History of informed consent might predict trend of greater protection

Ethicist discusses current controversies

Investigators and clinical research professionals who have worked in the clinical trial industry for two or more decades may find themselves astonished by current controversies and debates over informed consent of human subjects.

Last year, Lynn Jansen published an article in IRB: Ethics and Human Research, which questions whether investigators should be sensitive to excessive optimism among potential study participants.1

"It's not a matter of people's cognitive understanding, but their emotional understanding," explains Alan Wertheimer, PhD, senior research scholar in the department of bioethics at the National Institutes of Health in Bethesda, MD. Wertheimer is a political philosopher who has published several books about ethical issues in nonmedical contexts.

"They might be too optimistic about the benefits to them of participating in research," Wertheimer says. "So we might ask whether a person can give valid consent if they're too optimistic."

This is a long distance from the days when informed consent was a novel concept in the research industry.

"There are a lot of moral issues where at the beginning a kind of core ethical position gets established, and then people begin pushing the boundaries out," Wertheimer says.

For instance, when the 20th century civil rights movement began, segregation was commonplace and discrimination based on race was institutionalized across the United States, he notes.

First the government and concerned citizens moved to end segregation and make discrimination illegal. This big push in a new direction was soon followed by further changes, such as the elimination of more subtle discrimination and the initiation of affirmative action, Wertheimer says.

The same journey can be seen with informed consent. "In the history of disasters in research, there was no consent whatsoever, so we had cases of Nazi researchers and the Tuskegee study," he says. Now the concept of informed consent is a core ethical idea that is well established, and so there are trends and ethical debates about activities that would provide even further human subjects protection and refine the consent process.

"What's happening over the last couple of decades is that bioethicists and others are saying that this core ethical idea isn't enough, so let's worry about other things that weren't previously on the agenda," Wertheimer says.

The idea of therapeutic misconception is one concept that pushes the envelope further.

"Now a person has been informed and has given consent, but maybe the person doesn't understand what he or she consented to," Wertheimer says. "Maybe they really don't get it and continue to think that what's going to happen to them is what the investigators believe is best for them."

Bioethicists question whether the person has provided true informed consent when that misconception is the case, he adds.

Another new controversy involves financial incentives to participants of research studies. "Some people think when you offer money to people who need the money that their consent is really not voluntary," Wertheimer says. "So there are worries about whether financial payments are coercive and whether people really do have a choice."

The language sometimes used to describe what bioethicists see as excessive financial payments is "undue inducements," he notes.

"In the classic cases in the history of research, these are not the issues," Wertheimer says. "But the key ethical points are settled, and now we can say it's not enough that there be consent and that people have been given information, but we also need to worry about their level of understanding and their level of voluntariness."

For example, there has been some debate recently about the amount of money that was offered to the participants of the recent English clinical trial in which six young and healthy men became terribly sick on March 13, 2006, after being given the study product.

The volunteers developed symptoms of inflammation, vomiting, swollen heads, and became unconscious after being injected with TGN1412, a humanized agonistic anti-CD28 monoclonal antibody, created by TeGenero AG of Wurzburg, Germany. Four of the men developed multiple organ dysfunctions.

The men participated in a phase I clinical trial conducted by Parexel International of Boston, MA. They were studied at Northwick Park Hospital in London, Great Britain, and their emergency and medical care occurred there, as well.

When recruited, the men had been offered 2,000 pounds if they completed the study. This inducement raised two ethical questions:

  • First, was 2,000 pounds an undue inducement because it's a larger compensation than might be found in most other trials?
  • Secondly, was the requirement that they had to complete the trial to receive the payment an undue inducement to stay enrolled even if they were worried about whether the trial was in their own best interest?

Since the trial ended almost immediately after the men received the first study product, and the subsequent investigation found no evidence of wrongdoing on the part of the clinical trial organization and the study drug's sponsor, these questions were left unresolved. The investigators had no reason to think that the study product was dangerous or anything other than a low risk.

"It's not clear whether people acted unethically or whether it was a tragic case of things having gone wrong," Wertheimer says. "Even when people act in good faith things go wrong and people make mistakes."

However, there is controversy over whether it is ethical to have trial completion bonuses or to withhold all or some payment for participating in a trial until after the trial is completed, Wertheimer notes.

"Some have argued that it's only ethical to pay on a pro rata basis in proportion to the amount of time someone is in the study," he says. "Withholding payment until the end might coerce somebody into staying with the trial when it's in their best interest to withdraw."

Another area of controversy involving informed consent is the length and readability of informed consent forms, Wertheimer says.

"Some people have argued that consent forms are much too long and much too complicated and that they're designed more to protect the researchers than to give the subject information that they can really make sense of," he says.

While one solution is to design shorter consent forms and forms with less sophisticated language, there are concerns about how much information is necessary for subjects to know and how to impart that information, Wertheimer adds.

Informed consent issues and controversies will continue as the ethical debate over human participation in research continues to progress, he notes.

"Among the issues I see on the horizon involve contexts in which people cannot give consent," Wertheimer says. These might involve patients during a medical emergency situation in which there are no surrogate decision makers, he says.

"How do we justify research on people when they are in no position to give consent," Wertheimer says. "This is a context in which it's not a matter of how to improve informed consent, but whether it's permissible and under what conditions it is permissible to give consent."

Reference

  1. Jansen LA. The problem with optimism in clinical trials. IRB 2006;28:13-19.