(2) whether the Medicines and Healthcare Products Regulatory Agency assesses the size of doses to be administered to volunteers in clinical trials on the basis of minimum anticipated biological effect levels;
(3) pursuant to the answer of 23 January 2007, Official Report, columns 1735-36W, on clinical trials, whether the Medicines and Healthcare Products Regulatory Agency has established an expert advisory group to advise on applications for clinical trials on higher risk substances.
The Implementation Group established by the Medicines and Healthcare products Regulatory Agency (MHRA) to take forward the recommendations made by the independent Expert Scientific Group (ESG) held its first meeting on 27 September 2006 and has met a further four times since then.
The MHRA assesses the starting doses to be administered to volunteers in clinical trials based on available toxicology and pharmacology data.
In general, the calculation of the first dose in man is based on the no observed adverse effect level (NOAEL) determined in non-clinical safety studies performed in the most sensitive and relevant animal species. However, a calculation of the minimal anticipated biological effect level (MABEL) is also used and this approach is considered to be more appropriate than the NOAEL when the results of animal studies are thought less likely to predict the effect of the molecule in man.
The MHRA has established an Expert Advisory Group (EAG) of the Commission on Human Medicines (CHM) to advise on applications for clinical trials on higher risk substances, and it held its first meeting on 18 March 2007. Prior to this, and since the ESG formulated its interim advice in July 2006, advice on applications for clinical trials on higher risk substances was obtained from the CHM.
Progress is being made on implementing the ESG report recommendations as follows:
Recommendation one concerns the drug development process itself and the need for those involved in such programmes to be appropriately trained. The former will be addressed in the revised European Union guidance which we expect to be published by the end of July 2007. The MHRA is having discussions with relevant bodies on the latter with a view to developing a training and accreditation scheme for investigators for Phase 1 trials. We do not expect this recommendation to be implemented before 2008.
Recommendation two proposes a regular review of the regulatory process and has already been implemented as one of the responsibilities of the newly formed EAG.
Recommendations three and four propose that clinical and pre-clinical unpublished studies relevant to the safety of human exposure need to be collected in a format that can be shared confidentially between regulators. Discussions on the proposal have taken place with the European Medicines Agency (EMEA) and they will discuss the recommendations with the US Food and Drug Administration (FDA) and with the International Conference for Harmonisation (ICH) to involve the wider regulatory population. The EMEA will also ask the European Commission about raising the issue of data sharing with other countries. The EU databases will need amendment to enable the information to be collected. We do not expect these recommendations to be implemented before 2008.
Recommendations five and eight recommend earlier dialogue between regulator and drug developer, and better communication between regulator and ethics committees. The recommendation on earlier dialogue has been implemented through establishing a procedure that allows for informal discussion and submission of data on higher risk substances in advance of submission of the formal clinical trial application. This will avoid the need to lengthen current formal approval times.
The recommendation on better communication was implemented in October 2006 through adoption of a Memorandum of Understanding between MHRA and ethics committees.
Recommendations six and seven recommend the regulator should have access to additional advice from experts and were implemented by establishment of the EAG of the CHM in March 2007.
Recommendations nine to 17 concern determining and administering the initial doses of a drug in man and are addressed in the guidance being developed by the EU scientific committee, which should be published by the end of July 2007. In the meantime the MHRA is operating interim arrangements that take account of these recommendations.
Recommendation 18 refers to the training of principal investigators and is being progressed with recommendation 1.
Recommendation 19 proposes development of a treatment strategy when drawing up protocols for trials involving higher risk substances and will be addressed in the EU guidance.
Recommendation 20 specifies the facilities that should be available for first in man studies of higher risk substances. The MHRA is developing a voluntary accreditation scheme for Phase 1 units which will provide assurances that they have appropriate facilities available. This scheme will be available from April 2008, although we expect an informal self assessment scheme to be implemented shortly, prior to the scheme being finalised.
Recommendation 21 advocates widening availability of “hands-on” experience in the conduct of clinical trials and has wide-ranging implications for industry and those responsible for the training of medical personnel. Although discussions are under way, it is unlikely that this recommendation will be implemented before 2008.
Recommendation 22 considers the need for specialist Phase 1 centres, and we propose this should be addressed via the proposed accreditation scheme, which should provide assurance in the longer term that trials are conducted only in units with suitable facilities and staff.