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Richard Pazdur, MD: FDA tasked with protection of patients, promotion of their concerns
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SAN ANTONIO — Creating a dynamic regulatory environment requires the FDA is responsive to societal demands in conjunction with emerging scientific advances, according to Richard Pazdur, MD.
“The agency must be cognizant, not only in the scientific changes, but also the evolving societal changes regarding involvement of citizens — ie, patients and other stakeholders — in regulatory decisions,” Pazdur, director of the FDA's Oncology Center of Excellence, said during the San Antonio Breast Cancer Symposium 40th Anniversary Award Lecture. “In the end, the FDA is a public government agency, ultimately answering to the U.S. public, charged with protecting and promoting the health of the American public. The agency has to establish a balance between protection and promotion.”
Regulatory authority focused on safety and efficacy propagated in the 1960s, after birth defects were detected with use of thalidomide in Europe, Pazdur said.
Following that event, social movements of the 1960s through the 1980s revolved around the growing demand of citizens to have a voice in government decisions.
“Nowhere was this more pronounced than in the late 1980s by the AIDS community to apply pressure to the FDA to develop a more flexible regulatory environment responsive to the needs of patients,” Pazdur said. “This activism resulted in our accelerated approval regulations, and although accelerated approval had its origins in HIV infections, we in oncology are the predominant users of this novel regulator mechanism.”
Endpoints for approval
Scientific discovery of important drugs based on a cancer’s biology and how drugs interact with targets has shaped the status of the field of oncology, Pazdur said. This includes manipulation of the immune system with checkpoint inhibitors.
“This is rationale drug development based on a sound foundation of scientific discovery, built on decades of scientific discovery,” Pazdur said. “In contrast, throughout much of my career, cancer drug discovery was focused on what I call the ‘roulette wheel’ of drug discovery. Drugs were discovered on the basis of antiproliferative activity, tested in phase 1 trials to determine a maximum-tolerated dose, and then developed in a wide variety of tumor sites without good rationale based on either a glimmer of activity in an early phase 1 or phase 2 trial, or in economic models of high-prevalence tumors that would reap economic investments by the pharmaceutical company.”
This changed with the approval of imatinib in 2001 for chronic myeloid leukemia representing, for the first time, a tailored and rational approach to treatment.
However, a history of different endpoints used by the FDA preceded that approval.
In the 1970s, the FDA approved drugs based on overall response rates, leading to combinations of cytotoxic chemotherapies and cures for testicular cancer, acute lymphoblastic leukemia and Hodgkin lymphoma. Other cancers showed more incremental improvements, where the risk often outweighed the benefit.
By the 1980s, the FDA decided drugs should only be approved based on an improvement in OS due to the modest activity but marked toxicity profile assumed for most agents.
“With the advent of targeted therapies, it became apparent that a re-evaluation of the dogma that OS was the only acceptable endpoint was really needed for several reasons,” Pazdur said.
These reasons included the existence of:
Drugs with unprecedented response rates in early clinical development, thus compromising equipoise in clinical trials;
Cancers with long natural histories, due to the nature of the disease or therapeutic advances; and
Trials that have limited number of patients, which is increasingly more common as patients are subdivided based on their molecular rearrangements.
These issues caused the FDA to look at other endpoints, such as PFS, response rates, and health-related quality of life.
Because health-related quality of life is a broad concept, the FDA has concentrated patient-reported outcome analysis on key symptoms, side effects and physical function to sensitively capture the intervention’s effects. Wearable devices also are showing efficacy in capturing the patient’s experience on a novel therapy.
Having multiple endpoints available for drug evaluation has led to the approval of many therapeutic options for patients, which can be used in combination or sequentially.
“There are no perfect endpoints,” Pazdur said. “There are pluses and minuses with each endpoint. Although we look at other endpoints, we should not forget that OS is also an important safety endpoint. Irrespective of what type of endpoint may be the primary efficacy endpoint, we always look at OS to make sure there is not a detriment, that we are not doing harm to patients with the introduction of novel therapies.”
Approval pathways
Beyond endpoints, a dynamic regulatory environment also has led to the accelerated approval pathway, priority reviews and breakthrough therapies.
“Oncology is the most active area of drug development for the pharmaceutical industry, reflecting between 30% to 40% of all pharma activity,” Pazdur said. “Fifty percent of our breakthrough therapy areas are in oncology. Not only do we have a larger number of drugs being developed, but these drugs actually hold the potential for significant advances in the field of oncology.”
Breakthrough therapy designation, which requires ongoing communication with the drug’s sponsor, enables the FDA to ensure manufacturing abilities are in place to meet the demands of regulatory decision-making.
“It makes no sense to have an efficient clinical development plan if they’re problems with drug manufacturing, which would delay drug approval,” Pazdur said.
Several misconceptions exist about the FDA, Pazdur said. For example, he clarified that the FDA does not set standards of care, but rather the oncology community does. Also, the FDA does not have discussions with pharmaceutical companies about drug pricing, nor do they have a comparative efficacy standard.
Ultimately, although patients may not be focused on the intricacies of drug approval, their concerns are the driving force behind changes in the FDA’s regulatory environment.
“At the end of the day, patients with life-threatening disease are concerned about the progress in their disease,” Pazdur said. “They want to live longer; they want potential for cure. This probably will be the result of using multiple drugs over the course of their disease and in earlier disease settings.
“Patients probably care less about what endpoint the FDA is using and whether the trial is a randomized trial or a single-arm trial; they care about progress being made in their disease,” he added. “This dedication to progress-of-disease approach, rather than our typical FDA orientation looking at individual drug applications — a much broader approach — requires flexibility, calculated risk and committed people who work at FDA who thoroughly understand the disease and its processes.” – by Alexandra Todak
Reference:
Pazdur R. Past and future of cancer drug development. Presented at: San Antonio Breast Cancer Symposium; Dec. 5-9, 2017; San Antonio.
Disclosure: Pazdur reports no relevant financial disclosures.