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6:30 PM
Jul 12, 2019
 |  BioCentury  |  Tools & Techniques

Broadening role for external control arms in clinical trials

How companies are populating external control arms to speed clinical trial enrollment

External control arms are moving from theory to practice as drug developers begin to use them to make internal go/no-go decisions for clinical programs and to support regulatory applications. The field is largely split between those drawing on past clinical trials versus real-world data, and at least one company is pushing the approach further by simulating artificial patients to augment control arms in complex, chronic indications like Alzheimer’s disease.

Randomizing patients into experimental and control arms is critical to building confidence that the benefits observed in patients treated with a drug are due to the drug itself, and not the patients’ baseline characteristics. But the prospect of being assigned to a control group leads many patients to opt out of the clinical trial process all together, and filling control groups in rare and severe diseases is often infeasible or unethical.

External control arms offer a way to reduce the number of study participants treated with placebo or standard of care, decreasing trial size, duration and cost and incentivizing patient participation.

The idea is to replicate traditional randomization using control data from past clinical trials or real-world data (RWD) from electronic health records (EHRs) and other sources. RWD goes beyond natural history data because it can include patients undergoing treatment in real time and provides more detailed information at the level of individual patients.

At a Friends of Cancer Research meeting in November, FDA officials voiced cautious optimism for external control arms, identifying single-arm trials as the setting where the approach has the clearest benefit. The agency has already made a handful of regulatory decisions supported in part by external control data.

Examples include the 2017 approval of PD-L1 inhibitor Bavencio avelumab from Pfizer Inc. and Merck KGaA for Merkel cell carcinoma, where short patient survival times precluded recruitment of a prospective control group. The control arm used data from electronic medical records obtained in community and academic centers.

Another was the April label extension for breast cancer drug Ibrance palbociclib from Pfizer to include men with hormone receptor (HR)-positive, HER2-negative advanced or metastatic breast cancer. The expansion was supported by data from Pfizer’s global safety database, IQVIA claims data and EHRs from the Flatiron Health unit of Roche.

Pfizer Chief Development Officer Chris Boshoff said that for external control arms to go mainstream, they will have to build credibility through repeated use in guiding internal go/no-go decisions, like whether to advance a candidate to Phase II.

While some see any departure from prospective randomized control trials (RCTs) as dangerous, there is growing support for the idea that industry should make as much use of available data as possible to at least augment traditional approaches, particularly in settings that where RCTs are unattainable.

The approach is gaining visibility through company partnerships, pre-competitive...

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