2.4 - 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.

Study Question Section

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.

Study Sites Section

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?

Randomization Section

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?

Control Group Section

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.

Confidentiality Section

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.