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EMEA issues draft guidelines on clinical trials for potentially high-risk drugs

The European Medicines Agency (EMEA) has adopted draft guidelines for first-in-man clinical trials of potentially high-risk medicinal products.

The guidelines are released a year after six previously healthy volunteers taking part in a trial at London's Northwick Park Hospita...
EMEA issues draft guidelines on clinical trials for potentially high-risk drugs
The European Medicines Agency (EMEA) has adopted draft guidelines for first-in-man clinical trials of potentially high-risk medicinal products.

The guidelines are released a year after six previously healthy volunteers taking part in a trial at London's Northwick Park Hospital suffered severe, long lasting reactions to the drug TGN1412, which was being tested in humans for the first time. The new guidelines are intended to help those designing first-in-man trials for high risk products to identify and minimise the risks involved, to avoid a recurrence of the events at Northwick Park.

First-in-man trials, as the name suggests, are designed to investigate the safety and tolerability of a new product in humans. They are usually conducted on healthy volunteers, and these early trials do not have therapeutic objectives. When using a drug for the first time in humans, the safety of the people participating in the trial is the paramount consideration.

The document defines medicinal products as high risk 'when there are concerns that serious adverse reactions in first-in-man clinical trials may occur'. It goes on to explain that these concerns may be based on the mode of action of the drug, its target in the body and the absence of a relevant animal model where the drug can be studied.

The guidelines outline the information that researchers should gather before deciding to proceed with a trial in humans. This includes a characterisation of the product, a determination of its strength and potency, detailed information on how the drug will interact with the body, and how long the effects of the drug will last.

An important issue addressed in the guidelines is the calculation of the first dose. Usually, the first dose is calculated using the No Observed Adverse Effect Level (NOAEL) system, which is based on safety studies carried out in relevant animal species. However, the EMEA recommends that for high risk products, the Minimal Anticipated Biological Effect Level (MABEL) be used. The MABEL is the anticipated dose level leading to a minimal biological effect in humans, and the EMEA notes that it should take into account safety factors such as the novelty of the active substance, its biological potency and mode of action. Furthermore, drugs should be administered slowly, possibly as a slow infusion over several hours, and with careful observation.

Risks should be further minimised by leaving a long observation period between the first and second doses, and also between the first and subsequent cohorts to receive the drug. The trial designers should draw up a plan for monitoring adverse reactions, which identifies likely reactions. Staff working on the trial should be trained to spot these reactions and taught how to respond to them.

The draft guidelines also call on researchers to consider the long-term monitoring of trial participants who have received drugs which could have long-term consequences on physiological systems.

The guidelines are open for consultation until 23 May. Thereafter, the EMEA will hold a meeting with key stakeholders, including the European Commission, patients' organisations, the pharmaceutical industry and healthcare professionals' organisations, to discuss the feedback and finalise the guidelines for official publication.

Source: European Medicines Agency (EMEA)

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