2  Overview of Clinical Trials

Clinical Trials
Research Ethics
Clinical Trial Design
Regulatory Affairs
Biostatistics

Overview

This lesson provides an overview of clinical trials as a form of research and addresses the ethical obligations that govern their design, conduct, and reporting. We begin with the role of statistics in clinical research and the definition of a clinical trial, then turn to the ethical framework that every clinical investigator must understand. 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)1

Objectives

Upon completion of this lesson, you should be able to:

  1. Recognize a research objective that could be met through a clinical trial.
  2. Recognize a research objective that would be difficult to meet through a clinical trial.
  3. Discuss the relative contributions of clinical judgement and clinical trials in evaluating new medical therapies.
  4. Apply six characteristics of statistical reasoning to a research objective in a clinical trial setting.
  5. State at least 3 internationally recognized conditions that are necessary to justify conducting a medical experiment in humans.
  6. Define the condition that is required to justify randomizing a patient to a treatment.
  7. Differentiate between ethical and unethical use of placebo control.
  8. Recognize requirements for IRB approval of human research studies involving any product regulated by the U.S. FDA.
  9. 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.

References at the end of the lesson. 2 3 4 5 6 7

2.1 What is the role of statistics in clinical research?

Clinical research involves investigating proposed medical treatments, assessing the relative benefits of competing therapies, and establishing optimal treatment combinations. Clinical research attempts to answer questions such as “should a man with prostate cancer undergo radical prostatectomy or radiation or watchfully wait?” and “is the incidence of serious adverse effects among patients receiving a new pain-relieving therapy greater than the incidence of serious adverse effects in patients receiving the standard therapy?”

Before the widespread use of experimental trials, clinicians attempted to answer such questions by generalizing from the experiences of individual patients to the population at large. Clinical judgement and reasoning were applied to reports of interesting cases. The concepts of variability among individuals and its sources were not formally addressed.

As the field of statistics, the “theoretical science or formal study of the inferential process, especially the planning and analysis of experiments, surveys, and observational studies.” (Piantadosi 2005). has developed in the twentieth century, clinical research has utilized statistical methods to provide formal accounting for sources of variability in patients’responses to treatment. The use of statistics allows clinical researchers to draw reasonable and accurate inferences from collected information and to make sound decisions in the presence of uncertainty. Mastery of statistical concepts can prevent numerous errors and biases in medical research.

Statistical reasoning is characterized by the following:

(Piantadosi, 2005)8

  1. Establishing an objective framework for conducting an investigation
  2. Placing data and theory on an equal scientific footing
  3. Designing data production through experimentation
  4. Quantifying the influence of chance
  5. Estimating systematic and random effects
  6. Combining theory and data using formal methods

Carter, Scheaffer, and Marks (1986)9 stated that:

Statistics is unique among academic disciplines in that statistical thought is needed at every stage of virtually all research investigations including planning the study, selecting the sample, managing the data, and interpreting the results.

Clinical and statistical reasoning are both crucial to progress in medicine. Clinical researchers must generalize from the few to many and combine empirical evidence with theory. In both medical and statistical sciences, empirical knowledge is generated from observations and data. Medical theory is based upon established biology and hypotheses. Statistical theory is derived from mathematical and probabilistic models. (Piantadosi 2005), To establish a hypothesis requires both a theoretical basis in biology and statistical support for the hypothesis, based on the observed data and the theoretical statistical model.

What constitutes a ‘clinical trial’?

An experiment is a series of observations made under conditions controlled by the scientist.

A clinical trial actually is an experiment testing medical treatments on human subjects. The clinical investigator controls factors that contribute to variability and bias such as the selection of subjects, application of the treatment, evaluation of outcome, and methods of analysis. The distinction of a clinical trial from other types of medical studies is the experimental nature of the trial and its occurrence in humans.

Design is the process or structure that isolates the factors of interest. Although the researcher designs a trial to control variability due to factors other than the treatment of interest, there is inherently larger variability in research involving humans than in a controlled laboratory situation.

The term “clinical trial” is preferred over “clinical experiment” because the latter may connote disrespect for the value of human life.

In what contexts are clinical trials used?

Clinical trials are used to develop and test interventions in nearly all areas of medicine and public health. In many countries, approval for marketing new drugs hinges on efficacy and safety results from clinical trials. Similar requirements exist for the marketing of vaccines. The U.S. Food and Drug Administration (FDA) now requires manufacturers of new or high-risk medical devices to provide data demonstrating clinical safety and effectiveness. (Scott 2004). Surgical interventions pose unique challenges since surgical approaches are typically undertaken for patients with a good prognosis and may not be amenable to randomization or masking investigators and patients to the intervention, all conditions which can lead to biases. Clinical trials are useful for demonstrating efficacy and safety of various medical therapies, preventative measures and diagnostic procedures if the treatment can be applied uniformly and potential biases controlled.

In addition to testing novel therapies, clinical trials frequently are used to confirm findings from earlier studies. When the results of a study are surprising or contradict biological theory, a confirmatory trial may follow. Medical practice generally does not change based upon the results of one study. Design flaws, methodological errors, problems with study conduct, or analysis and reporting mistakes can render a clinical trial suspect. Hence, confirmation of results in a replicative study, or a trial extending the use of the therapy to a different population, is often warranted.

Clinical trials are time-consuming, labor-intensive, and expensive and require the cooperative effort of physicians, patients, nurses, data managers, methodologists, and statisticians. Patient recruitment can be difficult. Some multi-center (across institutions) clinical trials cost up to hundreds of million of dollars and take five years or more to complete. Prevention trials, conducted in healthy subjects to determine if treatments prevent the onset of disease, are important but the most cumbersome, lengthy, and expensive to conduct.

Many studies have a “window of opportunity” during which they are most feasible and will have the greatest impact on clinical practice. For comparative trials, the window usually exists relatively early in the development of a new therapy. If the treatment becomes widely accepted or discounted based on anecdotal experience, it may become impossible to formally test the efficacy of the procedure. Even when clinicians remain unconvinced of efficacy or relative safety, patient recruitment can become problematic.

Some important medical advances have been made without the formal methods of controlled clinical trials, i.e., without randomization, statistical design, and analysis. Examples include the use of vitamins, insulin, some antibiotics, and some vaccines.

Piantadosi (2005) gives the following requirements for a study based on a non-experimental comparative design to provide valid and convincing evidence:

  1. The treatment of interest must occur naturally
  2. The study subjects have to provide valid observations for the biological question
  3. The natural history of the disease with standard therapy, or in the absence of therapy, must be known
  4. The effect of the treatment must be large enough to overshadow random error and bias
  5. Evidence of efficacy must be consistent with biological knowledge

Examples of non-experimental designs that can yield convincing evidence of treatment efficacy can be found among epidemiological studies, historically-controlled trials, and from data mining.

2.2 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)

2.3 Requirements of Investigators

Physician-Patient Relationship

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)

In his traditional role of healer, the physician’s commitment is exclusively to his patient. By contrast, in his modern role of scientific investigator, the physician engaged in medical research or experimentation has a commitment to promote the acquisition of scientific knowledge.

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 (UCM341008.pdf) from FDA)

Competence:

Investigators should be competent technically (evidenced by education, certification, experience) and humanistically (showing compassion and empathy).

2.4 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)10

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:

Nuremberg Code

  1. Voluntary consent of the human subject is essential.
  2. There must be no reasonable alternative to conducting the experiment.
  3. 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.
  4. The procedures should avoid unnecessary physical and mental suffering and injury.
  5. There is no expectation for death or disability as a result of the trial
  6. The degree of risk for the patient should not exceed the humanitarian importance of the problem to be solved.
  7. The subjects should be protected against even a remote possibility of death or injury.
  8. The study must be conducted by qualified scientists, with a high degree of skill and care throughout the experiment.
  9. The subject can stop participation at will.
  10. 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 (index.html)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.

2.6 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

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

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

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)11

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

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

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 website on Health Information Privacy should be examined for further information about HIPAA requirements on research.

2.7 Conduct

Recruitment

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.

Monitoring

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 Integrity

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

2.8 Reporting

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.

Authorship

‘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.

2.9 Statistical Ethics

The American Statistical Association and the Royal Statistical Society have published similar guidelines for the conduct of their members:

  1. Maintain professional competence and keep abreast of developments
  2. Have constant regard for human rights
  3. Present findings and interpretations honestly and objectively
  4. Avoid untrue, deceptive, or undocumented statements
  5. Disclose financial or other interests that may affect or appear to affect professional statements
  6. Seek to advance public knowledge and understanding
  7. Encourage and support fellow members in their professional development.

In terms of data collection in clinical trials, statisticians should do the following:

  1. Collect only the data needed for the purposes of the inquiry
  2. Inform each participant about the nature and sponsorship of the project and intended uses of the data
  3. Establish the intentions and ability of the sponsor to protect confidentiality
  4. Inform participants of the strengths and limitations of confidentiality protections
  5. Process the data collected according to the intentions and remove participant-identifying information
  6. 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:

  1. Clarify their qualifications to undertake the inquiry
  2. Reveal any factors that may conflict with impartiality
  3. Accept no contingency fee arrangements
  4. Apply statistical methods without regard for a desirable outcome
  5. Outline alternate statistical methods along with the chosen methods
  6. Maintain confidentiality with regard to other sponsors/clients

ASA Ethical Guidelines for Statistical Practice

2.10 Summary

In this lesson, Overview of Clinical Trials, we learned:

  • The role of statistics in clinical research and the definition of a clinical trial.
  • What constitutes a clinical trial and the contexts in which clinical trials are used.
  • 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.

  1. 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)↩︎

  2. 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)↩︎

  3. 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.↩︎

  4. Scott PE. (2004) Medical device approvals: An assessment of the level of evidence. PhD dissertation: Johns Hopkins University, Baltimore, MD.↩︎

  5. Carter RL, Scheaffer RL, Marks RG. (1986) The role of consulting units in statistics departments. Am. Stat. 40:260-264.↩︎

  6. Annas GJ and Grodin MA. (1992) The Nazi doctors and the Nuremberg Code: Human Rights in Human Experimentation. New York: Oxford University Press.↩︎

  7. 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.↩︎

  8. 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.↩︎

  9. Carter RL, Scheaffer RL, Marks RG. (1986) The role of consulting units in statistics departments. Am. Stat. 40:260-264.↩︎

  10. Annas GJ and Grodin MA. (1992) The Nazi doctors and the Nuremberg Code: Human Rights in Human Experimentation. New York: Oxford University Press.↩︎

  11. 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.↩︎