EMA Clinical Data Disclosure Plan Under Fire

The European Medicines Agency really is between a rock and a hard place. Its earnest efforts to satisfy the critics who accuse it of obsessive secrecy seem to do little more than open it up to further criticism for not having done enough. And at the same time, drug firms — and many patient groups — become increasingly wary of the implications of the agency's direction of travel.

The agency might have expected that the latest stage in this continuing saga — the publication in October of its plan for proactive release of clinical reports — would receive a warm welcome. The agency aimed to assuage the appetites for data disclosure, and also to mollify the patients and drug producers who are anxious, each for their own reasons, to maintain a minimum degree of privacy. The plan is, after all, a judicious blend of ambition and caution. It goes further — the agency claims — than any other drug regulatory authority in providing access to the information on which marketing authorisation decisions are based. Yet it simultaneously offers some safeguards for industry and some discretion for trial subjects.

“Conspiring with industry"…

But the outcome is far from a roaring success. The critics continue to allege that the agency is conspiring with industry to conceal the important data. Industry says it needs to see how the plan works. And patients want guarantees of protection of their data, and more of a say in its functioning.

The most strident reaction has come from health campaigners, who have pointed to what they see as crippling deficiencies - a long list of historic failings that have now been consolidated by the EMA's new policy, so that they will stretch into the future too. A coalition of health campaigners, health insurance agencies, doctors and academics says that "for more than a decade, the EMA has failed to comply with EU rules on freedom of information", by neglecting to set up a register of documents that it holds — making it difficult for citizens to determine which document to request. The result, they say, has been endless exchanges with the EMA before documentation is provided.

The coalition consists of well-respected and well-informed organisations — although all with a strong declared interest in protecting the patient, the citizen, and independent research: Association Internationale de la Mutualité, the Medicines in Europe Forum, Health Action International-Europe, the International Society of Drug Bulletins and the Nordic Cochrane Centre. They say the new policy will not provide adequate transparency. The criticisms centre on the scope of the EMA plan: it will cover the reports only of trials submitted in support of centralised marketing authorisation procedure, and it offers no proactive access to clinical reports for medicines already on the market. In addition, the redaction it provides for "can hinder the interpretation of data (e.g., in the interpretation of a serious harm narrative) or delay access to information of public interest (e.g., redaction of results on exploratory endpoints)", they argue. Allowing redaction is a licence for "censorship by pharmaceutical companies under the guise of protecting commercial confidentiality", they say: "The policy gives pharmaceutical companies the upper hand in deciding the contents of the clinical reports by allowing them to redact data”. And they fear that companies will adjust the content of their clinical study reports to conceal as much as possible: "They will be written and structured in such a way as to withhold vital details of a pharmaceutical drug’s effects or present them in the best possible light".

Compounding a felony

To compound the alleged felony, the EMA has abandoned other plans, announced in November 2012, to routinely require pharmaceutical companies to submit all original clinical trial data in a format that would allow the EMA to re-analyse the data, complain the critics. This means that a medicine can still be approved by the EMA on the basis of incomplete evidence, say the campaigners. Pierre Chirac, coordinator of the Medicines in Europe Forum, comments: “It seems that the EMA has found an easy solution to avoid having to release much clinical data: by just not requiring it from pharmaceutical companies in the first place…” At the very least, as some small compensation, the EMA should now proactively provide a numbered, standardised table of contents for clinical study reports (including a list of appendices and attachments containing information on study design, conduct or results), so that researchers can identify relevant additional information that they might wish to request under freedom of information rules, says the coalition.

The critics have the wind in their sails. The EU Ombudsman, Emily O'Reilly, now on the brink of a further term of office and acclaimed for her energy, has already announced her engagement. She says she will monitor how the EMA deals with access to documents requests, and will verify the justification for the redaction of information and the conditions attached to gaining access to documents. The Ombudsman's office has had the EMA in its sights for a long time. "Transparency is a vital means by which EMA can ensure the accuracy of its decisions", it said earlier this year, and transparency "serves to foster scientific discussion and progress, by enabling independent scientists to scrutinise the conclusions of EMA, and the data and arguments taken into consideration by EMA when reaching those conclusions."

Support for disclosure

Further support for the pro-transparency camp is sure to come from the left wing of the European Parliament, now jubilant at its successes in resisting the shift of pharmaceutical policy (and control of the EMA) from the health portfolio to the industry portfolio in the new European Commission. And the new health commissioner, Vytenas Andriukaitis, is likely to be respectful of the views of the strident MEPs who have led that campaign, and accordingly vigilant in defending the information rights of the public and independent researchers.

On top of that, the World Health Organization has just issued a statement supporting the disclosure of clinical trial results, to enhance transparency for the public. It has launched a public consultation on its official position — which has already been welcomed by the UK's prestigious Health Research Authority. Tom Smith, HRA's director of quality standards and information, has greeted the WHO initiative as “a key step" along the road to seeing "all clinical trials results made available globally with parity in timescales". This, he added, would boost public confidence and reduce waste in research.

The WHO statement is a follow-up to the International Clinical Trials Registry Platform that it established to improve research transparency nearly a decade ago, based on its conviction that “the registration of all interventional trials is a scientific, ethical and moral responsibility”. This scheme has, however, proved insufficient, and WHO is now beefing up its approach. "Concerns have been raised that there may be selective publication of trials dependent on their results, with particular concern that trial results which may be viewed as 'negative' are less likely to be submitted, or accepted, for publication in the scientific literature or made public in other ways", it says.

"Multiple analyses have confirmed that a substantial number of clinical trials remain unreported several years after study completion, even in the case of large randomized clinical trials", states WHO. So it is now insisting that "all clinical trial registry sites are to be updated as necessary to include final enrolment numbers achieved, and the date of actual study completion". Trial results are to be reported within 30 months of the study completion date, both through submission for publication in a peer reviewed journal and through an open access mechanism. Key outcomes are also to be made publicly available by posting on the primary clinical trial registry.

And it's not over yet. WHO also says it is "actively engaged with multiple initiatives related to data sharing, and supports sharing of health research datasets whenever appropriate". On every front, the EMA risks looking as if it is dragging its feet rather than leading the pack in the search for appropriate transparency. At a recent hearing on clinical trials data disclosure in the European Parliament, the EMA executive director, Guido Rasi, was quietly composed and confident in setting out the complex pressures and duties that EMA has to balance as it moves into a new era of access. But in a sound-bite dominated world, where it is often easier to transmit radical positions than calibrated compromises, even the equable Rasi was less compelling to most of the audience than the critics of the EMA approach.