EMA revises methodological guidance for trials impacted by COVID-19

Regulatory NewsRegulatory News | 29 June 2020 |  By 

Following a four-week public consultation, the European Medicines Agency (EMA) on Monday revised its guidance on methodological considerations for ongoing clinical trials amid the coronavirus disease (COVID-19) pandemic.
The agency also says it will extend its decision to hold all upcoming committee and working party meetings virtually through September 2020. The agency adds that it will continue its practice of holding stakeholder events virtually or postponing them.
Revised guidance
EMA first released its methodological guidance in late March, emphasizing the imperative to protect patient safety while charting a course to continue trials throughout the pandemic. (RELATED: EMA offers methodological considerations for trials during COVID-19 pandemic, Regulatory Focus 25 March 2020).
The revisions to the guidance offer little in the way of new recommendations for sponsors, and in its draft response to comments submitted to the public consultation, EMA’s Biostatistics Working Party resisted calls to expand the document’s scope or get into more specifics.
“The text throughout the document was amended to acknowledge the stakeholders’ concerns that the impact of COVID-19 on trials and patients are expected to unfold in a great variety. It is not possible to give specific advice on how and when to collect which information that would be applicable to all trials. Instead, Sponsors are encouraged to reflect upon how their trials could be affected, to record the necessary information to their best ability to be able to assess the expected impact,” EMA says.
EMA acknowledges that patients within trials may be unequally affected by pandemic-related measures, as some patients may have completed study activities before the pandemic had an impact on a trial, while others may go through their individual study phases during a time more heavily impacted by the pandemic.
“Where preparation for the pandemic situation is still possible, investigators should consider which information is essential for the interpretation of the trial and whether an alternative method of data collection might be warranted,” EMA says. The agency notes that, “In a pandemic situation, capability and willingness to follow the trial protocol is expected to vary between and within trial participants.”
EMA also expands on what information about pandemic measures should be included in a sponsor’s data collection, such as the dates and duration of lockdowns and travel restrictions and other measures that would affect trial sites.
The revised document provides more insight on how sponsors should approach risk assessments for their studies: “Risk assessment should focus on quality and reliability of the data from a trial conduct perspective and should consider the impact of intercurrent events (e.g. treatment discontinuations) and missing data arising from the COVID-19 pandemic on the analysis and interpretation of the data.”
EMA points to the International Council for Harmonisation (ICH) E9(R1) addendum on estimands and sensitivity analysis in clinical trials, writing that, “The estimand framework provides a comprehensive approach to articulate this impact analysis.”
The revised guidance also re-emphasizes the importance of maintaining trial integrity and stresses that risk assessments should be based on blinded data and be conducted by independent committees if trial integrity is at risk.
“A more thorough analysis based on blinded review may be warranted, but the use of unblinded data is not recommended. Any analysis that bear the risk, however small, of unblinding should be specified a priori and conducted independently of the sponsor supervised by an independent data monitoring committee (DMC),” EMA writes.
Additionally, the guidance has been revised to say that sponsors should seek scientific advice from the agency early on, “If substantial modifications to the original protocol are considered necessary.” In response to comments related to scientific advice, EMA says it “will try to facilitate such requests to the best of [its] ability and further guidance should be provided if common and recurrent issues are seen.”


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