Euro Roundup: EMA shares draft paper on non-interventional studies using RWD

The European Medicines Agency (EMA) is seeking feedback on non-interventional studies (NIS) that use real-world data (RWD) for regulatory purposes.

In the draft reflection paper, EMA defines a NIS as a human study that does not fulfill any of the conditions defining a clinical trial. NIS collect data in normal clinical practice, often to assess safety after a medicine is authorized. The uncontrolled conditions, non-standardized treatments, absence of randomization, and uncertainties regarding data quality and completeness hinder the assessment of efficacy in NIS.

Electronic health data and registries have created new opportunities to use RWD to generate real-world evidence that reflects clinical practice, for example to describe patterns of drug use and validate outcome measures. Because NIS using RWD can generate a large amount of information for regulatory purposes, EMA wants people to understand the limitations of the studies and how to overcome them.

“A critical aspect when assessing the suitability of RWD for a regulatory purpose is the data quality, including data reliability and relevance ... and, depending on the research question, the extent to which RWD truly reflects routine clinical practice. In this context, the data quality frameworks discussed in this document should be considered,” EMA wrote.

EMA addresses data quality in one of the four main chapters of the draft reflection paper. The agency said RWD “are often used in NIS without the ability to influence the way they were collected, coded and recorded,” making it essential to “adequately characterize” the dataset. EMA recommends assessing the quality of the RWD and presenting it in the feasibility analysis.

The agency wants researchers to address at least the reliability and relevance of the data in the protocol. Reliability determines whether the data are complete, trustworthy, and credible. Relevance shows whether the size and characteristics of the data and study design are capable of fully answering the research question. EMA recommends using a data quality framework to determine if RWD is suitable.

Other sections of the reflection paper discuss study design, governance and transparency, and statistical analyses. In the section on study design, the longest of the four core chapters, EMA addresses topics such as feasibility assessment, the differences between studies with descriptive and causal objectives, and how to manage bias and confounding.

“The non-experimental nature of NIS may lead to bias that distorts the measure of association due to processes of selection, misclassification and confounding. Confounders may be unknown or inadequately measured,” EMA said. “These sources of bias should be clearly identified at the design stage. They are not easily controlled in the analysis and the design should attempt to minimize their impact on the results.”

EMA is accepting feedback on the draft until 31 August.

Draft Paper

EMA seeks feedback on plans to update approach to reproduction and lactation

EMA has published a draft concept paper on the planned revision of its guideline on the risk assessment of medicinal products on human reproduction and lactation.

The guideline, which took effect in 2009, describes how to assess and communicate the risk a medicine may pose to fertility, pregnancy, and the health of the fetus and child. EMA’s safety and human medicine committees identified the guideline as an area where they should cooperate to improve their regulatory advice in work plans for 2023.

That decision has led to a draft concept paper. The draft says only non-clinical data on fertility, pregnancy and breastfeeding is typically available in the summary of product characteristics (SmPC) and package leaflet (PL) at the time of authorization. Stakeholders have identified the data gap as a problem.

“The lack of clinical data on medicines safety for human fertility, during pregnancy and breastfeeding has long been highlighted as an area of public health need, and patients and healthcare professionals have expressed the need to have access to more information on the safety of medicines during pregnancy and breastfeeding. Currently, the guideline does not provide corresponding standard texts for the PL,” EMA said.

EMA is proposing to update the guideline in light of six European and international documents, including its own good pharmacovigilance practices for pregnant and breastfeeding women and pregnancy-specific risk minimization measures.

The draft describes considerations to ensure alignment with other guidelines and recommendations. EMA is focused on key adverse pregnancy outcomes such as teratogenic effects and assessing the causality of adverse effects on human reproduction. The agency also wants to update the guideline to cover new methods for estimating drug levels in breast milk and the potential for adverse effects.

Officials are also considering whether to develop standard texts for male and female fertility. Information on fertility risk assessment is “shortly described” in the guideline, EMA said, but there are no standard sentences provided in the SmPC.

EMA is accepting feedback on the draft until 31 August.

Draft Paper

MHRA-commissioned report reveals views on regulation of mental health tech

A report commissioned by the Medicines and Healthcare products Regulatory Agency (MHRA) has found the UK public is “broadly in favor” of regulating digital mental health technology (DMHT).

MHRA and the National Institute for Health and Care Excellence asked the research group Woodnewton to study the attitudes and experiences of current and potential users of digital mental health technology. Participants had limited knowledge of the regulatory environment and felt the devices were low risk. The only areas where the public wanted strong regulation were data security and interactions with doctors.

“They were broadly in favor of regulation, so long as it did not unduly restrict access to DMHT products,” Woodnewton said “Most participants did not see how self-regulation would be fully effective: developers and retailers were assumed to be more focused on profit, and some users of DMHT were particularly vulnerable to marketing, in-app purchases and data breaches.”

Woodnewton found no support for requiring a prescription to access the technologies. Participants saw minimal safety risks and even where they did were against banning or restricting access. Better guidance and the use of warnings where appropriate were the preferred ways to manage risk.

The report is part of an ongoing effort to clarify the regulatory and evaluation requirements for DMHTs.

Press Release, Woodnewton Report

EMA pushes back against AstraZeneca’s concerns with ICH bioanalytical plan

EMA has pushed back against concerns AstraZeneca raised in response to its implementation strategy for an International Council for Harmonisation (ICH) guideline on bioanalytical method validation.

AstraZeneca welcomed the EMA’s “useful and pragmatic position” but said the agency appeared to have aligned the dates for activities requiring revalidation with its earlier guideline. The company said the dates may differ when submitting in different regions, depending on the guidance the country had before adopting the ICH text. AstraZeneca said global alignment with other agencies may be needed.

In response, EMA said the dates are not aligned with its earlier guideline. The document refers to the implementation of the ICH text, not the old European guideline. EMA noted the point on global alignment but said “re-validation requirements are implemented at regional level.”

Industry Feedback

Other News:

The European Directorate for the Quality of Medicines & HealthCare (EDQM) is seeking feedback on the detection of viral extraneous agents in biological products. The proposed general chapter discusses the use of high-throughput sequencing to detect known and unknown viruses. EDQM sees benefits over conventional methods of detection and is accepting feedback until 30 June. EDQM Notice

Euro Roundup: EMA shares draft paper on non-interventional studies using RWD

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