Ed Silverman, Contributing Editor07.17.13
Over the past few weeks, there were two instances that highlighted the heated debate over the release of clinical trial data — specifically, patient-level data — and what this means for physicians, patients and payers who want to understand the true benefit and utility of medicines. Both episodes underscored the entrenched interests that may make it difficult for them to do so.
The issue is increasingly important as drug-makers struggle to remain competitive while at the same time try to fend off growing accusations that important data is unfairly and unnecessarily withheld. And the tension is mounting as patient advocates and independent researchers clamor for greater access and more transparency.
In the first instance, two independent analyses published in The Annals of Internal Medicine found that a Medtronic product that has been widely used as a bone graft substitute in spinal fusion surgeries offers little benefit over conventional procedures and may be linked to an increased risk of cancer, among other maladies.
The reviews were voluntarily funded by Medtronic, which had been widely criticized after reports that doctors with financial ties to the device maker were aware of serious problems with the Infuse spinal fusion product, but never disclosed potential health complications in medical journal articles. In fact, their articles boosted usage, including off-label use .
In an extraordinary move, The Spine Journal two years ago devoted an entire issue to reviewing 13 studies previously published elsewhere and discovered that side effects were downplayed or omitted. This followed a U.S. Senate probe. The ensuring ruckus prompted Medtronic to provide the Yale University Open Data Access (YODA) Project with patient-level data for independent review.
The publication “heralds a historic moment in the emerging era of open science,” according to an editorial that was written by YODA staffers in The Annals of Internal Medicine, which published the two reviews. They noted, “Nearly half of clinical trials are never published and many that are have long delays in publication. . . . Amid the current dialogue about open science in medicine, few imagined that such a prominent company would voluntarily make available all of its internal patient-level clinical research data on one of its major products. At a time when many companies express verbal support of open science, Medtronic joined the YODA project and demonstrated what is possible.”
Such pronouncements were a stark contrast from a widely held view just two years earlier that Medtronic, which paid YODA $2.5 million to fund the reviews, was a poster child for corrupt science. The Infuse product, which contains a genetically engineered version of a naturally occurring protein , was implanted in nearly one million people and racked up hundreds of millions of dollars in annual sales before the scandal broke.
The other instance concerning patient-level data involved a call by the American Diabetes Association for several drug-makers that sell a class of diabetes treatments known as GLP -1 inhibitors to release their data for an independent review to determine whether these medicines have a causal link to pancreatitis (not a new concern) and pancreatic cancer.
The ADA did so after a pair of studies published this past spring — along with a report by a watchdog group that analyzed FDA adverse event reports — raised pointed questions about a possible association. This prompted the National Institutes of Health to hold a two-day workshop and the FDA to consider moving for additional studies, although no decision has yet been made.
Whether the drug-makers — Merck, Bristol-Myers Squibb, AstraZeneca, Novo Nordisk, Eli Lilly and Boehringer Ingelheim — will comply with the ADA is unclear. So far, they say they are willing to work with the organization, but none has committed to releasing data, although Robert E. Ratner, M.D., ADA’s chief medical officer and chief scientific officer, expressed confidence they will cooperate.
“I do think there is a bully pulpit that we can actually speak to about the need and necessity to do this… If one company refuses to participate, does this impact the outcome? Yes, it probably would impact to a certain degree, but it would look awfully bad for that company to refuse when others have” agreed, Dr. Ratner said.
Maybe, but drug-makers regularly argue that releasing such data may compromise proprietary information. The PhRMA trade group took a decidedly sharp-edge stance recently by lambasting a campaign to release data on a widespread basis that is being championed Sense About Sciences, a charitable trust in the UK, and BMJ, a leading medical journal.
Releasing such data would be “irresponsible with potentially harmful consequences for future medicine development,” PhRMA growled. This “would jeopardize patient privacy and could serve as a deterrent to individuals considering participation in trials. It would also encourage second-guessing of the regulatory approval process, which would be disastrous for patients."
Meanwhile, AbbVie recently filed an injunction to prevent the European Medicines Agency from releasing data for its Humira rheumatoid arthritis treatment. That move was made after at least one rival filed Freedom of Information requests to the ema last year to release “raw data” on the safety and efficacy of the medication, which is the top-selling drug in the world.
On the flipside is GlaxoSmithKline, which is launching a project to make such data available for independent review. The move came after Glaxo last year agreed to plead guilty and pay $3 billion to resolve criminal and civil charges in connection with off-label promotion of several drugs, reporting false prices and failing to report Avandia data.
Roche has also agreed to make clinical trial data from all 74 studies for its Tamiflu treatment to a team of Cochrane Collaboration researchers who openly fought with the drugmaker. Roche committed to widen access more generally for clinical trial information for its medicines in response to increased pressure from academics and a widely publicized online petition.
Generally, though, gaining access to patient-level data is a difficult task. This may change to some extent in Europe, where the EMA plans to publicly release all submitted data once a decision has been made either to approve or reject a medicine. However, the legal challenges by AbbVie and another by a small biotech called InterMune suggest its plans may get delayed.
The battles embroiling the EMA underscore industry arguments about disclosing proprietary data that rivals may want. Not surprisingly, the Association of the British Pharmaceutical Industry has adopted the same stance as PhRMA, although has not been nearly as shrill. And the European Federation of Pharmaceutical Industries and Associations has expressed dismay with an effort by a European Parliament committee to expand access to trial data.
Unfortunately, the issue usually comes to the fore when a safety concern arises, which is why independent researchers, watchdogs and patient advocates agree that only by releasing such data can results be duplicated and a better understanding gained of safety and efficacy. This is why the YODA Project is so significant — because the effort is institutionalized.
To a certain extent, releasing such data is very much an after-the-fact event. By the time an issue arises with a drug or device, some damage may be done and running independent reviews take time. Even after a green light has been given to analyze data, months will go by until results are known and digested. Meanwhile, uncertainty reigns, confusing physicians and patients.
Just the same, the notion of releasing this sort of data can go a long way toward helping drug- and device-makers restore credibility. For more than a decade, these companies have been operating a proverbial black cloud thanks to countless scandals, some of which have involved allegations of withholding data.
This is not a secret, of course, but this notion allows people such as Harlan Krumholz, the Yale University cardiologist who is at the helm of the YODA project, and the ADA’s Bob Ratner, to maneuver and cajole as they do. At this point, drug-makers have very little leverage to evade and resist, and practically no leverage once a safety issues arises about one of their medicines.
There are legitimate concerns about protecting proprietary data, but this should not be used as a smokescreen for prevarication and delay. The bottom line is not whether the pharmaceutical industry deserves a chance to redeem itself, but whether it can help create an environment in which rigorous and open science can provide real answers for patients.
Ed Silverman is a prize-winning journalist who has covered the pharmaceutical industry for The Star-Ledger of New Jersey, one of the nation’s largest daily newspapers, for more than 12 years. Prior to joining The Star-Ledger, Ed spent six years at New York Newsday and previously worked at Investor’s Business Daily. Ed blogs about the drug industry at Pharmalot. He can be reached at ed.silverman@comcast.net.
The issue is increasingly important as drug-makers struggle to remain competitive while at the same time try to fend off growing accusations that important data is unfairly and unnecessarily withheld. And the tension is mounting as patient advocates and independent researchers clamor for greater access and more transparency.
In the first instance, two independent analyses published in The Annals of Internal Medicine found that a Medtronic product that has been widely used as a bone graft substitute in spinal fusion surgeries offers little benefit over conventional procedures and may be linked to an increased risk of cancer, among other maladies.
The reviews were voluntarily funded by Medtronic, which had been widely criticized after reports that doctors with financial ties to the device maker were aware of serious problems with the Infuse spinal fusion product, but never disclosed potential health complications in medical journal articles. In fact, their articles boosted usage, including off-label use .
In an extraordinary move, The Spine Journal two years ago devoted an entire issue to reviewing 13 studies previously published elsewhere and discovered that side effects were downplayed or omitted. This followed a U.S. Senate probe. The ensuring ruckus prompted Medtronic to provide the Yale University Open Data Access (YODA) Project with patient-level data for independent review.
The publication “heralds a historic moment in the emerging era of open science,” according to an editorial that was written by YODA staffers in The Annals of Internal Medicine, which published the two reviews. They noted, “Nearly half of clinical trials are never published and many that are have long delays in publication. . . . Amid the current dialogue about open science in medicine, few imagined that such a prominent company would voluntarily make available all of its internal patient-level clinical research data on one of its major products. At a time when many companies express verbal support of open science, Medtronic joined the YODA project and demonstrated what is possible.”
Such pronouncements were a stark contrast from a widely held view just two years earlier that Medtronic, which paid YODA $2.5 million to fund the reviews, was a poster child for corrupt science. The Infuse product, which contains a genetically engineered version of a naturally occurring protein , was implanted in nearly one million people and racked up hundreds of millions of dollars in annual sales before the scandal broke.
The other instance concerning patient-level data involved a call by the American Diabetes Association for several drug-makers that sell a class of diabetes treatments known as GLP -1 inhibitors to release their data for an independent review to determine whether these medicines have a causal link to pancreatitis (not a new concern) and pancreatic cancer.
The ADA did so after a pair of studies published this past spring — along with a report by a watchdog group that analyzed FDA adverse event reports — raised pointed questions about a possible association. This prompted the National Institutes of Health to hold a two-day workshop and the FDA to consider moving for additional studies, although no decision has yet been made.
Whether the drug-makers — Merck, Bristol-Myers Squibb, AstraZeneca, Novo Nordisk, Eli Lilly and Boehringer Ingelheim — will comply with the ADA is unclear. So far, they say they are willing to work with the organization, but none has committed to releasing data, although Robert E. Ratner, M.D., ADA’s chief medical officer and chief scientific officer, expressed confidence they will cooperate.
“I do think there is a bully pulpit that we can actually speak to about the need and necessity to do this… If one company refuses to participate, does this impact the outcome? Yes, it probably would impact to a certain degree, but it would look awfully bad for that company to refuse when others have” agreed, Dr. Ratner said.
Maybe, but drug-makers regularly argue that releasing such data may compromise proprietary information. The PhRMA trade group took a decidedly sharp-edge stance recently by lambasting a campaign to release data on a widespread basis that is being championed Sense About Sciences, a charitable trust in the UK, and BMJ, a leading medical journal.
Releasing such data would be “irresponsible with potentially harmful consequences for future medicine development,” PhRMA growled. This “would jeopardize patient privacy and could serve as a deterrent to individuals considering participation in trials. It would also encourage second-guessing of the regulatory approval process, which would be disastrous for patients."
Meanwhile, AbbVie recently filed an injunction to prevent the European Medicines Agency from releasing data for its Humira rheumatoid arthritis treatment. That move was made after at least one rival filed Freedom of Information requests to the ema last year to release “raw data” on the safety and efficacy of the medication, which is the top-selling drug in the world.
On the flipside is GlaxoSmithKline, which is launching a project to make such data available for independent review. The move came after Glaxo last year agreed to plead guilty and pay $3 billion to resolve criminal and civil charges in connection with off-label promotion of several drugs, reporting false prices and failing to report Avandia data.
Roche has also agreed to make clinical trial data from all 74 studies for its Tamiflu treatment to a team of Cochrane Collaboration researchers who openly fought with the drugmaker. Roche committed to widen access more generally for clinical trial information for its medicines in response to increased pressure from academics and a widely publicized online petition.
Generally, though, gaining access to patient-level data is a difficult task. This may change to some extent in Europe, where the EMA plans to publicly release all submitted data once a decision has been made either to approve or reject a medicine. However, the legal challenges by AbbVie and another by a small biotech called InterMune suggest its plans may get delayed.
The battles embroiling the EMA underscore industry arguments about disclosing proprietary data that rivals may want. Not surprisingly, the Association of the British Pharmaceutical Industry has adopted the same stance as PhRMA, although has not been nearly as shrill. And the European Federation of Pharmaceutical Industries and Associations has expressed dismay with an effort by a European Parliament committee to expand access to trial data.
Unfortunately, the issue usually comes to the fore when a safety concern arises, which is why independent researchers, watchdogs and patient advocates agree that only by releasing such data can results be duplicated and a better understanding gained of safety and efficacy. This is why the YODA Project is so significant — because the effort is institutionalized.
To a certain extent, releasing such data is very much an after-the-fact event. By the time an issue arises with a drug or device, some damage may be done and running independent reviews take time. Even after a green light has been given to analyze data, months will go by until results are known and digested. Meanwhile, uncertainty reigns, confusing physicians and patients.
Just the same, the notion of releasing this sort of data can go a long way toward helping drug- and device-makers restore credibility. For more than a decade, these companies have been operating a proverbial black cloud thanks to countless scandals, some of which have involved allegations of withholding data.
This is not a secret, of course, but this notion allows people such as Harlan Krumholz, the Yale University cardiologist who is at the helm of the YODA project, and the ADA’s Bob Ratner, to maneuver and cajole as they do. At this point, drug-makers have very little leverage to evade and resist, and practically no leverage once a safety issues arises about one of their medicines.
There are legitimate concerns about protecting proprietary data, but this should not be used as a smokescreen for prevarication and delay. The bottom line is not whether the pharmaceutical industry deserves a chance to redeem itself, but whether it can help create an environment in which rigorous and open science can provide real answers for patients.
Ed Silverman is a prize-winning journalist who has covered the pharmaceutical industry for The Star-Ledger of New Jersey, one of the nation’s largest daily newspapers, for more than 12 years. Prior to joining The Star-Ledger, Ed spent six years at New York Newsday and previously worked at Investor’s Business Daily. Ed blogs about the drug industry at Pharmalot. He can be reached at ed.silverman@comcast.net.
