Tom Jefferson: EMA’s release of regulatory data—trust but verify

The European Medicines Agency (EMA) has now released the final version of its policy on the prospective release of clinical reports of trials, which are submitted by sponsors to support marketing authorisation applications (MAAs). The agency has said that it will—at a future date—determine how to release individual participant data (IPD).

Scope
The policy—to become effective from 1 January 2015—explains what will be released and how. Full clinical study reports will not be released. Rather, selected parts of clinical study reports will be released, including the “core report” (although this is not labelled as such in the text), the statistical analysis plan, protocol and its amendments, and a blank case report form. (To those familiar with clinical study reports, these are sections 1-15, 16.1.1, 16.1.2, and 16.1.9 of the ICH E3 guidelines.) The policy document does not explain why full clinical study reports will not be released.

Redactions
The EMA’s policy states: “The Agency respects and will not divulge CCI [commercially confidential information]. In general, however, clinical data cannot be considered CCI.”  That said, commercially confidential information will be redacted, “where disclosure may undermine the legitimate economic interest of the applicant/market authorization holder” and in items that may facilitate identification of trial participants. Sponsors will have primary responsibility for redacting study reports for EMA’s approval prior to their being made accessible under the new policy.

Who gets access?
Two levels of access are described in the policy’s terms of use (TOU). The first level will be accessed through a simple registration process and will be a view on screen only mode. The second level (for academic and research use only) will require proof of identity in addition to the simple registration procedure. Users of this level will be able to download and save searchable clinical study reports. Both levels will be serviced by an electronic tool described as “user-friendly.” In a second phase the EMA plans to consult, and draft a policy, on access to IPD.

The policy is a landmark, as for the first time it ensures access to clinical study reports of drugs that have obtained a MAA or on which a decision has been made. The EMA may be the first regulator to allow such access and the Nordic Cochrane Centre, the European Ombudsman, and the EMA deserve credit for that.

There’s a lot of good news for researchers in the final version of the policy. Gone is the “Peeping Tom” clause of “viewing only” access to data—described by users of comparable policies as “science through a periscope”—and there is no trace of a threat of legal proceedings for those who produce research that is disagreeable to sponsors.

Peeping will be limited to first level users, possibly mostly members of the public (who may not be able to make sense of such vast and complex documents through a periscope).

Users of the data (academics and researchers) are encouraged to provide the EMA with a copy of their secondary analysis before publishing it. This is a welcome softening of the requirement from previous drafts, which appeared to give the EMA the right of veto on the release of any analyses. However, the motivation given for providing a copy (so that we can alert the EMA of any cases in which re-analysis may change conclusions and enable action to be taken) does not resonate with me. My review group has shown that the clinical study report evidence on oseltamivir in EMA’s possession did not support some of the drug’s approved indications, but no action has been taken so far.

The levels of redaction may also prove to be a hindrance to interpretation of the data by second level users. My review group has recently been the recipient of clinical study reports in which redactions impeded interpretation of a potential serious harms narrative.

The vagueness of exactly which parts of clinical study reports will be released is also worrying, as the main purpose of using regulatory data in research synthesis is to minimise the effects of reporting bias. It is possible that from now on clinical study reports 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—mirroring the unreliability of trial results published in journals (in their potential to be affected by reporting bias).

Finally, there’s a restrictive clause that requires non-European residents to have a proxy place of address in the European Union. The clause (which affects most of humanity) may prove a nice little earner for entrepreneurial organisations willing to provide an electronic abode.

In a previous post I urged users to adopt Reagan’s maxim of “trust but verify” when reading the EMA’s policies. Ultimately, we will not know how usable and transparent this policy is until it has been in use for some time.

Tom Jefferson, reviewer, Cochrane Acute Respiratory Infections Group, 00187, Roma, Italy.

Acknowledgements: Peter Doshi.

Competing interests: TJ was a co-recipient of a UK National Institute for Health Research grant (HTA – 10/80/01 Update and amalgamation of two Cochrane Reviews: neuraminidase inhibitors for preventing and treating influenza in healthy adults and children—http://www.nets.nihr.ac.uk/projects/hta/108001).
In addition: TJ receives royalties from his books published by Blackwells and Il Pensiero Scientifico Editore, Rome. TJ is occasionally interviewed by market research companies for anonymous interviews about Phase 1 or 2 pharmaceutical products. In 2011-2013, TJ acted as an expert witness in a litigation case related to oseltamivir phosphate; Tamiflu [Roche] and in a labour case on influenza vaccines in healthcare workers in Canada. In 1997-99 TJ acted as consultant for Roche, in 2001-2 for GSK, and in 2003 for Sanofi-Synthelabo for pleconaril (an anti-rhinoviral which did not get approval from the FDA). TJ was a consultant for IMS Health in 2013, and in 2014 was retained as a scientific adviser to a legal team acting on the drug Tamiflu (oseltamivir, Roche).

  • Prof. Karen Woolley

    TRUST, VERIFY, CERTIFY?

    Writing a clinical study report is different from writing a manuscript, but a writer of either document should adhere to ethical medical writing principles (ie, no ghostwriting, no ghost data!)

    Medical writing associations around the world (eg, AMWA, EMWA, ISMPP) have shown how intense education can increase knowledge of and compliance with ethical publication writing practices. A formal certification credential (requires candidate to pass a robust, psychometrically validated exam) has been introduced (see http://www.ismpp.org). Publication professionals typically know more about ethical writing practices than the authors they work with (see http://bmjopen.bmj.com/content/4/4/e004780.abstract)

    Writers of clinical study reports SHOULD adhere to ICH-E3 guidelines (http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E3/E3_Guideline.pdf), but is there a need to bring in certification of such writers, in the same way that certification has been introduced for publication writers?

    Trust, verify, certify?
    Professor Karen Woolley

    Disclosures: Nonfinancial: Trustee, ISMPP; researcher and advocate of ethical medical writing practices. Financial: Employee, Envision Pharma Group (writer – NOT ghostwriter – of many GPP2-compliant manuscripts with authors and ICH-E3-compliant clinical study reports with sponsors)