Over the past few years, the conduct of clinical trials has expanded beyond the long-established academic setting into private offices as more neurologists look for revenue streams outside of traditional patient care. As this trend continues, clinicians who are less experienced in this arena may first want to consider some of the potential ethical quandaries inherent in such studies and bear in mind the risks they may incur. These include inadequate consent, liability related to patient injury or death, negligence, allegations of privacy violations, improper compensation and accounting practices, and fraud and abuse.
“There is definitely a role for research that is conducted from a community practice or private practice setting in which subjects are more likely to represent typical patients,” said Michael A. Williams, MD, Assistant Professor of Neurology at the Johns Hopkins University School of Medicine in Baltimore, MD, and Chair of the Ethics, Law, and Humanities Committee at the AAN.
“At the same time, physicians will want to figure out if there is enough reward to warrant the potential risks involved. Even in major institutions, people have gotten into trouble for not following their research protocols or informed consent procedures. Neurologists in private practice will want to be particularly mindful of our errors,” he advised.
VALID INFORMED CONSENT
What are some of the issues that require careful consideration? Several other members of the AAN Ethics, Law, and Humanities Committee weighed in. Peter L. Jacobson, MD, Clinical Professor in the Department of Neurology at the University of North Carolina School of Medicine in Chapel Hill and Director of the Neurology Palliative Care Program, said attaining a valid informed consent is one of the most important responsibilities of a clinical trial investigator.
“Valid informed consent is a process, not just a signature on a piece of paper,” he said. “It protects the human subjects of clinical research and ensures their autonomy by giving them the ability to make a choice.
“There are several key components to this process. We need to ensure that subjects have the capacity to understand the information presented including risks, benefits, and alternative therapies; this information needs to be conveyed in language that is clearly understood; and consent must be voluntary and provided without coercion or undue influence – especially if the subject is a patient as well.
“There needs to be a firewall,” he suggested, “in the case in which the study participant is also a patient; it is best if the physician explains the information and makes certain that the patient comprehends all related issues and an associate attains the signed informed consent.” He added: “We want to advance science research and medicine, and we always want to keep in mind that the patient or subject comes first.”
Michael P. McQuillen, MD, Professor in the Department of Neurology and in the Division of the Medical Humanities at the University of Rochester School of Medicine and Dentistry in New York; said: “There is a need for true clinical equipoise in physicians considering referral of their own patients to clinical trials.” But, he asked, “Is that even possible when physicians get ‘finders’ fees' in today's difficult economic climate?”
Dr. Williams added, “Disclosure of support from a sponsor is important. Many people also believe that if a participant receives sponsor support for a separate activity, such as being part of a speaker's bureau, it should be disclosed as well.
“If there are entrance criteria for subjects, they need to be applied equally. There are subconscious ways of trying to get the ‘best’ patients for the study … and we need to be aware of these in order to avoid selection bias.”
“Having conducted a controlled clinical trial of therapeutic plasma exchange (TPE) in patients with chronic progressive multiple sclerosis receiving combined immunosuppressive therapy, I have a feel for some of the ethical dilemmas that are confronted,” Dr. Dr. McQuillen said. “Out of 200 consecutive patients who met criteria for entrance into a trial which required them to come for TPE once a week – half receiving ‘sham’ TPE, with their plasma given back to them – for five months, while taking hefty doses of prednisone and cyclophosphamide, not a single one refused the offer to participate.”
But, Dr. Williams said, “Patients are prone to a common therapeutic misconception – that they will always receive the study drug. Therefore, as part of the informed consent process, we need to make sure that they understand that this is not necessarily the case.”
Dr. McQuillen added, “There are additional concerns which are strictly ethical including questions relating to the kind of research conducted and the populations in which the studies are to be carried out – children versus adults and persons with and without capacity.”
CONSENT: COGNITIVELY IMPAIRED PATIENTS
Experts agree that doctors should be particularly cautious about ensuring proper informed consent when it comes to cognitively impaired patients. 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 interesting question in dementia patients is who can give informed consent. In cognitively intact people, it is the person you ask, of course, but in cognitively impaired people, the question is more complicated.
“There is no legal standard, but rather a state-to-state variability in the laws about consent in cognitively impaired people. Many Institutional Review Boards follow a common sense view – a mildly affected Alzheimer patient should be able to participate actively in the informed consent process – however, even in this case, the consent of a next-of-kin is usually attained.
“In more severely impaired patients,” he continued, “the consent of the next-of-kin is required, but the patient's assent is also sought. Although many practitioners use the Mini-Mental Status Examination, it provides only rough guidance as to whether a person understands the consequences of participating in a study.
“Other questions that arise in dementia research include whether currently approved drugs should be allowed to be used concurrently or – because there is some controversy as to whether they represent standard of care – is it ethical to discontinue them prior to entry into a clinical trial?”
S. Claiborne Johnston, MD, PhD, Director of the Stroke Service at University of California-San Francisco and a member of the AAN Clinical Research Subcommittee, said: “Lack of informed consent can also be a tricky issue in the stroke world. Often rapid treatment is required and issues about whether a patient is competent to make a decision are common.”
AN ETHICAL DUTY TO PREVENT HARM
“Consent is by far the biggest and most well-known issue in human clinical trials, but it is not the only issue,” said James L. Bernat, MD, Professor of Medicine (Neurology) at Dartmouth Medical School in Hanover, NH. Dr. Bernat, who wrote Ethical Issues in Neurology, 2nd ed. (Butterworth-Heinemann, 2002), said: “Investigators have an ethical duty to protect the subjects because they are exposing them to research risks and harms.”
Dr. Bernat said informed consent is absolutely essential but not sufficient. “We must ensure that the research will generate data that is conducted soundly and interpreted validly, because otherwise even trivial harm to the subject (such as venipuncture) is not acceptable,” he said. “We must promote fair subject selection, not target stigmatized or vulnerable individuals such as prisoners or residents of state institutions and not exclude groups such as women or children without adequate reason.
“We have an ethical duty to distribute risks and burdens of conducting research fairly with those who may share the benefits; we should always protect subjects’ rights to withdraw without penalty; and we should ensure their welfare so their privacy and safety is protected.”
Dr. McQuillen summed up: “The best strategy to reduce risk, prevent litigation, and ensure ethical practice is preemptive: since ethics are the business of being human, truly care for patients, and always tell them the truth – as gently and with as much compassion and understanding of their lot in life as you can.”