In last month's column, experienced colleagues shared their views on ethical dilemmas that may confront neurologists who engage in clinical research trials. Over the past few years, the integrity of clinical trials has come under legal scrutiny as well, and associated litigation has increased concomitantly. For this issue, legal experts discussed issues that may result in a trial liability lawsuit and provided advice on how neurologists may limit such exposure.
“The risks of an agent with any prospect of toxicity – which is in fact, most agents – should be carefully weighed,” said H. Richard Beresford, MD, JD, Professor of Neurology at the University of Rochester School of Medicine, Adjunct Professor of Law at Cornell Law School and Chair of the AAN Grievance Committee.
THE GELSINGER CASE
“Where risks are ‘more than minimal’ in clinical trial parlance, they must be fully disclosed,” he said. “A salient case is that of Jesse Gelsinger, an 18-year old from Arizona who had ornithine transcarbamylase (OTC) deficiency and who died in 2000 after participating in a gene therapy trial at the University of Pennsylvania” (Gelsinger v. University of Pennsylvania).
The experiment involved the use of an adenovirus vector to deliver a normal OTC gene to subjects who, like Jesse Gelsinger, had mild forms of OTC deficiency. “However, in his case,” explained Dr. Beresford, “things went awry, and within hours of receiving the viral construct, he developed fever and hepatic dysfunction. He died a few days later from what was believed to be an exuberant immune or inflammatory response to the agent.”
“The case was settled out of court, but it raised issues that are worthy of discussion,” noted Dr. Beresford. “The experiment had been vetted by the NIH Recombinant DNA Advisory Committee, the FDA had approved the vector construct as a biological device, and the institutional review board (IRB) had signed off on the trial. However, it was alleged that several aspects of the trial were improperly handled,” Dr. Beresford said.
“A lead investigator had a financial interest in Genovo, Inc., a private biotechnology company that stood to profit if the viral vector proved to be an efficient agent of gene transfer. Although the IRB did not view this as a disqualifying conflict of interest and the consent form disclosed that the investigator stood to benefit financially from a successful outcome of the trial, a central allegation of the lawsuit was that the scope of the financial interest was not adequately disclosed.
“It was also asserted that informed consent was lacking in other respects. In prior animal studies, four monkeys had died after receiving a similar virus construct, and a few human subjects who had previously received the same construct that was administered to Jesse Gelsinger experienced transient fevers and reversible hepatic enzyme elevations. It was alleged that these data were not disclosed to Jesse or his father, and that his consent to receive the agent was therefore not lawfully informed.
“One of the lessons of this case,” Dr. Beresford continued, “is that investigators should disclose all information that could conceivably influence a potential subject's decision to participate in clinical research, including adverse outcomes in animal testing, reversible side effects in human clinical trials, and the full extent of an investigator's financial stake in the outcome of the research.”
Dr. Beresford urges neurologists to “fully disclose even minor financial interests in clinical research, such as small per subject payments for enrolling patients in clinical trials.”
‘TRANSPARENT’ CONFLICTS OF INTEREST
Sheldon Krimsky, PhD, Professor at the Department of Urban and Environmental Policy and Planning, Adjunct Professor at the School of Medicine at Tufts University in Medford, MA, and author of the book Science in the Private Interest (Rowman & Littlefield, 2003), argues that there are some conflicts of interest for which even transparency is insufficient.
“The main lesson from the Gelsinger case,” he said, “is that there should be prohibitions against inclusion of clinical investigators who have a financial interest in a related clinical trial – this should be preventable and not just disclosable.”
Dr. Krimsky advocates that sponsors of trials – namely, the drug companies – have no control over the data and over the protocols. He proposes the establishment of an independent national institute for drug testing, which would be responsible for vetting the participants in drug testing for their conflicts of interest. “There should be a firewall between the developers of drugs and the testers of drugs so that drug developers would not even be selecting the centers that trial the drugs.”
Currently, that firewall almost never happens, experts say.
Dr. Beresford pointed out that more can be learned from the Gelsinger case. “Investigators should be charged with knowledge of uncertainties or questions raised by an IRB in its deliberations, even if the IRB has approved the trial,” he said. “They should also monitor the progress of the trial and be prepared to stop or interrupt it if some participants experience even transitory adverse effects.
“In addition, it is prudent to pay close attention to the adequacy of the process of obtaining informed consent. Consent forms are sometimes so long and detailed – much like forms used by stockbrokers or insurance agents – that they are difficult for subjects to read or understand. It is the obligation of the investigator not simply to transmit a consent form but to explain it in plain English to the potential subject or surrogates.”
Others experts told Neurology Today that the IRBs should assume responsibility, as well, to ensure that the forms are written in an accessible way.
“Most of the cases that land in court focus on whether consent was adequately informed,” Dr. Beresford said. “Courts by and large do not consider the consent form itself as determining the lawfulness of consent. Rather they look for proof that disclosure was made in terms an average person could comprehend.”
R. Wayne Bond and his law firm, Womble Carlisle Sandridge and Rice, PLLC, have provided defense counsel in more clinical trials cases than any lawyers in the US. Mr. Bond, a keynote speaker at last month's Center for Business Intelligence Annual Limiting Exposure to Liability in Clinical Trials Conference, said, “There are several issues relating to informed consent about which physicians engaging in clinical research should be aware, including the concept of therapeutic misconception.
“Studies show that a high percentage of patients believe that an experimental procedure will offer them more hope than anything on the market … people simply don't realize the true nature of research.”
Indeed, others told Neurology Today, patients with serious illnesses don't go into trials to help investigators obtain data – they are looking for benefit, and investigators rarely disabuse them of that idea for fear that they wont be able to recruit patients into their studies.
“If you are not straight in describing what the study entails, and its associated risks, the patient may convincingly testify, ‘That is not what I understood,’ or ‘It is not what was explained to me’ and there are a number of cases where this has happened,” explained Mr. Bond. Furthermore, even if the patient has signed an informed consent, it is potentially litigable if the patient was persuaded to do so, and the charge of fraud in the inducement is frequently raised.
Mr. Bond cited the case of Lett v. Zahenk (Southern District of Ohio, 2002), which was based on a patient's complaint that she was tricked into participating in a clinical study at Ohio State University Medical Center (OSUMC) when she sought treatment for Charcot-Marie-Tooth syndrome (CMT).
“Although it was acknowledged that a nerve biopsy would be performed for research purposes and not for diagnostic purposes, the consent form was allegedly not presented to the patient until she was on the operating table. Counts in the patient's lawsuit included Breach of the Right to be Treated with Dignity in which the Nuremberg Code, the Declaration of Helsinki, and the Code of Federal Regulations (that established the law with respect to the protection of human research subjects at institutions such as OSUMC) were alleged to be violated.”
David S. Knopman, MD, Professor of Neurology at Mayo Clinical College of Medicine and an investigator in the Mayo Alzheimer's Disease Research Center, said: “The possibility of serious adverse events underscores the need for investigators to have serious conversations about side effects with patients and families and not leave the discussion to a simple one-time reading of a consent form.” He added that any serious adverse event that occurs in the context of a clinical trial may lead to legal repercussions.
Dr. Knopman pointed out that “whenever a novel therapy is used, the unexpected can be expected to occur.” In fact, in the trial using vaccines for Alzheimer disease, 18 of 298 patients developed post-immunization aseptic meningoencephalitis compared with 0 of 74 on placebo, Dr. Knopman said. “Although I am unaware of any litigation related to this trial, it does remind us that the potential is real.”
Actually, Alzheimer disease studies have been the subject of numerous clinical trials lawsuits. “The case of Borison and Diamond, who were convicted of defrauding the Medical College of Georgia of more than $10 million in clinical research funds, illustrates an example of fraud in research,” offered Mr. Bond.
Richard L. Borison, MD, PhD, had been Chief of the Department of Psychiatry and Health Behavior, and Bruce I. Diamond, PhD, was a former Professor of Pharmacology – both ex-employees of the Medical College of Georgia. They were accused of diverting clinical research funds to private companies that they created for their own profit. Dr. Borison was convicted in 1996 of felonies under Georgia State law for racketeering, theft, and false statements and representations, and is serving 15 years in prison.
Dr. Diamond was convicted in 1996 of misdemeanors and felonies under Georgia State law for theft, written false statements, bribery, and violation of the Georgia Controlled Substances Act, and was sentenced to serve five years in prison.
“Plaintiff lawyers are always looking to explain greed as a motivation for anything that goes wrong. Conflicts of interest and ownership are clear examples, but there are other situations which may be less obvious,” said Mr. Bond. “For example, if you speak for a sponsor for whom you also perform clinical trials, you risk the perception of bias. This is another example of something plaintiffs' lawyers claim evidences bias and a greed motivation.”
Furthermore, the repercussions of fraud often extend beyond individual penalties to more global damage to the whole industry and even to patient care. S. Claiborne Johnston, MD, PhD, Director of the Stroke Service at the University of California-San Francisco and member of the AAN Clinical Research Subcommittee, said: “Common law fraud and intentional misrepresentation have undermined some clinical trials. For example, fraud by one investigator in the Second European Stroke Prevention Study (ESPS 2) trial, a study of aspirin, dipyridamole, and the combination for stroke prevention, led to broad mistrust of the trial results even after the offending neurologist's falsified subjects were removed from the analysis.”
The ESPS 2 study, involving 7,000 patients in 13 European countries, was tainted by allegations that a Dutch neurologist at one of the 60 centers involved in the trial fabricated data that led to the disqualification of over 400 patients.
Mr. Bond suggested that investigators remember what he dubs the “Marcus Welby” theory of risk prevention – that of treating patients with dignity and respect. “If you become so busy and don't take enough time with patients, you are much more likely to be a target of a lawsuit, whether it is a med-mal lawsuit or one that results from your participation in a clinical trial. If patients are treated poorly, they can become very creative with their allegations,” he said.