The Need for Increased Clarity and Transparency in the Regulatory Pathway for Gene Medicines in the European Union
Authors: Seppo Ylä-Herttuala
Journal: Molecular Therapy (2012)

At the October 2011 meeting of the European Society of Gene and Cell Therapy (ESGCT) in Brighton, UK, the society hosted an excellent symposium in collaboration with the Committee on Advanced Therapies (CAT) of the European Medicines Agency (EMA), with a view to discussing problems and road blocks that biotech companies face when trying to bring Advanced Therapy Medicinal Products (ATMP) through the regulatory process. Overshadowing the symposium was the recent decision by the EMA to reject approval of Amsterdam Molecular Therapeutic's Glybera (alipogene tiparvovec) despite an approval recommendation by the CAT. Thus, despite the considerable professional expertise of the CAT and their attempts to guide sponsors through the regulatory pathway in the EU, the process remains fraught with uncertainty and it was the clear consensus of the symposium that additional clarification of the authority of the CAT in the decision-making process was urgently needed. No gene therapy product has yet been approved for clinical use in either the EU or US. With a view to improving the regulatory approval process in the EU, in 2007 the EMA established the CAT to handle the review of gene and cell therapy products—now referred to as ATMPs. The establishment of this new committee instilled hope in members of the gene and cell therapy communities that regulatory uncertainty surrounding the development of ATMPs could be clarified in the EU. This hope was thus dampened by the Glybera decision, which indicated that an ATMP regulatory outcome might not always follow a CAT recommendation. Glybera comprises an AAV vector engineered to deliver a lipoprotein lipase cDNA to the muscle for the treatment of lipoprotein lipase deficiency, a very rare defect (less than 500 patients in the EU) that results in a decrease in an enzyme that is responsible for breaking down fats in lipoproteins. Without this enzyme, patients can develop pancreatitis, or inflammation of the pancreas. Glybera had initially received a negative opinion from the CAT, but after reapplication and reevaluation by two rapporteurs (representatives from the drug authorities of two EU member states that are charged with reviewing and assessing the application in question) and a scientific advisory committee appointed by the CAT, it eventually received recommendation for approval, albeit with a proviso that additional post-marketing studies be completed. However, according to the EMA regulatory structure, it is not the CAT who are authorized to recommend final approval of ATMPs, but rather the Committee on Human Medicinal Products (CHMP), which oversees drug marketing authorizations in the EU. Despite the positive opinion of the CAT, CHMP unexpectedly decided to turn down the Glybera application. The crux of the debate was the inability to generate statistically significant data in such a small number of trial subjects, and hence uncertainly over the long-term efficacy of Glybera. Many members of the CAT felt that a case-by-case analysis of the data showed that there was sufficient evidence of clinical benefit to approve the drug—but CHMP took a different view. In light of these developments, it is not surprising that the biotech industry and particularly investors remain unconvinced that their products will be handled in a transparent way and that the best expertise will be employed in the review process and final decision. Vigorous discussion of this issue at the ESGCT meeting has led to the consensus that while larger and more rigorous clinical trials are generally needed for ATMPs, the relationship of CAT and CHMP must be clarified, and in the case of ATMPs, greater emphasis should be placed on the CAT opinion, since many issues in the regulatory dossier of ATMPs require very specific understanding of gene and cell therapy products in addition to a robust general knowledge of the issues of traditional pharmacology. Researchers, clinicians, and both biotech and drug com­p­anies developing ATMPs desperately need greater clarity in the regulatory process moving forward if we are to capitalize on the many advances being observed in animal studies of ATMPs. In addition to increasing the importance of CAT in decision-making by the EMA, it appears that some additional categories of approval should be considered—such as a conditional approval with an obligation to conduct further clinical trials before final approval. Conditional approval would also be compatible with the EU orphan drug legislation that should have facilitated the approval process of Glybera, where limited numbers of patients are available worldwide for clinical testing. Another new route is the so-called hospital exemption legislation that permits experimental therapies to be used under the responsibility of an expert physician even if a fully char­a­cterized GMP dossier and efficacy data is not available for a drug that is aimed for the treatment of a serious disease that is lacking effective therapy. These steps should help to move early experimental therapies to clinical testing and also maximize the chances that a promising new ATMP will reach final approval in the EU.