Euro Roundup: MHRA seeks feedback on using external control arms based on RWD

The UK Medicines and Healthcare products Regulatory Agency (MHRA) is holding a consultation into the use of external control arms based on real-world data (RWD) to support regulatory decisions.

Using patient-level data collected outside of a clinical study for all or part of a control arm to estimate the comparative efficacy of an intervention frees sponsors from enrolling patients to receive placebo or standard of care. MHRA wants sponsors to continue running randomized controlled trials, when possible, but the draft guideline opens the door to submissions based on external control arms made from RWD.

“Any regulatory decision is based upon the data presented in the submission, and if those data are sufficiently convincing then a positive decision can be reached, even if alternative approaches may have ideally been preferred,” MHRA said in the draft guideline. “Therefore, there is no general scenario where the use of RWD external controls is explicitly ruled out.”

External control arms are more likely to be acceptable in “situations where conducting an adequately powered randomized trial is not ethical or feasible, would result in a significant delay or where the effect of the intervention is expected to be large enough to allow interpretation of the study results despite potential bias,” MHRA said.

The agency would prefer sponsors that face such challenges to run a randomized controlled trial with an internal control arm that is augmented with external controls. That design allows for better control of potential biases than single arm trials that rely solely on external controls. MHRA’s guidance covers both single arm trials with external control arms and randomized trials with RWD-augmented control arms.

The draft provides points to consider about the protocol, pre-specification and addressing bias that apply to both trial designs, although the focus is on fully external control arms. MHRA expects the protocols for the trials to “be of the same standard, style and level of detail” as for traditional randomized trials. The protocols should pre-specify the objectives, data to be collected, endpoints and analysis methods.

Adding an external control arm after the analysis of a single-arm trial “may inflate type I error if it is not clear which was the primary analysis,” MHRA said, but the agency is open to incorporating RWD after pre-specification in some cases. If an appropriate external dataset was not available when the trial was designed, a sponsor can amend the protocol, justify the switch and note the change in regulatory filings.

MHRA began the consultation on International Clinical Trials Day. The agency and UK government used the day to highlight work to create a faster, more effective clinical trials system, notably the move to a new regulatory framework that began last month.

The draft is open for comment until 30 June.

Draft Guideline, Press Release, More

EMA updates guidance on publishing clinical data on medicines for human use

The European medicines Agency (EMA) has published version 1.5 of its guidance on the publication of clinical data for medicinal products for human use.

EMA brought its policy on the publication of clinical reports into force in 2015. The following year, the agency shared guidance to help pharma companies comply with the requirements. EMA has continued to update the guidance, culminating in the publication of a new version last week that clarifies points, restructures sections, and incorporates changes to reflect the current requirements.

The agency summarized the changes in a separate document. EMA has provided clarifications on the possibility of sponsors proposing additional redactions to prevent the unblinding of studies and further guidance on the timelines for the invitations it sends to applicants. The agency is aiming to send redaction proposal invites by Day 121 of initial marketing authorization application procedures.

EMA updated a chapter on the anonymization of clinical reports. The agency added references to current data protection legislation and clarified that “risk assessment is the preferred methodology to achieve anonymization while preserving meaningful data utility.” EMA also clarified that any handwritten text is considered personal data and should not be disclosed.

EMA Guidance, Update Summary

MHRA shares guidance on reporting medical device incidents via MORE portal

MHRA has published guidance on the Manufacturer’s Online Reporting Environment (MORE) it has set up to facilitate the reporting, monitoring and management of medical device incident reports.

MORE is an online portal that manufacturers must use to submit reports relating to adverse incidents for devices that happen in the UK. The agency will not accept reports filed via other routes. MHRA has revised the system as part of the implementation of changes to post-market surveillance requirements that passed into law last year.

The guidance explains how to report incidents using MORE, outlining how to register on the portal or set up an API so reports are sent directly from a company’s internal IT system. MHRA has updated the data schemes for the transmission of manufacturer incident reports and field safety corrective action (FSCAs) reports to support submissions of incidents in Great Britain.

Manufacturers in Northern Ireland, which with Great Britain makes up the UK, must report serious incidents, FSCAs and trends to MHRA using European Union forms within MORE. Northern Ireland is covered by the EU medtech regulations, but manufacturers are continuing to use national reporting processes until the Eudamed Vigilance module is available.

MHRA Guidance, More

Swissmedic makes urgent change to Swiss Pharmacopoeia after legal dispute

The Swiss Agency for Therapeutic Products (Swissmedic) has made an urgent amendment to the Swiss Pharmacopoeia to address issues raised in a legal dispute.

Hearing a health insurance case, the Swiss Federal Supreme Court ruled on the remuneration payable for the reconstitution of cytostatics under aseptic conditions. The ruling involved interpreting the Swiss Pharmacopoeia’s rules on good manufacturing practice for medicinal products in small quantities. Swissmedic said the ruling had implications for the Swiss Pharmacopoeia.

“This judgment highlighted uncertainty regarding the distinction under therapeutic products legislation between the manufacture and reconstitution of medicinal products,” Swissmedic said. “To clarify the requirements under therapeutic products law, Swissmedic has elucidated the good manufacturing practice rules applicable to medicinal products in small quantities as stated in the Swiss Pharmacopoeia.”

The agency has changed definitions and introduced the concept of “preparation for administration” to refer to any processing subsequent to production that is required for making a medicinal product ready to use. Processing includes simple actions such as dissolving and more complex steps including the aseptic preparation of sterile medicinal products.

The changes take effect on 1 June.

Swissmedic Notice

Other News:

EMA has provided new information on which limits apply to nitrosamines in medicinal products. The agency updated its question-and-answer document to clarify the applicable acceptable intake limit for different routes of administration and in vivo study types. EMA also highlighted the expectations for the submission of variations to shelf-life and storage conditions in certain situations. EMA Q&A

Swissmedic and the Swedish Medical Products Agency (MPA) have agreed to exchange information. The memorandum of understanding provides a formal framework for closer cooperation on regulatory issues associated with medicinal products and medical devices. Under the agreement, Swissmedic and MPA can share data to promote reciprocal understanding of regulatory framework conditions. Swissmedic Notice

Euro Roundup: MHRA seeks feedback on using external control arms based on RWD

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