Paul Holmes 01 Jan 2005 // 12:00AM GMT
When it comes to pharmaceutical marketing, it often seems that where you draw the line between education and promotion is determined by which side of the line you’re standing on.
Drug companies have typically been criticized for communicating too much—for selling their products directly to consumers (either by educating them about hitherto obscure conditions or urging them to ask their doctors about specific treatment options) or for promoting existing drugs as treatments for ailments other than the one indicated on the label and sanctioned by the Food & Drug Administration.
The logic behind these criticisms appears to be that too much information is bad for consumers, or at least that consumers lack the critical faculties or the sophistication necessary to sort through the claims being made and distinguish the hype from the reality. But pressure from advocacy groups demanding that patients be allowed a more active role in their own treatment has helped to ensure that the flow of information has increased.
Now, however, the industry is focused on a case in which a pharmaceutical company appears to have shared too little information with the public rather than too much. In a recent lawsuit, New York attorney general Eliot Spitzer accused GlaxoSmithKline of fraudulently suppressing research suggesting its Paxil antidepressant was ineffective and unsafe in treating children and said internal company documents showed GSK had uncovered a possible link between use of Paxil and “an increased risk of suicidal thoughts and acts in adolescents.”
The suit describes five studies of Paxil’s use by children and adolescents. Two of the studies failed to show that Paxil was more effective than a placebo for treating depression in children and adolescents, according to the suit. And three of the studies suggested that certain possibly suicide-related behaviors were more likely among the Paxil users than those receiving placebo. In one study, 7.7 percent of the youth on Paxil exhibited behavior that included “suicidal thinking and acts,” compared with 3 percent of the placebo group, according to the suit.
(Spitzer insists he isn’t taking sides on the issue of whether Paxil causes suicidal behavior in children. His focus is exclusively on the failure to disclose negative information.)
An internal company document describes the company’s strategy to “effectively manage the dissemination of these data in order to minimize any potential negative commercial impact” and recommends that GSK publish a full article featuring only the one study out of the five that had some favorable conclusions. That study was later published in Journal of the American Academy of Child and Adolescent Psychiatry.
The suit, the first of its kind, cites New York Executive Law 63(12), which allows the attorney general to obtain restitution and damages from companies that make “any deception, misrepresentation, concealment or suppression” of material fact.
“By concealing critically important scientific studies on Paxil, GSK impaired doctors’ ability to make the appropriate prescribing decision for their patients,” says Spitzer, who is seeking restitution for children and adolescents in New York who were treated with the drug, along with the return of profits. The suit says about 2.1m prescriptions for Paxil were written for children in the U.S. in 2002 and revenue from those sales was $55 million.
GlaxoSmithKline makes a particularly tempting target. The company is headquartered overseas and has been at the center of a separate controversy over the compensation of its belligerent chief executive, Jean-Pierre Garnier, at a time when the company has been underperforming many of its major competitors.
There have been questions about GSK’s marketing activities, too. In a completely separate investigation, about 300 employees of GlaxoSmithKline are being investigated by Italian police following allegations that they used illegal incentives to persuade doctors to use their products. Police say GSK employees offered doctors holidays, pharmaceuticals, personal computers, and cash, worth a total of €228 million between 1999 and 2002.
And Paxil itself has been under intense scrutiny. Almost a year ago to the day, the U.K.’s healthcare regulator banned doctors from prescribing Paxil—known in Britain as Seroxat—to children under the age of 18, triggering questions about when GSK first realized the drug was potentially unsafe, and what the company did about it.
The FDA, meanwhile, has asked GSK to stop some ads for the controlled-release version of it’s the drug because the claims they make are too broad and because the and are misleading about safety issues. In a letter to Glaxo posted on the FDA’s website, the agency says a TV ad for Paxil Controlled-Release is “false or misleading” because it suggests the drug can be used by a broader range of patients than it is actually approved for and implies the drug is safer than actually demonstrated.
Says the head of the healthcare practice at a top 10 PR firm, “If you were going to send a message to the industry, you couldn’t pick a better company that GlaxoSmithKline, because it has a reputation for pushing the envelope when it comes to marketing, and Garnier is not a very sympathetic character. I can’t imagine the lawyers will want to take this to court, even though Garnier has come out fighting. There will be a settlement and that will send a very strong message to the rest of the industry that it needs to clean up its collective act.”
GSK’s initial response to the charges was a flat denial of any wrongdoing. Spokeswoman Mary Anne Rhyne said the company “has acted responsibly in conducting the studies in pediatric patients and disseminating results. All of our studies have been made available to the FDA and regulators worldwide.” She called the internal documents referenced in the suit “inaccurate and inconsistent with the facts” and insisted they did not reflect the company’s position.
And Garner himself says, “Of course we didn’t follow this advice. We didn’t selectively publicize the data. This is not a smoking gun. It’s a stupid memo, and there are lots of stupid memos in every company’s file and it is really unfair to look at the company’s actions through the small hole of one memo written among thousands and thousands in 1998. I do regret that those memos exist, but I’m not going to lose sleep over the fact.”
Garnier also lashed out at what he called the “litigation culture.”
“This is becoming an outrageous cost of doing business,” he told reporters shortly after the suit was filed. “The legal system is getting out of control. Lately the pharmaceuticals industry has been attacked on many fronts, and it’s a distraction factor for all companies.”
Garnier’s peers have so far declined to join in his criticism of the litigation, however. Instead, a report in British newspaper The Independent quoted an unidentified executive from a rival pharmaceutical company expressing concern over Garnier’s confrontational stance. “I think the reputation of the pharmaceuticals industry is lower than many in the industry have been prepared to realize,” the executive says. “Dr.Garnier’s combative response does leave a taste in the mouth, and we could all suffer because this all affects the environment in which we operate.”
Others were more sympathetic. While the company’s early response “lacked passion as well as compassion,” says Marybeth Belsito, president of New York healthcare PR firm Belsito & Company, “I also think GSK is shouldering far more of a media burden than its competitors.” Having said that, Belsito doesn’t expect any of the company’s competitors to voluntarily assume some of that burden.
“Human nature and competition being what it is, I would be surprised if other companies rallied around GSK. I would also love to be proven wrong. But any company that is remotely tempted to take advantage of GSK’s misfortune should make sure they take a long, hard look in the mirror first. The image reflected back could have easily been their own.”
Nor has the company received much response from the medical media. The Lancet, published by the British Medical Association, called on GSK to release all studies on Paxil. In an editorial, the medical journal said, “If GSK has nothing to hide, as it claims, it should open the files before being ordered to do so by a court—and do so right now.”
The company responded quickly, announcing that it would post summaries of safety and effectiveness data from all its studies on its website to while pointing out that the data had already been made available to U.S. and U.K. regulators.
“Data have previously been made available to healthcare professionals through publication in peer-reviewed journals, poster presentations at scientific meetings and medical letters to physicians,” said GSK in a statement. “This approach is accepted standard practice for making data available. However, to clarify that nature of these data, GSK will shortly be making available summaries of the safety and efficacy data from individual reports of the clinical studies conducted in adolescent and pediatric patients.”
GlaxoSmithKline says it never marketed Paxil for use in adolescents, and never sought Food & Drug Administration approval of the drug for pediatric use, but many doctors did prescribe it for children—a practice known of off-label use that is common for many drugs. Many doctors would presumably have stopped prescribing Paxil had they known of the other studies that showed the increased risk of suicide and lack of efficacy.
And the Spitzer suit includes a memo from a product manager to the company sales reps, telling them: “Paxil demonstrates remarkable efficacy and safety in the treatment of adolescent depression.” But the company says its sales people were never instructed to make those claims in their dealings with physicians.
But while Paxil provides an attractive opportunity for Spitzer to increase transparency within the pharmaceutical industry, there’s plenty of evidence that the attorney general has identified an industry-wide problem. Research conducted by a team at Oxford University suggests that scientists routinely publish the results of favorable clinical trials, while keeping inconvenient findings under wraps.
“The reporting of trial outcomes is not only frequently incomplete but also biased and inconsistent with protocols,” said the Oxford University team, led by Dr An-Wen Chan. “Published articles, as well as reviews that incorporate them, may therefore be unreliable and overestimate the benefits of an intervention.” In fact, concerns over potential harmful side-effects were omitted in almost two-thirds of the 100 cases studied.
Another recent study at the Yale School of Medicine showed 80 per cent of clinical trials backed by drug makers reported positive findings, compared with just 50 per cent of those carried out by independent academics.
It seems clear that the Paxil suit will have implications for other companies. For example, the suit came just days after a study by the National Institute of Mental Health claiming that Prozac—the only drug approved for treating depression in children, and marketed by GSK rival Eli Lilly—was remarkably effective in treating adolescent depression. Under the circumstances, the findings of that survey are likely to be greeted with at least confusion and at worst skepticism. Is Prozac really that much more effective in treating children than Paxil?
Says Peter Kramer, author of Listening to Prozac, “We just don’t know—precisely because drug companies manage the information about antidepressants, promulgating positive studies and suppressing evidence of harm or failure. For this reason, the Spitzer lawsuit is a very good thing. It promises to lead, if not through legislation then through the self-protective instincts of corporations, to greater openness about research results.”
But in the short term, it may create some problems, particularly if physicians become reluctant to prescribe anti-depressants to younger patients.
Says the head of the healthcare practice at an international public relations firm, “There’s already skepticism about the use of pharmaceuticals in treating mental health problems, and interest groups who have lobbied against them. A real concern here is that kids who really need treatment won’t get it because of all the negative publicity.”
There’s also concern that company-sponsored medical research in general will be regarded with greater skepticism.
“Thoughtful doctors now discount positive outcome studies funded by corporate money,” says Kramer, “because they suspect that comparable negative studies may have been suppressed. Information control is a game of diminishing returns.
“In a well-regulated society, all pre-marketing research on patients would be made public as a drug moves toward approval. Post-marketing follow-up would be taken out of corporate hands entirely.”
GSK says it never tried to prevent publication of the various studies into Paxil, and indeed some of the findings were presented at professional events. “There are many, many studies each year,” says company spokeswoman Rhyne. “It’s impractical to believe that every company in the industry will be able to publish from every study.”
The question is whether that’s sufficient. On the one hand, the FDA is supposed to be the consumer watchdog; on the other hand, with patients taking a more active role in their own healthcare decisions and physicians increasingly comfortable prescribing drugs for uses other than those for which they were approved, both groups expect more comprehensive communication from companies.
According to Belsito, “If all data is completely disclosed to regulatory authorities, it does not necessarily mean a pharmaceutical company or the FDA have an immediate ethical or pragmatic responsibility to issue an all points bulletin to the nation. Having said this, I think the real question is how GSK, or any company in a similar circumstance, communicates its clinical trial findings to its most critical constituency—prescribers.
“The extent that trial data is shared with regulatory bodies or publicly presented at medical meetings is certainly not the equivalent of full disclosure. Unpublished trial data, particularly for a marketed therapy that can be prescribed off-label to a pediatric patient population, and absent explicit understanding of the drug’s pharmacology in this population, potentially creates a distorted picture of the facts and far too much room for subjective interpretation of appropriate and safe utilization of the therapy.”
Other industry experts have pointed the finger at the editors of medical journals, who have the final say over what gets published and what does not. And activists suggest that critical studies are less likely to make it into print—a charge some publishers say they have recognized and are trying to fix.
“The decision to publish is based on the quality of the study,” declares Phil Fontanarosa, executive editor of the Journal of the American Medical Association. “Over the past five years, I think that if you look through major journals you do see studies with negative results appearing more and more frequently.”
The company also points out that it has shared all its findings with the FDA and regulatory agencies in other countries—a fact that is likely to increase scrutiny on those agencies.
Under FDA rules, any company seeking approval of a new drug must submit the results of all the clinical trial studies it conducts. But the agency considers that information proprietary and holds its in confidence, incorporating it into the approval decision, but disclosing only summaries and descriptions of the trials and not the underlying data.
Moreover, data related to off-label uses of the drug—such as prescribing Paxil for depression in youngsters when it is approved only the treatment of adults—need not be shared with the FDA until the company seeks approval for a new claim or use. GSK had not sought any new approval for the use of Paxil in treating children, nor had it marketed the drug for such use.
“The FDA has an obligation to make public, through labeling changes, all research that impacts not just on safety but also on the patient population for whom the drug is used,” says Wayne Pines, a former senior official with the FDA who now heads the healthcare practice at public affairs firm APCO Worldwide. “This is an obligation that has always existed but that is being framed differently due to the new environment that demands the release of all research. There is no mechanism within the agency to release certain data routinely due to confidentiality.
“The drug industry would be wise to meet collectively with the FDA, through PhRMA, to discuss whether this problem can be addressed on an industry-wide, uniform basis; the alternative is to have more companies face what GSK is now facing.”
That suggestion echoes calls for the industry establish a trial registry, a central resource to which all clinical trial studies—positive and negative—would be published. PhRMA has never called for such a registry and many individual members have opposed it, but the association’s vice president for regulatory affairs, Dr. Alan Goldhammer, has acknowledged that the industry might have to rethink its position in the wake of this latest controversy.
Years ago, Kramer proposed that pharmaceutical houses be assessed a fee based on the sales of a new drug, with the money going into a general fund that the Food & Drug Administration or National Institutes of Health could use to fund studies of side effects and of uses in under-researched populations, such as children.
“Drug companies might well come to favor such proposals, as a means of shedding liability,” he says now.
In 2002 the Pharmaceutical Research and Manufacturers of America agreed on a set of voluntary rules governing the communication of clinical trial results. Members promised to release “meaningful study results, regardless of the outcome” and agreed not to “suppress or veto publications.”
Some individual companies have gone further. Eli Lilly & Company, for example, has a set of internal rules governing the disclosure of clinical trial results, approved by the board, and has trained employees around disclosure. “We will publish all medical research, good or bad, that has relevance to patients, prescribers, and payers,” says Alan Breier, the company’s chief medical officer.
“My view is that there clearly is a trend away from selective release of significant research and more toward full disclosure, not just to the FDA but also to the public,” says Pines. “This trend is being driven by two factors: a growing sense of entitlement on the part of prescribers and patients to any and all relevant information about pharmaceuticals; and the reality that during litigation, such studies will be discovered and therefore made public and/or used against the company in court.
“I think all companies are looking at this case in light of the general trend toward disclosure and setting new policies in this area. If they aren’t already, they should.”
Whatever the outcome of his action against GSK, it seems certain that Spitzer’s lawsuit will achieve its most important goal, forcing the pharmaceutical industry to accept greater transparency, and providing more information to physicians and consumers alike about the drugs they prescribe and take.