On May 30, 2018, the four-year Right to Try (RTT) movement culminated in a new federal law, with the stated goal of providing terminally ill patients with a new route of access to early phase investigational drugs that are currently in clinical development and not approved or generally available to all patients in need.

RTT laws seek to remove federal Food and Drug Administration (FDA) oversight and regulations from the pre-approval process, in which patients seek to access experimental drugs in development outside of the clinical trials in which the drugs are being tested,¹ despite the fact that terminally ill patients have had the right to request such access under FDA regulations for decades through the Expanded Access Program (EAP). Indeed, thousands of patients have successfully gained access under the EAP mechanism; the FDA approves nearly 99% of all compassionate use requests,² usually in approximately three days. There have also been additional FDA initiatives to streamline and simplify the EAP process for both sponsors and requesting physicians, and to enhance public understanding of federal mechanisms for patients to request pre-approval access. (Additional available tools include the FDA Expanded Access: Information for Industry page and an Expanded Access Navigator.)

In spite of their titles, RTT laws do not provide an actual “right” to gain access to a drug in development upon request; they grant only a right to request access—a request that is already permitted under current FDA regulation. There is no included mandate to provide an experimental product upon a patient’s request, leaving the crucial aspects of access to the discretion of sponsors, manufacturers, and institutions. In lieu of such a mandate, the laws contain a host of provisions intended to make the practical environment around providing pre-approval access more hospitable, in hopes that this will encourage sponsors and others to grant the requests. These provisions, however, not only remove crucial safeguards for patients, but foreseeably could lead to patient harm—recourse for which is barred by the laws.

Despite these facts and statistics, proponents of the RTT approach have seized on highly sensitive issues surrounding terminal illness, including the rights of dying patients to choose how they spend their remaining days and frustration with lengthy timelines for drug development and approval, to successfully target the FDA as the major obstacle to patients’ ability to access potentially life-saving treatments. The success of this approach led not only to the new federal law, but to 41 US states enacting RTT laws, starting in May 2014. In contrast to the FDA’s long-standing EAP process for early access, however, there has not been a single confirmed case of a patient gaining access to an investigational intervention solely pursuant to a state RTT law.

This may change with the passage of the federal RTT law—although likely not in the positive ways suggested by the rhetoric around the law.

While at a high level, the federal RTT law takes the same theoretical approach to “solving” the pre-approval access “problem” as the state RTT laws—e.g., removing alleged barriers to access posed by the FDA and its applicable rules and regulations for pre-approval access—the language of the federal law doesn’t merely mirror the aspirational yet ineffective state RTT laws, which many have argued do little more than provide false hope to patients.³ Instead, the federal RTT law actually effectively manipulates the jurisdiction of the FDA by creating an alternative additional path for individuals to request early access. In addition to removing the FDA and key oversight rules from the pre-approval process, it eliminates the need for IRB oversight, insulates sponsors, manufacturers, and others from liability arising from harm caused by the access, allows insurers to decline any costs associated with administration of the experimental therapy, and arguably changes essential data-reporting requirements for clinical outcomes from pre-approval access.

All of this has left critics asking what exactly patients have gained under this new federal RTT law. At the same time, sponsors, research institutions, clinicians, and governmental entities are struggling to reconcile the new law’s provisions with existing federal rules and regulations.

How is RTT access different from access under existing federal regulation?

The new federal RTT law amends the Federal Food, Drug, and Cosmetic Act to give individuals an additional new route to request pre-approval access to investigational drugs, provided they have a diagnosis of a life-threatening condition or disease, have exhausted already approved treatments, and are unable to enroll in a clinical trial of the applicable investigational drug. These requirements must be confirmed by a certifying physician, who cannot be compensated directly by the manufacturer of the drug for that certification.

As two pathways intended to provide terminally ill patients access to experimental drugs that are under study, but not yet FDA approved, there are some similarities between expanded access and the alternative pathway created under the federal RTT law. But there are also key differences and ambiguities in the new law that raise significant concerns from the perspective of patient protections and safety:

• The federal RTT law explicitly lifts the vast majority of parts 50, 56 and 312 of title 21 of the Code of Federal Regulations (CFR), which contain rules and regulations for IRB oversight of drug testing, including jurisdiction for expanded access requests and informed consent requirements. Indeed, the federal RTT law (in contrast to some of the state laws) makes no mention of IRB or ethics review—or indeed, review by any independent third-party (e.g., a local governmental or institutional body). Further, while the RTT law states that patients or their legally authorized representatives must provide “informed consent” to the treating physician for use of the investigational drug, the RTT law explicitly exempts RTT access from all of the informed consent provisions contained in federal regulations at 21 CFR 50, which are applicable to requests under EAP. The law does not replace these key details with any alternative requirements, including regarding the validity of the information conveyed, the voluntariness of the consent provided, or review of the informed consent procedures by an IRB or other third party.
• Under the RTT law, the investigational drug eligible for request must also fulfill certain requirements contiguous with current federal law, including that it is the subject of an application filed with the FDA (pursuant to 505(b), or 351(a) of the Public Health Services Act). Investigational drugs are only eligible if they have already completed a Phase I clinical trial; are not FDA approved for any indication; are part of either a pending FDA drug approval application or a current trial whose data will be submitted to FDA as part of an application; and have not during development been placed on a clinical hold.⁴ These requirements may provide a base level of safety and at least some assurance about the drugs at issue. However, they also foreclose access to certain early compounds that may be allowed by the FDA for individual patients under the federal regulatory process.

  This arguably provides some counterweight to the removal of federal protections included within the existing expanded access process. However, loose language and undefined terms in the RTT law provide a number of potential loopholes. These include the lack of any requirement that the entity providing access to the drug via the alternative route is the same one that is the sponsor of the filed investigational new drug application (IND), and of any independent third-party review (in lieu of the FDA, or even an IRB) to ensure a level of integrity or meaningfulness of the “completed” Phase 1 trial.

• Unlike the EAP pathway, the federal RTT law specifies that clinical outcomes associated with the use of an eligible investigational drug typically cannot be used to adversely affect the review or approval of that drug, though any known serious adverse events (SAEs) must be summarized in an annual report and submitted in conjunction with the new drug application for the drug. Furthermore, the RTT law makes clear that the sponsor, manufacturer, or other “dispenser” of the investigational drug bears no liability for any act or omission with respect to an eligible investigational drug. This last provision is in tension with the federal regulations regarding informed consent for expanded access, which explicitly prohibit the inclusion of exculpatory language.

Implications and impact

The lack of a mandate in the federal RTT law to provide early access to an investigational drug upon patient request preserves drug manufacturers’ and other sponsors’ discretion in granting early access, similar to the discretion sponsors possess under existing federal regulation. Should a sponsor or manufacturer desire to grant early access to an individual, presuming all other requirements are followed, entities have the option of utilizing the alternative pathway created in the federal RTT law or following current federal regulation for expanded access.

Indeed, in the brief time that the new federal law has been on the books, several large pharmaceutical companies have publicly declared their intent to continue to adhere to existing federal regulation for individual expanded access and involving the FDA, rather than following the RTT pathway. However, regardless of company size and other attributes, it is clear that sponsors and manufacturers are devoting a lot of time and consideration to forming policy and strategy in this space.⁵ 

Although little public discussion has focused on the potential impact of RTT on entities carrying out clinical trials, academic medical centers, clinical trial sites, and IRBs arguably must confront and reconcile the conflicting duties between traditional federal requirements for clinical trials and expanded access, and the new federal RTT framework (for example, the conflict between RTT’s insulation of sponsors and manufacturers from liability, and standard federal requirements for informed consent, prohibiting exculpatory language).

While not explicitly stated in the law, institutions appear to have discretion as to whether or how they will follow the new rules (or, arguably, absence of rules) under RTT. Similar to the situation for sponsors, nothing in the RTT law precludes institutions from making one set of consistent rules for pre-approval access requests that hew closely to current FDA rules and regulations, for instance, requiring IRB review and elements of informed consent, even for requests under RTT. Institutions may choose to do this for a variety of reasons, including for consistency of overseeing clinical trial conduct, patient protection, risk-aversity, and other ethical and practical reasons.

We’d love to hear from you!

Has your institution discussed the new RTT law and how you will deal with RTT requests? How will your IRB be involved? If you have created any resources, would you be willing to share them with the community? Comment below.

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Beth E. Roxland, JD, MBioethics is an Attorney and Bioethicist with unique experience across industry, law, government and academia. She is a Senior Advisor on Law, Health Policy and Ethics at Roxland Consultants, Ltd., counseling law firms, life science and medical institutions, and professional and patient associations. She frequently lectures and publishes on a variety of cutting-edge regulatory and bioethical topics, and serves on several scientific and academic oversight boards at leading institutions. Ms. Roxland was previously Johnson & Johnson’s Bioethics and Strategy Leader, in the Office of the Chief Medical Officer. She was also the Executive Director of the New York State Task Force on Life and the Law, and concurrently served as the Special Advisor to the Commissioner of Health on Stem Cell Research Ethics. Prior to joining the government, Ms. Roxland was a Senior Litigation Associate at Simpson Thacher & Bartlett LLP, and a Federal Judicial Law Clerk in the Southern District of New York. She graduated from Columbia University with a Bachelor’s degree in Biology, and received a joint JD – Master’s in Bioethics magna cum laude from the University of Pennsylvania, where she was a Senior Editor of the University of Pennsylvania’s Law Review.

Elisa A. Hurley, PhD, is the Executive Director of PRIM&R. Find her bio on PRIM&R’s website.

PRIM&R hosted a webinar on March 7, 2018, titled Pre-Approval Access to Drugs in Development: Navigating the Changing Regulatory, Ethical, and Legal Landscape, to educate HRPP professionals about FDA guidance, recent legislation, and ethical questions related to expanded access and Right to Try. Beth Roxland was a co-presenter with Richard Klein on this webinar. The webinar recording is available for individuals to purchase in the online store. If you would like to purchase the webinar for group viewing, please download the order form (PDF) and send to registration@primr.org. Ms. Roxland can also can be reached for questions at beth@bethroxland.com.

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[1] Jonathan P. Jarow, et al. Overview of FDA’s Expanded Access Program for Investigational Drugs, ## Therapeutic Innovation & Regulatory Science ## (2017). See also Emily Jung, Patricia J. Zettler, & Aaron S. Kesselheim, Prevalence of Publicly Available Expanded Access Policies, ## Clin. Pharmacology & Therapeutics ## (Dec. 13, 2018)

[2] Amy E. McKee, et. al. How Often Are Drugs Made Available Under the Food and Drug Administration’s Expanded Access Process Approved? 57 J. Clin. Pharmacology (2017)

[3] Beth Roxland, Patients Deserve Better Than a “Right to [Hope to] Try,” The Hill (August 2016), available at http://thehill.com/blogs/congress-blog/healthcare/290003-patients-deserve-better-than-a-right-to-hope-to-try; see also Ed Silverman, Dear Vice President Pence: Stop peddling false hopes to dying patients, Pharmalot, (Feb. 2017), available at https://www.statnews.com/2017/02/20/pence-right-to-try/.

[4] “Right to Try Signed into Law, but Questions Remain About Implications for FDA and IRBs.” (2018, June 28). PRIM&R Member Newsletter.

[5] See, e.g., Amirah Al Idrus, Brainstorm Backs Down From Providing ALS Treatment Under Right to Try, FierceBiotech (June 26, 2018), available at https://www.fiercebiotech.com/brainstorm-backs-down-from-providing-als-treatment-under-right-to-try