Prying eyes want to know
By Ed Silverman firstname.lastname@example.org
Earlier this year, the National Institutes of Health ran a workshop to examine the safety of several widely used diabetes drugs called GLP-1 inhibitors and whether a definitive link can be established to acute pancreatitis and pancreatic cancer, which were the subject of a pair of recent studies that generated considerable controversy and raised fresh concerns in the medical community.
The outcome was inconclusive – it remains unclear if FDA will want new studies. But the American Diabetes Association did not wait for the session to end to take a stand. In an unexpected move, the organization called for several drug makers that sell these widely used medications – such as the Januvia pill marketed by Merck – to release patient-level data from their various studies over the years.
The idea is based on a fairly straightforward notion – researchers should be able to independently review and verify the results of clinical trials or at least adjudicate the findings in order to determine that the results match what was reported by a drug maker. In this way, regulators, physicians, and patients can feel reassured that clinical trials are reliable.
“There’s an enormous amount of opinions flying around,” says Robert Ratner, the ADA chief medical officer and chief scientific officer. “Our goal is to develop a system in which we can take a look at the data that are available …We want maximal transparency and a maximal degree of data to make rational judgments about the veracity of the data.”
But whether the drug makers – which also include Bristol-Myers Squibb, AstraZeneca, Lilly, Novo Nordisk, and Boehringer Ingelheim – will comply remains to be seen. With the exception of GlaxoSmithKline, the pharmaceutical industry has resisted releasing such data over concerns that proprietary information will be compromised and a health scare could ensue if data is misunderstood.
The pharmaceutical industry trade groups – the European Federation of Pharmaceutical Industries and Associations and the Pharmaceutical Researchers and Manufacturers of America – recently released voluntary principles that outline steps drugmakers are willing to take toward transparency. But the effort has been met with a mix of cautious optimism and derision over a series of caveats. As a result, Sense About Science, a charitable trust based in the United Kingdom, is proceeding with an online petition called AllTrials to pressure drug makers to make complete trial data available. Another backer is BMJ, one of the premier medical journals, which also adopted a new policy that studies would not be published so long as a drug maker declines to make data available.
Meanwhile, a battle is under way as drug makers are fighting an effort by the European Medicines Agency, which wants to release more data as part of a new policy toward transparency. The new voluntary principles are, in fact, designed to blunt the EMA changes and also thwart the European Parliament from adopting legislation that also calls for greater disclosure.
Also, AbbVie and Intermune went to court to block the regulator from responding to Freedom of Information requests from unnamed rivals for trial data on some of their drugs. And the trade groups are lining up patient advocacy groups, which are sometimes funded by drug makers, to lobby members of the European parliament to oppose a bill that would similarly require greater disclosure of trial data.
“EMA’s proposed policies on clinical trial information raise numerous concerns for patients,” PhRMA Senior VP Matt Bennett says. “We believe it is important to engage with all stakeholders in the clinical trial ecosystem, including patients who volunteer to participate in clinical trials, about the issue. The proposal could risk patient privacy, lead to fewer clinical trials, and result in fewer new drugs.”
Such a stance, however, may miss a crucial selling point. By embracing greater transparency, drug makers may be able to convince regulators and physicians that their clinical trial findings can, in fact, be verified independently. In doing so, they would be in a position to more consistently argue that their data is sound. And this could help restore some of the integrity lost during recent safety scandals.
In fact, this posture can have significant marketing potential. A more transparent pharmaceutical industry would be able to argue that its clinical studies have still greater value. This is a sales tool that drug makers simply do not have.
“There are certainly disadvantages to disclosing patient-level clinical trial data,” says Keith Vance, a marketing consultant to the pharmaceutical industry and an adjunct assistant professor at the Leonard N. Stern School of Business at New York University. “Chief among them is that the data is frequently ‘messy’ and difficult to interpret. As a result, it’s easy to find ‘facts’ in patient-level clinical trial data – such as the occurrence of a particular side effect – that arm the critics of pharmaceutical companies.
“But even then, those ‘facts’ and a causal relationship to the trial drug are unsupported by rigorous analysis. However, in an era where many – lawmakers, patients, even healthcare providers – view the pharmaceutical industry as untrustworthy and guilty of obfuscation (at best) or outright deception (at worst), release of clinical trial data could be a meaningful first step toward changing perceptions for the better.”
A recent example in which releasing trial data won praise involved Medtronic, which was widely criticized after reports disclosed that doctors with financial ties to the device maker were aware of serious problems with Infuse, a bone graft substitute in spinal fusion surgeries. The physicians never disclosed potential health complications in articles in medical journals, but their articles greatly boosted usage, including off-label use. The conflicts not only prompted an investigation by the U.S. Senate Finance Committee, but an entire issue of The Spine Journal was devoted to reviewing 13 previously published studies and discovered that side effects were downplayed or omitted. As a result, Medtronic agreed to provide the Yale University Open Data Access Project with $2.5 million in funding for an independent review of patient-level data. Two independent analyses found that the Medtronic product offers little benefit over conventional procedures and may be linked to an increased risk of cancer as well as the possibility of sterility in men. Moreover, both reviews found high levels of reporting bias in the papers that were published by Medtronic, which resulted in underreporting of adverse events.
The effort was heralded as “a historic moment in the emerging era of open science,” according to an editorial in the Annals of Internal Medicine, which published the two reviews and also noted that nearly half of all clinical trials are never published and many have long delays in publication. Such proclamations vindicated the decision by Medtronic CEO Omar Ishrak, who agreed to fund the review and provide the data as part of an effort to rebuild corporate image. “We recognize that our products and therapies must have the public and medical community’s trust,” he said at the time that the reviews were published.
This is a point some say has been lost on most drug and device makers, according to Harlan Krumholz, a Yale University School of Medicine cardiologist and advocate for releasing trial data who heads the Yale University Open Data Access Project.
“These companies have a lot to gain with regard to reputation and brand,” he says. “Their profile has sunk in the eyes of the American public and among healthcare professionals.
“Despite their good work, they are looked upon with some suspicion in many quarters – largely as a result of what has seemed to be an unending series of episodes of bad behavior that has overshadowed their outstanding work. Data sharing is an opportunity for them to demonstrate their commitment to transparency – and to ensuring that everything that can be known about the benefits and risks of their products is available to scientists to evaluate.”
Glaxo CEO Andrew Witty espoused much the same theory after the company paid $3 billion to the U.S. government to settle civil and criminal charges. Besides marketing medicines for unapproved uses, these included withholding clinical trial data for the Paxil antidepressant and failing to include safety data in reports about its Avandia diabetes pill that were given to FDA. In a bid to restore some confidence in its operations, Glaxo last fall agreed to publish case study reports for all of its medicines once they have been approved or discontinued from development and the results have been published. The drug maker also committed to publishing reports for all approved medicines dating back to its formation, but confidential patient information will be removed.
“We need to take a different approach – one focused on partnership, collaboration, and openness,” Witty said in announcing the plan. “By being more open with our clinical trial data, we also hope to help further scientific understanding.”
By May, Glaxo created an online system for researchers to request access to patient-level data and released the names of a group of experts who will review requests from researchers seeking to examine trial data.
The only other drug maker to so far walk down this path has been Roche, which last spring agreed to make available data from all 74 clinical trials for its Tamiflu treatment to a team of Cochrane Collaboration researchers. They had battled for more than two years over requests to obtain trial data in order to verify efficacy results. The drug maker also agreed to widen access more generally for clinical trial information for its medicines.
Most large drug makers have been silent on the issue, preferring to let their trade groups speak for them. The only instance that prompted a response was the challenge by the ADA, which was designed to put them on the spot. “If one company refuses to participate, does this impact the outcome? Yes, it probably would impact to a certain degree,” says Ratner, “but it would look awfully bad for that company to refuse when others have [agreed].”
Not surprisingly, the ADA was greeted with caution. Merck committed to working with the organization, while Lilly and Boehringer welcomed “future discussions.” AstraZeneca and Bristol-Myers Squibb issued a statement saying they “recognize there can be value in pooling patient level data from trials of agents in a class for the purpose of an independent meta-analysis” and support making “scientifically valid results of a pooled analysis of safety data available to the public and scientific communities through an independent review, and look forward to a discussion” with the ADA.
A more granular response came from Alan Moises, a corporate VP and the global chief medical officer at Novo Nordisk. “The ADA request, I’m interpreting, is really an expedition into what might be available, what sponsors will be able to share with an independent body that the ADA, through some as-yet undefined mechanism, might identify as an arbiter of the data is available,” he said. “…We certainly are open to more sharing rather than less sharing, and more than has been shared to date.”
The ADA gambit will take time, though, as will the AllTrials campaign. The effort has generated some unfavorable publicity, further underscoring what critics say is either a blind eye or a tin ear when it comes to seizing opportunities to restore confidence in business practices.
“If we’ve learned anything over the past decade of litigation, it is that the drug industry has repeatedly buried trials and manipulated trials to make their products look better than the raw data would indicate,” says Carl Elliott, a professor in the Center for Bioethics and the Department of Pediatrics at the University of Minnesota Medical School. “This is totally understandable; billions of dollars are at stake. But it makes no sense at all for the rest of us simply to trust industry without seeing the data.”
By adopting voluntary principles, the industry trade groups hope to silence such criticism, but this may be difficult to accomplish. “In terms of the principles for responsible clinical trial data sharing outlined by the EFPIA and PhRMA, these are to be broadly welcomed, says Carl Heneghan, a director at the Centre for Evidence-Based Medicine at the University of Oxford and a Cochrane Collaboration researcher. “Yet, there are many details that need to be fleshed out to ensure this is little more than just window dressing … This current document does little to move the debate on clinical trial transparency forward. The EFPIA should decide whether they are for the release of clinical trial data, which ultimately benefits patients, or not. The current document is clouded in caveats, which would certainly allow a company to refuse a request, simply because they deemed it not to be in their interest.”
Posted: August 2013