Khaled El Emam, Tom Jefferson, Peter Doshi: Maximizing the value of clinical study reports

In late 2010, the European Medicines Agency (EMA) became the first regulator in history to promulgate a freedom of information policy that covered the release of manufacturer submitted clinical trial data. Under a separate, new policy (policy 0070), the EMA will take an additional step and create a web based platform for sharing manufacturers’ clinical study reports (CSRs) upon a decision being made on a marketing authorization application or its withdrawal.

CSRs contain significant details that are often missing in journal publications of the same trials—for example, details pertaining to patient relevant outcomes and adverse events—and are an important new tool for those engaged in research synthesis. While the policy anticipates that the agency will require individual participant data (IPD) to also be shared, the EMA has not yet committed to a final timeline for this.

But as the EMA works towards finalizing its guidance on the anonymization of CSRs, some companies and industry initiated guidance may be promoting practices that would diminish the value of the data the regulator ultimately distributes.

For example, one recent industry guidance favors the redaction and removal of significant standard content in CSRs, ostensibly in an effort to have simple rules for anonymizing these documents. This includes the removal of patient narratives (for example, of serious adverse events and patient dropouts); line listings (tables of individual level information about participants); and the redaction of all patient demographics, dates of birth, and other items such as event or assessment dates.

Simple rules have the advantage of being easy to understand and do not require much sophistication to implement. Unfortunately, the major disadvantage is the resulting extensive information loss across the board. CSRs are already written without the use of directly identifying personal information, and maintaining as much of the original information in the CSRs is important to be able to perform accurate analysis—for example, to evaluate the risk of bias of trials.

Thus far, the EMA’s draft guidance has erred towards less redaction of already partially anonymized CSRs, and away from blanket removal and redaction. It instead advocates a more nuanced risk analysis in compliance with recommendations from EU data protection authorities in order to maximize scientifically useful information in the CSR. The suggested approaches for further anonymization include selective masking/redaction, randomization, and generalization techniques.

Other possible arguments to weaken the EMA’s policy by some in industry are hard to know with certainty, as minutes from the EMA’s ongoing industry consultations are not public. But the EMA may be facing the argument that substantial redaction of CSRs is not problematic because researchers can already get less redacted CSRs and individual participant data from manufacturers directly.

In anticipation of the EMA’s policy, some drug companies have begun sharing CSRs and individual participant data in adherence with the PhRMA/EFPIA principles. In May 2013, GlaxoSmithKline (GSK) made data from 200 of its clinical trials available for research purposes on a secure, web based environment. In January 2014, other trial sponsors joined the initiative, called, with 10 companies now advertising access to data from over 1200 trials. Another initiative is Project Data Sphere, which focuses on sharing IPD from the control arm of oncology trials. And other companies are making data available through their own portals.

However, that argument can be challenged. Firstly, the availability of data is contingent on voluntary efforts on a company by company basis, with many companies still yet to enact policies and systems for data sharing. Secondly, many manufacturers with advertised policies are waiting for specific requests from researchers before putting in place the necessary infrastructure to efficiently and routinely share trial data.

Today, demand for data is an important driver of investments in clinical trial data sharing infrastructure, and it is debatable whether demand is growing as rapidly as some have expected or hoped. The GSK initiated portal reports 104 valid requests (as of end of June 2015); Project Data Sphere reports 900 authorized users; and the EMA, under its 2010 freedom of information based policy, has released over 2 million pages of regulatory documents. While this access has resulted in some publications and high profile research, such as the Cochrane review of neuraminidase inhibitors, one hopes for more.

It may be that insufficient time has passed for researchers to develop ideas, submit grants, get funding, and develop the necessary expertise for secondary analysis of the available clinical trial data. Direct support from funders for secondary analysis of trial data could potentially accelerate reuse of trial data. But today, uncertainty remains around how demand for trial data will grow and the level of investment manufacturers will continue to make. Furthermore, some industry leaders have already argued that if data sharing becomes too onerous, they may not allocate additional investments in this area, which would mean less data becoming available.

The EMA is taking steps to introduce well balanced guidance for anonymizing CSRs. This balance maximizes information sharing and ensures compliance with privacy regulations, and, at the same time, builds on best practices that have been established in the disclosure control community for decades. The agency needs broad public support to resist any future push to weaken the utility of the data it ultimately will distribute. That way science will benefit, and patients will benefit.

Khaled El Emam is the Canada research chair in electronic health information at the University of Ottawa, an associate professor in the department of pediatrics, and is cross-appointed to the school of electrical engineering and computer science.

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

Peter Doshi, associate editor, The BMJ

Competing interests: TJ and PD were co-recipients 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. TJ is acting as an expert witness in a legal case involving the drug oseltamivir (Roche). TJ is a member of an Independent Data Monitoring Committee for a Sanofi Pasteur clinical trial.

PD received €1500 from the European Respiratory Society in support of his travel to the society’s September 2012 annual congress in Vienna, where he gave an invited talk on oseltamivir. PD gratefully acknowledges the American Association of Colleges of Pharmacy for its funding support ($10 000) for a study to analyze written medical information regarding the possible harms of statins. AACP had no involvement in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of this manuscript.

Competing Interest: KEE has financial interests (including equity) in Privacy Analytics Inc., a University of Ottawa and Children’s Hospital of Eastern Ontario spin-off company, which develops anonymization software for the health sector. He also receives royalties on his published books from Francis & Taylor, O’Reilly Media, Wiley, and Trafford.