Clinical trial problems in England raise ethical questions in US

Could IRBs require more information from protocols?

Three weeks after a phase I clinical trial ended terribly wrong, four of the six London, England, volunteers remained hospitalized, and one patient remained in critical condition. No one could have predicted such an outcome for the first trial for a drug to treat cancer and autoimmune diseases.

"I’ve never heard of anything like this before," says Greg Koski, MD, a senior scientist with the Institute for Health Policy at Massachusetts General Hospital, Partners HealthCare System, and an associate professor of anesthesia at Harvard Medical School in Boston, MA. Koski is the former director of OHRP.

TeGenero AG of Wurzburg, Germany, had been studying a humanized agonistic anti-CD28 monoclonal antibody, called TGN1412. TeGenero contracted with Parexel International of Boston to conduct a phase I clinical trial, which involved eight volunteers at the Parexel unit of Northwick Park Hospital in London. Early on Monday, March 13, 2006, six young and healthy volunteers were injected with TGN1412, and two volunteers were given a placebo. According to media reports, the six men given the compound almost immediately suffered serious symptoms, including inflammation, vomiting, severe pain, swollen heads, and unconsciousness. The two men receiving placebos were fine.

The sick men were transferred to critical care at Northwick Park Hospital, where they received organ support, and it was two weeks before the first two of the six men were discharged from the hospital.

The dramatic events of the clinical trial immediately raised questions among clinical trial and IRB experts about what could have been done to prevent the problem. Some say the six volunteers should not have been given the drug at the same time.

"Nothing in the regulations say you can’t give six people the drug at once, but one has to ask why would you want to, apart from the notion of being expeditious in the testing," Koski says. "If one seriously accepts that we need to put the interest of volunteers first and foremost, then the argument for expediency or efficiency doesn’t really hold up because the risk is obviously greater when you do several volunteers at once."

It’s not uncommon for phase I clinical trials of a drug that demonstrated low risk for toxicities in pre-clinical studies to use a design in which a cohort of eight people are simultaneously given the drug and placebo, says George "Trey" Turner, III, RPh, MA, RAC, an assistant clinical professor in the Clinical Research Management Program at Duke University School of Nursing. However, other trials are designed in a way that the drug is administered a week apart.

In the first week, one person would receive a placebo and two would receive the study drug; and in the next week the same would happen, says Anthony T. Dren, PhD, a consulting professor with the Duke University School of Nursing at Durham, NC.

How the doses are divided up is not a detail typically included in the protocol that is submitted to IRBs, but that may soon change as a result of the U.K. clinical trial disaster, Koski says. "I think that’s the take-home message here," he says. "If there had been one person taking the drug, then there’d be one person in the intensive care unit instead of six persons there."

Giving the drug to all six volunteers at once is not the way most people think these studies should be done, Koski notes.

IRBs might become more involved with clinical trial design issues, partly as a result of the disaster and partly as the continuation of a current trend, Turner says.

"For small single site studies, like phase I trials, IRBs that review those studies might require that there be more phase I expertise sitting on the review board," Turner says.

Also there might be closer scrutiny of phase I trials, especially in the United Kingdom, Turner says.

"I wouldn’t be at all surprised if IRBs start asking for detailed information about these designs now," Koski says. "With every incident where we see a tragedy, the closer we look we find out there are things we could have done better, and that’s what is likely to come out of this."

"I think there is closer scrutiny of phase I studies in the U.S. now than 10 to 15 years ago, but it’s somewhat still different than phase II or III studies," Dren says.

However, the England trial disaster is such a rare event that it probably will not have as large of an impact on IRBs and trials as it might first appear, Dren notes.

Compensation questions

Another issue raised as a result of the clinical trial disaster was participant compensation. The volunteers of the TGN1412 trial were paid about $3,500, according to media reports, and some IRB officials might find compensation a little too high.

"As people look at the web site for the trials there likely will be criticism for the ways in which it was advertised as having free food, a pool table, and digital TV," Koski says.

Participation in a study is not the same as attending a resort for the weekend and receiving $3,500, he notes. "That’s a lot for participating in a study, and that’s certainly an inducement for taking risks," Koski says. "For people who are needy and who may not have a steady income that may be an amount that’s excessive."

Koski believes U.S. guidelines would have prevented a similar inducement. However, it’s also likely that the England incident will highlight similar practices in the United States, some say.

"The U.K. subjects were going to be involved in a two-week study, and I have seen studies in the U.S. for around $2,000 for the same type of study," Turner says. "The $3,500 is a little bit high, but it’s not hugely exorbitant."

The compensation would seem very high if the subjects were expected to receive one dose of the drug, but if they were expected to participate for a number of weeks, then it probably wasn’t excessive, Dren says.

In the United States, subjects who enroll in phase I clinical trials often are professional research subjects who participate for a living, Turner notes.

While that in itself may raise ethical questions, it also provides an additional layer of protection to the subjects since they are experienced enough to understand informed consent forms and to know when they are willing to accept certain trial risks, Turner says.

When follow-up care is needed

Another issue that should concern IRBs is the medical care for the participants who fell ill, Koski says. "Who’s going to pay for the medical care for these individuals and for others who are really injured in clinical trials?"

This may be more of an issue in the United States than in a country with socialized medicine, but it does raise the question of how legitimate it is to have clinical trial companies and pharmaceutical companies provide themselves an exemption to long-term medical care when their trial and product are responsible for a volunteer’s illness.

"The form may say something to the effect that if you need immediate medical care it will be provided, but it doesn’t say who will pay for it," Koski says. "And most put the burden for paying for medical care back on the individual and the individual’s private insurance company."

When disasters occur, it underscores the huge need for an appropriate safety net for the clinical trial process, Koski says.

"We should have some sort of no fault indemnification that uses a trust fund or another mechanism established by industry or the government to provide the appropriate care for people harmed in clinical trials," Koski says. "When people participate in clinical trials and believe it is a way to get access to medical care without having insurance and then when the drugs you take in the clinical trial make you sicker, you have a real problem because who’s going to pay for that?"

The United States’ current patchwork system of conducting clinical trials provide an inadequate safety net, and this is something that IRBs and research industry entities will need to reconsider, Koski adds.

"If we want to get serious about it and do it right, we have to find the proper way to put resources into it and try to build an interconnected system," Koski says. "We need a system that works properly, efficiently, and safely."