29 Jun 23
In April 2023, the European Medicines Agency (EMA) published a draft reflection paper for public consultation (EMA/CHMP/564424/2021) on ‘Establishing efficacy based on single arm trials (SATs) submitted as pivotal evidence in a marketing authorisation (MA)’ (EMA, 2023) . This concept is different from the Food and Drug Administration(FDA) draft recommendation on ‘Clinical trials to support accelerated approval of oncology therapeutics’ published in March 2023 (FDA, 2023).
The EMA paper outlines important considerations in the design of SATs that might allow the treatment effect to be estimated and efficacy to be established for any indication without the need for further confirmatory studies. It does not aim to define conditions under which SATs may be considered acceptable as pivotal evidence for an MA. The applicant should justify that the SAT can provide clear pivotal evidence of efficacy by addressing the adequacy of the SAT, as well as the limitations and remaining uncertainties.
The FDA paper clarifies the current FDA thinking on the accelerated approval pathway that is commonly used for approval of oncology drugs in areas of high unmet medical need based on surrogate clinical endpoints. The initial study may be a SAT or a randomised controlled trial (RCT), typically followed by a post-marketing confirmatory trial to verify and quantify the anticipated clinical benefit.
Some of the concepts in the EMA paper may be relevant for any SAT, although they need to be stringently applied in the case of a pivotal study. Therefore, these important considerations regarding the SAT design are presented first below:
In summary, causal inference of a treatment effect from a SAT involves careful trial planning and understanding of the outcomes in the population without treatment. There are multiple sources of bias (15 are tabulated in the EMA paper) which can potentially be mitigated through the SAT design, conduct and analysis.
The FDA paper highlights that SATs with a primary endpoint of response rate (an accepted marker of drug activity) have commonly been used in oncology. Limitations of SATs are detailed. These include, as well as those mentioned in the EMA paper, the small safety database and the fact that clinical benefit for products with low response rates (e.g. immunotherapy) may not be predicted.
An RCT is the preferred approach to support accelerated approval (AA) by the FDA. Direct comparison to a concurrent control arm allows a more robust efficacy and safety assessment. This is particularly relevant for biomarker selected populations that lack historical trial data. It allows for assessment of potential regional differences in multinational trials and an RCT may allow evaluation in an earlier treatment setting where more patients may benefit, Sponsors can conduct two RCTs, one with an early endpoint for AA and the second powered for a longer-term clinical endpoint (PFS or overall survival [OS]). The confirmatory study should be well underway, if not fully enrolled, by the time of AA. To facilitate patient accrual, the confirmatory study can be in a different line of therapy (earlier disease setting).
Alternatively, follow-up in the same trial adequately powered for the longer -term clinical endpoint could fulfil the post marketing requirement to verify clinical benefit in a timely fashion; the ‘one-trial’ approach.
A ‘one-trial’ approach requires careful selection of the endpoint that is appropriate to evaluate earlier for AA. Depending on the disease course, endpoints other than response rate may be selected if supported by a strong rationale and discussed in advance with the FDA, with subsequent evaluation of clinical benefit endpoints. The effect on the surrogate/intermediate endpoint must be reasonably likely to predict clinical benefit and provide a meaningful advantage over available therapy.
Trial integrity is critical and the risk that regulatory action on the AA application introduces bias should be considered. Blinding of data for the clinical benefit endpoint should be maintained until the protocol specified analysis time point is reached to ensure a robust assessment. The FDA safety assessment may include evaluating the potential for harm from the investigational treatment (e.g. detrimental effect on OS). Sponsors should specify a plan to maintain study blind if a summary analysis of survival data is requested.
Type I error should be strongly controlled, and the sample size should ensure adequate power for both early and late endpoints. The trial design can incorporate adaptive design elements (e.g. sample size re-estimation). For a response-based endpoint, analysis to support AA could be based on a pre-specified number of initially randomised patients while, for a time-to-event endpoint it is appropriate to pre-specify the number of events. Efficacy analyses to support AA should be avoided until the trial is close to full enrolment to mitigate challenges in accrual if AA is granted.
For SATs, the adequacy of the primary response rate endpoint to support AA should be based on the magnitude and duration of response. Statistical inferential procedures are not needed. Stable disease or clinical benefit rate should not be used as these largely reflect the natural history of the disease rather than a direct therapeutic effect. Usually, a minimum of 6 months post response is needed to characterise durability, but the FDA may request additional data during review.
The sample size and analysis population (expected to be the entire trial population of patients who have received at least one dose of study drug) should be pre-specified. Multiple sample size increases with repeated looks at the data in the absence of a pre-specified plan should be avoided. Further, to reduce the potential for bias and to mitigate variance, blinded independent central review (BICR) of the response assessment should be performed in line with a BICR charter.
The FDA thinking on AA will be relevant for EMA conditional marketing authorisations, which also require comprehensive data post authorisation. Both papers highlight the agencies willingness to be flexible where trials are appropriately designed given the disease setting and intended patient population. EMA scientific advice and discussion with the FDA are strongly recommended to agree in advance the key aspects of the trial design.
EMA. (2023). Reflection paper on establishing efficacy based on singlearm trials submitted as pivotal evidence in a marketing authorisation https://www.ema.europa.eu/en/documents/scientific-guideline/reflection-paper-establishing-efficacy-based-single-arm-trials-submitted-pivotal-evidence-marketing_en.pdf
FDA. (2023). Clinical trial considerations to support accelerated approval of oncology therapeutics guidance for industry https://www.fda.gov/regulatory-information/search-fda-guidance-documents/clinical-trial-considerations-support-accelerated-approval-oncology-therapeutics
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