The speed with which the European Medicines Agency’s Committee for Medicinal Products for Human Use has adopted draft guidance on first-in-man trials of high-risk medicinal products is “probably unprecedented”, an official from the UK’s Medicines and Healthcare products Regulatory Agency said last week.

Speaking at the 28th Annual Conference of the Institute of Clinical Research in Birmingham, Dr Martyn Ward, head of the MHRA’s Clinical Trials Unit, said it was also unique that the EMEA would be holding a stakeholder meeting on the draft guideline, which addresses the scientific elements of first-in-man trials, at the end of the consultation period in June. The final version of the guidance drawn up by the CHMP’s safety working party is scheduled for publication in July.

Running parallel to this initiative is a review of the procedural aspects of taking high-risk medicines into humans, such as the trial protocol and information provision. The European Commission’s ad hoc group on clinical trials is working on a draft of this document, which will be a modification of existing guidance and/or new guidance, Ward noted.

Guideline drawn up after TeGenero trial

The CHMP’s draft guideline was drawn up in response to the disastrous Phase I trial of TeGenero’s monoclonal antibody TGN1412 at Northwick Park Hospital in London last year. It mirrored in some respects the final report released in November 2006 by an Expert Scientific Group on Phase I clinical trials, set up by the UK government under the chairmanship of Sir Gordon Duff.

The 22 recommendations of the Duff report were taken up wholesale by UK ministers and the MHRA. In his presentation to the ICR conference, Ward gave an update on how some of the key issues raised by the Expert Scientific Group are being addressed at European and UK level.

One area of emphasis was the need for information-sharing and proactive communication between regulators, trial sponsors, independent specialists and other concerned parties to mitigate the potential risks of human exposure to higher-risk medicines. The Duff report suggested that the EU’s existing EudraCT clinical trials database might be a suitable model for a database of relevant information from unpublished preclinical and Phase I studies, so that EU and international regulators could exchange signals of potential risks.

Option to use EudraCT

According to Ward, the MHRA has been talking with the EMEA about the possibility of using EudraCT for this purpose. The European Clinical Trials Facilitation Group, which Ward chairs, will be discussing the issue this week. The US Food and Drug Administration and the World Health Organization are also involved but the initiative needs input from industry and academia, he pointed out. This is probably the biggest hurdle to cross, he added, given these constituencies’ worries about the confidentiality of research data. Ward did not rule out a legislative solution, although he said this would be at “the bottom of the list”.

In terms of training and accreditation to support first-in-man trials, the MHRA has been talking to the relevant professional bodies about a potential diploma in human pharmacology, Ward said. Industry and academia alike have bemoaned the dearth of new clinical pharmacologists in the UK and warned that it could jeopardise efforts to tighten up the safety of early clinical studies. In addition, a working group convened by the MHRA is in early discussions about developing a national accreditation scheme for Phase I trial centres. According to Ward, there are some 27 commercial units of this kind in the UK, plus some academic centres.

As far as applications for first-in-man trials of higher-risk compounds go, the Expert Advisory Group recommended by the Duff report is now up and running. The expectation, Ward told the conference, is that the new group will assemble just before the monthly meetings of the Commission on Human Medicines, which will ratify the EAG’s decisions. The MHRA will then provide product sponsors with feedback on their data package before a normal submission for clinical trial authorisation is made. The whole process should take about 30 days, Ward said.

The MHRA published advice on this new procedure on its website on 7 February. The agency asks sponsors of first-in-man trials to make contact prior to filing a CTA if the products involved fall within the following categories:

- New compounds acting (directly or indirectly) via the immune system with a novel target or a novel mechanism of action, or having a secondary potential effect on the immune system via a mechanism of action which currently is not well characterised.

- Novel compounds acting via a possible or likely species-specific mechanism or where animal data are unlikely to be predictive of activity in humans.