Tone Deaf

I wish I had been invited to yesterday's briefing by Food and Drug Administration commissioner Andrew von Eschenbach. According to this morning's New York Times, the former cancer surgeon expressed dismay that patients may be getting the wrong message from the media about drug safety concerns. He also believes his agency should be working more closely with industry to develop new ways to get new drugs approved faster. And when pressed on the latter point, he demurred by saying the agency should be working more closely with academics, too.

Meanwhile, over in the FDA press office, ABC News ("Nightline," tonight at 11:35 p.m. EST) is reporting that a former drug industry p.r. guy now working for the FDA is running a disinformation campaign against Steve Nissen, who published the study warning of heart risks from the diabetes drug Avandia in the New England Journal of Medicine last week.

Water Cooler Conversations . . .

. . . I would have liked to have overhead yesterday:

The one inside the FDA safety department after learning that the former head of China's drug regulatory agency faced execution on corruption charges.

The one inside former FDA commissioner Lester Crawford's office (wherever that is these days) after hearing the same thing. (Crawford resigned in a conflict-of-interest scandal.)

The one inside the offices of America's Health Insurance Plans (the insurance industry trade association) after presidential aspirant Barack Obama proposed a National Health Insurance Exchange -- a form of national regulation of their industry.

On that latter point, this is something the Democrats in Congress can move on right away if they're really interested in showing they are interested in health care reform. We've never had national regulation of the insurance industry in the U.S. It's handled on a state-by-state basis. By imposing national health insurance rules that would forbid companies from discriminating against people with pre-existing conditions and establish so-called community rating pricing schemes that pool risk across entire populations (probably by state or region), Congress could show that America is indeed ready for health care reform.

What Price Innovation?

I participate in an off-line listserve discussion about contemporary issues that over the past few days turned to a discussion of the various health care reform plans being proposed by Democratic candidates. One commenter suggested the plans fell short because they didn't address how Democrats would promote medical innovation, which leaves them vulnerable to charges that plans to negotiate drug prices or restrict access to less effective drugs would choke off medical research. Here's my response, framed at the outset by a series of rhetorical questions:

What's your definition of "slowing" the pace of pharmaceutical innovation, the feared outcome of a tough payer stance on price and me-too drugs (the formulary question)? Is it the number of new drugs approved by the FDA? The number of "significant" new drugs approved by the FDA? Is it the number of additional quality-adjusted life years theoretically achievable by broad diffusion of a new drug approved by the FDA?

Is there any evidence to suggest that the pace of significant medical breakthroughs can be associated with higher drug industry sales, profits, profit margins or, perhaps most significantly, R&D expenditures? Or, put another way, given the past decade's very high rates of sales growth, profit growth and R&D expenditure growth, how does one explain the steady downward decline (trend line; there is, of course, year-to-year variation) in the number of significant new drugs emerging from industry labs?

Are we at a point in the history of the evolution of the U.S. health care system that medical progress is best advanced via new medical interventions? What do we need, a seventh or eighth class (I've lost track) of drugs to treat hypertension, or a public health program that treats the 10 million Americans, mostly poor and black, whose hypertension goes untreated with the drugs we have?

What is the cost of developing a new, effective Alzheimer's drug? The answer is an infinite amount of money, since the denominator in that equation is zero. We've spent billions looking at this disease, and we still don't have an effective drug. Anything divided by zero is infinite. Ditto for many cancers.

Why? Because our basic understanding of the natural history of the disease hasn't evolved to the point where _____ (fill in the blank with either industry or government given your ideological predilection) can deploy the skills of drug developers to rationally design effective ways to intervene in what appears to be one of the natural processes associated with aging.

If that is true, where would you put your marginal research dollar tomorrow for coming up for a cure for Alzheimer's, or the many forms of cancer, or ALS, or Parkinson's? Would you give it to industry via the mechanism of higher prices in the hopes that they will invest it wisely in these long-term, difficult research projects?

Or would you let the taxpayers via NIH invest it in a targeted research campaign aimed at diseases that would have the greatest public health payoff? By the way, the greatest breakthrough of the last quarter of the 20th century -- the triple cocktail for treating people with HIV/AIDS, which reached fruition in 1996/97 -- was achieved through precisely such a campaign.

Oil Price Sticker Shock

Now that gasoline prices have soared beyond $3 a gallon, I'm reading the business stories on the subject a bit more closely. I'm even reading those full page ads from "the people of America's oil and natural gas industry," which claim it's all about the price of crude oil, which accounts for 56 percent of each gasoline dollar.

If that were true, how do you explain the fact that when gasoline prices (in real, inflation-adjusted dollars) peaked at $3.29 per gallon in March 1981, the real, inflation-adjusted price of a barrel oil was $89. This month, according to the Energy Information Agency, the price of oil going into our $3.01 gallon of gas (national average) is $60 a barrel (this is the actual acquisition price, not the future prices, which closed yesterday just under $66 a barrel).

Nasty facts. They always did get in the way of a good story. And they certainly don't have to be taken into account by Big Oil's advertising departments.

A poll-driven story on the front page of the Washington Post business section suggests people won't change their driving habits until gasoline reaches $4.38 a gallon. It explains these results by pointing to higher average household incomes today (so fuel takes a smaller relative bite out of paychecks despite the high prices) and the absence of alternatives. People have to drive, to get to work, to get to shopping, and, for most people, to go on vacation.

It only mentions in passing the unequal impact of rising prices. If you're driving to a job that pays Wal-Mart wages, eliminating your daily latte to pay for gas isn't really an option.

The story left out another important factor, however. Fuel efficiency has gone up in the past quarter century -- from an average of 15.6 miles per gallon to 21.5 miles per gallon today. So while we're driving more miles, the average cost per mile driven today (including the vehicle depreciation, insurance, etc.), even with comparable gasoline prices to 1981, is just 14 cents compared to 20.9 cents per mile shortly after Ronald Reagan became president and the U.S. economy was still reeling from the second great oil price shock of the 1970s.

Which brings me to the oil industry press release masquerading as a news story that was on the front page of the New York Times this morning. Based almost exclusively on oil industry executive quotes, the story is premised on the idea that refinery capacity shortfalls are responsible for the current run-up in gasoline prices and that "uncertainty" in the current environment due to government support for ethanol substitution is causing the industry to cut back on plans to expand refinery capacity.

So what is it, Mr. Oil Industry Executive? Crude oil prices or refinery capacity shortfalls? The crude oil data suggests neither supply and demand nor the cost of inputs plays a determining role in pump gasoline prices. They matter, of course. But the ultimate driver of pricing in this oligopolistic industry is whatever the market will bear.

The falling price of driving and rising incomes, coupled with a compliant government whose Justice Department and Federal Trade Commission do not believe this nation still has antitrust, anti-price gouging and other statutes outlawing anti-competitive marketing practices, means the oil companies can charge whatever they can get away with. And it looks like this driving season --- the second-to-last of the man the oil industry put in the White House -- that is going to be a lot.

FDA Rejects Sunlight

"Sunlight is said to be the best of disinfectants," Supreme Court Justice Louis Brandeis famously wrote. Alas, if Mother Nature submitted sunlight as a new drug to the Food and Drug Administration, she would get turned down flat.

In the wake of the latest study showing heart attack risk in an FDA-approved drug -- a study that was only enabled by the company's public release of dozens of clinical trials on its own website -- there have been increased calls for greater transparency of clinical trial results. The FDA reform bill passed by the Senate two weeks ago had a limited disclosure requirement, which was backed by the Pharmaceutical Research and Manufacturers Association, the drug industry's powerful lobbying arm.

There was nothing in the bill requiring that companies and independent investigators post all trial results, including those conducted after drugs hit the market. Companies often run dozens of these trials to promote new drugs among the practicing physicians paid to enlist their patients in the trials.

What does the FDA think about public release of data? Barry Meier in today's New York Times elicited this quote from Steve Galson, director of the Drug Evaluation and Research division of the FDA: “I would be very concerned about wholesale posting of thousands of clinical trials leading to mass confusion,” he said.

Meier then noted the recommendations in last year's Institute of Medicine report, which called on the FDA to release summaries of all clinical trial data it collects on new drugs, both pre- and post-approval. The FDA sees the recommendation as overly burdensome. “It is not that we are philosophically opposed to it, but the work would be enormous,” Galson said.

I spoke yesterday with Steve Nissen of the Cleveland Clinic, who conducted the analysis of Avandia, GlaxoSmithKline's diabetes drug that probably carries an increased risk of heart attack compared to cheaper alternatives. "This whole situation shows how important transparency is," he said. "There are independent players out there without axes to grind who need access to this data."

Nissen's statistician (he himself is not an expert in manipulating statistics) pooled the results of 42 clinical trials to come up with the analysis. Would individual consumers, if given access to the data, get confused or misled if they looked up an individual trial and drew an incorrect conclusion?

It's a risk, of course. But would they be any more confused than they now are from the information they get from direct-to-consumer (DTC) advertising? Let's not forget that a provision in the FDA reform bill calling for a two-year moratorium on DTC ads on some new drugs was rejected because it limited commercial freedom of speech. In 21st century America, the right to misinform consumers is protected, but consumers' right to information is denied because they might misinform themselves.

"To have a drug on the market for eight years and still not have the outcomes data is too long," Nissen said.

What does the top official at the FDA think about greater and earlier disclosure? In a response printed alongside a USA Today editorial that pointed out that the company gave the FDA much of the latest data about Avandia last August, FDA commissioner Andrew von Eschenbach noted the warning issued Monday. "Oour policy, which we followed with Avandia, is to inform the public about potential risks at the earliest appropriate time, even if our investigation is not complete," he wrote.

The timing of this statement undermines its credibility. The warning was issued a few hours after the release of Nissen's study.

Art Levin of the Center for Medical Consumers, who serves as the consumer rep on the drug safety advisory committee at the FDA, yesterday outlined what he thought ought to be in the House version of the FDA reform bill:

* Complete transparency of data derived from all studies and trials; and FDA access to insurance industry (including Medicare) databases so the agency can determine how drugs are being used and what outcomes they are generating. "The public health can only benefit from having lots of good minds analyzing complete data and reaching their own conclusions," he said.

* Prescribers and the public should always be immediately alerted to any signals of serious toxicity – the duty to warn should take precedence over any other considerations; and

* An independent safety office, one whose culture is all about public protection and whose triumphs are uncovering safety problems and resolving them appropriately.

The IOM report noted problems in the internal culture at the FDA. Since passage of industry user fees in 1992, the mindset at the agency has gone from protecting the public from unsafe or ineffective drugs to one of helping industry get more and faster new drug approvals. Galson's comments are a perfect reflection of that mindset.

FDA Told To Act on Avandia Five Years Ago

Safety analysts at the Food and Drug Administration told the top brass five years ago that thiazolidinediones like GlaxoSmithKline's Avandia (rosiglitazone) posed a heart attack risk to diabetics. Public Citizen released the internal memo today.

Glaxo's Avandia Causes Heart Attacks -- NEJM

There’s just one word for fading drug industry hopes that the House discussion over reauthorizing user fees for the Food and Drug Administration will ignore safety reforms. That word is “Fuhgeddaboudit.”

The New England Journal of Medicine this afternoon released a pooled analysis by Steven Nissen of the Cleveland Clinic showing that the heavily marketed diabetes drug Avandia from GlaxoSmithKline increases heart attack risk in the millions of patients who have taken it since it was approved in 1999. In fact, it increased that risk by 43 percent over other drugs or placebo.

Nissen was one of the first doctors to raise similar concerns about Vioxx.

The impact was immediate. The House vowed to hold hearings. Here’s Energy and Commerce chairman John Dingell’s (D-MI) quote, taken from Reuters:

"It is incredible that the agency charged with protecting the public health has such a poor record when it comes to post market drug safety. Regrettably it is incidents like this that demand legislative changes in the way FDA deals with drug safety. The Committee will address these dangerous shortcomings while writing legislation to reauthorize PDUFA."

Indeed, the outlook now is that the House will pass much tougher legislation than the Senate, which passed its version two weeks ago.

Nissen and his colleague Kathy Wolski looked at 42 studies that tested Avandia (rosiglitazone), which reduces blood-sugar levels in diabetics. Some studies compared it to metformin, a generic commonly used for glycemic control. Others compared is to sulfonylurea, insulin or placebo. In every case, Avandia increased the risk of heart attacks or deaths from cardiovascular disease, although not all reached statistical significance. Pooled together, though, and the pattern was clear.

“In view of the potential cardiovascular risks and in the absence of evidence of other health advantages, except for laboratory measures of glycemic control, the rationale for prescribing rosiglitazone at this time is unclear,” wrote Bruce Psaty of the University of Washington and Curt Furberg of Wake Forest in an accompanying editorial. “Unless new data provide a different picture of the risk-benefit profile, regulatory action by the Food and Drug Administration is now warranted.”

The FDA issued a mild warning late Monday afternoon. "There is inherent risk associated with switching patients with diabetes from one treatment to another even in the absence of specific risks associated with particular treatments. For these reasons, FDA is not asking GlaxoSmithKline, the drug's sponsor, to take any specific action at this time. FDA is providing this emerging information to prescribers so that they, and their patients, can make individualized treatment decisions," the agency statement said.

Once again, millions of Americans have been subjected to unwarranted risks from a drug that had no real benefits over other, cheaper drugs already on the market. And now that they're on this more expensive drug, they face additional risk if they decide to get off because of what they just learned. Thanks a lot, FDA.

Where should the House go with this? Here’s some of the things that should be put in their bill that were left out of the Senate legislation:

• Anytime a drug is approved on a surrogate end point (like glycemic control), the FDA needs to demand that the company conduct a comprehensive post-marketing trial large enough to identify all risks and benefits associated with the drug. And if the company doesn’t complete the study in a timely manner, the FDA should immediately withdraw it from the market.

• All clinical trials must not only be registered at the outset of the trial, but there results must be posted. Moreover, researchers need to have access to the data, right down to patient level whether or not that information was sent to the FDA.

• The FDA needs to make all of its data available to outside researchers. “Further analyses of data available to the FDA and the manufacturer would enable a more robust assessment of the risks of this drug,” they wrote.

Moreover, the bill should include a total ban on conflicts of interest on the advisory committees that consider these drugs. In February, Glaxo sent a letter to physicians warning them about increased bone fractures in women who take Avandia. This finding was an outgrowth of a company-funded study released in December – also in NEJM -- that claimed Avandia used as monotherapy for newly diagnosed diabetics lengthened the time until patients need a second drug or insulin. The authors of that study, all of whom had some type of financial tie to Glaxo, admitted that it was “not designed to evaluate cardiovascular disease outcomes.” How did the Glaxo-funded physicians get their result? Their trial had a shorter follow-up period and younger patients who had better glycemic control when entering the study, they admitted.

Does Congress want those doctors on the advisory committee that will inevitably be called to consider this latest analysis of Avandia?

Sick and Sicko

The media bandwagon is starting to role on health care reform. Michael Tomasky gave a glowing review in the Washington Post to the new book, "Sick," from Jon Cohn of The New Republic. The book focuses on the individual struggles of families who fall through the cracks of our patchwork insurance system. The only criticism in the review is Cohn's failure to take on the special interests who benefit from the current system -- the doctors, hospitals and drug companies.

I also noted the first ads for Michael Moore's "Sicko." The film, which makes its debut at the Cannes film festival, promises to do for health care what the populist propagandist previously did for General Motors ("Roger and Me"), the gun lobby ("Bowling for Columbine") and the war in Iraq ("Fahrenheit 9/11").

Both efforts, I'm afraid, incorrectly characterize the health care mess as an insurance crisis. But Nick Kristoff in today's New York Times (I'd provide a link, but it is part of their proprietary product) hits some key notes in his positive review of Democratic candidate John Edwards' health care reform plan. Says Kristoff:

But universal coverage is only part of the answer. We also need far greater attention to public health programs focusing on prevention. Two of the most important life-saving health interventions in recent decades weren’t medical at all: the cigarette tax and laws mandating air bags and seat belt use. A national public health campaign on obesity (similar to the one Gov. Mike Huckabee started in Arkansas) should be an essential component of health care reform.

When will someone start doing studies comparing the cost-effectiveness of spending money on prevention interventions versus health care interventions? A few billion spent on identifying people with hypertension and pre-diabetes in poor and minority communities, and then helping them correct those situations, would save the health care system far more down the road than what these government programs would cost today.

Marcus Welby, Insider Trader

The abstracts from the upcoming American Society of Clinical Oncology meeting have arrived on physicians' desks and stock are jumping. And falling.

According to today's "Heard on the Street" column in the Wall Street Journal, physician/stock analysts on the payroll of the major investment banking houses are complaining to ASCO that its 20,000 members are trading on the abstracts. Other sources quoted in the story say, not so, it's just friends of these physicians who "hear" about what is contained in the abstracts.

An ASCO spokesperson says the group includes a cover sheet on the shrink-wrapped abstracts that clearly warns physicians who are planning to attend the meeting to keep the info to themselves.

That's clearly not working. Two years ago, there was a brouhaha over cardiologists serving as investment advisers to Wall Street firms. Now we have oncologists engaged in insider trading.

Where's the Securities and Exchange Commission? I've yet to see a news story reporting a single indictment. Early in this decade in the wake of the bubble collapse, Congress passed a "fair disclosure" law that required that all investors get equal access to relevant financial information when it is released. Abstracts of studies that could affect the price of a drug company's stock certainly would fall into that category.

As Jay Markowitz, a stock analyst for T. Rowe Price, told the Journal: "I'm disgusted by the fact that ASCO has continued this policy of releasing the abstract to thousands of members weeks ahead of the conference. I want to make sure there is a level playing field and people aren't trading in a way that disadvantages the rest of the market."

Science, Not The Market, Will Decide

Today's New York Times brought another one of those hyped, early-stage science stories that I hate. Any editor with half a brain should have told the reporter that (s)he only had half a story, and needed to do a bit more reporting.

This one involved a young Harvard researcher named Darren Higgins who is searching for vaccines using a new, proprietary technology for identifying pathogenic proteins that could "speed up the time it takes to discover vaccine candidates."

Of course, then vaccine developers would have to do what has already been done for Heptatis B and cervical cancer (Gardisil). The vaccine manufacturer expresses pathogenic protein targets in bulk, then sticks them in a vaccine to generate immune responses that wouldn't otherwise be generated because the target protein was inside the host's cells. Or, the pathogenic protein was expressed in such minute quantities by the invader that the immune system never noticed it.

Everyone pursuing vaccines today is using this technological approach since all the vaccines that could be done by injecting dead or attenuated pathogens already exist. Smallpox, polio, measles, chicken pox, mumps, etc. etc. were the low-hanging fruit of the vaccine revolution. Now we're on to the tough nuts.

But instead of a discussion about the scientific difficulty in identifying proteins that would make suitable vaccine targets, the story suggested that:

In 2006, the market gave him some validation. In two separate rounds of financing, venture capitalists invested about $5 million in Genocea (Higgins' start-up firm), giving the company seed money for two to three years of development. The company has about 15 full-time employees, and has begun applying its technology to numerous diseases to try to discover their immune-system-provoking proteins. (For competitive reasons, the company declined to say which diseases it is researching.)

I checked the Patent and Trademark Office for any patents, either granted or pending, in either Higgins' or Genocea's names. Nothing came up. What I did find (in the National Institutes of Health database) was that Higgins and Harvard have received two major National Institutes of Allergy and Infectious Diseases grants for research in this field.

I wish Higgins well in his quest. As Anthony Fauci, head of NIAID and funder pf Higgins' pre-clinical work pointed out in the story, vaccine research is indeed undergoing a renaissance as scientists pursue biotech-derived protein vaccines for a number of diseases, including many neglected diseases that affect the developing world like malaria and hookworm. But the road is long and tough, and I suspect those scientists that make the greatest progress will be the ones that share their setbacks and triumphs with other researchers in the field, not the ones that try to put a proprietary stranglehold on the research tools needed to do the work.

CMS Moves to Curb EPO Use

The Center for Medicare and Medicaid Services yesterday proposed sharp cutbacks in EPO use by oncologists treating cancer chemotherapy patients. The agency clearly had been waiting for the results of last week's Oncologic Drugs Advisory Committee meeting at the Food and Drug Administration.

The proposals can be found here. In brief, the agency proposes to turn down payment for EPO if the cancer patients have underlying heart conditions; if their anemia is related to radiation; if their anemia isn't cancer-related; or if they are taking anti-angiogenesis drugs like Avastin.

The agency also says it won't begin paying for Aranesp or Procrit (Amgen's and J&J's anti-anemia drugs, respectively) until red blood cell counts drop to 27 percent, which is a hemoglobin level of 9 grams per deciliter. CMS also will limit total usage within any four week period, cap payments to 12 weeks per year, and cut off payments if patients respond poorly to the drugs, according to the proposal.

Even though last week's meeting documented the higher mortality associated with excessive use of these drugs, expect Amgen and J&J, not to mention some oncologists who are profiting handsomely from higher usage, to issue howls of protest over these proposals. Deadline for comments is June 30th.

Health and Wealth

I attended an American Heart Association conference late last week where the most interesting thing I bumped into was a poster by Dr. Santiago Garcia and his colleagues at the University of Minnesota. The group followed 100 veterans who arrived at the local Veterans Administration hospital after heart attacks or strokes. They followed the patients for six months.

Then they tabulated their outcomes based on self-reported income. They divided the men into four equal groups. The top two quartiles (incomes of $11,800 to $22,800 and $22,800 to $116,000) had survival rates after six months of 94 and 91 percent, respectively. The bottom two quartiles (incomes of $1,200 to $8,500 and $8,500 to $11,800) had survival rates of 64 and 63 percent, respectively.

Each of these groups got the same exact health care -- at least, that is what Dr. Garcia and colleagues claimed in their poster. As a favorite professor of mine once said: "Discuss."

The health care debate would be a lot more interesting to most Americans if the media began paying attention to who gets sick in this society, why they get sick, and why they have worse outcomes even after receiving adequate care. I wonder if any politician will have the gumption to put the nation's health at the center of the health care debate. It would be a lot more interesting than endlessly fressing about the 15 percent of Americans who lack health insurance -- as tragic as that is.

Where's Waldo on Conflict of Interest Disclosure

The Massachusetts Medical Society, publisher of the New England Journal of Medicine, also publishes a popular line of journal digests for busy physicians. The latest issue, out today, of its "Women's Health" newsletter reviews the latest literature on giving antidepressants to pregnant women. Here's the bottom line from Harvard professor Claudio Soares:

Despite the cautionary remarks commonly made by most regulatory agencies and medical societies about the use of psychotropic medications during pregnancy, considerable data supporting the efficacy and reproductive safety of antidepressants have accrued. Conversely, evidence suggests that untreated depression has negative consequences for both mother and child.

It would have been nice if the article, one of the few from the publisher that is freely available on the Internet, had let subscribing physicians or inquiring consumers know that Dr. Soares receives consulting and speakers fees from a half dozen manufacturers of antidepressant drugs, and has conducted research for Eli Lilly. Instead of publishing that information at the end of the article, where most conflict-of-interest disclosure statements get placed, Journal Watch disclosed Dr. Soares' financial ties here, which is two clicks down from the journal's "site map" page.

Advisers Tell FDA to Curb EPO Use

An outside advisory panel has asked the Food and Drug Administration to issue new warnings that will dramatically scale back the use of anti-anemia drugs if the warnings are heeded by the nation's oncologists.

You've seen those television ads. They show beaming older cancer patients playing with their grandkids. Why? Now they have the energy because of J&J's Procrit and Amgen's Aranesp.

These are the same drugs that were the subject of a front page story in the New York Times yesterday that documented the lucrative rebates that physicians rake in from those companies for prescribing (and over-prescribing) the drugs. Most of the overprescribing is done in the name of reducing the fatigue that accompanies chemo.

The FDA reviewer who presented the agency's analysis to the Oncology Drugs Advisory Committee had a big problem with those claims. "Improved quality of life, fatigue and other symptoms associated with anemia has not been established in properly conducted, randomized, double-blind, placebo-controlled trials," he said.

What has been been in shown in a handful of recent trials is that raising red blood cell counts to near normal levels in chemotherapy patients actually leads to worse outcomes. FDA reviewer Vinni Juneja pointed to two head-and-neck cancer trials that had to be terminated early because they increased mortality. Another trial involving breast cancer patients increased mortality and shortened the time to tumor progression -- a key indicator that the cancer is spreading.

"How is it possible that something that was supposed to help me might have made things worse?" asked Lilla Romeo, a 60-year-old breast cancer patient who's been battling the disease since 2000. The false hope offered by the ads run by the companies was "both insulting and cruel," she said.

Once again, a drug company's efforts to expand the use of a blockbuster drug has boomeranged. Vioxx' cardiovascular risks were only conclusively proven when Merck paid for a massive trial that sought to show that the painkiller curbed colon polyps, which may be precancerous. In this case, Amgen wanted to show that taking high doses of EPO improved cancer outcomes. Several studies had suggested a "potential therapeutic benefit," Roger Perlmutter, Amgen's chief scientist, told the committee.

Stock analysts will spend years pondering why Amgen wanted to get an anti-cancer indication for Aranesp in the first place. Their lucrative rebates, coupled with numerous studies (never placebo-controlled) showing improved "quality of life" for patients, had turned the oncology profession into a willing accomplice to their marketing schemes.

"The problem is that the doctors get about $1,200 for every dose of the drug that they give," said Otis Brawley, a professor of oncology at the Wiship Cancer Institute in Bethesda, Md. and a member of the advisory committee. "They don't have to sign any conflict of interest statements like we do. That's a real problem." Given the high profile nature of the controversy, the FDA finally managed to put together an advisory committee without any conflicts of interest.

And at the end of the day, a committee without any ties to Amgen or J&J asked the FDA to specifically state in the label that EPO shouldn't be used in cancer patients where trials have shown adverse safety signals for that particular type of cancer -- like breast and head-and-neck cancers. They also voted to lower the red blood cell count at which anti-anemia treatment should be initiated.

And, they asked the FDA to demand more clinical trials from Amgen and J&J to definitively test the proposition that anti-anemia treatment actually makes people feel better (there's no doubt that it reduces the need for blood transfusions, its original approved indication, but that can be achieved at greatly reduced use of the drugs).

Curiously, the only time that Richard Pazdur, who heads the FDA's cancer drugs division, spoke at length during the meeting was to criticize his own agency on its monitoring of direct-to-consumer advertising. Just like in the Vioxx case, the ads played a major role in triggering this latest drug safety crisis. "We have a lot of problems with advertising, but the office (in charge of monitoring ads) has a lot of discretion," he said. "The FDA's chief counsel office obviously sets the tone.

"I want to thank the advisory committee for bringing this up," he continued. "They (the FDA) have to give the American people a good explanation for why these ads were allowed to continue."

Pazdur's comments provided a proper epitaph for yesterday's action in the Senate, which overwhelming passed reauthorization of FDA user fees. Admittedly, the bill included a few measures that give the agency more oversight powers. But one of the amendments tacked on at the last minute to placate the broadcast and publishing industries watered down the agency's ability to force ads off the air.

And another amendment, which would have severely limited the FDA's ability to appoint outside advisers with conflicts of interest, was narrowly defeated. Today's vote showed what happens when the FDA appoints committees without such conflicts. They do the right thing.

One Day in Iraq

If, as many say, a core problem at the Food and Drug Administration is its reliance on industry user fees to fund basic operations, then the following fact may be useful for lawmakers in the House who will consider changes to the just-passed Senate bill:

The money the FDA collects from industry to run its operations is about equal to one day's spending on the War in Iraq.

The FDA will collect under $400 million from industry this year, and in exchange is held to strict controls on how it can spend that money (not too much on safety) and how long it can take to review new drug applications (not too long).

The U.S. has spent in excess of $500 billion since the war in Iraq started four years ago. The latest supplemental appropriations bill for the war includes $84 billion to prolong the U.S. occupation of that beleaguered country for another six months. That's about $410 million a day.

Senate Rejects Limits on FDA Waivers, Then Passes Extension of User Fees

An amendment that would allow just one scientist with a conflict of interest to serve on a Food and Drug Administration advisory committee went down to a narrow defeat Wednesday. The vote on legislation offered by Senators Richard Durban, Jeff Bingaman and Barack Obama (the presidential candidate became a sponsor on Tuesday) was 47-47, with prominent Democrats like Sen. Ted Kennedy (D-MA), John Kerry (D-MA) and Christopher Dodd (D-CN) voting against the bill. Tie votes on amendments do not pass, according to Senate rules.

An amendment by Sen. Charles Grassley that would give greater voice to the FDA's safety division also went down to a narrow defeat. However, the Senate add stronger civil penalties to the bill.

After the conflicts of interest amendment went down to defeat, the reauthorization of drug user fees, which are used to speed the approval of industry's new drug applications, passed the full Senate with just one dissenting vote. That drew a heated reaction from Peter Lurie of Public Citizen, the safety watchdog group that closely monitors the FDA.

"It is a fundamental conflict of interest to have an industry be able to dictate to an agency the speed at which reviews will take place," Lurie told the Washington Post. "And yet that's exactly what happens and nobody challenged that in a fundamental way."

While there are some minor improvements in drug safety programs at FDA contained in the bill, the Senate in recent days rejected limits on direct-to-consumer advertising and refused to allow Americans to import drugs from Canada. Researchers will get better access to clinical trial data that companies submit to the agency, and companies will have to spell out their risk management plans for drugs with significant side effects that get approved by the agency.

The bill now moves to the House, where companion legislation sponsored by Henry Waxman (D-CA) and Edward Markey (D-MA) has conflict-of-interest language comparable to the bill that just passed the Senate. A number of representatives have indicated strong interest in authoring a total ban on scientists with conflicts of interest serving on FDA advisory committees.

EPO Kickbacks

They're perfectly legal, but let's not mince words. When physicians derive income from prescribing drugs, it's a kickback. And that's what the New York Times documents today in its eye-opening front-page story on oncologist payments from Amgen and Johnson & Johnson, which market anti-anemia drugs for cancer patients.

It's an old story, frankly. Some Congressmen have been complaining for years about excess EPO payments in the dialysis market, where Amgen's marketing department holds sway. I will never forget my first meeting with a high-ranking aide to Rep. Pete Stark (it was in 1998, as I recall; he remains a trusted source and colleague), who fumed about the "kickbacks" that the dialysis clinics got from over-prescribing the drug. A year ago, I broke a story in a now defunct publication, The Bay Area Oncology News, about alleged illegal bundling in the cancer market. Amgen, the story alleged, was tying rebates to physicians for its white blood cell factor drug to increased purchases of its red blood cell factor drug. It has since been reported that federal authorities in San Francisco are investigating the situation, a fact that I did not see in this morning's Times story, which focused only on the rebates.

Anyway, there's probably more to be found. Next up should be the last bastion of EPO over-marketing, the AIDS market. I'd love to hear some personal stories from doctors willing to spill the beans on what's going on in that field.

Today's Times story was timed to land just before a meeting of the Food and Drug Administration's Oncologic Drugs Advisory Committee. Thursday, that group will hear evidence that overuse of the drugs actually shorten cancer patients' lives. To read more about the studies that triggered this meeting, see my posts here, here, here, and here.

This FDA committee will probably recommend tighter warnings to avoid overusing the drugs by keeping patients within the narrow red blood-cell counts specified on the FDA label. Will it do any good in the face of pervasive kickbacks that are not illegal? The National Kidney Foundation's anemia management committee, which has a majority of its doctors on Amgen's payroll, recently issued a cautious warning prefaced by a statement that doctors can use their own judgment when it comes to treating individual patients.

The latest Health Affairs just crossed my desk with an article by former FDA deputy commissioner Scott Gottlieb attacking elements of the FDA reform legislation now moving through the Senate. He complains that the "risk management plans" called for in the bill would restrict physicians' ability to practice medicine the way they see fit. Is this the kind of freedom he means?

Durbin, Bingaman Push Conflicts Amendment

Good news! Senators Richard Durbin (D-IL) and Jeff Bingaman (D-NM) have introduced an amendment to the prescription drug user fee reauthorization act that would allow just one scientist with a conflict of interest to serve on any Food and Drug Administration advisory panel. Currently, about a quarter of all scientists who serve on these crucial panels have ties to companies whose products are regulated by the agency.

While there's still some behind-the-scenes maneuvering that could keep the amendment away from the full Senate, a vote is expected tomorrow morning.
If you're interested in writing your Senator to support the Durbin-Bingaman amendment to S. 1082, you can find a direct link on this website (click here) or you can send a message through the Center for Science in the Public Interest's "Take Action' website here.

PhRMA Power II

For the past decade, citizen activists and Democratic Party politicians fighting against high drug prices have bussed senior citizens to Canada to buy drugs at a fraction of their U.S. price. It was a good deal for the seniors, and good politics for the Democrats.

Yesterday, in the midst of a debate over reauthorizing drug industry user fees to fund the Food and Drug Administration, the Senate, now controlled by the Democrats, refused to legalize drug imports unless they have been certified as safe by the FDA. The FDA has neither the money nor the will to provide that certification, effecively dooming the legalization amendment offered by Sen. Byron Dorgan (D-ND).

The hypocrisy of the debate was overwhelming. Republicans cited yesterday's front page story in the New York Times about tainted medicine from China that had killed hundreds of people around the world, most recently in Panama. I wonder how Canadians feel about having their drug safety system compared to Panama (the Pharmaceutical Research and Manufacturers Association wasn't shy about making the comparison; it ran full page in U.S. newspapers in the weeks leading up to the vote showing a map of Canada's provinces labeled as foreign countries).

Sen. Ted Kennedy (D-MA), the sponsor of the FDA bill and at one time a proponent of legalized drug imports, voted in favor of requiring FDA certification. He at least had the courage to admit that his vote had nothing to do with insuring the safety of imports, but everything to do with saving the FDA user fee reauthorization bill. Last week, the president promised to veto the measure if it included the reimportation clause.

This brings us to the overall bill. At least one other amendment was included in the legislation yesterday. It was offered by Sen. Pat Roberts (R-KA). In the name of the first amendment, the bill now avoids placing greater restrictions on direct-to-consumer advertising. The publishers and broadcast executives of America can rest easy. There will be no slowdown in pharmaceutical industry marketing.

This change is emblematic of the changes that have marked the negotiating process at every step. A few months ago, with the drug industry's user fees up for reauthorization and newly installed Democrats in charge of Congress, the chances of serious reform at the FDA looked bright. The Vioxx scandal, high drug prices, popular disgust with ubiquitous drug ads and polls showing that a majority of the American public now believes the government isn't doing a good job ensuring the safety and efficacy of its food and drug supply had created what seemed like a powerful impetus for change.

But step by step, those hopes have been short-circuited. The more far-reaching proposals suggested by reformers (ending user fees entirely in favor of general revenue; a separate safety department within the agency; ending conflicts of interest on outside advisory committees) were never seriously considered. Senators Richard Durbin (D-IL) and Jeff Bingaman (D-NM) this morning may offer an amendment limiting the use of conflicted scientists on outside FDA panels, but as of late last night, the chances of it reaching the floor weren't bright.

There is some positive aspects to the bill the Senate will vote on either today or tomorrow. The agency will devote more resources to monitoring the safety of drugs once they're on the market. There will be greater public access to data in clinical trials. Companies will have to spell out their plans for monitoring the side effects and adverse events from drugs once they enter the market. Scientists at the FDA will have greater freedom to raise objections to agency decisions or publish their findings in the medical literature.

But the real bottom line is that industry will get its user fees, and no real restrictions on its marketing programs. Millions of Americans took Vioxx long after its safety risks were well anticipated. Tens of thousands died. It's hard to imagine that any of the safety provisions in this bill would have stopped that from happening.

Brazil and Innovation

The Wall Street Journal (subscription required) is in high dudgeon this morning on drug issues. An editorial attacks Brazil for its efforts to negotiate lower prices on AIDS drugs. The diatribe is based on a faulty premise, that reduced revenue for the research-based pharmaceutical industry from overseas sales will harm innovation. Here's what the editorial had to say:

Drug innovation is a risky business, and companies won't be willing to sink hundreds of millions of dollars into research and development, especially on diseases that affect the poor and sick in developing countries, if they fear their intellectual property will be stolen.

I'm sorry. I hadn't noticed the industry investing hundreds of millions of dollars in neglected diseases. The only organization that fits that description is the Bill and Melinda Gates Foundation. The drug industry doesn't invest in diseases that affect the poor unless the disease also affects the advanced industrial world, where people and/or health plans can afford to pay for drugs. That's why we have lots of drugs for AIDS.

On Saturday, I spoke with a leading Brazilian politician about the current flap. Sen. Eduardo Matarazzo Suplicy, who earned a Ph.D. in economics from Michigan State University in the 1960s and whose musical tastes run to Bob Dylan (he included the phrase "Blowing in the Wind" in the title of his latest book), said this is par for the course on negotiations over patented medicines. Brazil negotiated lower prices with Abbott in 2003 for AIDS drugs, and is now trying to do the same with Merck.

"The government is trying to negotiate a reasonable price that is consistent with the price in some countries that buy this medicine in Africa and Asia," he said. "This is no different than when we negotiate with Bolivia over the price of natural gas. I believe we will reach an agreement."

Brazil To Break Merck Patent

SAO PAOLO, Brazil -- It is fascinating to be sitting here reading today´s news that Brazil has moved one step closer to breaking a patent on an important HIV/AIDS drug produced by Merck. Brazil doesn´t have much of a generic manufacturing industry, but its state-owned drug producers are quite adept at buying drugs from India and China and repackaging them for the state-run health service, which services most of the population.

There are two Brazils. Beyond the post-modern facade of this sprawling metropolis (second largest city in the world after Mexico City) lies a country where the extremes between rich and poor defy easy description. I spent most of this week in the wilds of Minas Gerais province, where two-thirds of the 19 million people are at risk of parasitic diseases like hookworm, schistosomiasis and Chagas disease.

The least well off among them still eke out a living as subsistence farmers. They live so remotely that a Ford 4x4 took two hours to traverse the 20 miles that separated the village I was visiting from the closest paved road. These poorest of the poor live in mud huts without running water or electricity. Sanitation -- toilets or outhouses -- is non-existent. Many are illiterate.

Even the relatively well-off in the 1000-person village and the better-off farms that have electricity (and thus lights, small refrigerators, and satellite dish-fed televisions) live without proper sanitation facilities. As a result, upwards to 60 percent of the population in the district I was visiting suffers from a half dozen parasitic diseases like hookworm, Chagas disease, and schistosomiasis.

AIDS is not much of a problem in rural Brazil. But in a country that is struggling to provide health care for all of its people, every real (pronounced hey-al) that the health ministry spends for Merck´s drug is a real that can´t be spent on the health care teams that travel between villages deworming the peasants. If left untreated, they suffer from the iron deficiency anemia, lost work days and intellectual impairment caused by the parasitic worms that have infected their bodies.

I´ll have lots more to say about Brazil´s health care system and the state of its economy and politics when I return from this week-long working vacation. But from this vantage point, the argument that Brazil or other developing countries have to contribute to the drug industry´s profits on AIDS drugs in order to sustain research and development rings hollower than ever. These companies invest almost nothing researching cures for the diseases that are causing the most harm in countries like Brazil.

Not Obvious

The Supreme Court yesterday made it tougher to get patents on inventions that are obvious. All the news reports I have seen focused on information technology and the impact this may have on software developers and business use patents like one click shopping. Precious little was said about the pharmaceutical and biotechnology industries.

It is not like they were not interested. Here's one quote from the New York Times report.

“And we could see thousands of cases asking the Patent Office to re-examine patents it has already granted,” said Mr. Kreeger, who was one of the lawyers who had prepared a brief filed by the Biotechnology Industry Organization in support of the patent. “It doesn’t take a lot of resources to ask for a re-examination.” To be eligible for a patent, an invention must be novel, useful and not “obvious” to a person of “ordinary skill” in the field.

So here are my questions. Isn't it obvious and therefore non-patentable when a company separates out the enantiomer from a racemate mixture when there are no real side effects to eliminate, such as happened when AstraZeneca patented Nexium to be the follow-on drug to Prilosec. Isn't it obvious and non-patentable when a company first patents the molecule and then patents the use of that molecule, as has happened with numerous "surround" patents in medicine -- I believe there are several involving Amgen's Epogen.

Perhaps a patent attorney could enlighten readers on the implications of this ruling for medicine.