Since its creation in 1992 the Accelerated Approval (AA) program at the U.S. Food and Drug Administration (FDA) has been a boon for patients receiving new oncology drugs. One assessment cited in a new white paper from the Friends of Cancer Research (FOCR) found that therapies approved through this accelerated pathway became available a median of 3.4 years earlier than would be achievable through the traditional FDA approval pathway.
In the second of two virtual sessions of the FOCR annual meeting, speakers presented a new FOCR white paper, “Optimizing the Use of Accelerated Approval,” which addresses ways of enhancing and updating the AA program as drug development continues to evolve. Specifically, the new white paper states that the AA program could be enhanced by shifting the focus away from one based solely on predictive endpoints and toward a discussion about overall benefit-risk considerations for patients.
As previously reported by Oncology Times, the FOCR also released a companion white paper, “Modernizing Expedited Development Programs.” Both white papers come at an opportune time, since the FDA is adapting to the critical need for new therapies posed by the COVID-19 pandemic.
“Very early we realized we needed to adapt,” said Patrizia Cavazzoni, MD, acting Director of FDA’s Center for Drug Evaluation and Research (CDER). She noted that the pandemic has focused attention on flexibility and streamlining strategies, such as decentralized clinical trials and remote monitoring. She called the AA tool “incredibly important and useful,” because it gets safe and effective new drugs to patients sooner.
Agreeing on the need to adapt at FDA was Peter Marks, MD, PhD, Director of FDA’s Center for Biologics Evaluation and Research (CBER). Marks said the focus is on doing clinical trials in a more timely manner by reducing on-site monitoring and using more remote monitoring through telehealth tools. “The simpler the trial the better,” he said. “But the trial still has to be fit for purpose.”
“The whole idea of AA is that it is patient-centric,” said Richard Pazdur, MD, Director of FDA’s Oncology Center of Excellence (OCE). The AA pathway is not an incentive for the pharmaceutical industry, he emphasized, but rather a way to help patients. “My point of view is that AA is a way to modulate risk,” added Pazdur. The new white paper goes into detail on using a preliminary benefit/risk assessment in the AA program. Pazdur said the AA program has been especially beneficial for multiple myeloma patients, since many new multiple myeloma drugs were approved through AA. Pazdur added that it is important to ask what effect the AA program is having on a disease, such as multiple myeloma, rather than just focusing on one drug.
The AA program was originally created as a response to the HIV/AIDS epidemic, said George Demetri, MD, Director of the Sarcoma Center at Dana-Farber Cancer Institute, Director of the Ludwig Center at Dana Farber/Harvard Cancer Center, Executive Director for Clinical and Translational Research at the Ludwig Institute for Cancer Research and a member of the working group that produced the FOCR white paper on AA.
Demetri noted that the AA pathway is intended to allow for the initial approval of a drug for a serious or life-threatening condition based on a demonstration of effect on a surrogate endpoint such as objective response rate (ORR) or an intermediate clinical endpoint “that is reasonably likely to predict a clinical benefit,” taking into account the severity or prevalence of the condition and the lack of available treatments. Drug sponsors who apply for AA must agree to conduct post-marketing trials to confirm clinical benefit.
Although FDA’s AA program applies to all drug classes, AA has been most frequently used in oncology, the new white paper notes. In the past 10 years (2010-2019) 84 percent of FDA’s accelerated approvals were granted for oncology indications. The white paper notes that since the AA creation by FDA 148 new drugs or biologics to treat serious or life-threatening conditions have been approved through AA.
While overall survival is the gold standard in a controlled, randomized clinical trial, the white paper notes that, “As more transformative treatments are developed that extend survival by years or even decades, the ability to quantify overall survival will become increasingly difficult or impossible within the context of a clinical trial.” For a patient with a terminal illness, randomization to a control arm would be unethical.
The new white paper on enhancing the AA program includes the following recommendations regarding benefit-risk assessments.
1. There needs to be a better definition of an “available therapy.”
Over time, as the standard of care changes, some drugs become less relevant or not used at all in clinical practice. Thus at the time of a new AA submission these drugs should not be considered as “available therapy.”
2. There should be more clarity in surrogate endpoints.
In 2012 the AA program was amended to address the use of surrogate endpoints in a preliminary assessment of a drug’s efficacy. The new white paper states, “Surrogate or intermediate endpoints such as duration of response or ORR are tumor-based endpoints, and there is no consistency in the magnitude of improvement in response rates that would constitute a change in other endpoints such as overall survival.” The white paper adds, “In oncology, a high response rate with a duration of response that lasts more than 1 year is preferable…” The paper points out that less robust outcomes will require “more nuanced consideration, including the rarity of the patient population.”
3. Consideration of heterogeneity in patient populations.
It may be appropriate to award AA in an “excellent responder” subpopulation of patients, such as in the field of immunotherapy—where less than 10 percent of patients respond but those who do “exhibit dramatic and long-term responses.” Thus AA would be awarded for the minority subpopulation based upon a biomarker-positive response, even if the clinical trial does not demonstrate benefits in the overall trial population.
4. Development of surrogate endpoints.
More research is needed to develop new surrogate endpoints or to provide more substantial evidence of the likelihood to predict clinical benefit in support of AA. FDA could create a formal process, or expand upon the Drug Development Tool (DDT) Qualification Program, for pharmaceutical sponsors to submit data and patient outcomes used to support AA. The white paper notes that “FDA considers clinical outcomes assessments to be a DDT and has issued draft guidance to inform the qualification of these metrics.” This evidence could be compiled in a publicly available database.
5. Use of external control arms to support clinical trials.
Single-arm clinical trials are now used to support regulatory approval —especially important to the AA program—in settings where it would be inappropriate, not feasible or unethical to require randomization to a placebo or to an active comparator. In these cases, use of real-world evidence (RWE)—defined as evidence obtained from observational data outside the context of randomized, controlled clinical trials such as electronic medical records, medical charts or medical claims—could serve as external controls (also called synthetic controls). Expanding the use of external controls may provide additional context and supplementary evidence and reduce the patient trial participation burden for conditions that are difficult to study.
Long-term multiple myeloma survivor David E. Mitchell, a member of FDA’s Oncologic Drugs Advisory Committee (ODAC) and a member of the working group that wrote the white paper, said, “I’m not interested in a trial where I might get a placebo. So I’m interested in synthetic controls and real-world evidence.” Mitchell said he owes his life to drugs approved under AA.
The white paper makes the following recommendations on the post-approval confirmation of clinical benefit in AA drugs.
1. Initiation of confirmatory studies in the pre-market setting.
When a drug is approved under AA, “We don’t exactly know what the clinical benefit will be,” said Aaron Kesselheim, MD, JD, MPH, Associate Professor of Medicine at Harvard Medical School and a faculty member in the Department of Medicine at Brigham and Women’s Hospital. That, he said, is why post-approval confirmatory studies are so important, and why they need to be done in a timely fashion. But once a drug is widely available, the incentive for a patient to participate in a confirmatory trial and risk randomization to a placebo group or to an active control perceived as inferior is greatly reduced. As a solution to this dilemma, confirmatory trials could be required to be initiated and have a pre-determined number of patients when the sponsor’s marketing application (NDA or BLA) is filed. This strategy would require earlier communication between the drug’s sponsor and the FDA.
2. Consideration of subsequent confirmatory trials.
If a drug approved under AA fails in a confirmatory trial but meets a clinical need in a subpopulation of patients, FDA could allow the sponsor to retain AA for the drug and conduct additional post-market trials. FDA could also host a public discussion at an ODAC meeting to discuss the failed trial through transparent discourse which includes patients and consider whether other confirmatory trials or withdrawal of the drug may be appropriate.
3. Real-world evidence to support confirmation of benefit.
RWE is being increasingly used in drug development. In the context of AA, RWE could be used to supplement confirmatory trial results and give a more complete understanding of a drug’s efficacy. Kesselheim said, “I think real-world evidence has its place,” but he stressed that rigorous confirmatory trials are also needed for drugs approved through the AA pathway.