Taming the Wild West: the View From the FDA

Julia A. Beaver, MD

Although PD-1/PD-L1 immune checkpoint inhibitors have generated important treatment options for patients with many different tumor types, a hotly competitive drug development scene has resulted in an overabundance of clinical trials, often for redundant indications, an inefficient use of resources, and a lack of focus on earlier-stage disease, according to 2 leading FDA officials.

Julia A. Beaver, MD, and Richard Pazdur, MD, compared the environment to the Wild West in a recent article published in the New England Journal of Medicine.¹ They called for greater collaboration among industry sponsors on diagnostics, regulatory submissions, and multinational clinical trials. Beaver is the chief of medical oncology in the FDA’s Oncology Center of Excellence (OCE) and acting deputy director in the Office of Oncologic Diseases in the Center for Drug Evaluation and Research. Pazdur, a 2019 Giants of Cancer Care^® award winner for Community Outreach, is the director of the OCE.

In an email interview with OncologyLive^®, Beaver responded to questions about several points raised in the article.

OncologyLive^®: The article echoes some criticisms about the drug development and approval process that have been made over the years, such as the shortcomings of overall response rate (ORR) as a surrogate end point, the lack of clarity about biomarkers, and the redundancy in indications. However, the article expresses a sense of frustration about the FDA’s power to bring about changes in the drug development process that the agency feels are necessary and beneficial. Given these realities, where can the FDA go next in its efforts to tame the “Wild West”?

Beaver: There are a few areas FDA oncology is focused on encouraging and developing. We are stressing the need for multinational trials and collaboration. In particular, our Project Orbis allows for simultaneous review of drug and biologics applications submitted to multiple international agencies. Although the FDA maintains oversight on US review, this often allows for earlier submission to international agencies and thus earlier access to US standards of care for those countries involved in Project Orbis. This can facilitate generalizability to US standards when subsequent trials are conducted internationally.

We are also working with stakeholders on efforts to develop more platform trials or common controls and to encourage and incentivize drug companies to collaborate in this way. Diagnostics are also an area of interest, and we are evaluating our diagnostic paradigm for potential ways to improve testing challenges.

We also hope our new oncology accelerated approval database provides transparency to the accelerated approval process. The database lists all accelerated approvals, [whether] they are withdrawn, [have a] verified benefit, or have ongoing confirmatory trials, along with the expected dates of the confirmatory evidence.²

The article seems to declare the FDA will not view data from single-arm trials that use ORR as an end point as evidence for accelerated approval. Is this the direction the agency plans to take, or are there circumstances in which singlearm trials would still be considered?

For the anti–PD-1/PD-L1 antibody class of drugs, where we were seeing low response rates and variable correlation to outcome, we will not be accepting low response rate single-arm trials to support accelerated approval for this class of drug. For higher response rate trials with supportive duration, there is still a possibility of accelerated approval.

We are also encouraging companies to conduct a randomized trial with coprimary end points of response rate and PFS/OS [progression-free survival/overall survival] so that the trial has the potential to support accelerated approval based on response rate followed by confirmation of benefit in the same trial with the longer-term outcome end points. We are recommending this approach, as it will also allow a drug to be developed for accelerated approval for an earlier line of therapy, thereby bringing potential benefit to a greater number of patients, and having the confirmatory trial embedded into the study will create a shorter time to confirmation.

Concerning clinical trials conducted outside the United States, the article suggests studies conducted in a single country would not be adequate for supporting approvals in the United States. Is this a policy the FDA is pursuing now?

In order to receive a US approval, trials conducted outside the US need to demonstrate applicability and generalizability of their results to the US population. With large multinational trials―the preferred approach―we have the opportunity to examine both safety and efficacy in various regions and countries to ensure consistency of results. There are greater challenges to determining applicability and generalizability when there is a trial conducted in a single ex-US [non-US] country, and the burden is on the company to demonstrate how this data can be extrapolated to the heterogenous US population with its multiple ethnic and racial constituents and potentially different standards of care.

This article seems to signal we’re entering a more tightly regulated era for checkpoint inhibitor drugs. Is that the case? If not, how would you describe the FDA’s direction?

We continue to apply the same standards to drug regulation, and as the science and our knowledge evolve, we are able to apply these standards in a more educated manner. For instance, as we gathered evidence on checkpoint inhibitors and saw low response rates for this class of drug as not being reflective of an end point reasonably likely to predict clinical benefit, we have adapted our approach to accelerated approval for this drug class.

What is the potential clinical impact of more tightly regulating oncology drug approvals on patients and on practicing oncologists?

The intent is to use our learning from the checkpoint inhibitor class to apply the same regulatory standards to approve novel checkpoint inhibitors or indications that will benefit patients. Accelerated approval has been and will continue to be a very effective pathway for drug approval to bring promising therapies to patients years earlier. Even with the recent advisory committee meetings and withdrawals, there are still less than 10% of drugs approved under accelerated approval that have not verified benefit.

References

1. Beaver JA, Pazdur R. The Wild West of checkpoint inhibitor development. N Engl J Med. Published online December 15, 2021. doi:10.1056/NEJMp2116863
2. Project Confirm. FDA. Updated January 4, 2022. Accessed February 1, 2022. https://bit.ly/3ITFJ9c