Sanfilippo Syndrome & the Shortcomings of Randomized Controlled Trials

The Food and Drug Administration’s insistence on requiring Randomized Controlled Trials (RCTs) for new therapies that could treat Sanfilippo Syndrome is heartbreaking. Cara O’Neill, a mother to a daughter with Sanfillipo wrote about the situation on January 5th, and Matthew Ellinwood, Chief Scientific Officer of the National MPS Society wrote about it on January 17th. We want to echo their sentiments and continue to put the spotlight on the ongoing situation with Sanfilippo Syndrome and the FDA.

For some background, Sanfilippo Syndrome is a rare and fatal genetic disease which inhibits a person’s ability to break down certain carbohydrates (sugars). As the disease progresses, it results in progressive cognitive decline similar to dementia, difficulties with mobility, coordination, and a host of other physical symptoms. As of right now, there is no known cure and the life expectancy of people with this illness is around 10 to 20 years. Currently, there are no FDA-approved medical therapies for Sanfilippo Syndrome. 

When a condition is as rare and rapidly progressive as Sanfilippo Syndrome, the FDA has the option to grant freedom from the traditional requirements for therapy approval. This method of accelerated approval is vital in certain cases because it allows the trial to bypass the typical need for participants in a year-long placebo group and fill an unmet medical need. In the case of Sanfilippo Syndrome, participants who are in the placebo group face a year of having no alternative treatments and miss their window to stop progression of the disease. 

However, the FDA has not granted clearance for the use of the accelerated approval method for possible Sanfilippo trials. Instead, it is requiring the use of traditional RCTs for treatment approval. This lack of flexibility from the FDA is devastating because there are no current therapeutic options for Sanfilippo patients, meaning they are both leaving patients hung out to dry and delaying any possible assistance that could be just around the corner. Furthermore, RCT’s can have serious shortcomings when used for rare conditions. These challenges range from lack of ethics of preventing ethical concerns about denying patients from getting access to potential life-saving or life-altering care to impacting the flow of funding into Research & Development of new therapies.

Additionally, not only do the smaller populations of rare conditions make recruitment difficult for clinical trials, they also alter the economics of Research & Development and insurance coverage. Since the overall population of those who would ultimately pay for the therapy is smaller, it’s not as attractive to finance the investment of these therapies through longer and more intensive trial periods. If these therapies are not guided through the trial process, lack FDA approval, and are not covered by insurance companies, patients find themselves facing challenges in their health and their wallet. 

One Folia user expanded on this funding angle and how it has impacted them, saying “My personal experience is with being unable to access expensive biologics for my condition since they were officially off label. So supported by research, but no one has paid for the full clinical trial process for them to be on label for my condition. My chief challenge in [this] case is [my] insurance [company] refuses to cover expensive medication when it’s off label....we need funding from FDA and NIH to research rare disease treatments with public dollars since they will be less profitable and attractive for drug companies…the profit angle stops companies from drug development and funding clinical trials.” With no FDA approval, patients struggle to access all possible treatment options for their condition, even if there is research showing therapies as effective for managing their condition. 

Although RCTs are considered the gold standard, other alternative trial designs exist to allow patients access to novel therapies. One popular design is the use of Single Arm trials (SATs). In SATs, researchers can evaluate the effectiveness of a therapy when compared to the natural history of the condition without the need for a placebo group. When strong baselines are established within the trial population, you can measure the within-patient change across the study properly. One disease area that commonly uses SATs is in oncology. SATs have been used for several decades to assess the safety and efficacy of anticancer drugs (Ref). We have collectively determined that cancer patients have the right to experimental treatment options, and there are expected risks that come along with cancer treatments. It is clearly evident how patients with limited options would prefer more, and while some treatments may be less tolerable, ultimately they would have the freedom to decide not to take them. Oncology is a perfect example of why the FDA must re-examine how it is applying its own charter of a risk-benefit ratio in determining which type of trial a drug must go through for approval. 

Given the nature of SATs, the Folia dataset naturally proves itself highly valuable to this trial design. Day-to-day tracking can help shed light on both the natural history of a condition at the overall condition population level and the precise effects of the therapy through our method of establishing patient-to-patient baselines at the symptom level and measuring the daily change from those baselines.

The main question we raise is: does the FDA have the right to make these decisions on behalf of patients, parents, and doctors? Ultimately, the FDA is not the final medical decision-maker. The FDA is required to determine and make known to the public whether the risk of taking a therapy is likely to be significantly greater than the expected benefit. Patients, their families, and their doctors should have the liberty to decide whether or not to explore the available options. We hope that the FDA can broaden its perspectives and consider adopting new approaches to expand the scope of accelerated approval to include a wider range of conditions.