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December 13, 2012

GSK and other Pharmaceutical Companies Prepare to Release Global Patient Level Clinical Data

Clinical Trial Data
“In an unprecedented move that could signal dramatic changes in the drug industry, GlaxoSmithKline is promising to make detailed data from its clinical trials available to independent researchers so that scientists can draw their own conclusions about the safety and effectiveness of its new drugs,” reported Forbes

The change was announced in a speech earlier this year by GSK CEO Andrew Witty, where he also described how the company “made its chemical libraries available to researchers working on drugs against tuberculosis and malaria.”  “Because of our unique role, we recognize that society holds us to higher standards than for other industries,” Witty said in his prepared remarks.  “This is how it should be. Over the last four or so years we at GSK have been working hard to be more open and transparent.  As I have shown these new approaches are helping to provide new solutions for serious global health issues.  They will also help build society’s trust.” 

The change may be a result of the company’s $3 billion settlement announced in July 2012, when the GSK pled guilty to U.S. misdemeanor charges that it had marketed the anti-depressants Paxil and Wellbutrin for unapproved uses and had not disclosed clinical data related to the diabetes medicine Avandia, which eventually had its use severely restricted because it may increase the risk of heart attacks.  

As the article notes, “these scandals had at their root the idea that patients were being endangered because data were not made public.”  New York Attorney General Eliot Spitzer sued Glaxo in 2004 for not disclosing negative data that linked Paxil to suicidal thoughts in children.  As part of a settlement, GSK agreed to post all the results of its clinical trials on a company Web site.  In 2007, Steven Nissen, chair of cardiology at the Cleveland Clinic, pooled studies found on that site to produce a New England Journal of Medicine (NEJM) article that started a firestorm of controversy around the pill, then the best-selling diabetes medicine in the world, that eventually resulted in its sales dropping to close to nothing.  In the ensuing controversy, it was revealed that Glaxo had told the Food and Drug Administration (FDA) about a study that mirrored Nissen’s own results, but had not made the results public except in a place on its website where they were particularly difficult to find. 

Earlier this year, the Department of Health and Human Services (HHS), transferred authority to FDA to oversee information that is filed with ClinicalTrials.gov – the clinical trial registry data bank – and seek out those who fail to file, or file misleading or false data, which was announced in the Federal Register.  Companies that fail to file information or are in non-compliance must may have up to 30 days after notification from FDA to submit revised clinical trial information.  Otherwise, companies face fines up to $10,000 for each day of the violation.  In addition, if the trial is government funded, such funding could be frozen or withdrawn.   

A recent paper published in the British Medical Journal (BMJ), however, noted that only 22% of entities adhered to mandatory clinical trial result reporting.  Several other studies over the past few years have looked into unpublished data.

According to Forbes, Glaxo publishes results from its clinical trials on its own Web site and on another site run by the National Institutes of Health (NIH), and it says it tries to publish scientific papers on every study in research journals.  But doctors outside the company don’t have access to vast databases of how each patient in a clinical trial did.  “What Glaxo is promising to do is to create a process through which researchers can request this raw data and use it to do new analyses.”  In other words, GSK is not merely providing summary data, but is sharing patient-level data, which will support a broader array of research and is a higher level of transparency. 

“It’s hard to be anything but enthusiastic when you see industry stepping forward, and this is clearly a step forward,” says Harlan Krumholz, a Yale University School of Medicine epidemiologist who has campaigned for drug and device companies to make data public at a recent Institute of Medicine panel and in opinion pieces he has written for Forbes.  “I can only hope their execution of this strategy is successful and as wide-ranging in the press release,” he says.  “If it is they’re going to advance science.” 

Krumholz applauded GSK’s decision in a separate blog post with Forbes, where he noted that “the data behind closed doors can have an important effect on the assessment of a product’s risks and benefits – sometimes providing more support and sometimes less.”  He also applauded Witty’s apology for the company’s past behavior, recognizing its virtually unprecedented nature in the pharma industry.  Krumholz noted that GSK’s announcement is “a major step forward and a signal that the company is serious about promoting open science.”  

He hopes that such disclosure is accompanied by a willingness to share protocols and other key information and data.  Krumholz also pointed out that, “Academics need to catch up to GSK and also embrace the wisdom of sharing data – in many cases their record is currently no better than industry’s.”  Finally, he called on other companies to adopt GSK’s changes, quoting Witty who recognized that the complex problems science faces “cannot be solved alone,” and instead, must be approached through “partnership, collaboration and openness.” 

Forbes explained that “Glaxo would put in place a system by which independent researchers could request the data about what happened to individual patients in its clinical trials, and would be granted access if an independent group of experts thought the idea had scientific merit.” 

“We think that it’s the right thing to do for patients, we think it’s the right thing to do for understanding our medicines,” says Patrick Vallance, the senior vice president in charge of drug research at Glaxo. “I think if you volunteered to be in a clinical trial, your legitimate expectation is that your data will be used to insure that future generations of patients get the maximal advantage.”  Vallance denied that the initative was a response to past scandals. “It’s absolutely what I’ve believed for a long time. It’s what Andrew believed. It’s what many people in the company believed.” 

Medtronic has taken a similar step, working with Harlan Krumholz to let two groups of academics re-analyze the data on bone morphogenic protein-2, whose safety has been questioned, yet is close to seeing billions of dollars in revenues.  But the idea Glaxo is sketching out goes far further, affecting current and many, but not all, completed clinical trials and both approved and experimental drugs. 

Stephen Nissen hailed the idea of the initiative, but warned that the devil is in the details.  “If this is implemented as described, it’s an important step forward that I hope would be mimicked by other companies in the industry.” 

Forbes noted that one potential problem is the panel of experts, convened by Glaxo: “who will decide which independent scientists get access to the company’s data?  Will the panel allow critics, like Nissen, to look at this patient-level data, as the this information is known?”  “We’re not asking that panel to make judgments on the value of the questions being asked,” says Vallance.  “We’re asking that panel to take a view on the scientific validity.  So the answer to that question is yes, someone like Steve Nissen would be able to access patient-level data if he had a protocol that would answer a scientifically valid question robustly.” 

Vallance also warned, however, that it would be “anti-public health” for researchers to trawl the data for side effects without clear questions, because it would lead to unwarranted side-effect scares.  But he said that even in the case of Glaxo’s best-selling asthma drugs, which some doctors warn can sometimes hurt patients, what he wants are the real answers.  “We are not looking to hide something about our medicines,” says Vallance.  “If it is a scientifically valid question, answered robustly and comes up with an answer, I think we need to know that answer.” 

More recently, GSK “hung on to its perennial top spot in the new Access to Medicines Index released last week,” although competitors are closing in reported the New York Times.  Johnson & Johnson shot up to second place, while AstraZeneca fell to 16th from 7th. 

Every two years, the index ranks the world’s top 20 pharmaceutical companies “based on how readily they get medicines they hold patents on to the world’s poor, how much research they do on tropical diseases, how ethically they conduct clinical trials in poor countries, and similar issues.”  The index also looks at whether a company offers “lower prices or donate drugs in poor countries, whether they license generic versions of their products or fight to prevent them, whether they donate expertise or money to struggling health systems and whether they do research on neglected diseases.” 

The index was introduced in 2008, with some skepticism from industry, but the Times noted that now “19 of the 20 companies have a board member or subcommittee tracking how well they do at what the index measures, said David Sampson, the chief author.”  The index is supported by the Bill and Melinda Gates Foundation, the Dutch and British governments, Oxfam and other donors. 

More Clinical Trial Transparency  

In addition to GSK’s recent announcement, Johnson & Johnson, Merck & Co Inc and Eli Lilly & Co, plan to launch a one-stop database of global clinical trial sites aimed at streamlining paperwork and speeding the process for testing new drugs, reported Reuters.  J&J estimated that the investigator databank will be operational by the end of the year. 

The partners have begun securing approval from as many as 100,000 clinical investigators to enter their details into the database, Andreas Koester, head of clinical trial innovation/external alliances at J&J's Janssen unit, said in a telephone interview.  “The feedback we have gotten so far is ... they can't wait to get rid of the administrative burden and red tape,” he said. 

The initiative was limited to three companies while the kinks are ironed out, but the goal is for additional pharmaceutical companies to join in. 

Ten drugmakers - J&J, Lilly, Abbott Laboratories Inc, AstraZeneca Plc, Boehringer Ingelheim, Bristol-Myers Squibb Co, GlaxoSmithKline Plc, Pfizer Inc, Roche Holding AG and Sanofi SA - announced in September the formation of the nonprofit TransCelerate BioPharma with the wider goal of simplifying and standardizing trial practices. 

The clinical investigator database will contain key information such as infrastructure details and good clinical practice (GCP) training records.  “GCP doesn't get any better if the investigator takes it repeatedly,” Koester said.  “We wouldn’t have to ask each site - do you have a centrifuge, or do you have a minus 70 degrees freezer?” 

European Medicines Agency (EMA) and Clinical Trial Transparency 

The EMA has also recently focused attention on clinical trial transparency, holding a workshop in November on access to clinical-trial data.  The workshop was intended to elicit the views and concerns from a broad range of interested parties.  These included representatives of the European Federation of Pharmaceutical Industries and Associations, the Cochrane Collaboration, and Ben Goldacre, author of Bad Pharma

EMA executive director Guido Rasi told PharmaTimes that the agency “is committed to proactive publication of clinical-trial data, once the marketing-authorisation process has ended. We are not here to decide if we publish clinical-trial data, but how.”  The EMA claimed the workshop marks the first step in the process, in line with a decision the agency made earlier this year, a move which “aims to build trust and confidence in the system by allowing re-analysis of clinical-trial data by stakeholders.” 

The agency added that it is “aware that there are practical issues and other considerations that need to be addressed and resolved” and its senior medical officer, Hans-Georg Eichler, noted that the EMA will establish policies “in close dialogue with its stakeholders in five different areas identified during the workshop.”  These are:

  1. protecting patient confidentiality; 
  2. clinical-trial-data formats;
  3. rules of engagement;
  4. good analysis practice and 
  5. legal aspects. 

The EMA concluded by saying that “advisory groups with broad representation from all parties will be formed” and will start working on these topics in early 2013.  Final advice from each group is expected by the end of April 2013 and the proactive publication of clinical-trial data is expected to come into force on January 1, 2014.  Details about how to express interest in participating in these advisory groups will be published shortly on the agency’s website.

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