Your first patient of the day is a 59-year-old man with advanced stage IV head and neck cancer, who will be meeting with you and his medical oncologist in a discussion regarding future management of his recurrent and metastatic cancer. In spite of chemo-radiation therapy, surgical excision, and adjuvant immunotherapy, the patient’s cancer has continued to spread, and there appears to be no other approved treatment available to him. The discussion today with the patient and his wife will be to examine what options might be available to the patient at this late stage of his disease, and determine how the patient would prefer to handle what is now an end-of-life decision process.
During your last appointment with the patient, you indicated that the patient should consider palliative care and hospice with a physician in that specialty. In a separate discussion with his medical oncologist, both of you were unable to identify a current clinical trial which addressed his specific cancer state and for which he would qualify, given his near-terminal condition.
At the onset of your discussion, the patient indicates that he and his wife have learned about a new federal law that provides an accelerated pathway for patients to work directly with a drug manufacturer to utilize a drug under investigation without involving the FDA—the so-called “right to try” (RTT) law. They are hopeful that there might be an investigational drug that could be appropriate for his cancer, and want to discuss how to proceed with this process.
How should you and the medical oncologist provide a balanced analysis of the risks, benefits, and alternative choices for the patient and his wife on this critical and current topic in bioethics and clinical medicine?
Since 2014, an increasing number of states have passed RTT laws based on the premise that some patients with terminal medical diseases are unable to access traditional Federal Drug Administration clinical trials owing to their advanced disease or exclusionary patient selection criteria. RTT laws offer the opportunity for such patients to directly petition, in conjunction with their physicians, drug manufacturers for the opportunity to be treated with a drug (or device) that has passed Phase I clinical trial testing, and is in Phase II or III testing. The drug in question will not yet have been approved by the FDA, but the clinical trial is addressing the specific disease pertinent to a specific patient. In May 2018, the “Trickett Wendler, Frank Mongiello, Jordan McLinn, and Matthew Bellina Right to Try Act of 2017” was signed into law by President Trump.
The fundamental premise behind RTT is the concern of libertarians and patient advocates that the bureaucratic processes inherent in the FDA regulations regarding entry into clinical trials or applying for exceptional access have been onerous, time-consuming, and often approved too late for a terminally ill patient to receive the experimental treatment. From the general public standpoint, the FDA is a “black box,” and its processes and regulations are poorly understood, giving rise to frustrations regarding individual patient access to experimental therapy. Paperwork for both the patient and physician has been voluminous, which has discouraged many patients from even beginning the process. Proponents of RTT have touted state and federal laws as giving patients the “right” to have access to experimental therapies—some have suggested that RTT is akin to “right to die” laws in several states—as part and parcel of medical self-determination and a “right to live.” To date, 41 states have passed RTT laws in addition to the recent federal law.
RTT laws provide a mechanism for patient and physician to identify an experimental therapy (usually a drug) that is pertinent to the patient’s disease, and to jointly request the opportunity to try that therapy outside of FDA-approved clinical trials. The manufacturer must agree to the request, and would work with the patient’s physician to develop a specific treatment program for that patient. Who bears the costs of the treatment is usually determined on a case-by-case basis, and this determination may have an impact on the patient’s decision to proceed. There is an informed consent document that must be signed by the patient, and it is the physician’s responsibility to provide the clinical risks and benefits information—which may be problematic for an experimental treatment that has only been tested in a Phase I study. The physician is nominally required to receive approval from an Institutional Review Board for the treatment plan, which may or may not be expedited by the Board. The physician is required to provide outcomes data to the drug manufacturer for the course of therapy. Of note, the drug manufacturer is under no obligation to provide the experimental therapy to a patient via this pathway. The RTT laws explicitly provide protection for both the treating physician and the drug manufacturers from liability of death and serious outcomes from treatment through this access system.
There are a number of plausible alternatives to RTT for the patient to consider, including clinical trials, expanded access programs, and single-patient expanded access. Typically, for a patient and physician to be thinking of requesting RTT, it has already been determined, after a thorough investigation (ClinicalTrials.gov), that there are no available clinical trials for which the patient would be eligible. Expanded access programs (EAP) may have some similarities to clinical trials, but are coordinated by drug manufacturers through permission from the FDA. These programs are designed to enroll patients who are not candidates for a specific clinical trial but who may benefit from the treatment before the drug is approved by the FDA. Unlike formal clinical trials, there is no control group. Single-patient expanded access can be considered if there are no clinical trials or expanded access programs that apply to a specific patient. Typically, the physician requests this access from the FDA as the patient’s provider, under either emergency or non-emergency conditions. This process has historically been time-consuming for the physician (although recent changes in regulations have reduced the paperwork burden), and a successful access is not guaranteed. Further information on navigating the various treatment options can be found at http://navigator.reaganudall.org/physicians.
Ethical Decision Making
The main ethical challenge here for clinicians is balancing the possible risks and benefits for the patient’s consideration, a task that must take into consideration all four of the ethical principles—self-determination (autonomy), beneficence, non-maleficence, and social justice. As with all ethical dilemmas, there are some generalizable precepts for all patients and some specific issues particular to each patient’s condition. Furthermore, in the present debate, the polarity seems to be primarily public opinion versus the medical-scientific community.
Self-Determination: Proponents of RTT posit that the federal regulations (FDA) and requirements for the patient and physician that were in place until recently have been excessively burdensome, and response time has been so long, that near-terminal patients who are seeking the opportunity to participate in a non-clinical trial have died before a decision was made. Some patients want direct access to the drug manufacturers without onerous governmental oversight, and feel it is their “right.” Opponents believe that there is no given “right” in the laws, because the drug companies have the final decision on providing the drug; therefore, RTT does not provide a guarantee for access to therapy, so patient self-determination may not be fulfilled.
Beneficence: Even with therapeutics that have passed FDA approval, there are always questions about benefits, especially for drugs given in terminal stages of a serious disease. Because the treating physician must bear the responsibility for assessing what is known about a drug or other therapy that may have only completed a Phase I trial, the clinician may be at a disadvantage when it comes to providing adequate information to the patient about potential benefits for their consideration. Early salutary reports from a Phase I study may not be sufficient data to support a patient’s interest in seeking an RTT therapy exception. Even after standard therapy has failed, there are acceptable alternative care methodologies, including hospice and palliative care in a terminal patient. The treating physician must honestly explain the possible benefit(s) to be derived from an experimental therapy that has not yet been approved by the FDA. This is also the case with expanded access programs and single-patient expanded access, although these programs have additional oversight from the FDA for comfort.
Non-Maleficence: Long thought to be the primary responsibility of the physician (“do no harm”), non-maleficence addresses the potential negative effects of experimental drug therapy that the patient needs to consider in an informed consent. All of the potential side effects and complications cannot be known, for those drugs and devices that have only passed Phase I trials and may be in Phase II or III have limited discoverable data on adverse effects, including death. Each terminal or near-terminal patient may have unique organ compromise or risks that could enhance the potential for catastrophic side effects. Explaining this inadequate data effect to a patient and their family can be unsettling for them and stressful for the physician. Additionally, electing to petition for a RTT may disqualify the patient from subsequent hospice or palliative care.
Social Justice: Depending on the state, RTT laws may require manufacturers to provide the experimental therapy without cost to the patient (i.e., Texas), but in other states, the patient may be held responsible for the cost of the therapy. Raising funds for treatment takes time, and some patients do not have sufficient time remaining in their lives. Additionally, those patients with lesser resources and inadequate healthcare access may be at a disadvantage with respect to ability to secure physician support to apply to RTT and to pay for the drug if required.
Both proponents and critics of RTT tend to agree that there is a failure of communication between the scientific community and the public with respect to the issues and policies associated with clinical trials, expanded access, and right to treat—this must be improved. There should also be additional clarification of the risks to clinical trials for catastrophic adverse outcomes associated with patients in the RTT access pathway, for drug manufacturers may be reluctant to jeopardize their clinical research by providing experimental drugs to terminal patients. Conversely, there is justifiable concern in public discourse that the federal government has been slow to streamline the processes for expanded access for patients who do not qualify for clinical trials, and the RTT movement has stimulated positive changes in procedures and policies.
In the balance, only the patient and treating physician, working together, can develop the best approach for terminal illness care if the patient wishes to consider an exception to FDA clinical trials. The physician must become as knowledgeable about the available data as possible in order to counsel the patient and family in their deliberations. Serious discussions should focus on both the objective information on the patient’s condition and how that might affect experimental therapy, and the subjective disclosure of the patient’s personal wishes for the remainder of life. Supportive care, palliative care, and hospice remain the gold standard for end-of-life care for terminal patients, with physicians providing empathy, honesty, and compassion along the path. Patient self-determination must be balanced with the prospects of benefit, risks of catastrophic adverse events that could further shorten meaningful life, and an equality of care access for all terminal or near-terminal patients as appropriate.
Dr. Holt is professor emeritus in the department of otolaryngology–head and neck surgery at the University of Texas Health Science Center in San Antonio.Multi-Page