In his address at the 2017 San Antonio Breast Cancer Symposium, Richard Pazdur, MD, Director of the FDA’s Oncology Center of Excellence, described a dynamic regulatory environment at the FDA in which the patient voice has been adopted and end points for clinical trials have evolved from overall survival to other efficacy measures. Dr Pazdur recounted the role that the FDA has played in 2017, in which oncology became the most active area of drug development for the pharmaceutical industry, reflecting 30% to 40% of the industry’s activity; 50% of breakthrough therapy designations are in oncology; and patients with cancer receive treatment in the community rather than in an academic setting. He emphasized the transition from the “roulette wheel” of drug discovery, in which drugs were tested in cancer based on their antiproliferative activity, to rational cancer drug discovery, such as with targeted therapies. For example, in 2001, imatinib (Gleevec) was the first drug to be approved based on a true molecular target that revolutionized the treatment of chronic myeloid leukemia (CML) and provided a conceptual framework for other drug development, recalled Dr Pazdur. As a result of these discoveries, “selected patients with CML now have projected life expectancies that are similar to age-matched controls without CML,” he said. Subsequent indications for imatinib in rarer cancers would not have occurred without an understanding of the underlying mechanism of the cancers, and how the drug interacts with that mechanism.
Patients’ Input in Drug Development
The FDA played an important role in this changing scientific and clinical environment. “This change is what I call a dynamic regulatory environment,” said Dr Pazdur. “This activism…resulted in our accelerated approval regulations.” The regulations providing the FDA with the regulatory authority to require not only the drugs’ safety but also efficacy data were promulgated in the early 1960s after problems were discovered with thalidomide. Since then, massive social changes have led to greater citizen demand to have a voice in government decisions. This demand was most pronounced in the 1980s when the AIDS community applied pressure on the FDA to develop a more flexible regulatory environment that was responsive to the needs of patients. Today, in addition to being cognizant of the scientific changes, the FDA also is considering the societal changes regarding the involvement of patients and other stakeholders in regulatory decisions. Oncology is now the predominant user of this novel regulatory mechanism.
Incorporating Multiple End Points
The FDA had at one time demanded 2 randomized clinical trials demonstrating an improvement in overall survival to gain drug approval, because of the perception that oncology drugs had modest activity, with marked toxicity. The end points in clinical trials have evolved based on a changing risk–benefit analysis over many decades, said Dr Pazdur. In the new millennium, the dogma that overall survival is the only acceptable end point was re-evaluated and resulted in the use of other end points, such as progression-free survival, clinical benefit, and patient-reported health-related quality of life. With drugs with markedly improved response rates entering the picture, the equipoise in randomizing patients to marginally effective drugs in clinical trials was lost. Responding to demands by investigators and patients, the FDA introduced the allowance of patient crossover to drugs with significant activity, which limited the ability to demonstrate an improvement in overall survival. In addition, “improvement in overall survival may not be practical in cancers with long natural histories, or histories that are prolonged because of recent therapeutic advances,” such as CML, chronic lymphocytic leukemia, and multiple myeloma, all of which are now associated with 5-year survival rates exceeding 50%, said Dr Pazdur. Insisting on overall survival as an end point would deny thousands of patients facing life-threatening diseases access to effective drugs. Furthermore, overall survival may not be feasible as an end point in clinical trials of less common cancers, because of the small number of patients, he argued. “This is increasingly more common as we subdivide diseases into molecular subsets,” said Dr Pazdur. Having accepted novel end points for regulatory approval, Dr Pazdur stated that “there are no perfect end points,” reminding the audience that overall survival is also an important safety end point. Irrespective of the primary end point of a clinical trial, “we always look at overall survival to make sure that there is not a decrement” with the introduction of novel therapies, he said. The FDA has become an advocate of patient-reported outcomes, such as key symptoms, side effects, and physical function. These outcomes may be a more sensitive measure of a therapeutic intervention, and, along with progression-free survival and clinical benefit, should not be dismissed as surrogates. Tumor shrinkage and delaying progression of a rapidly progressive disease are outcomes of direct value to patients, he said. Response rates are even used in everyday practice to determine which patients will continue to receive a therapy. Using multiple end points allows the approval of multiple drugs, “and having multiple drugs is a good thing,” Dr Pazdur said. “Many are approved on nonsurvival end points, and they have transformed the diseases. These drugs can be used in combinations or sequentially and have the potential of significantly impacting a disease,” he argued.
Breakthrough Therapy Designation
Breakthrough therapy designation has provided the FDA with the ability to interact with drug companies on a more iterative basis, with a continuous discussion about the progress of a drug’s development. “These continuous interactions with the FDA and the sponsors are very important,” said Dr Pazdur. “We here focus on the clinical development of the drugs, but we should also be aware that one of the other major areas is the manufacturing of the drugs, and to make sure that these manufacturing processes are in place to meet regulatory decision-making. It makes no sense to have an efficient clinical development plan if there are problems with drug manufacturing, and that would delay drug approval.” Approximately 50% of breakthrough therapies are cancer drugs, which “shows us that not only are we having more drugs, but these drugs also show greater promise, and to get breakthrough therapies, you have to show substantial improvement over available therapy,” concluded Dr Pazdur.