Ethical practice starts when study is designed and should be ongoing

Goal should be winning back the public’s trust

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, and in some ways, that poses as great a conflict as financial conflict," he says. "Also, in clinical practice, there is this issue of conflict that exists between the investigator role and the patient-subject role."

Because of these ethical challenges, the NIH Director’s Council of Public Representatives (COPR) 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. (See recommendations, at bottom.)

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.

The regulations were never intended to be black and white, she says. "Each situation may be different, and we need to address that and balance it with educating the public."

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

• Address challenge inherent in physician-investigator roles. "Possibly, the most inherently conflicted person is the physician who is also the investigator," Strause says.

"I believe physicians make decisions based on what’s best for the patient," she says. "However, that decision may be conflicted when the physician is also the investigator and the patient is also the research subject."

In this case, the physician has agreed to follow a protocol and comply with good clinical practices, Strause says.

Part of the challenge is the traditional relationship between doctors and patients in which patients ask their doctors to tell them what to do, Strause 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, she notes.

"This is potentially coercive and may put undue influence on the potential subject," Strause says. "Some subjects are more vulnerable than others, such as children, individuals with life-threatening illness, or those facing end-of-life care." So the answer resides in better education for both physician investigators and potential research subjects, she adds.

• Be 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 says. "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.

"There was a perception in the community that not enough was done for those individuals," he says. "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.

• Learn 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 ethics analysis, at bottom.)

Using an ethical process model in making decisions is one way of making the process a more neutral one, she says.

"When you’re talking about making ethical decisions on what to do in a protocol, whether to involve older adults who might be depressed and in a nursing home or older adults in a community population, you don’t want a specific perspective," DeRenzo says. "You want a full-blown, expanded neutral ethics analysis."

Also, the use of an ethical model provides guidance that is not persuaded by personal relationships and opinions.

"Part of the problem with ethics is it’s really not quite like other fields," DeRenzo says. "It’s the art of justification."

For example, it doesn’t provide clear-cut answers, only an opportunity to select between a weak ethical argument and a strong ethical argument, she says.

For instance, no one would consider asking a nonmedical family member or friend for a cardiology consultation, but everyone naturally seeks moral guidance from their family and friends, DeRenzo notes.

"You can see this qualitative difference about moral analysis and decision making," she says. "Most people think, and rightly so, of themselves as well-intentioned, decent people."

• Incorporate 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.

For example, suppose an investigator wanted to study depression in the elderly and believed that enrollment could be achieved by using nursing home residents as subjects, she says. The investigator should be following an ethical analysis model before even deciding between the nursing home population and a community population, DeRenzo notes.

"If I don’t stop and think at that point about what are the ethical issues raised by contemplating doing a study of depressed nursing home residents, then I’m already going down the wrong path," she explains.

Ethical questions to consider for the previously mentioned scenario include these:

— Could an investigator study late-life depression without studying nursing home residents?

— How would the nursing home residents’ constraints on their liberty and rights affect the study?

— Is there something about depressed nursing home residents that would be more complex?

"Right from the get-go, ethical issues are going to be embedded in every aspect of running a clinical trial," DeRenzo 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."

COPR Recommendations for Building Public Trust

The NIH Director’s Council of Public Representatives (COPR) held a workshop Oct. 26, 2004, called, "Inviting Public Participation in Clinical Research: Building Trust through Partnerships," in Bethesda, MD, for the purpose of learning more about strategies to build trust and partnerships in clinical trial research. Here are COPR’s recommendations for improving and enhancing the state of clinical research in the United States:

  • Incorporate into the NIH mission and philosophy that it values the involvement of the community in research and create language that expresses this value.
  • Encourage change in the culture of the scientific community to ensure that medical research is viewed in the context of a long-term commitment to the community, not a one-time research study.
  • Investigate ways to provide mechanisms that allow for follow-up health care when a clinical trial or treatment ends.
  • Educate and reorient the current research community to the importance of treating the public as a partner in the research process.
  • Set the expectation across the entire research community, NIH-funded research, and beyond that study results and outcomes should be shared with research participants and the larger community promptly and consistently. This will ensure that the research conducted in communities promotes translational research.
  • Take action to interest community providers in clinical research and maintain their involvement.
  • Provide incentives (not just financial) for primary health care providers and community specialists to play a role in clinical trials.
  • Engage researchers, educators, and academic institutions in incorporating the public’s perspective consistently at every level of training and in both the conduct of clinical research and the publication of findings from that research.
  • Continue to develop and fund efforts to build a national identity for the NIH based on what NIH does best, research and education, as a basis for enhancing public trust in clinical research.
  • Review the role and impact of institutional review boards and other patient protections in the clinical research process because the public views these protections as less effective than they should be.
  • Document and publish best practices from efforts to re-engineer the clinical research enterprise as soon as the NIH begins to see results, so that progress in improving public trust in medical research grows rapidly and steadily.

Ethics Analysis and Thinking Through Issues

Titled "Thinking through the issue/problem case: Applying a systematic approach to ethics analysis," this concise process for ethical analysis was developed by Evan G. DeRenzo, PhD, a bioethicist at the Center for Ethics at Washington (DC) Hospital Center and an adjunct faculty member at Johns Hopkins University in Baltimore.

  1. Who are all the possible interested parties? Think broadly — include not only persons and categories of persons, but institutions/organizations/professions/communities.
  2. 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.
  3. How might various duties and obligations clash/ conflict?
  4. What might be short/long-term consequences of each possible course of action? How confident are you of your predictive accuracy?
  5. What ethical principles are at stake? In tension?
  6. What might be the intentions of the various players? Evaluate the praiseworthiness, or lack thereof, of persons’/organizations’/institutions’ motives.
  7. What appear to be the full range of the possible courses of action?
  8. 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.
  9. 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.
  10. Act with moral courage.
  11. Reflect on outcomes.