New guidelines for first-in-man clinical trials

The guidelines have been prepared by experts in clinical trials and non-clinical research, based on principles in European legislation and existing guidelines. Dr Jean-Marc Vidal from the European Medicines Agency, explains the new draft guidelines.

NGP. What was the situation in Europe pre the guidelines that have been devised by the EMEA and European commission?

JMV. Before EU and international guidelines where prepared by the International Conference on Harmonisation (ICH), in the early 1990’s, non-clinical and clinical studies sometimes had to be repeated to fulfil different regional or national requirements. This led to the unnecessary duplication of studies and use of animals. This situation has improved dramatically since the requirements for the development of pharmaceuticals have been harmonised internationally and within Europe.

NGP. How important is it that there are guidelines for ‘first-in-man’ clinical trials?

JMV. First-in-human clinical trials are the most critical ones in terms of safety as they are based on data extrapolated from animal and in-vitro testing for substances unknown to humans. Guidelines for first-in-human clinical trials are aimed at optimising this approach, using state-of-the-art scientific knowledge and strategies to mitigate, as much as possible, the risk to humans.

NGP. Do the guidelines cover the whole of Europe? Do they cover all pharma clinical trials? Are certain types of drugs excluded?

JMV. The requirements of this guideline apply to the whole of the European Union. It also represents the current thinking of experts in the area, which could be used beyond Europe. The guideline covers only phase I and phase II first-in-human clinical trials.

The scope of the guideline excludes very specific medicinal products such as gene and cell therapy for which particular guidelines are being prepared.

NGP. The guidelines were devised after the first-in-man clinical trials of TGN1412. Do you think the guidelines will stop instances like these occurring?

JMV. The aim of this guideline is to remind sponsors and investigators of the principles of good practice, both for the interpretation and extrapolation of non-clinical data and for the planning and design of clinical trials, in order to apply a risk mitigation strategy in accordance with suspected risks of each specific substance to be investigated in humans.

Historically, phase I clinical trials have been very safe, and thankfully dramatic adverse events have been exceptional. However, the risk should always be considered, recognising, that the likelihood of unforeseen events occurring can only be reduced but never completely avoided.

NGP. The draft guidelines were released in March 2007 for a two-month public consultation period. What were your findings in this period? Will you have to make changes to the draft? When do you expect this to happen? When will the final guidelines be in place?

JMV. There was a huge interest in this guideline, as reflected by the large amount of comments received. The comments were either quite positive or constructive criticisms. A workshop was organised to reinforce the feed-back from stakeholders. The main finding of the public consultation was that the approach to classify medicinal products as high-risk or not should be changed to an approach based on risk identification and mitigation. This has been reflected in the final guideline, which was adopted by the CHMP in July 2007. The final guideline has now been published on the EMEA website. It will come into effect on 1st September 2007.

NGP. Do you believe these guidelines will slow down the clinical development of drugs?

JMV. This guideline should not slow down the vast majority of clinical trials. It should help improving the quality of data to ensure the safety of volunteers and patients.

NGP. What are your predictions of the future regarding clinical trials in the pharmaceutical industry?

JMV. Clinical trials will always be necessary for the development of new medicines. However, the design of clinical trials will probably change significantly in the mid to long-term, given the extraordinary progress made in the area of innovative medicines and innovative investigation methodologies (e.g. biomarkers).

“the risk should always be considered, recognising, that the likelihood of unforeseen events occurring can only be reduced but never completely avoided”