ON MAY 30, 2018, President Donald J. Trump signed into law the Trickett Wendler, Frank Mongiello, Jordan McLinn, and Matthew Bellina Right to Try Act of 2017.1 This law creates an additional and alternative pathway for patients with a “life-threatening disease or condition” to access investigational medicines outside the clinical trial system. Since there are more than 1,100 cancer medicines currently under investigation, this law will materially impact oncology patients and clinicians.2 Specifically, because of the sense of hope and expectation that the new law has created, increasing numbers of patients with cancer will be asking their oncologists questions about the Right to Try Act.3
Thaddeus Mason Pope, JD, PhD
Here, we offer guidance on how oncologists should respond to these questions and outline strong concerns regarding the right-to-try program. The U.S. Food and Drug Administration’s (FDA’s) long-standing expanded access program to investigational drugs—also referred to as compassionate use—already provides a way for patients to access unapproved medicines outside a clinical trial, offering all the same benefits as the right-to-try law with fewer risks. Because the extra risks posed by the Right to Try Act are not offset by any countervailing benefit, it would be unethical for oncologists to use it to gain access to an experimental drug for their patients.4
Access to Investigational Medicines Under the New Right to Try Act
THE RIGHT to Try Act allows drug manufacturers to provide patients with investigational medicines without approval of the FDA, so long as six conditions are satisfied:
1) The patient must be diagnosed with a life-threatening disease or condition.
2) The patient must exhaust all approved treatment options.
3) The patient must be unable to participate in a clinical trial involving the investigational medicine (usually for clinical or geographic reasons).
4) The patient must provide the treating physician with written informed consent.
5) The investigational medicine must have completed a phase I clinical trial.
6) The investigational medicine must be the subject of an FDA investigational new drug application or its equivalent.1
Furthermore, because 40 states have their own right-to-try laws, additional qualifying conditions may be required in some jurisdictions.5 It remains unclear how the federal Right to Try Act will interact with state laws.
Notably, the right-to-try law only “permits” manufacturers to provide investigational medicines; it does not “mandate” their participation. Manufacturers may decline requests for various reasons,6 such as insufficient supply of the drug; insufficient administrative resources to respond to patient requests; concern about the impact on clinical trial participation; and concern about the impact of publicly reported adverse events on investors or on the FDA review of the drug. In short, because manufacturers may—and do—decline patient requests, ASCO and others have suggested that the law would be more accurately described as a right to “ask” rather than as a right to “try.”7
Access to Investigational Medicines Through Expanded Access Program
MORE THAN 30 years before passage of the Right to Try Act, during the HIV/AIDS epidemic of the 1980s, the FDA established an expanded access program that helps patients obtain investigational medicines outside the clinical trial system.8 This program is also known as “compassionate use,” “early access,” and “preapproval access.”9 The eligibility conditions are similar to those of the right-to-try program but with two major differences. Under right to try, obtaining the manufacturer’s agreement to provide the investigational medicine is the final step in the process. In contrast, the FDA’s expanded access program requires two additional steps.
First, the physician must obtain FDA approval, by establishing satisfaction of the eligibility conditions and by certifying that the probable risk to the patient is not greater than the probable risk from the disease or condition.10 Second, the physician must obtain institutional review board approval.11 This means that there is a second independent party assessing the risks, benefits, and alternative procedures. And there is a second independent party reviewing the adequacy and accuracy of information in the informed consent documents.12
Right to Try Offers No Advantages Over Expanded Access Program
THE FDA receives about 1,000 applications under its expanded access program annually.13 It approves 99% of these requests.14 Therefore, to the extent patients are denied access to investigational medicines, it is due to the manufacturer’s refusal for access to the drug, not the FDA’s. Once the patient, his or her physician, and the manufacturer all reach agreement, the FDA almost always approves the request.15
“Because the extra risks posed by the Right to Try Act are not offset by any countervailing benefit, it would be unethical for oncologists to use it to gain access to an experimental drug for their patients.”— Thaddeus Mason Pope, JD, PhD
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Over the years, the FDA’s expanded access program has gone through growing pains. Initially, many physicians did not know about the program or how to prepare an application for drug access, and they were reluctant to invest the significant time required to complete the paperwork.16,17 But the FDA has since removed these obstacles. Today, more physicians know about the expanded access program, the FDA website is more user-friendly, and the application form is shorter.
In 2017, the FDA even launched an online tool called the Expanded Access Navigator (http:// navigator.reaganudall.org) to help facilitate the process.18 In one centralized online location, this comprehensive resource collects links to drug manufacturers’ expanded access policies, procedures, and points of contact. The Expanded Access Navigator also includes information to help guide patients and physicians through the steps to obtain investigational treatments.19
Because of these improvements, the only plausible advantage of the right-to-try law over the FDA’s expanded access program is speed.20 Arguably, patients can access investigational medicines under the Right to Try Act slightly faster than under expanded access, because the physician does not need to prepare an FDA application and the agency does not need to review it. But this timing advantage is minimal. The FDA has streamlined the expanded access process, so it takes a physician only 45 minutes to complete the application form.14 Once the FDA receives the form, its median time to proceed is only 4 days. In emergency cases, the FDA acts within hours. Moreover, even though expanded access may entail a comparative slight delay, it is more than justified by the patient safety advantages of FDA and internal review board review.
Right to Try Poses Material Risks to Patient Safety
MANY LEADING cancer organizations opposed passage of the Right to Try Act, including ASCO, the American Cancer Society, the Lung Cancer Alliance, and the Association of Pediatric Hematology/Oncology Nurses. These and nearly 40 other health-care organizations all concluded that the law would “likely do more harm than good.”21 In addition, most peer-reviewed literature opposes the Right to Try Act.22
This reaction is not surprising. The right-to-try program poses material risks to patient safety. Although patients who are eligible for the program have a “life-threatening disease or condition” and have exhausted all approved treatment options, it is not true that they have “nothing to lose,” as many proponents of the law declare. Patients have at least four things to lose. First, investigational medicines that have passed only phase I testing are more than likely (> 90%) not safe and effective.23,24 Therefore, the drug could reduce the patient’s quality of life. Second, the drug could shorten the patient’s life. Third, using investigational medicines could jeopardize insurance coverage.25,26 And, fourth, patients may empty retirement accounts or take other financial risks to pay for the drug, which is probably not covered by private insurance, Medicare, or Medicaid.
In contrast, the FDA’s expanded access program includes five safeguards that help protect patients from these risks. First, there is an application process to guide both the physician and patient to carefully consider the risks and benefits of the investigational medicine. Second, there is an FDA review to deter the submission of ill-considered applications.27 Third, the FDA can deny a request either when adequate alternative therapies are available or when the requested drug has not demonstrated efficacy for its intended use. Fourth, there is an institutional review board review to ensure adequate informed consent. And, fifth, there is expert guidance about the drug for the physician’s review. The Right to Try Act does not include any of these protections.
“The only plausible advantage of the right-to-try law over the FDA’s expanded access program is speed.”— Thaddeus Mason Pope, JD, PhD
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The FDA provides meaningful changes to approximately 11% of approved expanded access requests.18 For example, the FDA may make modifications to adjust dosing amounts or schedules, increase safety monitoring, or bolster informed consent. The FDA is uniquely positioned to do this, because it collects confidential information from product sponsors during development that is usually not available either to the treating physician or the larger medical community until after the drug is approved.
Conclusion
PATIENTS NOW have two pathways to access investigational medicines outside the clinical trial system: (1) the Right to Try Act and (2) the FDA’s expanded access program. These two programs are equally effective in helping patients obtain medicines still in development. But the Right to Try Act offers patients fewer safeguards and protections. It exposes patients to additional health threats but offers no greater access to investigational medicines. The FDA may address these shortcomings with regulations or guidance.28
In the meantime, clinicians who want to help their patients access investigational medicines should use the FDA’s expanded access program. Clinicians who choose instead to participate in the Right to Try Act should obtain extraordinary informed consent modeled on processes designed for medical aid in dying, sterilization, and electroconvulsive therapy.29 ■
Dr. Pope is Director of the Health Law Institute and Professor of Law at the Mitchell Hamline School of Law in Saint Paul, Minnesota (www.thaddeuspope.com).
DISCLOSURE: Dr. Pope reported no conflicts of interest.
Disclaimer: This commentary represents the views of the author and may not necessarily reflect the views of ASCO or The ASCO Post.
Editor’s Note: The Law and Ethics in Oncology column is meant to provide general information about legal topics, not legal advice. The law is complex, varying from state to state, and each factual situation is different. Readers are advised to seek advice from their own attorney.
REFERENCES
1. Public Law No. 115-176. Available at www.congress.gov/115/ bills/s204/BILLS-115s204enr.pdf. Accessed July 11, 2018.
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8. 21 C.F.R. §§ 312.300 to 312.320.
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10. 21 C.F.R. § 312.310(a)(1).
11. 21 C.F.R. § 312.305(c)(4).
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19. Reagan-Udall Foundation: Expanded Access Navigator. Available at http://navigator.reaganudall.org. Accessed July 11, 2018.
20. Puthumana J, Miller JE, Kim J, et al: Availability of investigational medicines through the US Food and Drug Administration’s Expanded Access and Compassionate Use programs. JAMA Network Open 2018. June 15, 2018 (early release online).
21. Letter to Speaker Paul Ryan and Minority Leader Nancy Pelosi; February 6, 2018. Available at www.asco.org/sites/new-www.asco.org/files/content-files/February-2018-Right-to-Try-Coalition-Letter.pdf. Accessed July 11, 2018.
22. Carrieri D, Peccatori FA, Boniolo G: The ethical plausibility of the ‘Right to Try’ laws. Crit Rev Oncol Hematol 122:64-71, 2018.
23. GAO, Investigational New Drugs: FDA Has Taken Steps to Improve the Expanded Access Program but Should Further Clarify How Adverse Events Data Are Used, July 2017. Available at www.gao.gov/assets/690/685729.pdf. Accessed July 11, 2018.
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25. Baumann J: No assurance about insurance under experimental drug law. Bloomberg News, July 2, 2018.
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28. Sutter S: US FDA’s Plan on Right to Try: Big on Congressional Engagement, Short on Policy Details. Pharma Intelligence. Available at https://pharmaintelligence.informa.com/resources/product-content/us-fdas-plan-on-right-to-try-big-on-congressional-engagement-short-on-policy-details. Accessed July 11, 2018.
29. California Hospital Association: Consent Manual, chapter 4, 2016.
