Sunshine at the European regulatorBMJ 2012; 344 doi: https://doi.org/10.1136/bmj.e976 (Published 15 February 2012) Cite this as: BMJ 2012;344:e976
Professor Guido Rasi is tall, tanned, and likes to go swimming and sailing. While the view of the Thames from his Canary Wharf office may remind him of these hobbies, he will be hard pressed to find time for them as he makes the European Medicines Agency more open and transparent.
The agency, which was set up in 1995 and is 80% funded by industry fees, has been criticised in the past for not providing enough access to clinical data for drug researchers and for being secretive over its decision making processes for medicines.1
It has been (and still is) subject to inquiries by the European ombudsman over access to documents and is being investigated by the EU anti-fraud office in relation to the withdrawn anorectic drug benfluorex, the continued licensing of which resulted in a revamp of the regulatory landscape in France.2 3
“The more we are transparent, the more we will be able to communicate to the people, to build trust,” the 58 year old Italian says. Before taking up his post at the EMA three months ago, he was head of Italy’s drug regulatory agency (AIFA), where he replaced the previous sacked director general in 2008.4
He thinks the EMA has done well on its drug safety record, but “of course, there is a lot of room for improvement.” He points to the “tremendous opportunity” provided by the new pharmacovigilance legislation that comes into force in July to strengthen EU drug safety monitoring.
The legislation creates a new agency committee—the Pharmacovigilance Risk Assessment Committee (PRAC)—to look at drug safety concerns for nationally and EU approved medicines. Importantly, the committee will hold hearings on urgent safety concerns in public. This is a first for the agency, and the openness may be contagious.
Professor Rasi tells me that he expects that “After we get experience from the PRAC public hearing, I will certainly encourage public hearings for the Committee for Medicinal Products for Human Use (CHMP) , ” the committee responsible for approving new drugs. Any such decision is likely to cause waves in the pharmaceutical industry because the hearings could cover both safety and efficacy.
One of the key questions the agency is debating is how far to involve the public. It also has to consider how to conduct these hearings when the EU has such a plethora of languages.
Professor Rasi does not disapprove outright of the style in which the US Food and Drug Administration holds its public hearings, but he does not praise them either. One of his top advisers, Hans-Georg Eichler, the EMA’s senior medical officer, says patient groups have told the agency “loud and clear, whatever you do, not that [FDA] way.”
According to the agency, some patient groups think FDA hearings are “increasingly a media driven and a financial analyst driven event rather than something that adds to the scientific knowledge of the debate.” Furthermore the FDA hearings are held by advisory groups external to the FDA, with the FDA still going behind closed doors to make its final decisions.
“So there is this misperception. Somehow the FDA is gloriously open and we are gloriously fundamentally closed. The truth is somewhere inbetween,” adds Martin Harvey Allchurch, the EMA’s head of communications.
The agency says that “the committees will decide when and whether to hold a public hearing, in which they will be involved. They will make recommendations after the hearing.” Professor Rasi adds: “It is more complicated than the FDA hearings. We are not a federal agency, we rely on the experts given to us from 27 countries, so language barriers could be a problem with the public hearings—that’s why we have to find our way to handle this … we could broadcast them.”
He is adamant the hearings will “help improve the quality of the decision.” PRAC plans to have its first meeting on 19 July, with two public hearings expected later this year, the first one likely to be in English. He is uncertain when CHMP’s hearings will begin.
Access to documents and commercial confidentiality
Later this year, the EMA plans to start publishing the agenda and minutes of its scientific committee meetings (it already publishes recommendations and opinions). These should be “useful” to researchers, says Professor Rasi, although he adds that there still needs to be protection of private patient information, commercially sensitive documents, and the decision making process itself.
The EMA wants its experts to base judgments on science not external pressure so it will not release documents while a committee is still debating. “I don’t think it is good that whoever bears an interest in a decision can place some kind of pressure during the [committee] debate. But as soon as the decision is taken, I think it is good to make these documents public. And to let the public know how we came to a decision,” he says.
The agency released one million pages in 2011 after requests for access to documents, a steep rise from the 8000 pages for 2010. It has already released 100 000 pages this year. About half of the requests come from industry (some 52%).
In the past the agency has resisted releasing certain clinical and safety data but complied after complaints were upheld by the European Ombudsman. Well known cases include requests for clinical data on obesity drugs by Danish researchers at the Nordic Cochrane Centre (the agency complied in December 2010) and suspected adverse drug reactions to acne drug isotretinoin (August 2010) and the antibiotic co-trimoxazole Septrin (January 2012). “We are great friends now with Cochrane, “says Professor Eichler.
Professor Rasi accepts that the cases have “certainly stimulated discussion and helped speed up the process” to access documents, but notes that there is a “cultural driver” pushing this.
As there is no legal definition on what constitutes commercial confidential data, who will make the decision? “It is us,” he declares. The agency insists that all clinical data, including adverse drug reaction reports, are not commercially confidential; there is only data protection from a patient’s point of view. In the first half of this year, the agency will be launching a new website providing access to adverse drug reaction reports.
Conflicts of interest
About a quarter (17 out of 64) of the pool of experts that make up the CHMP have declared direct or indirect interests with the drug industry. The database of declarations was published on the agency’s website in September 2011, following a new conflicts of interest policy in October 2010.5 Not all experts were supportive of the database, though. Professor Eichler says: “We had experts who said, once you do this, I will strike my name off your list. We lost a number of experts.”
Although the database lists the experts’ declarations of interests, it does not rank the risk that the agency attributes to each expert. Professor Rasi says that this information will be published soon. Experts with direct interests (previously worked for a drug company, done consultancy work, financial interests, etc) will be ranked at the highest risk level (level 3); those with indirect interests ( such as an investigator in a trial) will be classed level 2, and those with no declared interests level 1.
Professor Rasi thinks the conflicts of interest policy is working in terms of protecting public health, but he would also like to see the industry declare its experts. So is 17 out of 64 experts with interests as good as it gets? It seems so. “For some diseases like cardiovascular diseases, we can find experts without interests, but for rare diseases and for new advanced technological drugs, the number of experts is so limited it will be difficult. There is competition in looking for the best expert,” he says.
Drug assessments: value judgments and innovation
The agency recognises that it needs to do a better job in communicating why drug decisions are made so it has started a new project called benefit-risk methodology to inform the public about the benefits and risks of a drug and the value judgments it made to reach those conclusions. This information will be published in a drug’s European public assessment report (EPAR).
Pharmaceutical innovation is waning, drug developments costs are increasing, and there are calls for the use of comparative trials so that drugs show superiority to existing treatments. Professor Rasi thinks comparative trials can be beneficial but that they can’t always be used because some drugs have multiple comparators. “Which one should you use? All of them? If you choose all of them, you will have a never ending process. So case by case, I think is a good idea. An increase in comparative trials is an idea to support and encourage.”
Enforcing these trials on the industry could increase the size of trials by a “factor of ten,” which the agency believes would really stifle beneficial innovation. But it has delineated a few scenarios where comparative trials are required.
Professor Rasi sees innovation as simply “something that benefits the patient. While increasing the need to raise the standard of evidence for drugs is contributing to a more lengthy and costly drug development process, the agency cannot compromise on the level of safety,” he says.
The EMA is helping drug development by making faster assessments and using more post-marketing studies. The idea of staggered approvals (or adaptive licensing), whereby the drug comes to market faster while safety data are collected, is something he supports. But he won’t forecast how many drugs may go down this route.
“What I will strongly encourage is the post-marketing monitoring of medicines because there is a limit to whatever trial we decided to have for the marketing authorisation. Much knowledge will come from the real life use of a medicine.” He hopes to see the routine collection of data from the real use of a drug coming to the agency in a “sort of continuous reassessment of the risk-benefit ratio.”
The EMA’s public hearings and transparency moves are a step in the right direction for drug safety, but the agency is still not well known to the public, which was one of Professor Rasi’s first concerns. “I would like to certainly improve the level of communication of the agency. To be a point of reference for those who are seeking information on medicines… It is very easy to lose trust through misinformation or lack of information.”
The fact that the agency is some 80% funded through industry fees has no influence on its decisions he strongly believes: “There is a very robust administrative machine that keeps these two poles apart. There is no pressure from receiving industry fees, so we are neutral, independent. It is not an issue, I think.”
Cite this as: BMJ 2012;344:e976
Competing interests: The author has completed the ICJME unified disclosure form at www.icmje.org/coi_disclosure.pdf (available on request from her) and declares no support from any organisation for the submitted work; no financial relationships with any organisation that might have an interest in the submitted work in the previous three years; and no other relationships or activities that could appear to have influenced the submitted work.
Provenance and peer review: Commissioned; not externally peer reviewed.