Many rare disease patients use drugs off-label based on limited data because they have no better options available. In fact, it is estimated that 95 percent of rare diseases do not yet have a single FDA-approved treatment. One of the authors of this article, David Fajgenbaum, is a physician-scientist and a patient with a rare and incurable condition called idiopathic multicentric Castleman disease (iMCD). An off-label treatment saved his life one day after he was administered his last rites in 2010. He has had multiple relapses and received 11 off-label treatments with varying effectiveness. He is currently on an off-label treatment that he identified from lab research, which is approved to prevent transplant rejection, but had never been used for iMCD. He is in his longest remission ever.
While off-label use has proved to be an important tool in the physician's toolkit, the Food and Drug Administration (FDA) has released a recent memo highlighting the increased likelihood of adverse events from off-label use (often due to lack of sufficient evidence) and points out that with off-label use there is a greater potential for wasted health care dollars. Unfortunately, the current system does not incentivize the evaluation of already approved drugs in rigorous clinical trials for rare indications. Thus, most rare disease patients never have the chance to receive a repurposed treatment that could potentially save their lives (which may be sitting at a neighborhood drug store) and others receive off-label treatments with poor clinical data that were destined to fail from the start.
The OPEN ACT
We believe that the OPEN ACT (Orphan Product Extensions Now, Accelerating Cures and Treatments) would begin to fix this serious gap in the drug development landscape. The legislation, which first passed in the House in 2015 as part of the 21st Century Cures Act, but was later removed before final passage, would provide six months of extended exclusivity for any FDA-approved drug repurposed for a new rare disease indication. The legislation was reintroduced by Reps. Gus Bilirakis (R-FL), GK Butterfield (D-NC), and Michael McCaul (R-TX) on February 27, 2017. We believe this legislation could double the number of treatments available to rare disease patients and do so at a cost that is lower than the average orphan drug price.
Some critics, including Aaron Kesselheim and colleagues in the February 2017 issue of Health Affairs, have argued that providing extended exclusivity, as the OPEN Act would do, offers returns that are too generous for industry compared to costs. We disagree, and believe that Kesselheim and colleagues' research falls short in two key areas.
Long-Term Cost Savings
First, Kesselheim and colleagues did not include the law's major benefit in their cost/benefit analysis: the short and long-term cost savings (and lives saved) of effective new treatment options for patients without an FDA-approved treatment. As the vast majority of rare diseases do not have a single FDA-approved treatment, the resulting hospitalizations and administration of off-label treatments with limited data are major health care cost drivers. The cost savings related to any reduction in morbidity and mortality from a new treatment will continue ad infinitum, because once a drug goes generic, it will continue to be used to reduce morbidity and mortality long after patent expiration. Under the current paradigm, as drugs transition to off-patent status, original sponsor companies have no incentive to test these therapies for potential uses in rare disease patients and generic companies do not do any development work. The drug expertise, financial resources, and will to do the repurposing is gone. Family foundations and academics do not and cannot make up the difference.
But the OPEN Act would change this dynamic to encourage needed repurposing clinical studies by the experts that know the drug and can fund the expensive work. Once approved, repurposed orphan therapies could present a lower-cost option priced for the larger markets, unlike specialized drugs specifically developed only for a rare disease. For a sponsor to receive an exclusivity extension through OPEN, companies must fund many pilot, dose finding, and pivotal clinical studies and the results must pass FDA review to get the disease on the label to get the exclusivity extension. These clinical studies would be carried out at academic medical centers, infusing investment into high-quality research jobs even before any potential clinical benefit might or might not be received.
The Cost Of Clinical Trials
The second area where Kesselheim and colleagues' have made inaccurate assumptions is in their decision to base clinical trial cost data on an arbitrary modification of large market drug development costs, without any reference or basis in rare disease development. True costs are many fold higher for rare diseases due to the much smaller numbers of patients per site and extensive efforts required to design evaluations and assess a poorly understood disease. Kakkis et al provide numbers derived from rare disease treatment programs which are two to four times higher. Validation of new assays, clinical methods, Good Clinical Practice compliance procedures, data management and controls, pharmacovigilance reporting, negotiating with regulatory authorities, and establishing the development plan is extensive and should be factored in to any cost/benefit analysis. Kesselheim et al assume that all trials will succeed, but in reality, roughly 70 percent of the trials may fail to succeed, substantially lowering profitability. Even a failed high-quality clinical trial would provide valuable efficacy or safety data for physicians considering off-label use. In these instances, no exclusivity benefit would accrue, but valuable clinical evidence will have been uncovered that would otherwise be unknown to health care providers
Kesselheim et al cite 13 examples of largely oncological drugs with very high price tags that have been repurposed to treat relatively large (albeit rare) cancer patient populations. In these situations, sufficient incentive for repurposing already exists hence the claim that additional incentives are not necessary, but these are only a few examples and hardly illustrative of the true potential impact for rare diseases which are not economically viable. The current situation for follow-on indications is not sufficient in the case of many "ultra-rare" diseases. For most companies, additional incentives are critical for driving and scaling the level of investment needed for clinical trials and navigating the regulatory process. The OPEN ACT would provide an equal incentive for repurposing "ultra-rare" diseases like pediatric cancers that have little financial benefit and are not being sufficiently addressed today. The return does not come from the tiny pediatric cancer population but the extension, which means that extremely small pediatric cancers might finally have a reason for directed development.
Building On A Proven Model
For patients with rare diseases, public policy has been indispensable in helping to jumpstart the clinical development process and save lives. In particular, the Orphan Drug Act of 1983 is widely credited with incentivizing the development of hundreds of new therapies. Similarly, the Best Pharmaceuticals for Children Act (BPCA), which serves as the legislative model for the OPEN ACT, has been called "extremely successful" in incentivizing clinical research for pediatric indications. Since BPCA was signed into law in 2002, there have been over 500 labeling changes which have provided a substantial expansion of the body of evidence used in treatment decisions by health care providers. This has resulted in decreased off-label use of medications and helped identify more promising treatment pathways in pediatrics. Drugs that would have never been expected to be active for a particular rare disease are being tested preclinically and evaluated in clinical trials.
We, along with nearly 180 national patient organizations are eager to see the OPEN ACT become law. Given the record of success and evidence of the positive impact of BPCA, we believe deploying the same incentive for the OPEN ACT could be transformative for millions of rare disease patients.
Authors' Note
Dr. David Fajgenbaum receives research funding from Janseen Pharmaceuticals.
Dr. Emil Kakkis is the CEO of Ultragenyx, a clinical-stage biopharmaceutical company developing novel products for the treatment of rare and ultra-rare diseases.
from Health Affairs BlogHealth Affairs Blog http://ift.tt/2n9Yq1i
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