The primary mission of the FDA and other regulatory agencies is to foster innovation while keeping patients safe and protected from preventable harm. Executing this mission is never simple, especially with the continued explosion of discovery around new and novel oncology therapies. It requires massive resources, active cooperation from industry – and above all, the willingness and flexibility to learn from emerging evidence and adopt new strategies best suited to the most current circumstances.
The FDA’s latest draft guidance does just that: refining the agency’s thinking on the use of single-arm trials and randomized controlled trials (RCTs) for the accelerated approval of oncology therapies.
If the draft guidance is finalized, oncology clinical trial sponsors will need to adjust their approach to the accelerated approval process and invest in next-generation strategies to prove the safety and efficacy of novel therapies to the FDA before getting sign off on new drugs.
What does the draft guidance say?
The FDA would like industry to consider relying less heavily on single-arm trials, which cannot always accurately identify rare, serious side effects and often suffer from other data limitations that prevent strong predictions of clinical efficacy or comparisons around superiority over existing standards of care.
Instead, sponsors should expand the use of RCTs, which may provide better insight into safety and efficacy while providing a more direct comparison of the new therapy to established standards.
While RCTs are more challenging, time-consuming, and expensive to conduct than single-arm trials, the FDA points out that sponsors have several options when designing RCTs.
“Sponsors can, as appropriate, elect to conduct a single randomized controlled trial to support an accelerated approval and to verify clinical benefit (i.e., follow a “one-trial” approach), or they can conduct separate trials – one to support the accelerated approval and another, a confirmatory trial, to verify clinical benefit,” the agency states.
Either of these options is now preferable over the use of a single-arm trial, except in cases where an RCT is truly not feasible, the guidance continues. Regardless of the chosen pathways, the agency strongly recommends “early discussion with the Agency before initiating and, as appropriate, during the conduct of, a trial(s)” to ensure sponsors are meeting the parameters for successful research.
Why is the FDA taking this approach?
Since the FDA instituted the Accelerated Approval Program in 1992, surrogate endpoints, or an alternate clinical trial endpoint meant to predict a clinical trial’s primary endpoint, have become widely used. Since then, single-arm trials have become an increasingly utilized trial design to bring much-needed therapies for serious illnesses to market quickly: a must in a clinical environment where patients are very sick and need options as soon as possible.
Single-arm trials avoid the ethical quandary of putting patients with serious illnesses such as cancer into a control arm, and offer a way to study ultra-rare diseases or very specific indications without requiring an unattainably large number of participants.
Some sponsors augment these single-arm studies with external control arms (ECAs), or cohorts of real-world individuals who may have received standard-of-care treatments in the past. This strategy makes the single-arm trial somewhat more similar to the gold-standard RCT, but may not satisfy statisticians who believe that such historical data is not truly adequate as a comparator.
Single-arm trials can also suffer from scope creep. In an effort to bring therapies to market quicker for cancer patients, sponsors and regulators have been asking for single-arm trials to do more and more over time. Efficacy endpoints are being analyzed earlier in the process while sponsors sometimes add extra arms to answer additional questions. This can lead to challenges with data interpretation and therapeutic and safety analysis.
As a result of these limitations, as well as the concerns over the inability to identify rare adverse effects, the pendulum is swinging back toward the RCT as the go-to method for therapeutic effectiveness research.
What does this mean for clinical trial sponsors?
The draft guidance makes clear that single-arm trials aren’t going away completely. In fact, the FDA just recently released separate guidance on how to design and use ECAs, which is proof that the agency is still invested in developing the methodology. But single-arm trials will need to evolve if they are to meet the FDA’s standards.
Real-world data (RWD) and ECAs will continue to play a crucial part in ensuring that next-generation trials of all types are hitting the mark.
For example, by using RWD to create an ECA for supplementing single-arm investigations, sponsors will be able to better replicate the rigor of an RCT without the same required investment in time and resources. RWD is increasingly being used for concurrent prospective ECAs, where current patients are followed via their electronic record data. While these patients aren’t truly randomized to the trial in the same way as an RCT, the strategy could reduce concerns about using more historical patient information.
Real-world data can augment RCTs as well, by facilitating the creation of “hybrid” control arms, in which some patients are on the concurrent control arm (as part of the RCT) and the rest are augmented from the RWD source. This novel clinical trial design can reduce the number of trial participants who are not receiving the new therapy, thereby lessening patients’ concerns over being randomized to the control arm.
In all cases, sponsors will need to invest in regulatory-grade, real-world data that allows them to answer the safety and efficacy questions regulators are constantly asking. Access to clean, standardized, and accurate fit-for-purpose data means sponsors will be able to meet regulators’ needs and questions in a flexible and expeditious manner.
Overall, the draft guidance reaffirms the FDA’s commitment to ensuring safety and efficacy in a rapidly changing clinical development environment. As a result of the guidance, clinical trial sponsors may need to reexamine how they approach study design for promising molecules. At the same time, sponsors will need to continue to develop RWD competencies and work more closely with the FDA earlier in the clinical trial design process as the regulatory agency adjusts its expectations.
