Quintiles’ European Regulatory Clinical Trials Unit has seen an average 57% jump in Phase II/III clinical trial applications over the past two years, following the 2004 advent of the European Union Clinical Trials Directive, the company’s Jacqueline O’Brien told an audience at the recent Institute of Clinical Research conference in Manchester, UK.
“There have been clear benefits of the Directive in terms of faster timelines, increased patient safety, centralised and streamlined processes and improved regulatory control of complex European and global clinical trials,” she added.
The comments came in a talk spotlighting issues for non-EU pharmaceutical companies in conducting EU clinical trials.
“There are similar challenges for non-EU pharmaceutical firms as for those within the EU,” she noted, “the most important differences being the need for Qualified Person declaration for investigational medicinal products manufactured in third countries and additional requirements for legal representation.”
It is not acceptable to divorce responsibilities for liability for trial conduct, she added. In the absence of a sponsor in the EU, the legal representative should be responsible for the civil and criminal liability of the sponsor. Legal representation must be sought, for example in the shape of the legal department in a contract research organisation or a designated law firm. And, in terms of QP declaration, manufacturing sites must work in compliance with Good Manufacturing Practice to a level at least equivalent to EU GMP.
But these are not the only issues to be aware of. Comparators and non-investigational medicinal products – such as rescue medication – should be sourced in Europe if possible and have a marketing authorisation in at least one European country to avoid approval problems. Placebo-controlled studies are not always a popular route, meaning that researchers may end up with country-specific trial protocols that may otherwise have been avoided.
For US companies wishing to conduct trials in Europe, there are some differences around regulatory requirements in later phases, for example, expanded access programmes are generally not allowed in most EU countries.
The provision of medicines on a named-patient basis or for compassionate use is permitted, but cannot be sponsor driven. “One option is to conduct an open label study,” O’Brien pointed out, which would require full regulatory approval prior to initiation.
She also noted the need for upfront planning in terms of product labelling. “Companies now need a mock-up label for the EU clinical trial application, translated into the respective languages of the EU. This can be a challenge on timelines inducing sponsors to label IMPs upfront, ie before Competent Authority approval.”
And, although timeframes for CA and EC approvals have speeded up, with a decision in 60 days under the Directive, there are still improvements that can be made. (Some CAs work to shorter approval timelines such as Germany and the UK.)
“There has to be a central ethics committee approval within each member state. Currently the number of ECs able to act as CECs varies from country and to country and some still have local ethics committees in place.” However, she noted, companies must also ensure they are good communicators in the case of requests for supplementary information, as there is only a 15-day window to respond in many cases.
The key, says O’Brien, is to think ahead. An upfront regulatory strategy is now even more vital, she concluded