Randomized, placebo-controlled clinical trials have long been the gold standard for drug approval. Patients are assigned to either drug or placebo and the comparison between the two groups can provide meaningful data to allow the Food and Drug Association (FDA), pharmaceutical companies, physicians, and patients to understand whether the perceived drug effect (or safety signal) results from the drug or is the result of the placebo effect. While this approach to drug approval is undoubtedly good and often best, is it optimal for all patients? Specifically, is it optimal for children (and families) who have a rare debilitating disease that lacks reasonable treatment options?
Many of you will answer yes to these questions. Perhaps you believe that children living with rare and debilitating diseases are the most vulnerable and most deserving of protection. The parents of these children are also the most susceptible to the placebo effect and the most helpless when confronted with the claim of a miracle cure. You might say that these patients and families, perhaps above all others, deserve the full regulatory strength of the FDA to protect them from pharmaceutical companies.
But what if I told you that there is another way, a way that would allow patients to have more agency and accelerate breakthrough drug deployment? I challenge you to imagine that such a pathway should not only be possible but, under certain circumstances, would be the ethical choice. These circumstances would include the repurposing of an approved drug from one indication to another indication.
Perhaps other special situations would be rare diseases, or children, or grim medical conditions for which there are few options. I believe that there is a moral mandate to create such a pathway, and I urge the FDA and pharmaceutical companies to work together to create a path that allows special groups of patients under special situations to have accelerated access to 21st century cures.
My son belongs to such a special group, and I have led a small cohort of families to observe, document and publish improvements in our children with Prader-Willi Syndrome (PWS). These improvements are unprecedented for this rare disease and the pathway I am proposing would acknowledge the experiences of our small group and place patients like my son in the center of the drug approval process. Such an approach would hasten the approval of therapies that appear to be safe and effective and improve the odds that patients like my son will live through the 21st century.
In particular, I urge the FDA to work with the pharmaceutical company that licensed the new drug pitolisant to leverage our published real-world patient experience data to create an alternative pathway that would allow the pharmaceutical company to expand its label from a first indication of narcolepsy to a second indication of PWS.
HOW I GOT HERE
My perspective comes from my experiences as a scientist and a mother of a child with a rare disease. My formal training in biology began at Macalester, a small liberal arts college, where I fell in love with the scientific process and developed fluency in discussing paradigm shifts and scientific explosions. I was fascinated by the story of Pasteur who demonstrated the efficacy of the rabies vaccine by administering an untested vaccine to a child doomed to die. He did this in response to a mother’s plea to save her son’s life.
After college, I went on to earn a PhD in immunology from Northwestern’s medical school. I did my thesis work in neuroimmunology and postdoctoral work in cellular immunology. While I never lost my love of benchwork, I chose to leave the laboratory, and stay home to raise my children.
While I missed science, I started a career as a medical writer, a job that I could do from home. I covered the incremental steps of medical research, the sporadic controversy and, occasionally, the breakthroughs. I was thrilled to write about the renegade ophthalmologist who treated a patient who was going blind from macular degeneration with a novel therapy. This doctor decided that the patient’s case was hopeless and thus acted on a scientific hunch. He injected a cancer drug, an antibody to vascular endothelial growth factor A, into the eye of the patient. The patient regained sight and the treatment of age-related macular degeneration was forever transformed.
I interviewed scientists and physicians, wrote about medical research, and raised children. I had two beautiful healthy girls followed by a beautiful boy with the rare disease PWS. PWS is known primarily as an endocrinological disease because it has the hallmark features of hyperphagia (constant eating) and obesity.
Once my son was born, I became immersed in the world of PWS. I observed my son closely; I read the medical literature; and I joined the tribe of PWS Moms that formed first on listservs and then on Facebook. As I observed, and read, and shared, I grew to see PWS as a neurological disease—one best treated with neurological supplements and a ketogenic diet.
With this novel approach, my son did well. When he turned 11, however, our world stopped as he experienced a crisis that resembled severe cataplexy and, on multiple occasions, rendered him unresponsive for agonizing minutes. I dove into the medical literature and found a drug recommended for approval in Europe for the treatment of narcolepsy. This first-in-class drug had not yet been approved anywhere in the world, but it was being investigated for many different endpoints. I read the mouse studies and the human studies, and, in totality, the data seemed to be a perfect fit for PWS. The only real disconnect was that it required thinking about PWS as a neurological condition as opposed to an endocrinological condition.
Of course, as a new drug, pitolisant lacks long-term human studies assessing its safety (and efficacy). That said, pitolisant has an excellent safety profile. It is an effective treatment against narcolepsy, and it has a demonstrated ability to normalize sleep-wake states, so much so that it was given breakthrough drug status by the FDA for the treatment of narcolepsy. Pitolisant also had the potential to affect many other problems associated with PWS such as hunger, cognition and muscle tone. For all these reasons, my husband and I reached out to our pediatrician and endocrinologist for help accessing pitolisant. Our son’s response to pitolisant was extraordinary and we caught sight of a future that before pitolisant would have been impossible.
To further assess the benefits of pitolisant, we partnered with a technology-minded PWS Mom to form Chion Foundation and recruited PWS families who wanted to try the drug. We brought the drug to the U.S. via personal importation allowed at the FDA’s discretion and crowdsourced our patient experience data. These dedicated families paid a great deal of money for the medication and reported their experiences, good and bad. We published these novel results in the medical literature as a clinical vignette last month and we have presented our findings at the annual meeting of the American Academy of Neurologists and the national SLEEP meeting. We now have years of data in 10 children with PWS aged two to 16 years.
At approximately the same time that we discovered pitolisant and began to systematically document our patient experience, the U.S. Congress enacted the 21st Century Cures Act. This act tasked the FDA with developing a program to evaluate the use of real-world evidence (i.e., multiple sources of information on health care outside of typical clinical research settings, including patient experience data) in the development of medical products. One such designated use of patient experience data is to add an indication to labeling of an approved drug.
The FDA has responded to the congressional mandate by developing a framework for the use of real-word evidence as well as some initial guidance on patient-centered drug development. We gathered our data in agreement with and in response to this growing realization that there should be a role for real-world data in the drug approval process.
WHAT DO WE KNOW ABOUT PITSOLIANT AND PWS?
In children with PWS (based on the initial sample of 10), pitolisant normalizes sleep-wake states, improves cognition, and appears to normalize the children’s relationship to food. It is well-tolerated, with only one of 10 children having to discontinue the drug because of irritability and behavioral issues. These issues returned to baseline quickly after the child stopped taking pitolisant.
A pharmaceutical company has licensed pitolisant to bring it to the U.S., and it will likely be approved for the treatment of narcolepsy in adults this fall. An investigation for the same use in children is under way in Europe. The pharmaceutical company has indicated a willingness to begin clinical trials in PWS.
THE IMPORTANCE OF PATIENT EXPERIENCE DATA
Unfortunately, while stakeholders agree that patient experience data should be used, there is little precedent for implementing it into the drug approval process. So, here we stand: we have collected the data; we have published the data; but we have no path for directly using the data to improve our population’s access to pitolisant. Our experience is thus a demonstration of the substantial hurdles between the intentions of the 21st Century Cures Act and the reality of the current drug approval process.
Yet, we continue to collect patient-reported outcomes from children with PWS who are benefitting from pitolisant. Each week, as word of the benefit of pitolisant spreads, new patients request prescriptions from their physicians and reach out to Chion Foundation for advice on how to access pitolisant for their children. For many families, the cost of pitolisant is an insurmountable barrier.
Nevertheless, the families begin to collect baseline data in hopes that once FDA has approved pitolisant for narcolepsy, their insurance company will cover it for PWS and they can contribute their experience to the overall understanding of the role of pitolisant as a treatment for PWS. They input their data on the TREND Community data collection platform, an online platform created in response to the Patient-Focused Drug Development initiative expanded by the 21st Century Cures Act to allow for the systematic gathering of patient experience data.
Each additional voice on TREND Community amplifies the message: pitolisant normalizes sleep-wake states, improves cognition and improves relationship with food. These effects translate into improved quality of life not only for our children with PWS but for their siblings and for us as caregivers. The FDA and the pharmaceutical company know of our patient experience data. They have been receptive and encouraging. While their interest and engagement are appreciated, however, it is not enough.
CREATING A NEW APPROVAL PATHWAY
Despite the enthusiasm for real-world evidence, patients continue to queue up for years as clinical trials unfold. Or rather, some patients do. Most families will find ways to access pitolisant, including, once it is approved, turning to insurance companies in the hopes that the insurance companies will cover pitolisant and allow them to see for themselves if pitolisant could help their children. The current reality is that as they do, we at Chion Foundation will continue to work as volunteers to collect patient experience data (both positive and negative) from those families that generously donate their time to document their experiences with pitolisant. Unfortunately, as it stands right now, underresourced parents (those who are poor, have poor health insurance, etc.) will not be able to access pitolisant.
Since we know that the reality is that patients with PWS will attempt to access pitolisant once it is available in the U.S., we ask that the pharmaceutical company and the FDA work together to take on the role that we are performing as volunteers. One way for this to happen is for the pharmaceutical company to perform not a randomized, controlled and prescriptive clinical trial but rather an open-label access study designed to gather both efficacy and safety data on patients with PWS who are aged two years (the age of the youngest child in our cohort) and older.
This would mean that physicians who would like to prescribe pitolisant to our patient population would enroll in the program and report data (both efficacy and adverse events) per the protocol. The protocol would suggest treatment guidelines but, unlike traditional clinical studies, administration of the drug would not be blinded and there would be no placebo. All patients would receive pitolisant free of charge.
The prescribing physician would maintain a primary loyalty to the patient and pitolisant dosing would be established according to each patient’s response to the drug. The data and patient response would be reported to the FDA and the pharmaceutical company as part of the open-label access program. Patients would be free to withdraw from the program at any time and for any reason.
The pharmaceutical company would likely be amenable to this idea. An open access program would have the benefit of facilitating rapid enrollment in the protocol and the freedom to explore more endpoints. Enrollment of rare-disease patients in such a program would almost certainly mean, however, that the pharmaceutical company would not have enough naive patients to enroll in a randomized clinical trial. Thus, accepting the open access path would mean rejecting the traditional clinical trial path. The pharmaceutical company would therefore need assurances from the FDA that data collected under an open access protocol can provide a foundation for adding a second indication to an already approved drug.
I believe that FDA will ultimately determine a path to drug approval that utilizes patient experience data. I also believe that the use of pitolisant as a treatment for PWS is an ideal candidate for a demonstration project of this path. It has several advantages: it is safe; it is not addictive; and, based on our experience, it appears to have a large treatment effect. As with all rare diseases, recruitment for a randomized PWS clinical trial will be challenging and an open access protocol offers a more effective approach to accelerating access to a promising, much-needed therapy.
Moreover, since PWS affects so many issues (cognitive, developmental, behavioral and physiological), any improvement in any one of those domains has the potential to change the trajectory of life for the child and the child’s family. Finally, physicians have successful experience prescribing this drug to children in the U.S. and in Europe.
An open access path to drug approval will require a rethinking, however, of some of the key aspects of how the FDA evaluates drugs for use in a given indication. For example, typically, drugs are approved based upon a dose-response curve. Clinical trial protocols often specify doses without actually knowing how individual patients will respond to doses. The open access approach would mean that data would be collected using a protocol that is dosed in a patient-centered way.
In addition, while it may be possible to consistently measure excessive daytime sleepiness across childhood and use this as an efficacy endpoint, other endpoints such as caregiver burden or clinical global impressions improvement in clinical symptoms may more effectively capture the patient experience. Use of these endpoints would be a recognition of our published real-world, patient experience data. It would also be an acknowledgement that children with PWS on pitolisant are experiencing global improvements in their symptoms beyond what we as parents would have believed possible.
THE ETHICAL SOLUTION
I thus propose that the ethical solution to the problem confronting families with PWS, a solution that is consistent with 21st Century Cures, is for the FDA to specify a path to drug approval that involves real-world, patient experience data. Such a path could take the form of an open access protocol that captures data from physicians prescribing pitolisant to patients with PWS aged two years and older. I acknowledge that the pharmaceutical company that is bringing pitolisant to market in the U.S. would be taking a risk by being the first to explore such a path. This risk, however, would likely save money, lives and families. I also note that this risk has also already been partially assumed by the PWS patients on pitolisant who have systematically gathered and published their data.
Rare-disease patients and caregivers live with an urgency that can be difficult to describe to scientists and those in the traditional drug development and approval pathway. We as patients and parents are left to play the role of the mother who brought her mauled son from rural Alsace to Paris to find Pasteur. We can deliver the patients and we can plead, but ultimately the scientists, the physicians and nowadays the regulatory authority, must help us find the path to access the drug.