Plan B for Adults?

One day before Andrew von Eschenbach's nomination to head the Food and Drug Administration goes before a Senate committee, the FDA announces it has called on Plan B's manufacturer, Barr Laboratories, to meet within seven days to discuss steps for making the emergency contraceptive available over-the-counter for women over 18. Senators Hillary Clinton and Patty Murray had threatened to hold up von Eschenbach's nomination unless he resolved the Plan B matter, which the Bush administration has held up for years to please the religious right.

So who is responsible for this latest move: Karl Rove or von Eschenbach? I doubt we'll ever see the memo.

Raid!

When officials at Bristol-Myers Squibb and Sanofi Aventis announced last March they would pay an undisclosed sum to Apotex Inc. to hold off selling a generic version of their blockbuster blood thinner Plavix ($3.8 billion in sales a year), they told investors that there "significant risk that required antitrust clearance will not be obtained."

Investors got phase II of that message yesterday when FBI agents working for the antitrust division of the Justice Department raided the offices of BMS chief executive Peter Dolan looking for documents related to the transaction. The company's stock plunged.

When the Hatch-Waxman act was passed in 1984, industry got longer periods of exclusivity for new drugs to account for delays at the FDA in exchange for more rapid entry of generics into the market once those patents expired. What all too many generic manufacturers like Apotex learned is that it was just as lucrative to sell back those rights as to actually make and market the drug.

Congress needs to either prohibit such payoffs entirely, or rescind the additional exclusivity given big Pharma for delays at the FDA. Maybe somebody should attach it as a rider to the FDA appropriations bill moving through Congress.

Stark Weighs in on National Health Care

I reprint this from the Kaiser Family Foundation daily digest of news events since it's an important story:

Rep. Stark Proposes Universal Health Insurance Plan That Includes Employer-Sponsored Insurance Mandate

Rep. Pete Stark (D-Calif.) on Tuesday announced a bill that would provide health insurance for all U.S. residents through contributions from employers, states and individuals, the San Francisco Chronicle reports. The AmeriCare Health Care Act would establish a program that uses the low-cost Medicare administrative structure, as well as discounts obtained as a result of the large number of participants, to maintain lower premiums, Stark said. Under the legislation, employers would have to provide health insurance for all full-time and part-time employees, and states would help fund coverage for low-income residents. In addition, the bill, which would not establish a "single payer," would allow program participants to retain their current health insurance and continue to visit their current physicians. The legislation would cost the federal government an estimated $50 billion to $60 billion annually for the first several years. However, supporters "estimate that over time, savings would kick in," in part through a reduction in the number of uninsured residents, who often do not seek health care until their conditions become more serious and expensive to treat, the Chronicle reports. AFL-CIO and Consumers Union have endorsed the bill. Stark said, "The question is whether society will provide coverage for everyone or for just a wealthy few," adding, "Everyone should benefit from this bill, with the exception of the bankruptcy bar and collection agencies" (Epstein, San Francisco Chronicle, 7/26). Rep. Jan Shakowsky (D-Ill.) said, "AmeriCare is more than a solution for the uninsured, it is a solution for the underinsured."

Second Bill
In related news, a bipartisan group of lawmakers led by Rep. Tammy Baldwin (D-Wis.) on Tuesday introduced a bill (HR 5864) that would help states develop programs to provide insurance to uninsured residents. The Healthcare through Creative Federalism Act -- co-sponsored by Reps. Bob Beauprez (R-Colo.), Tom Price (R-Ga.) and John Tierney (D-Mass.) -- would establish a grant process to encourage states to develop such programs. The legislation, which would have to remain budget neutral over five years of authorization, would establish a committee operated under HHS that would include federal and state appointees to administer the grant process (Abruzzese, CQ HealthBeat, 7/25).

Hearing Slated for von Eschenbach

The Senate Health, Education, Labor and Pensions Committee will hold a hearing next Tuesday on whether Dr. Andrew von Eschenbach's appointment to head the Food and Drug Administration should be made permanent. The headlines will be dominated by his stance on Plan B, the over-the-counter morning-after pill. Senators Hillary Clinton and Patty Murray are threatening to hold up his approval unless he lets the FDA scientists call the shots on this one -- not the religious right.

I hope the Senators also look into the question of conflicts of interest stemming frmo his tenure as head of the National Cancer Institute. NCI, as I've pointed out numerous times in this space, has a structural conflict with FDA since one of its jobs is to bring new therapies to market, which the FDA must approve. The public has been repeatedly told that von Eschenbach has severed his ties with NCI and now that he is at FDA, he will recuse himself in any matters that he worked on during his years at the cancer research shop.

Yet how do you explain this listing on the Health and Human Services Department website? It says he is still an employee of NCI. And if you go here, you'll see he's also listed as an employee of FDA. The Senators might want to ask him about that.

That FDA Pledge

At a Center for Science in the Public Interest forum yesterday, Scott Gottlieb, the deputy commissioner of the Food and Drug Administration, promised to revamp the agency’s rules for granting conflict-of-interest waivers when physicians with ties to drug manufacturers sit on its advisory panels. I look forward to seeing the new guidance when it actually comes out. If I understood the intent correctly, the FDA will start excluding those docs who are actively engaged in marketing drugs and devices, but continue to put them on committees if their relationship with the companies was purely scientific – as in having done clinical trials.

The announcement drew major news coverage (see here and here, for instance). Since I have been a major proponent of a total ban on granting conflict-of-interest waivers to scientists who have ties to industry in any capacity, let me lay out once again why I think this proposed new rule doesn’t go far enough.

First, there are plenty of people out there who don’t have any financial ties to firms who can provide just as good advice as the FDA is currently getting from folks on industry’s payroll. There are 125 medical schools in the U.S. About a third of all clinical trials conducted in the U.S. are sponsored either by government – primarily through the National Institutes of Health – or health charities and non-profits. Those trials require all the same skils as industry-funded trials: physicians to enroll patients, biostatisticians, data safety monitoring boards, etc. Why can’t the FDA find experts from that crowd? Either they’re not trying or they don’t want to.

Why does it matter? Isn’t an industry-funded clinical trialist just as “objective” as someone who has not worked for industry? I think not. When one has been part of a study that comes up with a certain result, one becomes intellectually committed to that result. It is only natural to defend your previous conclusions, even when confronted with new evidence. Sometimes the new evidence becomes overwhelming and anyone who is intellectually honest eventually changes their mind, but letting go of previous conclusions takes time – it’s only human. Can that happen in the course of a one-day meeting at FDA where the clinical trial specialist is not only hearing contrary evidence but is hearing evidence presented by the company?

It’s the rare scientist who would arrive at anything other than their pre-conceived wisdom under that scenario. If these advisory committees are going to be real science courts that weigh the evidence, the FDA needs to appoint jurors who don’t have preconceived opinions about the new drug or device under consideration. Period.

That is the theory. Now to the practice. The New York Times Science section this morning has a pretty good
commentary analyzing the machinations of the hired brains behind the Cyberonics Vegus Nerve Stimulator for severe depression. Harold Sackeim, a professor of psychiatry and radiology at Columbia, told the paper that if device makers could not hire the field’s top experts, effective new devices would never be approved. “This is not like pharmaceuticals, where the companies are much bigger and have their own experts,” he said. But a few paragraphs down, we learn that:

Now the company has focused on promotion, as have some of its consultants. At an American Psychiatry Association meeting in May, Dr. (John) Rush sat in the Cyberonics booth, describing the benefits of the therapy to curious psychiatrists. In one of several presentations about the device, doctors reviewed its use for obesity, anxiety and Alzheimer’s disease, purposes for which it is not approved.

This isn’t science, it’s marketing. If the FDA does in fact come out with the new guidance promised yesterday, and it does in fact end forever the inclusion of such scientists on its advisory committees (whether their promotional activities take place for the company with a new drug up for approval or one of its competitors), then it will be a major improvement over the current rules and I’d applaud it. Hopefully, we’ll get to see the new rules sooner rather than later.

The Times on Our Conflicted Medical Journals

Last week, the Wall Street Journal's David Armstrong wrote several stories raking the Journal of the American Medical Association and Neuropsychopharmacology over the coals for failing to disclose to readers that their contributors had ties to drug manufacturers. The most notable part of the New York Times editorial today that played off that news was the paper's call for journals to "try much harder to find authors free of conflicts. That is the best hope for retaining credibility with doctors and the public." It took a few years, but even the Times now realizes that disclosure doesn't go far enough.

The Politics of Stem Cells

I thought the president made a serious error on Wednesday when he vetoed legislation that would open up the federal spigots for embryonic stem cell research. Despite eroding support in his own party and careful restrictions written into the bill to deal with ethical concerns, the president proved once again that he is either the most inflexibly ideological president in American history or a political panderer of the worst sort.

This is the most promising medical technology to come along in a generation. It's a long shot, but so it all medical research that is looking for cures that are truly innovative. U.S. firms and researchers that want to compete are being held back for the most arbitrary of political reasons: the desire to cater to a narrow, religious constituency. The Tom Toles cartoon in today's Washington Post said it all: it showed a garbage can outside a fertility clinic with a disembodied voice from inside the can saying, "Well, I for one would like to fill out a stem cell donor card."

Beyond the obvious scientific, medical and economic competitiveness reasons for pursuing this research, there are political benefits, too. It is beginning to look like the president and his party will pay a political price for his embrace of the narrow views of the religious right. In today's Wall Street Journal (subscription required), reporter Jackie Calmes visited the Republican heartland (DuPage County just west of Chicago; I know it well, my daughter, son-in-law and grandchildren live there) and discovered that, lo and behold, most people, especially those who know sickness in their families (hey, isn't that everyone?) backed the stem cell research bill.

"Embryos count, people don't," George Strejcek, 62, said. He and wife Elizabeth, 58, described themselves as former Republicans. "Goldwater I could tolerate," he said. "But with these Republicans, they forget we live in a democracy, not a theocracy."

So there you have it: bad politics; bad science; bad medicine; and, lest we forget, bad for the drug industry, which could use a few promising leads for its drug development pipelines. To find out what their political supporters were saying about this travesty, I visited Drugwonks,, a pro-industry website, run out of the conservative Manhattan Institute. It is part of what its founders, Robert Goldberg and Peter Pitts, call the Center for Medicine in the Public Interest. Well, if there is any new endeavor that would further medicine in the public interest more than expanded stem cell research, I'm not aware of it.

Alas, I found not a word on their site about passage of the bill. I found not a word on the president's veto. They had plenty of time the past two days to attack FDA safety expert and whistleblower David Graham, who was prominently quoted in a New York Times story earlier this week about the problems with Ketek, a relatively new antibiotic from Sanofi-Aventis. (That's an interesting issue I will address at another time.) They also had time today to attack Sen. Byron Dorgan for calling for Medicare to negotiate lower prices for drugs. They also had time to attack the very idea of Medicare adopting formularies, which virtually every private insurance plan uses, but the Republican Congress, in its desire to please its funders in the drug industry, denied the government as a matter of law.

Embryonic stem cell technology holds out the promise of personalized regenerative medicine -- the use of one's own DNA to grow regenerative cells that will exactly match and thus avoid rejection problems. Personalized medicine is something the "Drugwonks" have written about repeatedly on their website. Even their patrons in the drug industry are supportive of this line of research.

Yet, as I said, not a word this week. What's up guys? Are we only web-wonky about drugs when it doesn't cross the White House line?

"Military Intelligence And You"

The disastrous foreign policies of the Bush administration have spawned a generation of satiric filmmakers that should enlighten and enliven our lives for years to come. I was just sent a promotion piece for filmmaker Dale Kutzera's new satire, Military Intelligence And You!, which he hopes will be playing soon in a movie theater near you. Watch the trailer, and I think you'll agree, when it comes to movie satire, this incoming round is too close for comfort.

FDA Scientists Pressured to Change Findings

Nearly one in five scientists at the Food and Drug Administration have been pressured to exclude important data from agency documents, a new survey of nearly a thousand FDA scientists shows.

The Union of Concerned Scientists (UCS) today released survey results that demonstrate, in their words, "pervasive and dangerous political influence of science at the Food and Drug Administration (FDA)."

Among the most revealing findings:

* 18.4 percent said that they "have been asked, for non-scientific reasons, to inappropriately exclude or alter technical information or their conclusions in a FDA scientific document."

* More than a third of the respondents did not feel they could express safety concerns even inside the agency.

* 61 percent of the respondents knew of cases where "Department of Health and Human Services or FDA political appointees have inappropriately injected themselves into FDA determinations or actions."

* Only 47 percent think the "FDA routinely provides complete and accurate information to the public."

* 81 percent agreed that the "public would be better served if the independence and authority of FDA post-market safety systems were strengthened."

* 70 percent disagree with the statement that FDA has sufficient resources to perform effectively its mission of "protecting public health."

The FDA has been underfunded, understaffed and, as this new survey shows, subjected to outside pressures from the industries it regulates and political operatives whose sole motivation is satisfying electoral constituencies like the right-to-life crowd. Yet this agency has the job of regulating a quarter of the U.S. economy -- the nation's food, drugs, medical devices and veterinary medicine industries -- to ensure their products are safe and effective.

How can the public think it is doing its job well if four of five scientists inside the agency think its safety system sucks; two-thirds think the agency lacks adequate resources to do the job; and half believe the public isn't getting adequate information?

Senators Ted Kennedy and Mike Enzi will be introducing legislation next week to reform the FDA. At first glance (and it is only the briefest glance), it seems to be aimed at making the FDA even more industry-friendly while taking a few halting half steps to improve its drug safety system, which is the only impetus for reform. I'll write more on that legislation after I've had a chance to give it a closer read.

Gates Foundation Discovers Directed Research

Grantees Will Have to Share Data

The Bill and Melinda Gates Foundation will require recipients of $287 million in research funds aimed at developing an HIV/AIDS vaccine to share all data prior to publication. The foundation's well-founded idea is that medical progress works best under conditions of scientific collaboration. "The whole field recognizes that in order to meet this humongous challenge, we have to change the way we work," Dr. Nick Hellmann, who runs the program for the foundation, told the Wall Street Journal. "There have to be better networks and collaborations."

Perhaps it took a monopolist to understand the efficiencies of having everyone working on a common platform of scientific understanding. It was the same "directed research" approach, documented in my book, that developed the AIDS triple cocktail. Perhaps Bill Gates' foundation can enforce the same kind of discipline on the AIDS vaccine community, whose government grantees have suffered from the government's laissez faire approach toward developing a vaccine since the late 1980s.

Journal Editor Again Misled

Catherine DeAngelis, the editor of the Journal of the American Medical Association, says that for the third time in as many months researchers have ignored JAMA's policy requiring disclosure of conflicts of interest in published articles. The excuse by the six physicians who studied the link between migraines and cardiovascular disease was that they didn't think their relationships with drug companies were relevant since the study didn't involve a test of any company's drug.

Some people just don't get it. The study authors, led by Dr. Tobias Kurth of Harvard, had relationships with numerous firms that sell drugs for treating migraines. Yet the authors, after being confronted by their failure to disclose those relationships, claimed those financial ties were not "relevant to our describing a biological link between migraine and cardiovascular disease."

DeAngelis snapped back: "Financial interests and relationships with manufacturers of products that are used in the management of migraine or cardiovascular disease certainly are relevant and should be disclosed." The authors' letter contained the disclosure.

This situation graphically points out why conflicts of interest must be taken into account when judging the results of "basic science" studies conducted by physicians or scientists with financial dealings with the drug industry. Those ties can subtly influence the interpretation of results in many ways. After all, if I'm committed to a treatment regimen for treating migraines, wouldn't it be nice to think that it was also helping my patients prevent heart disease?

Many researchers, like Dr. Kurth and colleagues, continue to think that their attitude toward a field of research has no impact on the way they conduct that research. Yet study after study has shown that the financial ties of researchers do in fact correlate with positive outcomes for their sponsors. This can only be explained by almost impossible-to-detect influences like how they framed the questions for study, how they chose patients for their sample, and how they interpreted the data.

For years, critics of the growing influence of private corporations over scientific research have fought for conflict-of-interest disclosure policies as one way to alert readers to these potential biases. Yet most of them now recognize that disclosure doesn't go far enough. They say it is time to reduce the influence industry exerts over research by setting up independent institutes for the conduct of clinical trials and basic health research. Attitudes like those exhibited in this most recent exchange by Dr. Kurth and colleagues graphically demonstrate why such changes are sorely needed.

CNN Tackles Conflict of Interest Issue

CNN Headline News last night had me on for about three minutes talking about the Journal of the American Medical Association's failure to disclose the drug industry ties of physician-researchers, a story broken last week by the Wall Street Journal. If you want to rate my television performance skills, click here, watch the video and then send me an email voting Good, Fair or Poor. (Hit the "Contact" link above.) If I get more than 10 votes (one way or the other), I'll report the results.

Switch to Medicare Costs Taxpayers $2.5 Billion

The New York Times reports that switching the elderly poor from Medicaid to Medicare's new drug benefit will cost taxpayers as much as $2.5 billion. Why? State Medicaid directors operate under laws requiring that the poor get the lowest negotiable price. But when Congress passed the Medicare drug benefit in 2003, it specifically forbade the federal government from negotiating with drug firms.

That's $2.5 billion straight from your pocket to theirs, courtesy the Republican Congress. Thanks guys.

Stem Cell Patents on Trial

With the Senate about to vote on opening the federal research spigots for stem cell research, the California-based Foundation for Taxpayer and Consumer Rights has petitioned the Patent and Trademark Office to void James Thomson's keystone patents on the technology, the Wall Street Journal reports this morning. You can read what I've written on this subject in PLoS Medicine, here and here.

The folks at WARF should have seen this coming. They've been making unreasonable royalty claims for using their stem cell lines, which is discouraging academic researchers and small firms from pursuing certain lines of research. It also would up the ante for researchers funded by the California Institute for Regenerative Medicine, which will be spending $3 billion of taxpayer money on stem cell research. Supporting patent lawyers at another state's university is probably not what the taxpayers had in mind when they approved Prop 71 in California.

This is a classic case of how the rush to patent every basic science insight can hamstring medical research, especially when a field is in its early stages like stem cells. Bravo to John Simpson at the Foundation for taking on this fight.

Having Your Trials and Eating Them, Too

Government collaborates with industry all the time, especially in the development of new drugs. The National Cancer Institute pioneered in this process (it is the oldest of the National Institutes of Health) and continues to push collaborative clinical trials to test new cancer therapies emerging from industry's labs.

Over the weekend, the Los Angeles Times reported how one researcher at NCI, Thomas Walsh, between 1997 and 2003 worked on a succession of clinical trials for new antifungal drugs for treating serious lung infections associated with cancer, and, at the same time, took consulting fees from the companies that manufactured those drugs, including Pfizer and Merck.

The investigation also went on to question the protocols of the second of the two trials, which compared the newer Merck drug to the older one made by Fujisawa and marketed by Pfizer, which Walsh had also worked on. Critics complained that the NCI-funded trial underdosed the older drug, a classic drug industry tactic for showing that a new drug is superior to an older, often off-patent drug.

There wasn't enough evidence in the article to prove that latter point. But a number of physicians in letters to the New England Journal of Medicine raised questions at the time. Based on David Willman's reporting, it would seem that there are still serious questions about whether the nearly $1 billion spent on Merck's drug is doing patients any more good than previously available generics, which would cost a fraction of that amount.

These are precisely the types of questions that government-funded studies should be answering. Whether Dr. Walsh violated one of NIH's rules for disclosing conflicts of interest is hardly the most important question here. What's really important is giving health care professionals the best information possible for conducting the most effective and most cost effective medicine.

When NIH was debating its new rules in 2004 in the wake of Willman's previous articles documenting undisclosed conflicts of interest at the agency, I was one of the few people to stand up and call for a total ban on such arrangements. It's not that the government shouldn't collaborate with industry to bring exciting new therapies to market, I said. Rather, the government has a crucial role to play as independent designer of those trials and arbiter of the evidence. It must ensure that the information generated by government involvement in clinical trials testing the drug industry's latest medicines furthers public health.

It would appear that the government-funded studies that Walsh conducted failed these basic tests. I said it then. I'll say it again. NIH should prohibit all consultancies, stock dealings, speakers gigs or whatever for its scientists since they will inevitably bring at least some of those scientists into conflict with the agency's basic public health mission.

Campaign '08

Here's some campaign slogans for Massachusetts Governor Mitt Romney if he seeks the GOP presidential nomination:

"If elected President, I won't appoint some Chicken Little to run the Army Corps of Engineers!"

"You can trust me to rebuild New Orleans!"

"I'll find Jimmy Hoffa's body if it takes all four years!"

Info to the People!

Here's the latest statement on public access to research findings developed on the taxpayer nickel. Alas, it is from Great Britain. courtesy of the British Medical Journal:

Publicly funded research must be made accessible and free of charge to the public, recommended a statement published this week by research councils in the United Kingdom.

The statement said that information derived from publicly funded research must be made available at no charge for public use as widely, rapidly, and effectively as is practical.

It also advised that published research findings must be subject to rigorous quality assurance, through effective peer review mechanisms, and that mechanisms for publication and access to research results must be efficient and cost effective. Finally, the outputs from current and future research must be preserved and remain accessible for future generations.

The recommendations were developed by the executive group of Research Councils UK, which represents the eight research councils in the country, including the Medical Research Council.

Contrast that with the policy of the National Institutes of Health, which a) only asks that taxpayer-funded research be made publicly available one year after published in a journal and b) such open access publishing is voluntary.

JAMA's Inadequate Response

David Armstrong of the Wall Street Journal followed up his scoop (see yesterday's post if you didn't see the original story) with a report on the Journal of the American Medical Association's plans to "toughen up" its conflict-of-interest disclosure rules. Pretty damn weak, in my view, which was reported in the paper. Here's the relevant parts of the story:

Under the journal's new guidelines, its authors -- often medical researchers from top-flight universities and hospitals -- are instructed to more broadly report their connections to drug companies and medical-device makers. Some critics say the measures don't go far enough and called for a publication ban on authors who fail to disclose they are receiving money from industry. . . . "Authors should err on the side of full disclosure," the new policy states. JAMA has experienced at least three cases this year where authors failed to disclose industry ties.

The Center for Science in the Public Interest, a Washington, D.C., advocacy group, published a report two years ago that found JAMA had the highest rate of nondisclosure of conflicts among four medical journals studied. Merrill Goozner, who studies scientific integrity for the center, said the JAMA changes were inadequate and urged the journal to adopt penalties such as a three-year publishing ban on authors who don't disclose industry ties.

"It's clear that [JAMA] does not evaluate conflict-of-interest disclosures when articles are submitted," Mr. Goozner said. "As a result, some authors with blatant conflicts of interest apparently feel they can ignore the journal's policy with impunity."

Mr. Goozner said the International Committee of Medical Journal Editors, a group including the editorial heads of the most prominent journals, should agree to apply a ban by one of its members to all of its members.
. . .
Catherine DeAngelis, JAMA's editor in chief, says she is averse to a publication ban, but she rejected the idea that offending authors go unpunished. She says in several cases where researchers failed to disclose industry ties, she asked the medical schools where they work to investigate their behavior. In some cases, those probes resulted in sanctions, she said.

"We take this very, very seriously," Dr. DeAngelis said, but added she is "not an FBI agent" and "there has to be a certain level of trust" between the publication and authors who publish their research in it. "The day that certain level of trust disappears, I will hang it up," she said.

Memo to Dr. DeAngelis: That's how the Securities and Exchange Commission treated the accountants before Enron. And look what it got them: Sarbanes-Oxley.

We could use a Sarbanes-Oxley for medical research. But that's a subject for another day.

A Major Failure at JAMA

Two years ago, in my role as director of the Integrity in Science project at the Center for Science in the Public Interest, I conducted a study that warned the editors of the Journal of the American Medical Association and other leading scientific journals that there was a persistent pattern of non-disclosure of conflicts of interest by physicians and scientists publishing original articles within their pages. At that time, CSPI said a voluntary disclosure policy needed teeth – a ban on publishing if an author failed to disclose – if it was going to work. The advice was ignored.

Today’s Wall Street Journal documented a major failure to disclose relevant conflicts by seven authors of a JAMA article involving the safety of anti-depressant use by pregnant women. At least two of those authors, including lead author Lee S. Cohen, a Harvard Medical School professor and director of the perinatal and reproductive psychiatry research program at Massachusetts General Hospital, had their conflicts of interest documented in the Integrity in Science Database at www.integrityinscience.org prior to publication of the article.

It’s clear now that the editors of the Journal of the American Medical Association take no steps to evaluate conflict of interest disclosures when articles are submitted. As a result, physician-authors with numerous conflicts of interest feel they can ignore the journal’s policy with impunity.

The only solution is to adopt strong penalties for authors who fail to disclose – a three-year ban from publishing in the pages in the journal. The International Committee of Medical Journal Editors should also make any ban by any of its member reciprocal.

The FDA's Slippery Slope

Who could be against making the process of getting new drugs through the Food and Drug Administration more efficient as long as the end products were still safe and effective? Today’s Wall Street Journal reports that the FDA has launched yet another program to help its primary client – the drug industry. It’s called “adaptive clinical trials,” which, if I understand them correctly, are trials that switch protocols mid-stream if early results suggest the change is warranted.

There’s no doubt that more flexibility in clinical trial design could teach drug makers and physicians a lot during the early stages of drug testing. Dosing could be adjusted, for instance, or patient-types on whom the drug has no effect could be eliminated from the trial so that it could be tested in more people for whom it looks like it is working. One could even imagine a safety problem arising in a subset of patients, who could then be eliminated from a trial when the drug looked promising for another subset or even majority of patients.

I have no problem with the FDA moving toward this approach for some drugs as long as it understands the pitfalls and builds in protective mechanisms. One such mechanism mentioned in the story was requiring these trials to have totally independent data monitoring committees with the power to set these mid-course corrections. That seems like a fair tradeoff to me.

But I was struck by a related piece of FDA news today, this one from the Reuters newswire. The inspector general of the Health and Human Services department says the FDA doesn’t closely monitor the status of the post-marketing trials that it ordered (these are trials designed to get real world feedback from patients who are on drugs whose recent approval had been based on skimpy data). The FDA has requested post-marketing trials for nearly half of all drugs approved since 1990.

According to Reuters, 35 percent of 336 annual reports due in 2004 "were missing entirely or contained no information.” The FDA politely disagreed with the report’s conclusions, but didn’t contradict the data.

Bottom line: the agency is moving toward more flexibility in pre-approval testing and conducting less follow-up on post-marketing testing. If I were running the FDA right now, I would want to tread carefully on this slippery slope. One more misstep – another Vioxx, for instance – will shred what’s left of its reputation.

More Doctors, Not Better Care

The Dartmouth Medical School and the associated Veterans Administration hospital consistently churn out some of the most intriguing comparative health care studies being done today. This morning's New York Times brings word of a new study that looked at the ratio of doctors to senior citizen care in various states and cities. Even though seniors in Florida have 40 percent more doctors than seniors in Minnesota and get commensurately more care, they don't live any longer (Sorry, Ponce de Leon; it apparently isn't a fountain of youth). New York has nearly three times more doctors than San Francisco, yet doctors rate the quality of care about the same.

Bottomline for Dartmouth pediatrician David Goodman, who authored the op-ed:

By training more doctors than we need, we will continue to fill more hospital beds, order more diagnostic tests — in short, spend more money. But our resources would be better directed toward improving efforts to prevent illness and manage chronic ailments like diabetes and heart disease.

Which politicians will bring that insight to the health care reform debate?

Public Health -- The Best Approach to Health Care Reform

The mayor and health commissioner in Louisville, Ky. have launched an intriguing program aimed at reducing health disparities in their city. What do they mean by health disparities? Infant mortality among black mothers is one-a-half times the rate of white mothers. Deaths from heart attacks and strokes among blacks is one-and-a-third times that of whites. Latino diabetes rates are significantly higher than either the white or black rates.

That's a key reason behind the fact that, when discussing the need for health care reform, so little political traction comes from pointing out that the U.S. lags so far behind other industrialized countries in key health indicators like infant mortality and longevity. Two-thirds of the population -- the white, non-poor population -- intuitively understands that it is not really their problem.

So if you want to reduce the diabetes rate in the Latino community (which would, probably, bring the U.S. rate down to rates seen in other industrialized nations), or the cardiovascular disease rate in the black community, what do you do? You could target preventive health care programs at the communities that are most at risk.

That's precisely what they're attempting to do in Louisville, where the mayor recently launched a new Center for Health Equity. The Center "will focus on the social determinants of health such as a person's job, neighborhood, income and education, as well as personal responsibility," according to an op-ed in the Louisville Courier-Journal written by Adewale Troutman, the city's health director. "It will also examine the potential for discrimination in the delivery of health care and seek solutions."

One of the Center's first projects involves the start-up of 10 to 15 track clubs for elementary and middle school children in low-income neighborhoods. The clubs will include "instruction on nutrition, attention to self esteem, and the importance of education, as well as fitness assessments." The Center also plans to establish intervention programs aimed at lowering the disproportionate rates of heart disease, diabetes and AIDS in minority communities in Louisville.

Here's my guess. Every dollar spent on the kind of interventions being tried in Louisville will be accompanied by a fivefold reduction in illness care expenses. Someone needs to do a cost-benefit analysis of their program, the same type of analysis that drug companies routinely do in order to justify the high prices charged for new drugs.

Public health approaches to health care need to become part of the health care reform debate. A city like Louisville can probably throw, at best, a few million dollars at targeted prevention efforts. But if reformers were armed with a few decent studies showing the cost-effectiveness of such programs, it could lay the basis for spending billions at the national level on programs that could substantially reduce the nation's health care bill.

That's the best way to make the national health care system affordable. Spend money to keep the American people well.

Can This Health Care Reform Plan Win? Part 2

The Center for American Progress, led by President Clinton’s former chief of staff John Podesta, is widely perceived as a policy shop for Sen. Hillary Clinton’s expected bid for the presidency. Anyone interested in health care reform needs to play close attention to its Plan for a Healthy America (PHA), which was published last year in the journal Health Affairs.

The plan would provide universal coverage by expanding the Federal Employees Health Benefits Program, which offers a choice of traditional private insurance plans to federal employees and their dependents. Anyone without job-based insurance could join this new national insurance pool. Employers could merge their own plans into the pool if they so desired. To make coverage affordable for everyone (whether in this new national pool or not), the PHA would cap individuals’ payments for insurance at 5 to 7.5 percent of income. The government would offer a tax credit to make up the difference.

Unlike every other health care plan offered on either the right or left, the PHA deserves high marks for making disease prevention and health promotion a priority. The surest way to lower health care costs is by having fewer people get sick, and this plan would attempt to do that by creating a new “prevention services” benefit.

“The U.S. health insurance system now focuses on treating diseases instead of reducing their incidence in the first place,” the CAP authors wrote. “With no guarantee that enrollees will remain in their plans, insurers have little incentive to invest in keeping enrollees healthy over time.”

People could use the new benefit to reimburse physicians and other providers who sell prevention services, just as they are now reimbursed for providing illness care. The contents of these prevention services are not spelled out. “A major goal of this benefit would be to train people to be better managers of their own health,” they write, leaving it up to the reader to imagine what those personal management tools and prevention services might be.

The plan also calls for major investments in generating better information about what constitutes quality health care, including comparative clinical effectiveness and cost-effectiveness studies for various medical interventions. Comparative studies would test a range of therapeutic options for a condition (generics versus brand name drugs for acid indigestion, for instance) to determine which works better or whether they work about the same. Presumably done by a government agency like the National Institutes of Health, these studies would then be made available to insurers, who could insist that their patients use the cheaper but comparable intervention.

Cost effectiveness studies take this concept one step farther. They compare the actual medical benefit of therapeutic interventions to the cost of delivering those benefits. This information could allow insurers to ration care on a rational basis. For instance, if it costs $100,000 for cancer drugs that extend life for, say, two months on average, does it make sense for the health care system to pay for those drugs?

Electronic recordkeeping would also get a boost under the PHA. Analysts at the Center for American Progress estimate the subsidies, new benefits and system investments would cost somewhere between $100 billion and $160 billion. They'd fund this new spending through a new value-added tax (a new national sales tax levied on the exchange of goods prior to retail) in the range of 3 to 4 percent.

There are some attractive features to the CAP plan on the benefit side. Its emphasis on prevention is long overdue. But it still sees prevention primarily as a service delivered by individual practitioners to individual patients within the current system. This ignores public health interventions that could have the greatest impact in reducing the incidence of certain diseases.

The plan also envisions creating better information for providers and consumers by sponsoring studies to improve clinical practice, and better information for insurers by sponsoring studies on cost effectiveness. But adoption of those guidelines would remain voluntary and leave physicians vulnerable to commercial pressure from drug and device manufacturers or imaging equipment makers, not to mention the self-interest of fee-for-service practicing physicians.

On the tax side, their plan suffers from the same fatal flaws as the Furman plan discussed yesterday. It maintains the existing employer-based system, whose plans are becoming less comprehensive every year. And while out-of-pocket health care expenses are rising precipitously, a household with combined family income of $100,000 would have to pay over $400 a month in co-payments before reaching the 5 percent threshold.

So while the VAT tax would be felt immediately, the benefits for most middle-income voters would be somewhere off in the future. This plan will likely be perceived as a way to help the poor by raising taxes on everyone – hardly a prescription for success in recent American politics.

Can This Health Care Reform Plan Win?

Health care will likely be a top domestic policy issue in 2008. The ranks of the uninsured have swelled to over 45 million. Costs are rising at twice the rate of inflation. Employers are pushing more and more of the costs onto individuals and their families. With the Republicans pushing tax breaks for personal health savings accounts, the field for Democrats who want to offer comprehensive solutions is wide open.

Over the next several days, I'll be taking a look at proposals from leading Democratic Party-oriented think tanks. The first, from Democracy Journal, a new quarterly edited by former speechwriters for candidates Al Gore and John Kerry, sees tax reform as the key to providing health insurance for all.

Most Americans are not aware that hidden health care subsidies in the tax code makes the public sector (which includes Medicare, Medicaid, the Veterans Administration, and government health insurance premiums for its own workers) the largest payer in the health care system. The subsidy comes from the fact that employer-provided health insurance benefits are not taxed as income. That amounts to a $200 billion annual tax break for everyone with employer-provided health insurance. When added to existing public sector programs, the “public” tab for health care rises to nearly 60 percent of the nation’s $1.9 trillion tab.

The tax break portion of the public’s bill is regressive in the same way the home mortgage deduction is regressive. When General Motors offers its $100,000 engineer (with a 30 percent marginal tax rate) the same $10,000-a-year family health plan as its $50,000 assembly line worker (with a 15 percent marginal tax rate), the government forgoes $3,000 in taxes from the engineer but only $1,500 from the assembly line worker. In addition, health care benefits for high-income workers are usually more generous than those offered low-income workers. That makes this tax subsidy even more regressive.

The reform plan outlined in Democracy Journal would redraw this subsidy to create a universal plan. Jason Furman, a former special assistant in the Clinton administration, called for capping the tax break for high earners and using the new tax collections to pay for health insurance for the uninsured. Furman sees this plan as a transition to scrapping deductibility entirely and replacing it with a progressive tax credit that would enable individuals and families to buy insurance, which would be mandatory as in the Massachusetts plan. “The principal goal of universal insurance is to provide more health care for the uninsured and to reimburse them for more of the costs they are currently paying themselves,” he writes. Estimated price tag: $50 billion to $200 billion.

I see several major problems with this idea. Furman would provide the poor with the same inefficient and non-preventive health care offered to the 84 percent of Americans who already have insurance. His plan does nothing to hold down costs. And he would make those on the upper end of the income distribution pay for it. This is redistributive tax policy at its worst – taxing the upper third to pay for benefits for the lower third.

It may be “fair.” But it’s a political loser. It wouldn’t take a Karl Rove to write Republican talking points attacking such a plan.

Wisdom from the Fathers of Our Country

As we all pause for this July 4th holiday, ponder these thoughts from some great patriots:

"When people speak to you about a preventive war, you tell them to go and fight it. After my experience, I have come to hate war. War settles nothing." --Dwight D. Eisenhower

"Guard against the impostures of pretended patriotism."
--George Washington

"The spirit of this country is totally adverse to a large military force."
--Thomas Jefferson

"Wars are not paid for in wartime, the bill comes later."
--Benjamin Franklin

"No nation could preserve its freedom in the midst of continual warfare."
--James Madison

"I'm fed up to the ears with old men dreaming up wars for young men to die in."
--George McGovern

"The statesman who yields to war fever...is no longer the master of policy but the slave of unforeseeable and uncontrollable events."
--Sir Winston Churchill

"To announce that there must be no criticism of the president...is morally treasonable to the American public."
--Theodore Roosevelt

"Our country is now geared to an arms economy bred in an artificially induced psychosis of war hysteria and an incessant propaganda of fear."
--General Douglas MacArthur

And my favorite comees from the FDR Memorial along the Potomac River. FDR served as assistant secretary of the Navy during WWI, and visited the frontlines in France. In 1936, as president, he gave a speech at Chatauqua, NY that included these memorable lines:

"I have seen war. I have seen war on land and sea. I have seen blood running from the wounded. I have seen men coughing out their gassed lungs. I have seen the dead in the mud. I have seen cities destroyed. I have seen 200 limping, exhausted men come out of line—the survivors of a regiment of 1,000 that went forward 48 hours before. I have seen children starving. I have seen the agony of mothers and wives. I hate war." --Franklin Delano Roosevelt

AND THIS PRESIDENT?

"I just want you to know that, when we talk about war, we're really talking about peace." --George W. Bush

Integrity in Science Watch -- July 3

President to Name Anti-Regulation Zealot to OIRA?

Greenwire reports that the Bush administration is about to announce the appointment of Susan Dudley to run the Office of Information and Regulatory Affairs, the White House arm that reviews all agency regulations. Dudley is director of regulatory studies at George Mason University's Mercatus Center, which opposes most regulations on ideological grounds and received $40,000 grants from Exxon Mobil for "regulatory improvements (climate change)" in 2003 and 2004.

Industry-Supported Food Scientists:
Cutting Antibiotics in Food Won't Slow Growth of Resistant Strains

Eliminating antibiotic drugs from livestock production may have little positive effect on resistant bacteria that threaten human health, according to a report released last week at the annual Institute of Food Technologists (IFT) meeting in Orlando. Michael P. Doyle, director of the Center for Food Safety at the University of Georgia, chaired the 15-member panel that wrote the report. While most of Doyle's research is supported by the U.S. Department of Agriculture and the Food and Drug Administration, he has also received numerous grants from the American Meat Institute and is currently principal investigator on food safety projects funded by Kraft Foods and Great Eastern Mussel Farms. The IFT, a 22,000-member society made up of food scientists from industry, academia and government, receives financial support from the food industry as well as from its membership.

FDA Sides with Industry Consultant on Breast Implant Toxicity

Citing a recent review in the science journal Biomaterials, the Food and Drug Administration two weeks ago told consumers that platinum leaks from silicone breast implants pose no threat to women's health. What the FDA failed to note was that the review author, Michael Brook of McMaster University in Hamilton, Ontario, appeared last year at an FDA hearing as a paid consultant for Inamed, which manufactures the devices.

Both the Brook review and the FDA review dismissed a recent study in Analytical Chemistry, which determined women with breast implants had elevated levels of the toxic form of platinum in their breast milk and blood. Platinum in some forms is a known neurotoxin, and consumers fear the inert version used to manufacture implants may become toxic once in the body. That study's corresponding author, S. Maharaj of the Center for Environmental Medicine in New Market, Md., disclosed she has no ties to either manufacturers or plaintiffs' attorneys. The study's lead author, E. Lykissa, has consulted with plaintiff attorneys in the past, but has no current ties, according to Maharaj. The study was funded in part by Chemically Associated Neurological Disorders, a patient advocacy group that does not disclose its funding sources on its website. Consumer groups are seeking an independent study of the issue before the FDA rules on Inamed's application to market a silicone breast implant.

Doctor-Run Charities Create Fertile Ground for Conflicts of Interest, Bias

Tax-exempt charities set up by doctors to engage in medical research or education are a growing channel for industry money and have become a niche for conflicts of interest, the New York Times reports. Corporate donations to these charities may lead to bias in the treatment decisions of physicians, suspect research findings and violations of federal anti-kickback laws, especially when the money is used for fellowships or covering business expenses.

The Midwest Heart Foundation, created in 1988 by the for-profit group Midwest Heart Specialists, has doubled corporate funding in the last few years to $1.7 million, including hundreds of thousands of dollars from Amgen, AstraZeneca, and Scios. Earlier this year the foundation was subpoenaed by the Justice Department as a part of an investigation into the marketing of a potential harmful heart failure drug made by Scios. According to the Times, Mitchell Saltzberg, a paid consultant for Scios at Midwest Heart, was telling Medicare that the drug posed no risks at the same time Scios was sending safety alerts to doctors.

FDA Inspections and Serious Warning Letters Drop by Half

Rep. Henry Waxman (D-CA) released a report last week showing that the Food and Drug Administration's severe warning letters to industry and on-site inspections at manufacturing plants have been halved over the last five years. In32 cases, the agency sent letters to food and drug companies noting only possible problems even though field inspectors had recommended that they issue serious warning letters, seize the product or seek a court injunction. The agency's Center for Devices and Radiological Health, which oversees defibrillators and other devices that have been recalled, showed the biggest decline, issuing 66 percent fewer warning letters in 2005 than in 2000. The FDA's Center for Drug Evaluation and Research dropped its number of warning letters by 39 percent. "Under the Bush administration, enforcement efforts have plummeted and serious violations are ignored," Waxman said.

Rhode Island AG Defends Contributions from Lead Defendant

The Attorney General for Rhode Island last week defended contributions made to his campaign by a company who was being sued by the state in a lead-paint case. Patrick C. Lynch, who accepted over $4,000 in campaign donations from a DuPont Corp. lawyer and lobbying firm while settling with the same company in litigation over clean up of lead paint manufacturing, said there was no reason to return the contributions because he had fought as hard as possible "on behalf of all Rhode Islanders against the paint producers." Lynch's opponent in the upcoming election, J. William W. Harsch, has filed a complaint with the state Ethics Commission, saying Lynch's acceptance of money from a company he was prosecuting is in "substantial conflict with his duties."

Odds and Ends

National Institutes of Environmental Health Sciences has abandoned efforts to privatize Environmental Health Perspectives, its award-winning journal. But director David Schwartz says he is seeking an outsider to serve as editor-in-chief while cutting back its news and commentary sections and discontinuing foreign translations to save money. . . Unions representing 10,000 Environmental Protection Agency scientists, over half the agency's workforce, sent a letter to Congress Thursday protesting the Bush administration's proposed 80 percent cut in the agency's library budget.

One Cost of Privatized Medical Science

Scott Hensley of the Wall Street Journal, always one of my favorite reporters, has an excellent column in today's paper (subscription required) lamenting what's lost when industry funds clinical trials for new medicines. The case in point is Pfizer's research on an "anti-aging" pill, which the company discontinued a few years ago after getting the page-one treatment from Hensley.

Bravo for the reporter who follows up his own wrong-headed stories. Turns out that the drug, which promoted muscle growth to prevent frailty, falls, and the like, had the serious side effect of promoting obesity -- not exactly what you're looking for in a pill aimed at aging Baby Boomers. It also caused insomnia and raised blood sugar.

The data from that clinical trial, which was suspended several years ago, has never appeared in a peer-reviewed medical journal. Even the researchers who participated in the trial have had problems gaining access to the data on a timely basis. Hensley makes the important point that "the research behind medicines that get nixed in the trial stage could be valuable to the scientific community. . . who might be able to solve the problems or otherwise build on the results."

One other group that would like access to data, of course, is Pfizer's competitors, who might be working on something similar. By knowing where and how Pfizer's drug candidate failed, they might either drop their own programs or make changes to avoid the same pitfalls. That's why Pfizer wants to keep it secret.

The FDA is currently involved in a "critical path" initiative to help the pharmaceutical industry's research and development arms become more productive. Here's an excellent place to start. The agency should require that all human clinical trials data be made public, even data that will never be published. Publication would be a tremendous boon to companies whose developments efforts might otherwise get stuck in a blind alley for years, substantially saving resources for other, more potentially useful projects.

There's an easy answer for companies like Pfizer that say they don't want to help our their rivals. Publication is not for them. It's for the people who volunteered to be part of those trials. They deserve to know that the uncompensated risks they took to participate in clinical trials contributed to the sum total of human knowledge.