After several years of debate over whether to create a federal Right to Try (RTT) law, and, if so, which of the several bills under consideration should be enacted, on May 30, 2018, President Trump signed Senate Bill 204 into law.
The new law allows certain patients to access investigational drugs outside of clinical trials if they have no other FDA-approved treatment options and cannot participate in a trial. This is the second such “compassionate use” pathway: the first, the FDA’s Expanded Access program (EA), has been in existence for decades. In this, the first of a two-part blog post about the new law’s implications, I examine how RTT differs from EA and ask how we might expect the FDA to engage with RTT. In a part 2, tomorrow, I outline a number of key research questions that deserve attention in this new era.
How Does Right To Try Differ From Expanded Access
In EA, the treating doctor asks the company developing the desired investigational product for access, either for a single patient or for a group of patients. If the company agrees to provide the product for a single patient, a proposed treatment protocol is sent to the FDA for review. The agency permits almost all such requests, although some protocols are modified. Next, the proposed protocol goes to the Institutional Review Board (IRB) at the institution where the investigational product would be used for review and approval. When these steps have been completed (emergency requests are handled a bit differently), the patient may receive the investigational agent. Severe adverse events resulting from use of the investigational product must be reported to the FDA and the company that provided the product. RTT follows this same process, but it cuts out both FDA and IRB review of the protocol. It also eliminates the required reporting of severe adverse events to the FDA, except in certain circumstances. Importantly, neither EA nor RTT requires a company to provide the investigational product being requested, meaning that under Right to Try patients actually have only the “Right to Ask” — as they have had for years via EA.
There are notable differences between the two pathways. RTT applies only to investigational drugs; EA includes all types of medical products. RTT requires drugs to have completed a Phase 1 (dosage-setting) trial, while EA can permit access to products in any stage of development. RTT provides liability protection to companies and everyone else involved in therapeutic attempt; EA does not. The biggest difference concerns oversight: in EA, the treating physician, drug company, FDA, and IRB work together to ensure that only patients who have no other treatment options receive access; that costs are appropriate; that informed consent is legally and ethically sound; and that the proposed treatment plan offers a favorable risk/benefit profile for the patient. Under RTT, only the treating physician and the drug company — neither of whom is a neutral party — provide oversight. In the best case, the physician and company can together plan an ethical protocol that offers the highest chance of benefit and the least risk to the patient. In the worst case, an unscrupulous physician and company can work together to sell useless, possibly risky, treatments to patients.
The Goldwater Institute, a libertarian organization, was a key driving force behind the development and passage of RTT. In my assessment, it seems to have focused like a laser on reducing the role of the FDA in compassionate use and crafted a law that does so. But the fact of the matter is that a far bigger obstacle than the FDA for patients seeking access to investigational drugs is companies’ unwillingness to provide their experimental drugs outside of clinical trials. This means that regardless of whether one tries to use the EA or RTT pathway to gain access, the primary obstacle encountered by patients – companies’ denials of requests – remains. Thus, while RTT was a political win for those looking to roll back the power of the FDA, it has not led to patients getting experimental drugs more easily or quickly than they would have via EA.
Of note, however, some pharmaceutical and biotech company executives have told me that they’ve experienced an uptick in the number of requests for investigational drugs — requests that they are handling via EA. (Many companies do not favor RTT because they appreciate having the FDA involved in vetting compassionate use proposals.) In a way, patients may have benefited from RTT after all: not because it created a new pathway that cut the FDA out of the picture, but because it raised awareness that non-trial access was possible, thus galvanizing patients and their doctors to request it.
The NYU School of Medicine Working Group on Compassionate Use and Pre-Approval Access (CUPA), which I co-chair, has argued that high on the list of what is needed to increase access to investigational medical products for patients with no other options is educating doctors, patient advocates, and other relevant stakeholders about EA: when it is appropriate, how to access it, when to seek single patient access versus group access, etc. This identified need for education is in line with my hypothesis that anecdotal reports of an increased number of requests is likely due to the fact that the debate over RTT has raised awareness of pre-approval access, mobilizing doctors and patients to contact companies and seek access.
The first step of testing this hypothesis will be to confirm that there has, indeed, been an increase in requests. For years, the FDA has been transparent about EA requests, making public the number of requests it receives and permits. Thus, a year or two from now, researchers should be able to see if there was an uptick in EA requests received after RTT became federal law. Obviously, the numbers reported by the FDA are only a portion of the requests received by companies, for the company must approve a request before it goes to the FDA for review. So, a more complete accounting of how many requests are being made would rely on numbers that the companies, not the FDA, possess. These numbers, currently and historically, have not been available. However, I perceive a new industry trend for companies to make access request and approval numbers public. (In 2018, Johnson and Johnson, Novartis, and Pfizer have all made at least some of their EA request and approval numbers known.) If companies release these numbers, it would provide insight into the request volume companies are experiencing; however, as there is no such data from before passage of RTT, comparative analysis will not be possible.
Also, if it is only individual companies releasing this data, it will not provide industry-wide data. (Perhaps it is time to revisit the idea, introduced by U.S. Representative Michael McCaul, for the industry to have to annually report aggregated request and response numbers?)
Although I have not yet heard reports of any companies granting access to their products via RTT, I foresee a small number of companies will toy with the idea of making their investigational drugs available via that pathway. In some instances, this could be a ploy to increase visibility of their drugs-in-development (and hence the appeal of their stock). In other instances, companies may actually want to make their drugs available to patients via RTT. In the latter cases, it will be important to learn why a company sees potential in a pathway that many other companies have been choosing to ignore.
During the protracted debate, RTT opponents like myself repeatedly warned of the scenario in which a doctor sold a proprietary investigational drug to patients: in other words, a situation in which the physician and the drug developer were one and the same. In the months since the law has been passed this scenario has not yet been identified, but the press has identified one doctor who has been selling an unapproved product to patients with cancer, claiming the new RTT law allows this.
An Open Question: How Do RTT And The FDA Work Together?
RTT is solely a pathway by which patients can access investigational drugs. The FDA maintains jurisdiction over many areas involving unapproved drugs: for example, a company must receive the agency’s approval to ship its unapproved drugs across state lines, etc. Furthermore, during the congressional negotiations over the legislation, the FDA was given a role in RTT itself: companies that make products available via RTT must submit an annual report to the agency, as well as notify it of severe adverse events in certain situations. It is ironic that RTT, an attempt to diminish FDA authority over investigational medicines, established new agency oversight provisions. However, the filing of an annual report of serious or fatal adverse reactions that might have been caused directly by the investigational drug does not provide timely protection for other patients receiving the product either through a clinical trial or under EA or RTT.
FDA commissioner Scott Gottlieb stated soon after the law was signed that his agency would work quickly to create guidelines for the use of RTT. S204’s sponsor, Senator Ron Johnson of Wisconsin, angrily responded that the purpose of the law was to reduce FDA involvement and that he didn’t want it creating RTT-related guidance. However, if the FDA can’t create guidance, then the law is effectively dead, as no prudent company will use a pathway for which there are no instructions. The RTT law has enough vagueness that someone, or some entity, must translate it into usable rules. In the current stalemate, long-time FDA official Janet Woodcock stated that questions about RTT should be directed to the drug companies, not the FDA.
Not only has the FDA not yet created RTT-related guidance, it has shifted primary responsibility for EA education and assistance away from its widely-respected Office of Health and Constituent Affairs into a new Office Of Patient Affairs. This move is contrary to recommendations made by CUPA, one of which was to increase the authority and staffing of the Office of Health and Constituent Affairs.
The FDA received a good deal of criticism during the push to enact RTT legislation. Most of this was undeserved, as EA has been largely successful in enabling patients to access investigational drugs outside of clinical trials, according to, among others, both the FDA’s own statistics and a 2017 report by the Government Accountability Office. I fear that the effectiveness of EA may be jeopardized, given the agency’s recent changes, and I encourage the community at large to remain vigilant to ensure that a program that has served patients well is not sabotaged, unintentionally or intentionally.
Tomorrow, in Part 2 of this blog post, I will discuss a number of outstanding research questions raised by the passage of RTT.