Striking the Balance Between Placebo and Harm: Using Epilepsy as a Case Study for How Philanthropy Can Help
The use of placebos in clinical trials is a staple of trial design, in that it serves as a control for comparison and meaningful interpretation of the data. Understandably, as patients enroll in clinical trials, they would prefer to be in the investigational treatment group and not the placebo group; however, clinical trials are designed with the future patient in mind. While there is an ethical obligation to treat the current patient, there is an equally important obligation to ensure that the trial gives interpretable results to treat future patients. But what happens when administration of placebo compromises the well-being of the patient? How can placebo exposure be limited while still maintaining the integrity and interpretability of the trial results?
But what happens when administration of placebo compromises the well-being of the patient?
Researchers across disease communities, are grappling with this question. In 2013, The Helsinki Declaration delved into the ethical issues of placebo use, stating that use of a placebo group is unacceptable when there are clinically proven therapies available or when withholding the intervention poses the risk of permanent harm or death.
This issue has recently come under intense debate in the epilepsy community as a meta-analysis of clinical trials conducted in epilepsy shows that a patients in placebo groups were six times more likely to die from Sudden Unexpected Death in Epilepsy (SUDEP). The meta-analysis conducted by Philippe Ryvelin at Lyon University suggests that ineffective seizure control significantly increases risk for SUDEP. This meta-analysis raised the question of whether patients have limited access to effective standards of care during a clinical trial.
A typical epilepsy clinical trial requires the collection of lead-in information which typically includes 2 months of baseline measurements from the participant. The patient is then randomized to a treatment group receiving either standard of care control drug plus the investigational drug or standard of care control drug plus placebo. At this time, the patient increases onto the test dose over another month. The patient is then treated for 3 months. Overall this results in a 6 month period, in which a clinician cannot make any changes to the standard of care control drug. This extended wait period makes clinicians uneasy because they cannot give their patients the normal standard of care.
In the real world clinical setting, these adjustments happen frequently within the first 6 months and in some ways has become a component of the care standards. Normally, if a patient begins to have worsening seizures, the doctor would typically wait 2-3 months to see if this is disease progression or random chance. But following the 2-3 month time period, if seizures have worsened, the doctor would respond by switching medications or adjusting dosage. These types of adjustments are imperative when seizures worsen, thus the inability to make treatment adjustments in response can be detrimental to the patient and increase the likelihood of SUDEP.
This year, the Epilepsy Foundation hosted the first annual Epilepsy Research Roundtable to discuss this problem as well as solutions related to how clinical designs can be optimized to reduce exposure to ineffective treatments. The roundtable included senior scientists from industry, regulators from the Federal Drug Agency (FDA) and European Medicine Agency (EMA), a bioethicist and senior staff and advisors from the nonprofit epilepsy foundations. As a Senior Associate at the Milken Institute’s Center for Strategic Philanthropy, I was invited to observe the discussions. My goal was to assess what opportunities, if any, philanthropists could have in improving clinical trial designs.
Out of the resulting conversations, it became clear that one of the ways that philanthropists could play a role is by funding the start-up costs to set up a comprehensive database of patients for clinical trial cohorts. Such a database would eliminate the need for the 2 month clinical trial period baseline measurements as they have already been collected throughout the patients care. Although it is only a two month reduction of time spent in a clinical trial, it is a step towards reducing the time a patient spends in a controlled clinical trial arm, thus reducing the potential for harm.
The Milken Institute, Center for Strategic Philanthropy, has launched an Epilepsy Giving Smarter Program, to inform philanthropists on the state of the science for the epilepsy field and potential funding opportunities that they can invest in.
Please click here for our in-depth landscape report highlighting the promising research efforts and critical funding gaps that need to be filled to advance treatment and care.