When a 54-year-old civil engineer broke out in a severe rash while in a clinical trial for a brain tumor treatment, Morris Groves, MD, JD, who was leading the trial, didn't panic. The rash was a known side effect that he had explained might occur, and it was also mentioned in the signed consent form.
Dr. Groves, associate professor of neuro-oncology at the University of Texas M.D. Anderson Cancer Center, admitted the patient to the hospital, gave him steroids, and stopped the experimental drug.
The man's insurance company paid for his care, and he recovered. This scenario is what researchers hope for if a study participant becomes ill as a result of an experimental intervention.
Yet last September, the family of a woman who became ill while taking part in a Parkinson disease study filed suit against two drug makers — Titan and Berlex — and the University of California-Los Angeles (UCLA), whose neurologists had recruited her into the trial. The case was reported by The Wall Street Journal on Jan. 31.
Almost immediately a f er surgery to implant an experimental cell therapy called Spheramine in her brain, the 71-year-old retired kindergarten teacher became incontinent, could not walk, and had severe cognitive impairments. She now resides in a nursing home. Her family sued to recover past and future medical expenses.
Federal law recommends, but does not require, that consent forms spell out whether a patient will be compensated if injured as a result of a trial. (See “Federal Consent Guidelines.”)
THE DAVENPORT CASE
Suzanne Davenport had signed two consent forms: one from UCLA, and another from the University of South Florida, where neurosurgeons had implanted the device. The UCLA consent form stated: “If you are injured as a direct result of research procedures, you will receive treatment at no cost. The University of California does not provide any other form of compensation for injury.”
The second consent form, however, included three statements regarding compensation. The first, from USF, said payment would be provided “to the extent that negligent conduct of a University employee caused your injuries.” The second, from Tampa General Hospital, stated the cost of treatment for any injury “may be the responsibility of you or your insurance company.” The third statement, from Berlex, said: “If because of your participation in the study you require additional care that would not ordinarily be necessary for your condition, this will be provided at no additional cost to you.”
Margaret Holm, JD, the attorney who represented the Regents of the University of California, said the university provided Davenport with routine follow-up care after her surgery in Florida and that the suit against the university has been dismissed. At issue was whether Davenport's symptoms were caused by progression of the disease or by the experimental drug, she said. That question was left to Berlex to be resolved.
“We definitely followed her through and provided her treatment and care for whatever she needed,” Holm said. “The family was contending that there were additional things she needed that in their opinion were related to a reaction to the surgery and the use of the experimental therapy. For that extraordinary care they were dealing with Berlex.”
Rose Talarico, a spokesperson for Bayer, which acquired Berlex in April 2007, told Neurology Today that the parties agreed on a settlement and the lawsuit was dismissed.
Dr. Groves expected more such suits may occur, but not because research trials are badly run. One reason is that with the increased longevity of the population, people entering clinical trials may be frailer and thus more likely to experience side effects. Further, although recently in decline in the US, the number of active clinical trials conducted here may increase in the future, he said.
“In a clinical trial, there are unknown downsides [to the treatment] so it is potentially more hazardous for the neurologist if he or she is an investigator in the trial” compared to the risks of being sued for malpractice in providing basic patient care, he said.
Another sign that liability for investigators may be increasing is a Feb. 20 Supreme Court decision that gave medical device manufacturers protection from legal challenges once a device had been approved by the FDA, but it left open the right to sue the researchers, which may make physicians more of a target, said Margaret Riley, JD, a member of the law faculty at the University of Virginia and its institutional review board.
But be assured that the penalties are typically civil, such as fines, or debarment from Medicare and Medicaid. “No one has ever been jailed because of the outcome of a clinical trial,” said Edward Goldman, JD, associate vice president and deputy general counsel for the University of Michigan. He also teaches a course on legal and ethical issues in clinical research for the AAN at its annual meetings.
If a patient is harmed in a trial, malpractice liability would depend on whether there was negligence or deviations from an acceptable standard of care. “Generally, as long as a physician is carrying out his or her duties or obligations to the patients, there should not be any liability in the context of a clinical trial,” Dr. Groves said. A suit would be less likely to be successful if the harm resulted from a foreseen or known side effect of a medication or device being studied, Goldman said.
INFORMED CONSENT DOCUMENT
This is where the informed consent document plays a key role. According to regulations that govern federally funded research, but can also be applied to all research, a consent form should explain the purpose of the research, expected duration of participation, and procedures to be followed; as well as identifying procedures that are experimental; and describing foreseeable risks.
To create an adequate consent document, “have a long talk with the study sponsor so you really understand what the risks are,” Riley said.
Consent forms should never ask the research participant to agree not to sue the physician, Goldman said, because that provision would not be enforceable.
Most experts also advise that the consent form state any financial agreements you might have with the study sponsor. This includes payments for study-related activities, but also fees received for being in a speaker's bureau, or engaging in promotional activities. Federal law does not require this, but the office overseeing federally funded research recommended this disclosure in 2004.
In the process of obtaining consent, Goldman warned you should be alert to possible “therapeutic misconception,” the impression a potential research participant might have. Even though the investigator is saying that he or she will not benefit personally, “the patient will say, ‘why are you doing it? You must secretly think I will benefit,’” Goldman said. Then if the patient does not benefit, or is in fact harmed, he or she may be more likely to bring a lawsuit because he or she may feel betrayed or misinformed.
Private practice neurologists who are approached by a pharmaceutical or device representative about enrolling patients in a trial must be alert to a host of risks that could increase liability, which are not faced by academic neurologists who may have a legal department and an institutional review board to ensure they stay out of trouble.
“They need to ensure they are not pushing inclusion, Riley said. “When you are trying to get someone in your study, you psychologically downplay the risks, and may overplay the benefits.”
ADDRESS FINANCIAL OBLIGATIONS UPFRONT
Informed consent documents should address the cost of caring for a person who is injured, Riley said.
In a phase 1 trial, where there is no therapeutic intent or benefit to the researcher participant, Medicare and Medicaid probably will not pay, she said, a position that may also be adopted by private insurers that typically follow the government's lead.
Dr. Groves said his own institution does not offer to pay for the care of a patient who is injured in a trial (though it will make an exception if the person is indigent), and checks with the person's insurance company before enrollment to see what might be covered. Trial sponsors, including drug companies, are increasingly unwilling to offer reimbursement, and typically the patient is asked to agree to pay for costs not covered by either the insurance or the sponsor, Dr. Groves said.
And don't forget that states also have laws governing research, including financial disclosure requirements, although they technically only apply to state-funded research, Riley said.
Federal Consent Guidelines
For all federally-funded research, the following information must be conveyed to each subject:
- A statement that the study involves research, an explanation of the purposes of the research and the expected duration of the subject's participation, a description of the procedures to be followed, and identification of any procedures which are experimental;
- A description of any reasonably foreseeable risks or discomforts to the subject;
- A description of any benefits to the subject or to others which may reasonably be expected from the research;
- A disclosure of appropriate alternative procedures or courses of treatment, if any, that might be advantageous to the subject;
- A statement describing the extent, if any, to which confidentiality of records identifying the subject will be maintained;
- For research involving more than minimal risk, an explanation as to whether any compensation and an explanation as to whether any medical treatments are available if injury occurs and, if so, what they consist of, or where further information may be obtained;
- An explanation of whom to contact for answers to pertinent questions about the research and research subjects' rights, and whom to contact in the event of a research-related injury to the subject; and
- A statement that participation is voluntary, refusal to participate will involve no penalty or loss of benefits to which the subject is otherwise entitled, and the subject may discontinue participation at any time without penalty or loss of benefits to which the subject is otherwise entitled.
Source: Ivor Pritchard, PhD, acting director of the Office for Human Research Protections. For more information, visit: www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm.
About the Experimental Drug
Spheramine is made of retinal pigment epithelial cells that are placed on microcarriers and injected into the brain to provide a continuous source of dopamine in brain regions deficient in the neurotransmitter. Titan is developing Spheramine in partnership with Bayer Schering Pharma AG for the treatment of advanced Parkinson disease.
For more information visit titanpharm.com.