Euro Roundup: EMA finalizes reflection paper on establishing efficacy based on single-arm trials

The European Medicines Agency (EMA) has finalized a reflection paper on establishing efficacy based on single-arm trials (SATs) submitted as pivotal evidence in a marketing authorization.

EMA published a draft version of the paper for consultation in April 2023. The final document retains the focus and structure of the draft, but EMA has made extensive changes to the text in response to the 45 comments it received from stakeholders.

The agency highlighted two major changes it made to the draft. First, EMA said it has included “a clearer statement that as a regulatory standard, randomized controlled evidence is expected and that deviation from this standard by proposing a SAT needs justification.” Second, the agency has clarified the scope of the paper to exclude guidance on the use of external controls, including by removing a section.

Both documents start with the statement that “randomized controlled trials (RCTs) are the standard for providing confirmatory evidence on the efficacy of an investigational treatment.” EMA has strengthened the prioritization of RCTs in the final text by stating applicants need to “justify to regulators the reasons for deviating from the expected standard and the appropriateness of the SATs as [an] alternative.” As part of the justification, sponsors must show SATs provide adequate pivotal evidence of efficacy.

The second major rethink led to the removal of a subsection titled “role of external information.” In the draft, EMA discussed how the lack of a comparator cohort in SATs makes external information critical for interpreting the results of the trial. The agency also changed its description of single-arm trials to clarify the scope of the reflection paper.

“This paper does not address specific considerations for the situations where results of a SAT are contrasted against an external control that is constructed outside of the original trial protocol, e.g. as part of the totality of data submitted by applicants. In such settings, the present paper fully applies to the respective SAT,” EMA said.

Designs that prospectively include a non-randomized external control arm in the trial protocol may not be considered SATs, EMA said, but key considerations from the reflection paper may still apply because of the lack of randomization.

EMA also highlighted smaller changes to the document. The agency said the final version has “a more targeted implementation of ICH E9(R1),” as shown by changes to the section on key definitions and terminology.

The updated section “expresses more clearly that regulatory assessment of efficacy of an investigational treatment conceptually requires comparative information and that single-arm trials only allow to observe outcomes under the investigational treatment,” EMA said. The agency removed a subsection on “internal validity” and introduced a subsection on estimand attributes such as treatment condition.

EMA Notice, Reflection Paper

Swiss agencies share advice on filing clinical trial applications in transition period

Swiss authorities have published instructions for submitting applications to run clinical trials ahead of changes to the Human Research Act (HRA) that will take effect on 1 November.

The revisions to the HRA affect the protection of study participants and the conditions for research. Once in effect, the updated Act will establish new rules on aspects of informed consent, liability provisions, the use of e-consent and other topics. Changes to the transparency requirements will become mandatory in March 2025.

The Swiss Association of Research Ethics Committees (Swissethics) has incorporated the changes into its templates for writing study protocols and participants information documents. The new templates are available now, but the old versions will remain in use until 31 October. Data and documents uploaded before 31 October but not sent to the Ethics Commission will automatically move to the new forms.

Applications submitted before 1 November but approved after that date can be authorized under the old law. However, sponsors in that situation will need to submit the requirements under the new ordinances via a protocol amendment before the first participant is included in their studies. Swissethics has agreed the transition with the Swiss Agency for Therapeutic Products (Swissmedic).

Swissethics Statement, Swissmedic Notice

MHRA posts guidance for manufacturers on adapting to revised Brexit agreement

The UK Medicines and Healthcare products Regulatory Agency (MHRA) has published guidance for wholesalers and manufacturers in light of the Windsor Framework that revised the terms of Brexit.

Through the framework, the UK and European Union established long-term arrangements for the supply of medicines into Northern Ireland. MHRA is regaining the power to license medicines across the UK and the EU’s Falsified Medicines Directive safety features will stop applying to products in Northern Ireland. The measures will take effect at the start of next year.

Ahead of the change, MHRA has published guidance for Qualified Persons (QPs) and Responsible Persons for Import (RPis). The QP guidance explains the rules on adding the “UK Only” label that all medicines will need to carry to be placed on the UK market starting next year.

“‘UK Only’ may be presented anywhere on the outer packaging of the medicine so long as it is in a conspicuous place in such a way that it is easily visible,” MHRA said. “It shall not in any way be hidden, obscured, detracted from, or interrupted by any other written or pictorial matter or any other intervening material.”

The other section of document states wholesalers that import QP-certified goods under the RPI process after midnight on 31 December 2024 should ensure the products are compliant with the conditions of MHRA guidance and feature a “UK Only” label.

MHRA Guidance

EMA makes early talks with HCPs part of new drug reviews after 1-year trial

EMA has made early talks with healthcare professional (HCP) organizations “a systematic methodology considered for all new applications with new active substances.”

The agency piloted early dialogue with patient organizations on orphan drug applications in 2021 and 2022. The success of the pilot led EMA to make the dialogue part of its routine practice and expand the model to non-orphan drugs and HCP organizations. EMA began consulting with HCPs in relation to new drug applications in May 2023 and published a report on the first year of the engagements this week.

Through the dialogue, EMA aimed to capture HCP insights on the targeted condition and available treatments early in the evaluation of marketing authorization applications. The agency sent 77 requests related to 44 medicinal products during the first year of the program, leading to 54 responses from HCP organizations. The response rate trended upward over the course of the year.

Some organizations focused their responses on the medicinal product rather than the indication but the “completeness of the input received generally increased during the first year, as organizations became more familiar with the methodology,” EMA said. The agency deemed the project as a success and has moved to make early dialogue with HCP organizations a routine part of its process.

EMA Report

Other News:

EMA’s Committee for Human Medicinal Products (CHMP) has elected Bruno Sepodes as chair. Sepodes, who will start a three-year mandate on 21 September, has worked as senior expert for the Portuguese National Authority for Medicines and Health Products since 2005. At EMA, Sepodes has held posts including vice-chair of CHMP. Sepodes succeeds Harald Enzmann, who completed his maximum term as CHMP chair. EMA Notice

Euro Roundup: EMA finalizes reflection paper on establishing efficacy based on single-arm trials

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