Pfizer manipulated the publication of clinical trials to increase use of its Neurontin epilepsy pill for other illnesses, while suppressing studies that did not validate those uses, according to several experts who reviewed Pfizer documents for plaintiffs in a lawsuit against the drugmaker.
Pfizer’s tactics included delaying publication of studies that had found no evidence the drug worked for some other disorders, “spinning” negative data to place it in a more positive light, and bundling negative findings with positive studies to neutralize the results, according to written reports by the experts, who analyzed the documents at the request of the plaintiffs’ lawyers, The New York Times writes.
One expert who reviewed the documents, Kay Dickersin of the Johns Hopkins Bloomberg School of Public Health, concluded that Pfizer documents spell out “a publication strategy meant to convince physicians of Neurontin’s effectiveness and misrepresent or suppress negative findings,” according to her report (look here and here for plenty of leisurely reading).
Pfizer issued a statement Tuesday to the paper denying it manipulated Neurontin data, saying “study results are reported by Pfizer in an objective, accurate, balanced and complete manner, with a discussion of the strengths and limitations of the study, and are reported regardless of the outcome of the study or the country in which the study was conducted.”
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The negative studies would have increased doubts about the drug’s value for several unapproved uses - treating bipolar disorder, controlling certain types of pain and preventing migraine headaches, according to the expert opinions. Off-label use helped propel its sales to nearly $3 billion a year before it lost patent protection in 2004, the Times notes. A report submitted by Harvard Medical School's Meredith Rosenthal says that 43 million Neurontin scrips were written due to off-label promotion.In one example, the experts concluded Pfizer had deliberately delayed release of a study showing the drug had little effect against pain that is a complication of long-term diabetes, even as the outside researcher who was a lead investigator for the study, John Reckless of Bath, England, pushed to publish the unflattering findings on his own, the Times writes, adding that Reckless’s office said Tuesday that he could not be reached for comment.
According to one September 2000 e-mail by a Neurontin team leader at Pfizer, “The main investigator in the UK (Dr. Reckless) is keen to publish but this will have several ramifications.” The team leader later wrote, “I think we can limit the potential downside of the 224 study by delaying publication for as long as possible.”
Pfizer tells the Times thats it submitted the Reckless study to two journals which declined to publish it. The results were not published until 2003 and, according to plaintiffs’ experts, when they did appear they were combined with two other studies and together the findings concluded Neurontin was effective for treating neuropathic pain.
Another series of e-mails had the subject line “Spinning Serpell,” a reference to an investigator on the study, Michael Serpell of Glasgow, Scotland. In the e-mail exchange, a senior marketing manager for Pfizer and a professional medical writer discussed how to cast the results in a more favorable light for a poster presentation at a medical conference, the experts concluded, the Times writes.
“If Pfizer wants to use, present and publish this comparative data analysis in which two of the five studies compared make the overall picture look bad, how do we make it sound better than it looks on the graphs?” the medical writer asked.
In 2002, Angela Crespo, then Neurontin's senior marketing manager, emailed an outside firm that was contracted to write up the study's results: "We are not interested at all in having this paper published because it is negative!!" Pfizer declined to make the three employees in the emails available for interviews, according to The Wall Street Journal.
Pfizer discontinued its marketing program for Neurontin in 2004 after the drug became available as a generic. That same year, the company paid $430 million to settle federal criminal and civil claims that Warner-Lambert, which Pfizer acquired in 2000, promoted Neurontin for unapproved uses during the 1990s.
At the time, the newspaper reminds us, Pfizer said the illegal marketing had occurred before Pfizer acquired the company or drug. On Tuesday, Pfizer repeated that it had instituted procedures when it acquired Warner-Lambert to make sure there was no off-label promotion of Neurontin.
Despite that settlement, separate legal action involving the drug is still pending in Boston, where consumers and third-party payers including insurance companies and trade unions want Pfizer to repay them billions of dollars for Neurontin prescriptions. The plaintiffs accuse Pfizer of fraudulently misrepresenting the drug’s benefits.
Thomas Greene, a lawyer for the plaintiffs, said the documents in the case revealed that even after the Neurontin settlement. “Pfizer continued with the medical marketing firms and planted marketing messages in journal articles that Neurontin was effective while they knew that their own clinical trials had failed to demonstrate it was effective,” he tells the Times.
Johns Hopkins' Dickersin tells the paper that of 21 studies she reviewed, five were positive and 16 negative, meaning they did not prove the drug was effective. Of the five positive studies, four were published in full journal articles, yet only six of the negative studies were published and, of those, two were published in abbreviated form.
Source: The New York Times
22 Comments
Companies do the same thing when they submit drug applications to the FDA.
Typically companies study not only the primary indication that will be the basis of approval but they will also study other indicaitons. Sometimes they don't even decide which indication will be submitted first until they see the way the data is going. They will include the major studies for the primary indication, and studies for other indications may either be submitted under other studies or may be delayed and at best only part of the data will be submitted as 'ongoing' studies. Companies will typically come in and get approval from FDA prior to submitting the NDA and this is the first tipoff.
The primary reason for doing this is not so much hiding lack of efficacy (companies still push these indications off label) but rather to hide safety issues especially in more vulnerable or specific populations.
Once they get approval in one indication they then progressively get approvals for more indications in progressively more vulnerable populations but since these smaller groups that are studies you can make it so the chance of seeing a severe toxicity as being small or explain the true risk away by using saying the population at risk is for all users and not just the special population at risk, (e.g. younger teenagers and children who are likely to be receiving higher doses because the company doesn't want to manufacture pediatric strenghts).
This has been referred to by both Glaxo and Lilly as staged marketing.
Even within FDA, reviewers are told not to review these other studies and with the new automated computer systems and with all the new junior reviewers it will be even easier to hide this information. I know of several reviewers who found safety issues under these types of circumstances and most were then forced out of their jobs.
I think that time will tell if Pfizer is misleading patients about the safety of other products. While I do wish Pfizer survives and flourishes (I do own stock in Pfizer), I hope it does so while being honest. Chantix comes to mind. It is imperative that Pfizer be honest in it's representation that Chantix is a safe and effective product.
What a surprise! Selective publishing by a Big Pharma company in order to drive off-label prescriptions. This is exactly why the FDA is very cautious about giving approvals. They can't trust the companies to market within label. Therefore, a drug that has some nasty side-effects may be over-prescribed to too many patients who it doesn't benefit, but may harm. Oh, by the way, if they get caught doing these despicable things, they get a fine (paid for by shareholders), admit no wrongdoing, and laugh all the way to the bank with their outrageous bonuses. Isn't corporate America wonderful?
Just to clarify - As I read the piece, there is no charge of withholding data from FDA, yes? Or am I wrong? That is, if there was fraud, it was in journals - spinning and non-publication - rather than in FDA submission.
If this is right - and it is, indeed, common - does FDA have any power at all to raise questions about what is published (or not published) in journals (so long as FDA itself as the full data set) Once again, does FDA's authority cover defrauding doctors and patients if FDA itself has not been defrauded? (In the context of publications, not "obvious" promo materials.) Has FDA _ever_ acted in a way that questioned journal publication?
If not, preemption would once again be entirely bankrupt as a doctrine.
Not sure that the company has any obligation to disclose results of off-label studies to the FDA if company is not seeking additional indications. Anybody know for certain?
Chris, That's my understanding too. JiM - as far as I know FDA does not involve itself in those matters which almost always involve peer-reviewed scientific data, especially when no regulatory apect is involved.
There may not be a definitive legal obligation, but what about an ethical or moral obligation? Or can you continue to deceive doctors, patients, and the rest of the public just to make more money? Sure you can! it's the Big Pharma way!
Prescription Access Litigation (PAL), a nonprofit organization that works to end illegal pharmaceutical industry tactics, has posted all the expert reports and documents referred to in this article. They are blog.prescriptionaccess.org/?p=304
Other drugs, like Chantix, have been proposed for treating other medical issues. I remember reading that Chantix could be effective in helping patients stop nail-biting. I know that seems a little outragous, but the article was clearly trying to claim Chantix could work wonders in treating other ailments. I think that is appropriate for the FDA to look into the practice of off-label uses. In the meantime, it would be helpful if Pfizer was honest about the safety and effectiveness of it's products.
This drug is prescribed almost universally to those experiencing serious and disabling leg pain from statins. I've never known anyone to say it helped.
Re: the question I raised, as an example: When JAMA published the CLASS study, and wrote a glowing editorial about Celebrex, they didn't know that Pharmacia left out half the data (which negated the GI benefit that CLASS claimed).
FDA had the full data set and, indeed, did not approve anything about a GI benefit on the Celebrex label. But the study was out there. It took a FOIA to get the original data which negated the published study. Even Bob Temple said (quote coming) it made no difference - "the hype counts more than our labeling does."
So it sounds like FDA can do nothing (even if they were inclined) over torqued published studies. And thus this arena of fraud - which may be the most important - is entirely outside their jurisdiction. (But would still be shielded if FDA preemption is upheld.)
That said, the preemption preamble, as I read it, claims to cover any and all company-sponsored communications about a product (most of the author's of the JAMA/CLASS study were Pharmacia employees or consultants).
So I remain unclear whether it is, or isn't, technically true that FDA has any regulatory powers related to published studies (assuming they are not also distributed by reps).
Which they frequently are - distributed that is - in wonderfully colorful and professionally done reprint holders which usually also have implicit claims. Nothing is held back when it comes to making big bucks in Big Pharma. Up with profits and to hell with the public!
I am not seedy enough for this world.
FYI, JiM, a friend wrote me regarding a story he saw on MSNBC which mentioned the Levine case. He thought it was to be heard sometime in the last couple of days and was not aware of the FDA preemption movement. I was confused because I knew it was to be in November. Ed explained to me that the MSNBC report was the Supreme Court discussing the things coming up for their new session. So word has gotten out to some tiny extent. Of course it is also being over-shadowed by Wall Street and the election season. Is it any wonder that the case will be heard in November when our votes will be cast. I have become cynical enough to think that is by design. Ruling possibly depending on who wins?
For those who think the FDA is careful and that this industry is an example of morality: I'd like to set you up with a low adjustable rate mortgage so you can buy the mansion of your dreams.
Meanwhile, we still have the FDA proposing allowing the distribution of off-label journal articles by pharma companies.
Re: Justice's comments. I'm not aware of any regulatory authority FDA has over publications.
No matter what the data says a company may make whatever claims they want about what it means when they submit it. It's the FDA's job to separate wheat from chaff. I have seen numerous examples where even after the company has been told no to what they claim they still go ahead and publish the same claims even after FDA has rejected them.
I've even seen where companies have been told no to advertising claims multiple times and still go ahead and then even when the FDA advertising division is aware of it the FDA does absolutely nothing.
This was known by the DOJ years ago about these issues with Neurontin via David Franklin, a Harvard PhD CSL who pushed off- label with Neurotonin using constructed Parke- Davis (Pfizer bought this company's parent, Warner Lambert, about a decade ago)studies to physician targets by coercion of his employer. They settled in 2004, as a result of reporting this activity to the US Attorneys and others in 1996. He only worked for them for a few months. You can read about the case on the DOJ or TAF websites, or via a search engine.
FDA Reviewer wrote: "I have seen numerous examples where even after the company has been told no to what they claim they still go ahead and publish the same claims even after FDA has rejected them."
This was precisely the case with the CLASS study as published in JAMA. FDA did nothing, of course. beyond an untypically quoteable expression of exasperation from Bob Temple.
To Dan - What is "newsworthy" in the current story is that this is independent of the off-label scam of 2004. If true, this is fraud on docs and pts for _approved_ uses of Neurontin.
To Just a Thought - I have had the same thoughts.. In some respects, not all bad. If a likely anti-preemption Congresss is elected, and one assumes the Supreme Court does not live in a political vacuum, a more narrow ruling in Levine becomes more probable.
Shouldn't the FDA request that any published studies on any drug be written by the PI's tmeselves and only after the PI's can firmly attest to having seen all the raw data?
We know that Pharma does not always provide all the raw data back to the PI's and we know that very often these studies are written by either people in the medical department of the drug in question or ghost writers hired by pharma.
If the PI realizes that action can be brought against them for not reviewing all the raw data, well this should certainly help to curtail these malicious activities.
You know, the line between snake oil sellers and pharma is getting thinner and thinner, or has it already disappeared?
As I understand it (not that well), the major journals are now requiring more along the lines of what you write.
But I'm not sure how they "police" it. And, if violated, I still doubt it is within the purview of FDA.
So the core of my point: Here is a way to commit hard-core fraud, with serious consequences, yet be fully protected if preemption becomes law - even though this is an arena FDA doesn't even regulate!
Talk about a power grab....
After reading all of these articles and comments I want to thank Justice in MI for all your thoughtful comments. I agree with Just A Thought. Thanks to for the FDA and Ex pharms folks too. All this supports my descision to not use products of the strength to harm me that Pfizer and others like them have developed. It seems the more of them you use the more you need to kill the side effects the first one caused. Is there a problem with treating the disease in this country? Maybe it is all about money; which will doom us all.
it help my pain so I say its a keeper