Euro Roundup: EMA seeks feedback on platform trials; MHRA to recognize CE-marked devices indefinitely
The European Medicines Agency (EMA) is holding a consultation into the methodological aspects of confirmatory platform clinical trials.
EMA defines a “platform trial” as a multi-arm study that is run as a single clinical trial but may address more than one primary objective. Key elements include the investigation of multiple treatments in separate experimental arms in a single target population. Patients are randomized to experimental arms that are compared to a control and may be added or terminated at different times.
With platform trials becoming more common in recent years, EMA has drafted a reflection paper to describe the “concrete circumstances and methodological constraints” that the studies need to deliver reliable evidence for regulatory decisions. The paper focuses on studies designed to provide pivotal evidence for drug approvals.
The reflection paper covers seven key methodological topics: pre-specification, randomization, controls, blinding, type 1 error control, trial operating characteristics, and estimands. A shorter concluding section addresses how the complex interplay between different platform trial design features can increase uncertainty.
EMA’s advice starts at the planning stage, reflecting its belief that the complexity of platform trials necessitates additional efforts before a study starts. Sponsors must thoroughly document the objectives, estimands, and overarching testing strategy in the platform trial at the start of the study, EMA said.
Such documentation is essential to confirm that the design corresponds to the objectives and to inform the control of type 1 error risk. Type 1 errors are false positives. Because platform trials evaluate multiple experimental treatment arms, the probability of making at least one type 1 error is higher than in traditional studies. Unadjusted multi-arm designs inflate the family-wise error rate (FWER).
The reflection paper covers the requirements for strong FWER control, the risk of multiple false-positive decisions, and when confirmatory hypotheses can be separated into unrelated families. EMA addressed the increased risk of multiple false-positive decisions in platform trials designed to support more than one regulatory decision.
EMA is accepting feedback on the draft paper until 31 January.
UK confirms indefinite recognition of CE-marked medical devices cleared for EU use
The UK government has confirmed that it will continue to accept CE-marked medical devices indefinitely, ending plans to split from the European Union on medtech authorizations in the wake of Brexit.
When the UK left the EU at the end of 2020, the government planned to stop accepting CE-marked devices in June 2023. However, the government subsequently dropped that target, leading to a February consultation about indefinite recognition of CE-marked medical devices. The consultation received more than 1,000 responses.
Having reviewed the feedback, the government this week confirmed that it will continue to accept CE-marked medical devices on a long-term basis. Devices already approved for the EU market will not require additional authorization to be sold in the UK. More than 90% of medical devices registered for use in Great Britain have a CE mark.
The government framed the decision as supporting safe, uninterrupted access to medical devices. Steve Lee, executive director of regulation at health technology trade group ABHI, welcomed the government’s action.
“Regulatory predictability and avoiding unnecessary duplication are fundamental to industry investment decisions, which ultimately determine how quickly patients can access new technologies,” Lee said. “Long-term recognition of CE marking is therefore a significant and welcome decision.”
The UKCA route created to replace CE marking remains in place. The government is also developing a new licensing approach for medical devices. Last month, the government discussed providing the legal basis for the Medicines and Healthcare products Regulatory Agency to issue licenses for medical devices. Medtech products currently come to market following third-party conformity assessments.
EMA starts consultation into planned changes to blood pressure clinical trial guideline
EMA is seeking feedback on its plans to update a guideline on clinical trials for drugs to treat high blood pressure.
The current version of the guideline came into effect in 2017. Since then, understanding of resistant hypertension (rHTN) and primary aldosteronism (PA) has evolved, new diagnostic and therapeutic options have become available, and the European Society of Cardiology (ESC) has provided new definitions and treatment targets. EMA plans to update the guideline to reflect the changes.
The update will address the acceptability of 24-hour ambulatory blood pressure measurement (ABPM) as a primary endpoint. The current guideline prohibits the use of ABPM as the sole basis for efficacy in the approval process. However, EMA wants to discuss the merits of 24-hour ABPM as a primary efficacy endpoint, in part because its placebo effects are less pronounced in rHTN patients.
EMA’s current guideline lacks a specific discussion of rHTN and PA. Despite that, EMA has accepted rHTN as an indication. PA is increasingly recognized as a reason for secondary HTN, the agency said. EMA plans to amend the guideline to reflect experiences and expectations in patients with rHTN and PA.
The agency also plans to review the acceptability of technologies such as wearables for assessing efficacy and safety parameters in patients with arterial HTN. Healthy subjects and patients increasingly use digital technologies to control physiological parameters such as heart rate and blood pressure, as well as to monitor physical activities and sleep, EMA said. The agency sees a role for such devices in clinical trials.
Other planned changes include bringing the definition of normal blood pressure in line with recent ESC guideline recommendations and contextualizing the concept of estimands in HTN clinical trials. EMA may recommend stricter blood pressure targets for otherwise healthy individuals while allowing more lenient goals to be set on an individual basis, for example in very old or frail patients.
The consultation ends on 31 January. EMA expects to release a draft guideline 18 months after adopting the concept paper. The draft guideline will undergo a six-month consultation and be finalized about one year after EMA receives comments.
EMA gathers views on proposed update to guidance for kidney transplant studies
EMA is seeking feedback on plans to provide new guidance on clinical trials of products used in kidney transplant patients.
Currently, kidney transplant studies are covered by an overarching guideline on clinical trials of immunosuppressants for solid organ transplantation. EMA is considering revising or adding to the text, which took effect in 2009, to provide specific advice on kidney transplant studies. Kidney transplantation plays a key role in driving innovation in the broader solid organ transplant space, EMA said.
To support sponsors of kidney transplant trials, EMA plans to address study design, criteria for patient selection, the definition of short- and long-term efficacy endpoints, and the use of biomarkers and surrogate endpoints. The agency also plans to incorporate aspects of an International Conference on Harmonisation guidance document.
Specific goals include elaborating on the design of trials for calcineurin inhibitor (CNI)-free regimens. CNI nephrotoxicity is a significant barrier to long-term kidney graft survival, but the risk of early rejection when using alternatives to the drugs necessitates careful patient selection, EMA said.
Highly sensitized patients, delayed graft function, and tolerance induction are other priorities for EMA. By addressing those clinical scenarios, the agency plans to support the stratification of rejection risk, the minimization of ischemia-reperfusion injury, and the elimination of lifelong immunosuppressive therapy.
The agency is accepting feedback on the draft until 31 January.
