Arrant Transparent

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  • 07/29/2013

Speaking of clinical trial data transparency – here’s an excellent analysis from the August edition of the Burrill Report ...

Fight for Transparency Heats Up: Industry turns to courts to stop policy in EU, offers own approach

Daniel S. Levine

Tom Jefferson had nagging concerns about his review for the Cochrane Collaboration of clinical studies of the flu drug Tamiflu, but they crystallized in 2009 when a Japanese pediatri­cian raised a question about the work via email. The doctor want­ed to know why the review in­cluded eight unpublished trials that Jefferson and his colleagues hadn’t seen, and had only been included as summaries in an­other study funded by the drug’s producer Roche?

The solution seemed simple enough. Jefferson, an epidemi­ologist based in Rome who was conducting the updated analy­sis for the Cochrane Collabora­tion, an independent group that provides guidance to health­care professionals on the use of drugs, would reach out to the authors of the studies and get them. But the authors either told him they didn’t have the data, said they had never seen the data, or ignored him completely. When he asked Roche for the studies, it said it would provide them, but insisted at first that he sign a confidentiality agree­ment, a condition that he found unacceptable.

The controversy came against a backdrop of worldwide fear of a global pandemic of bird flu that sent the World Health Or­ganization, the Centers for Dis­ease Control and Prevention, and governments around the world spending billions of dollars to stock­pile Tamiflu. Despite the spending, Jefferson says there were questions about whether the drug did anything to prevent transmission of flu, mini­mize complications, or whether the health benefits the drug provided jus­tified the risks of using it. Roche, in a statement posted on its web site and updated at the end of February 2013, said that it had disagreed with the analysis plan Cochrane Collaboration shared with it because it was at odds with how Tamiflu has been reviewed and approved by regulatory authori­ties in more than 80 countries. The company said it stood by the “robust­ness and integrity” of its data support­ing the safety and efficacy of the drug.

“The fight for the last four years hasn’t been so much for clinical study reports,” Jefferson says, “but to have clinical study reports without having to sign confidentiality agreements, funny handshakes, rolling up our trouser leg, and so on.”

The four-year battle to obtain clini­cal trials data—he believes that there have been 123 studies (74 of which Roche sponsored)—has made Jeffer­son a flag bearer in an international fight over clinical trials data transpar­ency. The controversy, which is by no means limited to Tamiflu and Roche, is now reaching a critical point. A le­gal battle is underway in Europe over a European Medicines Agency trans­parency policy expected to take effect at the start of 2014 that would make public clinical trial data once a drug is approved. At the same time, in the United States, the Institute of Medi­cine is at work on a consensus study on the issue and the U.S. Food and Drug Administration is seeking com­ment on a clinical data transparency policy of its own.

Much is at stake as the policymak­ers embrace comparative effectiveness and the advent of Big Data provides a new means to ferret out untapped information hidden within clinical study reports—the detailed narrative reports at the individual patient level that can run to tens of thousands of pages in a single trial.

Proponents of clinical data transpar­ency argue that it will provide doctors with greater insight into the safety and efficacy of the drugs they prescribe, improve care, cut waste, and minimize scientific misconduct and fraud. Peter Doshi, a post doctoral comparative ef­fectiveness researcher at Johns Hop­kins University, who is also working on the Tamiflu review for the Cochrane Collaboration, points to a list of block­buster drugs that were marketed only to have significant health risks come to light through academicians analyzing clinical trials data. “The whole system has depended on trust in medicine, trust in people to report properly, trust in people to have enough information to credibly analyze trials,” he says. “We know enough not to be so trusting anymore.”

Industry, while not of one mind, says that in principle it doesn’t oppose transparency, but expresses concerns about how it is done. These concerns include the threat to confidential com­mercial information, the challenge to the authority of regulators, the risk to patient privacy, and the opening of the data to inappropriate uses that could lead to the publication of misleading results and public health scares.

Lawsuits in Europe

In May, the General Court of the European Union prohibited the Euro­pean Medicines Agency from releas­ing data from two AbbVie and Inter­mune trials in an interim ruling, part of a challenge by the two drugmakers to the agency’s decision to grant access to information the companies provid­ed as part of their market approval ap­plications. The challenge is the first to be made to the EMA’s three-year old access-to-documents policy.

Since November 2010, the Agency has released more than 1.9 million pages in response to such requests. The legal battle involves documents relat­ing to AbbVie’s rheumatoid arthritis drug Humira and InterMune’s Esbriet, a treatment for idiopathic pulmonary fibrosis, an unexplained chronic and progressive scarring of the lungs. In both cases, competitors of the compa­nies were seeking the data.

“Biopharmaceutical companies support responsible data sharing that protects patient privacy, maintains the integrity of the regulatory review pro­cess, and preserves incentives for bio­medical research,” said Matt Bennett, senior vice president for the Pharma­ceutical Research and Manufacturers of America in a statement at the time. “Unfortunately, the EMA’s current and proposed policies fail to respect these principles.”

The ruling comes amid increasing pressure from medical journals and patient advocates on pharmaceutical companies to provide complete trans­parency and make public all of their clinical trials data. It also comes as the EMA readies implementation of a new policy to proactively publish data from clinical trials supporting the approval of new drugs once a decision has been made. The EMA said it would continue the process of drafting its policy on publication of clinical trials data.

Ben Goldacre, author of “Bad Phar­ma” and co-founder of the AllTrials campaign, which seeks publication of all results from all clinical trials, called the ruling “a disgrace.” “There is no justification for withholding informa­tion about the methods and results of clinical trials from doctors, research­ers, payers and patients, who need all the information on a medicine to make truly informed decisions,” he says.

The EMA says it welcomes the op­portunity for legal clarification of the concept of commercially confidential information, but expressed “regret” over the decision to grant interim re­lief to AbbVie and InterMune.

FDA, IOM, weigh transparency

In the United States, although ef­forts to bring about transparency have moved slower, they are advancing. In October 2012, the Institute of Medicine held a two-day workshop to explore the benefits of sharing clinical research data, the issues surrounding it, and how best to do so. The IOM is now working on a consensus study that some hope could provide a roadmap for the devel­opment of a clinical trials data transpar­ency policy in the United States.

A group of leading pharmaceutical and biotechnology companies has been involved in the IOM process and issued a press release hailing the effort. “This industry group is strongly in support of enhanced access by third party re­search to clinical trial data generated by industry and academia in a manner that ensures that patient confidential­ity is preserved, scientific integrity is maintained, and intellectual property rights and confidential company infor­mation are protected,” they said in a joint statement.

The Food and Drug Administration is seeking public comments through August 5 on a policy to make available de-identified and masked data derived from medical product applications. But advocates of transparency say such data will be of limited utility because the policy under consideration would de-identify it and remove the data’s link to a specific product, study, or application.

Peter Pitts, president of the Cen­ter for Medicine in the Public Interest and chairman of a conference on clini­cal trials data transparency held by FDANews July 23-24, says it’s “a non-arguable fact that FDA is at the nexus of vast amounts of clinical data that if it was appropriately shared it would be of tremendous value.” He says that sharing information, among other things, could help companies fail faster, which would save a lot of money and allow for reinvestment of diminishing resources. But such an effort, he says would require information technol­ogy resources the agency is without, decisions on what is and isn’t redacted, discussions about intellectual property rights and commercial confidentiality, and funding for it all.

“We’ve come to the point now, rela­tive to clinical trials data, that transpar­ency is a good thing. The question now becomes, ‘How do you accomplish that and what exactly does transparency mean? And how quickly does it be­come transparent? And how much of it becomes transparent and how much of it remains confidential? Is it transpar­ent through corporate entities, or is it transparent through a consortium of corporations? Is it transparent through a government organization? And who ultimately decides? Can people opt out? And if people opt out, can you really have transparency?’” says Pitts. “They are all very tough questions.”

(Note: For more on the FDA News conference, see Cry “havoc,” and let slip the dogs of data transparency.

Progress, but no victory

Four years after Jefferson began his efforts to access clinical study reports from Roche and GlaxoSmithKline, which produces the Tamiflu competi­tor Relenza, both of which are in the class of drugs known as neuramini­dase inhibitors, it is Roche and GSK that arguably have the clearest defined and most advanced efforts to provide clinical trials data to outsiders.

Roche has complied with the origi­nal request the Cochrane reviewers made in 2009, although the researchers continue to pursue access to additional trials data of which they subsequently learned. The Cochrane Collaboration expects at the start of 2014 to publish a new review of neuraminidase inhibi­tors based on 23 clinical studies on Re­lenza and up to 20 studies on Tamiflu.

In February, GSK announced it had signed on in support of the AllTri­als campaign and has vowed to pub­lish clinical trials data of all approved drugs dating back to 2000, the date the company was formed through the merger of Glaxo Wellcome and Smith­Kline Beecham.

“We are committed to being trans­parent with our clinical trial data to help advance scientific understanding and inform medical judgment,” Patrick Vallance, President, Pharmaceuticals R&D, GlaxoSmithKline, said in an­nouncing support for the campaign. “Our commitment also acknowledges the very great contribution made by the individuals who participate in clin­ical research. All those involved in the conduct and publication of clinical re­search, whether healthcare companies like GSK, academia or research organi­zations, have a role to play in ensuring that the data they generate are made publicly available to help bring patient benefit.”

In response to questions from The Burrill Report, GSK said it believes a broader solution for providing access to trial data from across the research com­munity needs to be developed and it has been in discussion with trials sponsors from industry, academia, and research charities working in partnership to cre­ate one. GSK says one solution would be the establishment of an independent data custodian to which research spon­sors would deposit anonimized data after a project has been completed and clinical studies are published. Research­ers could then submit scientific propos­als and analysis plans to independent custodian to request access.

The Pharmaceutical Research and Manufacturers of America and the Eu­ropean Federation of Pharmaceutical In­dustries and Associations at the end of July jointly issued a list of principles for clinical trial data sharing. They call for a voluntary plan that would make data available to only to “qualified” research­ers who sign non-disclosure agree­ments. They say they would only share data for which they have the informed consent of study participants to do so.

(Note: The full principles can be found on the PhRMA website. PhRMA said implementation of the commitments in the principles will begin on January 1, 2014.)

Companies will start reviewing requests for data from researchers at that point, but Castellani said companies will need to take into account patients’ informed consent. He said it will not be possible to share data from many earlier trials because patients participating in them did not consent to such release.)

But advocates worry that the vic­tories in studies extracted from phar­maceutical companies to date may be short lived, in large part due to the legal battle in Europe over the EMA’s transparency policy. “Societal expec­tations have dramatically moved in a direction of greater transparency, but there remain serious risks to the pro­cess that could potentially derail a lot of the progress that has been made,” says Johns Hopkin’s Doshi. “The prog­ress we’ve seen with Tamiflu may have been a one-off victory for what other­wise may be a return of data secrecy. Many people think the goals of trans­parency have been achieved, but they have not.”


Center for Medicine in the Public Interest is a nonprofit, non-partisan organization promoting innovative solutions that advance medical progress, reduce health disparities, extend life and make health care more affordable, preventive and patient-centered. CMPI also provides the public, policymakers and the media a reliable source of independent scientific analysis on issues ranging from personalized medicine, food and drug safety, health care reform and comparative effectiveness.

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