Ethical issues in the conduct of clinical trials

BRAF targets in melanoma. Biological mechanisms, resistance, and drug discovery. Cancer drug discovery and development. Volume 82. Ed. Ryan J. Sullivan. Springer (2015)

Regulation and oversight

The independent review process in clinical research is an integral part of minimizing financial and academic conflicts of interest [21, 47, 48], and in the United States these functions are carried out by a diverse group of regulatory bodies; institutional review boards (IRBs), data and safety monitoring boards (DSMBs), the FDA, as well as independent and private review boards.

The major role of the IRB is the determination of the ethical acceptability of a proposed study. The board is typically comprised of at least five members consisting of both men and women without conflicts of interest, at least one of whom has scientific training, one whose focus is on nonscientific issues, and one member from the community (not affiliated with the institution) [49]. The IRB typically determines whether a submitted proposal is exempt for IRB oversight or may undergo expedited review. The main functions of the IRB are: initial and ongoing review of research activities, determination of informed consent, records retention, communication with investigators, and expedited reviews [50].

Ongoing monitoring of clinical trials is typically carried out by DSMBs. The nature of the research study (i.e. phase of drug development, blinded vs. unblinded, single center vs. multicenter) often determine the need for and extent of involvement by the DSMB [51]. The DSMB members must be independent of the investigators and have no competing financial conflicts of interests. Perhaps inevitably, there may be situations in which board members have intellectual conflicts of interest, which are more difficult to avoid.

The primary duties of the DSMB are to: (1) ensure the ongoing safety of clinical trial participants and (2) assess the integrity of the trial design and data analysis in order to increase the chance of valid results [51, 52]. At the conclusion of each DSMB session, recommendations are made regarding continuation, amendment, or cessation of the study. Trials are typically terminated for one of several reasons: unanticipated effectiveness of therapy, unacceptable toxicities, poor accrual, and the low likelihood that collecting additional data would alter a negative result. Additionally, the DSMB may recommend halting a trial if the study question has been answered by evidence that has become available during the course of the trial [51, 53, 54].

Informed consent

Due to the many historical abuses perpetrated against clinical research participants throughout history, informed consent has been incorporated into the existing major ethical guidelines for research. In the United States, the Common Rule (45CFR 46) mandates that research studies obtain informed consent from study participants, and that this process is overseen by the IRB [28], Code of Federal Regulations, (Title 45, part 46). The three concepts that are central to valid consent are generally accepted to be: (1) information, (2) voluntariness, and (3) competence. Informed consent has been written about extensively in the research ethics literature, and an exhaustive review of its history and components exceeds the scope of this chapter. Readers are encouraged to refer to the Oxford Textbook of Clinical Research Ethics [55, 56] for an exploration of the philosophical justifications and regulatory standards of informed consent in research.

Respect for participants

Despite the emphasis on enrollment and consent procedures, ongoing attention to the treatment of study subjects is needed to meet the requirements for respect for participants. Emanuel et al list five areas that must be satisfied [21]:

  1. Protection of privacy and confidentiality of research participants
  2. Revocability of consent (ability to withdraw informed consent and disenroll from the trial at any time, without fear of redress
  3. Access to new information available throughout the course of a study
  4. Proper measures to record and prevent adverse events and undue harm
  5. A means of communicating results from the study to participants

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