New study dismantles myth of high drug development costs

I'm embarrassed to admit that when I was a medical reporter for The Boston Globe in the '90s, I (along with many other journalists) would unthinkingly use the $800 million that the pharmaceutical industry said it cost to develop a new drug product. Industry apologists routinely threw out that exorbitant figure whenever anyone complained about high drug prices, and they made sure to note that it was based on "real research," studies done by the Tufts Center for the Study of Drug Development.

What I didn't realize then was that the $800 million was a highly inflated cost estimate produced by a center that received substantial industry funding and has very little credibility. The same goes for the latest cost estimate of $1.3 billion per new drug bandied about by the same folks.

Now, in a newly published report in Biosocieties journal, researchers at Stanford and the University of Medicine and Dentistry of New Jersey have taken apart both of these inflated cost estimates and shown exactly where they are wrong. Don Light and Rebecca Warburton note, for instance, that neither the $800 million or $1.3 billion estimate includes the substantial contributions made by taxpayers through tax write-offs for research and development. As it turns out, taxpayers indirectly pay for about 39 of drug company R&D. In addition, the industry-based figures are based on clinical trials (and number of participants) much larger than actual trials reported by the FDA and the National Institutes of Health.

Perhaps most disingenous, half of the industry estimates are not real costs, but exaggerated estimates of profits that companies might have made if they had not developed the drugs but just put their money into the stock market. As Light and Warburton note, "even if one were to accept the argument that profits foregone should be included as a 'cost' (which no other industry does), US government guidelines call for using three percent, not the 11 percent used by (the Tufts group). Light and Warburton argue that the pharm industry "cannot have it both ways."

They cannot treat R&D costs as if they are a long-term capital investment when tax authorities do the industry the favor of treating them as an ordinary business expense, fully deductible each year.

In their report, Light and Warburton attempt to reach a more realistic estimate for drug development, which, as they acknowledge, is hampered by the fact that the pharmaceutical industry is exceedingly secretive about its R&D data. But building on some of the data gathered by the Tufts Center and research done by Merrill Goozner of gooznews among others, they conclude that the real cost per "self-originated" drug product is closer to $180-231 million, a big reduction from the estimates that continue to be thrown out by industry spokesmen whenever they want regulatory concessions or more government spending. The latest example of this can be found in Christoph Westphal's op-ed in The Boston Globe, which I blogged about here.

The myth of high R&D costs not only exerts a destructive influence on state and federal policy, but it provides drug companies with an excuse for focusing on high-priced me too drugs (like Paxil and Seroquel), instead of developing lower priced drugs that might really save lives -- such as vaccines and treatments for disease. As Light and Warburton note:

The mythic costs of R&D are but one part of a larger, dysfunctional system that gives us mostly new medicines that have few or no advantages and serious side adverse reactions that have become a leading cause of hospitalization and death.

I couldn't have said it better.

Are we seeing a concerted drug industry campaign against the FDA?

There must be something in the air. Either that, or the drug and medical device industry has embarked on a concerted campaign to improve its tattered public image and bully the FDA into backing down from recent efforts to ensure that unsafe drugs and medical devices are kept from the market.

First appeared an op-ed piece in The Boston Globe early this week complaining that the average number of new drugs approved by the FDA since 2005 has dropped 33 percent and urging the FDA to once again speed up the process. The op-ed was penned by none other than Christoph Westphal, a biotech entrepreneur who made a mint when he sold his startup, Sirius, to GlaxoSmithKline in 2008 for a whopping $720 million.

Then comes a double whammy today in The New York Times: an op-ed piece by a former vice president at Merck calling for Congress to allow drug companies to work with other on joint direct to consumer advertising campaigns (as if the current barrage of television drug ads isn't bad enough), and an article in the business section decrying regulatory delays of medical devices and arguing that this slowdown is forcing some patients to go overseas. The article by Andrew Pollack raises the old canard that the pharm industry brings up whenever it wants concessions: that U.S. industry will lose its global competitive edge if the FDA doesn't relax its regulatory standards.

In his op-ed piece in The Globe, Westphal specifically criticizes the FDA's recent rejection of a drug to treat obesity, even though the agency had serious concerns about the drug's effectiveness and safety and its possible over-use as a treatment of first instead of last resort. He then goes on to urge $1 billion in additional funding by the federal government for early and late-stage drug development. The implication is that taxpayer money would be well-spent by supplementing research funding by the industry, which now pretty much controls drug testing and development with all the resulting conflicts of interest. Now, I would love to see the NIH take over control of clinical trials for new drugs if only to ensure less biased trial results and have blogged about that before. But somehow I don't think such independent research is what Westphal has in mind.

Speaking of possible conflicts, Westphal seems to have become a regular guest contributor to The Globe's op-ed page, which is interesting because his wife, Sylvia Pagan Westphal also is a regular op-ed contributor to the paper on medical issues. (I'll give Westphal this much: he's a brilliant marketer. He sold Sirius to GlaxoSmithKline on the promise that its one product, resveratrol, a basic ingredient in red wine, would become an anti-aging bullet. Yet just last year GlaxoSmithKline had to stop a clinical trial of resveratrol after a number of patients taking it developed kidney failure).

The Times' op-ed piece, disingenuously headlined "Better Drug Ads, Fewer Side Effects," essentially argues for weakening anti-trust regulations to allow the drug companies to work together on joint advertising campaigns that, in my mind, would be even more misleading than the television ads now dominating the air waves. The author of this piece, the former Merck exec who now works for law firms that represent drug companies, argues that these joint ads would inform consumers about diseases and treatment options (including drugs) and spare viewers "the assault of promotional messages, often unintelligible warnings about side effects and cloying images..." Yes, we could all do without the cloying images, but I guess I'd rather have unintelligible warnings than no warnings at all. Better yet, as I've blogged about before, what would really protect consumers is if Congress passed legislation prohibiting all direct to consumer advertising by pharmaceutical companies, period.

Why is the industry mounting what looks like a carefully orchestrated campaign to sway public opinion now? Perhaps because its lobbyists smell blood in the water. The House is now under the control of pro-business Republicans, and in recent weeks, even President Obama has gone out of his way to cozy up to big business interests. So industry officials must think this is the time to put pressure on regulatory agencies like the FDA, which in the last few years has shown an increased willingness to hold new drug and medical device approvals up to a higher level of scrutiny for safety and effectiveness. I just hope that, in the interest of public health and safety, the FDA stays strong.







.

Psychiatric journal refused to retract flawed antidepressant study

The Journal of the American Academy of Child and Adolescent Psychiatry has refused to retract a study finding that the antidepressant Paxil was safe and effective in adolescents despite evidence of fabrication, plagiarism and failure to disclose conflicts of interest on the part of its authors, according to two academic researchers.

In a paper published yesterday in the journal Accountability in Research, Jon Jureidini and Leemon McHenry recount the myriad flaws of study 329, the same clinical trial that prompted a New York State Attorney General's lawsuit against Paxil's maker, GlaxoSmith Kline, in 2004. The story of that lawsuit and how it helped propel reforms in the way drugs are tested and marketed is the subject of Side Effects. In that book, I exposed how the authors of study 329 failed to fully disclose their lucrative financial ties with GlaxoSmithKline and how they misrepresented the data in the study to make Paxil look safer and more effective than it really was. I've also written about the study's extensive flaws in my blog here and here.

In this week's paper, Jureidini and McHenry concluded that study 329 violated JAACAP's written policy in several ways:

1. Failure to disclose conflicts of interest of "authors."
2. GSK concealed commercially damaging data (about the study).
3. Fabrication (creation of a strong false impression that one primary outcome measure was positive by deliberately confusing it with another measure).
4. Falsification (post hoc changes to secondary outcome measures and misrepresentation of severe adverse effects).
5. Plagiarism (submittting a ghostwritten manuscript).

The two researchers said they brought evidence of these clearcut violations to the attention of the journal's current editor, Andres Martin, but he has so far refused to retract the study. In their paper, Jureidini and McHenry said this case makes them wonder how many industry-sponsored publications of clinical research are equally flawed. As they note:

It is unclear to what extent one can extrapolate from Study 329 since relatively few industry-sponsored clinical trials have been exposed to this level of scrutiny. Given, however, the vast operations of "publication planning" conducted by pharmaceutical marketing, there is little doubt about the degree to which industry-sponsored research is suspect.

As a result, they reach the conclusion that other researchers have: that publication of industry trials should be banished from the journals. Instead, "pharmaceutical companies should be obliged to post results of their trials on websites, leaving journals to independently and critically examine the raw data and conclusions," they argue.

That's one solution. Here's another, long espoused by Dr. Marcia Angell, the author of The Truth about Drug Companies: prohibit pharmaceutical companies from funding randomized clinical drug trials and instead have those trials funded by the National Institute of Health and conducted by independent researchers who are not on the drug companies' payroll.

Researchers call on journal to retract notorious Paxil study

The retraction of questionable scientific papers seems to be on the rise, due in large part to increased media scrutiny of scientific misconduct and conflicts of interest among researchers who fail to disclose they have skin in the game, i.e. lucrative financial ties to the drug and medical device companies whose products they are studying. Indeed, retractions are becoming so common that Ivan Oransky, executive editor of Reuters Health News, has started a popular new blog called Retraction Watch.

Sad to say, actual retractions may be the tip of the iceberg. Consider the 2001 study of Paxil in adolescents, the subject of my book, Side Effects. According to a recent article in the British Medical Journal, two academic researchers have called on the journal that published the Paxil trial, known as study 329, to retract it because of the way its authors manipulated and omitted data to make Paxil look safer and more effective in adolescents than it really was. As I reported in Side Effects and subsequent blogs, Dr. Martin Keller, then chief of psychiatry at Brown University and the lead author of this study, miscoded several teenagers who had become suicidal as a result of taking Paxil as being noncompliant instead of as developing adverse side effects from the drug. In addition, Keller and his co-authors concluded that Paxil was effective in treating depression when in fact the drug was not more effective than a placebo on either of the two primary outcome measures of the study and most of the original secondary outcome measures.

As the BMJ article notes:

The drug only produced a positive result when four new secondary outcome measures, which were introduced following the initial data analysis, were used instead. Fifteen other new secondary outcome measures failed to throw up positive results.

It is important to note here that Keller, along with most of the co-authors of this paper, had lucrative consulting or speaking arrangements with GlaxoSmithKline, the maker of Paxil, the full extent of which they failed to disclose when the paper was published. Indeed, as I reported in Side Effects, the 2001 paper itself was ghost-written by Scientific Therapeutics Information (STI), a medical company hired by GlaxoSmithKline and the same one that helped the former psychiatry kingpins Charles Nemeroff and Alan Schatzberg write an entire psychiatric textbook promoting Paxil, according to the New York Times.

Even though peer reviewers for the Journal of the American Academy of Child and Adolescent Psychiatry said that the results of study 329 did not show efficacy for Paxil and had a host of other methodological problems, the journal accepted the study for publication anyway. One wonders whether the fact that one of the co-authors, Dr. Graham Emslie, was on the journal's board at the time had anything to do with its precipitous publication in July 2001.

Before making the decision to put black box warnings about increased suicidal risk of Paxil and antidepressants in children and young adults in 2004, the FDA looked closely at study 329 and concluded that its conclusions were indeed misleading and did not demonstrate the drug's efficacy over placebo; read about this here.

Two academic researchers, Dr. Jon Jureidini,associate professor of psychiatry at the University of Adelaide, and Leemon McHenry, lecturer in philosophy at California State University, are now calling for the retraction of this study, which was used by Glaxo to heavily market Paxil to doctors treating depression in children and adolescents.

As the BMJ piece notes, the Committee on Publication Ethics (COPE) recently advised journal editors to retract a paper if “they have clear evidence that the findings are unreliable.” If any published paper fits this category, study 329 does.

Hat tip to Neuroskeptic for making me aware of the BMJ article.

Panelists to share tips on how to become a health and science blogger

On Wednesday, Jan. 19, I'm moderating a panel on blogging about health and science, sponsored by the New England Science Writers. We are fortunate to have attracted some top-notch bloggers, including Gary Schwitzer, whose HealthNewsReview blog was named the best medical blog of 2009 by Epocrates; Daniel Carlat, of the Carlat Psychiatry blog (who blogged about the upcoming panel here); Ivan Oransky, executive editor of Reuters Health News, who blogs at Embargo Watch and Retraction Watch; and Rachel Zimmerman, who curates the CommonHealth blog for WBUR radio.

It promises to be a very stimulating evening of conversation. You can learn more about the event at the NESW website. And you can follow Tweets from the event by following the Twitter hashtag #nesciblog11.

One more reason why Genzyme might want to resist Sanofi's overtures

For weeks now, The Boston Globe has been running stories about Sanofi Aventi's hostile bid to acquire Genzyme, the Boston-based biotech giant. One recent story talked about how the CEOs of both companies attended the same conference in San Francisco without talking to each other. Genzyme has repeatedly rebuffed Sanofi's offer largely on the grounds that the share price being offered is inadequate.

But here's another reason why Genzyme might want to be wary of Sanofi's overtures: its new CEO, Christopher Viehbacher, comes from GlaxoSmithKline, where as head of its US operations, he presided over some less than savory business decisions. He was, for example, at the helm when top Glaxo officials ignored problems with a production plant in Puerto Rico, according to a former Glaxo employee turned whistleblower. (Glaxo recently agreed to pay a $750 million fine and plead guilty to a felony for manufacturing fraud that led to untold bottles of contaminated meds, mislabeled packaging and incorrect dosages at this plant, according to Pharmalot.)

Viehbacher also headed up the company's US operations during the tempest over news that its anti-diabetes drug, Avandia, increased the risk of heart disease in patients. Even though a meta-analysis done by Dr. Steven Nissen, a cardiologist at the Cleveland Clinic, reported the increased heart risks in a major journal article in 2007, Glaxo executives kept insisting on the safety of their top-selling drug. It wasn't until an FDA advisory panel this past year recommended that Avandia either be pulled from the market or see its sales severely restricted that the company agreed to put black box warnings on the drug; read about this here. And Viehbacher was in charge when the New York State Attorney General's office sued GlaxoSmithKline for not telling doctors and consumers the full story about the suicidal risks of its blockbuster antidepressant, Paxil, and its lack of effectiveness in children and adolescents (which is the subject of Side Effects).

Viehbacher, of course, was not in charge in the late 1990s when company officials first decided to suppress data about Avandia and Paxil's risks. But since he became head of US operations in early 2003, there's a good chance that he was briefed about the dangers of these drugs and chose to do nothing about them, until forced to do so by regulatory officials. Indeed, according to the New York Times, after Nissen's study was published, Glaxo officials conceded that they had known of the drug’s potential heart attack risks for a number of years. But instead of pulling Avandia off the market, they reacted by defending the drug and threatening lawyers who were advertising on TV for patients who might have been harmed by taking Avandia; read about this here.

I have no idea whether Viehbacher was passed over for the top job at GlaxoSmithKline because of the less than ethical corporate behavior that occurred on his watch. But it is one more reason why Henri Termeer, the CEO of Genzyme, might want to think twice before handing over his company to Sanofi-Aventis.

More Americans harmed by prescription drug misuse than illegal drugs

Just last night, a friend of mine mentioned that an acquaintance of hers, a woman in her 50s who was taking prescription drugs for several conditions including diabetes and high blood pressure, died from an overdose of legally prescribed drugs. Which is why I was not surprised by today's story in the New York Times about new data showing that the number of emergency room visits in the U.S. from the misuse of prescription drugs has nearly doubled over the last five years. I was, however, surprised by the news that these prescription overdoses outstrip emergency care for people taking illegal drugs.

Perhaps we should all be shocked by such news -- shocked enough to do something about it. The reason for these latest statistics, which come from the Substance Abuse and Mental Health Services Administration, is obvious: the number of Americans taking prescription drugs has soared nearly 40 percent over the past 10 years and many of those people are imbibing multiple drugs, according to a Kaiser Foundation study. The impact on health care costs is well-known: spending on prescription drugs has doubled in the last decade, thanks in large part to the pharmaceutical industry's successful marketing of expensive drugs to a much wider segment of the American public than ever before.

We've also heard about the occasional celebrity who overdoses on legal drugs -- Heath Ledger and Brittany Murphy to name two, and I've blogged about the over-medicating of children with psychoactive drugs before; see here. But now we are seeing real evidence of the damage this pattern of overuse is wreaking on many people's lives.

There is no question that many health problems are treated or effectively managed through the use of prescription drugs and that some new drugs, particularly treatments for cancer and other diseases, are keeping people alive. But too many Americans are popping pills of questionable efficacy for conditions like high cholesterol, hypertension and depression. And because the drugs are "legally" prescribed by trusted medical professionals, consumers are much too sanguine about the side effects of these medications and how they interact with each other.

The best doctors closely monitor the drugs they prescribe to their patients and are very aware of possible drug interactions. The real danger comes when patients go to more than one doctor to get prescription drugs, a much too common occurrence. That, sadly, was the case with my friend's acquaintance: she had gotten her drugs from several caregivers and simply assumed they were safe.

The Times article today talks about a give-back program instituted by the Drug Enforcement Administration, where people have been able to drop off old or unused drugs at designated locations around the country. But I think health officials should be taking a more aggressive approach, perhaps by requiring patients to sign off with one primary caregiver before they fill their prescriptions. That's just one idea; I'll leave it to wiser heads than mine to come up with some workable solutions.

In the meantime, I hope the media keeps hammering home the message -- that just because the drugs you're taking are legally prescribed doesn't mean they're any safer than the drugs you might buy from the dealer down the street. If the latest finding is any indication, they can actually be more dangerous.