Dr James McBlane
Regulator’s perspective on preclinical testing of advanced therapy medicinal products (ATMPs)
Use of ATMPs as regenerative medicine in the UK has thus far been limited to clinical trials or to instances of use in individual patients, lacking alternatives. The current framework for market access were introduced in 2009 and thus, in 7 years, there has been no commercial use of an ATMP in the UK. Why not?
To ensure that there are no unreasonable obstacles posed by regulation of the pharmaceutical industry, regulators may need to explain those systems that developers of ATMPs need to navigate to bring such products to patients. This is what this talk is about.
ATMPs are licensed in Europe through the centralised procedure in accordance with Regulation 1394/2007, allowing for one decision for all EU member states. In this, the Committee for Human Medicinal Products (CHMP) and the Committee for Advanced Therapies (CAT) consider scientific data in relation to quality, safety and efficacy. For products with a favourable opinion, CHMP informs the European Commission who issues the marketing authorisation.
However, for clinical trials, the situation is completely different: regulation of applications for clinical trials is at the national level, currently in line with Directive 2001/20; for up to 28 EU countries, this can involve up to 28 national applications. The directive will be replaced with Regulation 536/2014 which will simplify administrative steps to allow one procedure, no matter how many EU countries are involved: this will include Ethics Committee review.
Review of clinical trial applications address whether the specific proposals are judged safe: if so, the trial can go ahead. This says nothing about whether the trial is optimal, or even relevant, for generating data to obtain a marketing authorisation. Review of preclinical data in a marketing authorisation application addresses further issues relating to the evidence supporting the claims for mode of action, and the detail of studies claiming safety.
In terms of preclinical data, principles are similar between an ATMP and conventional product: information on the mode of action, and why this is of benefit to a defined patient population should be presented, including justification of dose, complemented by evidence as to why the specific proposed intervention is considered likely to be safe in the population defined. However, the type of study used to provide this information for an ATMP can differ, with combined biodistribution and toxicity studies often used: also the timing of these studies in relation to clinical development may differ, as even from the first human dose, once the product is given, it may be that there is life-long exposure thereafter. The implication of this is that all, or almost all, preclinical safety studies are needed to support the first clinical dose.
In relation to the UK leaving the EU, firstly, the regulatory procedures outlined above will continue in the UK until the UK leaves but will thereafter continue in the 27 member states. The procedures implemented after that point in the UK are not defined but will be influenced by the nature of the UK’s future relationship with the EU.
Preclinical Assessor, Biologicals Unit, Licensing Division, Medicines & Healthcare products Regulatory Agency (MHRA), 151 Buckingham Palace Road, London SW1W 9SZ.
After degrees in pharmacology at Dundee and Aston universities, Dr McBlane worked for Wellcome and then at the UK Medicines Control Agency before moving to the Japanese biopharmaceutical company, Chugai, for 10 years, latterly specialising in preclinical development. He returned to the Licensing Division of the UK’s Medicines & Healthcare Products Regulatory Agency where he has spent the last 11 years as a preclinical assessor. He has worked on >3000 clinical trial applications and hundreds of marketing authorisation applications and has also given advice on development of hundreds of pharmaceutical products. He has been the UK’s alternate delegate to the European Medicines Agency's Committee for Advanced Therapies (CAT) since 2013.