Tom Jefferson: EMA confidential—the EMA continues consultation on its 0070 policy and concerns appear

Following on from its recent webinar I blogged about, the European Medicines Agency (EMA) held a consultation meeting with industry and selected stakeholders to discuss specific aspects of its policy 0070 on prospective access to regulatory data.

Readers should refer to my previous posts for the salient points of policy 0070.

The latest meeting (like the preceding webinar) was concerned only with phase 1 of the implementation: the publication of clinical reports submitted to the EMA since 1 January 2015 as part of the centralised procedure to gain market authorisation (MA). “Clinical reports” includes clinical study reports (CSRs) and modules 2.5 and 2.7 of the MA application. Individual Participant Data (IPD) are excluded from this phase.

Two specific aspects of the implementation of policy 0070 were discussed, both relating to draft guidance for industry: the redaction of commercially confidential information (CCI) and the anonymisation and redaction of clinical reports. The drafts were circulated prior to the meeting but are not for public reading—their completed counterparts will be.

CCI is defined by the EMA as any information which is not in the public domain or publicly available, and where disclosure may undermine the economic interest or competitive position of the owner of the information.

The EMA maintains that applicants will have to submit two versions of clinical reports: one with and one without redactions. Applicants will have to certify that the reports are identical except for the redactions. A “redaction proposal document package” will be submitted with the clinical reports containing proposals for redaction and their justification in a special table (for which participants saw a template). Proposals for redaction of CCI may be accepted or not by the EMA after a structured “redaction consultation process,” but those accessing the clinical reports will not see the table or its content, only the redactions.

The second topic regarded guidance on how to anonymise clinical reports for publication (on the EMA website). The discussion on this topic was more detailed. This is strange given that many of the pharmaceutical industries represented at the meeting are already web publishing CSRs of their trials. In addition, the CSRs that the EMA will release under phase 1 contain only aggregate data.

The EMA clearly lays the responsibility of anonymisation (the process of formatting data in a form to prevent identification of individuals) of clinical reports on pharma. In its draft guidance, the EMA lists several methods (ranging from aggregation of data to noise generation) to remove any obvious links between individuals and data. The process of anonymisation is being left up to individual applicants, but whatever methods they choose will be described in an anonymisation report, which will be made public with the clinical report.

If my readers so far think that anonymisation and redactions are topics of little practical interest, I can assure them from experience that this is not so. The lengths of redactions have little to do sometimes with their impact on the readability and reproducibility of the trial. Batch numbers of placebo and active principle capsules can allow you to cross-reference them to their aspect and content reported in a certificate of analysis, regardless of the number of trials they have been used in. Redacting serious adverse events (SAE) narratives (as someone suggested during the conference) to protect anonymity usually means wrecking any chance of understanding a SAE and its possible association with exposure.

Many good points came out of the conference. The EMA knows that it has to strike a balance between readability and protection of CCI, but refuses to anonymise the names of the principal investigators. It points out that the names are available on trial registers anyway.

I believe that those who have had a major input into experiments with humans should always be held publicly accountable for their conduct—this is the main legacy of the Nuremberg trials. Every physician should safeguard this absolute requirement against the notion of corporate responsibility, which seeks to dilute accountability. We will input into the development of the anonymisation report and will have sight of the whole package with the clinical reports.

I cannot, however, complete this brief account of the meeting without airing some worries.

The content of the redaction justification table will remain confidential until accessed through a freedom of information request, a process which may take years.

The issue of multiple versions of the same CSR reared its ugly head again during the discussion around the risk of identifying participants. It seems that some pharmaceutical companies may already be thinking of producing more than two versions of the same CSR: one for the scientific review by the EMA, one for the EMA’s web publication, and one for “data sharing agreements,” which I think is code for pharma web access. The other deciding factor on the differences appears to be the degree of control of the data that pharma can allow. Multiple versions of the same CSR are not a good thing, and extreme vigilance is now required on the wording of the self-certification, which requires applicants to vouch for the similarity of the clinical reports they’ve submitted.

The whole rationale of using regulatory data for research synthesis is the minimisation of reporting bias. The introduction of multiple versions of the same CSR would introduce another form of bias. Extensive redactions, undescribed manipulation of data in an effort to further anonymise, and intermediate forms of CSRs— such as developments for different indications with interim analyses— would also make reproducibility and basic understanding of the trial more difficult. For now, the EMA has been pretty open on consultations and seems to be willing to listen to more than one voice.

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

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—

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 a 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 Food and Drug Administration). 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). In 2014-15 TJ was a member of two advisory boards for Boerhinger and is in receipt of a Cochrane Methods Innovations Fund grant to develop guidance on the use of regulatory data in Cochrane reviews. TJ has a potential financial conflict of interest in the investigation of the drug oseltamivir.