Previous trial disasters resulted in major changes

Gelsinger case is one example

The rare times when serious injuries and deaths occur during clinical trials typically have a long-lasting impact on research institutions’ policies and, sometimes, on governmental regulations, particularly when lawsuits are involved, experts say.

"Everyone is taking a closer look at research because there’s more at stake on all sides," says Jerry Menikoff, MD, JD, an associate professor of law, ethics, and medicine at the University of Kansas, department of history and philosophy of medicine, in Kansas City, KS. Menikoff is a co-author of the book The Ethics and Regulation of Research with Human Subjects, published in 2005 by LexusNexus. He’s also written a book that will be published later this year by Oxford Press, titled What the Doctor Didn’t Say: The Hidden Truth About Medical Research.

Each time the international media publishes reports about a research tragedy, more attention is paid to best practices, and the latest incident involving the six United Kingdom volunteers who became critically ill after their first injection of a phase I compound called TGN1412, created by TeGenero AG of Wurzburg, Germany, proves the point.

In this case, the research industry already is discussing ways to obtain more accurate safety information from pre-clinical testing and how to change dosing practices during phase I studies.

Depending on the results of an investigation into the trial’s serious adverse events (SAEs), there may be modifications to rules, Menikoff says. "But that would involve a careful analysis of, one, what would be the costs — not just monetary — of changes that would prevent this from being repeated, and, two, how common this type of event is."

At present, it’s difficult to say what will be learned from the disastrous study and how it will lead to changes in phase I studies, Menikoff notes.

It’s safe to assume that some changes will be made to the front end of testing, however, says Marc Cardinalli, JD, an assistant general counsel at the University of Nevada, Las Vegas. "We need to await the full story on the English studies," Cardinalli says. "And let’s hope some reason can come out of it rather than an immediate reaction that will serve little good."

Historically, clinical trial problems have created opportunities for plaintiff’s attorneys, as well as for increased regulatory oversight.

For example, litigator Alan C. Milstein has become nationally recognized for his high profile lawsuits on the behalf of participants in clinical trials. His most famous case involved a traditional medical malpractice claim against the University of Pennsylvania after study volunteer Jesse Gelsinger died as a result of a gene therapy trial.

Media reports estimated the university settled the case for between $5 million and $10 million.

"The Gelsinger case had a huge impact," Cardinalli says. "There was a settlement of over one million dollars to the federal government with the University of Pennsylvania paying one-half million and the Children’s Hospital paying one-half million."

Also the doctor researcher involved in the study was banned from research for five years, and the incident resulted in mandatory training for all researchers, Cardinalli adds.

In recent years, the clinical trial field has grown and become more legalized, Menikoff says. "The role of research in our society has changed," Menikoff says. "We’re seeing more and more growth in clinical trials, in particular, and we’re seeing more people participating in research studies."

The growth has resulted in more attention from regulators. For example, within the past 10 years, federal regulators have started to take action against medical centers and shut down noncompliant ones, Menikoff says.

Research studies as a niche field have grown into funding sources with millions of dollars at stake, and the biggest problem from the perspective of pharmaceutical companies has been the human subjects research side of the equation, he says.

"Imagine a big pipe with water in it and there usually is one place where things get clogged and slow down," Menikoff says. "Well, in many cases the human subjects research is the narrowest section of the pipeline."

Clinical trials are where the process slows down and where it takes more time and effort, he adds.

Each study accident contributes to the slow down, but also brings about necessary changes that provide greater protection to the volunteers involved in research.

"Informed consent was brought about by legal challenges and court developments," Menikoff says. "To some extent, it’s certainly a recognized theme that a lot of protections accorded patients came from lawsuits."

The Maryland Court’s decision in Grimes v. Kennedy Krieger Institute of 2001 is expected to have a long-term impact on informed consent and studies involving children.

"The court held that a parent may not consent to painful or harmful research that has no therapeutic benefit to the child," Cardinalli says. "The Grimes case was an extreme example, involving lead paint, and the opinion in the appellate court has encouraged the federal government to enact stricter regulations."

The case also has had a big impact in awakening federal regulators and university research protection offices to the need for additional oversight, Cardinalli notes.

The Grimes case involved young children in Maryland who were enrolled in a Kennedy Krieger study of the impact of various lead abatement procedures, including some with only partial modifications.

According to the Maryland Court’s judicial review of 2001, the researchers went so far as to ask the landlord of the lead-contaminated apartments to give rental priority to families with young children following the abatement interventions.

When the children, who came from poor families, had increasing levels of lead in their blood at study check ups, the parents became worried and some eventually sued the research institute.

The Maryland Court ruled that the informed consent was inadequate, saying, "There was no complete and clear explanation in the consent agreements signed by the parents of the children that the research to be conducted was designed, at least in significant part, to measure the success of the abatement procedures by measuring the extent to which the children’s blood was being contaminated. It can be argued that the researchers intended that the children be canaries in the mines, but never clearly told the parents."

The court further said, "Moreover, in our view, parents, whether improperly enticed by trinkets, food stamps, money, or other items, have no more right to intentionally and unnecessarily place children in potentially hazardous nontherapeutic research surroundings, than do researchers. In such cases, parental consent, no matter how informed is insufficient."

What the Maryland Court missed was the true nature of the relationship between a researcher and a research subject, Menikoff says.

"What the court misunderstood is it seemed to think the whole point of the duty of the researcher is supposed to be protecting the research subject," Menikoff says. "And that misses the point that the researcher exposes the subject to risk for the benefit of others."

The key is to let subjects know what they’re getting into, he says. "The Grimes court basically was saying you can’t impose anything except a minor risk on a kid when enrolling them in a research study," Menikoff says. "A lot of people would say that’s inappropriate and too narrow a rule."

The bottom line is that people do many things that involve their children in greater than minor risk and society condones these activities, Menikoff says.

What each new clinical trial problem brings to the table is a fresh look at the relationship between researchers and research participants, Menikoff says.

"Because the legal system didn’t pay attention to this for a long time it hasn’t been well articulated about what happens between a researcher and a research subject," Menikoff says.

On the state side there are tort laws that allow people to sue if something bad happens to them, but despite common misconceptions, the federal common rule does not create rights for research subjects, he says.

"In many areas the federal government will pass rules and not give anyone a right to sue, and that’s what happened in the research regulations," Menikoff says. "So the common rule does impose responsibilities on researchers, but if the researcher has screwed up, the person who is harmed doesn’t have the right to go into federal court and sue."

Instead, lawsuits are brought in state courts, using medical malpractice conventions.

"We’re at the start of a whole new era of recognizing what the relationship is between doctor researchers and patient subjects," Menikoff says.