting, falsification of data results in risks to patients due to clinical decisions that were made based on erroneous evidence. Research fraud also fails to acknowledge the risks taken by research subjects in studies that are, in reality, fruitless.
Investigators owe a duty of care to patients who are enrolled in their clinical trials.32 They are responsible for the well-being of the subjects in their studies. Investigators on studies funded by external sources (granting agencies, private foundations, biopharmaceutical companies) may find themselves in a conflict of interest: duty toward their subjects may be at odds with the agenda of a study sponsor. This is especially so if the investigator is contractually obligated to disclose only those study results that are satisfactory to the sponsor. In some instances, confidentiality agreements between investigators and sponsors have acted as barriers to informing research subjects of risks that have been discovered as clinical trials have progressed. The case involving Dr. Nancy Olivieri, the Hospital for Sick Children, the University of Toronto and Apotex, Inc. is a well-publicized example. Briefly, Dr. Olivieri was an investigator on a trial of a treatment for a hereditary blood disease. When she discovered evidence of both inefficacy and chronic hepatic toxicity, she reported this concern to the trial subjects and changed their treatment to standard therapy. The study sponsor argued that Dr. Olivieri violated a confidentiality clause in the study sponsorship contract and questioned the quality of her scholarship. Neither the hospital nor the university adequately defended her academic freedom or supported her in the face of the accusations from the study sponsor and some of her colleagues.33 The International Committee of Medical Journal Editors has condemned research contracts that prohibit investigators from independently reviewing and publishing the results of sponsored studies.34
It is also feared that financial relationships with private companies may influence an investigator. An investigator may be unwilling to publish data that is damaging to a sponsor to which she or he has a financial allegiance. For this reason, biomedical journals require full disclosure of potential financial conflicts of interest.34 The Canadian Institutes of Health Research requires that the institutions it funds develop policies for the identification, disclosure and management of potential conflicts of interest.35 The TCPS requires investigators to disclose to subjects, at the time of study enrolment, any potential conflicts of interest (Article 4.1A).14 It is unclear whether disclosure of potential conflicts of interest prevents bias in study reporting. Disclosure statements probably best serve as alerts to journal readers of potential biases in study reporting.
It is also conceivable that conflicts of interest with industry connections may influence the REB review process. This may occur as a result of personal connections that REB members may have with industry or through institutional pressure on the REB because of close ties between an institution and a particular study sponsor. These conflicts can be minimized if REB members excuse themselves from the review of studies sponsored by companies to which they have ties and if REBs maintain an arm’s-length relationship to their institution.
The term innovative therapy refers to the use of novel medical devices, procedural techniques or off-label medications outside of a clinical study to evaluate their efficacy. Common examples of innovative therapies include “next generation” prosthetic devices, or surgical or interventional equipment that has not been formally evaluated in a clinical trial. Some physicians have used “innovative therapy” as a means to avoid REB scrutiny for research. A physician or surgeon may choose to employ a novel device or off-label medication in an effort to provide better care to a patient. However, that practitioner should inform his or her patient that the technique or medication differs from standard treatment and of the reasons for choosing the novel approach, as well as the risks and potential benefits of the proposed innovative therapy. The standard treatment should be available as an alternative if the patient chooses not to proceed with the innovative therapy. If a novel technique or treatment is being evaluated systematically with the aim of generating generalizable data, this constitutes research and should be subject to REB review.
Throughout the 1950s and 1960s, peer review of research proposals was commonplace. The first regulatory requirement for committee review of consent procedures was issued by the U.S. Surgeon General in 1966, in relation to research performed by the U.S. Public Health Service. Requirements for multidisciplinary ethics board membership became formalized by the late 1960s and early 1970s.31
Research involving human subjects that is intended to develop generalizable knowledge is subject to review by an REB (TCPS Article 1.1).14 The REB is a social oversight mechanism, whose mandate involves assuring that research conducted at a particular institution is consistent with the norms and values of that institution’s community.
The societal norms to be enforced by a Canadian REB are formalized in the TCPS guidelines. However, an REB may require further protections beyond what is specified in the TCPS. The REB is composed of a minimum of five members, including two members with scientific expertise, one member with ethics expertise, one member with expertise in the law and one member of the community not affiliated with the institution (TCPS Article 1.3).14
All research involving living humans subjects must be reviewed by an REB. This includes research on human tissue (including fetuses and fetal tissue) and research using patients’ medical information. While full REB scrutiny of a protocol is typically standard procedure, expedited or limited review may be feasible for projects involving no more than minimal risk, for renewals of previously approved studies or for projects involving only the review of medical records by hospital personnel. Studies involving vulnerable subjects or invasive procedures must be subject to more intense REB scrutiny (TCPS Article 1.6).14 If an investigator is unsure whether his or her study requires REB approval, she or he should consult with the REB chair.
REBs tend to devote a significant amount of time to the consent process and consent documents associated with a study. Of equal or greater importance, though, is the thorough assessment of the risks and potential benefits associated with a study. When an REB determines that the risks of a study are acceptable in relation to its anticipated benefits to subjects, it ensures that participation in a research study is a reasonable thing to do. This is the paramount protection for research subjects, regardless of the consent process employed.
Critics of the REB review process have argued that the system of oversight for REB quality assurance is underfunded and ineffective.36 There are no benchmarks for REB performance, and little time is devoted to REB member training or quality assurance. In the long term, governmental oversight to assure REB review quality will be required. In the short term, investigators are advised to engage in REB education prior to an REB submission if they believe that the review of their study will be challenging.
Appendix 1 offers some practical advice regarding REB submissions, and Appendix 2 provides more detailed information about informed consent forms, including examples.
- Weijer C, Dickens B, Meslin E. Bioethics for clinicians 10: Research ethics. CMAJ: Canadian Medical Association Journal 1997; 156(8): 1153–7.
- Nuremberg code: directives for human experimentation. In: Trials of war criminals before the Nuremberg military tribunals under control council law. Vol. 2, No. 10. Washington, D.C.: U.S. Government Printing Office; 1949. pp. 181–2. Available from: https://www.loc.gov/rr/frd/Military_Law/pdf/NT_war-criminals_Vol-II.pdf
- Beecher H. Ethics and clinical research. New England Journal of Medicine 1966; 274: 1354–60.
- Faden RR, Beauchamp TL, King NMP. A history and theory of informed consent. New York: Oxford University Press; 1986.
- Clinton WJ. Remarks by the President in apology for the study done in Tuskegee. Washington, D.C.: The White House, Office of the Press Secretary; 1997. Available from: http://clinton4.nara.gov/textonly/New/Remarks/Fri/19970516-898.html
- National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. The Belmont report: ethical principles and guidelines for the protection of human subjects of research. Washington, D.C.: Government Printing Office; 1979.
- Collins A. In the sleep room: the story of CIA brainwashing experiments in Canada. Toronto: Lester & Orpen Dennys; 1988.
- Glass KC. Research involving humans. In: Downie J, Caulfield T, editors. Canadian health law and policy. Markham: Butterworths Canada Ltd.; 1999.
- Freedman B, Glass KC. Weiss v. Solomon: a case study in institutional responsibility for clinical research. Law, Medicine and Health Care 1990; 18(4): 395–403.
- World Medical Association. Declaration of Helsinki: ethical principles for medical research involving human subjects. World Medical Association [adopted 1964; last updated 2004]. Available from: http://www.wma.net/e/policy/b3.htm
- Council for International Organizations of Medical Sciences (CIOMS). International ethical guidelines for biomedical research involving human subjects. Geneva: CIOMS; 2002. Available from: http://www.recerca.uab.es/ceeah/docs/cioms.pdf
- World Health Organization. Guidelines for good clinical practice for trials on pharmaceutical products. Geneva: World Health Organization; 1995.
- UNAIDS (Joint United Nations Programme on HIV/AIDS). Ethical considerations in HIV preventive vaccine research. Geneva: UNAIDS; 2000. Available from: http://data.unaids.org/Publications/IRC-pub01/JC072-EthicalCons_en.pdf
- Medical Research Council of Canada, Natural Sciences and Engineering Research Council of Canada, Social Sciences and Humanities Research Council of Canada. Tri-council policy statement: ethical conduct for research involving humans. Ottawa: Public Works and Government Services Canada; 2003. Available from: http://www.pre.ethics.gc.ca/pdf/eng/tcps2-2014/TCPS_2_FINAL_Web.pdf
- Health Canada. ICH guidance E6: good clinical practice: consolidated guideline. Ottawa: Health Canada; 1997 [updated 2004]. Available from: http://www.hc-sc.gc.ca/dhp-mps/alt_formats/hpfb-dgpsa/pdf/prodpharma/e6_e.pdf
- Health Canada. Health Canada’s Research Ethics Board [web page]. Ottawa: Health Canada [updated 2005 Aug. 9]. Available from: http://www.hc-sc.gc.ca/sr-sr/advice-avis/reb-cer/index_e.html
- Freedman B, Fuks A, Weijer C. Demarcating research and treatment: a systematic approach for the analysis of the ethics of clinical research. Clinical Research 1992; 40: 653–60.
- Weijer C, Miller PB. When are research risks reasonable in relation to anticipated benefits? Nature Medicine 2004; 10: 570–3.
- Freedman B. Equipoise and the ethics of clinical research. New England Journal of Medicine 1987; 317(3): 141–5.
- Sackett DL. Why randomized controlled trials fail but needn't: 1. Failure to gain "coal-face" commitment and to use the uncertainty principle. CMAJ: Canadian Medical Association Journal 2000; 162: 1311–4.
- Miller PB, Weijer C. Trust-based obligations of the state and physician-researchers to patient-subjects. Journal of Medical Ethics 2006; 32(9): 542–7.
- Department of Health and Human Services Rules and Regulations. Protection of Human Subjects. Title 45, Code of Federal Regulations, Part 46.116(d). Federal Register 46: 8386 (27 January 1981); revised Federal Register 48: 9269 (4 March 1983); revised Federal Register 56: 28003 (18 June 1991).
- Wendler D, Miller FG. Assessing research risks systematically: the net-risks test. Journal of Medicine and Philosophy. In press 2007.
- National Cancer Institute. Children’s assent to clinical trial participation [web page]. National Cancer Institute, U.S. National Institutes of Health [updated 2005 May 26]. Available from: https://www.cancer.gov/about-cancer/treatment/clinical-trials/patient-safety/childrens-assent
- Freedman B, Fuks A, Weijer C. In loco parentis: minimal risk as an ethical threshold for research upon children. Hastings Center Report 1993; 23(2): 13–9.
- Biros M. Research without consent: current status, 2003. Annals of Emergency Medicine 2003; 42(4): 550–64.
- McRae AD, Weijer C. Lessons from everyday lives: a moral justification for acute care research. Critical Care Medicine 2002; 30(5): 1146–52.
- National Bioethics Advisory Commission. Ethical and policy issues in international research: clinical trials in developing countries. 2001. [NOT OBVIOUSLY] Available from: https://bioethicsarchive.georgetown.edu/nbac/clinical/Vol1.pdf
- Marshall M, Von Tigerstrom B. Confidentiality and disclosure of health information. In: Downie J, Caulfield T, editors. Canadian health law and policy. Markham: Butterworths Canada Ltd.; 1999.
- Office of the Privacy Commissioner of Canada. Personal Information Protection and Electronic Documents Act. Statutes of Canada 2000. Ottawa: Government of Canada; 2000. Available from: https://www.priv.gc.ca/en/privacy-topics/privacy-laws-in-canada/the-personal-information-protection-and-electronic-documents-act-pipeda/
- Levine RJ. Ethics and regulation of clinical research. 2nd edition. Baltimore: Urban & Schwarzenburg; 1986.
- Weijer C, Miller PB. Therapeutic obligation in clinical research. Hastings Center Report 2003; 33(3): 3.
- Thompson J, Baird P, Downie J. Report of the Committee of Enquiry on the Case Involving Dr. Nancy Olivieri, The Hospital for Sick Children, The University of Toronto, and Apotex, Inc. Toronto: The Canadian Association of University Teachers, 2001.
- International Committee of Medical Journal Editors. Uniform requirements for manuscripts submitted to biomedical journals: writing and editing for biomedical publication. ICMJE [updated 2007 Oct.]. Available from: http://www.icmje.org
- Bernstein A. New ethical requirements at the NIH: implications for CIHR and Canada. CMAJ: Canadian Medical Association Journal 2005; 173(4): 353–4.
- McDonald M. Canadian governance of health research involving human subjects: is anybody minding the store? Health Law Journal 2001; 9: 1–21.
Practical Advice for Research Ethics Board (REB) Submissions
Know whether your project needs to undergo REB review
As a rule, any project involving human subjects that is designed to produce generalizable knowledge is considered research and requires REB review. Quality assurance reviews that are intended to evaluate the performance of an institution, physician group or the like do not require REB review, unless publication is planned (which would make the knowledge generalizable).
Know when informed consent is required from subjects
As a general rule, studies including any kind of intervention that will be performed on subjects require the informed consent of the subject or a substitute decision-maker. Epidemiologic or observational studies, studies involving chart reviews that do not record any identifying information and studies posing only a minimal risk to subjects may not require the informed consent of the subjects. Investigators who believe their study may not require consent should discuss the need for informed consent with their REB prior to submission.
Know the relevant ethical guidelines
This is particularly true when a study’s subjects are drawn from a vulnerable population, such as children or incapacitated emergency patients. Awareness of the additional protections that are owed to these subjects and of the limits on permissible risk makes it easier for investigators to design a study protocol that complies with ethical guidelines. This will make the REB process go more smoothly. The most important ethical guideline is the “Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans.” Studies may also be subject to the rules outlined in Health Canada’s Good Clinical Practice guidelines.
Know your local REB’s procedures
This information can be obtained from the REB’s administrator. Important information includes REB meeting dates, submission deadlines, required signatures, necessary forms and submission format. Some REBs hold closed-door meetings with no investigator input into the review process. Others require investigators to be present for the meeting. Others may require that the investigator be available to answer questions during the meeting should the need arise. Awareness of the local REB’s procedures will help the submission and review process to proceed more efficiently.
Informed Consent Forms — Evidence and Examples
Investigators must be aware that obtaining a subject’s consent to research participation is not simply the act of obtaining a signature on the form. It is a process involving the exchange of information between researcher and potential subject and of ensuring that the subject comprehends the necessary information in order to make an informed choice based on a stable set of values.
For this reason, the consent form itself cannot act as a subject’s sole source of information about a particular study. However, the consent form is a reference for the subject that summarizes the study’s purpose, methods, risks and potential benefits. To this end, it must be both comprehensive and understandable. Meeting these two different goals can sometimes be difficult.
Multiple analyses of informed consent documents have demonstrated that the reading difficulty of research consent forms exceeds recommended levels.i,ii In one analysis of 107 cancer clinical trials, the mean length of the consent forms was almost 11 pages. No consent forms were readable at the eighth-grade level, only 1.5 per cent were readable at the ninth-grade level and 10.5 per cent were readable at the 10th-grade level.ii
Empirical studies have shown that the language of informed consent documents can be made simpler and more readable without omitting required information. Simpler consent forms are more easily understood by subjects, lead to greater information retention and cause less anxiety.iii.iv
A typical consent package includes both an information sheet, which describes the relevant details of the study to the potential subject, and the consent form itself, which the subject signs after making an informed choice to participate in a study.
The Tri-Council Policy Statement requires the disclosure of several material facts during the consent process (Article 2.4).v These facts should be included on the information sheet: that the subject is being invited to participate in a research study; the identity of the investigator, the goals of the study, the procedures involved in the study, and the duration and nature of participation; the potential harms and benefits that may accrue as a result of study participation; that the potential subject is free to refuse participation or to withdraw from the study at any time with no effect on ongoing care; that the results of the study may result in commercial opportunities for the study sponsors, but that research participants give up the right to any commercial gain; and the disclosure of any potential or apparent conflicts of interests of the investigators, institutions or sponsors.
REBs may require that the following additional information be included on the information sheet: that subjects will be provided with any new information that may influence a subject’s decision as to whether or not to continue participation; the identity of a resource person who can answer questions about the scientific aspects of the research; additional resources about any ethical issues that may be raised by the study; a description of the means used to protect subjects’ privacy and a list of individuals having access to confidential information; an explanation of the subject’s responsibilities; information on the circumstances in which a researcher may terminate a subject’s participation; information on subjects’ costs, payments, reimbursements or compensation for injury; in randomized trials, the probability of assignment to each study arm; for research on biomedical procedures, including health care interventions, information about (a) forgoing alternative procedures that might be advantageous to the subject, (b) which aspects of the research involve the use of procedures that are not generally recognized or accepted; and, (c) particularly in trials of therapeutic interventions, the care provided if the potential subject decides not to consent to participation in the study; and information on the means by which study results will be disseminated and how subjects will be informed of the results (Article 2.4, Table 1).v
Examples of consent forms from REBs of the University of Manitoba, the University of Ottawa and the College of Physicians and Surgeons of Alberta are available at the following Internet links (active as of August 10, 2006):
Note that these consent forms include information over and above what is required by the Tri-Council Policy Statement. Different REBs will have different requirements as to what information is required in a consent form or information sheet. Some will have requirements in addition to the information required by the Tri-Council Policy Statement, but this additional information may hinder a consent form’s readability.
On the following page (after the References) is a sample information sheet that complies with the requirements of the Tri-Council Policy Statement.
- Franck L, Winter I. Research participant information sheets are difficult to read. Bulletin of Medical Ethics 2004; 195: 13–6.
- Sharp SM. Consent documents for oncology trials: does anybody read these things? American Journal of Clinical Oncology 2004; 27(6): 570–5.
- Coyne CA, Xu R, Raich P, Plomer K, Dignan M, et al. Randomized, controlled trial of an easy-to-read informed consent statement for clinical trial participation: a study of the Eastern Cooperative Oncology Group. Journal of Clinical Oncology 2003; 21(5): 836–42.
- Bjorn E, Rossel P, Holm S. Can the written information to research subjects be improved? — An empirical study. Journal of Medical Ethics 1999; 25(3): 263–7.
- Medical Research Council of Canada, Natural Sciences and Engineering Research Council of Canada, Social Sciences and Humanities Research Council of Canada. Tri-council policy statement: ethical conduct for research involving humans. Ottawa: Public Works and Government Services Canada; 2003. Available from: http:/www.pre.ethics.gc.ca/english/pdf/TCPS%20June2003_E.pdf
SAMPLE INFORMATION SHEET
You are being invited to participate in a research study called (name of study), performed by (name of investigator) and sponsored by (name of sponsor).
The purpose of the study is (purpose of study).
If you choose to participate in the study, you will undergo (therapeutic procedures and non-therapeutic procedures described here). The likelihood of receiving (Treatment A) or (Treatment B) is (likelihood of assignment to each treatment arm). Your participation in the study is expected to last (expected duration). During this time, you will be expected to (responsibilities of subject, including number and timing of follow-up visits or additional non-therapeutic procedures).
The potential benefits to you are the following: (potential benefits listed here).
The risks of study participation are the following: (risks listed here).
If you do not wish to participate in the study, your treatment options are these: (list and risks/potential benefits of alternatives).
You are free to choose not to participate in this study. If you choose not to participate, your decision will not affect your medical care in any way. If you do choose to participate, you are free to withdraw from the study at any time and for any reason. If you choose to withdraw, this will have no effect on the quality of medical care you receive.
If any new information about your condition or the treatments being studied arises during the study, you will be informed in a timely fashion so that you can decide whether or not to continue in the study.
You (will/will not) be compensated for your participation. (Provide amount of compensation.) Any injury incurred as a result of study participation will be cared for at no cost to you.
Your privacy is important. Only (names of investigators) will have access to your medical information. My file will be identified by a code. Only (name of principal investigator) will know which coded file is yours. The confidentiality of your medical information will also be protected by (additional safeguards).
Your participation in this study might be ended early if (list indications for early termination).
If you have any questions about the study, you can contact (name and contact information of principal investigator or study coordinator).
If you have any questions about your rights as a study subject or if you have any ethical or moral concerns about this study, you can contact (name and contact information of REB).