Euro Roundup: MHRA issues guidance on clinical trial risk assessments and oversight

The UK Medicines and Healthcare Products Regulatory Agency (MHRA) has published guidance on risk assessment, monitoring and follow-up of clinical trials in two new documents.

The MHRA requires sponsors to carry out and document a risk assessment for each proposed clinical trial as soon as possible to determine whether it falls under clinical trials legislation, how the agency will classify the trial and whether there are obstacles to its execution.

“The risk assessment should be specific to the proposed trial and although the process may include templates or guidance on areas to consider in the risk assessment, care should be taken to consider the potential risks of the proposed essay, which may introduce new areas that have not been considered in previous essays, which is why this is a tailored approach,” the guide states.

The MHRA expects sponsors to form multidisciplinary teams, including a statistician and a physician familiar with the therapeutic area, to carry out the risk assessment and determine whether further examination is required. The additional review could involve senior management or be an independent peer review. The MHRA advises sponsors to carry out a review commensurate with the risks identified in the trial.

Sponsors should retain the risk assessment in the master trial file and, where appropriate, inform site personnel of its contents. As new information becomes available, for example after an interim analysis, the MHRA expects sponsors to revisit the risk assessment. The guide also presents three examples of risk assessments.

The MHRA published the guidelines on the same day that it published a document on monitoring and tracking investigational trials of medical products. The second guidance document lists important factors in determining monitoring and follow-up strategy, explaining that sponsors should establish processes that reflect the known risks of a study. If an error in an activity negatively impacts participant safety and trial outcomes, sponsors should make this a goal for monitoring and follow-up.

The guidelines represent a departure from the traditional approach of assessing compliance with every protocol detail and verifying every data point against source documents. The MHRA said this way of working is “extremely resource intensive”. The risk-based approach aims to protect the rights, safety and well-being of clinical trial participants and the reliability of results without verifying everything.

MHRA Advice, Following

MDCG publishes general principles of clinical evidence for in vitro diagnostics

The Medical Devices Coordinating Group (MDCG) has published guidelines on the general principles of clinical evidence for in vitro diagnostics. MDCG released the document to support the assessment process defined in the new In Vitro Diagnostics Regulations (IVDR).

Once the IVDR takes effect, manufacturers will need to define the intended purpose of the tests they plan to bring to market and generate clinical evidence showing that the products work as claimed. To support these activities, the MDCG has outlined the general principles of clinical evidence, explained how they differ from therapeutic principles, and detailed the performance review process.

“When determining what data is needed to demonstrate the safety and performance of IVDs, it is important to consider what existing data is available and how to fill the gaps. In the event that data is not available in quality or in sufficient quantity, they will have to be generated, ”says the guide.

MDCG has established a four-step performance review process, beginning with establishing a performance review plan and ending with ongoing monitoring and updates. The committee cited scientific validity, analytical performance and clinical performance as the three essential pillars of performance evaluation.

Elsewhere in the guide, MDCG provides more detail on each of the essential pillars, stating that scientific validity must be demonstrated and documented for each device and explaining what this means in practice for IVD developers.

MDCG Guidelines

European Commission updates Q&A on Clinical Trials Regulation

The European Commission has updated a Q&A document on the recent Clinical Trials Regulation (CTR). The Q&A features over 10 new questions and updates to even more existing queries.

New questions relate to how to proceed in the event of discrepancies between the CTR and the Good Clinical Practices of the International Council for Harmonization (ICH). In response, EU officials said the CTR prevailed over conflicting rules, including ICH guidelines. Documents that are not “planned” by the CTR, such as the progress report in ICH E.6, “should not be requested or submitted based on the recommendations of different guidelines”.

The Commission has also extensively updated a selection on informed consent and other “substantial requirements” for conducting clinical trials. Through a series of new responses, EU officials explained how the rules apply to studies conducted in emergency situations.

“In situations where the subject dies before informed consent has been provided and the data already collected has been collected in accordance with Article 35, the data should remain in the trial. In situations where the subject or their legally appointed representative does not consent but does not agree to continued participation in the trial, no further research data may be collected,” the Q&A states.

Questions and answers about commissions

Legislation strengthening EMA’s crisis preparedness powers comes into force

The European Union has passed legislation to strengthen the role of the European Medicines Agency (EMA) in crisis preparedness and management. The EMA acquires powers to coordinate a response at European Union level to public health emergencies.

The new regulation entered into force as soon as it was published in the Official Journal of the EU earlier this week and will become broadly applicable on March 1. The exceptions are the provisions on shortages of critical medical devices, which will apply from February 2023. Maintaining the provisions on shortages is part of the phased implementation of this key element of the regulation.

The EMA has until the beginning of 2025 to set up, maintain and manage a European shortage monitoring platform. The platform will allow the EMA to collect data from companies and Member States on shortages, supply and demand for critical medicines.

EMA Notice

Pfizer’s oral COVID antiviral tops latest round of positive CHMP opinions

The Committee for Medicinal Products for Human Use (CHMP) recommended approval of Pfizer’s COVID-19 oral antiviral Paxlovid and six other drugs at its January meeting.

As the European Commission moves quickly to grant conditional marketing authorisation, Paxlovid is now cleared for use across the EU. This authorization makes Paxlovid the first oral antiviral treatment against COVID-19 to be marketed in the region. The CHMP based its positive opinion on a study linking the drug to a reduction in hospitalizations and deaths in patients at risk of developing a severe form of COVID-19.

The committee also issued a positive opinion on Breyanzi, a CD19-directed CAR-T cell therapy from Bristol Myers Squibb. The CHMP expressed support for the use of cell therapy in certain lymphoma patients.

Two of the other positive reviews were for biosimilars. The CHMP has recommended approval of Sondelbay from Accord Healthcare, a copy of Forsteo from Eli Lilly, in the treatment of osteoporosis, and Stimufend from Fresenius Kabi, a copy of Neulasta from Amgen, in the treatment of side effects of chemotherapy.

EMA Notice, Following

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Elna M. Lemons