FDA Thoughts on Accelerated Approval
Posted: Wed Jul 18, 2018 7:34 pm
I found these articles to be of interest with respect to the FDA's approach to supporting accelerated approvals of single-arm studies that do not include a placebo/control arm. The articles are authored/co-authored by Gideon Blumenthan, MD, who is the Deputy Director (acting) of the Office of Hematology Oncology Products, Office of New Drugs, for the FDA's Center for Drug Evaluation and Research:
Top 10 Myths About FDA’s Office of Hematology and Oncology Products
http://www.ascopost.com/issues/november ... -products/
Myth #3: FDA’s OHOP requires randomized trials with overall survival as the endpoint, requires enrollment of U.S. patients, and does not permit crossover.
Fact: Actually, there are at least three myths embedded in this one statement. In oncology, as opposed to other therapeutic areas, FDA approves most drugs based on a single trial due to the challenges involved in repeating a positive trial given the high unmet medical need in oncology. Although randomized controlled trials are the gold standard design, and overall survival is considered the ultimate clinical benefit endpoint because it captures critical efficacy and safety data, OHOP has repeatedly approved drugs on the basis of single-arm trials with high objective response rates and long durations of response.
and
Oncology Drug Approvals: Evaluating Endpoints and Evidence in an Era of Breakthrough Therapies
http://theoncologist.alphamedpress.org/content/22/7/762
Overall Survival Endpoint: Limitations
An improvement in overall survival may be impractical or unreasonable to demonstrate in randomized controlled trials in selected disease areas. Unlike other therapeutic areas where placebo‐controlled trials can provide a comparator for the demonstration of overall survival, the use of placebo‐controlled trials is limited in life‐threatening diseases, especially for novel drugs demonstrating improved biologic activity in early drug development. For drugs demonstrating unprecedented activity in early clinical development in cancers with few effective options, the ability to randomly allocate patients to either an agent with markedly improved durable response rates or to a toxic and marginally effective comparator may not be feasible because equipoise may not exist [27], [28]. If a randomized trial is conducted, many investigators and patients request a cross‐over to the investigational arm. Cross‐over may confound the demonstration of improvement in overall survival and require that the trial have an alternate endpoint. As was observed in trials randomizing patients with EGFR‐mutant or ALK rearranged advanced NSCLC to either targeted therapy or chemotherapy, high cross‐over to the experimental arm confounded the interpretation of overall survival [29], [30], [31], [32]. The use of alternative endpoints, such as progression‐free survival, provides a clinically relevant endpoint and allows expeditious access of important drugs to patients.
A demonstration of improvement in overall survival may not be practical in cancers with long natural histories. In part due to improved systemic treatments, patients with advanced cancers such as CLL, MTC, multiple myeloma, and CML now have 5‐year survivals upwards of 50% [33]. In these diseases, the time required and large patient numbers needed to power a trial to detect a survival improvement would not be practical and could deny effective treatment to patients, which would also negatively impact innovation.
It's hard to read those passages and not think of imetelstat and IMbark as a prime candidate for accelerated approval.
Top 10 Myths About FDA’s Office of Hematology and Oncology Products
http://www.ascopost.com/issues/november ... -products/
Myth #3: FDA’s OHOP requires randomized trials with overall survival as the endpoint, requires enrollment of U.S. patients, and does not permit crossover.
Fact: Actually, there are at least three myths embedded in this one statement. In oncology, as opposed to other therapeutic areas, FDA approves most drugs based on a single trial due to the challenges involved in repeating a positive trial given the high unmet medical need in oncology. Although randomized controlled trials are the gold standard design, and overall survival is considered the ultimate clinical benefit endpoint because it captures critical efficacy and safety data, OHOP has repeatedly approved drugs on the basis of single-arm trials with high objective response rates and long durations of response.
and
Oncology Drug Approvals: Evaluating Endpoints and Evidence in an Era of Breakthrough Therapies
http://theoncologist.alphamedpress.org/content/22/7/762
Overall Survival Endpoint: Limitations
An improvement in overall survival may be impractical or unreasonable to demonstrate in randomized controlled trials in selected disease areas. Unlike other therapeutic areas where placebo‐controlled trials can provide a comparator for the demonstration of overall survival, the use of placebo‐controlled trials is limited in life‐threatening diseases, especially for novel drugs demonstrating improved biologic activity in early drug development. For drugs demonstrating unprecedented activity in early clinical development in cancers with few effective options, the ability to randomly allocate patients to either an agent with markedly improved durable response rates or to a toxic and marginally effective comparator may not be feasible because equipoise may not exist [27], [28]. If a randomized trial is conducted, many investigators and patients request a cross‐over to the investigational arm. Cross‐over may confound the demonstration of improvement in overall survival and require that the trial have an alternate endpoint. As was observed in trials randomizing patients with EGFR‐mutant or ALK rearranged advanced NSCLC to either targeted therapy or chemotherapy, high cross‐over to the experimental arm confounded the interpretation of overall survival [29], [30], [31], [32]. The use of alternative endpoints, such as progression‐free survival, provides a clinically relevant endpoint and allows expeditious access of important drugs to patients.
A demonstration of improvement in overall survival may not be practical in cancers with long natural histories. In part due to improved systemic treatments, patients with advanced cancers such as CLL, MTC, multiple myeloma, and CML now have 5‐year survivals upwards of 50% [33]. In these diseases, the time required and large patient numbers needed to power a trial to detect a survival improvement would not be practical and could deny effective treatment to patients, which would also negatively impact innovation.
It's hard to read those passages and not think of imetelstat and IMbark as a prime candidate for accelerated approval.