EMEA issues guidelines for 'high risk' clinical trials

EMEA has published new guidelines that appear to directly address a number of apparent faults in the system that led to the TeGenero clinical trial disaster last year.

The CHMP has adopted draft guidance on first-in-man trials of 'high-risk' investigational medicines in the aftermath of the study, which endangered the lives of six volunteers after they developed severe side-effects.

'The safety of subjects participating in first-in-man studies is the paramount consideration in proceeding to clinical trials in man,' the agency said. The draft followed 'extensive review and discussion' among European regulators.

However, the guidance, which will be finalised after a two-month consultation period, will not be binding. Sponsors will be able to deviate from the recommendations of the guideline provided they can substantiate their approach.

The TeGenero trial has come under fire from experts for an apparent 'miscalculation' of the initial dose, attributed to the limited relevance of preclinical studies in animals. In addition, experts said in retrospect it was unwise to dose all patients within a short period and to give all the drug at once in a bolus injection, rather than a slower administration in an infusion, which could be halted if necessary.

The new recommendations could address these criticisms.

Sponsors should determine the strength and potency of high-risk drugs using relevant criteria, including assays, the guidelines state. In certain cases 'the doses given to animals may be poorly defined and mislead the interpretation of a safe dose,' they add.

Assays are strongly encouraged for high-risk biologicals, for which 'the lack of a potency assay measuring the expected in vivo activity should be fully justified'. It is important that the product prepared for clinical studies is comparable to that used in preclinical trials, EMEA says. Manufacturing changes could change the biological properties of the molecule and 'could have clinical consequences'.

In addition, 'applicants should demonstrate that the intended formulation of the doses to be administered provides correct dosing', it says. Correct dosing may be of particular concern when the product needs to be diluted - this can lead to miscalculations of the dose if some of the product remains adsorbed to the wall of the container of infusion system.

It also suggested that for high-risk products the first dose should be calculated using the 'minimised anticipated biological effect level' rather than the traditional 'no observed adverse event level'.

According to the CHMP, 'high-risk' products are those raising concern of serious adverse events because of the mode of action, the nature of the target in the human body or the limited relevance of animal models for the prediction of the drug's pharmacology or toxicology in humans.

The recommendations are designed to help pharma companies move from preclinical to clinical trials. They cover non-clinical aspects, including pharmacokinetics, pharmacodynamics, safety, toxicology and the calculation of the first dose in man. Clinical aspects covered include protocol design, choice of subjects, route and rate of administration, precautions, dose escalation, stopping rules and monitoring for adverse events.

They were drawn up by clinical trial experts, non-clinical research from national regulatory authorities and working parties at the EMEA's CHMP. EMEA is seeking feedback on the draft guidelines from interested parties during a two-month consultation period. It will then hold a meeting with the European Commission, national regulatory agencies, pharmaceutical companies, patient groups, healthcare professionals bodies and academia.