By Gary Evans, Medical Writer

The FDA “remains committed” to reviewing and approving investigational drugs through its expanded access “compassionate use” program, which will continue in conjunction with the recently enacted federal Right to Try law, according to FDA Commissioner Scott Gottlieb, MD.

“Those suffering from a terminal illness who’ve exhausted available options should be able to access promising treatments being studied in clinical trials, or products under active review by the FDA,” he said in a May 30, 2018, statement after the law was passed. The FDA will “implement this legislation in a way that achieves Congress’ intent to promote access and protect patients … so that patients facing terminal conditions have an additional avenue to access promising investigational medicines.”

There was some question whether the law — which opens a new path for terminally ill patients to receive experimental treatment directly from pharmaceutical companies without being in a clinical trial — would effectively bypass the FDA process and render the agency review moot. However, Gottlieb said in an interview that the FDA’s “compassionate use program will sit alongside ‘Right to Try.’ Nothing’s going to change about our current approach. [Drug companies] will still want to offer drugs through the expanded access pathway because they see value in having FDA affirmatively adjudicate these individual patient requests.”1

Gottlieb made the comments recently at the American Society of Clinical Oncology Annual Meeting in Chicago, where he updated other FDA actions. (For more information, see related story in this issue.)

The issue is far from resolved, as one of the backers of the bill emphasized in a letter to Gottlieb that the intent was to minimize FDA oversight, not to enable it to issue more guidelines or regulations.

“This legislation is fundamentally about empowering patients to make decisions in cooperation with their doctors and the developers of potentially life-saving therapies,” Sen. Ron Johnson, R-WI, wrote in the letter. “This law intends to diminish the FDA’s power over people’s lives, not increase it. It is designed to work within existing FDA regulations, definitions, and approval processes.”2

On the other side of the political debate, former FDA associate commissioner Peter Lurie, MD, MPH, said the legislation was “heedless of the facts, driven by emotion, mindlessly anti-regulatory, and certain to be exploited for political purposes despite its failure to solve anything.”3

This Right to Try law amends the Federal Food, Drug, and Cosmetic Act to establish a new pathway aimed at increasing access to investigational products for those with life-threatening illness who have no other medical options and are unable to join a clinical trial.

To be eligible, the investigational drug cannot be approved for any FDA use, but Phase I of a clinical trial must be completed. Either an FDA marketing application must have been submitted or the drug must be in a clinical trial aimed at establishing an efficacy claim. Under these conditions, FDA approval would not be required.

The FDA’s compassionate use path already allows patients with life-threatening illness to use investigational medical products outside of clinical trials through its “expanded access” program. Prior IRB approval is waived in emergency situations, but the IRB must be notified within five days of approval.

This process has been considered onerous by some, but with Right to Try on the books IRB oversight may become more critical, says Kelly McBride Folkers, MA, research associate in medical ethics at New York University (NYU) School of Medicine.

To the extent the FDA is cut out of the process, there may be more support for IRB review as a patient safety assurance, she notes. While the Right to Try law does not require IRB review, many institutions may keep ethics oversight in place for patients seeking access to experimental therapies through this new pathway, Folkers explains.

“Without the FDA review and the fact that a federal Right to Try law is giving terminally ill patients and their clinicians the ability to make a direct interaction and transaction with a pharmaceutical company without this regulatory oversight, it appears that IRB review may be more necessary for patient protection,” Folkers tells IRB Advisor. “It is unclear whether institutions will still require IRB review with the Right to Try pathway.”

The law firm of Verrill Dana, LLP, in Westport, CT, weighed in on the nuances of this point, noting that law “removes the FDA and IRB from the process, permitting — but, notably, not requiring — manufacturers to make certain ‘eligible investigational drugs’ available to certain ‘eligible patients’ without preapproval by the FDA or IRB oversight. … Written informed consent to the treatment is also required, but unlike in the context of expanded access the elements are not specified.”5

Wide IRB Variation

Moreover, there is wide variation among IRB policies currently following the FDA compassionate use path to consider expanded access for qualified patients, Folkers and colleagues found in a recent study. Analyzing publicly available IRB policies, they concluded it is “difficult to find, interpret, and understand IRB policies on expanded access.”3

The researchers reviewed 95 policies, finding that 88 of them contained language referencing non-emergency expanded access and/or expanded access for emergency requests for a single patient.

“Of the 88 policies that mentioned expanded access in non-emergency situations, 11.5% did not explicitly specify whether full IRB review was required, as was the rule at that time,” they noted. “There was considerable variation in other aspects of these policies, including charging patients for use of investigational products and the use of data from expanded access.”

Providing some historical perspective on this issue is the Government Accountability Office (GAO). In congressional testimony last year, John E. Dicken, GAO director of healthcare, said, “Several stakeholders we spoke with, including the selected manufacturers we interviewed, raised concerns that FDA is not clear about how it uses expanded access adverse events data in its review of drugs being considered for sale and marketing in the United States.”6

However, Dicken gave the FDA credit for reviewing some 5,800 expanded access requests from Fiscal Year 2012 to 2015, saying 99% were allowed to proceed.

“Almost 96% of these requests were for single patients — either emergency or non-emergency — while the rest were for multiple patients,” he said. “FDA typically responded to emergency single-patient requests within hours, and responded to all other requests within 30 days.”

The cases when FDA blocked expanded access were primarily due to incomplete applications, unsafe dosing, demonstrated lack of efficacy or the availability of adequate alternative therapies, and inadequate information provided in the application on which to base a decision.

Folkers is a member of the NYU working group on Compassionate Use and Pre-Approval Access (CUPA), which was founded in 2014 to address ethical issues involving investigational products prior to FDA approval. In a group email to academic colleagues and supporters, CUPA said the following are some of the central unanswered questions in the immediate aftermath of Right to Try (RTT) passage:

• how and whether stronger informed consent requirements will be implemented over and above the new law’s provision, which is much vaguer than the FDA’s;

• whether manufacturers and/or healthcare providers and institutions will require IRB oversight of right to try requests in the absence of a provision for it in the law;

• what role the FDA, or any regulatory body, will play in enforcing the law’s adverse event reporting requirements and interpreting its other provisions;

• how and whether manufacturers will allow access to their drugs in development via that pathway. Drug manufacturers/sponsors are in the best position to answer questions about investigational products’ availability via RTT. CUPA has heard that several companies plan to consider requests only via expanded access;

• how and whether healthcare institutions will allow the RTT pathway to be used by their employees, in their facilities. CUPA knows of two universities that have stated that the expanded access pathway must be used;

• whether patients/physicians will use the law to try to seek access to other types of unapproved agents; for example, medical marijuana.

REFERENCES

1. Loftus, P. Scott Gottlieb reacts to new ‘Right to Try’ law aimed at weakening FDA’s power in such cases. Wall Street Journal June 3, 2018. Available at: https://on.wsj.com/2JgB07l.

2. U.S. Senate Committee on Homeland Security and Governmental Affairs. Johnson to FDA: Agency Should Comply with Right to Try Law. May 31, 2018. Available at: https://bit.ly/2J6gVfJ.

3. Folkers KM, Bateman-House A. Improving Expanded Access in the United States: The Role of the Institutional Review Board. Ther Innov Regul Sci 2018;52(3):285-293.

4. Lurie, P. Right to Try is an ill-considered bill. The Hill May 23, 2018. Available at: https://bit.ly/2J515VM.

5. Heffernan KG, Helou MS. “Right to Try” Comes to the Federal Stage: What Stakeholders Should Do Now. Verril Dana, LLP. Available at: https://bit.ly/2HvgeuP.

6. Dicken, JE. United States Government Accountability Office. Investigational New Drugs Expanded Access Program. Testimony Before the Subcommittee on Health, Committee on Energy and Commerce, House of Representatives, Oct. 3, 2017. Available at: https://bit.ly/2JCWvhT.