Regulatory evaluation of Glybera in Europe — two committees, one mission
Nature Reviews Drug Discovery
(2013)doi:10.1038/nrd3835-c1
Published online 19 August 2013
Representing the first gene therapy to be approved in the Western world, alipogene tiparvovec (Glybera; Uniqure) has recently been said to have had a “substantial impact from a regulatory perspective” (Nature Rev. Drug Discov. 11, 664; 2012)1. The therapy was granted marketing authorization in the European Union for the treatment of lipoprotein lipase deficiency, which results in a clinically heterogeneous condition with a risk of potentially life-threatening pancreatitis2, at the end of 2012. The decision followed a positive opinion by the European Medicines Agency (EMA)'s Committee for Medicinal Products for Human Use (CHMP)3, and a previous recommendation of the EMA's Committee for Advanced Therapies (CAT)4, 5.
The approval process for Glybera was extensively discussed in the scientific community, sometimes critically6, 7, 8, 9, 10, 11, 12. During the process, the opinions of the CHMP and the CAT differed: although the opinion of both committees was originally negative, in a “re-examination procedure” the opinion of the CAT became positive5, whereas the CHMP maintained its negative opinion13. However, both committees finally recommended approval of the medicine. As regulators who have been involved in this approval process, we would like to provide insight into why the Glybera procedure was challenging, and give assurance to the scientific community regarding confidence in both orphan drug and gene therapy regulation in Europe.
In Europe, gene therapies undergo a centralized approval procedure via the EMA. For advanced therapy medicinal products (ATMPs), which include gene therapies, the CAT as an expert committee first performs a scientific assessment of the application dossier and prepares a draft opinion on its approvability for a final decision by the CHMP, a committee with considerable long-term expertise, which also ensures consistency in the opinions.
The assessment process for Glybera was long and complex owing to multiple reasons. These included the complexity of the product class for which there was little previous regulatory experience (this was the first procedure for a gene therapy to correct a genetic deficiency); the long product development time, during which science evolved and specific regulatory requirements were about to be established; the complex disease scenario (a very rare disease) with a fluctuating clinical outcome (pancreatitis); and the fact that the company was small with academic origins (as usually also seen for other ATMPs)14.