In October 2014, the European Medicines Agency (EMA) promulgated its policy 0070 on the release of regulatory data acquired and held in the course of its regulatory function. At the time, some of us advised caution in accepting the policy at face value, although we recognised the great contribution that the policy and the EMA’s attitude were making to a culture of openness in human experiments.
One of the undoubted difficulties that such a policy would entail was the sheer complexity of publishing huge amounts of very complicated documents on regulatory websites. There are no precedents for this.
A recent webinar held by those responsible for the implementation of the policy allowed a detailed glimpse of what is in store. I attended as a researcher, or more precisely as a systematic reviewer, and what follows is my take on the policy roll-out.
First and foremost, the EMA is at pains to point out that it is working on phase 1 of what it calls the implementation project. This means that access to individual level data, such as individual participant data (IPD), periodic safety update reports (PSURs), and case report forms (CRFs) will not be covered by this phase.
Phase 1 covers the release of clinical overviews (Module 2.5 in regulatory speak), clinical summaries (Module 2.7), and the all important clinical study reports (CSRs). CSRs will include the main body (a sort of IMRAD style document), the trial protocol with its dated amendments, blank (or sample) case report forms (CRFs), and the statistical analysis plan or SAP (appendices). See this exploratory review for a description of each cited document.
The value of these documents available at the click of a button to a researcher is difficult to overplay. For example, Module 2.5 contains a complete description of the manufacturer’s trial programme. For those of us who laboured for six months to reconstruct trial programmes, cross-referencing fragments of information from disparate sources, this is the honey pot served on a plate. CSRs are the most detailed accounts of the setting up, conduct, and analyses of trials on pharmaceuticals by their sponsors.
Currently, the only CSRs and regulatory documents available from the EMA are those under the so called retrospective policy covering all qualifying parts submitted as part of a market authorisation application (MAA) up to 31 December 2014. Access through the retrospective policy is a long and convoluted process. However, the roll-out of policy 0070 will include all qualifying documents submitted to support a MAA from 1 January 2015, or in some cases—such as licence extensions—six months later. Going live is likely to take place around mid-2016. Since the EMA estimates that it manages around 14 000 documents a year, when the lights are switched on, some 20 000 documents should be available.
Documents will be published within 60 calendar days of a decision being made to grant or refuse a licence, or 180 days from withdrawal of a MAA.
The management of the documents will be a complex undertaking. Although the published modules I have described will be the same as those submitted at the same time for scientific review to the EMA, the published text will bear redactions in places. The redactions will be proposed for each CSR and justified by the sponsor in a justification table (which will not be published). Redactions will be assessed by the EMA who will allow them, reject them, or ask for further information.
This is a particularly delicate process as it involves a balance between protecting what the EMA regards as legitimate commercially confidential information (or CCI) and making the CSRs sufficiently legible to allow trial assessment and replication of findings. The EMA will not consider the names of clinical research organisations (CROs) or vendors as CCI, as well as information which is already publicly available or known to the scientific community, which has no innovative value, or for which redaction reasons are expressed in vague terms by failing to explain how its disclosure would harm the applicant’s interests.
Companies will be able to appeal in court within 20 days against a redaction decision they disagree with, but appealing will not hold the process up—the EMA will just publish the relevant document without the disputed parts.
Further protection for industry will come from the watermarking of each CSR page with a legend warning that the material may not be used to support applications from competitors and that web access will be governed by terms of use (TOU).
The implementation of policy 0070 is a major undertaking for the EMA. There are no crib sheets and management and IT systems have been built from scratch. The pharmaceutical industry also faces a hefty bill, with extra work involved in document redaction and unprecedented levels of public scrutiny, although the EMA says that industry has remained broadly supportive. However, the EMA plans to assess compliance with its policy, even via publication of annual reports.
My only remaining gripe is access to the industry guidance documents that the EMA is planning on producing. When I asked the EMA, I got an evasive answer.
Read the second blog on this webinar: Are we ready for the EMA revolution?
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—http://www.nets.nihr.ac.uk/projects/hta/108001).
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.