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HD InsightsFeatured Story: Reflections on Right to Try

By Alma Farooque

Policy aims to provide terminally ill patients access to experimental therapies.

The U.S. Food and Drug Administration (FDA) has overseen the responsible commercialization of new drugs and therapies since 1938.1 Pre-clinical (laboratory and animal) and clinical (human) trials data must provide sufficient proof to convince the FDA that a new therapy is both safe and effective before it is approved for marketing. Over time, the FDA’s responsibility has been better defined and expanded into a distinct process, in which drug developers must be approved with their pre-clinical data before they continue into the standard four phases of human trials.

It is not a simple feat to be accepted as a participant into a clinical trial for a new drug. Spots are limited and enrollment criteria can be very strict. Old age, being under- or overweight, and common comorbid conditions like heart disease or migraines can all be exclusionary. The drug-developing companies or their sponsors set these criteria to remove as many competing influences as possible to obtain the clearest picture of the safety and efficacy of their treatment. Ideally this expedites the process to market. Setting these criteria can significantly decrease the chances of serious adverse events like death or disability from occurring during a trial that can cripple a drug’s development, whether by FDA ruling or by plummeting investor confidence. However, this rigidity leaves many ineligible patients to face their fate without access to options and without hope. This is especially true in an incurable disease population like Huntington’s, where some first-of-their-kind therapies are undergoing clinical trials with limited eligibility and a demand that far surpasses the available spots.

As a study coordinator involved with the newest clinical trials in HD, I speak to patients and loved ones about research possibilities daily. Limited spots, challenges in travelling to our site, and, of course, exclusionary criteria are the most common reasons we must turn hopeful people away. These are difficult conversations to have with those suffering from a terminal illness, especially when many are willing to go to extreme lengths to participate. Families that are willing to leave their jobs, move across the country, or spend enormous sums of money in order to travel to our site have become a norm in our center. But about six months ago, when discussing a patient’s prospects for a popular new clinical trial, the patient’s husband told me something I had yet to hear: he said that, by law, his wife had the “right to try.”

On May 30, 2018, the S.204 Trickett Wendler, Frank Mongiello, Jordan McLinn, and Matthew Bellina Right to Try Act was signed into federal law by President Donald Trump. This policy aims to help terminally ill patients in the United States access experimental therapies that are otherwise only available through clinical trials. Eligible therapies must have passed at least a Phase I clinical trial, which are typically small studies that test basic safety of a drug by measuring side effects at increasing dosages. Patients who qualify for Right to Try (RTT), in addition to having a diagnosis of a life-threatening condition, must also have exhausted approved treatment options and be unable to participate in a clinical trial for the drug they are trying to access.2 A licensed physician must certify these qualifications and appeal to the developing company or sponsor directly to exercise a patient’s Right to Try. However, RTT does not mandate companies to provide their product, nor to bear the financial burden if they decide to do so, which brings up a couple questions: how effective is the policy really at reaching its goals, and are those goals truly desirable for patients and the medical community at large?.

Expanded Access

The idea of improving access to experimental therapies outside of highly controlled clinical trials is actually not new. In fact, 41 U.S. state legislatures had passed a version of an RTT law in the years leading up to the federal motion.3 But even before RTT, the FDA itself had established a “compassionate use” program to accomplish the same goal, albeit with some distinct differences. Formally called expanded access (EA), this program began informally in the 1970s and has been codified and overhauled over the decades.4

Under EA, a patient’s physician must submit a formal request to a company to provide the drug to either a single patient, an intermediate-size group, or a large “widespread” population.5 If the company agrees, which they are not required to do, the FDA must then approve an application for a proposed treatment protocol, which is usually drawn up by the requesting physician. This application must clinically describe the patient or group and explain the rationale for compassionate use. It also must detail a treatment plan that ensures patients give fully informed consent, explains the methods and timeline of treatment, and outlines how patients will be monitored for safety. An application must also be approved by an Institutional Review Board (IRB) of the institution where the patients will be treated, and IRBs typically have their own sets of local policies and requirements. If both the FDA and the IRB approve, which may require some protocol modifications, a physician can begin treating his or her consented patient(s) per that approved protocol, making sure to document treatment outcomes and adverse events to report back at regular intervals to both organizations.

Similar to RTT, companies are not financially responsible for providing their product under EA, and they also are not permitted to turn a profit from a product pre-market approval. Under either program, companies can charge the patient to recoup costs directly associated with making the drug available to them. This does not include indirect costs like administrative effort or IRB fees and expenses. However, to avoid revealing the actual cost of their drug and impacting potential profits post-approval, the few companies who do agree to provide their product under EA do so for free. As these compounds can be incredibly expensive, it may not be possible for companies to supply both clinical trials and compassionate use cases with their product. When companies do charge, insurance companies, Medicare, and Medicaid are not required to cover the cost of accessing therapies obtained through EA or RTT, creating financial uncertainty for all patients seeking compassionate use, save for the significantly wealthy.2,4,6

A New Model

If both EA and RTT provide a pathway to experimental therapies, but neither program can force companies to comply or foot the bill, why was RTT instated? The main difference lies in oversight. With EA, a physician works with both the FDA and an IRB to bring an investigational therapy from industry to patient in a process that prioritizes safety, accountability, and rationalized risk. RTT’s attractiveness lies in its simplicity; it is a direct agreement between a physician and a company that does not require FDA or IRB approval. This cuts out not only the administrative burden traditionally associated with these organizations, but also the business risk from reporting safety data.

Indeed, proponents of RTT criticize the FDA’s program as fraught with obstacles that complicate and delay access.7 According to a May 2018 FDA report, surveyed physicians reported that the total time taken to complete the entire EA approval process was approximately 30 hours, and that it was a notably challenging experience, especially for first-time applicants with less familiarity working with IRBs, manufacturers, and the FDA.4 While 30 hours of typically unreimbursed time is no small commitment for a physician and his or her staff, the FDA did do their part to reduce this burden, overhauled their piece of the application (the form that physicians must use to request FDA approval of a proposed treatment protocol), and created a new form in 2016, which now takes 45 minutes to complete instead of eight hours.8,9 It is important to note this form is specifically for individual patient protocols and EA applications to the FDA for intermediate-size groups and larger populations, and expectedly takes longer – around 120 hours – by a 2009 FDA estimate.10 The FDA also concedes that they have numerous areas of improvement in terms of providing more resources to help patients and physicians understand and navigate the program and in terms of easing the use of FDA systems that navigate EA.4 It is difficult to compare RTT’s application process with EA’s due to the recency of the RTT legislature and because RTT’s access process differs by company.

Once an EA application is submitted, the FDA has a surprisingly speedy turnaround. Various factors can shorten or lengthen the review time, including known risks of the investigational therapy, whether it’s an emergency, and whether modifications to the application need to be made for safety purposes. Emergency requests for single patients are generally reviewed in less than one day, as they have much less stringent oversight requirements. Non-emergency requests take approximately eight days for single patients and roughly 30 days for groups. Roughly 1,800 EA applications, individual and group, are received by the FDA annually, and this number has been growing consistently, with an overall approval rate of 99%.4 Of course, there is no way of knowing how many patient requests for EA are denied by a physician or company before an application is prepared for the FDA. Neither physicians nor drug companies are required to keep track of how many requests they receive, let alone how many are rejected or why.11

Industry refusal to participate is cited often as the greatest obstacle to accessing investigational therapies through compassionate use.2,4 This is where RTT’s essential difference of limited oversight is once again key. Not only does RTT include a blanket “no-liability provision” to protect companies from facing patient litigation when providing their investigational drug, but they are also not required to report serious adverse events, including death or disability, immediately. Instead these are compiled in an annual report to the FDA. The FDA is only allowed to use this data to slow or halt review or approval of the drug if it is determined to be “critical to determining safety.”11 In contrast, EA requires companies to immediately report any serious and unexpected event that may be causally related to the study drug, which can provide early identification of important risks.11 While EA data are taken into consideration when the FDA reviews clinical trial data for continued development, safety labeling, and market approval, the FDA does state that it is “not aware of instances in which adverse event information from expanded access has prevented FDA from approving a drug.” The FDA must take into account the less controlled environment of EA treatment and that EA participants are often more advanced in their condition, making them more likely to experience adverse events than their corresponding clinical trial subjects.12

RTT thereby seems to remove one of the perceived disincentives of the EA program to industry, though it has not yet effected industry participation. The first patient received an investigational drug under RTT just in November of 2018, under the California state RTT law set in 2017.13 As a relatively recent federal legislation, time will tell how RTT is developed and redefined, and whether it will change the landscape of compassionate use. There is no doubt that the passage of RTT is an ideological win for those in favor of individual freedoms and government deregulation, but at what cost?

Returning to my patient’s husband who invoked her Right to Try, to my knowledge, none of the companies sponsoring the newest, most promising HD investigational therapies are participating in any compassionate use. In reality, Right to Try is only another right to ask to try, which translates to false hope when key players do not participate. Not only does that request come with no guarantee of physician or industry cooperation, but it disrupts an existing system by bypassing significant measures developed over decades to ensure human safety on a larger scale. This may be attractive to some drug companies looking to gain public approval, but it can pose catastrophic and almost entirely unregulated risk to desperate, easily exploited patients. The EA program is by no means perfect, but the FDA has proven to be willing to balance the interests of seriously ill patients with those of the industry. The agency shows a commitment to adapting and improving EA appropriately, while prioritizing safety of clinical trial participants and, later, consumers.

1Junod SW. U.S. Food and Drug Administration. 2013. FDA and Clinical Drug Trials: A Short History.

Alma Farooque is a Clinical Research Coordinator II in the Department of Neurology at Vanderbilt University Medical Center.

About HD Insights

Our mission is to promote, disseminate, and facilitate research on Huntington’s disease. To fulfill this mission, we are guided by an outstanding editorial board that includes representatives from three continents, academia, industry, and the HD community.