Introducing some element of independent research into the approval requirements for new drugs or indications assessed by the European Medicines Agency (EMEA) would be one way of eliminating the bias that inevitably creeps into an industry-driven system, argue the director and the head of the regulatory policies laboratory at Italy’s Mario Negri Institute for Pharmacological Research.

Writing in the 20 October edition of the BMJ (Vol 335, pp 803-5), Silvio Garattini and Vittorio Bertele’ not only claim that the licensing system administered by the EMEA is weighted in favour of pharmaceutical companies but criticise the agency for perceived lack of transparency and an inadequate system of pharmacovigilance. Their calls for tougher approval procedures are tempered, though, by the suggestion that industry could be compensated with longer patent terms for innovative new drugs.

Noting the EMEA’s widening influence both in terms of mandatory centralised approvals and the agency’s binding authority in situations where national regulators disagree, Garattini and Bertele’ attack the current EU regulatory system for being over-reliant on placebo-controlled clinical trials that avoid defining efficacy in relation to existing treatments, surrogate endpoints “that are not validated predictors of therapeutic endpoints” and industry-sponsored research in which applicants “will clearly tend to maximise the benefits and minimise the risk” of their product.

Even when new drugs are compared with existing treatments, they say, the trials often aim to show only equivalence or non-inferiority, which “could allow drugs into the market that are less active and safe than those in current clinical use”. And while some companies do proceed from surrogate to hard endpoints with efficacy comparisons in long-term post-marketing studies, doctors and patients “need to know relative efficacy at the time of approval if they are to make objective decisions about drugs”, the authors complain.

Added value

New drugs should be required to show some added value in relation to existing treatments (e.g., better efficacy, less toxicity) or to be cheaper than them, Garattini and Bertele’ contend. One way of remedying the EMEA’s shortcomings and offsetting biases in industry-sponsored trials, they suggest, would be to give non-profit organisations (such as the Mario Negri Institute) responsibility for injecting some independent research into the process.

“For example, the regulatory agency could require one Phase III trial (usually two pivotal trials are needed) to be planned and carried out by an independent organisation credited by the agency, particularly for drugs that are going to be reimbursed by national health services,” the authors propose. At the moment, they note, independent research occurs only after approval.

In Italy, for example, drug companies have to contribute 5% of their annual promotional expenses to a fund held by the licensing authority for this purpose. Funds are allocated according to a priority score established by discussion groups including international reviewers, with projects ranging from trials to optimise the use of orphan drugs to comparisons of products licensed for the same indications and observational pharmacovigilance studies.

“This initiative could be extended to the premarketing phase and co-ordinated at European level,” Garattini and Bertele’ suggest. They go on to question the independence of the EU regulatory system and the EMEA itself. “For instance, it is anomalous that EMEA is part of the EU general directorate of enterprise and industry rather than the general directorate of health and consumers,” they comment. “It is also strange that the general directorate of enterprise regulates compliance [with] good clinical practice by non-profit organisations. It is equally surprising that about 70% of the agency’s budget comes from fees paid by the applicants.”

Poor transparency

Another target is the EMEA’s record on transparency. “Unlike the FDA, the EMEA keeps almost all its information secret,” Garattini and Bertele’ say. While disclosure of documents on production and drug technology could aid competitors, “there is no reason to hide data on toxicology and clinical evaluation”, they argue. The EMEA does release a European Public Assessment Report but this is “a generic document written under the supervision of the company concerned”.

Among other information that should be made generally available, the authors claim, is the size of the [presumably advisory committee] majority that approved a given drug, the reasons of the minority for opposing approval, any conflicts of interest, post-marketing commitments by the sponsor and whether these are fulfilled. “When drugs are approved under exceptional circumstances on evidence from surrogate endpoints, the manufacturers usually have to commit to do further research,” the authors comment. “However, in many cases they ask for extra time or do not meet the commitment at all.”

Garattini and Bertele’ also make a number of suggestions for improving pharmacovigilance in the European system, such as actively looking for toxicity rather depending on spontaneous reports of adverse events, and establishing a new pharmacovigilance committee independent of the Committee for Medicinal Products for Human Use (CHMP).

Some of the proposals for tightening up the EMEA’s regulation of medicines “will make the approval of new drugs and new indications more difficult and prolong the time needed for their introduction into the market”, the authors acknowledge. This calls for more flexibility in encouraging industry research. One possibility, they write, would be to extend pharmaceutical products patents “in exchange for better, safer, more trustworthy, and more affordable innovation. We believe the changes will not only be important for patients but will help stimulate innovative research by drug companies.”