IS THERE ANYTHING IN THIS PAPER WHICH WILL RESULT IN DC VAX L GETTING APPROVAL FASTER ?
The On- and Off-Ramps of Oncology Accelerated Approval
List of authors.
Lola A. Fashoyin-Aje, M.D., M.P.H., Gautam U. Mehta, M.D., Julia A. Beaver, M.D., and Richard Pazdur, M.D.
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The accelerated approval (AA) pathway was created by the Food and Drug Administration (FDA) in 1992 for drugs intended for serious and life-threatening diseases. This approval pathway aimed to speed drug approval on the basis of a surrogate end point deemed reasonably likely to predict clinical benefit or an intermediate clinical end point other than irreversible illness or death. The AA pathway has provided patients earlier access, frequently measured in years, to new and practice-changing drugs. AA may require sponsors to conduct confirmatory trials to verify the drug’s clinical benefit and obtain traditional approval.
Recent scrutiny of this program has focused on AA end points and their relationship to clinical benefit, the time to completion of confirmatory trials, and the process for withdrawing indications if confirmatory trials fail to show clinical benefit. In two meetings in April 2021 and April 2022, the Oncologic Drugs Advisory Committee (ODAC) discussed such negative confirmatory trials, and these meetings and preceding discussions led pharmaceutical companies to voluntarily withdraw 11 oncology indications.
To address ongoing concerns about the implementation of AA in oncology, we at the FDA Oncology Center of Excellence believe a comprehensive strategy is needed — one that equally emphasizes “on-ramp” and “off-ramp” considerations. On-ramp considerations include trial design, end points, study population, and timelines for obtaining data to support the AA and to confirm clinical benefit. Off-ramp considerations include confirmation of clinical benefit leading to granting of traditional approval and removal of indications if clinical benefit is not verified.
AA was initially used for drug approvals for HIV infection based on plasma concentrations of HIV RNA, a surrogate end point deemed likely to predict reduced risk for AIDS progression and death.1 AAs were typically based on demonstration of a drug’s short-term (e.g., 24-week) effects on HIV RNA concentrations, and the durability of HIV RNA suppression (e.g., for at least 48 weeks) was used to verify clinical benefit, often in the same study. Since HIV RNA concentration is now a validated surrogate for predicting antiretroviral efficacy, a paradigm of AA followed by traditional approval is no longer required for antiretroviral drug development.
Currently, AA is predominantly used in oncology, with cancer drugs accounting for about 85% of all AAs granted in the past decade — more than 172 indications.2 For 86 of these indications (50%), clinical benefit was verified by demonstrating improvement in survival, delay of disease progression, or durability of response. A total of 21 AA indications (12%) were withdrawn. The median time to verification of clinical benefit and granting of traditional approval was 3.1 years (range, 0.5 to 17.6). The median time to withdrawal of an indication was 3.8 years (range, 1.3 to 12.5). In the majority of the 38% of cases for which confirmatory trials are ongoing, the AA was granted within the past 3 years.
We believe that a comprehensive AA strategy should provide sufficient evidence of effectiveness and adequate assurance of safety, while expediting access to drugs and minimizing the time between AA and demonstration of clinical benefit or lack of clinical benefit. Before embarking on this AA plan, a sponsor should conduct adequate dose-optimization and activity-finding studies.3
In oncology, the efficacy end point most frequently used for AA is a durable overall response rate. This rate is a reliable marker of drug activity, since malignant tumors generally do not shrink without therapeutic intervention. Unlike the surrogate end point for HIV antiretroviral therapies, which has been validated, the overall response rate bears an uncertain relationship to improvement in overall survival in diverse cancer types and new drug classes. For checkpoint inhibitors, such as antibodies directed toward the programmed cell death 1 pathway, for example, robust improvements in overall survival have been observed in the absence of large effects on overall response rate; this disconnect raises questions regarding the suitability of overall response rate as an end point to support AA for this drug class.2
Historically, small, nonrandomized, single-group studies were used to evaluate safety and preliminary evidence of drug activity in a specific tumor type to determine whether larger, randomized, controlled trials were warranted. The dose-finding and activity-seeking studies typically enrolled only 25 to 39 patients.4 Because single-group studies are now used to support AA, they frequently enroll more than 100 patients to provide greater statistical precision in the observed overall response rate. Yet these studies provide limited additional information on the drug’s risks and do not permit assessment of time-to-event end points, such as overall or progression-free survival.
A comprehensive AA strategy should also focus on the timely generation of evidence to confirm or refute clinical benefit. With the exception of rare diseases, for which the FDA has accepted the further characterization of the overall response rate and response durability as verification of clinical benefit because of the infeasibility of conducting randomized trials, oncology drug sponsors have typically conducted a single-group study to support AA and subsequently conducted a randomized, controlled trial evaluating a long-term outcome such as survival to verify clinical benefit. Although the FDA has recommended that confirmatory trials be well under way, if not fully enrolled, at the time of the AA, sponsors frequently delay initiating these trials until the single-group study is completed or AA has been granted.
Time from Accelerated Approval to Subsequent Action, Stratified According to Whether the Confirmatory Trial Was Ongoing at the Time of Accelerated Approval.
Among oncology indications that have been granted AAs, the median time to off-ramp action was longer if the confirmatory trial was initiated after the approval (see figure). This difference was most striking among withdrawn indications, with a median time to withdrawal of 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. Delayed withdrawals in this latter scenario represent the greatest risk to patients.
Most AA studies enroll patients for whom there are limited or no available therapies. Subsequent confirmatory trials are usually performed in a population with less refractory disease, since it may be infeasible after approval to initiate a randomized trial in the original population. Rather than waiting to initiate the trial after AA, sponsors could pursue a single randomized trial, potentially in an earlier treatment setting, that could both support AA and subsequently verify clinical benefit. AA could be granted on the basis of a planned interim analysis of overall response rate, and traditional approval granted on the basis of clinical benefit (usually improvement in overall survival) at the trial’s conclusion.
This approach would provide a more thorough safety assessment and earlier definitive evidence of the benefit–risk balance. It would also reduce the risk of prematurely halting development of a drug with a limited overall response rate that might nevertheless improve overall survival. Moreover, the randomized trial could be conducted in patients in an earlier treatment setting, so the drug would reach more patients in whom efficacy might be greater.
An alternative strategy is to conduct two concurrent studies: a single-group AA study examining the overall response rate in patients without other available therapies, and a randomized trial with the potential to demonstrate clinical benefit in patients who have received fewer treatments. If these studies enrolled patients around the same time, an interim analysis of safety and overall response rate in the confirmatory trial could provide supportive evidence and greater confidence for the AA based on the single-group study. A clinically meaningful effect on overall response rate in this interim or a subsequent analysis could support an additional AA indication for the randomized-trial population. In this scenario, the FDA and the sponsor would agree in advance on the criteria for attaining AA and criteria for withdrawing the indication.
The time between AA and verification or refutation of clinical benefit is a period of uncertainty. The pathway’s success should be measured in part by the length of this period. Currently, withdrawing an AA indication when confirmatory trials have failed to demonstrate clinical benefit, and when sponsors do not voluntarily remove the indication, involves a complicated hearing process that has been used only once in oncology — to withdraw the indication for Avastin (bevacizumab) in the initial treatment of metastatic breast cancer. This process took 16 months from the initial ODAC meeting recommending the indication’s removal and required considerable time and effort.
Public discussion has focused on improving the AA off-ramp, suggesting specific time limits for completing confirmatory trials, patient enrollment milestones for evaluating timely trial completion, and alternative procedures for withdrawing indications. But equally important are procedures to build quality and efficiency into the AA on-ramp, which should include a prospective comprehensive strategy detailing plans for AA and the verification of clinical benefit, with the aim of expediting therapeutic advances and shortening this period of uncertainty.
Disclosure forms provided by the authors are available at NEJM.org.
This article was published on September 21, 2022, at NEJM.org.
Author Affiliations
From the Office of Oncologic Diseases, Center for Drug Evaluation and Research (L.A.F.-A., G.U.M., J.A.B., R.P.), and the Oncology Center of Excellence (L.A.F.-A, J.A.B., R.P.), Food and Drug Administration, Silver Spring, MD.
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