Lesson 2: Ethics of Clinical TrialsLesson 2: Ethics of Clinical Trials
A well-designed clinical trial should answer important public health questions without impairing the welfare of participants. Ethical obligations to trial participants and to science and medicine pertain to all stages of a clinical trial: design, conduct, and reporting results. (Friedman, Furberg, DeMets, Reboussin, Granger, 2015, Chapter 2)
- State at least 3 internationally recognized conditions that are necessary to justify conducting a medical experiment in humans.
- Define the condition that is required to justify randomizing a patient to a treatment.
- Differentiate between ethical and unethical use of placebo control.
- Recognize requirements for IRB approval of human research studies involving any product regulated by the U.S. FDA.
- Recognize U.S requirements for investigators to report financial interests that may affect design, conduct or reporting of research regulated by the U.S. Public Health Service.
- Annas GJ and Grodin MA. (1992) The Nazi doctors and the Nuremberg Code: Human Rights in Human Experimentation. New York: Oxford University Press.
- Carter RL, Scheaffer RL, Marks RG. (1986) The role of consulting units in statistics departments. Am. Stat. 40:260-264.
- Friedman, L.M., Furberg, C.D., DeMets, D., Reboussin, D.M., Granger, C.B. (2015). Chapter 2 Ethical Issues. In: Friedman, L.M.,Furberg, C.D.,DeMets, D.,Reboussin, D.M.,Granger, C.B. Fundamentals of Clinical Trials. 5th ed. Switzerland: Springer International Publishing. (Notes will refer to Friedman et al 2015)
- Piantadosi Steven. (2005) Clinical trials as research, Why clinical trials are ethical, Contexts for clinical trials. In: Piantadosi Steven. Clinical Trials: A Methodologic Perspective. 2nd ed. Hobaken, NJ: John Wiley and Sons, Inc.
- Scott PE. (2004) Medical device approvals: An assessment of the level of evidence. PhD dissertation: Johns Hopkins University, Baltimore, MD.
2.1 - Requirements of Investigators2.1 - Requirements of Investigators
One area of ethical dilemma of physicians and health care workers can be attributed to the conflicting roles of helping the patient and gaining scientific knowledge, as stated by Schafer (1982)
When properly set, designed, and conducted, a clinical trial is an ethically appropriate way to acquire new knowledge. Clinical decisions for treatment that are based on weak or anecdotal evidence, opinion, or dogma, without the evidence of rigorous scientific support, raise their own ethical questions.
It is not easy to distinguish between clinical research and clinical practice. How often is a physician certain of the outcome from a specific therapy for a particular patient? If the patient’s reaction is predictable, applying the treatment would be described as practice. In the cases when the physician is unsure of the outcome, applying the treatment could be considered research. Many actions by the physician for the benefit of individual patients have the potential of increasing scientific knowledge. Analogously, scientific knowledge gained from research can be of benefit to individual patients. Ethical questions arise when unproven therapies are proposed to replace proven ones and are particularly acute for chronic or fatal illnesses.
Clinical trials are only one of several settings in which the physician’s duty extends beyond his responsibility to the individual patient. For example, vaccinations against communicable disease are promoted by physicians, yet the individual vaccinated incurs a small risk to benefit the population as a whole. Triage is another situation where for the sake of maximizing benefit to the whole, the needs of an individual may not be met.
The American Medical Association has a code of professional ethics that includes the obligation of a physician to conduct medical research: “ A physician shall continue to study, apply and advance scientific knowledge, maintain a commitment to medical education, make relevant information available to patients, colleagues, and the public….” (AMA, 2001). There is also a statement of the physician’s responsibility to the patient as ‘paramount’. Both ethics must be considered when the health professional considers entering a patient in a clinical trial.
Responsible Conduct of Research Training:
All clinical investigators should have training in research ethics. The US NIH website has resources for training in the areas of scientific integrity, data, publication, peer review, mentor/trainee relationships, collaboration, human and animal subjects, and conflict of interest. Many funding sources, including the US NIH and NSF, require responsible conduct of research training for all students, trainees, fellows, scholars, and faculty utilizing their funds to conduct research.
Conflict of Interest:
A crucial component of ethical medical research is investigator objectivity. Investigators are required by the US Public Health Service, the umbrella organization for the FDA and the NIH, to report any significant financial interest would appear to affect the design, conduct, or reporting of research. (See Guidance from FDA)
Investigators should be competent technically (evidenced by education, certification, experience) and humanistically (showing compassion and empathy).
2.2 - Historical Perspective2.2 - Historical Perspective
The current requirements for investigators and considerations in conducting ethical research should be understood within the context of past abuses, some horrific.
The 1946-1947 Nuremberg trials brought notoriety to the numerous atrocities in WWII concentration camps committed by Nazi physicians under the guise of “experimentation.” Of the 23 individuals tried for such crimes at Nuremberg, 20 were physicians. Sixteen of the 23 were convicted and given sentences ranging from imprisonment to death. (Annas and Grodin, 1992)
At the time of the Nuremberg trial, there were no international standards for ethical conduct in human experimentation. This resulted in the Nuremberg Code, or directives for human experimentation, adopted in 1947:
- Voluntary consent of the human subject is essential.
- There must be no reasonable alternative to conducting the experiment.
- The anticipated results must have a basis in biological knowledge and animal experimentation such that the experiment has potential for yielding fruitful results for the good of society.
- The procedures should avoid unnecessary physical and mental suffering and injury.
- There is no expectation for death or disability as a result of the trial
- The degree of risk for the patient should not exceed the humanitarian importance of the problem to be solved.
- The subjects should be protected against even a remote possibility of death or injury.
- The study must be conducted by qualified scientists, with a high degree of skill and care throughout the experiment.
- The subject can stop participation at will.
- The investigator has an obligation to terminate the experiment if injury, disability or death of the subject seems likely.
The World Medical Association (WMA) held a meeting in 1964 in Helsinki, Finland, and adopted a formal code of ethics for physicians engaged in clinical research. The Declaration of Helsinki reiterates the principles of Nuremberg Code, with particular attention to the duty of the physician to protect the life, health and dignity of the human subject. The Declaration states that research involving human subjects must be formulated in a written protocol which has been reviewed by an ethical review committee distinct from the investigator, must conform to generally accepted scientific principles and should include written informed consent from the participants. Negative as well as positive results should be disseminated and funding sources disclosed.
The Declaration has been revised regularly by the WMA. Considerable discussion has ensued regarding the statements on the ethics of placebo control and the duty of the study planners to provide post-study access for all study participants to what is regarded as a beneficial treatment. The 2008 revision affirms the WMA position on the primacy of the patient and outlines required consents for research on human material, such as blood, tissues, and DNA, and human data as well as requiring clinical trials to be registered in a publicly accessible database.
One well-known example of abuse of ethical research in the USA occurred in 1936 when the US Public Health Service began a study of untreated syphilis in Tuskegee, Alabama (399 men with advanced disease and 201 controls). The study continued long after the availability of penicillin, a proven cure, in the 1950s. The study was stopped in the early 1970s after it was publicized and became an embarrassment to the country. In response to the Tuskegee Syphilis Study, the US Congress established the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research through the 1974 National Research Act. This Commission produced the Belmont Report in 1979 which distilled basic ethical guidelines in research with human subjects to three principles: respect for persons or individual autonomy, beneficence, and justice.
Respect for persons (individual autonomy) means that patients have the right to decide what should be done for them with respect to their illness unless the result would be clearly detrimental to others. Respect for persons means that potential subjects for clinical trials are informed of alternative therapies and risks and benefits of participation in a particular trial before they volunteer to participate in that study. Since clinical trials often require participants to surrender some measure of autonomy in order to be randomized to treatment and follow the established protocol, these aspects will be described to the potential subject, along with their freedom to choose to discontinue the study at any time.
Beneficence reflects the patient’s right to receive advantageous or favorable treatment. Investigators are obliged to make practical and useful assessments of the risks and benefits involved in research, which necessitates resolving the potential conflict between risk to participants and benefit to future patients. The beneficence obligation extends to both the particular subjects in a study and to the research endeavor.
Justice addresses the question of fairly distributing the benefits and burdens of research. Compensation for injury due to research is an application of justice. Injustice occurs when benefits are denied without good reason or when burdens are unduly imposed on particular individuals, such as the poor or uninsured.
These principles are applied in the requirements for informed consent of subjects, in the assessment of risks and benefits and fair procedures and outcomes, and in the selection of subjects.
Other international guidelines have been proposed.
- The World Health Organization (WHO) and the Council for International Organizations of Medical Sciences (CIOMS) issued a document entitled International Ethical Guidelines for Biomedical Research Involving Human Subjects, with its latest revision published in 2002.
- UNESCO set forth a Universal Declaration on Bioethics and Human Rights in 2005.
- Timeline of Laws Related to the Protection of Human Subjects
2.3 - IRB and Informed Consent2.3 - IRB and Informed Consent
The U.S. National Institute of Health Policies for the Protection of Human Subjects (1966) established the IRB (Institutional Review Board) as a mechanism for the protection of human participants in research. In 1981, U.S. regulations required IRB approval for all drugs or products regulated by the US Food and Drug Administration (FDA), without regard to the funding source, the research volunteers, or the location of the study. In 1991, core US DHHS regulations (45 CFR Part 46, Subpart A) were adopted by most Departments and Agencies involved in research with human subjects. This Federal Policy for the Protection of Human Subjects, known as the "Common Rule.”, requires Institutional Review Board (IRB) review for all research in human subjects funded in whole or in part by the U.S. federal government.
An IRB may approve research in human subjects that meets specific prerequisites set forth by the FDA.
- The risks to the study participants are minimized
- The risks are reasonable in relation to the anticipated benefits
- The selection of study participants is equitable
- Informed consent is obtained and appropriately documented for each participant
- There are adequate provisions for monitoring data collected to ensure the safety of the study participants
- The privacy of the participants and the confidentiality of the data are protected
Every accredited medical research organization maintains an IRB. An investigator must submit his/her research plan, called the protocol, and the informed consent form to an IRB for approval prior to the conduct of the study.
The IRB also requires the investigator to provide the following:
- Progress reports on an annual basis
- Reports of any serious adverse events in the human subjects when they occur
The principle of respect for persons implies that each study participant will be made aware of potential risks, benefits and costs prior to participating in a clinical study. To document this, study particpants (or parents/legally authorized representatives) sign an informed consent document prior to participation in a research study. The patient assents to having been informed of the potential risks and benefits resulting from their participation in the clinical study, to understanding their treatment alternatives and that their participation is voluntary. There are numerous examples of studies in which patients have been exposed to potentially or definitively harmful treatments without being fully apprised of the risk. The consent document should be presented without any coercion. Even so, ill or dying patients and their families are vulnerable, and it is questionable how much technical information about new treatments they can truly understand, especially when it is presented to them quickly.
In the United States and many other countries, an IRB must evaluate and approve the informed consent documents prior to beginning a study.
The informed consent must describe explicitly the following information:
- The research nature of the study
- The reasonable foreseeable risks and discomfort
- The potential benefits and alternatives
- Procedures for maintaining privacy
- Treatment for injuries incurred
- Individuals to contact for questions
- The voluntary nature of the study and the possibility of withdrawal at any time
- Not entering the study does not lead to loss of benefits
Research in emergency settings in which informed consent is not possible is a special situation. The FDA and the National Institutes of Health (NIH) have offered guidance for research in emergency medical situations.
2.4 - Planning and Design2.4 - Planning and Design
Applying ethical considerations in the planning and design phase of a study requires optimal study design. All involved in clinical research have a responsibility to promote high-quality clinical trials in order to provide evidence to guide medical decisions. (Friedman et al 2015), weighing the balance of risk vs benefit, consideration of patient confidentiality as well as plans for impartial oversight of informed consent procedures.
The question addressed by a clinical trial should be important enough to justify possible adverse effects of the treatment that will be administered. A study design that cannot answer the biological question is unethical. Studies that pose unimportant questions are unethical as well, even if they pose minimal risk. What marketing question would have enough benefit to justify risks to subjects? What about situations where there is an approved and available therapy?
The study question also involves the choice of the study population. Which population can answer the question? Does the potential benefit outweigh the risk of these study subjects? Is the selection just?
ethical considerations of respect for persons, beneficence, and justice imply three requirements for the conduct of research, namely, informed consent, disclosure of the risks and benefits, and the appropriate selection of research subjects. Applying ethical principles also requires optimal study design, a balance of risk, and benefit for study participants, consideration of patient privacy, impartial oversight of consent procedures.
The choice of the study population is also related to the place(s) the trial will be conducted. There is greater generalizability and potentially faster enrollment if a trial is conducted in multiple and varied geographic locales. The concept of justice should be applied--is the location selected due to prevalent disease and relevance of the results? Or for sponsor conveniences such as lower cost and fewer administrative and regulatory burdens? Is the standard of care in this country less than optimal care and thus event rates higher? What obligations do the trial sponsors have to the participants or to residents of the country once the trial is complete? Will the treatment be available in this locale once the trial is complete?
Some physicians and patients feel that it is inappropriate to base a patient's treatment on chance, as is done in a randomized clinical trial. Some feel that the physician is obligated to have a preference, even when the evidence does not favor any particular treatment. Randomization is justified when there is relative ignorance (collectively) about the best treatment. The situation in which there is genuine uncertainty as to the best available therapy is called equipoise. (Piantadosi 2005)
Patients and physicians with firm preferences for treating a particular disease, even those based on weak evidence, should not participate in a clinical trial involving that disease. Patients with strong convictions about preferred treatments are likely to become easily dissatisfied with randomization to a treatment in the clinical trial. Physicians with strong convictions could bias the clinical trial in a different direction, especially if they are not “blinded” to treatment assignment.
Although most often individual subjects are randomized to treatment, in some situations, the unit of randomization is a larger entity, such as a hospital or community. How would individuals consent to such research?
Inclusion of a placebo group in a comparative trial can yield a straightforward comparison with the experimental treatment to determine if the treatment is safe and effective. Patients assigned to placebo may receive a facsimile of the active therapy without the knowledge of whether or not the active ingredient is present; thus, any observed effect is considered a result of the active agent and not the process of being treated.
Assigning patients to a placebo treatment, however, is not always ethical. Placebo control is untenable when the disease is life-threatening and an effective therapy is available. A better approach when there is an effective and available therapy and/or the condition is life-threatening is to use the standard accepted therapy as an active control treatment. Comparison is made between active control and the experimental therapy. Another possible option if the new therapy can be given in combination with standard therapy: all subjects receive standard therapy and randomization is to new therapy plus standard or placebo plus standard.
Should the new intervention be compared with the best-known therapy or with a placebo? Will a placebo control result in significant harm to subjects? What if there is no accepted optimal therapy? What if the optimal therapy is very costly or not available in some locations? The selection of the control group has many ethical considerations.
The U.S. Department of Health and Human Services (HHS) issued the Standards for Privacy of Individually Identifiable Health Information (the Privacy Rule) under the Health Insurance Portability and Accountability Act of 1996 (HIPAA) to provide the first comprehensive Federal protection for the privacy of personal health information. This became effective on April 14, 2003.
While certain provisions of the Rule specifically concern research and may affect research activities, the Privacy Rule recognizes that the research community has legitimate needs to use, access, and disclose Protected Health Information (PHI) to carry out a wide range of health research protocols and projects. The Privacy Rule protects the privacy of such information while providing ways in which researchers can access and use PHI when necessary to conduct research. The DHHS web site should be examined for further information about HIPAA requirements on research.
2.5 - Conduct2.5 - Conduct
Although it is vital to enroll enough subjects to answer the study questions adequately, recruitment must also follow ethical norms. Coercion should be avoided. For this reason, any financial compensation for the subject's time and travel will reflect actual expenses or small amounts that would not entice a person to enroll in the study for financial gain; study personnel other the primary investigator or the patient's doctor may be designated to ask for informed consent.
During the course of a comparative trial, evidence may become available that one treatment is superior. Interim statistical analyses may be incorporated into the study design to provide periodic investigations of treatment superiority prior to study completion without sacrificing the statistical integrity of the trial. (discussed later in this course). Should patients receiving an inferior treatment continue in this manner? If there is evidence that a particular type of patient is unlikely to respond to therapy, should entrance criteria be modified? Is the adverse experience profile markedly worse for one therapy? Investigators are required to report such circumstances to their IRB.
Most multi-center clinical trials involve an independent board of scientists to monitor the trial results and render decisions as to whether the trial should continue or be modified in some manner. Safety monitoring is required. These committees have various names, such as Data and Safety Monitoring Board, External Advisory Committee, etc.
Early Termination for other than scientific or safety reasons
Related to planning, studies should only be conducted if resources are adequate to complete the study. Early termination for reasons other than science or safety reflect a lack of ethical concern. Subjects agreed to participate so an important question could be answered. There should be an answer.
Data falsification must not be tolerated in any manner. Central statistical monitoring and other procedures may help detect potential fraud. See George and Buyse, (2015) Data Fraud in Clinical Trials
2.6 - Reporting2.6 - Reporting
Investigators should report trial results completely and in a timely manner. Registration of trials on clinicaltrials.gov and publishing associated results online can reduce publication bias, the bias resulting from journals favoring studies with significant results. Publish or find mechanisms to disseminate results effectively.
'Ghost authorship' occurs when people writing a paper are not fully disclosed (i.e. draft written by contract writer) or when authors are included who did not actually participate in the research project (for example, an influential name). Journals combat such deception by asking authors to specify the contribution of each person listed as an author.
2.7 - Statistical Ethics2.7 - Statistical Ethics
The American Statistical Association and the Royal Statistical Society have published similar guidelines for the conduct of their members:
- Maintain professional competence and keep abreast of developments
- Have constant regard for human rights
- Present findings and interpretations honestly and objectively
- Avoid untrue, deceptive, or undocumented statements
- Disclose financial or other interests that may affect or appear to affect professional statements
- Seek to advance public knowledge and understanding
- Encourage and support fellow members in their professional development.
In terms of data collection in clinical trials, statisticians should do the following:
- Collect only the data needed for the purposes of the inquiry
- Inform each participant about the nature and sponsorship of the project and intended uses of the data
- Establish the intentions and ability of the sponsor to protect confidentiality
- Inform participants of the strengths and limitations of confidentiality protections
- Process the data collected according to the intentions and remove participant-identifying information
- Ensure that confidentiality is maintained when data are transferred to other persons or organizations
In terms of dealing with sponsors/clients, statisticians should do the following:
- Clarify their qualifications to undertake the inquiry
- Reveal any factors that may conflict with impartiality
- Accept no contingency fee arrangements
- Apply statistical methods without regard for a desirable outcome
- Outline alternate statistical methods along with the chosen methods
- Maintain confidentiality with regard to other sponsors/clients
2.8 - Summary2.8 - Summary
In this second lesson, Ethics of Clinical Trials, we learned:
- 3 internationally recognized conditions necessary to justify conducting a medical experiment in humans.
- The condition that is required to justify randomizing a patient to a treatment.
- To differentiate between ethical and unethical use of placebo control.
- Requirements for IRB approval of human research studies involving any product regulated by the U.S. FDA.
- U.S requirements for investigators to report financial interests that may affect design, conduct or reporting of research regulated by the U.S. Public Health Service.