NEJM Spiked Story Exposing NKF

We're take a break from our holiday break (I'm still reading the papers, of course; my thirst for a daily fix remains as strong today as when I took up the habit 45 years ago when I was 11 and began my first paper route) to point out an interesting story in today's Wall Street Journal. David Armstrong, who is turning the corporate takeover of medicine into an interesting beat, reports that the New England Journal of Medicine had originally commissioned Robert Steinbrook's story exposing Amgen's control of the National Kidney Foundation guidelines on anemia management.

You can see the Journal story here.

You can see my coverage of this story in real time (as the original stories appeared in NEJM and the Lancet, where Steinbrook's story eventually appeared, here, here, here and here.

Hope everyone is having a happy holidays. Back to the papers.

Prizes, Not Profits

The Nobel Prize-winning economist Joseph Stiglitz in the current British Medical Journal has endorsed proposals to finance drug innovation through a prize fund. This approach has been championed for several years by the Consumer Project on Technology, which is run by Jamie Love.

Earlier this year, Love won one of the coveted MacArthur Foundation "genius" grants. His dogged determination to get the idea of the prize into the public domain is proof of the age-old concept that genius is one-tenth inspiration and nine-tenths perspiration. As we get set to power down for the Xmas holidays, it's fitting that I salute Love's latest endorsement. I've always operated as if only the power of an idea mattered in the so-called marketplace of ideas. But as in most markets, ideas need grease to gain traction and his obviously has.

Way to go Jamie.

For those not familiar with the concept, a prize fund would be established by government (or a consortium of governments) to reward innovations in medicine based on their usefulness. So a vaccine for malaria would take a bigger share of the fund than the fifth or sixth statin drug, which would probably get very little. The intellectual property would then be turned over to generic manufacturers to provide health care systems around the world with the lowest possibly priced medicines, so the maximum number of people would get to use them.

As Stiglitz put it, the prize fund "holds the promise that in the future more money will be spent on research than on advertising and marketing of drugs, and that research concentrates on diseases that matter."

Gas Pedal Case May Limit Abusive Rx Patents

The European Patent Office on Tuesday voided a patent on AstraZeneca’s Nexium, the best-selling acid indigestion pill. This is good news for European consumers, since the drug is nothing more than the mirror image molecule of Prilosec, which went off patent a few years ago.

While the EPO's reasoning won’t be released until early next year, observers say the decision hinged on the drug’s lack of originality, known as “obviousness” in the patent trade. A similar case was recently argued before the U.S. Supreme Court. Patent lawyer Robert Goozner explains why KSR vs. Teleflex, which involved an adjustable gas pedal, could wind up benefiting U.S. drug consumers:

The dispute over U.S. Patent 6,237,565 held by Teleflex involved an adjustable gas pedal that combined two elements, an electronic throttle control with an adjustable pedal system. Both inventions were well-known to automotive engineers.

Since most patents are modifications or combinations of previous inventions, the first question facing the patent examiners was whether the new invention was novel or obvious. If the latter, it can’t be patented.

The current test for determining obviousness is the teaching-suggestion-motivation or TSM test. Under TSM, if one of the known “prior art” patents or publications explicitly teaches, suggests or motivates someone to modify a known technology or combine with other known technology to produce a new invention, then that new invention can't be patented. However, the patent examiner must point out a specific passage in the published patent that actually does the teaching, suggesting or motivating, i.e., the logical road map to produce the obvious and therefore unpatentable invention. The result? The test can almost never be met and trivial inventions like painting a face on the side of a bag wind up getting patent protection (In re Dembiczak).

This low standard of patentability has been exploited by the pharmaceutical industry to reap enormous profits. When a patent for a drug is about to expire, many pharmaceutical firms frequently get another bite at the exclusivity apple by obtaining a patent for a minor variation of the compound coming off patent, an enantiomer (a compound having the same formula and structure, but with mirror image symmetry), for instance, or a prodrug (a compound that produces a known drug when metabolized by the human body). Nexium is the enantiomer of Prilosec.

During oral arguments in November, conservatives on the Supreme Court bench oozed contempt for the TSM test. “It is misleading to say that the whole world is embraced within these three nouns, teaching, suggestion, or motivation, and then you define teaching, suggestion, or motivation to mean anything that renders it nonobvious. This is gobbledygook," Justice Scalia said.

When Teleflex’s counsel Tom Goldstein retorted by noting that “every single major patent bar association in the country has filed [Amicus Briefs] on our side,” Chief Justice Roberts snapped: “That just indicates that this is profitable for the patent bar.” Justice Scalia piled on. “It produces more patents, which is what the patent bar gets paid for, to acquire patents, not to get patent applications denied but to get them granted. And the more you narrow the obviousness standard to these three imponderable nouns, the more likely it is that the patent will be granted,” he said.

The Supreme Court appears eager to raise the obviousness bar for obtaining a patent. If it closes this patent loophole, it could eventually lead to lower prices at the pharmacy. – Robert Goozner

GAO: Drug Innovation Lags Despite High Drug Prices

The drug industry's mantra that it costs over $1 billion to develop a new drug gets trotted out every time someone in Congress wants to do something about the high price of drugs. With the incoming Democratic Congress pledging to force Medicare to wrestle lower drug prices from drug firms, the industry's counteroffensive has begun. I've already seen several full page image ads (as opposed to product-specific ads) in the nation's leading newspapers.

The industry's claim rests on a simple proposition. Without high prices, research and development will be cut back. For the millions of Americans suffering from cancer, heart disease, Alzheimer's, and (fill in the blank with your most feared disease here), the fervently hoped for miracles that are just over the horizon will not emerge from industry's labs.

It's a compelling story, and total hogwash, as a new report from the Government Accountability Office released by leading Congressional Democrats today shows. Rather that replicating the Tufts Center for Drug Development methodology that generates the industry's much ballyhooed "cost per drug" number, the GAO investigators interviewed dozens of experts in an effort to explain why medical innovation is lagging.

The numbers are stark. Industry's inflation-adjusted investment in R&D jumped 147 percent to nearly $40 billion between 1993 and 2004, but the number of new drugs rose just seven percent. If one looks at all the new drug applications approved by the Food and Drug Administration over that decade, one finds that just 23 percent were rated as "priorities" by the agency. In other words, three out of every four drug applications involved drugs that either replicated the action of medicines already on the market or were new formulations that at best added minor conveniences for patients and doctors.

"Increases in research and development expenditures during the period have not led to a commensurate increase in the innovative potential of NDAs (new drug applications) submitted to the FDA," the report said.

Okay, so why hasn't more money for the drug industry led to more innovative drugs? The most important reason, the report said, was that "the complexity of the diseases to be addressed have increased." In other words, the low-hanging fruit of the drug revolution has been picked. The diseases that an aging population needs to address are diseases that have defied man's ingenuity for decades -- no, centuries. Is more money the answer? Or must we await a better understanding of the underlying mechanisms?

I think it is the latter. Yet, between 1983 and 1998 there was a 22 percent decline in the number of physician-scientists working on these questions, the report noted. Physicians willing to test new drugs in their patients are a dime a dozen, and industry has hired plenty of them. But "lengthy training and relatively lower compensation for physicians who are scientists" has undercut our society's ability to do the hard work that might one day lead to real innovation.

The second major reason for lagging innovation in the drug industry most innovative drugs "do not offer the same revenue-generating potential as blockbuster drugs," which frequently must be tested on thousands of patients because they offer only marginal health benefits -- like cholesterol-lowering drugs, for instance. Moreover, once one company comes up with a blockbuster, then the rest of the industry follows suit with their own versions, the so-called "me-too" drugs.

Even if you buy the industry's argument that that these me-toos offer "choice" for patients (I'm skeptical, but let's accept the premise for argument's sake), the bottom line is that they require huge investments for marginal gains in health, thus driving up the overall cost of industry R&D that ultimately gets passed along to consumers.

I'm glad to see the GAO, no bastion of radicalism, saying that drug innovation depends on the further evolution of basic science, and not pouring more money into the coffers of the drug industry. This is a point I've made over and over in the speeches that I've given since my book, "The $800 Million Pill," came out in 2004. The GAO analysis suggests that high prices for drugs will only lead to more me-toos, not real innovation.

That powerful grist for the mills of Senators Ted Kennedy (D-Mass.) and Richard Durbin (D-Ill.) and Rep. Henry Waxman (D-Cal.), who released today's report. The bottom line is that in the coming debate over Medicare drug price negotiations, industry's trump card is a joker.

If Congress is really concerned about innovation, it would take some of the money saved from lower Medicare prices and put it into the training a new generation of physician-scientists who are willing to work in the public sector and dedicate their lives to understanding and curing disease.

Illegal Marketing?

Today's New York Times has a much better story than Sunday's front pager about the information in the Eli Lilly files on the anti-psychotic Zyprexa. The files reveal damaging revelations about the off-label marketing of these drugs to physicians treating seniors with early signs of dementia.

Schizophrenia and bipolar disorder, the indications for which Zyprexa (olanzapine) was approved by the Food and Drug Administration, are young persons' diseases, the story accurately points out. Physicians who treat seniors wrote the FDA about these illegal marketing efforts. Nothing was done.

Where was the FDA?

The off-label marketing of drugs should be a major topic of hearings next year as the new Congress grapples with the twin issues of FDA reform and reauthorization of the Prescription Drug User Fee Act, which critics say has led to a too-cozy relationship between the industry and its federal overseers.

Weight Gain on Anti-Psychotics

It's always interesting to watch the mainstream press catch up with an ongoing debate. Case in point today: The New York Times' front page story that included "revelations" that Eli Lilly sought to downplay the risks of diabetes and severe weight gain from its blockbuster anti-psychotic Zyprexa (olanzapine).

Now, if there is anything that qualifies as a "dog bites man" story in journalism, it is one that reveals that anti-depressants and anti-psychotics are associated with weight gain, and that companies that make the drugs try to dismiss those concerns. As a relative who works in the health professions said to me this morning, "If you think you're depressed now, take one of those drugs and see how fat you get. That will really depress you."

The real essence of the story, of course, had more to do with Eli Lilly's efforts to throw a cloud of obfuscation over the connection for its own drug, which appears to be among the worst in its class for having this effect.

Out of curiosity, I checked the medical literature this evening to see if there have been any recent reviews that might shed some light on the situation (and given inquisitive health reporters a good medical source for exploring this story rather than waiting for a frustrated trial lawyer to leak internal company documents). Here's the full abstract from a review that appeared last July in the Canadian Journal of Psychiatry (written by an American at Washington University in St. Louis; why he had to go to Canada to get his review published is probably a story in its own right):

The metabolic effects of antipsychotic medications.

Newcomer JW, Haupt DW. Department of Psychiatry, Washington University School of Medicine, St Louis, Missouri 63110, USA.

contact: newcomerj@psychiatry.wustl.edu

OBJECTIVES: To review current evidence for the hypothesis that treatment with antipsychotic medications may be associated with increased risks for weight gain, insulin resistance, hyperglycemia, dyslipidemia, and type 2 diabetes mellitus (T2DM) and to examine the relation of adiposity to medical risk. METHODS: We identified relevant publications through a search of MEDLINE from the years 1975 to 2006, using the following primary search parameters: "diabetes or hyperglycemia or glucose or insulin or lipids" and "antipsychotic." Meeting abstracts and earlier nonindexed articles were also reviewed. We summarized key studies in this emerging literature, including case reports, observational studies, retrospective database analyses, and controlled experimental studies. RESULTS: Treatment with different antipsychotic medications is associated with variable effects on body weight, ranging from modest increases (for example, less than 2 kg) experienced with amisulpride, ziprasidone, and aripiprazole to larger increases during treatment with agents such as olanzapine and clozapine (for example, 4 to 10 kg) (emphasis added). Substantial evidence indicates that increases in adiposity are associated with decreases in insulin sensitivity in individuals both with and without psychiatric disease. The effects of increasing adiposity, as well as other effects, may contribute to increases in plasma glucose and lipids observed during treatment with certain antipsychotics.
CONCLUSION: Treatment with certain antipsychotic medications is associated with metabolic adverse events that can increase the risk for metabolic syndrome and related conditions such as prediabetes, T2DM, and cardiovascular disease.

Robert Wilson and Breast Cancer

An interesting side note to today's big story in the New York Times, which reports that the sharp seven percent decline in breast cancer rates reported in 2003 was probably due to declining use of hormone replacement therapy. Robert Wilson, author of the book that stoked the movement to stay Forever Feminine, was receiving substantial financial assistance from Wyeth, the maker of the estrogen pills, while promoting his book and the drug's use.

Gina Kolata mentioned Wilson in her story this morning in the Times. But she didn't mention his well-documented background. That's unfortunate, because it would have educated the millions of women who will avidly read that story about a phenomenon that is still with us. If you read about a drug that is too good to be true, it probably is; and not only that, the guy touting it is probably on the take.

Report Absolute Risk!

Lisa Schwartz, Steve Woloshin and colleagues at the Veterans Administration hospital in White River Junction, Vermont are among my favorite researchers because they continually point out the flaws in standard medical reporting. Today's British Medical Journal carries their report on the failure of medical journals to note the absolute risk of a disease and an intervention when reporting the results of clinical trials.

What is absolute risk? Think of all the times you read a news account of a new drug that said it CUTS the risk of heart attacks IN HALF! Sounds pretty good, doesn't it? But what if you knew that only 1 in 10,000 people who didn't get the drug got a heart attack. That means the drug cut the risk from 1 in 10,000 to 1 in 20,000. Would you pay a thousand bucks a year for that level of protection?

Accurate reporting of such a study would not only report that the relative risk was cut in half, but that absolute risk was just one-one-hundredth of one percent (0.01%), and the drug cut the risk to five-one thousandths of a percent (0.005%).

Another way to report absolute risk is the number needed to treat (NNT) in order to reduce an incidence of a disease. So in this example, the number needed to treat to eliminate one heart attack is 20,000. This is an import concept for calculating the cost-effectiveness of treatments. Again, using this example, if the drug in question cost a thousand bucks a year, the health care system would have to spend $20 million to eliminate one heart attack.

Thinking about absolute risk allows clear thinking about the relative value of various health care interventions. So what did Schwartz and Woloshin find? They looked at 222 clinical trial reports in various journals and found that 68 percent failed to report the absolute risks in the abstract and half of those or nearly a third of the total did not report the absolute risks anywhere in the article.

Their conclusion: "Absolute risks are often not easily accessible in articles reporting ratio measures and sometimes are missing altogether—this lack of accessibility can easily exaggerate readers' perceptions of benefit or harm."

If that's what is happening in the journals, what is going on in the press? The answer is obvious. Most reporters never even ask, much less report the absolute risk numbers. It's an easy concept to master, and an easy question to ask the clinical investigators when reporting on the results of clinical trials. Keep that in mind the next time you read a news account of the latest "breakthrough" in medicine. Ask yourself, "Have they reported my absolute risk of suffering from this disease?"

Why Does Medicare Subsidize Industry Seeding Trials?

One of the worst-kept secrets in medical research is that much of what passes for cutting edge knowledge is actually thinly-veiled advertising by the drug industry for drugs that have already been FDA-approved. Example: A company has an anti-inflammatory pain pill that has been approved for arthritis pain; they now want to test it on dental patients with tooth aches. Such studies add almost nothing to medical science, yet they routinely appear in the medical literature, especially in the less prestigious journals that cater to specialists.

These trials are sometimes referred to as seeding trials because their real aim is to encourage the physicians who enroll patients in the trial (at a nice fee per patient, of course) to continue prescribing it for them and other patients once the trial is over. Another major benefit for the drug firm is that after the study appears in a specialty journal, the sponsor can buy thousands of reprints for its salesmen to distribute to the offices of physicians in that specialty, even though it hasn't been approved for the condition they're actually treating. While the law prohibits drug industry salesmen from promoting the off-label use of drugs, they are allowed to drop off published literature that accomplishes the same thing.

It now appears that industry has gotten Medicare involved in the game. Yesterday, I attended an all-day hearing at the Center for Medicare and Medicaid Services (CMS) where an advisory committee debated whether Medicare should continue reimbursing the routine costs of caring for seniors who are enrolled in clinical trials. At the end of the day, they said yes with a few limitations that may not stop the abuses.

Some background: Older people have historically been underrepresented in clinical trial research, which is unfortunate since older people consume well over half of all drugs. To rectify the situation, President Clinton in 2000 issued an executive order requiring Medicare to pay for their participation. His order was triggered by an Institute of Medicine report calling for the change, and it was widely heralded as a good thing.

But earlier this year, the agency announced it wanted to revisit the issue. While the rule has provided some researchers, especially in cancer research, with needed support, not all the Medicare-funded studies were so noble. "There were trials (funded) that we think were inappropriate," Steve Phurrough, the director of the coverage and analysis group at Medicare, told the 18-member advisory committee. Pressed for examples, he was vague, citing studies that "lacked scientific merit" and one study of a drug "with significant side effects."

The advisory committee endorsed a number of restrictions for industry-funded trials seeking government support. They included requiring future trials to register with ClinicalTrials.gov, the government-run registry; the trial sponsor must also explicitly outline the method and timing for releasing data from the trial; and the study should make an attempt to enroll patients that demographically reflect the overall Medicare population.

About half of the 250 clinical trials registered each week with the government-run database originate in the U.S., and just half of those are funded by the National Institutes of Health or other government agencies. That leaves lots of industry-funded trials eligible for the program. With the new rule expected early next year, it remains to be seen if CMS will come up with a scheme that puts a halt to the abuses.

Blaming the Victim

David Leonhardt of the New York Times had an excellent column today that dissected the medical economics of invasive cardiology. Angioplasty and stents don't help most patients; at least 20 percent are unnecessary, according to Eric Topol of the Scripps Research Institute. But physicians and stent manufacturers are making money hand over fist. Who's going to say no, he asks.

The article sounded one off-key note. "We patients deserve some of the blame, too. We’ve come to believe that aggressive treatment somehow offers us the best chance to stay healthy, even when the evidence says otherwise," Leonhardt wrote.

That doesn't sound right to me. I know people demand particular drugs, especially after they've seen them advertised. But I have a hard time imagining patients with heart troubles demanding a particular invasive procedure from their doctor. "You mean you're not going to insert a drug-eluting stent?"

I think I'm on safe ground when I say that this is one area where providers are wholly to blame for chronic overuse of these procedures.

Patented Plavix for Life

The upshot from last week's hearings on drug-eluting stents, as reported in today's papers, suggested that these devices will see declining usage while those who have them implanted will face a life-time of taking blood-thinning drugs like Bristol-Myers Squibb/Sanofi Aventis' Plavix. This anecdote caught my eye in today's Wall Street Journal story:

Kevin Graham, director of preventive cardiology at Minneapolis Heart Institute in Minnesota, said he recently saw an elderly woman who already had a drug-coated stent and was on Plavix, at $6 a day, and a host of other medicines typical of a regimen for heart patients. She told him her monthly prescription bill was $436, while her social-security check was just over $900. "She was literally crying," Dr. Graham says. She had hit the "donut hole," a gap in Medicare drug coverage when patients have to pay the full cost of their medications themselves.

He reluctantly took her off the drug, and so far, she is okay, he says. "In those scenarios, people have to decide whether to pay the rent, pay their lights bills, buy food or buy the drugs."

Then, I found this brief item on the WSJ website:

A federal appeals court upheld an injunction halting Apotex Inc.'s sales of a generic version of the blockbuster heart drug Plavix. The U.S. Court of Appeals for the Federal Circuit in Washington upheld an August injunction issued by the U.S. District Court in Manhattan, a legal victory for Bristol-Myers Squibb Co. and Sanofi-Aventis SA, the marketers of the blood thinner. The appellate-court ruling means that Apotex, a Weston, Ontario, generic-drug maker, may not resume selling a cheaper, copycat version of Plavix in the U.S., pending the outcome of a patent-rights trial set to begin in January. Apotex began selling generic Plavix in August despite the existence of a Sanofi U.S. patent for Plavix that doesn't expire until 2011. Apotex argues that the patent is invalid and unenforceable, a contention disputed by Bristol-Myers and Sanofi.

Put them together and here's a good headline for a Page One leader in the Journal:

An Xmas Story:
Medicare, Patent laws
Force Woman to Choose
Between Meds and Food

SSRIs and Conflicts of Interest

An FDA reviewer last week concluded that antidepressant medicines trigger suicidal thoughts and even suicide in some young adults suffering from depression. This week, the Food and Drug Administration will hold an advisory committee meeting to air this issue.

This is a subject where opinions are highly predictable -- where you stand depends very much on where you sit. The psychiatry profession is among the most compromised in modern medicine. Its practitioners, having lost their ability to command reimbursement from the insurance companies for talk therapy, have become purveyors of pills, and have allowed the drug industry through consulting deals and other emoluments to make up for some of their lost revenue.

However, there are some psychiatrist-physicians who aren't on the take from the drug industry. And, when a high profile meeting like the one that will take place this week comes up, you'd think the FDA would reach out to find them. Alas, the FDA organizers of this meetings still haven't gotten the message. The agency placed three people with ties to the drug industry on the panel.

They include Andrew Leon, a professor of public health at Cornell's Weill Medical School who is a permanent member of the committee. Leon has received between $10,001 and $50,000 per year as a member of a data monitoring board for an undisclosed firm that sells antidepressants, according to the FDA waiver that will allow him to sit on the committee. According to independent research by the Center for Science in the Public Interest, Leon has also consulted for Cyberonics, makers of the Vegus Nerve Shock Therapy System which treats severe depression, and Cortex Pharmaceuticals, which make a class of compounds used for Alzheimer's and depression. In addition, Leon's research has been sponsored by Forest Laboratories, which make Celexa, a selective serotonin reuptake inhibitor (SSRI).

Another panelist will be Bruce Pollock, who works at the Rotman Research Institute in Toronto. He will not be allowed to vote in on the issue because he receives as much as $10,000 per year sitting on the advisory board and speakers bureau for an antidepressant maker. Pollock also advises and speaks on behalf of Forest Labs, which makes the best-selling antidepressants, Celexa and Lexapro; for GlaxoSmithKline, maker of the antidepressant Paxil; and for Pfizer, maker of Zoloft, a popular anti-depression drug.

A third waiver was issued to Jean Bronstein, a retired nurse who will be the consumer representative on the committee. She owns stock valued from $5,001 to $100,000 in two drug firms that make antidepressants. Dozens of affected "consumers" will be speaking during the public portion of the meeting. It will be ineresting to see how much support they receive from Bronstein.

Survey: Americans Shun Health Savings Accounts

I'm not surprised by the results of a Commonwealth Fund/Employee Benefits Research Institute survey that found just one percent of Americans with health insurance have chosen to open the health savings accounts enabled by the 2003 Medicare Modernization Act. That's unchanged from a year ago, when the two groups did their first poll.

I'm also not surprised by findings that the reason that 7 million Americans with high deductible health insurance plans (where medical bills must exceed $2,000 per family before insurance coverage kicks in) have not opened HSAs is that they don't have the money to put away for medical emergencies.

And while the survey showed that people with these accounts do not skimp on care for chronic conditions (perhaps leading to the uptick in personal bankruptcies caused by overwhelming, unpaid medical bills), it confirmed what most objective analysts have feared from this conservative approach to the health care finance crisis. "Adults over age 50 in consumer-driven plans are significantly less likely than those with more comprehensive coverage to have had a colon cancer screening test in the last five years, and all adults in CDHPs were less likely to have had their blood pressure checked in the last year," the report said.

An ironic note: Adults in CDHPs were more likely to say that they had had their cholesterol checked in the last five years. It suggests that drug industry marketing does work in getting people to ask about treatment for conditions for which there are patented medicines. Most blood pressure control drugs (at least the ones prescribed first by doctors) are generic. So even when there are low-cost solutions available, people on these "consumer-driven" plans don't purchase life-saving therapies because they don't want to pay for the initial visit to the doctor.

This survey suggests that consumer driven healthcare based on high-deductible insurance coverage would be a disaster for preventive medicine.

Amgen Confident in Storm

As I was leaving the House Ways and Means Committee hearing room where outgoing chairman Bill Thomas (R-CA) pledged to spend his "retirement" changing Medicare's payment policies for Amgen's Epogen, I caught the impromptu press conference being held by the company officials in the hallway outside the room. I didn't catch their names; I was in a hurry to get back to my office. But one identified himself as a nephrologist. He repeatedly said that Amgen does not promote off-label use of Epogen; in other words, it does not encourage physicians to go beyond the Food and Drug Administration-approved indication that red blood cell counts should not go beyond a 36 hematocrit (normal red blood cell counts range from 39 to 42).

I almost burst out laughing. Amgen has successfully lobbied the Center for Medicare Services (CMS) to reimburse clinics up to hematocrits of 39. Two-thirds of the physicians and "representatives" on the CMS advisory committee that approves those guidelines have financial ties to either Amgen or the dialysis clinics that make money by selling more of the drug, according to Rep. Pete Stark (D-CA). The National Kidney Foundation calls for higher hematocrits in its guidelines, the creation of which was paid for by Amgen. The subcommittee that wrote the chapter in the NKF guidelines on anemia management had 10 of 16 physicians with consulting contracts with Amgen.

So as I listened to the Amgen representatives claim they never told any physicians to raise hematocrits, I thought to myself: No, and the Godfather never pulled the trigger, either. He just sent his flunkies out to do the job.

Thomas stole the show at yesterday's hearing. He was passionate in his anger. "You have to seriously consider that your payment policy is killing people," he told Leslie Norwalk, the acting director of CMS. She replied, "I don't think our payment policy is in any way killing people." It was a curious response given that three expert researchers had just testified that CMS' payment policy, which abetted overuse of Epogen, was in fact leading to an excess of deaths among those on the highest doses.

Thomas was visibily angry, a rarity in the halls of Congress. He is retiring, and will probably become a big-time lobbyist, as so many ex-Congressmen do. He's clearly not leaving Washington because he pledged to spend his valuable time in the new year engaging in "pro bono" work to ensure that Congress changes CMS' policies if CMS doesn't do it itself.

A Democratic Congress with the former Republican chairman of Ways and Means lobbying against Amgen? Has the company finally met its match? If yesterday's stock market reaction is any indication (the stock was down a penny), Wall Street is betting that Amgen will weather this storm, too.

FDA Finds SSRIs Elevate Suicide Risk in Young Adults

The Food and Drug Administration late yesterday released its meta-analysis of the relationship between antidepressant use and suicide in adults, and found that for young adults under 25, the risk approached that previously found for youths. However, the agency's reviewers found no risk for older adults. The FDA will hold an advisory committee hearing on the issue next week.

Here's the relevant paragraph from the FDA's internal study:

In contrast with the previous FDA review of pediatric studies, the pooled estimates of studies of the adult population support the null hypothesis of no treatment effect on suicidality. The most obvious explanation for this difference in results is that the effect may be age related. When results are analyzed by age it becomes clear that there is an elevated risk for suicidality and suicidal behavior among adults younger than 25 years of age that approaches that seen in the pediatric population. The net effect appears to be neutral on suicidal behavior but possibly protective for suicidality for adults between the ages of 25 and 64 and to reduce the risk of both suicidality and suicidal behavior in subjects aged 65 years and older.

Beating Malaria

Last summer, I traveled to the Thai-Burmese border to report on the pioneering physicians who have been on the front lines of developing artemisinin, the World Health Organization's drug of choice for combating malaria. That trip is now the cover story in The Scientist magazine, which can be viewed here (subscription required).

Here's an excerpt:

If a research team led by Francois Nosten and his mentor, Nicholas White of Mahidol University in Bangkok (whom many consider the world's leading malariologist), lead the way to better protocols for treating pregnant women and others with artemisinin-combination therapy (ACT), it won't be the first time that the duo has used the tools of clinical science to teach the world new methods for combating this age-old scourge. In 2001, the World Health Organization (WHO) declared ACT the preferred method for treating malaria, especially the most deadly form of the parasite, Plasmodium falciparum, which in most parts of the world has evolved resistance to older drugs such as chloroquine. WHO's 2001 decision was based largely on clinical trials that SMRU had conducted during the early 1990s.

This breakthrough came despite the fact that artemisinin's mechanism is poorly understood. When the parasite invades a red blood cell to reproduce, it destroys the hemoglobin and frees up iron. In the presence of artemisinin, this free iron forms highly reactive oxygen radicals that some scientists believe inhibit the parasite's ability to digest more hemoglobin, thus breaking the chain in its lifecycle. By contrast some older drugs such as chloroquine disrupt membrane function, thus disabling the invaded blood cell's ability to disgorge the newly formed parasites.

Not knowing the chemistry hasn't stopped the drug's deployment in the field, though. Early in this decade, Nosten and colleagues at the Shoklo Malaria Research Unit spearheaded a joint public health program with the Thai government that trained rural health workers, most of them recruited from local villages, to use test kits to diagnose malaria and then administer ACT. The campaign also attacked the Anopheles mosquito that spreads the disease by conducting indoor home spraying with deltamethrin, a pyrethroid ester insecticide considered one of the safest in the world. (DDT, recently resuscitated by WHO, was banned in Thailand in 1997.) Distribution of insecticide-treated bed nets was also part of the campaign.

The result? Malaria in mountainous Tak province was reduced by 34% and mortality was cut in half. Though the program was cut short when the Thai government's funds were depleted, it proved that even in remote areas, where people live exposed to the elements and have no formal healthcare system, it is possible to roll back malaria.

That's the goal of the campaign that world health officials launched in 1998 to cut the incidence of malaria in half by 2010. The campaign has so far fallen woefully short of expectations. This year will see an estimated 500 million cases of malaria, two-thirds more than the 300 million cases estimated in 1999. Somewhere between one and two million people will die of the disease, most of them children under the age of five in sub-Saharan Africa.

To Nosten, who has devoted his life to fighting the resurgence of drug-resistant malaria, it's inexplicable that global health officials and policymakers haven't moved faster to deploy the knowledge and tools that he helped to create - especially the three-day regimen of ACT. (Two combinations tested by Nosten and colleagues included artemether-lumefantrine and mefloquine-artesunate, both of which proved more than 96% effective against P. falciparum.) "The death toll is enormous. It's like five jumbo jets filled with children crashing every day," he says. "By 2010, there could be twice as much malaria. That, to me, is a failure."

Epstein's Take on Big Pharma

And The Trials of Pfizer

Richard A. Epstein is a law professor at the University of Chicago and a senior fellow at the Hoover Institution. His new book is "Overdose: How Excessive Government Regulation Stifles Pharmaceutical Innovation" (Yale). He has from time to time consulted for Pfizer and PhRMA, an industry trade group.

So concludes an essay in today's Boston Globe headlined "What's Good for Big Pharma Is Good for America." Consider this essay and Professor Epstein's book the opening salvo in the coming war over drug pricing, which the Democrats vow to join in January.

What was shocking to me in reading this essay was how the good law professor could get so many basic facts wrong. For instance, at one point, he trots out the tired argument that it costs over $1 billion to develop a new drug. "In addition, their successful drugs must generate additional revenues to cover the predictable flops," he adds. Actually, the series of Pharma-funded Tufts University studies that generated the $1.2 billion number INCLUDES the cost of failure in its calculation.

But I long ago gave up expecting the various law and economics professors hired by Big Pharma not to trot out the big lies. And, as a journalist, I am saddened by the fact that the editors of the Boston Globe, whose circulation area includes Tufts, are unable to catch such grievous errors.

But let's press on with our critique. Woe betides us, Epstein asserts, because $21 billion in annual industry sales will go off patent this year, and $24 billion over the next three years, "a sharp dent for an industry that today generates about $250 billion in revenue." With the FDA making it harder and harder to approve new drugs, the future of drug innovation is grave indeed.

Let's subject this shibboleth to some scrutiny. Add the two numbers up and we get an estimate (from Standard & Poors) that the industry will lose patent protection on $45 billion or 18 percent of its total sales over four years. Patents run for 20 years. Therefore, you'd expect to lose about five percent of revenue per year to generics. Over four years, that's 20 percent. So, if anything, the loss to patents over the next four years is running slightly below what you'd expect.

Having established his fact foundation on quicksand, Epstein begins building his real argument. Critics are making unreasonable safety demands, he argues, making it almost impossible to bring "innovative" new drugs to market. "The FDA has consistently upped the number and type of clinical trials for companies seeking approval of new drugs, so that today as many as 60 separate trials are often required. Fewer drugs make it through these hurdles, and those that survive the ordeal cost ever more to bring to market, "he writes.

Let's take today's Pfizer example, a new drug for raising good cholesterol (and thus lowering heart attack risk). The company's trial combined it with standard of care -- Pfizer's best-selling Lipitor ($13 billion in annual sales). Forget for a moment that the company originally planned to sell the new drug as part of a combination pill that included Lipitor so that it could extend the patent life of its biggest franchise, which runs out in 2010.

Over the weekend, the company had to pull this promising drug after learning the definitive clinical trial (the one aimed at FDA registration) turned up an excess of heart attacks. Whoops.

On the surface, the numbers did seem awfully small: a 60 percent increase in deaths, but only on a 51-death baseline. There were 7,500 people in the trial. But what does that increase mean when you give the drug to millions of people? If half the patients were in the new drug arm (3,750), and that resulted in an excess of 30 deaths, then that would add up to 8,000 extra deaths for every million people who took the drug combination. Since there's nearly 20 million people on Lipitor in this country, if even half of them were successfully switched to this new combination pill, that could have resulted in 80,000 excess deaths -- twice as many as die in car accidents every year.

No, Professor Epstein, I don't think the FDA has become "too strict." I think Pfizer did what any responsible company would do.

But now let's get to the real bottom line of his argument. All this cash flow is to get real innovation through the pipeline. But are new cholesterol management pills really what's needed to launch a major assault on heart disease in this country (it's the leading killer at nearly 900,000 deaths per year).

My apologies to Steven Nissen (he's the Cleveland Clinic cardiologist who was running the trial for Pfizer), who was widely quoted this morning lamenting the outcome of the trial. He's still looking for the next big thing in cholesterol management.

But I would humbly submit that the nation doesn't need to spend an extra $20 billion a year once Lipitor goes off patent on the next generation of pills. It needs to use half that money to hire an army of public health nurses to go out into communities that are being devastated by uncontrolled hypertension, poor diet, lack of exercise, excessive drinking, and unrelieved financial and social stress that are the real causes of the heart disease epidemic in this country.

We need the nation's preventive cardiologists to start sending that message -- every day, and in every way.

Spend A Million, Make A Billion

I was called yesterday by a young reporter asking for my "comment" on the Food and Drug Administration advisory committee decision approving Celebrex for children with rheumatoid arthritis. Specifically, he wanted to know my views on the safety of this drug. I said, "no comment."

Having thought about it for a day, I am now ready to comment.

Wrong question.

There are about 30,000 to 60,000 children in the U.S. with juvenile rheumatoid arthritis. They can take ibuprofen, naproxen or a half dozen other non-steroidal inflammatory drugs for this condition. Pfizer tested 242 kids, comparing its drug to generic naproxen. No difference in pain relief, both better than placebo (which was not tested; the FDA presentation said that other studies have shown that 47 percent of children respond within three months to placebo).

So why did Pfizer bother testing this best-selling ($3 billion a year) drug on this small population, which would take small doses for short periods of time? If all 60,000 kids (or their parents) bought $100 worth of Celebrex a year, that would only be $6 million. Hmmm. Testing 242 kids at about $10,000 per kid in the clinical trial (it's a high number, but let's give them the benefit of the doubt) would cost about $2.5 million. So it's profitable, but for Pfizer, so what?

Wait. What do I see near the bottom of this news report? Pfizer will be using this data to apply for the pediatric patent extension, which gives a company six months additional exclusivity if they test their drug in kids. Let's see, a half year of $3 billlion is $1.5 billion. (The original patents on Celebrex expire in 2013.)

They'll have to wait a few years, but a thousand to one is, as they like to say on Wall Street, a hefty return on investment.