Maurie Markman, MD, shares his thoughts on the right-to-try bill, which would allow terminally ill patients to receive investigational drugs that have been studied in phase I trials without applying through the FDA’s expanded access program.
Maurie Markman, MD
The “right to try” is probably the most controversial issue in cancer medicine today. The concept that patients should be allowed greater access to experimental medicines has been transformed from a serious discussion about a remarkably complex and often personally gut-wrenching debate into what at times appears to be political grandstanding from commentators with limited understanding or appreciation of the potential benefits and risks to patients as well as the steps required to convert desire into reality.1 On March 21, the US House of Representatives passed a right-to-try bill that would allow terminally ill patients to receive investigational drugs that have been studied in phase I trials without applying through the FDA’s expanded access program.2 At press time, the Senate had not yet voted on the legislation.
It is important to acknowledge that this column reflects solely my opinions on the topic of right to try based on nearly 40 years of involvement in cancer care and clinical cancer research.When I began my career in cancer drug development several decades ago, “early-phase” clinical trials were designed essentially to test an agent’s overall safety and to define an appropriate dose/schedule for possible future investigative efforts. In this era, objective responses in such studies were rarely observed, improvements in disease-specific symptoms were very uncommon, and any noted clinical benefit was quite short-lived. In fact, any focus on “symptoms” was related almost exclusively to adverse effects resulting from the anticancer agent. Some involved in drug development during this era described the selection of agents as “the drug-of-the-month club,” meaning there was limited justification to study a particular agent in a specific patient other than the simple and rather distressing fact it was that drug’s turn to be examined in the clinic.
Now fast-forward to 2001 and the landmark publication of the phase I trial of imatinib in chronic myeloid leukemia (CML). The selection of patients for this trial was based on the presence of a molecular biomarker hypothetically considered to be clinically relevant—a drug development process now known as precision cancer medicine.3 Of the 54 patients treated with imatinib at a daily dose of 300 mg or greater, 53 achieved a complete hematologic response. Of course, it is now well established that this class of agents has dramatically transformed the prognosis for individuals with CML.Multiple other examples can be provided of an unequivocal clinical benefit associated with participation in early-phase clinical trials, justifying the conclusion that a patient’s desire to receive such therapy is neither irrational nor “false hope.” However, translating what is likely a common goal to provide patients with the opportunity to consider such therapies—the right-to-try concept—is extremely difficult today. Those who suggest otherwise almost certainly do not fully or even partially appreciate what is required to permit this to occur.
For example, consider that the first patient with lung cancer who received crizotinib for the rare ROS1 mutation—which is now the standard of care in this setting—was cared for at an academic institution with access to the agent and with considerable experience dealing with complex regulatory requirements and manufacturer/ pharmaceutical/biotech company issues, as well as the significant healthcare cost/payment challenges.4 I would hope that no thoughtful person would consider advancing the theory that it is ethically acceptable that only patients who are fortunate enough to find themselves in the rarefied environment of such a tertiary care center would be given the opportunity to participate in such a study.
But realistically, could such an undertaking be accomplished today in a community hospital or a nonacademic oncology practice in the United States, where most patients with cancer actually receive their care?
Further, what incentives should a pharmaceutical/biotech company be provided to agree to spend the potentially enormous amount of time, effort, and likely cost to help an individual patient? I am not in any manner denigrating the strong personal desire that multiple corporate employees may have to provide such assistance. Rather, I am highlighting the pragmatic requirements of these companies to focus their efforts on moving the product being investigated forward to achieve regulatory approval for ultimate commercial sale.
What would be the responsibility of the treating physician, the medical institution, and drug manufacturers to provide data to the FDA, and who would pay for the costs associated with regulatory requirements? Also, although it is simply irrational to declare that toxicity data obtained in individual right-to-try experiences cannot be examined and considered by the FDA in its deliberations, it is equally concerning and unsettling for drug developers to be required to encounter major bureaucratic review delays resulting from a mandated evaluation of what likely would be rather extensive uncontrolled single-patient experiences.
Further, one must ask about the incentives required for third-party payers to agree to assume the potentially considerable costs associated with an individual patient’s desire to receive an early-phase antineoplastic agent. In addition, although the decision to pursue such a strategy may be highly rational in the presence of a potentially clinically relevant biomarker, delivery of the agent must also be considered in the context of the patient’s overall performance status, presence of relevant comorbidities, and the known, or at least suspected, toxicities associated with the drug in question.
In summary, this commentary is not an attempt to begin to solve the dilemma associated with the rational implementation of the concept of a patient’s right to try but rather an acknowledgment that the successful resolution of this debate requires meaningful input from multiple parties, a willingness to compromise on what at times appear to be rigid positions on the issue, and the motivation to develop and explore novel pilot approaches to this critical problem.