Therapeutic Orientation to Clinical Trials

1
Therapeutic Orientation to Clinical Trials

• Henry Silverman

2
Overview

• Diagnose the therapeutic orientation to
  clinical trials
• Point out ethical problems with the therapeutic
  orientation
• Make recommendations for overcoming the
  therapeutic orientation

3
What is Research?

• Definition of Research
• a systematic investigation designed to develop or
  contribute to general knowledge.
• Definition of Human Subject
• A living individual about whom an investigator
  conducting research obtains
• data through intervention or interaction with the
  individual, or
• identifiable private information (e.g. record
  review)

4
The Development of RCTs

• The randomized controlled trial (RTC) emerged in
  the mid 20th century and has become the gold
  standard for evaluating treatments.
• RCTs were conducted in academic medical centers
  in context of a close connection between
  research, education, and patient care.

5
Ethical Distinction Between Clinical Trials and
Medical Care

• RCTs differ from medical care
• Purpose
• Characteristic methods
• Justification of risks
• Relationship between investigators and research
  subjects

6
Purpose of RCTs

• To produce generalizable knowledge about
  treatment efficacy by controlled experimentation
  in groups of patients with the aim of promoting
  improved medical care.
• Contrasts fundamentally with goal of medical
  therapy to provide personal care for particular
  patients.

7
Characteristic Methods

• RCTs include randomization, blinding, placebo
  controls, protocols restricting treatment
  flexibility, and research procedures to measure
  study outcomes.
• All of these methods employed to answer
  scientific questions are foreign to standard
  medical care.

8
Justification of Risks

• RCTs include procedures for scientific purposes
  that carry risks of discomfort or harm to
  subjects without a prospect of benefit to them.
  These are justified by anticipated value of
  knowledge.
• In medical care, the risks of diagnostic
  procedures and treatments are justified by
  potential medical benefits to patients.

9
Relationship

• In medical care, the physician has a fiduciary
  relationship creating the obligation to do what
  is best medically for the patient.
• The investigator cannot have a fiduciary
  relationship, since the primary focus of the
  activity is research, and procedures are involved
  that are not aimed at the best medical interests
  of patient-subjects.

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Distinction Between Research and Medical Care
Therapeutic Orientation to Clinical Trials
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The RCT Dilemma

• How is it possible for physicians to fulfill
  their therapeutic obligation to provide optimal
  medical when enrolling patients in RCTs?

12
RCTs and Medical Care

• In 1981, Thomas Chalmers described the
  relationship between the clinical trial and
  routine medical care as follows
• The practice of medicine is in effect the
  conduct of clinical research . . . Every
  practicing physician conducts clinical trials
  daily as he is seeing patients. The research
  discipline known as the clinical trial is the
  formalization of this daily process.

13
The Therapeutic Orientation To Research

• The therapeutic orientation to clinical trials
  fosters the misconception among patient subjects
  (and also among investigators and ethicists) that
  research is equivalent to medical care.
• If investigators are not clear about how RCTs
  differ ethically from medical care, it is
  unlikely that subjects will understand and
  appreciate the key differences.

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The Current Scene

• Within evidence-based medicine the RCT is
  understood as providing the best evidence for
  guiding treatment decisionmaking.
• Increasingly, industry-sponsored RCTs are being
  conducted by community physicians recruiting
  their own patients.
• The contemporary practice of RCTs promote the
  therapeutic orientation to clinical trials.

15
Clinical Setting Reinforces the Therapeutic
Orientation

• RCTs are conducted in clinical settings.
• Investigators and members of the research team
  wear white coats.
• Research procedures used to answer scientific
  questions are performed with the same medical
  technology used in standard medical care.

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Evidence for the Therapeutic Orientation

• In recruitment advertisements, consent documents,
  and the language reporting the results of RCTs
  investigators are described as physicians and
  research subjects as patients.
• It is frequently claimed that the RCT offers
  patients optimal or state of the art medical
  care.

17
The Therapeutic Orientation in Research Ethics

• Declaration of Helsinki, principle 3
• The Declaration of Geneva of the World Medical
  Association binds the physician with the words,
  The health of my patient will be my first
  consideration.
• Does this belong within a statement of ethical
  principles governing research with human subjects?

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Clinical Equipoise

• Uncertainty regarding the comparative
  risks/benefits between experimental intervention
  and standard of care.
• Investigational Drug A Standard Drug B
• Clinical equipoise is invoked to maintain the
  ethics of the physician-patient relationship
  within RCTs by ensuring that patients are not
  randomized to treatments known to be inferior to
  the standard of care.

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Ethical Problems with Therapeutic Orientation

• Interferes with realizing informed consent
• Diverts attention from moral conflict inherent in
  clinical research
• Obstructs development of a conception of
  professional integrity proper to clinical research

20
Informed Consent and the Therapeutic Misconception

• A variety of evidence suggests that many
  patient-subjects confuse participation in RCTs
  with medical care.
• If subjects fail to comprehend how RTCs differ
  from medical care, then they fall short of full
  informed consent.

21
Moral Conflict

• There is an inherent tension within clinical
  research between pursuing valuable science and
  protecting and respecting subjects.
• When RCTs are seen as optimal medical therapy
  attention is diverted from this moral conflict.
• The therapeutic orientation can promote
  exploitation and overprotection.

22
Exploitation

• When investigators recruit and obtain informed
  consent from their own patients, patients may
  believe that research participation must be in
  their best medical interests or that they ought
  to comply to preserve the relationship.

23
Overprotection

• The therapeutic orientation, bolstered by
  clinical equipoise, would make it impossible to
  perform Phase I trials on healthy volunteers and
  some valuable placebo-controlled trials that do
  not pose undue risks to subjects.
• Placebo controls are no different in principle
  than research procedures that pose risks without
  compensating direct benefits.
• Ethical design and conduct of RCTs should be
  guided by principles appropriate to clinical
  research, not medical care.

24
Professional Integrity

• Professional integrity in clinical research is
  not well developed, owing to lack of clear
  differentiation between the roles of physician
  and investigator.
• To maintain a therapeutic orientation to RCTs
  while acting in a way that is contrary to the
  ethics of medical care constitutes a professional
  stance that compromises integrity.

25
Ethical Requirements of Clinical Research

• To protect subjects there is no need to appeal to
  the ethics of the physician-patient relationship
  or to therapeutic principles such as equipoise.
• Ethical requirements geared to nature of clinical
  research provide adequate protection of subjects.

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7 Ethical Requirements

• Scientific/Clinical Value
• Scientific Validity
• Fair Subject Selection
• Favorable Risk-Benefit Ratio

• Independent Review
• Informed Consent
• Respect for Enrolled Subjects

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Risk-Benefit Assessment

• Differs in clinical research from medical care.
• Minimizing risks and maximizing benefits
  consistent with answering the scientific
  question.
• Permits risks that are not justified by benefits
  to subjects but by value of knowledge to be
  gained.

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Distinguishing Research Procedures from Medical
Care

• Clinical research and medical care for study
  participants are closely connected.
• Professional integrity of investigators demands
  clear focus on the research question and
  recognizing what procedures are being provided
  for care and what for research.

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Overcoming the Therapeutic Orientation

• Raising consciousness about ethically significant
  differences between clinical trials and medical
  care.
• Reconstructing research ethics to focus on
  avoiding harm and exploitation and promoting fair
  terms of cooperation between investigators and
  research participants.

30
Overcoming the Therapeutic Orientation

• Careful attention to the language describing
  clinical trials
• Recruitment advertisements and consent documents
  should be scrutinized with an eye to avoid
  contributing to the therapeutic misconception.

31
Informed Consent Process

• When the investigator has a prior treating
  relationship with the prospective subject,
  someone other than the investigator should obtain
  informed consent (American Medical Association
  Council on Ethical and Judicial Affairs).
• Morin K et al. Managing conflicts of interest in
  clinical trials. JAMA 200228778-84.

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Conclusion

• Clinical research is a socially valuable but
  ethically challenging activity, which calls for
  balancing the pursuit of science and the
  protection of subjects.
• The ethical conduct of clinical research requires
  clarity about how clinical trials differ from
  medical care.