We applaud the Committee on undertaking the 21st Century Cures Initiative. The status quo for discovering, developing, and delivering treatments is failing the rare disease community. We welcome the opportunity to offer our input on behalf of The Race to Yes.
The Race to Yes is a very recent and current effort, formed in December of last year, with the initial purpose of convincing the FDA to provide guidance for accelerated approval for the first-ever treatment for Duchenne Muscular Dystrophy, a rare, universally fatal childhood disease that is the leading genetic killer of children. Duchenne is a devastating, unimaginably brutal disease that robs children of their muscle function, and eventually costs them their lives. Children with Duchenne will need help going to the bathroom at the age when most kids are getting their driver’s license. They will lose the ability to feed and care for themselves. The will endure countless dangerous surgeries to relieve pain. And after only a few precious years, they will leave an empty seat at the dinner table.
The Race to Yes has a mandate – to do everything possible to persuade the FDA to act quickly on behalf of these children. As a direct result of our efforts, in April, the FDA finally relented and provided guidance to the company developing this promising therapy. But what we went through to get there is proof beyond any reasonable doubt that the current system, despite the tools provided to the FDA by Congress, does not work in the best interests of patients, and the need for change is immediate and urgent.
It’s one thing to hope and wait for a treatment that has not yet been developed. But when the treatment exists and it remains out of patients’ reach because of bureaucratic hurdles that block the way, that is wrong. Given the investments made by your Committee in early scientific discovery into diseases like Duchenne through the National Institutes of Health, how can we tolerate a system where those investments are left to languish just short of the finish line of the drug approval process? Your Committee and Congress recognized this challenge when you passed the Food and Drug Safety and Innovation Act (FDASIA) and codified the standard that promising drugs for rare and fatal diseases with no other treatment options can be granted conditional approval while additional testing is carried out to confirm initial indications of safety and efficacy. Like so many other rare diseases, Duchenne has no treatment and no cure, and Duchenne patients have had very little reason to hope – until recently.
A company has been developing a promising therapy for Duchenne called eteplirsen, and by the fall of 2012 had clinical data showing production of novel dystrophin in 100 percent of the 12 patients in the study. In addition to this biomarker data, the study results demonstrated that the kids on the drug fared better clinically than the kids on placebo. While the trial was small and therefore not statistically powered to determine clinical benefit, the efficacy trend was pronounced.
With the passage of FDASIA and its emphasis on applying existing authority for Accelerated Approval to rare and orphan diseases in the same way it was leveraged for HIV and cancer, members of the patient community mobilized in early 2013 to meet with the FDA to communicate that Duchenne was a perfect candidate to benefit from Accelerated Approval and that the results from eteplirsen studies warranted its broader use. The FDA was receptive and in July 2013, the company developing eteplirsen announced that, based on FDA feedback, they would be submitting a New Drug Application before the end of 2013.
But then in November, the FDA inexplicably reversed its position and indicated that before considering even conditional approval, the agency was likely to require a large- scale, placebo-controlled trial. This traditional regulatory path would result in years of delay. Children with Duchenne who could directly benefit from this drug would instead lose their ability to walk and possibly die before getting access to a treatment that had shown a high degree of probability that it would slow the progression of the disease.
We rely on the FDA to expedite, not further drag out, the process of developing safe and effective drugs for our children. The law states that the FDA should be flexible when considering approval of drugs for rare, fatal diseases. But just because you’ve passed a law doesn’t mean it is automatically or consistently followed. As your Committee knows, it takes hard work and significant advocacy and education to change cultures and mindsets to bring them in line with both necessity and the law. Our advocacy campaign was aimed at urging our government to do its job and to do it efficiently, to act on a promising therapy for a rare, fatal childhood disease – a therapy with no adverse effects and significant evidence of efficacy in a population that faces progressive loss of muscle function and certain death at an early age. Nevertheless, patients were needlessly forced to wait for months upon months for action.
There are plenty of disincentives to pushing for change within our existing approval process. The Race to Yes was warned repeatedly that trying to pressure the FDA would backfire and cause the agency to dig in its heels even more. We were not deterred. We will not be deterred as long as our children’s lives hang in the balance and there is something we can do – and that the government should do – to help.
Given our direct and recent experience, it comes as no surprise to us, and should not be surprising to your Committee, that so-called “Right to Try” laws are sweeping the country, that requests for compassionate use are exploding, or that companies are turning to the European regulatory system for earlier approvals. The U.S. system is unreliable and inconsistent, plagued by failures and refusals to communicate, subject to inexplicable and costly delays, and lacking disease-specific expertise and experience. Worse still, there are the implied threats of retribution for pushing too hard and too often the outright dismissal of the patient voice as uneducated on the process and ignorant on the science.
We realized after too many months of delay that it was going to take something extraordinary to get the FDA to move. Many of us have been working for years to encourage action. But we believed an unprecedented, concerted effort was necessary. That is when we as patient advocates formed the Race to Yes. The Race to Yes is a movement and a call to action to change the mindset at the FDA that has failed to evolve consistent with the science and that all therapies should be treated the same. Our goal is simple: to break down the many unnecessary barriers that exist to developing and gaining access to and approval for treatments for rare diseases. We initiated the following actions:
- Launched a formal White House petition to appeal to the FDA’s boss, the President of the United States, to urge the FDA to act. On the first day of our petition drive, we tapped most of our families and friends and cobbled together only 500 signatures. We were competing on the White House petition site with a paid-for petition to make baseball’s opening day a National Holiday. How would we get stadiums of people to sign our rare disease petition – and do so within the 30-day deadline that would guarantee a response? We mobilized on all fronts, in our communities, at work, at school, online. And we appealed to people well beyond the Duchenne community, people who saw a broken system and who wanted to see it fixed. Amazingly, we succeeded in getting more than the required 100,000 signatures in 26 days in March.
- Brought the world’s leading scientists to the meet with the FDA. The scientists came from all over the world. In the 90 minutes we were granted by the FDA, these scientists reviewed both the safety and efficacy data that merited accelerated approval.
- Came to Capitol Hill with these scientists and briefed 100 Members of Congress and congressional staff.
- Sought your help to question the FDA regarding FDASIA and its application to Duchenne muscular dystrophy directly in letters, meetings, and hearings.
- Asked concerned persons to send letters, make phone calls, and transmit emails directly to the FDA.
- Shared our stories with the news media, on CNN, Huffington Post, Fox News, the Washington Post, and in major and local papers and TV stations from coast to coast.
- Repeatedly pressed the company and FDA officials for timelines, for feedback on outstanding issues, and for any shred of information they could share or information on when they would make a decision on how the company could move forward.
Finally, in April of this year, the company announced that the FDA had provided guidance on how they could proceed on eteplirsen, as well as very limited guidance on follow-on therapies. The path forward defined by the FDA will eventually allow for boys around the country to access eteplirsen while the definitive answers needed through further study are collected and without the need for a placebo-arm. While we are pleased that FDA has provided this guidance, it is what we have been requesting from the beginning and what was merited as early as the fall of 2012. And while we are gratified to have achieved this outcome, it has come with a price: lives lost for children who died while waiting for access to this drug; and for countless other children, function lost, including the ability to walk, climb stairs, hug their parents, and pull up their blankets up at night. As parents, our daily lives were consumed and exhausted by the efforts noted above to get the attention and action of the FDA, all while caring for boys suffering from Duchenne. These extraordinary efforts and campaign-style tactics should not have been necessary, but they were. Until the system is fixed, they’ll be required over and over again.
As the Committee seeks and receives recommendations for how to improve the existing process and keep America the global leader in developing treatments and cures, we should start by looking at what the goal is – quick approval for safe, effective therapies for diseases – and work backward to figure out the best way to get us there. To that end, we wanted to share some specific answers to questions raised in your White Paper.
“[A]re there areas or opportunities where the agency is not using [expedited review] authorities to their maximum potential where it should be?”
The FDA is not using expedited review and accelerated approval authorities to their maximum potential. If it was, it would have given guidance regarding eteplirsen almost a year ago. The culture must change.
The path forward for eteplirsen is about so much more than this one specific drug. It’s about creating a new culture, about opening doors and blasting through walls when there aren’t any doors. We believe that in eteplirsen’s specific case, future therapies that use the same mechanism – exon-skipping – should automatically be put on the same accelerated approval track. We believe the FDA should apply this notion to any promising treatment for a rare disease that is based on the same chemistry as a previously approved treatment, implementing a policy of “platform approval.” There is no reason to make the next treatment start over at square one.
“Is the FDA structured and managed to enable the agency to rapidly incorporate innovative new approaches and technologies in its review processes?”
The FDA currently is not structured and managed in a way that facilitates rapid review of treatments for rare, multidisciplinary diseases, and certainly is not structured to “rapidly incorporate innovative new approaches.” The FDA must improve its internal communication and collaboration among its own offices and divisions to ensure everyone who should play a role in the regulatory process for each specific treatment is included. For example, eteplirsen is in the hands of the Division of Neurology. The Office of Orphan Products Development should be much more involved, and we have had to beg the Division of Ethics to get involved and communicate with the Division of Neurology on this treatment. For all treatments, but especially those for rare diseases, from the very start of communication with the drug sponsor, there should be automatic representation from ALL offices and divisions that should play a role in regulating a particular drug’s development.
“What roles can NIH and other outside experts play in the process?”
In the case of Duchenne, there are relatively few clinical experts. None of them work for the FDA. The FDA needs to implement a process in which the most qualified independent clinical experts are consulted and encouraged to share their knowledge at every step of the process. In addition, members of advisory committees and review panels must be required to have some baseline knowledge of the disease in question.
The FDA also needs to collaborate more effectively with patient experts. To be clear, we are not ancillary to the process. We are parents of children subjected to invasive surgical procedures in the name of science and drug development. We are, by painful necessity, smart on the disease and the process. We are significant financial investors. Our children are the end-users. And we are taxpayers. Our role in this process is significant, and the FDA must give us a seat at the table, not lip-service and platitudes. To work well, the process must include reliable dialogue that informs and ensures consideration of relevant information, and that leads to transparent, accountable, sound, and timely decision making. The FDA should not be allowed to hide behind a proprietary curtain to shield substantive communication with patient experts, who may be the only people who have enough knowledge about the disease to accurately evaluate a potential treatment.
“[I]s the randomized, double-blinded, placebo-controlled [trial] model the best approach in all cases?”
The answer is a resounding NO. In the modern age of developing medicines for rarer and more specific forms of diseases, this model no longer applies, and actually unnecessarily harms people. Particularly in the case of rare diseases, the small patient population often cannot reasonably support a traditional trial design. Several considerations should inform the design of a trial, including but not limited to:
- First, the risks to trial participants, both to the participants who are on the treatment, and those who may be on a placebo. In the case of Duchenne, participants who receive the placebo must still undergo painful muscle biopsies – losing muscle and function that they will never get back – without any potential benefit from the therapy being evaluated. The natural history of Duchenne is well understood by the clinical and patient experts. Ethically and clinically, requiring a placebo-controlled trial in this case is unwarranted.
- Second, the size and makeup of the patient population. In the case of Duchenne and other rare diseases, the size of the patient population simply cannot support a traditional trial design. There is a finite number of patients with this disease. Every potential treatment must be evaluated using this same population. There must be an acknowledgement that a traditional large scale trial may be impossible and alternative models must be identified.
- Third, whether the alternative – progressive loss of muscle function and death at a young age, in the case of Duchenne – is worse than any side effects that may occur. The benefit-risk calculation is and must be vastly different for rare, fatal diseases. Particularly in cases where there is no existing treatment and strong evidence of safety and efficacy in a treatment under development, we must err on the side of giving earliest possible access to patients who want it.
- Fourth, too often it seems that regulators are overly focused on the process by which the evidence of efficacy and safety was collected rather than on the data itself. We must urge regulators not to ask, “Does the process by which this data was collected conform to the traditional methodology I am used to?” but rather, “Does this data answer my question? If not, what additional data do I need?” As you note in your White Paper, this is a historic moment in time for scientific advancements. Americans have a chance to take advantage of this miraculous progress and as a result live longer, healthier lives. To grasp that opportunity and ensure that these advancements bring to bear real improvements in the lives of real people, we must make sure that the science serves the patients and not the other way around.
We are grateful for the opportunity to share our views and we are especially grateful that you are listening. We hope you will carefully consider our recent and direct experience with the existing drug approval process, and that you will use us as a resource as this initiative moves forward. We look forward to working with you.
Tracy Seckler and Marissa Penrod On behalf of The Race to Yes www.theracetoyes.org
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