Ethical practice starts when study is designed

Winning back the public’s trust should be the goal

Public trust in clinical trial research was damaged in the past year because of conflicts of interest issues that arose with the NIH and by front-page media reports about drugs that had been studied and approved, yet were found later to result in deaths among some people who used them.

"What people don’t often realize is that virtually every decision we make has an ethical component to it," says Evan G. DeRenzo, PhD, bioethicist at the Center for Ethics at Washington Hospital Center and an adjunct faculty member in the graduate program in biotechnology at Johns Hopkins University in Baltimore. "We live in a world where we compartmentalize things. [Researchers] think of it as science, and then they think about ethics after thinking about science; and that’s not the way it works."

Many researchers often fail to understand the ethical components to their decisions, including their ties to industry that could be construed as conflicts of interest, several ethical experts say.

Likewise, most researchers will think of conflicts of interest with regard to financial matters, but there also are other types, including process conflicts, says Edward Fuchs, PA-C, MBA, a research associate on the faculty at Johns Hopkins University School of Medicine in Baltimore. Fuchs also is the associate director of the Johns Hopkins Drug Development Unit.

"Investigators, in order to get promoted, need to publish and get data; in some ways, that poses as great a conflict as financial conflict," he says.

Thinking through Issues

The following questions should be part of an ethical analysis:

  • Who are all the possible interested parties? Think broadly — include not only persons and categories of persons, but institutions/organizations/professions/communities.
  • What are the full range of duties and obligations of each potentially interested party? Or at least the primarily interested parties? Think of parties as not only individuals, but institutions and groups, also.
  • How might various duties and obligations clash/ conflict?
  • What might be short-/long-term consequences of each possible course of action? How confident are you of your predictive accuracy?
  • What ethical principles are at stake? In tension?
  • What might be the intentions of the various players? Evaluate the praiseworthiness, or lack thereof, of persons’/organizations’/institutions’ motives.
  • What appears to be the full range of the possible courses of action?
  • Weed out those possible courses of action that appear not to be justifiable based on potentially bad consequences, inability to meet duties and obligations, and/or the ethical soundness of intentions.
  • With the possible courses of action that are left, make explicit — either to oneself, or with colleagues/friends/family whenever possible — the justifications for taking each. Then vigorously scrutinize whether or not those justifications are ethically robust.

Source: Evan G. DeRenzo, PhD, Baltimore.

Because of these ethical challenges, the NIH Director’s Council of Public Representatives held a workshop in Bethesda, MD, last fall — "Inviting Public Participation in Clinical Research: Building Trust through Partnerships." More than 80 participants discussed issues related to public participation and trust and developed a set of recommendations designed to enhance and improve the state of clinical research and build trust.

Regulatory guidelines, recommendations, and an institution’s own policies regarding conflict of interest and ethical responsibility all are part of the base foundation for the house of ethical decision making, notes Linda Strause, PhD, executive director of global site development at Cancervax Corp. in Carlsbad, CA. Strause also is the chair of the IRB for San Diego Hospice and Palliative Care.

Strause, Fuchs, and DeRenzo discuss some of the chief ethical issues the clinical trial industry faces today:

• Addressing inherent challenges in physician-investigator roles. "I believe physicians make decisions based on what’s best for the patient," Strause says. "However, that decision may be conflicted when the physician is also the investigator and the patient is also the research subject."

Part of the challenge is the traditional relationship between doctors and patients in which patients ask their doctors to tell them what to do, she explains. In the case of a physician serving in the role of investigator, the doctor cannot make this decision and cannot apply any influence over the patient/research subject’s decision-making process, Strause notes.

• Being aware of changes in ethical perceptions. Research in recent decades has relied on an ethical model based on the Belmont Report, focusing on issues of respect, beneficence, and justice, Fuchs reports. "We may be in a period where we’re looking at something beyond the Belmont Report. In some cases, it’s described as a relationships model."

According to the relationships model, there is a relationship established between the investigator and community and the investigator and research subjects, and this relationship begins before the trial and should continue after the trial has ended, he explains. "There are issues that may not be what one considers directly relevant to the trial, but they play a role in issues of trust and perception."

For example, although HIV investigators visited sites in the developing world and tried to do everything they could to protect subjects, the communities haven’t always felt enough was done, Fuchs notes. "The community wondered whether the subjects would receive the standard of care that the individual with HIV in the United States would have and, if so, whether they would get access to those medications once the study was concluded."

That disconnect between investigators’ ethical perceptions and the community’s ethical perceptions resulted in some trials being closed briefly until investigators met with local leaders to discuss and define the investigators’ obligations to the community, Fuchs explains.

• Learning an ethical process or analysis. DeRenzo has been working on an ethical process model that would apply to whatever issue arises, and the result of this is an 11-step approach to decision making. (See ethical analysis, on right.)

• Incorporating ethics into the entire research process. Ethical decision making should be a part of the thought process from the time a study is imagined, DeRenzo says.

"Right from the get-go, ethical issues are going to be embedded in every aspect of running a clinical trial," he adds. "So not to approach clinical research and development and design of clinical trial and its context with a heightened sensitivity to moral issues embedded in the study puts us at risk of ignoring those things and not paying enough attention to those things."