Richard P. Kline, Ph.D.
September 1, 2014
New York, New York
Informed consent for all subjects is a basic requirement for IRB approval of clinical research in the US. However, what if the subject is unable to give consent? This happens in trials with neonatal or pediatric subjects. Here, it is accepted that parents play an important role in consent, with the child’s assent required in many cases. However, at the other end of the life cycle, failing cognitive assets related to dementia again result in the subject’s inability to consent on his/her own behalf. Increasing life expectancies predict greatly increased numbers with Alzheimer’s Disease, other dementias or cognitive impairment. Such eventualities deprive the stricken elderly of the ability to live productive and independent lives, as well as causing enormous stress on the family, health care providers and the healthcare system. Thus, medical researchers anticipate significant focus on clinical trials designed to test therapies and diagnostics for these cognitive pathologies.
The definitive approach to studying diagnosis and therapy for Alzheimer’s Disease (AD) and related conditions is the longitudinal clinical trial, designed to follow a disease process which can progress slowly over several decades, ending with subjects who are incompetent to consent just at the point when the symptoms are most apparent and intervention most needed. Even a physician, who feels that his best chance, if he himself were to become afflicted, is to be in a clinical trial, can’t insure this option, because he can’t consent to trials whose protocols he has not yet seen and which will occur at some point in the distant future. Even if he were to enroll and consent in a long term longitudinal study, he might not be allowed to remain a participant if the trial requires re-consenting, he is no longer capable of informed consent, and proper preparation was not done during the crafting of the trial documents. Thus, planning for such prolonged trials requires anticipation that subjects’ mental competence may fail right at the most critical point in the trial, requiring careful crafting of the trial documents and procedures during the initial planning.
Thus, to protect the health and rights of the subjects, the integrity of the trial and the large investment of the sponsor, it is a responsibility of the IRB to make sure that the subject’s intent is clearly documented and regulatory due diligence has been done, giving the trial the best chance of success. There is an inherent conflict, unfortunately, between honoring the subject’s wishes at enrollment, at a time when he/she is cognitively intact, while at the same time heeding the subject’s rights later at the point where he/she is not. These rights include the ability to learn and comprehend new information that could affect his/her desire to continue in the trial, as well as exercising the right to discontinue participation at any time (voluntary nature of clinical trials).
What must the IRB consider? Under the circumstances, and particularly for non-minimal risk trials, the consent must be scrupulously complete in terms of spelling out all the potential risks and benefits so that the subject – at the point where he/she is competent - can make the best possible decision. Secondly, since the subject, toward the end of the trial, can no longer knowledgably communicate his/her preferences, steps must be taken to document and monitor the subject’s philosophy, feelings, fears, values and desires in terms of trial participation. Just as with cognitively normal subjects, desires may change and one must be aware that this could happen with subjects diagnosed with early or progressed AD.
At intermediate points, beyond initial enrollment, where there is some diagnostic indication that AD symptoms have started, a psychiatrist or psychologist, with no ties to the study, should interview the subject to determine whether he/she is still competent to consent directly. At the point where a subject is not competent, a pre-identified surrogate, authorized to consent for research on behalf of the subject, should then be asked to participate in the consent. The surrogate, as well as family members and care givers, should be interviewed to determine whether they feel that the subject is steadfast in their original intent, to the extent that can be determined.
For minimal risk studies (e.g. imaging without contrast or radiation; biomarker blood tests requiring small volumes; cognitive testing), the federal waiver of consent may apply, although the subject’s inability to comprehend the study or exercise the right of voluntary participation makes use of this provision less than clear cut. For greater than minimal risk studies, for example, if the risky intervention were therapeutic, one could expect greater IRB leeway than if the risk were associated with a test diagnostic that could would not directly contribute to therapy.
The attached article (Kim, 2012) suggests ways that consent can be explored in more detail using the concepts of autonomy and authenticity. The prior term refers to acts of self determination by competent subjects, a state of competence that must be determined. Although many studies will employ unbiased professionals to determine competence, eventually all advanced AD patients will lose the ability to consent. Furthermore, the consistency of different impartial ‘raters’ to assess competence is not very good. The latter term, authenticity, refers to use of a surrogate judgment substituted for that of the subject. The issue here is not autonomy, but how valid the surrogate’s formulation of the subject’s values and preferences actually is. If a surrogate is aware that the subject has consistently placed “making a real difference by helping others” and “potentially benefiting themselves” as the most important factors in their continuing consent, then a surrogate could decide that, if these factors have not changed, the subject would still presumably favor participation. Using subject’s past performance, and expressed values and desires, allows the surrogate to make an authentic judgment. Likewise, if the subject has consistently expressed disapproval of genetic research, then the surrogate would generate a more “authentic decision” by honoring this choice if the study was modified with an optional genetic component. Clearly, that option would be avoided.
Although advanced dementia subjects may appear cognitively inadequate to formulate the complex reasoning and choices underlying their consent, they can very often articulate a well defined choice about their desire to continue participation, which presumably is consistent with previous choices they have made. These choices can be compared to their values as known to family members and caregivers. Responses to sample clinical trial vignettes, in terms of interest in trial participation, are fairly similar between normal subjects and dementia patients, such that aberrant reasoning can be the basis for invalidating a consent choice. Internal consistency of the expressed desires of an AD subject lends support to the validity of his/her expressed desires.
This issue is further complicated by differences in state law in relation to surrogate consent. For example, New York State (NYS) does not define the pecking order for surrogate consent amongst family members. Thus even though the Federal Government has a waiver of consent IND, it only allows for the waiver as consistent with state law. Since NYS law does not define this ordering, it is unclear who the surrogate is – even though a surrogate is allowed by Federal law. Thus in NY, it is critical for subjects to identify their surrogate consenter (plus a plan for defining a backup) while they are competent. At the time that the Terri Schiavo case was making national headlines as a symbol of patient rights, the minimal risk imaging trial that established the science underlying her father’s court injunction to maintain supportive measures was in jeopardy of being discontinued due to this issue of surrogate consent and NYS law.
This brief outline of issues related to surrogate consent in Alzheimer’s trials illustrates that it is complex and requires prior planning to assure that long and costly trials are brought to completion.
Dr Robert P Weinberg, D.O., J.D.
For the past century, randomized clinical trials (RCT) have become the standard for proving the safety, efficacy and potency of new drugs and medical devices. Medical experimentation with human subjects has undergone a dramatic transformation since the early 20th century when horrendous scientific experiments were conducted by Nazi physicians without any regard for voluntary consent by prisoners with the development of the Nuremburg Code, Helsinki Code and International Bill of Human Rights, which has resulted in a comprehensive set of protections for the rights of persons who may participate in medical experiments and clinical trials.
Today the enforcement and oversight of these protections for human subjects of clinical trials or experiments is embodied in the Institutional Review Board (IRB). In the U.S., any clinical trials involving human subjects must undergo IRB approval or risk loss of sponsorship, loss of federal/state funding, prohibition from publication in peer-reviewed journals, termination of staff privileges at academic centers, and other potent sanctions.
Although there is now a well-established code and protocols for the protection of the rights of human subjects, there continues to be some controversy concerning complex and controversial studies in situations such as: drugs needed in an emergency setting involving life-threatening conditions; treatment of serious illnesses which through their natural course may lead to permanent disability; treatment of minors in the absence of parental consent; treatment of persons who are impaired and may not be able to understand informed consent. There are some guidelines for these difficult situations but they are not always clearcut and without controversy.
Today we are facing an epidemic in West Africa of enormous magnitude involving the Ebola virus, for which there is no known cure and has a 70-90% mortality rate for those who succumb. A few persons have been treated with experimental drugs, and some have survived and others have not. Without an RCT to demonstrate efficacy and potency of these experimental treatments, we will never know whether survival was due to an effective treatment or simply the 30% probability of surviving without treatment.
It is now estimated by the Centers for Disease Control that 1.5 million persons will have become infected by the end of 2014. Pharmaceutical companies have an ethical mandate to test new drugs in a safe and responsible manner, protecting the rights of those human subjects being tested. Yet in many third-world countries there are not IRBs to enforce and protect the rights of human subjects. The international community has taken cognizance of the urgency of this Ebola epidemic and the need to act quickly. Some believe that clinical norms and the validity of RCTs should be relaxed to allow prompt and immediate treatment with any experimental drugs or vaccines that may be available, but this does raise difficult ethical questions.
Regarding the development of a vaccine against Ebola, there has been a steady decline in the number of pharmaceutical companies interested in manufacturing vaccines. Currently there are only four pharmaceutical companies making vaccines, compared with some 26 companies 50 years ago. This decline in vaccine manufacturing is due to economic forces which result in a relatively low return on their investment, owing to a long lead-in time from the validation procedures and manufacturing constraints. Another factor is the development of public distrust of vaccines. During the 1990s, there was a strong rebellion against the mumps, measles and rubella vaccine because of this public distrust. The New York Academy of Medicine ran a survey which showed that about twice as many people were concerned about the side effects of the smallpox vaccine than were concerned about the disease itself.
A recent announcement by GlaxoSmithKline, along with the U.S. National Institute of Allergy and Infectious Diseases, informed that they are now beginning testing of an experimental vaccine against Ebola which is just starting phase I trials to test toxicity. With subsequent phase II and III testing to follow, this vaccine would not be ready for distribution until late in 2015 at the earliest.
The World Health Organization (WHO) is actively involved with the current Ebola epidemic and they have declared that the use of ZMapp, a cocktail of genetically engineered antibodies against Ebola, is ethical for the attempted treatment of Ebola in spite of the fact that its efficacy, potency and safety has never been proven in an RCT. ZMapp is not licensed by the U.S. Food and Drug Administration and has never undergone systemic human trials.
Currently there is only inventory of a small number of ZMapp doses and it may take 4-6 months to manufacture a modest supply of the drug. Another ethical questions is raised by this shortage: with such a limited supply, who should receive the drug first? There will be obvious economic and political pressures to provide the limited supply to the socio-economically advantaged persons in spite of the lack of fairness or justice in such action.
The initial results with ZMapp have been mixed. It was administered to American medical missionaries Kent Brantly and Nancy Whitebol as well as the Spanish Priest Miguel Pajares. Brantly and Whitebol survived the infection, but Pajares died. We do not know if ZMapp is effective against Ebola. Some attempt to make pragmatic arguments that with a limited supply, the health care workers taking care of Ebola victims should be treated first. However, this has translated to Westerners receiving the experimental doses before the Africans.
Unfortunately using social arguments will rarely reach a consensus for the ethical action to follow. In fact, using such social or utilitarian arguments in place of medical criteria for rationing treatment will lead one down the slippery slope. Such arguments lead to the infamous "God" committee in Seattle during the 1960s, when the allocation of the then-scare resource of kidney dialysis machines were decided on the basis of social criteria like church involvement, salaries and wages, and Scout membership. The subsequent use of social criteria for the allocation of scarce resources has since fallen into disfavor.
There are several serious ethical questions raised by the current Ebola epidemic, and we must all join in a concerted effort to address these in a timely manner because close to one million West Africans may die by the end of the year unless action is implemented immediately. We must carefully consider the mortality of this epidemic and the fact that there are currently no known treatments or drugs which would be deprived by running some trials with these experimental drugs and vaccines.