On September 30, 2022, President Biden signed into law the reauthorization of the Prescription Drug User Fee Act (PDUFA VII), which will be in place for the next 5 years. Despite extensive bipartisan efforts to include reforms of the accelerated approval (AA) pathway as so-called “policy riders” in the bill, ultimately a “practically clean” version of the bill was signed.
While this news may have led to a sigh of relief for some sponsors, in the absence of formal measures to explicitly codify the FDA’s authority to tighten restrictions on AAs, it appears that the FDA has taken matters into its own hands.
To learn more about the accelerated approval (AA) pathway, see our blog series on this topic: Part 1 – Introduction to the Accelerated Approval Pathway, Part 2 –Surrogate Endpoints for Accelerated Approval, and Part 3 – Pitfalls of Accelerated Approval: What Happens When Confirmatory Trials Fail?
FDA to ADC Therapeutics: “A randomized confirmatory phase 3 study must be well underway and ideally fully enrolled at the time of BLA filing.”
According to ADC Therapeutics, the FDA has “provided strong guidance that, for it to consider an accelerated approval path, a randomized confirmatory phase 3 study must be well underway and ideally fully enrolled at the time of any BLA filing.” As a result, ADC Therapeutics has taken a step back to reevaluate its experimental CD25-targeted antibody drug conjugate camidanlumab tesirine, which is being developed for patients with relapsed/refractory Hodgkin lymphoma. ADC had been planning to submit a BLA under the AA pathway based on a demonstrated ORR of 70.1% (95% CI, 60.9%-78.2%) in their phase 2, open-label, single-arm study in 117 heavily pretreated patients.
Because of the FDA’s guidance, ADC Therapeutics will no longer be submitting their BLA, and the future of the drug is uncertain. Enrollment for the planned confirmatory phase 3 trial for camidanlumab tesirine is estimated to take 2 years.
FDA regulatory policy shift for AA
A requirement for a fully enrolled confirmatory trial prior to granting AA represents a large shift in regulatory policy from the FDA.
This move reflects the reforms advocated by the FDA’s Oncology Center of Excellence (OCE) to require confirmatory trials to be underway before an AA is granted. Such a requirement would likely lead to quicker confirmation of benefit and more timely withdrawal of an AA if clinical benefit is not confirmed. In support of this measure, studies have shown that among AAs that were withdrawn, the median time to withdrawal was 3.8 years if the confirmatory trial was ongoing at the time of AA, as compared with 7.3 years if such a trial had not been initiated.
Unfortunately, a requirement to have an ongoing, fully enrolled confirmatory trial at the time of filing for AA places a much greater burden on smaller drug development companies. Smaller companies in particular may depend on revenue from drugs marketed under the AA pathway to finance phase 3 confirmatory studies. Greater restrictions on the AA pathway may force smaller companies, such as ADC, to scrap certain drug development programs entirely.
The OCE has been vocal about improving the quality and efficiency of the AA pathway, and it does not appear to be waiting around for legislation to follow through on instituting more requirements for granting AAs and in rapidly withdrawing AA indications that fail to confirm benefit in subsequent phase 3 trials.
Angela W. Corona, PhD
Scientific Director, Scientific Services
Angela is responsible for helping sponsors navigate complex regulatory communications, such as FDA advisory committee meetings. She develops clinical and regulatory strategy along with high-quality scientific and medical content across a wide range of therapeutic and drug development areas. Angela received her PhD in Neuroscience from The Ohio State University and completed her postdoctoral training at Case Western Reserve University. Connect with Angela on LinkedIn.
- Fashoyin-Aje LA, Mehta GU, Beaver JA, Pazdur R. The on- and off-ramps of oncology accelerated approval. N Engl J Med. 2022;387(16):1439-1442. https://www.nejm.org/doi/full/10.1056/NEJMp2208954.