In response to March 5th OC Register article on stem cell therapy
Clinical trials: Trust the process
Patients with Alzheimer’s disease and their families are desperate. Currently, no treatment can cure or even slow the course of this insidious and unrelenting brain disease. Scientists are desperate too. Many of us have committed our lives to improving the way we understand, diagnose, and treat this terrible disorder.
A few weeks ago, I was asked to comment on an anecdote: a single patient whose own fat was liposuctioned and injected into his brain. I was told that the patient and his neurosurgeon were convinced that he had Alzheimer’s disease and that his condition had improved since the procedure. My response was that I hoped this was true because the need for new treatments is dire, but that science must be performed in a careful and rigorous manner in order to produce the evidence necessary to change the way clinical care is provided. I have not seen a protocol for the harvesting of stem cells from human fat (though basic science confirms the possibility) and injecting them into the brain nor a scientific report or presentation of this treatment or studies testing it. Reading the article describing this anecdotal case compelled me to write this essay, which I hope is clarifying and informative.
Patients and families need to understand the importance of the clinical trial process. Simply put, the only path to either incremental (such as a new oral medication that must only be taken once a day instead of twice) or paradigm-shifting (such as a new cancer drug that extends life by months or years) improvements in treatment is through clinical trials. Yet, the most common reason clinical trials fail is because of a lack of volunteers. Thus, for every area of medicine, it is crucial that more people participate.
In clinical trials, we only test promising therapies that we hope will help patients. We never offer a guarantee of benefit, however. In part because of this fact, we never charge people to participate in a clinical trial. Charging someone for an unproven therapy is unjustified. It risks exploitation. In well-designed clinical trials with control groups, trust could be degraded if a patient comes to believe they have paid to receive an inactive or inert intervention. Charging participants risks fairness and justice. Research participants must be selected for scientific reasons. To enroll only wealthy participants who can afford it is akin to enrolling only disadvantaged people who lack other options; it should be impermissible (Science Translational Medicine, July 2015). Lastly, charging participants, rather than securing traditional scientific funding through grants averts one primary step of the scientific review process and protection of participants.
People who volunteer for clinical trials are protected at multiple levels. The first level is the investigator. Every researcher performing human studies is held to standards and laws in this country and is expected to adhere to the basic principles of ethical research. By those same laws, research must be reviewed and approved by an independent ethics board, called an Institutional Review Board, whose primary purpose is to protect the health and rights of the volunteers enrolling in studies. Since most clinical trials aim to test an intervention that ultimately would need to be approved by the US Food and Drug Administration (FDA), the FDA also provides a level of regulatory protection to participants.
Human clinical trials should only be performed after extensive “preclinical” research has been completed and supports both the safety and the potential benefit of the treatment. Only then can human trials begin, but they must be undertaken in a very careful and prescribed manner. Every patient must demonstrate a series of “inclusion” criteria, such as meeting diagnostic criteria for Alzheimer’s disease and being age-appropriate. They also must not meet “exclusion” criteria, such as having had a recent stroke. These criteria ensure that the results can be interpreted (i.e., if the therapy doesn’t work, you aren’t left wondering if it was because the patient’s stroke prevented the benefit) and are more likely to be generalizable (i.e., if you give the therapy to other similar patients you are likely to see the same results).
Most well-designed clinical trials will include a control group. Phase 1, or “first-in-human,” trials test safety and don’t always include a control group but many do. Like in later phase trials that test efficacy, the reason for a control group is that it would otherwise be difficult to know if the observed results are due to the therapy under study or if it is attributable to just being in the trial. This is more commonly known as the placebo effect. Placebo effects can occur in Alzheimer’s disease and in other neurodegenerative conditions. In fact, in Parkinson’s disease, placebo response is greater in surgical trials than it is in trials of oral medications, suggesting that the need to utilize a control group in surgical intervention trials is as great or greater than it is in oral medication trials. The use of placebo in neurosurgical trials brings added challenges. The numerous risks involved in neurosurgery may impact the type of placebo that can be incorporated or the type of patients who are eligible. For example, in one previous neurosurgical intervention trial for Alzheimer’s disease, only patients who maintained the capacity to provide informed consent (another requirement for ethical research) were eligible to enroll.
Thus, despite their critical nature, clinical trials are extremely difficult and even more difficult for brain disease and neurosurgical interventions. The process of developing a new FDA approved drug takes, on average, 13 years. This includes the many phases of clinical trials (Phase 1, 2, and 3) and the multiple studies that typically are included within each phase to achieve the rigorous level of evidence necessary to change the way clinical care is provided. Efforts are underway to expedite this process by streamlining regulations, adapting the process to combine studies when possible, and ensuring that the public understands the essential role of volunteer participants. Though we cannot waste time in our pursuits of improved therapies, we cannot sacrifice the integrity of the scientific process or the need for ethical research. To do so would betray the trust of the people we aim to help, including the patients and families who choose to partner with investigators who are desperate to help them, the right way.