The limitations of single-arm studies:

The FDA has recently announced draft guidance on accelerated approval for oncology drug development. The agency has very much set this new guidance in the context of the limitations of single-arm study designs, noting the following limitations with single-arm designs:

1. Safety databases are often limited not just in size, but the need for a comparator arm makes safety event attribution complex.
2. Difficulty in assessing time-to-event endpoints (TTE) with them considered as exploratory in the context of single-arm trials.
3. Low-magnitude treatment effects are unlikely to translate into a clinical benefit.
4. For combination treatment regimens, the influence of each component on the treatment effect is challenging to establish.
5. The need to often rely on cross-trial comparisons with differing I/E criteria, endpoints and follow-up time can lead to erroneous conclusions.

The agency highlights that a well-designed randomised controlled trial (RCT) can mitigate the above limitations and estimate comparative safety & efficacy in biomarker-defined cohorts precisely. The guidance also states that an RCT could be used to grant accelerated approval in earlier treatment settings as opposed to the typical refractory setting often seen in current accelerated approvals.

Do single-arm studies still have a place in accelerated approvals?

The FDA recognises that randomisation may not be appropriate in specific situations & that a single-arm study may be unavoidable, namely in the context of trial feasibility, such as in rare diseases.

The agency has issued recent guidance on using real-world evidence & external control arms for regulatory purposes, emphasising robust study conduct and methodology. As with each guidance on trial design, the agency once again stipulates the need for early engagement if a sponsor is considering a single-arm study for accelerated approval.

What do the new guidelines suggest as an alternative?

The agency rather unsurprisingly recommends using RCTs for accelerated approval applications and postulates two different scenarios: a two-trial or a one-trial approach.

The Two-Trial Approach

The agency has suggested that sponsors seek accelerated approval using two separate RCTs. The first study would be smaller, powered on a response rate primary endpoint, with a secondary confirmatory study powered for a time-to-event endpoint such as OS or PFS.

If the two-trial approach is used, the agency would expect that the confirmatory study is actively enrolling or fully underway at the time of accelerated approval action.  

Advantages of the two-trial approach:

1. A smaller first study may be easier to recruit
2. The confirmatory study could be potentially conducted in the same cancer type at an earlier line of therapy, providing an opportunity to widen the eventual label.
3. The methodological dividend from randomisation may enhance access and re-reimbursement discussions.

Challenges In the two-trial approach:

1.  If accelerated approval is granted before the full enrolment of the confirmatory trial, recruitment challenges are likely to occur due to patients opting for the commercially available drug.
2. If accelerated approval is granted after the full enrolment of the confirmatory study and the confirmatory study is in the same line of therapy as the earlier study, the potential for patient withdrawal could increase.
3. Compared to a single-arm study, there is a significant conduct and cost delta.

The One-Trial Approach:

The FDA suggests that sponsors could design a single RCT to support accelerated approval that is also powered for longer-term clinical endpoints & follow-up to verify the treatment effect. The agency stresses the need to cautiously assess preliminary clinical data before starting such a trial to decide on the most appropriate endpoint that can be evaluated earlier during trial conduct.

Advantages of the one-trial approach:

1. Accelerated approval, as well as confirmatory endpoints, are derived under a singular protocol.
2. Operationally less taxing than running two independent studies.
3. This approach may lend itself to adaptive designs

Challenges in the one-trial approach:

1. If accelerated approval is granted, there may be an increased risk of patient withdrawal in the confirmatory study phase. This could be mitigated by ensuring potential cross-over is addressed from both a design and analytical perspective.
2.  Unlike the previous design, label extension may require further clinical studies.
3. Changes to the treatment landscape affecting SoC could have significant implications.

InovaSight's capabilities to facilitate development teams pursuing accelerated approval:

InovaSight offers a robust platform that empowers development teams to create trial prototypes and designs rapidly and precisely. The platform allows users to generate crucial assumptions regarding treatment effects, establish relevant endpoints, and optimise inclusion-exclusion criteria. Additionally, InovaSight can forecast potential changes in the standard of care and calculate the probability of technical success (PTS) for specific trial designs. The platform's capacity to accurately identify and prioritise indications for a given drug and its ability to seamlessly connect teams to pertinent key opinion leaders (KOLs) renders InovaSight an indispensable resource for development teams.

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