Kids and the Speed Patch

This week's big shindig at the Food and Drug Administration involves treating teenagers with attention deficit disorder with a Ritalin skin patch. On Friday, the Psychopharmacologic Drugs Advisory Committee will hear evidence supporting this new way to administer the drug from Shire Pharmaceuticals and Noven Pharmaceuticals.

The committee will be chaired by Dr. Wayne Goodman of the University of Florida Medical School, even though he had to receive a special waiver to sit in judgment of Shire's application. The University of Florida has hundreds of thousands of dollars in contracts and/or grants with Shire and its direct competitors.

By doing a little digging, I discovered that Shire over the past two years awarded Dr. Regina Bussing, who is the chief of child and adolescent psychiatry at Florida, at least $44,000 to study the next big thing in treating kids with ADHD. Guanfacine hydrochloride (it apparently doesn't have a trade name yet) reputedly has the same effect as Ritalin without being a stimulant. Bussing has also done work for Shire testing Adderall on kids. (The tests on the skin patch were led by psychiatrists at another university.)

Should Dr. Goodman be allowed to vote or even participate at Friday's meeting? On the one hand, his own research over the past few years has been mostly funded by the Veterans Administration and the National Institutes of Health, although he did receive a large number of small grants from various drug companies earlier in this decade. On the other hand, is he likely to take a hard line stance against Shire, even if the evidence warrants it? After all, the company has a close relationship with one of his colleagues down the hall.

Here's my take on those questions: We shouldn't have to ask them. When the FDA leaves scientists with conflicts of interest on federal advisory committees, the agency inevitably taints the public's perception of the integrity of the process, especially those who have real concerns about the wisdom of giving powerful drugs to kids who can't sit still for the tedium of high school work.

The Immortality Hustle

Dreams of immortality – or at least delayed senescence – never die. This past summer I joined the crowd by signing up for the Ponce de León 48-and-over baseball league near my home in suburban Washington. This hardball league provides the Boys of Autumn with an opportunity to relive past glories on the diamond. Given that 38 years had passed between starts, my sepia-toned memories of a mediocre high school baseball career had morphed into a few standout moments. I entertained notions of becoming a star.

I quickly got my chance. Down by a run in the late innings of our first game, I led off by slapping a fastball into center field (full disclosure: batting practice machines are 15 mph faster than high hard ones in “Ponce” ball). The next hitter blooped a single to right. Obeying ancient instincts, I took off at the crack of the bat and promptly pulled my left hamstring. Limping gamely into second, I waived off medical assistance and took a short lead. Our best hitter lined meekly into left center. As I shuffled around third, my soft spikes caught on the turf. Pitched forward, I jammed both thumbs into the ground. After brushing off my acute embarrassment, I hobbled home where the ball had mercifully arrived in sufficient time to prevent further harm from sliding.

With the lead platoons of the 75-million-member Baby Boom generation nearing retirement, it is inevitable that some portion of the Me-generation will, like me, get seduced by the Ponce de León myth. And there are plenty of enablers. A small sea of academic entrepreneurs, venture capitalists, government funders, credulous science reporters and think tank gurus are touting prospective biomedical interventions that will lead to a never-ending promised land. Have you heard about the genetically-altered nematode worm that doubled its life span? The magic elixir is just around the corner. And, if you buy now, you can get in on the ground floor.

Science writer Stephen S. Hall helped unleash the longevity bubble in January 2000 with a cover story in the New York Times Magazine that was illustrated by geezers in convertibles living well into their 100s. Though his ostensible subject was the emerging field of stem cell research, he succeeded in publicizing the speculative musings of scientist-entrepreneurs like Michael West of Advanced Cell Therapeutics and William Haseltine of Human Genome Sciences, who predicted the new cellular therapies “may keep us young and healthy forever. The fountain of youth is likely to be found within our own genes.” By the time Hall finished his 2003 book on the subject, which he called “Merchants of Immortality: Chasing the Dream of Human Life Extension,” potential treatments for serious diseases had taken a back seat to longevity research. He knew what sells.

Bioethicists have also been having a field day with this new “field.” Leon R. Kass and his colleagues on the President’s Council on Bioethics took a break from their embryo protection labors to ponder what it all means to have “ageless bodies.” To be fair, their 2003 report “Beyond Therapy” also grappled with the medicalization of childhood hyperactivity, sports doping and mood-altering drugs. But alongside these serious ethical concerns, they included a long section that confounded still undiscovered treatments for the symptoms of aging like memory loss with extending the maximum human lifespan. “The anti-aging medicine of the not-so-distant future would treat what we have usually thought of as the whole, the healthy, human life as a condition to be healed,” the report lamented.

This not-too-distant future became the jumping off point for Charles C. Mann’s Atlantic Magazine article this past May that was headlined “The Coming Death Shortage.” If the optimists are right, Mann worried, we’re headed for a world where grandparents have grandparents, the young wander aimlessly through an endless adolescence waiting for the old to retire, and the miracle of compound interest creates a class of 100-year-old investors who will make today’s wealth divide seem like the golden age of equality. “Instead of helping their juniors begin careers and families, tomorrow’s rich oldsters will be expending their disposable income to enhance their memories, senses and immune systems.”

Mann fretted that these miracle potions will only be available to the rich. Quoting a Centers for Disease Control official, he extrapolated from the $15,000 annual cost of keeping an AIDS patient alive to estimate that paying for anti-aging medicine for the Boomer generation will cost the health care system $1.2 trillion a year. He cited implantable defibrillators as one example of these life-saving technologies that we’ll never be able to afford. Note the sleight of hand. This device allows some people with heart disease to live to their allotted lifespan. But it doesn’t alter its potential length by a single day.

What’s absent from all the talk about longevity is any discussion about what it might take to translate a few elegant science experiments that retard senescence at the cellular level into anything approaching a drug or therapy that might one day be used in humans, not to mention pass regulatory muster at the Food and Drug Administration. Mann’s article predicts the future will be an unequal society where “the very old and very rich (are) on top, beta-testing each new treatment on themselves” while the less well off elderly go without.

During the 1990s, the U.S. government spent billions of dollars researching cures for rare diseases using gene therapy, only to see the field largely collapse after 19-year-old Jesse Gelsinger died in a clinical trial where the researcher failed to disclose his financial stake in the experiment. Memo to future longevity researchers: good luck in getting rich old people to substitute for Jesse.

Before long, the inherent implausibility of this line of research will send its boosters to greener pastures. Already Geron Inc., whose hourglass logo denotes its initial fascination with telomerase, the protein that programs cell death, has switched to pursuing cancer cures. West’s Advanced Cell Therapeutics has moved on to using stem cells to treat disease. But judging from the latest entry in the field, Washington Post reporter Joel Garreau’s “Radical Evolution: the Promise and Peril of Enhancing Our Minds, Our Bodies—And What it Means to be Human,” the speculative bubble still has a ways to run.

Perhaps recognizing that immortality is a thin reed on which to hinge his consulting practice (besides penning an occasion article for the Post, Garreau is a member of the Global Business Network, a scenario-planning organization that lists a number of Fortune 500 companies as clients), “Radical Evolution” reports on a transhumanist movement that seeks to link a high-tech smorgasbord of genetic germ-line manipulation, robotics, infomatics and nanotechnology (he calls them the GRIN technologies) to arrive at a whole new race of beings, which Garreau dubs The Enhanced.

Unless I missed it, he never once uses the word eugenics to describe this movement, freighted as it is with Hitlerian connections. But he does say that “the ability to tinker with our genes offers the astounding promise – and peril – of immortality, which mythically has been the defining difference between gods and mortals. It also offers the possibility of an even greater variety of breeds of humans that there is of dogs.”

Typical of the genre, Garreau sees the emergence of this uber-race as a foregone conclusion. He relies heavily on the work of Gregory Stock, who heads the program on medicine, technology and society at the University of California at Los Angeles’ School of Medicine. Stock, whose 2002 book, “Redesigning Humans” was subtitled “Our Inevitable Genetic Future,” tells Garreau that future parents’ ability to order designer babies with extra chromosomes “does not hinge on some cadre of demonic researchers hidden away in a lab in Argentina trying to pick up where Hitler left off. The coming possibilities will be the inadvertent spin-off of mainstream research that virtually everyone supports.”

Laying aside for a moment the morality of such fantasies, one hungers for some admission that it would take a lot of society’s resources to engineer such a trick. The U.S. government has spent in excess of $60 billion since President Nixon declared war on cancer. The private sector has spent billions more. Yet physicians are still attacking these mutant cells with knives, flame-throwers and poison. Decades of intensive research has recently allowed scientists to add targeted therapies to the mix. So far, it’s added months, not years, to some patients’ lives.

Garreau sweeps away any discussion of scientific difficulties by alluding to Moore’s Law, the famous dictum from the former chief of Intel that the circuitry that can be etched on a single computer chip doubles every 18 months (a law, by the way, that is only a few years away from reaching its physical limits). Technology is advancing so fast that what scientists learned in the past 20 years will be equaled in the next 8 and so on. By 2030 at the latest we’ll reach a point where supercomputers have greater-than-human intelligence; the Internet will have so much power it is a “superorganism”; and biologists will have re-engineered the human genome to produce super-smart people.

Garreau calls this endless scientific speed-up The Curve and its crossover point in the not-too-distant future The Singularity. Consultants must need such titles for their Powerpoint slides. At The Singularity, we will suddenly have living among us (most Boomers, don’t forget, will still be alive) “an ultra-intelligent critter.”

Besides having major implications for how we administer the SATs, these ultra-intelligent critters are going to have a host of technological enhancements at their command. They will be able to stay up for days; live off their fat; rapidly heal wounds; and use thoughts to communicate with similarly equipped people or robots (if I live long enough to get one of these devices, I sure hope no one gives my number out to telemarketers). To bolster these claims, Garreau takes readers on a whirlwind tour of some of the more outlandish projects being pursued by the Defense Advanced Research Projects Agency (DARPA), where the government is seeking to produce the super-soldiers of the future.

DARPA has come up with some amazing things over the years – the Internet, for one. But most of its projects, like any other form of way-out research, never see the light of day because they fail. “The civilian implications of this technology have not escaped us,” especially the fat-burning pill, the researchers tell Garreau. Is there any reason to think they’ll do any better than the billions spent by the pharmaceutical industry on a similar quest?

Assuming the inevitable, Garreau uses the last two-thirds of his book to explore the possible ways mankind might react to this “turning point in history.” His heaven scenario comes from techno-touts like Stock and Ray Kurzweil (who has his own new book out, The Singularity). Kurzweil gobbles 250 pills a day so that he can live long enough to embrace the arrival of the super-intelligent computer

His hell scenario comes largely from Bill Joy, the founder of Sun Microsystems, who, after reading Ted Kaczynski’s “Unabomber Manifesto,” spent six months at his Aspen hideaway penning a long article for Wired magazine entitled “Why the Future Doesn’t Need Us.” Joy believes everything predicted for the GRIN technologies will come to pass, and will either enslave or destroy mankind. Biotechnology will eventually allow crazed individuals like the Unabomber to unleash incurable plagues and nanotechnology will eventually turn into unstoppable gray goo. In a post-9/11 world, this is not an irrational fear.

Garreau stirs environmentalists like Bill McKibben and politicians like Tom Hayden into his hell scenario stew. The former is understandably concerned that rapid technological advance is undermining our fragile ecology. His solution is to encourage mankind to say enough is enough and live a simpler life. Hayden fears we’re opening the door to morally repugnant technologies like human cloning and organ farming. Garreau dismisses those arguments by trotting out the neo-liberal faith that advancing technology will feed the earth’s hungry millions and cure the sick.

How germ-line bioengineering a race of 200-year-old uber-humans will lead to these laudable goals is left to the reader’s imagination. Garreau embraces his prevail scenario. “I elect to light out for the Territory,” he concludes. “I choose to examine the possibility that human nature might continue to evolve and be improvable, and to consider what transformation might actually look like and what it might mean.”

If there is any political philosophy linked to the technology-driven musings of futurists like Joel Garreau, it is libertarianism. Many scientists and technologists fall into this category. It has often been said that scientists want nothing more than to be ignored by the governments that fund them and left alone by the regulators that might one day be called upon to pass judgment on their work products.

In that sense, scientists and futurists are somewhat like the Bubble-era acolytes that gathered around Ken Lay of Enron, whose own technological imperative was that the free market could be imposed on any and every economic activity. California’s ratepayers and Enron’s stockholders paid a heavy price for that hubris before regulators stepped in to clean up the mess.

There’s still plenty of time for us lesser mortals to exert control over what may one day emerge from the billions of dollars our government and capital markets are pouring into the emerging GRIN technologies. That is unless we buy into their promise of everlasting life, always smart and beautiful children and hamstrings that won’t pull. Then, of course, anything goes.

Industry-Funded Drug Studies Once Again Under the Microscope

Last week, I raked the Journal of the American Medical Association over the coals for its failure to question a study and an accompanying editorial that pushed increased statin use to curb cholesterol among people who’ve already suffered a heart attack. This week’s edition carries a fascinating exchange between the drug industry’s chief lobbying arm and the editors regarding managing conflicts of interest in the conduct of research. The two issues are related.

Last July, JAMA adopted new author guidelines that made it more difficult for industry to exert control over research and publication. The key new elements required the principal investigator in a clinical trial to certify the accuracy of the data in the study and insure he or she had access to all of it. The guidelines also distinguished between purely academic and industry funded studies. In the latter case, JAMA added a requirement that the certification of data come from someone not employed by the company sponsoring the study.

The new guidelines drew a heated response from the drug industry, which appeared in this week's Journal. Dr. Caroline Loew, science and regulatory affairs vice president at the Pharmaceutical Research and Manufacturers of America, claimed drawing a distinction between academic and industry studies “has no basis in experience.” The group resented the implication that industry-sponsored studies were somehow “at higher risk of bias and fraud than other types of studies and thus require special scrutiny.” Peer review would ferret out any flaws, she claimed.

JAMA editors Phil Fontanarosa and Catherine DeAngelis fired back with a laundry list of particulars from recent industry-funded studies:

1. The key Celebrex trial published in the British Medical Journal included only six months of data, even though the company had 12 months of data that showed no benefit in reducing gastrointestinal side effects of taking pain pills;
2. The key Vioxx trial downplayed that drug’s cardiovascular risk in favor of an erroneous interpretation that the comparison drug naproxen had cardioprotective effects;
3. Trials showing Paxil increased the risk of teenage suicide or lacked efficacy were suppressed;
4. The manufacturer of a new HIV-AIDS drug tried to stop researchers at the from publishing negative results from its clinical trial; and
5. The maker of an implantable cardioverter-defibrillator failed to report a potentially fatal design defect for more than three years.

“We will continue to require an independent statistical analysis for studies in which the analysis was conducted only by statisticians employed by the sponsor,” the editors wrote.

A few years ago, then editor of the New England Journal of Medicine Marcia Angell decided to stop publishing editorials, reviews and commentaries from authors with financial ties to companies whose products were under discussion. She was roundly criticized within the medical profession. Shortly after assuming the reins in 2002, new editor Jeffrey Drazen repealed the rule. He thought merely disclosing those ties would be enough.

As last week’s study and editorial on statin use show, even having someone outside the company but still being paid by the company to review data doesn’t ensure that its interpretation will be free from bias. At some point, even this added layer of oversight will fail to stop a study that overlooks some safety problem from creeping into the regulatory decision making or into the scientific literature.

Editors and regulators need to recognize that the best way to eliminate bias from interpreting clinical trial results is to put the conduct of those trials into the hands of an entirely independent body, perhaps a new institute at the National Institutes of Health. The entire purpose and ethic of this new institute would be to generate validated medical evidence -- not sales for a sponsor's product.

While industry user fees could fund such an institute, the companies would have no input into the design of the trial, no influence over its conduct and no role in the interpretation of its results. Only then will the public – and the regulators charged with the public's protection – get truly independent scientists evaluating new drugs, vaccines and medical devices.

Spreading Fear Like A Virus

Today's Washington Post carries my review of two new books that deal with the much-feared avian flu threat. They are "The Monster At Our Door" by Mike Davis and "Epidemic of Fear" by Marc Siegel. You can find the review here.

L.A. Times scoop: CIA duped by Iraqi visa seeker on chemical/biological weapons threat

The bulk of the pre-war case for invading Iraq rested not on the threat Saddam Hussein might use nuclear weapons (the “mushroom cloud” made famous by Condolezza Rice), but on the administration’s claim that he possessed chemical and biological weapons (CBW). Ex-New York Times reporter Judith Miller staked her reputation on reporting those threats and embedded herself with the special units searching for CBW in the early days of the war. At one point, she even reported the unit uncovered a chemical weapons cache – a report that later turned out to be false.

That’s why Sunday's Los Angeles Times report by reporters Bob Drogin and John Goetz (a freelancer) is so significant. They revealed that German intelligence agents repeatedly told their U.S. counterparts BEFORE THE WAR that their source for information about Iraq's CBW program – an Iraqi defector codenamed Curveball – didn’t have a clue and was completely unreliable.

From the article: “CIA officials now concede that the Iraqi fused fact, research he gleaned on the Internet and what his former co-workers called ‘water cooler gossip’ into a nightmarish fantasy that played on U.S. fears after the Sept. 11 attacks. Curveball's motive, CIA officials said, was not to start a war. He simply was seeking a German visa.”

Why did the Bush administration believe him? Near the end of the lengthy story, the Bush administration is castigated for never correcting the President’s comments in the 2003 State of the Union address that Iraq harbored chemical weapons or his subsequent statement that some had been found. But the story’s upshot is that this bit of false pre-war intelligence was largely the CIA’s fault. Perhaps when Congress investigates this element of the story during hearings next week on prewar intelligence, they’ll find out whether folks in the White House (or, more likely, in the Vice President’s office) were ordering up the intelligence they wanted to hear. Thanks to Curveball, the CIA had the goods to deliver.

Meanwhile, Colin Powell, who delivered the now infamous February 2003 speech at the United Nations justifying the U.S. rush to war, was once again left out on a limb defending his honor by claiming he was out of the loop. He said that he was unaware of a debate within the intelligence community about the veracity of Curveball’s claims.

There have been huge domestic ramifications to the false claim that the U.S. faces a significant threat from bioweapons experts abroad (most accounts of the still unsolved anthrax murders of October 2001 suggest the perpetrator isn't a foreigner, but someone who had access to U.S. stockpiles of weaponized anthrax). The failure to find and arrest the real perpetrator has left the American people fearful and politically vulnerable. The CIA report, based on evidence from serial fabricators like Curveball, gave the Bush administration the ammunition it needed to play to those fears and take the country to war.

It also gave the President and Congress the political capital needed to channel billions of dollars into researching drugs and vaccines for bioweapon threats like anthrax and smallpox, which, from a public health point of view, pose no threat to Americans. And, it would now appear, that research was equally meaningless from a national security point of view.

What a waste of human capital. Over the past four years, scientists sidetracked into studying anthrax could have been addressing the infectious diseases that actually pose a threat to Americans and the developing world – like tuberculosis, malaria and avian flu.

When It Comes to Flu, What You Don't Know Can Hurt You

Here’s an interesting tidbit that came out of today’s Food and Drug Administration hearing on possible adverse events among kids who’ve taken Tamiflu, Hoffmann LaRoche’s blockbuster anti-flu drug: The U.S. does not track who gets the seasonal flu, who dies from it or how they die.

The spur for the hearing was reports out of Japan that at least a dozen kids who’d taken Tamiflu died from central nervous system disorders like brain swelling and convulsions. FDA reviewers, who tracked down the individual reports by consulting with Japanese regulators and its national health care service, concluded there were confounding factors in most cases. They and Roche promised the advisory committee they’d continue monitoring reports from around the world and issue an update in two years.

The presenters for both the FDA and Roche seemed to suggest that the instances of reported encephalopathy (brain diseases) in Japan may have been related to the flu virus itself and not the drug, perhaps like the brain swelling associated with West Nile Virus. They pointed out that Japan has been aware of this phenomenon for over a decade (i.e., before Tamiflu came out) and has a number of scientists studying it.

How could Japanese scientists tease out this phenomenon while Americans remain in the dark? It turns out their national health service with its comprehensive individual records provides an excellent database for scientists investigating medical outbreaks and outcomes. Japan’s national health service also does a far better job than us at diagnosing the disease. How else can one explain the fact that a country with less than half the population of the U.S. reported 18 million influenza cases during the 2004-05 flu season, twice as many as in the U.S.?

The result is that Roche’s partner in Japan, Chugai, sold 24.5 million Tamiflu prescriptions in Japan since its approval five years ago compared to just 6.5 million in the U.S. Among children, the ratio was an even more lopsided 11.6 million to 1.3 million.

Since so few American kids have been taking the drug when they get the flu, perhaps then the U.S. would be a good “control” for testing whether there are rare but noticeable cases of encephalopathy among children who catch the flu each winter here. Then we might know that it was the flu and not the drug.

Alas, Centers for Disease Control and Prevention epidemiologist David Shay told the hearing that influenza is not a reportable disease in the U.S. Moreover, without a national health service to provide a common database, the only way the CDC can construct its estimate for how many flu deaths there are each year is through sophisticated computer modeling. In other words, they’re guessing.

Moreover, our "best health care system in the world" does a miserable job identifying kids sick with the flu. It extends beyond the fact that millions are uninsured and never see a doctor. “We’re not all that good at diagnosing influenza,” complained Janet Englund, an advisory committee member from Children’s Hospital in Seattle. “We don’t do a rapid test for flu like the Japanese do.” Indeed, a child with the flu here is just as likely to be fed useless antibiotics as an antiviral medication like Tamiflu.

Paul Krugman of the New York Times has been writing some excellent columns this week on the emerging fiasco of the Bush administration’s senior citizen prescription drug plan. He correctly argues a national health plan would make it less costly and easier to navigate for seniors.

It’s really exciting that someone is finally putting the need for a single payer system – a national health plan – on the policy agenda. But one important issue he hasn’t talked about yet is how critical national health services are to understanding the state of public health and public health needs. This is especially crucial when nations are trying to figure out the best way to prepare for potentially worrisome disease outbreaks like avian flu.

The Statin Mafia Strikes Again

Can somebody help me out here? Am I off base in this analysis?

The Journal of the American Medical Association today published an editorial urging older patients who’ve already had heart attacks to step up their intake of statin drugs to super shrink their “bad cholesterol” levels. The editorial was written in response to the latest clinical trial – funded by Pfizer – showing that high doses of its drug Lipitor, which is already the best selling drug in the world, is allegedly superior to routine doses of Zocor, which is made by Merck and will come off patent next year.

I write “allegedly” in the last sentence because that’s what the Scandinavian doctors, at least three of whom were on Pfizer’s payroll, concluded from the data in the so-called IDEAL trial (Incremental Decrease in End Points through Aggressive Lipid Lowering).

Here’s my problem: more people died from cardiovascular disease including heart attacks in the high dose Lipitor arm of the trial.

You read that right. Here’s the details. Over 4,400 people up to 80 years of age who had already had one heart attack were in each arm of the trial. After four years, 223 of the men and women on high dose Lipitor (80 milligrams daily, average “bad cholesterol” of 81) had died of some form of cardiovascular disease, including heart attacks. Only 218 of the folks on low-dose Zocor (20 milligrams daily, average “bad cholesterol” of 104) had suffered a similar fate.

It took me a while to figure that out because the authors never revealed the number. They instead reported that slightly more people died from other causes in the Zocor arm (156 versus 143 on Lipitor) and slightly more on Zocor died overall (374 versus 366 on Lipitor). Subtract the numbers and you’ll see what I mean.

My first instinct as a journalist was to ask, Don’t they have editors at JAMA? In a trial testing drugs on people with a previous history of heart attacks, this higher mortality stat sure seems relevant to me.

The Pfizer-funded docs chose to dwell on the positive. They led their report with the fact that their primary endpoint showed there were 52 fewer major coronary events in the Lipitor arm of the trial, 411 versus 463. However, this was not statistically significant, so the bottom line is that the trial failed. They then went on to highlight the fact that the high-dose Lipitor folks had 54 fewer non-fatal heart attacks, 267 verus 321, which did creep into the statistically significant territory.

A word of warning, though, before all you heart attack survivors out there sign up for high dose statin treatment to marginally lower your risk of suffering a second heart attack (even though it won’t reduce your risk of dying). About 5 percent or 220 people on high-dose statins developed seriously elevated liver enzymes and 43 had to withdraw from the trial compared to just 5 withdrawals from the Zocor group.

Even more amazing than the sleight of hand in the study was the over-the-top enthusiasm for high-dose statin therapy in the accompanying editorial by Dr. Christopher Cannon of the Harvard Medical School (whose financial disclosures showed he’s consulted for most major drug companies including Merck). “Lower is better,” he wrote. The study should “motivate any patients who have been hesitating about treating their cholesterol to talk to their physicians to get the benefits of intensive cholesterol lowering.”

Does that wording, “talk to your physician,” sound familiar? It the same language used in most statin drug ads.

Company-funded studies that bury significant data and editorial touts filled with Madison Avenue clichés. The editors at JAMA should be ashamed.

What the FDA Needs for Xmas

One of the major points University of Chicago economist Steven D. Levitt makes in “Freakonomics” is that information is power. I was reminded of that truism yesterday as I sat listening to presentations at the Food and Drug Administration’s hearing on the Prescription Drug User Fee Act. The law expires in 2007 and the FDA wanted public input as it begins the process of seeking renewal from Congress.

That law, enacted in 1992 after extensive pharmaceutical industry lobbying, was designed to reduce the time it takes the FDA to approve new drugs. And by that sole metric, it has been successful. The amount of time from a company’s new drug application – when it’s completed clinical trials and wants the FDA to approve marketing a drug – to the final FDA decision has been reduced from three years in the mid-1980s to slightly over a year today.

Over the same period, however, the amount of time that the average new drug remains in clinical development, which is measured from the time a company files an investigative new drug application (which takes place at the beginning of human safety studies) to its new drug application (after all the efficacy trials have been completed) has risen sharply, from about six years to over eight years. In other words, the total time for the average new drug to move through the pipeline hasn’t budged in a quarter century.

During a break in the hearing, I asked Janet Woodcock, the deputy director for operations at the FDA, for the agency’s analysis of the slowdown in the clinical trial phase, which is largely under industry control. Since agency staff interact with company officials throughout the process, they would know why one drug got dropped from development or why another had to go back to do a second safety trial before moving onto the next phase of testing for efficacy. Properly captured and analyzed, this data would be crucial information for companies hoping to understand where they had gone wrong. It also inform other companies about unproductive pathways, help them avoid meaningless clinical trials (and the heartbreak that causes the test subjects) and reduce overall drug development costs.

Woodcock told me neither she nor anybody else at the agency had ever studied the reasons why most drugs in the FDA system fail. They have no data on which experimental classes of medicines may have caused severe safety problems in early human testing. There is no databank that aggregates all clinical trial data for particular classes of drugs or that can be tapped to compare different classes of drugs aimed at the same condition.

I asked her why. She began describing the FDA’s computer system, which as near as I can tell from her description is still in the pre-Windows mainframe era.

Bringing the FDA’s information systems into the 21st century would do a lot for safety, too. Right now, the agency’s self-reporting MedWatch program, where physicians are supposed to report adverse events among their patients on drugs, has no capacity to provide those physicians with feedback about what other doctors are experiencing with those drugs. The result is that not many physicians use the system and safety problems remain locked away in physicians’ files.

During a presentation at the outset of the hearing, deputy commissioner Scott Gottlieb flashed a picture on the overhead screen of a white-coated technician screwing in vacuum tubes in the original Univac computer. He said it was a snapshot of the FDA’s Information Technology department. One item that should be high on Congress’ agenda when they get around to reauthorizing PDUFA is buying the agency a new computer system.

The Medical Innovation Downturn

It’s often been said we live in the greatest era of medical progress known to man. The problem with such statements is that you wouldn’t know it by hanging out at the Food and Drug Administration, the gatekeeper for medical innovation.

New statistics posted on the FDA website this week reveal that new drug approvals in the first ten months of this year fell 37 percent to 12 from 19 a year ago. This year’s decline is typical of the drug and biotechnology industries’ performance in this decade. New drug approvals in the new century are averaging about half the level of the 1990s.

Clearly, the industry that never tires of telling consumers that high drug prices bring new drugs to market is falling down on the job.

What gives? The drug industry, one of the most profitable industries in the nation, has poured billions into research over the past decade. Its lobbyists are among the most potent political actors in Washington. They've all but captured the agency responsible for regulating its products. User fees instituted in 1992 now cover half of the Food and Drug Administration's new drug evaluation budget and, as a result, the time needed to review a new drug application has been slashed to just a few months. Yet fewer and fewer drugs are moving through the pipeline.

While newspaper headlines focus on the safety problems of a handful of previously approved drugs, the agency’s leaders, who recognize their budgets are increasingly driven by industry user fees, are focused on this innovation drought. Deputy director Janet Woodcock last year launched a “critical path” initiative to look for ways to help the industry step up the pace of new drug development. Interim commissioner Andrew von Eschenbach, who simultaneously runs the National Cancer Institute, is pledging to “streamline” the FDA drug approval process, which as a practical matter means allowing the industry to win approval for new drugs that still have huge question marks hanging over their effectiveness.

Yet a decade’s experience with an “accelerated approval” process at the FDA is not encouraging. If the agency’s new leaders pursue this path, there’s little evidence to suggest it will help solve the problems plaguing the industry.

While most people think accelerated approval means the FDA has rushed a really important new drug to market because of its effectiveness, it actually means a potentially important drug has been given an early, conditional approval based on limited data regarding its efficacy. In exchange for this early access to market, the company promises to complete clinical trials within a reasonable amount of time to prove that the new drug is in fact a useful new therapy.

This has been a favorite path for many new cancer drugs. Since 1995, 25 cancer drugs for 29 indications have received accelerated approval. However, only 10 have completed trials confirming their benefit. Three have either been withdrawn or had their use restricted. Of the remaining 16 drugs, six have been on the market for at least four years without submitting new data to the FDA.

Earlier this week the FDA’s Oncology Drugs Advisory Committee (ODAC) heard testimony from the sponsors of those six drugs. One after another the companies complained about the difficulty of recruiting patients for trials or the arrival of superior therapies that made their planned trials superfluous. In one case, that of a marginally effective treatment for a rare skin cancer known as Karposi’s Sarcoma, which is almost exclusively the result of untreated HIV/AIDS, the drug’s sponsors admitted the disease had virtually disappeared due to the arrival of effective AIDS drugs.

Yet all six drugs remain on the market. “The companies don’t lose a lot if they don’t do the trials,” complained Silvana Martino, chairperson of the ODAC.

Next week, the FDA will hold hearings on the reauthorization of the Prescription Drug User Fee Act, which expires in 2007. Representatives of the Pharmaceutical Research and Manufacturers Association will undoubtedly testify that the payments associated with its new drug applications should remain focused on evaluating new drug applications. Otherwise, innovation will fall even farther than it already has.

The law, written with the help of their lobbyists, endorses this restricted use of the fees. Consumer groups will press to use those fees in other ways, such as analyzing the safety of drugs once they’re on the market, reviewing direct-to-consumer advertising or toughening oversight of clinical trial investigators. But they'll be told the law doesn't allow it.

Okay. Here’s an alternative suggestion for bringing some additional revenue into the agency to expand its lagging oversight responsibilities. The FDA should slap hefty penalties on companies that fail to complete those clinical trials promised when they received accelerated approval.

In the long run, such penalties will be good for innovation. They will encourage companies to stop dithering on marginally effective drugs, which can only be sold through expensive marketing campaigns, and focus their attention on bringing real breakthroughs to market, which, as every doctor knows, sell themselves.

Roche's Patent on Tamiflu Under Attack

In the wake of reports by Taiwanese scientists that generic manufacturing of the flu drug Tamiflu (oseltamivir) isn't that difficult, James Love of the Consumer Project on Technology launched a blistering attack on the Bush administration's failure to rapidly build a stockpile of the drug in anticipation of a bird flu pandemic.

I remain somewhat skeptical about the need for stockpiling a vaccine against an as-yet-undermined strain of flu (the annual flu vaccine always comes out about six months after the strains that pass easily from human to human are identified; the much-feared avian flu H5N1 isn't easily transmissible and wouldn't be the mutation that causes a pandemic, should one occur). But stockpiling flu drugs make sense. While Tamiflu isn't very effective -- in its clinical trials, Tamiflu reduced the severity of fever and associated symptoms of flu by about a day -- even a minor reduction in symptoms could mean the difference between life and death when combating a killer strain of flu.

So far, the U.S. government has refused to negotiate with Roche to license its drug to generic manufacturers or force it to do so. Instead, it's relied on market mechanisms. If we just give them enough money, perhaps they make enough drug.

Here's CPTech's response, sent out over the weekend on their listserve, IP Health:

1. Roche has clearly exaggerated and mislead government officials
about the difficulties of manufacturing generic Tamiflu (oseltamivir
phosphate). Government officials like US Health Secretary Michael
Leavitt or Australian Health Minister Tony Abbott have relied upon
this self-serving inaccurate information, and rejected measures that
would enhance the public's security. From here on, government
officials must be held to a higher standard, and be expected to do
some measure of independent due diligence. It's their job to be
right, not simply gullible, when preparing for a possible pandemic.

6. Governments that do issue compulsory licenses need to consider
the appropriate remuneration schemes for the patent owners. CPTech
recommends a different system for royalties for government stockpiles
than for private sector sales. A system of contingent royalties for
government stockpiles should be considered, as CPTech has proposed
(James Love, October 28 2005, "A better way of stockpiling emergency
medicines," Financial Times, http://www.cptech.org/ip/health/tamiflu/love10282005.html).

Last Week in GoozNews:

Flu Fever (Nov. 2)

Is the Bird Flu Vaccine Ineffective? (Nov. 2)

A Mystery Solved (Nov. 3)

Is Tamiflu Effective Against Avian Flu? (Nov. 4)

And Is the Season Flu Shot Effective? (Nov. 4)

To read these stories, go to:
http://www.gooznews.com/archives/2005_11.html

And is the Seasonal Flu Shot Effective?

Today's Toronto Star (registration required) reports on a recent Cochrane Collaboration review of the annual flu shot Americans are encouraged to take. It found that universal innoculation was not supported by the evidence. The Cochrane Collaboration is an international non-profit that analyzes the effectiveness of health care interventions.

According to the Star, a Cochrane group "reviewed 12 randomized control trials of the impact of the flu vaccine on healthy adults under 65 found it didn't meet any of its specific goals — to reduce the spread of the disease, the number of days lost from work or deaths and hospitalization from it."

On the other hand, the review found 19 per cent of those who had a flu shot got sick with influenza, compared with 23 per cent of those who didn't. That level of protection would be significant if the flu involved had a high mortality ratio. The avian flu strain H5N1, though not easily transmissible from person to person, has nearly a 50 percent mortality rate.

Is Tamiflu Effective Against Avian Flu?

There's been very little informed news coverage about the effectiveness of Roche's Tamiflu in curbing avian flu in the 150 or so people who've so far contracted the disease. Yet governments around the world are stockpiling the drug. Roche reports it plans to increase production this year with sales rising to nearly $1 billion, up from under $300 million a year ago. The company has even begun restricting supplies to curtail indivduals who are hoarding the drug.

Yet today's British Medical Journal reports that experts are questioning the drug's effectiveness against avian flu. Joe Collier, professor at St. George's Hospital Medical School in London and former editor of the Drug and Therapeutics Bulletin asks "what evidence there is that Tamiflu actually alters mortality? And if it doesn't then what are we doing? What it certainly does is shorten the illness by a day, but the question is—does that matter?"

The BMJ also reports the latest comment of Canada's federal health minister, Ujjal Dosanjh, who told listeners in an interview on a Canadian Broadcasting Corporation radio program that oseltamivir (Tamiflu) did not prevent infection with the flu virus and that at best it would reduce the severity of the illness."

How many billions for Tamiflu were in the Bush plan? And don't forget that Gilead Pharmaceuticals, which invented the drug, gets royalties for all sales of Tamiflu. Secretary of Defense Donald Rumsfeld is the former CEO of Gilead and remains a major stockholder.

A Mystery Solved

It took a few days, but I finally figured out the logic behind the Bush administration’s plan to spend $1.2 billion for 20 million doses of avian flu vaccine. This comes out to $60 a dose, far higher than previous flu vaccines which have been made available to public health authorities at $10 a dose or less.

Why the disparity? A spokesman for the Health and Human Services Department late Wednesday explained it this way:

Earlier this year, the National Institutes for Allergy and Infectious Diseases (NIAID) developed an experimental vaccine that prompted a weak immune response against H5N1 avian flu in about 400 test volunteers. In order to get that response, the government investigators had to inject two 90-microgram doses of vaccine – about 12 times the size of the seasonal flu vaccine, which weighs in at 15 micrograms.

On top of this weak response, there is a strong likelihood that the H5N1 avian flu vaccine won’t be very effective against the mutation that causes a pandemic. After all, it will be different from H5N1, which doesn’t easily move from human to human.

Despite these weaknesses, the government late last month ordered 20 million 15-microgram units of the H5N1 vaccine from Sanofi-Pasteur for $100 million ($5 per 15-microgram unit) and 12 million 15-microgram units from Chiron for $62 million (also about $5 per 15-microgram unit).

In outlining the advanced purchase program Tuesday, officials at HHS assumed it would take 12 of these 15-microgram units per vaccine if it was going to provide any help at all. That comes to about $60 per vaccine. This is nearly as high a price as gougers charged last year when the seasonal flu vaccine ran short, but it is reasonable in this case because the volume (and hence the amount of chicken eggs needed to produce it) is 12 times the size of the seasonal flu vaccine.

Meanwhile, Dr. Daniel Vasella, the chairman of Novartis, told the Wall Street Journal yesterday that the company wanted immunity from lawsuits before launching into manufacturing this “experimental” vaccine, which hasn’t been adequately tested in human. The company earlier this week offered to buy the 58 percent of Chiron it doesn’t already own for $5.1 billion and the last thing it wants on its hands is a Johnson & Johnson scenario (that company is backtracking from its offer for Guidant, the medical device manufacturer which has had numerous manufacturing problems with its cardiovascular stents).

The Journal also carried an interesting op-ed today by Johns Hopkins infectious disease specialist Donald S. Burke, who endorsed the Bush administration’s $7.1 billion program. But in doing so, he pointed out that beefing up the nation’s public health infrastructure and response capability was really the most important part of the plan.

“Can we stop it?,” Burke asked. “My public health and computational modeling colleagues have been furiously at work devising strategies to stop an epidemic or mitigate its impact. Our models show that it may be possible to identify a human outbreak at the earliest stage, while there are fewer than 100 cases, and deploy international resources -- such as a WHO stockpile of antiviral drugs -- to rapidly quench it. This 'tipping point' strategy is highly cost-effective. More reactive strategies, in which the U.S. protects its own borders in the face of a growing global pandemic, will have limited success. U.S. leadership in the International Partnership of Avian and Pandemic Influenza is a visionary step. Epidemics are global in nature, and demand a concerted international response if they are to be thwarted. The new mindset should be one that focuses upstream on the earliest events, emphasizing prediction and prevention before a pandemic begins.”

Burke still wants the government to pour money into stockpiling antivirals and vaccines. But like most public health experts, he knows that the best way to prevent a pandemic is to nip it in the bud with a strong public health response.

Is the Bird Flu Vaccine Ineffective?

The Effect Measure blog, by public health specialist "Revere," reports this interesting perspective on the $1.2 billion the Bush administration wants to spend on H5N1 vaccines (see my previous post):

"There is no vaccine yet. The experimental batch that went through clinical trials a few months ago showed itself unable to protect people unless unrealistically high doses were used. And the strain it was directed against has already changed, so the best one could hope for would be some residual cross protection."

$1.2 billion for that while state public health agencies, who could really do something to protect the public by rapidly identifying and isolating initial cases, gets a few measly millions while being asked to subsidize the purchase of vaccines? It looks like the Katrina responders are still in charge.

Flu Fever

President Bush yesterday called for spending $1.2 billion for 20 million doses of an avian flu vaccine that may not work and may never be used. Details of the program are sketchy, so it is hard to know how that money will be spent. Does it include money for research for alternative vaccine manufacturing techniques? According to news accounts this morning, research is included elsewhere in his $7 billion program. My calls to the National Institutes of Health seeking details were not returned. So as now reported, the government announced a plan to pay $60 a dose.

Previous flu vaccines cost $10 a dose or less. There was one experience with higher prices. Last fall, when Chiron's plant in Great Britain was shut down by regulators because of lax manufacturing practices and many nursing homes couldn't get shots for their vulnerable clientele, distributors of existing stockpiles began charging as high as $80 a dose for the routine innoculation.

Is the administration planning to pay gouger rates for its stockpile? Is this the latest Halliburton-style contract about to be awarded by the Bush administration?

The president's announcement came one day after Novartis bid $45 a share or $5.1 billion to acquire the 58 percent stake in Chiron it doesn't already own. This represents a 23 percent premium to Chiron's price last fall after its plant was temporarily shuttered.

Last month, the National Institutes of Health awarded Chiron a $62 million contract to produce an flu vaccine that NIAID director Tony Fauci confidently predicted would be effective against the H5N1 strain of avian flu. I called NIAID yesterday to find out how many doses that represented, but my query disappeared into the maw of the agency's public relations department and wasn't answered.

While this strain of bird flu has killed about half the 120 people who have been infected worldwide, the strain has not yet shown it can be spread by human-to-human contact -- the necessarily precondition for a human pandemic. If it mutates into the global threat feared by public health officials, there is a strong likelihood the avian flu vaccine about to be purchased won't be effective against that mutation.