FDA Issues Info Release Guidance

The Food and Drug Admnistration has released guidance for manufacturers when they submit data to the agency in advance of advisory committee meetings. Nothing yet, though, on a new policy aimed at eliminating conflicts of interest on those committees, which should be one of the many issues discussed later today by Commissioner Andrew von Eschenbach when he appears before the House Appropriations subcommittee.

In the latest guidance, the agency promised to release their own analysis and industry-submitted data to the public at least two days in advance of public meetings. This would be a slight improvement over current practice. It usually releases the briefing documents about a day ahead of time.

The document, which was vetted by former American Enterprise Institute fellow Randall Lutter, who now runs the FDA's Office of Policy, gave industry plenty of leeway for redacting information it considers confidential business information. It also gave industry the right to review the FDA's presentation and make comments. If a company doesn't like the final document and goes to court to stop its public release, the agency might postpone the meeting, the document warned.

Gardisil Update

The latest Journal of the American Medical Association contains a report showing that a quarter of American women older than 14 carry the sexually-transmitted human papillomavirus virus, but only 3.4 percent carry the strains that may cause cervical cancer. About 70 percent of those infections are the cancer-causing strains that the Merck vaccine Gardisils protects against. Younger women had the highest infection rates, about twice the national average. There are about 3,700 deaths a year from cervical cancer in the U.S., but a quarter million worldwide, most of them in the developing world.

CSPI: FDA Failing to Find Advisers Without Conflicts of Interest

The Food and Drug Administration's latest report on the make-up of its advisory panels reveals that little has changed in the 15 months since Congress required the agency to document its efforts to find scientists without ties to industry, the Center for Science in the Public Interest's Integrity in Science Watch reported today.

In a report sent to Capitol Hill on Jan. 31, FDA Commissioner Andrew von Eschenbach reported that 24 percent of advisers to the agency’s seven centers and offices received conflict-of-interest waivers between November 2005 and January 2007. The Center for Drug Evaluation and Research (CDER) had the worst performance, with 146 of 417 advisers, or 35 percent, requiring waivers because they owned stock in, consulted for, or served on the speakers' bureaus of firms with products up for approval or their competitors.

The agency's ability to identify advisers without conflicts of interest has not budged since Congress acted. Although the agency says it reviewed the resumés of 724 candidates to fill the 175 open slots on its committees, its ratio of waivers per meeting was nearly identical over the period. For instance, CDER granted 42 waivers for the 8 meetings in the first quarter of last year compared to 30 waivers for 6 meetings in the fourth quarter.

The advisory committee that met last November to discuss Pfizer's application to use the painkiller Celebrex for juvenile arthritis was typical. While just 2 of the 8 permanent members required waivers, 4 of the 8 temporary specialists appointed to the committee for their expertise had conflicts.

When questioned about the agency's failure to reduce its reliance on outside advisers with ties to industry, acting deputy commissioner Randall Lutter said that "it is very difficult to get the quality of the expertise we want without going to people who have some sort of relationship with industry related to product development."

But as a Lancet (subscription required) editorial  noted in 2005 shortly before Congress passed its law, "it is hard to believe that in a country with 125 medical schools – not to mention the pool of international experts – the FDA cannot find experts who do not have financial ties with companies whose products are under review." A New York Times editorial has pointed out that "unless the FDA makes a more aggressive effort to find unbiased experts or medical researchers start severing their ties with industry, a whiff of bias may taint the verdicts of many advisory panels."

Lutter said that FDA plans to issue a guidance document aimed at reducing its reliance on conflicted advisers "very soon." Former deputy commissioner Scott Gottlieb promised the new guidance last July at a meeting sponsored by CSPI.

More Bad News for EPO

Roche has halted a trial of its new anti-anemia drug Cera in lung cancer patients after those taking the medication died at a quicker rate compared to those not on the drug, the Wall Street Journal reports (subscription required). Cera is basically the same drug as Amgen's Epogen and Aranesp, and Johnson & Johnson's Procrit. Some European researchers believe boosting red blood cell counts -- done to improve the energy levels and psychic well-being of cancer chemotherapy patients -- may actually feed cancer tumors.

FDA User Fees Under Assault

Former New England Journal of Medicine editor Marcia Angell has a column in the Boston Globe this morning where she lays out the arguments for scrapping industry users fees at the Food and Drug Administration. User fees now account for nearly half of the agency's revenue (at least that part of the agency that reviews new drugs). The 1992 Prescription Drug User Fee Act is up for renewal this year, as it is every five years, and the new Congress has the chance to change the way it operates.

User fees are not necessarily a bad thing. While it would be better if the government funded the agency out of general revenue, a use-based fee on the industries that are the FDA's major responsibility is one way to raise revenue for the government. The key is prohibiting industry from having any say over how the agency uses the money. Indeed, the user fee principle could be extended to food and cosmetic companies, slaughter houses and device-manufacturing plants, which also come under the FDA's purview. If Congress pleads poverty and says it can't get rid of the user fees, it needs to eliminate all industry controls over how it spends the money.

That's not the case now. PDUFA required the agency to meet a set of performance goals, which largely had to do with reviewing new drug applications more rapidly. For the first ten years of the law's existence, the FDA was specifically prohibited from using the money to monitor the safety of drugs once they were on the market. Even now, safety issues get a tiny fraction of the money that pours into the FDA from industry.

If Congress doesn't want to get rid of user fees and substitute general revenue, it should double the existing user fees for new drugs, biologics and devices. But at the same time, it should repeal all the existing performance goals, and take the extra $300 million to $400 million and dedicate the money to improving the government drug safety system along the lines suggested by last fall's Institute of Medicine report.

There He Goes Again

President Bush used his Saturday radio address to push his proposal to scrap the tax break for health insurance premiums paid by employers in favor of a standard deduction for those who buy their own health insurance plans. Although he touted it as a way to help the uninsured buy their own plans, it would, in fact, add to the ranks of the uninsured. For an analysis, see this GoozNews.

Earlier this week, a coalition of liberal tax policy analysts suggested some changes for the president's proposal that they said would make it more palatable. This is what happens when people who know very little about health care (like most economists) try to tinker with the system. They wind up endorsing solutions that do nothing about the underlying cause of America's collapsing health insurance system, which is skyrocketing costs.

Here's what Linda Blumberg and John Holahan at the Urban Institute had to say about the president's plan, comments that are equally applicable to "liberal" variants that accept the premise that tax tinkering that encourages individual plans can help solve our health insurance mess:

The president's approaches to reform have consistently emphasized moving individuals into coverage with higher deductibles and lower benefits—intending to rein in systemwide spending by making individuals feel the financial bite when using services. If premiums go down because people use less care, the thinking goes, more people can afford coverage and the number of uninsured will fall. But this ignores a key fact at the heart of why our system is so costly.

Most health care spending is on a small percentage of individuals with very high medical costs. That means to dramatically cut costs, we'd have to reduce spending in the range well above even the higher deductibles the president would like to see. These costs are attributable to people with chronic and other serious conditions and are largely driven by the use of advanced medical technologies. The president's assumption that overly insured individuals are the problem behind premium growth and the number of uninsured is just plain wrong.

Liberals who try to tinker with tax subsidies as a way of getting at the problem of the uninsured ultimately have to turn to some kind of individual mandate to ensure that their program actually achieves universality. Leif Wellington Haase of the Century Foundation recently demolished their arguments in this well-reasoned piece.

Funding the NIH Trial on MD

The Wall Street Journal gives front page attention this morning to the National Institutes of Health-sponsored trial of Genentech's two rival treatments for macular degeneration. One, Lucentis, costs $2,000 a shot; the other, Avastin, costs around $40. The trial was covered by GoozNews last fall here and here.

Near the top of the story, reporter Marilyn Chase calls this trial the "first" such NIH-funded comparative effectiveness trial, but later on qualifies that statement by saying that it is the first comparing two patented drugs. I doubt that's the case, since the government funds trials comparing cancer drugs all the time. But that quibble aside, it's important to recall that the NHLBI during the 1990s spent nearly $80 million comparing various blood pressure control medications as part of its ALLHAT trial, which eventually showed that generic diuretics were just as effective as first-line treatment as more expensive, still patented drugs.

Will the results this trial drive coverage decision by Medicare, which could save $1 billion a year if the two drugs proved equivalent (which they will, since they are basically the same thing)? Not necessarily. Unless Medicare is given the power to set formularies, there is nothing in the law that will allow it to deny coverage for an FDA-approved drug (Lucentis), and only pay for a drug that, while FDA-approved for other conditions (cancer), has not been approved for macular degeneration. And nothing requires Genentech to submit the results of this trial to the FDA.

That's why this paragraph, inserted in the middle of a discussion about NIH's struggle to finance this trial, jumped out at me. The Eye Institute at NIH has appropriated $16 million for the trial, but will probably need more since it will have to buy both drugs at retail prices.

Barry Straube, chief medical officer of the Center for Medicare and Medicaid Services, says he welcomes the trial as a guide for reimbursement policy, but lawyers for the agency have said it lacks legal authority to use the Medicare trust fund for such research expenses.

Someone should show Medicare's lawyers the 2000 Clinton presidential directive allowing Medicare to pay for the routine expenses of seniors who participate in clinical trials. Since Lucentis, the more expensive drug, is now FDA approved, why can't the agency pay for the more expensive arm of the trial and let NIH pay for the $50-a-pop arm? Sounds like a reasonable approach to me, since it's Medicare that will save the $1 billion a year should the two drugs prove comparable.

Good Idea: Pay for Medical Value

British regulators are toying with the idea of setting drug prices based on their medical value. Besides saving money, one interesting side effect of this policy, according to these wire stories, would be to focus drug industry research and development on pressing health care problems, which is long overdue.

However, drug industry officials do not appear interested in "pricing for value" schemes. One official, quoted near the end of the story, suggested that pricing for value will put a floor on the price of generics and wind up costing consumers more money for those particular drugs.

Is this really such a bad thing? Setting an accurate price-to-health value for generics sends the proper signal to companies interested in developing potential new entries in that particular "market" (the disease that a particular drug or class of drugs treats). If the payoff for better new drugs is slightly higher prices on some older generics, so be it. It's a better deal than the one we now have, which is very high prices on all new drugs, many of which don't provide much in the way of additional medical benefit, but, through the adroit marketing enabled by their high prices, achieve dominance in their field.

Merck Backs Off on HPV Vaccine

The Wall Street Journal is reporting that Merck has suspended its campaign to convince state legislatures to make its new human papillomavirus vaccine mandatory for pre-teen girls "in the face of a growing backlash among parents, physicians and consumer advocates."

Where's the World Bank Plan on Fake Drugs?

Last June, the free online journal Public Library of Science - Medicine ran an important article warning about the proliferation of fake drugs in the developing world. It focused largely on artemisinin, the wonder drug derived from traditional Chinese medicine that is now the world's best hope for combating malaria, which has become largely resistant to older drugs. Last summer, while reporting a story on the development of artemisinin for The Scientist magazine, I learned about World Bank efforts to develop a plan that would largely eliminate the problem.

The plan would implement the Institute of Medicine proposal -- the committee was headed by Nobel Prize-winning economist Kenneth Arrow -- that the Global Fund centrally purchase sufficient quantities of pre-packaged artemisinin-based combination therapy, and then provide it at very low cost (about 10 cents a dose) to normal distribution channels throughout the developing world. This would push out both chloroquine, which is largely ineffective because the parasite that causes malaria has grown resistant to that drug, and fake drugs, which, of course, don't work.

Today's New York Times story on the problem of fake drugs reports that Global Fund is "considering" centralized purchasing. It's been three years since the IOM report. It's been two years since the World Bank began exploring ways to raise the money needed to implement the centralized purchasing/subsidization strategy. Isn't it time to move past considering and begin acting?

The HPV Vaccine Backlash

A national backlash is brewing against Merck's campaign to make the cervical cancer vaccine mandatory for teenage girls. I'm not surprised. I have a 13-year old daughter. After she watched one of Merck's ubiquitous commercials on television, she asked me when she was going to get hers. I replied that it really wasn't necessary until she became sexually active with someone who had already had at least one sexual partner, to which she said "yuck" and decided she could wait.

A lot of basic information has been overlooked by public health officials pushing this national vaccination campaign on behalf of Merck. First, cervical cancer has been sharply reduced in the U.S. We're down to under 12,000 cases a year, with fewer than a quarter of them fatal. Even those could be wiped out if the health care system targeted regular pap smears (the long-standing test for the disease) at the women who are most at risk: women who've had multiple sexual partners, especially if they were uncircumcised males; women who have co-infections like veneral diseases, HIV or hepatitis; smokers; and women of lower socio-economic status.

By insisting that all young women get this vaccine, public health officials (the Centers for Disease Control last June endorsed universal vaccination, although its recommendations are not binding on the states, which carry out public health policy in the U.S.) are in essence saying it is impossible for the health care system to identify and treat older women who have already become infected and are at risk of getting cervical cancer.

You know who really needs this vaccine? Poor women in the developing world. There are nearly a half million deaths a year from cervical cancer around the world. But the women in Africa or south Asia who might suffer that fate don't have the $400 for the three-shot course. Although no one will say so, I suspect Merck will make this vaccine available at low cost in the developing world once they've got a routine market in the U.S. (About a million girls turn 11 every year; at $400 a tri-pop, that's about a $440 million-a-year market.)

Since we don't yet know the long term risks, if any, from this vaccine, from a medical point of view it makes the most sense to give it to young women who are most at risk from the disease, for whom the reward-risk ratio is highest. That's not upper-middle class kids in the U.S., whose parents' health insurance will pay for the vaccine. A better strategy would be to have the U.S. and donor countries buy Merck's vaccine for the developing world in sufficient quantities to make a major dent on the disease, which will simultaneously guarantee Merck a fair return on its investment.

There another downside to this misguided lobbying campaign by Merck and its allies in the public health establishment. The backlash will further undermine the public's willingness to go along with vaccination campaigns when they really become necessary. It's the old story of the little boy who cried wolf.

My daughter can't catch the human papillomavirus while sitting next to someone on a bus or train who has the infection. But she can catch the flu that way. What will happen if bird flu becomes transmissible between humans? Will people respond to public health pleas that everyone get the vaccine?

Cancer Study Deals Blow to Amgen

The Cancer Letter (subscription required) scooped everyone today with a report that Danish researchers halted an independent study last October after discovering that patients who took erythropoietin (EPO) during radiation treatments for head and neck cancer fared worse than those who didn't get EPO. Amgen has been encouraging oncologists to use its latest version of EPO, called Aranesp, as a way to boost energy and improve outcomes from chemotherapy and radiation treatments.

This is the second major blow for the biotech giant in recent months. Late last year, researchers found that raising of red blood cell counts to near normal levels using Amgen's flagship product, Epogen, resulted in higher mortality rates among dialysis patients.

Amgen claimed to have little knowledge about the study in its comments to Paul Goldberg, the Cancer Letter's editor, even though the results have been available over the Internet since last November. But immediately after the story broke today, Morgan Stanley put out an investors' alert that sent Amgen's stock price plunging. Late this afternoon, Amgen's chief executive Kevin Shearer scheduled an emergency conference call for investors and reporters to shore up investor support.

Amgen isn't the only company that may get hurt by this study. J&J's Otho-Biotech division is the dominant player in the oncology market with Procrit, which is essentially the same thing as Aranesp. According to the story, Michael Henke, a German oncologist who has been raising similar concerns about Roche's version of EPO (which is about to hit the U.S. market), believes that there are EPO receptors on all cancer tumors, and that may account for the higher mortality. According to this theory, high EPO dosing to raise "energy" levels may actually be protecting tumors from chemotherapy and radiation, and even may be helping them grow.

"If it is really a cytoprotective effect, which is going through EPO receptors, it must happen at lower hemoglobin levels as well," Henke said. "I think the time has come that people have to reconsider how to prescribe EPO to cancer patients."

ACT in Pregnancy

Malaria Journal has just published a meta-analysis of all the clinical trials that have examined the unwanted effects of using artemisinin combination therapy in pregnant women with malaria. The conclusion? Not enough studies have been done to know for sure if there are negative consequences for the developing fetus.

While traveling in southeast Asia last summer, I interviewed Francois Nosten of the Shoklo Malaria Research Unit, who has conducted most of the handful of trials that have looked at ACT use during pregnancy. He complained that there was simply no financial support from donors for such research. "These are precisely the kind of studies that the World Health Organization ought to be financing," he complained. This latest study echoes that sentiment.

McKinsey Study Gets It

Judging by today's column by Steven Pearlstein in the Washington Post, a new study on why the U.S. health care system is so expensive by the McKinsey Global Institute pins the tail on the right donkeys' asses. I haven't had a chance to peruse it myself, but Pearlstein took a hard-left turn after reading it (a few weeks ago, he was praising Bush's tax plan, which would undermine existing employer-based plans and add to the growing ranks of the uninsured). I took him to task for that column. But today, he starts by:

* Going after physician salaries, which, because they're paid on a fee-for-service basis, are a third to half higher than other advanced industrial nations;

* Going after the high prices charged by hospitals and drug companies. "McKinsey found that drug companies are able to charge, on average, 60 to 70 percent more for branded prescription drugs" here. "We can debate whether drug companies really need the extraordinary returns they get to sustain the level of innovation they produce; one can certainly point to other innovative high-tech industries that manage to thrive on more reasonable returns"; and

* Going after the insurance industry, which skims $30 billion in after-tax profits after spending $32 billion a year in marketing.

He concludes his column today with a statement on the importance of cost control, which I have been trying to hammer home to proponents of reform (see my posts here and here, for instance).

"Any effort to reduce these excess costs faces determined opposition from well-financed lobbies, which is why many reformers prefer to focus on the goal of extending coverage to the 47 million Americans who don't have health insurance. But doing the one without the other, the McKinsey researchers warn, would be economic folly. Offering universal coverage without reining in costs would add another $77 billion each year in unnecessary and unproductive health spending."

Way to go McKinsey. And way to go Steve. Welcome to the real world.

Generic Biologics

Henry Waxman, Chuck Schumer and Hillary Clinton will introduce a bill Wednesday that provides the Food and Drug Administration with a roadmap for approving generic biologics. The Biotechnology Industry Association claims that each cell line used to manufacture biologics is different and therefore needs to go through all the same clinical trials as the original drug to prove comparable efficacy. The FDA has so far gone along with that logic, and as a result, some of the original biologics, like Amgen's Epogen, are now well into their third decade of patent protection (the original patent on Epogen was issued in 1984; it should have gone generic in 2004 at the latest).

Amgen, which rakes in over $2 billion a year in government payments for Epogen, has one of the best-organized and well-funded lobbying operations in the drug industry, which, as readers of this blog know, is not exactly full of slouches in that department. BIO, meanwhile, is headed by former Congressman James Greenwood, who has many powerful friends on the Hill. However, the bill already has a couple of Republican co-sponsors and the political stars are finally aligned for Amgen to suffer its first political defeat -- ever. It should be an interesting fight. We can worry about a Bush veto later.

Crichton Gets It Right

After his jeremiad against global warming, I figured Michael Crichton, whose novels have long been a guilty pleasure of mine, had gone over to the dark side. State of Fear was not only bad science. It was a lousy read.

Today, though, he's on the New York Times op-ed page with an attack on gene patents that may allow me to once again contribute to his royalty checks. He sounds all the right themes: they impede research and they needlessly run up the costs of diagnostic tests. He touts legislation introduced last week by Xavier Becerra (D-CA) and David Weldon (R-FL) that would ban gene patents. I hadn't heard about the bill until now, but I will be interested in taking a look at it. Do they propose to invalidate the 20 percent of the human genome (about 6,000 genes) already owned by entrepreneurial university-based scientists?

One way to promote scientific collaboration without a long court fight over legisation is to have the National Institutes of Health require that any gene patent awarded as a result of a government-financed project (the vast majority) be made part of a common patent pool. That would guarantee that any researcher could get access to the use of that "invention" at minimal cost. The trade-off for that researcher is a requirement that any downstream invention they come up with also must become part of the common pool. Should the patents lead to a successful therapy down the road, all the patent owners can share in the royalties. Pooling is one way to preserve the incentives of the patent system while promoting scientific collaboration, which is being undermined by the current system. I proposed a patent pool for the emerging stem cell field in an article that appeared in PLoS Medicine a year ago.

Crichton makes one telling mistake in today's article. He says scientists working on the Human Genome Project were "surprised" when the patent office allowed gene patents. Au contraire. Scientists like Craig Venter of Celera Genomics filed hundreds of patent claims on the information generated by their efforts to decode the naturally-occurring building blocks of life. Oh well. He's a novelist. You can't expect him to get everything right.

The Future of Non-Profit Drug Development

This is a summary of a talk I will be giving to the Association of European Hospital Pharmacists in March.

The United States is the world leader in investing in biomedical research and development. In the public sector, the National Institutes of Health spent $28.6 billion in 2005, largely for basic science research. The pharmaceutical industry spent an estimated $39 billion in 2004. This includes investment in the U.S. by U.S.-based firms, investment overseas by U.S. firms, and foreign companies’ R&D expenditures in the U.S. Indeed, over the past quarter century, the private sector’s investment in the search for new medicines has grown eight percent per year on average, faster than the industry’s growth in sales and profits.

Despite this massive public and private effort, output, as measured by the number of new drugs, biologics, vaccines and devices approved for use by regulatory bodies like the U.S. Food and Drug Administration, has slowed in recent years. Last year, the FDA approved just 21 new drugs and biologics, the second lowest total since 1993. Moreover, about half of these new drugs were not given priority status by the FDA, which meant they were not considered a significant new advance in medicine. This significance ratio has held steady for over a decade. Clearly, the steady increase in private and public R&D spending is generating diminishing returns, whether measured by return on investment or public health.

This falloff in R&D productivity has occurred despite extraordinary advances in the technology of drug discovery. The public sector’s massive investment in basic science, mostly conducted at universities, has uncovered the complex details of how cells work and the chemical interactions of their constituent parts. A government-led project decoded the human genome; scientists are rapidly identifying the functions of the proteins that the genome produces; and, for over 30 years, we have had the bioengineering skills to reproduce those proteins and monoclonal antibodies in mass quantities. We can use these tools to identify the biochemical interactions of many diseases. This in turn has given scientists hundreds of potential targets for drug therapy.

To go after those targets, scientists have developed new tools like mass screening and sophisticated bioassays affixed to computer chips to identify potentially effective new drugs. Advances in biochemistry and x-ray crystallography have given medicinal chemists the ability to design and synthesize new drugs capable of affecting those targets faster and more accurately than ever before. Finally, the drug industry and government have financed and built an infrastructure for conducting clinical trials that far surpasses what existed in previous eras.

So why is output slowing down? I would offer two simple hypotheses for the decline in R&D productivity. First, the scientific drug revolution pioneered by Europeans like Paul Erhlich and Gerhard Domagk has evolved to the point where it is now a mature industry. In the past century, scientists have developed drugs for most of mankind’s common maladies. We can kill most of the microbes that invade our bodies. We can control blood pressure, allergies, minor aches and pains, and acid indigestion. We can cure a few cancers and prolong life for a few more. We can give drugs to prevent some heart attacks. We have even engineered a few proteins like recombinant human erythropoietin or granulocyte-colony stimulating factor that are remarkably effective because they replace factors that, when certain diseases strike, are no longer produced in sufficient quantities by the body. And, for many of these disease states, we are now on the second or third generation of drugs.

In other words, the low-hanging fruit of medicinal chemistry has been picked. To be an innovator today, you must discover cures for chronic diseases like diabetes, most cancers, dementia (Alzheimer’s disease), rheumatoid arthritis, and the other maladies of aging societies. Will there ever be a pill to slow the aging process, or the diseases that accompany aging? That is going to require a lot more investment in basic research to understand the chemical cascades that affect many of us as we age, and then a lot more research beyond that to understand how we can safely intervene in the process. I wouldn’t count on rapid success.

The second reason for declining productivity is that industry R&D largely ignores areas where it is possible to have a tremendous impact very quickly and where there is tremendous need: the neglected diseases of the developing world. Industry does not seek the cures for drug resistant tuberculosis, malaria, leishmaniasis, Chagas disease or hookworm. It could spend its vast resources developing drugs and vaccines for these conditions, but it doesn’t because there is no market. It’s not that there aren’t billions of potential customers for these treatments. It’s that those potential customers have very little money. And when there is no discretionary income for medicine, there is no drug market. This is a classic case of what economists call market failure.

But rather than look for ways to artificially stimulate demand in these needy countries (by lobbying for greater aid, for instance), the drug industry instead devotes a substantial share of its R&D budgets to developing new drugs in their existing market that are nothing more than replacements for older drugs that are losing patent protection. Upon occasion, they are superior to the older drugs. But even when they are, it is usually not by much. This strategy may be good for their bottom lines, but it provides a very small return for public health.

In the years ahead, the greatest advances in biomedicine will come from two arenas: greater investment in the basic science behind the chronic diseases of aging; and concerted campaigns to develop drugs and treat the infectious diseases that are ravaging the two-thirds of the globe inhabited by poor people. Since the private sector is poorly placed to tackle either problem, it will be the public and non-profit sectors that will have to play the leading role.

To leap ahead in our efforts to come up with therapeutics for chronic diseases of aging, governments will need to increase their investment in basic science. Let’s take one example: the fight for a cure for Alzheimer’s disease (AD). Great Britain’s National Institute for Health and Clinical Excellence is under pressure from the two companies that make cholinesterase inhibitors, including donepezil or Aricept, to make them available for the early stages of the disease. Yet the Cochrane Collaboration last year said that “there is little evidence that donepezil improved cognitive function, and no evidence that donepezil delays progression to AD.” Does this mean that the years of basic and applied research that went into developing the cholinesterase inhibitors was wasted? No. It only means that the mechanism that they inhibit does not by itself halt the progression of the disease.

To make progress against AD and other degenerative diseases of aging, our governments need to step up targeted research. We must learn so much about the natural history of this disease that drug developers not only have targets, but have validated targets. This strategy has a proven track record. The targeted research campaign that developed the drugs that can now control HIV/AIDS was initiated and largely funded by the U.S. government. Governments also need to rethink the global intellectual property regime, which maximizes commercialization but in its present form may be inhibiting the scientific collaboration crucial to innovation by building walls of secrecy between researchers.

In the neglected diseases arena, non-profit drug developers like Medicines for Malaria Venture, based in Geneva, One World Health, based in San Francisco, and the Global Alliance for TB Drug Development, based in New York, are blazing the trail to the future. Funded largely by the Bill and Melinda Gates Foundation and other charitable foundations, these organizations are not only developing drugs, but are reaching intellectual property agreements that ensure that their products will be affordable in the developing world if and when they are developed. Since the private sector’s profit imperative prevents it from tackling the world’s most pressing public health problems, this emerging non-profit sector will have to step into the breach. And I’m sure it will. Because as we’ve seen so many times before in medical history, it is human needs and the tireless efforts of committed scientists that drive pharmaceutical innovation, not private profit.

Success! Or Is It?

Today's Wall Street Journal had an interesting front page story (subscription required) about the development of a new drug to control blood pressure. The main thrust of the story was how a small, creative firm succeeded on a project that Big Pharma had abandoned.

The story caught my eye for a couple of reasons. First, I was familiar with its contours from the research on my book. This new class of drugs for lowering blood pressure inhibits renin, an enzyme that starts the biological cascade that leads to higher blood pressure. The molecule that inhibits renin is complex and hard to make, which is why most companies abandoned research in this area in the 1980s. However, renin is very similar to an enzyme in the human immunodeficiency virus (which causes AIDS) called the protease. The scientists who worked on the industry's abandoned renin inhibitor programs became the lead scientists in the race to discover protease inhibitors.

Long way around to my point, which is: Why is Novartis now willing to bankroll the development of renin inhibitors? Does the world really need an eighth (or is it ninth?) class of medicines for controlling blood pressure?

The story suggested there will be one advantage for this drug (which will be a very expensive patented medicine for a field where most drugs have gone generic): it stays in the body at sufficient levels for over a day. And since most heart attacks occur between 5 a.m. and 8 a.m. when blood pressure spikes because the person's medications are wearing off, that will make this new drug very popular with prescribing physicians, the story informs us.

I immediately wondered: So, isn't there anything on the market already that stays in the body at sufficient levels for a full day? And if not, why hasn't the drug industry, after all these years of selling highly-profitable drugs for blood pressure control, not formulated one of its existing drugs (through time-release capsules, for instance) that would accomplish the medically necessary task?

I posed those questions to Dr. Steven Nissen of the Cleveland Clinic, outgoing president of the American College of Cardiology. Here's his reply:

24-hour blood pressure control is VERY important. Take a look at the VALUE trial where a long-acting agent (amlodipine) beat a short acting agent (valsartan). There are long-acting therapies that are either currently generic or going generic soon:

1. Amlodipine (50 hour half life!) - goes generic in 2007.
2. Hydrochlorothiazide – dirt cheap generic. Sustained effects when given once per day.
3. Lisinopril – generic ACE inhibitor with 20 hour half life.

So I can treat patients with three classes of long-acting anti-hypertensive agents for a dollar a day once amlodipine goes generic!

Thanks Steve. So, it turns out that this miraculous new drug is nothing more than another me-too. I can already see the commercials: "Did you know that early mornings are the most dangerous time for people with high blood pressure? Take long acting . . . "

"Misplaced Priorities"

If you haven't seen all the entries in the discussion over at The American Prospect website on health care reform, I invite you to do so by clicking here. Most of the respondents to Ezra Klein's original essay (me included) agreed that controlling costs will be crucial to passing meaningful reform, since a public that already spends 16 percent of GDP on health will reasonably look askance at spending even more to cover the uninsured.

My call for prevention medicine as cost-effective medicine was echoed in more authoritative terms in an essay in the
Journal of the American Medical Association by Steven H. Woolf, a physician at Virginia Commonwealth University.

I believe the public interest is served by making this essay widely available. You can read it by clicking on . . .

Excerpts reprinted without permission from the Journal of the American Medical Association.

Potential Health and Economic Consequences of Misplaced Priorities

. . . The "silo" mentality that pervades so much of clinical practice and policy in the United States often finds decision makers focusing their attention and resources on a specific patient or disease—any one is a worthy cause—without stepping back to examine the balance of their efforts. Most practitioners and policy makers rarely pause to consider whether more rational priorities would offer better outcomes for their patients.

Lacking this "big-picture" perspective, many choices in clinical practice, policy, and research end up concentrating resources on interventions that do less for health while shortchanging alternatives that would save more lives. Reordering priorities to maximize health benefits is essential not only on moral grounds—to lessen disease burden on the public—but also as a necessary countermeasure to increasing health care costs. To illustrate the importance of reordering priorities, this Commentary presents examples from 4 areas of practice and policy: choosing effective services, delivering care, preventing disease, and fostering social change.

Choosing Effective Services

The United States spends more on health care—16% of its gross domestic product—than does any other country, yet its health outcomes are below average on major indices. One reason for the enormous health budget—$2.0 trillion in 20051—is that society overspends on unnecessary tests and treatments, many of which lack evidence of effectiveness and some of which induce net harm.

While the nation spends profligately on such services (overuse), it fails to deliver effective services that do improve health (underuse). Patients receive only 55% of recommended health services, and disadvantaged patients and minorities fare worse. Giving greater priority to effective care while curtailing overuse of ineffective services would enhance outcomes and has been advocated for years, but the imbalance persists. Practice conditions encourage overuse, such as advertising campaigns that promote marginally effective drugs, lucrative reimbursements for procedures, and medicolegal liability for physicians who withhold these therapies. These circumstances fuel spending, consuming resources that would provide greater health gains and reduced mortality if redirected to effective care.

The most effective interventions to achieve the main goal of medicine—to help patients live longer in good health—do not always receive commensurate priority in practice. The magnitude of differences in the effectiveness of available options is often unrecognized. For example, regularly offering smoking cessation counseling would save society an estimated 1.3 million quality-adjusted life-years (QALYs), whereas improved breast cancer screening would save an estimated 91 000 QALYs (a ratio of 14:1). A health system that ignores these differences and concentrates on mammography screening with little attention to smoking cessation can expect progress in reducing breast cancer but ultimately more of its patients may die (of smoking-related diseases). The disproportion may also cost more. Paying for smoking cessation counseling yields a net savings for society, whereas breast cancer screening incurs a net cost (more than $35 000 per QALY). Both interventions should be pursued, but giving measured emphasis in proportion to benefit would optimize results in both lives and dollars.

Delivering Care

Singling out the most promising treatments rightly occupies the attention of academia and industry, but the billions of dollars spent on this endeavor obscure a potentially more effective way to save lives: improving the fidelity with which the treatments are delivered. Defects in the US health care delivery system prevent patients from receiving the interventions they need, delivered correctly, precisely when they need them. Quality and patient satisfaction in the United States are worse than in many other developed countries, such as the United Kingdom, Canada, and New Zealand. Widely recommended transformational system changes to improve access, streamline care, improve communication, and reduce errors are progressing slowly.

Amid these conditions, society invests heavily in medical advances (eg, breakthrough drugs and technologies), but such advances hold little promise for improving health if patients cannot receive them. It is therefore important to consider how the United States should balance its investments in (1) biomedical advances and (2) building a system that can deliver those advances reliably. A logical approach would be to allocate resources for the 2 in proportion to the relative good that each provides. Breakthrough treatments, delivered poorly, could save fewer lives than improving the delivery of established therapies. According to one analysis, more strokes could have been prevented in the last decade by ensuring that all eligible patients took aspirin than by developing more potent antiplatelet drugs.

It follows that the United States should focus as many or more resources on restoring quality as on biomedical advances, but reverse priorities prevail. In 2006, Congress allocated $28 billion to the National Institutes of Health, mostly for research on basic science and new treatments. In the same year, however, Congress allocated only $319 million to the Agency for Healthcare Research and Quality. That is, for every dollar spent on developing treatments, one penny was spent to ensure that patients actually receive them. The blueprint for translational research—the "bench-to-bedside" progression from basic science to new treatments—gives little attention to the question of how those treatments will reach patients.

Preventing Disease

Few crises are easier to predict than the impending surge in chronic illnesses. The ingredients for the crisis are clear: an aging population, longer life spans in which chronic diseases can progress, and increasing costs to care for those illnesses. The inevitable outcome—a large population of seniors with costly chronic diseases—threatens the solvency of the Medicare program and the capacity of hospitals and clinicians to provide effective care.

This climate makes the logic of prevention difficult to ignore. Most major chronic diseases are amenable to prevention because their causes are generally known. It is estimated that 38% of US deaths are attributable to 4 behaviors: smoking, poor diet, physical inactivity, and alcohol use. Weight loss and exercise can curb the progression of diabetes by 50%. By stemming the increase in chronic diseases, prevention can reduce costs for employers and payers and contribute to a healthier workforce. The logic of prevention has always been compelling, but the obesity epidemic makes it paramount. The burden of disease that obesity could inflict on the next generation could overwhelm the capacity of the health care system.

Evidence supports the intuitive notion that the prevention of disease is more effective than treating its complications. In an analysis of 7 studies of the decline in heart disease mortality between 1970 and 2000, reducing risk factors (eg, smoking, lipids) had greater influence (by a median ratio of 1.3:1) than medical care. Tobacco use alone accounts for 430 000 US deaths each year, whereas full delivery of some cardiovascular treatments (eg, -blockers, warfarin) would each avert no more than 17 000 US deaths annually. In one British study that compared the benefits of cardiovascular treatments vs risk-factor reduction, the latter accounted for 79% of the life-years gained.

Such compelling data and the threat of chronic diseases make a strong case for society to invest decisively in prevention, perhaps more than in treatment, but reverse priorities prevail. Although precise data are lacking, estimates are that prevention accounts for only 2% to 3% of health spending. The health system concentrates resources on late-stage disease; 25% of Medicare expenditures are for care in the last year of life. Some have acted boldly to address obesity and smoking. For example, several governors have launched statewide healthy lifestyle initiatives, municipalities have banned smoking in public places, and school vendors are replacing snacks and sodas with nutritious alternatives. In general, however, society tends to underemphasize risk reduction and to tolerate conditions—eg, advertising, fast foods, workplace policies, built environments—that discourage healthful habits. The United States' propensity to spend heavily on treatment but comparatively little for prevention may imperil the nation's health and economy.

Fostering Social Change

The health of the poor and of minorities is markedly worse than for others. Income, education, race, ethnicity, and social inequality collectively exert profound influence on health. A black newborn is 2.4 times more likely than a white one to die by age 1 year (in 2003, 13.5 infant deaths per 1000 live births for blacks vs 5.7 infant deaths per 1000 live births for whites). The disparities are so large that eliminating their underlying causes could rival medicine and public health interventions as means to control disease. With all of medicine's advances, mortality rates over the past century have declined at a consistent, modest rate of 1% per year. Throughout these decades, however, age-adjusted black mortality rates have been 30% higher than those of whites (in 2003, 1066 deaths per 100 000 blacks vs 817 deaths per 100 000 whites). Closing so wide a gap has the potential to save more lives than the modest year-to-year reductions achieved incrementally by biomedical advances. By some estimates, for every life saved by such advances, 5 lives would be saved if blacks experienced the mortality rates of whites and 8 lives would be saved if adults with lesser education experienced the mortality rates of college-educated adults.

Addressing the root cause of these disparities conveys benefits beyond the health sector. Education, for example, not only promotes better health choices but also enhances job opportunities, improving earnings and access to health insurance. A more educated populace can make the workforce more competitive, strengthen the economy, lower crime rates, boost tax returns on higher earnings, and reduce welfare demands. A study that took these broader societal benefits into consideration estimated that reducing grade school class sizes would add QALYs to students' lives and generate net savings for society ($168 000 per graduate; P. A. Muennig, MD, MPH, Department of Health Policy and Management, Mailman School of Public Health, Columbia University, New York, NY, unpublished data, January 2007). Seldom can medical advances do as much for health and society and save money.

If this is true, the US strategy to reduce disease should emphasize the alleviation of social distress at least as much as medical advances, but reverse priorities dominate government today. Budget pressures fomented by increasing health expenditures, along with political concerns, have caused the government to reduce funding for social programs, thereby undercutting an upstream strategy to curtail health spending. Social distress is worsening—severe poverty increased by 20% between 2000 and 2004—while trillions of dollars are spent on health care.

Why Disproportion Prevails

This Commentary portrays a society that invests attention and resources in disproportion to their potential to do good, permitting greater disease and deaths, which begs the question of why this occurs. One possibility is that the public and its leaders are unaware of the disproportion. They may see virtue in a good cause, such as treating cancer or diabetes, and may not realize that the same energy, redirected, could do greater good. Some leaders may sense that more effective options exist but demur because they doubt the feasibility of actionable policy.

However, there are other potential explanations. Leaders would not make choices that compromise population health and increase costs unless there were competing priorities. Shifting attention and resources to more effective options meets resistance from those who stand to lose, such as federal agencies and research laboratories that will receive less funding, specialties and facilities that will perform fewer procedures, industries that will forfeit profits, politicians who will disappoint constituents, and taxpayers who must subsidize publicly financed programs. Such tensions pit 2 prevailing ethics against each other—American individualism vs the utilitarian commitment to the common good—and the resulting deadlock has, for years, mired the status quo in place.

What now moves the issue beyond a debate in ethics, however, is the hard reality of the health care crisis. Those who would be morally content to preserve self-interests at the expense of greater disease must now confront the looming economic ramifications. As the hardship from spiraling health spending intensifies for corporate America, government, and the economy, pressure may build to eschew self-interest and deploy health dollars in ways that more wisely maximize benefit.

What It Will Take to Reorder Health Priorities

A society unaccustomed to basing priorities on population needs also lacks the infrastructure to do so. To rectify disproportion, policy makers need data to determine which options will accomplish the most good. The extensive literature on cost-effectiveness provides only a few examples in which the relative effectiveness and cost-effectiveness of all treatment options are displayed for comparison.4 Funding for this kind of inquiry is scarce. Even when congressional committees and other decision makers can access such data, their operating procedures rarely require analysis of the information, or even consideration of the big picture, before setting priorities.

Such procedures exist in other countries that apparently have stronger interests in rational allocation of resources. Leaders in Scandinavia, Britain, and elsewhere in Europe often apply evidence-based priorities,25 and they use agencies funded by government to assemble the data needed for such decisions (eg, UK National Institute for Health and Clinical Excellence, Health Evidence Network of the World Health Organization). The acceptance of rational priorities in these countries, along with other factors, may explain why they enjoy better health than in the United States despite spending less.

To reorder health care priorities in the United States will require resolve, from which the rest will follow. Health care leaders, elected officials, and the public they serve must embrace the concept that lives are lost by disproportion and should resolve to do something about it. Until the nation devotes resources to interventions in proportion to their ability to improve outcomes, its citizens will pay extra for health care—in lives and dollars.

Bush Endorses Drug Price Negotiations!

Rep. Pete Stark (D-CA), chairman of the House Ways and Means subcommittee on health, uncovered this gem in the president's budget (pg. 59, HHS "Budget in Brief,” section “FY 2008 Proposed Legislation,” subsection “Medicaid Pharmacy Reforms”):

"Allow Optional Managed Formulary: Allows States to use private sector management techniques to leverage greater discounts through negotiations with drug manufacturers.”

“Shortly after the President released his budget, I criticized it as radically partisan and divisive and characterized his regressive tax proposals and draconian Medicare cuts as a declaration of war against America’s low- and middle-classes,” Stark said. “Upon further review, I’ve identified a diamond in the rough. President Bush has finally waved the white flag on drug price negotiation.”

Then he added (in his press release): “What’s good enough for states should be good enough for the federal government – and for the millions of seniors and people with disabilities currently being overcharged for necessary drugs. If Medicaid can successfully negotiate for lower prices, Medicare should also be able to get beneficiaries a better deal. I applaud the President’s change of heart and look forward to joining him in the Rose Garden for the signing of the Medicare Prescription Drug Price Negotiation Act.”

They do have fun up on Capitol Hill.

Taxes and Universal Health Care

Efforts to achieve universal health care without taking on the insurance industry or the providers will require higher taxes. And, as I've predicted before, calls for higher taxes will doom any comprehensive plan. I could be wrong. But here's a taste of the rhetoric that will greet any proposal -- like John Edwards' released yesterday -- that requires higher taxes:

Patrick Toomey, president of the Republican antitax group Club for Growth, said Mr. Edwards's plan wouldn't sit well with most voters, who, he said, "already think taxes are too high." The idea is "very good news for the Republican candidate, whoever that may be." -- from the Wall Street Journal

Maybe Edwards knows something I don't and the American people are ready for to reject reactionary attacks on "tax and spend" liberals. But why the avowed "populist" in the race couldn't find a way to redirect enough of the 16 percent of GDP we already spend on health care to achieve universal care without raising taxes is, as the King of Siam said in "The King and I," a puzzlement.

Pharma's Failures

Why has pharmaceutical innovation fallen on hard times? The Food and Drug Administration approved just 22 new drugs last year, one of the lowest levels in decades. Moreover, only half of those were considered priorities by the agency, in other words, they were a significant medical advance over existing drugs on the market.

To listen to Robert Goldberg at the pro-industry and conservative Drunkwonks.com, the problem stems from the FDA's failure to properly understand the emerging science of "personalized medicine," which will require jettisoning the existing efficacy testing system. Goldberg also called the Institute of Medicine report on drug safety "scientifically illiterate." In his view, legislation that would strengthen the FDA's weak safety surveillance systems, like the recently introduced Kennedy-Enzi bill (which, according to most consumer groups who follow these issues, doesn't go far enough), would be a grave setback for innovation. Here's a typical comment on that legislation's proposal that every newly approved drug have a risk management plan, which he dubs Risk Aversion:

Risk Aversion also applies to every new indication and supplemental approval. What if a doctor want's to use a drug in an off-label way based on his or her clinical judgement to help a dying or sick patient. Is that doctor a criminal under Kenzi (Kennedy-Enzi)? Is the company now responsible for any off-label use. Is this tort situation? Will purchase of this drug for off-label use be racketeering?

Given this front-end hysteria, what will these people be saying by the time Congress actually holds hearings and considers legislation? I'm sure we'll be hearing that overly tough safety rules will result in the FDA never approving a new drug again, that innovation will dry up, that capital will flee the industry and that plagues and locusts will sweep through the population. We've already begun hearing that safety concerns in the wake of the Vioxx fiasco are responsible for the fall-off in new drug approvals.

That's why this quote, from a pseudonymous Big Pharma R&D chief in the latest Scientist magazine (subscription required) caught my eye. What causes new drugs to fail their final hurdle at the FDA? Is it too much concern for safety? He answered:

Half of the failures come from inability to demonstrate superiority to a placebo, 30% are due to safety concerns, and 20% occur because no advantage relative to available therapies can be shown.

In other words, better than two-thirds of new drugs fail to get FDA approval because the drugs aren't worth much, and in half the case, are no better than placebo. From a medical standpoint, taking the sugar pill would make more sense because there is no chance of side effects.

This executive also echoed my own views on the dearth of innovation in the pharmaceutical industry, which I wrote about in depth in my book. Again, here's Mr. Pseudonym's direct quote:

Pharma's productivity woes are a consequence of two distinct factors. One, which is difficult to change, is the dearth of "low-hanging fruit" now that easy pharmacologic targets have been exploited. The other, more malleable factor is the current managerial structures in pharma that not only do not foster creativity and innovation but also tend to extinguish it.

It would be nice to find a few pharma execs willing to discuss these issues in an open forum . . . like when Congress holds hearings. But don't hold your breath.

Evaluating Me-Too Drugs for Diabetes

Nearly 20 million people in the U.S. suffer from diabetes -- a 54 percent increase in the past seven years. We're fat, getting fatter, and suffering the consequences. How should the health care system tackle this rising epidemic? Should we launch social programs to combat obesity, like those being tried in West Virginia and Arkansas? Or should we intensify the search for new drugs?

If there is anyone who still harbors doubts about the folly of the latter strategy, a fine review in this week's New England Journal of Medicine by David Nathan of Harvard Medical School will dispel them. He reviews the latest entry into this crowded drug market, Januvia by Merck, which was approved by the Food and Drug Administration last October. Another drug in its class, Galvus from Novartis, could be approved any day. These new drugs represent the first entries from the ninth, I repeat, the ninth class of medicines developed to to reverse the chronically high blood sugar associated with diabetes.

His conclusion about the value of these new drugs appeared right near the top of his review:

In theory, newer classes of antidiabetes medications might be welcome additions to the existing armamentarium; however, those that have been developed recently are generally no more potent, and often less effective in lowering glycemia, than the three oldest classes (insulin, the sulfonylureas, and the biguanides), all of which are more than 50 years old. Moreover, the newer classes are uniformly more expensive and are associated with adverse effects — some that are shared by the older drugs, but others that are new.

The FDA had very little information about Merck's new diabetes drug before approving it. "There was only one published, peer-reviewed, moderately large clinical trial; it included 392 treated patients who were followed for 18 weeks to judge the efficacy and safety of the drug," Nathan wrote. And the results of that paltry trial? The drug "is one of the less effective glycemia-lowering drugs introduced in recent years."

Never underestimate the power of marketing to win a place for this inferior drug in the marketplace. Within two months of its introduction, Merck's new drug had captured 14 percent of the diabetes market, according to business reports. How could that be? "The ability of clinicians to judge the merits of new medications is already limited — most receive their information about them from drug companies' representatives and promotional materials. The dearth of peer-reviewed, published studies on sitagliptin makes it difficult for physicians to weigh the benefits and risks of the medication or to describe them to their patients," Nathan wrote.

His bottom line:

The failure of clinicians and their patients with diabetes to implement currently available interventions aggressively and effectively is, I suspect, the major barrier to good care. This problem will not be fixed by making more medications available. Ensuring the effective and cost-effective use of the medications that have already been established by high-quality clinical trials to control glycemia or prevent diabetes should be a higher priority than flooding the market with ever more medications.