FDA Approval Processes in the Era of Targeted Therapies: A Conversation with Dr. Richard Pazdur

Dr. Richard Pazdur

Richard Pazdur, MD, is director of the U.S. Food and Drug Administration’s (FDA’s) Oncology Center of Excellence. Below, he discusses the current status of and future directions for the FDA’s approval of oncology drugs.

Q: Has the accelerated conditional approval process been a success in your view? Are there aspects you would like to tweak or improve?
A: The accelerated approval process has been highly successful in bringing anti-cancer drugs to patients sooner based on earlier endpoints and smaller trials. We recently published a study that showed that, since its inception in 1992, we granted accelerated approval to 64 oncology drugs for 93 new indications, including 53 new molecular entities.1 Of the accelerated approvals that fulfilled their post-marketing requirement, benefit was verified a median of 3.4 years after the initial accelerated approval. Failure to confirm benefit is rare; in the few instances (5%) in which accelerated approval was withdrawn, several drugs were able to return to the market once the correct biomarker population was identified (e.g., EGFR tyrosine kinase domain mutations with gefitinib in advanced NSCLC) or the dose and schedule of the drug was optimized (e.g., gemtuzumab ozogamicin).

Tweaks or improvements to accelerated approval would require changes in the law. One possible improvement would be to align better with the European concept of conditional approval (a preliminary benefit–risk assessment, followed by confirmation of benefit–risk).

Q: What is your perspective on the approval process in rare oncogenic-driven disease (e.g., RET– or ROS1-positive NSCLC) based on phase II, rather than phase III, studies?
A: Recent approvals of crizotinib for ROS1 NSCLC or dabrafenib with trametinib in BRAF-mutant NSCLC show that for rare oncogene-driven subsets, durable response rates in a single-arm trial may be sufficient. A response, depending on its depth, location, and durability, may be meaningful to patients. Sometimes a randomized trial looking at survival improvements may not be feasible for several reasons: a rare patient population, which limits accrual; high response rates in early clinical development, which render a randomized trial of a new agent versus toxic chemotherapy lacking in equipoise; and crossover to the targeted therapy following progression, which diminishes the ability to detect an improvement in survival.

Q: Assuming phase II studies lead to approval in oncology, what are the thresholds for response rates, progression-free survival rates, and overall survival rates?
A: We don’t have any absolute thresholds for approval; it very much depends on the context of the cancer, the setting, the availability of other treatments, the toxicity profile, and the magnitude and durability of effect. We did perform a meta-analysis published in the Journal of Clinical Oncology in 2015 that showed that drugs with high response rates, such as targeted therapies, are likely to also have large progression-free survival gains over traditional chemotherapy.2

Q: Can activity in the neoadjuvant setting lead to approvals, or is this premature?
A: We held a workshop with the IASLC in March 2018 to discuss issues with neoadjuvant lung cancer trials. One key area for discussion was how can we learn from the breast cancer community, which has a long history of conducting neoadjuvant trials. In fact, in 2014, we finalized a guidance describing the pathway to using pathologic complete response rate for accelerated approval for high-risk neoadjuvant breast cancer. In 2013, pertuzumab was granted accelerated approval in neoadjuvant HER2-positive breast cancer and was granted regular approval in 2017.

There are still many issues to sort out in lung cancer, including how to optimally design neoadjuvant studies, how to standardize pathologic assessment of response, and what endpoints to use. There is certainly a lot of interest within the industry in using neoadjuvant trials to expedite drug development, as evidenced by numerous recently launched randomized trials investigating immunotherapy in this setting.

Q: How much bio-correlative work is mandatory from the perspective of approvals based on phase II studies?
A: Bio-correlative work is critical. As demonstrated by the development of oncogene-directed targeted therapies for EGFR and ALK, it is crucial to understand the biology of how the genomic changes drive the growth and progression of cancer and how inhibiting the pathway leads to regression of the tumor. In addition, bio-correlative work through serial biopsy at progression has led to a deeper understanding of underlying resistance mechanisms, which, in turn, has led to second and third generations of these oncogene-directed targeted therapies.

Ultimately, we need to do what is right for patients—both current patients, by ensuring timely access to safe and effective drugs, and future patients, by ensuring that high-quality evidence is generated.

Q: Do you perceive pressure, either political or societal, to approve more agents more quickly?
A: There are ebbs and flows in the sociopolitical environment surrounding the FDA. A lot has changed in society since the 1962 Kefauver-Harris Amendment to the Federal Food, Drug, and Cosmetic Act that granted the FDA pre-market authority to review drugs based on safety and efficacy. In the past few decades, there has been a call for the FDA to be more responsive to society at large and to incorporate the voice of the patient into its decision-making process. Some criticize the FDA either for being too cautious or for being too quick to approve drugs. Ultimately, we need to do what is right for patients—both current patients, by ensuring timely access to safe and effective drugs, and future patients, by ensuring that high-quality evidence is generated.

Q: Finally, what is your perspective on “right-to-try” laws? Are they ethical? Are they safe? Are there ways to monitor adverse events?
A: It is premature to comment on “right-to-try” laws, as the legislation is recent, and the agency is still adopting its position on these laws. ✦

1. Beaver JA, Howie LJ, Pelosof L, et al. A 25-Year Experience of US Food and Drug Administration Accelerated Approval of Malignant Hematology and Oncology Drugs and Biologics: A Review. JAMA Oncol. 2018;4(6):849-856.

2. Blumenthal GM, Karuri SW, Zhang H, et al. Overall response rate, progression-free survival, and overall survival with targeted and standard therapies in advanced non-small-cell lung cancer: US Food and Drug Administration trial-level and patient-level analyses. J Clin Oncol. 2015;33(9):1008- 1014.