FDA draft guidance addresses use of external controls to assess effectiveness of new drugs and biologics

Regulatory NewsRegulatory News | 02 February 2023 |  By 

The FDA Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) have issued draft guidance describing sponsors can leverage external controls, such as use data from registries and electronic health records, in lieu of data from randomized controlled trials (RCTs) to demonstrate the safety and effectiveness of new drugs and biologics.
 
The draft guidance also describes how sponsors can communicate with FDA on using data from externally controlled trials.
 
The guidance is part of a series of documents the FDA has issued under a mandate of the 21st Century Cures Act to specify regulatory considerations for RWE. FDA announced last year that such a guidance would be forthcoming (RELATED:  RWD in clinical trials: External control arms take the lead, Regulatory Focus, 23 June 2022).
 
External control arms use data collected from outside of the current trial to provide a comparator group and are especially useful for studies of rare disease treatments where it is not feasible or ethical to collect data from randomized trials.
 
Since externally controlled trials do not involve randomization of the study population to the treatments being compared, “the treatment and control arm populations should be as similar as possible regarding known factors that can affect the outcome being measured,” according to the draft guidance.
 
These include demographic factors, comorbidities, disease attributes such as severity and symptoms, duration of illness, concomitant therapies, and the clinical observations collected.
 
Before choosing to conduct a clinical trial using an external control arm as a comparator, “sponsors and investigators should consider the likelihood that such a trial design would be able to distinguish the effect of a drug from other factors that impact the outcome of interest and meet regulatory requirements.”
 
The draft guidance specifies that sponsors should specify how they will measure and analyze data on “important” confounding factors and sources of bias.
 
The guidance states that “although unmeasured confounding, lack of blinding, and other sources of bias cannot be eliminated in externally controlled trials, an assessment of the extent of confounding and bias, along with analytic methods to reduce the impact of such bias, are critically important in the conduct of such trials.”
 
The suitability of using an externally controlled trial design “warrants a case-by-case assessment” and should be informed by such factors as the heterogeneity of the disease; including the clinical presentation, severity, and prognosis; preliminary evidence regarding the drug product under investigation, and whether the goal of the trial is to show superiority or non-inferiority.
 
Sponsors should consult with the agency early on to determine whether it is reasonable to conduct an external control trial instead of a RCT. Sponsors should also describe the reasons why the proposed study design is appropriate, list the external control arm and explain why it is fit for use, and submit a proposed statistical analysis.
 
The deadline for submitting comments is 2 May 2023.
 
Guidance
 
 

 

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