Applied Clinical Trials
The two-year inquiry into possible maladministration at the EMA has intensified.
Persistent concerns that European drug evaluators are too cozy with pharmaceutical companies are unlikely to be fully allayed by a recent decision from the European Ombudsman that “no further inquiries are justified” into the provision of early scientific advice. The two-year inquiry into possible maladministration at the European Medicines Agency (EMA) has intensified as much as it has resolved long-running controversies over potential conflicts of interest and lack of transparency within the agency.
It was two years ago that the Ombudsman-an official European Union body-decided to follow up on anxieties among many healthcare campaigners and academics about the risk of what they saw as a hazardous overlap: the EMA’s roles both in giving early scientific advice to drug developers, and its subsequent engagement in evaluating marketing authorization applications from the very same products it had advised on. “These ‘pre-submission activities’ may have some positive consequences for public health,” said the formal inquiry, but it insisted that it was also “important to avoid even the perception that the eventual opinions of EMA on medicines were influenced by these earlier interactions.”
This summer, after extensive consultations and discussions, the outcome was nothing more than “a number of suggestions for improvement”-and the decision to, in effect, drop the case. The Ombudsman merely urged that “EMA should carefully manage the contacts its evaluators have with medicine developers during the pre-submission phase,” and that “EMA should provide greater transparency on its pre-submission activities, with the aim of maintaining public trust in its work.” But some of those who have levelled strident and repeated attacks on the agency’s operations in the last five years will not be so easily appeased.
EU law specifically allows for medicine developers to seek advice from EMA’s experts long before they submit a marketing authorization application. It is considered legitimate for companies to seek advice on the relevant procedures, the requirements for demonstrating that medicines are safe and effective, or the design or conduct of clinical trials.
But questions have been posed for years about whether EMA’s recommendations on authorization of a medicine is influenced by the prior interaction its evaluators have with medicine developers. The Ombudsman chose to assess how far this may have happened, or even be perceived to happen. And it concluded that not much needs to change.
Among the numerous representations made to the Ombudsman during the inquiry, national medicine evaluation authorities and the pharmaceutical industry felt the system was broadly sound and protected the public adequately from risk of overlap. But “by way of contrast, many civil society organizations and academics argued that the current practice concerning pre-submission activities needs be improved to enhance the objectivity of how medicines are evaluated,” remarked the Ombudsman’s decision.
The criticisms focused partly on the risk of bias where the same individuals are involved in providing scientific advice and in subsequently evaluating that same medicine. EMA should widen its pool of experts, and where it was absolutely necessary to have such overlap, EMA should publicly justify it. And there was also frequent criticism of the lack of transparency over the procedures and calls for the scientific advice provided to be open to public scrutiny.
Health Action International (HAI) cited allegations purporting to come from EMA staff that “manufacturers see pre-submission processes as a way to lobby the agency.” The European Public Health Alliance warns of “regulatory capture.” The International Society of Drug Bulletins says: “EMA’s confidential pre-submission “scientific advice” to companies jeopardizes its ability to make independent decisions. Pre-submission activities effectively make EMA a co-developer of the medicine, yet it is subsequently called upon to issue its opinion on whether or not the medicine should be granted marketing authorization.”
Critics make complaints about the negative impact of the confidentiality surrounding the process. EPHA warns of the dangers of giving scientific advice “behind closed doors” and of how EMA “black boxes” and “revolving doors” impede transparency. ISDB says “companies that request pre-submission scientific advice could exert control from an early stage over everybody involved in the assessment of marketing authorization applications at both national and European level.” According to HAI, “It is impossible to know from the onset the advice a company has requested, and the EMA has subsequently provided, even though this would be relevant information to patients who are considering enrolling in a clinical trial, and to independent clinical trial reviewers.” By providing “tailored and confidential advice to one company only,” EMA may even be in breach of competition law, it suggests.
HAI has made clear its concerns that “at the time of assessing an application for marketing authorization, (the relevant committee) members might feel bound by the advice that the very same committee they represent gave in the past to a company/marketing authorization applicant.” It says EMA should draw a firm line to prevent overlaps: “A clear separation of roles between advisors and marketing authorization assessors should be established.”
And the European Consumer Organization (BEUC) says it wants to know how EMA’s pre-submission activities contribute to the development of safe and effective medicines. “A growing number of medicines seem to come to the market for which less robust data is available. How do pre-submission activities contribute to the availability of robust and useful data, while also minimizing the number of unnecessary clinical trials?,” the bureau asks.
The Ombudsman came down firmly in the middle of this divergence of views. Yes, there is an element of risk in overlap, in acknowledgement of the critics-but, overall, the system offers protection against undue influence, it concluded, in line with most comments from regulators and industry. So there is not a lot that needs to be done. The toughest recommendation the Ombudsman makes is that “to the greatest extent possible, EMA should ensure that there is a separation between those responsible for providing scientific advice to a medicine developer and those subsequently involved in evaluating” it.
The operational result is that EMA’s own arguments-essentially that scientific advice is a force for good and should not be tampered with lightly-largely prevailed in the Ombudsman’s decision.
EMA argued that the provision of scientific advice can minimize the risks of exposing patients to useless or less useful clinical trials, and maximize the value of the data that clinical trials generate; and by avoiding misunderstandings in the assessment process, it can ease administrative burdens and cut can minimize the risks of exposing patients to useless or less useful clinical trials, and maximize the value of the data that clinical trials generate; and by avoiding misunderstandings in the assessment process, it can ease administrative burdens and cut the risk of preventable delays at a later stage.
The agency maintained stoutly throughout that a scrupulous distinction is maintained between the two levels of interaction, so as to give a guarantee of fair dealing and impartiality, Scientific advice is not a pre-evaluation of the data gathered during clinical trials. It is prepared by nominated experts who report to a specific working party, and not by the committee that conducts evaluations of marketing authorization applications. In the rare cases where the same expert contributes to both scientific advice and product evaluation, it is because of scarcity of experts in certain areas of science and medicine, and public health could be impaired by a prohibition of this practice. If EMA identifies possible conflicting interests among any of the experts, it can exclude them from participating in discussions on particular topics. And it is not binding, since it is based by definition on the current state of the art and may consequently be superseded as understanding advances.
The Ombudsman’s decision leaves the situation unchanged. EMA will continue to maintain that on balance, the system is good and fair. Critics will continue to say the balance is wrong, and that partiality remains built into the system. And the Ombudsman’s views, taking some from column A and some from column B, and offering no more than a heavily-qualified suggestion of maximum caution, fully satisfies neither side. The flurry of soft diplomatic words of welcome from EMA for some elements of the decision cannot disguise the reality that it will continue to proceed as before, despite its commitments to a few equally soft additional gestures toward transparency.
The more trenchant criticisms of the system will, therefore, remain unsatisfied-and, hence, they will continue to feature just as much as before in the public discourse about EMA’s independence from industry influence.
The fact that the sharpest criticisms are made by only a relatively small number of contributors to the inquiry does not reduce their significance. Both HAI and EPHA are influential organizations-both of them are represented on EMA’s own bodies-and they command a prominent position in European public debates about health and medicines. They and the other organizations that share their views will ensure that the debate will continue to grow over the role of EMA and the influence of the drug industry on regulatory decision-making. And this at a particularly crucial moment for European rulemaking in general, with a new European Parliament and European Commission just about to take up the management of policy for the next five years.
Peter O'Donnell is a freelance journalist who specializes in European health affairs and is based in Brussels, Belgium