How Will The Federal Right To Try Law Impact Drug Development?

A conversation with Christine MacCracken (Janssen Pharmaceuticals), Beth E. Roxland (Consultant), and Tom Watson (Bionical Group)

Last month, U.S. President Donald Trump signed into law the Right to Try Act (Pub. L. No. 115-176, 132 Stat 1372 [2018]), which allows patients to request the use of investigational drugs — without any involvement from the FDA and regardless of whether the state in which they live has a right to try (RTT) law in place. The passing of the legislation came after years of debate among politicians, the pharmaceutical industry, and other stakeholders about the potential legal, ethical, regulatory, and business impacts of RTT. That debate is unlikely to end any time soon.

To unpack some of implications of this new law, Clinical Leader reached out to three experts on RTT:

• Christine MacCracken, Director, Patient Support, Office of the Chief Medical Officer, Janssen Pharmaceuticals
• Beth E. Roxland,  Senior Consultant on Law, Health Policy, and Ethics
• Tom Watson, EVP of Early Access Programs, Bionical Group

In this Q&A, they share their perspectives about how the RTT law will impact the FDA and its compassionate use pathway, the practice of investigational medicine, and the business of small to mid-size pharmaceutical companies.

---

How is the RTT legislation recently signed into law differ from the FDA’s compassionate use pathway that was already in place?

Christine MacCracken, Janssen: First, it is important to note that the common thread between RTT and compassionate use (also called single patient request (SPR) or expanded access) is to provide a mechanism for patients with life threatening illnesses to access investigational medicines. With that said, the similarities end there.

In the RTT federal legislation, a physician may request an investigational medicine from a company after Phase 1 is complete. For clarity, Phase 1 studies are first-in-human studies, usually conducted with very small groups of people, and are the first assessment as to whether the drug is reasonably safe. Completing this phase means neither that the drug is, in fact, safe, nor that it is effective in treating the disease in which it is being studied.

RTT also does not include an FDA review of the request, as is the case in the compassionate use pathway. This review is an opportunity for the FDA to provide a unique perspective on its understanding of the safety profile of other investigational medicines in the same class as the requested investigational medicine.  This safety check is critical to protect patients.

Beth Roxland, Consultant: In general, both the RTT federal law and the FDA’s expanded access framework (commonly referred to as “compassionate use” when applied to individuals) ostensibly provide pathways for patients suffering from serious or life-threatening conditions, and who have exhausted all other viable treatment options, to request access to experimental interventions currently in development. While there are a few other high-level similarities — including involvement of a patient’s clinician in the request for access, some form of patient informed consent, and, importantly, that neither compel a sponsor to provide an investigational drug to a patient who requests pre-approval access — the federal law and the FDA framework are vastly different.

The FDA does not merely have a process for individuals to request access to experimental interventions outside of clinical trials, but has jurisdiction over all clinical trial testing and approval of drugs (as well as biologics and devices) for market, where the vast majority of patients in need access effective treatments. FDA also has a robust framework for expanded access to experimental interventions, under which thousands of protocols have been approved to treat patients.

The RTT law “fixes” this early access problem by cutting out the FDA or any other independent third-party, such as an institutional review board (IRB), from overseeing provision of these barely-tested therapies to very ill patients. This effectively leaves the public with no entity other than the sponsor of the research in a position to determine whether there is enough data to make any assurances of safety and efficacy of the intervention, and to provide information about the therapy to help patients and their caregivers make key healthcare decisions. Not only does RTT remove — and fail to replace — any third-party that may catch intentional wrongdoing or unintentional errors in proposed dosing or other aspects of the treatment protocols, it also removes all guidance to companies and others trying to balance the many ethical considerations involved in deciding whether compassionate use is appropriate. RTT implementation also has a high likelihood of stymying efficient and appropriate conduct of trials at the site-level for the research entities conducting the clinical trials under FDA rules and regulations, as they must reconcile arguably competing requirements and duties, including with IRB oversight, specific informed consent requirements, and data responsibilities.

Despite the many promotional statements to the contrary, RTT does not mandate that the research sponsor actually provide the experimental drug or device once a patient makes a request. So, the most crucial parts of the pre-approval access situation — whether or not a patient can, in fact, gain to access the intervention, and how long it may take to consider that request for access — is still left to the complete and sole discretion of the sponsor of the research.

RTT laws only affect surrounding aspects of the pre-approval access process — e.g., barring FDA oversight of the process, preventing patients from bringing suit for any harm done (even intentional harms, such as misrepresentation of crucial health information), and allowing insurers to decline any costs associated with administration of the experimental therapy — that are addressed by the laws, often to the detriment of the potential patients, rather than to their benefit.

Do you believe there are ways expanded access could be amended to improve the process for patients?

Tom Watson, Bionical: I believe expanded access, and more broadly FDA regulation, could be improved. The FDA has recognized this in many ways recently and made the process more simple and streamlined for healthcare professionals.

The two additional areas of improvement I would like to see moving forward are:

1. A review of the charging/reimbursement regulations related to expanded access.  These are currently not fit for purpose and, as a result, very few (if any) companies utilize charging for cost recovery.  This limits companies with heavy financial constraints (particularly smaller companies) and leads to lower patient access.
2. Mandatory early-stage discussions with companies on their expanded access strategy.  This sometimes happens but is not currently formalized or mandatory.

Roxland: There are some things the FDA could do, but to truly improve the situation, we should not focus solely on the FDA as if it was “the problem” here. While supporters of RTT assert that the laws are necessary to give terminally ill patients access to experimental interventions that they would not otherwise have access to under current federal mechanisms. This claim has been shown time and again to be inaccurate, as the FDA has for decades had a route for individuals to gain early access, approves nearly 99% of all early access requests that reach its door, and turns around review of such requests in approximately one day if made on an emergency basis, or in three days otherwise.

FDA has also taken several measures in recent years to streamline and simplify the application process, and to provide user-friendly guidance documents and improvements to its public websites.

One area that it might improve upon is explaining to the public why and/ or under what circumstances denying a compassionate use request may be ethical, and/ or explaining how compassionate use is part of the larger picture that ultimately gets effective therapies approved.

Similarly, if FDA believes that the majority of the compassionate use requests should be approved — albeit with necessary changes to proposed protocol, such as dosing — one could argue that instead of preapproval access being a “loophole,” it could be more formalized, like expanded access cohort programs. Also, although the FDA has made many statements that it would consider any data collected outside of controlled clinical trials relative to the context (including the high likelihood of comorbities of patients receiving compassionate use), many, including the Government Accountability Office (GAO), have called for the FDA to formally enunciate how it would treat any such data.

In addition, thoughtful legislation may also play a key role. Two pieces of recent federal legislation that have gone largely ignored in the RTT debate are the 21^st Century Cures Act, and the Hatch Amendment to the Food and Drug Administration Reauthorization Act (FDARA) — These have had significant, positive impact on planning and preparing for expanded access programs and compassionate use requests, transparency of companies’ preapproval access policies, and comprehensively studying and attempting to alleviate some of underlying causes of the vast need and demand for preapproval access to drugs in developments. In conjunction with the policy and transparency requirements in the 21^st Century Cures Act, sponsors and other entities should be encouraged to have robust internal discussions, early in the development process, to prepare for and strategize for early access.

MacCracken: I believe that more can be done to educate and raise awareness about the FDA compassionate use process. RTT was created on the premise that no process exists to request access to investigational agents. That is false. Since the 1970s the FDA has reviewed compassionate use requests, and recent statistics indicate that 99% of those requests are approved.

It is important to note that, while some may criticize that the number of compassionate use requests that have been approved are “small,” many requests received by pharmaceutical companies are triaged to an alternative option and, as a result, are not treated as single-patient or compassionate use requests. 

As current FDA Commissioner Scott Gottlieb has noted, the FDA has indeed taken measures to broaden awareness and understanding of the existing FDA expanded access process. Both the streamlining of the physician application as well as the launch of the Expanded Access Navigator are significant steps forward for patients, providers, and caregivers. As long as there are patients in need of alternative options, awareness and education will always be important.

Do you foresee the new law impacting current practices around investigational medicines? 

MacCracken: In anticipation of the RTT legislation, Janssen assembled a cross-functional work group in 2017 to examine our policy and position relative to RTT. We elected to maintain our established process of reviewing and triaging requests for investigational medicine, and of continuing to require FDA and IRB review and approval of single patient (compassionate use) requests. That position was supported by our chief medical officer and is reflected in our policy.

Preserving FDA input during the request review process was important to us, as the FDA is uniquely positioned to provide guidance on class safety effects, information that companies are not privy to, which helps ensure patient safety.

Watson: I believe the way in which companies respond to requests for their investigational treatments will remain the same, in the short term at least, as I believe companies will continue to utilize expanded access regulations rather than RTT routes. However, I feel they will be under pressure to take a stance on access sooner in the development pathway.  As these laws will inevitable raise patients’ expectations, this will increase pressure on companies.

Will a new law like RTT have a more significant impact on small- to mid-sized pharma companies?

Watson: Not necessarily. As I mentioned previously, I don't believe many companies will respond differently in terms of plans they put in place to provide access. The pressure on companies remains the same, whether large or small. The resource constraints smaller companies have don't get any worse under RTT. However, I foresee that since they will have to provide earlier decisions on access, some may take a stance of not providing access, something that RTT does nothing to address.

MacCracken: It’s too early to say what impact, if any, RTT would have on any size company, large or small. However, regardless of company size, these decisions are always a delicate balance of the needs of the many with the needs of “one.” RTT might increase requests for investigational medicines, so all companies must be prepared to handle requests in a timely and consistent manner. Organizational size does not preclude important discussions around preparation, and where such discussions have not occurred, families who felt they were not heard have made their case in social media campaigns. All companies with drugs in development that have life-saving, or even life-altering, potential must prepare to consistently handle requests for investigational medicines.

There seems to be politicians and patient groups on both sides of this issue. Why does RTT spark such a debate?

MacCracken: At the very heart of this debate are individuals who often are terminally ill and may be without other treatment options. This situation is highly stressful and emotional and forces each of us to examine our mortality and that of our loved ones. It is natural to have hope and to seek additional options — and understanding those options and what they mean relative to a person’s safety and comfort is imperative.  Today, we are fortunate to have such a process through the FDA that allows a treating physician to request an investigational medicine on behalf of a patient, with the assurance that the request will be reviewed in a manner befitting the individual case that it is.

Watson: RTT is a hot-button because it directly taps into what many believe is a fundamental human right ... the right to fight for our own survival and that of our loved ones. Equally, many believe that it is our right, not anybody else's, to decide on how we will do this. As a result, RTT has strong support. It is hard to deny people this right, and the headlines and straplines surrounding RTT are impactful and emotive to large numbers of people, most of whom vote. There are many arguments against the laws, the strongest (in my opinion) being that they do not do anything to improve these fundamental rights for patients, as they do not deliver on their promise of access (or right to try) in their current form. Patients still only have the “right to ask” — that has not changed.

What would be one or two key items you would want patients and their physicians to understand about seeking access to investigational medicines?

Roxland: There are effective mechanisms to request access on the federal level that are at least as effective — and very likely will prove much more effective — than the RTT process. Importantly, the current FDA structure that efficiently allows preapproval access also includes important patient protections, including third-party review of protocols to help ensure safe and efficacious treatment, and accurate information provided in the course of obtaining informed consent.

“Right to try” is not a guarantee of access — as Tom said, it is merely a provision of a right to ask for access, which is a “right” that patients already had under federal law. All stakeholders involved and impacted by access should be encouraged to continue to engage with each other on the very challenging considerations for compassionate use, including standards for decision making, potentially new avenues of regulatory approval and data collection.

Watson: The first would be current expanded access regulations. There is a lack of understanding of the pathways to access to investigational drugs. RTT is likely to confuse this further.

Second would be the importance of real world data collection. Every access point is an opportunity to learn for the benefit of future patients. While the priority is access, meaningful data collection is not mutually exclusive.

MacCracken: A pathway to request investigational medicines already exists in the compassionate use process. It is important that all stakeholders — industry, patients, and others — work collaboratively to educate the healthcare community and the general public about this process, streamline it where possible, and continue to protect the safety of patients.

About The Participants:

Christine MacCracken, MSHEd, BSN, is director, patient support in Global Medical Organization, Office of the Chief Medical Officer, Janssen Pharmaceuticals, where. In this role, she is responsible for developing and implementing programs to support and elevate critical needs of people around the world. She is a passionate advocate for patients and operates by the tenet that “every patient is a person first” to ensure fair and equitable frameworks for access to investigational medicines. In her current role, MacCracken is responsible for CompAC, Janssen’s innovative collaboration with NYU Langone Health to ensure ethical, solutions-based decision frameworks for investigational medicine requests.

Beth E. Roxland, J.D., M.Bioethics, is a senior consultant on law, health policy, and ethics to law firms, life science and medical institutions, and professional and patient associations. She is also affiliated with a number of academic and research entities, and is a frequent author and public speaker. Roxland previously served as Johnson & Johnson’s bioethics and strategy leader in the Office of the Chief Medical Officer. In this role, she relaunched and chaired J&J’s Ethics Committee, created an enterprise-wide consultation service for teams and individuals confronting complex research ethics issues, and provided guidance on issues such as expanded access/ compassionate use.

Tom Watson is EVP of early access programs at Bionical Group. For the last 6 years, he has partnered with pharma and biotech companies to design their strategy for pre-approval access and develop global programs, allowing patients to gain access to treatments that would otherwise be unavailable to them while supporting traditional development pathways. Within this time, Watson has been involved in setting up and running over 200 global programs. He is a member of the New York University School of Medicine Working Group on Compassionate Use and Pre-Approval Access, and he is deeply committed to helping companies with promising medicines in development and the patients they serve.