- FDA —
- Food and Drug Administration
I sat across from my patient with recently confirmed relapsed pulmonary osteosarcoma. Having previously endured multiple rounds of chemotherapy, an amputation, and debilitating and, at times, recalcitrant phantom limb pain, he had slowly pieced his life back together and had returned to some semblance of normalcy; he now had a job, was living on his own, and was attending university.
Although osteosarcoma is the most common primary bone cancer affecting children and young adults, it is still a rare disease, with only ∼400 new cases each year in the United States. Osteosarcoma has a predilection for spreading to the lungs and, once there, is considerably more difficult to cure. Treatment of osteosarcoma includes combination chemotherapy and surgical resection. Survival rates have remained stagnant for >30 years.1 If there ever were a disease in need of novel approaches and new therapies, osteosarcoma is it.
In discussing with my patient how best to move forward, I explained that traditional cytotoxic chemotherapy no longer seemed like a viable option and suggested that he consider a clinical trial investigating an innovative approach. We discussed various novel therapies before settling on a phase II study investigating an immunotherapeutic administered with cytokine support.2 In discussing the trial, I explained that phase II trials seek to determine if an experimental therapy is effective and safe in larger numbers of patients, and that there exists the possibility for both known and unforeseen harms. I shared my concerns regarding his existing phantom limb pain and the experimental therapy’s penchant to cause debilitating pain that necessitated a continuous narcotic infusion. Similarly, I was concerned by the potential for capillary leak syndrome, another known toxicity. Ultimately, after several discussions and in consultation with his parents (who remained actively involved in his care), he opted to enroll in the trial.
Throughout the United States, countless clinicians engage with their patients in similar discussions about participation in a clinical trial. Clinical trials are critically important in promoting research agendas and guaranteeing more effective and less toxic treatments as well as offering the opportunity for potential cures of diseases. At the same time, medical research is a risky endeavor. It is important not to lose sight that medical progress often entails risks; risks assumed by research participants.3 Many participants, including children and some adults, are at increased risk of harm by virtue of their vulnerability.
With this in mind, statements made by Dr Scott Gottlieb, President Trump’s pick to lead the US Food and Drug Administration (FDA), should give patients, physicians, clinician investigators, and research oversight bodies pause. Dr Gottlieb4 has suggested relaxing oversight for drugs tested in clinical trials. He has criticized the FDA for emphasizing patient safety over the speed of drug approval, going so far as calling the culture of consumer protection “counterproductive.” As reported in The New York Times, Dr Gottlieb decried the FDA for requiring conclusive evidence before allowing a medication onto the market,5 suggesting instead a lower threshold of efficacy, therein departing from decades of accepted practice in determining drug effectiveness on the basis of the gold standard of randomized controlled trials.
Most experts agree that the current US regulatory system for drug approval is not ideal. Given the lengthy time required for drug approval (time that many ill and dying patients may not have), drug manufacturers, patient advocates, and supporters of so-called right-to-try laws have long sought to streamline the drug approval process, and recent efforts by the FDA suggest that the agency is listening.6 Through various mechanisms, approval for some drugs has been drastically shortened.
Under specific conditions, relaxed access may be appropriate. For experimental treatments with relatively few side effects and/or a significantly positive response, allowing more patients to receive the experimental drug (as in a 2:1 or a 3:1 randomization) may be acceptable. Additionally, once a drug begins to show promise, less stringent statistical end points and easier crossover to receive the experimental agent should be considered. Similarly, stakeholder engagement with attention to patient-centered outcomes bears consideration when designing trials. Finally, these decisions should involve public discussion and comment. Simplifying drug approval is a positive step; neglecting the FDA’s role in guaranteeing drugs that are safe and effective however, is misguided.
My patient was admitted to the ICU for the immunotherapy infusion to monitor and to provide appropriate supportive care, which is accepted practice at my institution. Once again, with grit and quiet determination, he endured a variety of assaults on his body, including pain, extreme fluid shifts, drastic weight gain, and hypotension necessitating pressor support. With excellent care, he rebounded. Unfortunately, after a second cycle, reevaluation scans confirmed progressive disease, and he was unable to receive further trial-directed therapy.
Research participants willingly assume risks associated with experimental treatments for various reasons. Most, like my patient, hope that the intervention will prove effective, even if this means uncertainty, a degree of discomfort, or harm. As a society, we owe patients timely access to medications. However, ensuring access should not compromise sound science or our patients’ well-being. Good medicine and good ethics require that medications not only be safe, but that they are effective. History is ripe with medications initially thought to be effective, only subsequently found not to be. The authors of a recent FDA study identified 22 cases of promising phase II trials that investigated drugs, vaccines, and medical devices that were not confirmed in follow-up phase III testing.7 One-third of the phase III trials analyzed in the FDA study failed to confirm phase II safety and effectiveness; in several cases, the investigational agent actually increased the frequency of the health-related problem it was meant to prevent. Phase III trials play an important role in assuring that patients and the medical community are not misled by preliminary and unconfirmed data, no matter how seemingly promising. Furthermore, and as appreciated by the authors of the FDA study, phase III trials prevent patients from taking medications with no potential benefit, avert unnecessary toxicities, and limit wasteful spending.
Tipping the approval scale in favor of speedy commercialization over safety and efficacy is highly problematic. Once approved, drugs become commercially available; they can be marketed and advertised, priced beyond what some patients can afford, used freely (and sometimes inappropriately) off-label, etc. Although always present to some extent, these concerns become more acute when commercialization takes precedence over safety and efficacy.
A patient’s choice to enroll in a clinical trial is in part determined by their trust in the research enterprise in general and their physician specifically. Patients trust that clinician investigators, including their physician, will help them choose wisely when making treatment decisions that reflect their interests. Approving drugs not yet proven to be effective directly violates patients’ trust and jeopardizes the entire clinical trials system.
Medications are inherently risky; the therapeutic index for medications proven to be effective is deemed an appropriate rationale for their use. Relaxing this threshold is inappropriate, just as knowingly allowing ineffective medications onto the marketplace is wrong. Ill patients lack the luxury of wasting valuable time on ineffective medications, time that may be unrecoverable. Streamlined drug approval must not become an avenue to allow medications not yet proven to be effective onto the marketplace.
Dr Gottlieb would be well served to heed the words of the agency he now directs. Business interests, market forces, commercial considerations, and political motivations should never compromise the integrity of medicine and science, nor should they trump patient safety, which remain paramount. Our patients and their families deserve no less.
My sincere gratitude to Tyler Farmer and his parents, Tammy and Greg. Tyler and his parents have shown remarkable strength, honesty, and character enduring the unedurable. My utmost thanks for sharing a small piece of their journey and for allowing me the privilege of learning from each of them.
- Accepted May 4, 2017.
- Address correspondence to Yoram Unguru, MD, MS, MA, Division of Pediatric Hematology/Oncology, The Herman and Walter Samuelson Children’s Hospital at Sinai, 2401 West Belvedere Ave, Baltimore, MD 21215-5271. E-mail:
FINANCIAL DISCLOSURE: The author has indicated he has no financial relationships relevant to this article to disclose.
FUNDING: No external funding.
POTENTIAL CONFLICT OF INTEREST: Dr Unguru offers research ethics consultation to Solid GT regarding a first in-human gene transfer trial. He has not received payment for this service.
- Bajpai J,
- Jaffe N
- ↵Dinutuximab in combination with sargramostim in treating patients with recurrent osteosarcoma. Available at: https://clinicaltrials.gov/ct2/show/NCT02484443?term=AOST1421&rank=1. Accessed February 7, 2017
- National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research
- Gottlieb S
- Thomas K
- U.S. Food and Drug Administration
- U.S. Food and Drug Administration
- Copyright © 2017 by the American Academy of Pediatrics