On TWA Flight 800 and Other Press Failings

During the summer of 1996, I found myself, recently returned from Tokyo, sitting in a bar in a Holiday Inn on Long Island, covering the investigation of the demise of TWA Flight 800. The guy sitting next to me was an engineer from Boeing. Both of us had been reading, day after day, headlines in the New York Times about the traces of chemical explosives that bomb-sniffing dogs had found in the wreckage. The stories, based on undisclosed sources, had been leaked to the reporters, presumably by government agents. I say presumably because it was my job to compete on those stories, and I couldn't get anyone associated with Louis Freeh's office, he was then head of the FBI office in charge of the investigation, to open up to me, a lowly Chicago Tribune reporter.

So what did you think of the latest story, I asked the Boeing engineer. I remember his laugh and snarky reply as if it were yesterday. "It's the central fuel tank. Sparks. It happened in Manila, too." He took another drink. "And you can't use my name with that."

Yesterday, the Times
reported that the government has finally gotten around to rewriting the rules so that the fumes in those empty fuel tanks do not pose even a remote risk to passengers. And if you're wondering what happened to the reporters who "broke" all those wonderful investigative stories about the terrorists behind the destruction of TWA Flight 800, their bylines would later be seen on other "investigative" pieces about Monica Lewinsky and weapons of mass destruction in Iraq, other stories that were entirely dependent on deliberate "leaks" by government investigators.

Other stories that left my head scratching the last couple of days included this one in the Wall Street Journal on the failure of electricity deregulation in Texas, where ratepayers will be absorbing huge increases later this year and could be subjected to brownouts and blackouts. Reporter Rebecca Smith won widespread plaudits earlier in this decade for her coverage of the Enron collapse, but I was mystified by her conclusion at the end of this story. She quoted a Republican legislator saying the "toothpaste is out of the tube."

That's absurd. We've seen this before, in California, and what has been deregulated can be re-regulated. Interested readers may want to read this article that I wrote for the American Prospect in August 2001.

Finally, the scientific quest to come up with an AIDS vaccine hit another stumbling block yesterday. Training the body's immune system to fight diseases that it does not naturally develop immunity to after the initial exposure (assuming you survive that initial bout with the disease) is one of the hardest intellectual challenges in modern medicine. The ongoing failure to develop an AIDS vaccine doesn't mean it is impossible, only that the evolution of science hasn't reached the point where scientists know what to do. Maybe they'll never know. One thing we do know, though, is that success does not hinge on how much money gets poured into the project. Money is necessary. But it certainly isn't sufficient.

That's why I had to laugh yesterday when reading about the Clinton Foundation's deal to use advance purchase agreements to get a consistent supply at a fixed cost of the plant that produces artemisinin for treating malaria. Why are global drug companies continuing to rely on Chinese farmers, who seem more than willing to price gouge when suppliers are tight? This is a weed that can grow anywhere (when it first appeared on the cover of Science magazine in 1984, the picture came from the banks of the Potomac River near Washington, DC). What has happened to efforts to get poor farmers in Africa, where most of it will get used, to grow it as a cash crop? Alas, the story was silent on that subject.

The other mysterious part of yesterday's announcement involved the comments of Novartis chief executive Daniel Vasella. The Swiss drug company has been supplying the overwhelming majority of artemisinin-combination therapy to the developing world -- 66 million treatment courses last year alone. The company complained its investment in the drug and associated losses exceeded $100 million, "including research-and-development costs."

Vasella was also quoted as complaining that the Clinton agreement "doesn't address the need for new drugs and the incentives for innovators to engage more. . . How was it possible that we have a product that completely transformed malaria treatment, saving 500,000 lives? It's only possible by innovation," Dr. Vasella said.

Readers not intimately familiar with the world of malaria drug development might have been led to believe that Novartis was somehow involved in bringing artemisinin to market (their role, if I understand it correctly, has been in coming up with a once-a-day version that includes all the necessary drugs in one pill -- an innovation to be sure but hardly the kind of breakthrough that requires massive investments).

Two years, I spent time on the Thai-Burmese borders with the physicians who have struggled for two decades to make the world aware of this revolutionary treatment for malaria. It was the cover story in The Scientist in December 2006. If you read that and these two sidebars (here and here), you'll get a much better sense of the history.

FDA Seeks Scientist Trainees

Public Service Announcement

The U.S. Food and Drug Administration (FDA) today announced it is launching a two-year fellowship program aimed at attracting scientists, engineers and health professionals to the agency. The FDA Commissioner’s Fellowship Program will provide participants with advanced training in the scientific analysis involved in the safety and regulatory decisions unique to the agency’s mission.

"Attracting the best scientists to FDA helps us make timely decisions and give doctors and patients helpful and accurate advice about treatment options. And timely decisions encourage more investment in developing new drugs and better medical devices,” said Deputy Secretary of Health and Human Services Tevi D. Troy. "The FDA Commissioner’s Fellowship Program will not only bring great fellows in the door, but encourage them to make FDA their career.”

Applicants are being considered for the first entering class of the program, which will begin in October 2008. The agency is seeking physicians, microbiologists, chemists, statisticians, pharmacists, biomedical engineers, nutritionists, veterinarians and other science professionals. Applicants should have a doctoral degree in medicine or another scientific field; engineers must have at least a bachelor’s degree. Between 30 and 40 applicants will be accepted for the first entering class.

"The FDA is a science-based regulatory agency, and to fulfill our mission over the coming decade we will need to recruit thousands of highly skilled scientists and others with specialized and relevant expertise,” said Frank M. Torti, M.D., M.P.H., principal deputy commissioner and chief scientist. “The FDA Commissioner’s Fellowship Program is designed to attract these people to the FDA and provide them with in-depth knowledge of the science that underpins regulatory decisions as we meet the challenges of both globalization and rapid changes in science and technology."

The FDA Commissioner’s Fellowship Program will include coursework and extensive hands-on experience in FDA regulatory science including regulatory review opportunities. More than 20 courses and seminars will be offered on topics including FDA law, ethics and decision making, biostatistics, clinical trial design, population science and epidemiology, risk assessment, international activities, budgeting and operations, leadership, and public policy.
A full listing of courses is available here. The courses will be taught at the agency's new, state-of-the-art campus at White Oak, Md., and at other facilities by senior FDA staff and faculty from universities in the region.

During the first semester, each fellow will identify an in-depth research project to be completed during the program, allowing each fellow to explore a specific area of interest under the guidance of a senior FDA scientist who will serve as a preceptor. Fellows will devote about 70 percent of their time to the scientific project and 30 percent to coursework.

More information about the FDA Commissioner’s Fellowship Program and instructions for applicants are available here.

NEJM Issues Strong Editorial Against Preemption

The Supreme Court next fall will hear a landmark case that could rob consumers of the right to sue drug manufacturers in state courts when the Food and Drug Administrations fails to protect them from unsafe drugs. Drug manufacturers are claiming in Wyeth v. Levine that federal regulation preempts state product liability laws, even though the Food, Drug and Cosmetic Act -- unlike the Medical Devices act, which the court has already ruled preempts state laws -- contains no such language.

A few weeks ago, I was critical of the New England Journal of Medicine for failing to take a strong stand against federal preemption. Well, that blog post is no longer operative. In Thursday's edition, the top editors of NEJM authored a strong editorial warning "Why Doctors Should Worry About Preemption."

In stripping patients of their right to seek redress through due process of law, preemption of common-law tort actions is not only unjust but will also result in the reduced safety of drugs and medical devices for the American people. Preemption will undermine the confidence that doctors and patients have in the safety of drugs and devices. If injured patients are unable to seek legal redress from manufacturers of defective products, they may instead turn elsewhere.

Only that last sentence, which hints that injured patients might turn to suing their doctors, rang false. I'm sure that a Supreme Court willing to rewrite laws to give drug manufacturers a "but the FDA said it was safe" defense, will be more than happy to legislate from the bench giving doctors something similar to ward off malpractice suits.

No, it's the patients who will be the real losers if the high court invalidates state efforts to protect their citizens from unsafe prescription drugs. But it is nice to know that the prescribers -- or at least the leading editorial voices who speak on their behalf -- are on their side.

Industry-Funded Think Tank Organizing for Preemption

A correspondent from Harvard warns that deregulatory zealots affiliated with the conservative American Enterprise Institute are circulating an unidentified amicus brief in the Supreme Court case of Wyeth v. Levine, which will be heard next fall and could result in federal drug regulations preempting state product liability laws. If the court rules in favor of Wyeth, it would remove the public's right to file suit in state courts whenever the Food and Drug Administration fails to protect consumers from unsafe drugs, such as happened in the Vioxx, Trasylol, Paxil and all too many other cases.

According to the brief's abstract:

Fundamental principles of economics and numerous studies of FDA drug regulation reveal that FDA in fact errs on the side of overregulation of prescription drugs. Product liability litigation focused solely on one side of the prescription drug public health equation leads to further distortions of the drug approval and labeling process and exacerbates FDA's inherent overly cautious approach. Preemption of state tort law where it conflicts with FDA requirements will minimize these distortions and thereby maximize public health.

The brief's authors are seeking additional signatories from the academic community. The lead author is John Calfee, who isn't identified on the brief, but is a drug industry-funded scholar at AEI. Another author is Robert W. Hahn, who is only identified as associated with the Reg-Markets Center. That group is also affiliated with AEI (it used to be a joint project with Brookings, but the mildly liberal wing of the consortium dropped out). The Center is largely funded by conservative think tanks and major corporations, including several major pharmaceutical firms.

Are any consumer groups writing and circulating briefs? If so, send me a link and I'll be glad to invite any academics who read this blog to get in touch about signing on.

"Trials on Trial"

My effort to call attention to the Food and Drug Administration's decision to withdraw from the Helsinki Declaration that protects people in clinical trials is finally starting to make waves. This week's Nature magazine (subscription required) editorialized that the FDA "should rethink its rejection of the Declaration of Helsinki."

The FDA argues that it should not be bound by Helsinki because of the declaration is devised by a group it does not control, and is subject to periodic revisions that could confuse trial sponsors or contradict U.S. law. But it is tempting to conclude that the FDA is dropping Helsinki not because it is changeable, but because the agency disagrees with the way it has been changing -- in particular with its constraints on the use of placebos.

And our earlier post received a trenchant comment from Abbey Meyers, the about-to-retire chief of the National Organization of Rare Disorders. She was a tremendous help to me when I was writing "The $800 Million Pill," and her thoughts on this subject deserve the wider notice that top billing for a few hours on this website gives them. So here they are:

Forget about Helsinki! What about the Common Rule? All federal government agencies that are involved in any way with clinical research signed on to the Common Rule EXCEPT THE FDA! They have not even had a bioethicist on staff until about three years ago when they hired one bioethicist. It's no wonder they approved clinical trials for the blood substitutes when human research protections were the last thing on their priority list, and it continues to be ignored not only in third world countries, but New York, Chicago, L.A., etc. And they wonder why fewer patients are volunteering for clinical trials!

The Preemption Threat

It can't come naturally for the Journal of the American Medical Association to be consistently more liberal than its rival New England Journal of Medicine. JAMA, based in Chicago, is housed within the reliably conservative physicians' guild, while NEJM is firmly nestled within Brahmin Boston's ivy-covered institutions.

A commentary in this week's JAMA (registration required) by Georgetown law professor Lawrence O. Gostin is a case in point. This non-physician properly warns physicians and the public that the Supreme Court's recent decision in Riegel v Medtronic Inc. removes the final safety net that protects consumers from unsafe medical devices: the right to sue when federal regulation has failed.

The case involved a New York man who sued after his arterial balloon catheter ruptured and almost killed him. Medtronic, the device manufacturer, claimed that since the Food and Drug Administration had approved the device, the company was no longer liable under state product liability laws. In legal parlance, federal regulation preempted state legislation. Last February, Chief Justice John Roberts' Supreme Court agreed.

According to Gostin, this misrepresented Congress' intent in passing the Medical Device Amendments in 1976, which gave the FDA the responsibility for the first time of approving medical devices for their safety and efficacy. Even its sponsors said "the legislation was to provide additional protection to consumers, not to withhold existing safeguards against defectively designed or labeled devices," he wrote. (It's interesting to note that a comparable NEJM commentary earlier this month drew similar conclusions about the negative consequences of the court's decision, but didn't buy the Congressional intent argument. "The fact that this question was answered in the affirmative by a vote of eight to one indicates that the issue was not a difficult one for the justices," its authors wrote.)

For 25 years, even the FDA held to the view that its regs didn't preempt state laws. But in 2004, after President Bush had appointed drug industry lawyer Dan Troy as FDA general counsel, the agency reversed its position and argued the preemption case.

In an era where the FDA has been systematically underfunded and its postmarket surveillance systems are clearly inadequate to identifying serious risks that emerge once the product is on the market, the courts provide a final line of defense for consumers where they can get compensation for injuries, Gostin argues. But just as importantly, it deters industry negligence and encourages a constant search for safer products. Litigation can also improve product labeling by bringing risks to light, which serves both patients and physicians.

Litigation also can uncover fraud committed against the FDA. Studies showing that companies knew about the risks of certain drugs and devices have frequently been revealed only because someone sued and their lawyers uncovered the documents during discovery. Alas, far too often that kind of information remains under seal when the cases are settled out of court. But that's a separate problem. Under this decision, that avenue of uncovering corporate wrongdoing will be shut down entirely.

Next year, the Supreme Court will hear a companion case involving drugs: Wyeth v. Levine. Dan Troy may have returned to Sidley & Austin to represent his drug industry clients. But his influence lives on at the FDA. The agency's legal office is still backing the idea that the obviously inadequate federal regulation of drugs preempts state product liability laws.

Concludes Gostin: "If the FDA's view were to prevail, patients would have no safety net in the likely event that the agency fails to detect and correct safety hazards."

FDA Set to Approve Ghost-Writing

All the major newspapers that circulate in the nation's capital (the New York Times, the Wall Street Journal, and the Washington Post) carried stories this morning about a new study in the Journal of the American Medical Association that showed about half of articles that appeared in the medical literature touting Vioxx had been ghost-written by employees or contractors working for Merck, the drug's manufacturer.

What none of those stories or the study mentioned was the regulatory context in which this study (and an accompanying one alleging Merck manipulated the data in one of those studies to hide the mortality risk among Alzheimer's patients who used the drug) appears. The Food and Drug Administration wants to give drug manufacturers like Merck a blank check to distribute to physicians nearly any article advocating off-label use of drugs that appears in the medical literature.

The only substantive criteria in the proposed guidance is that the article be peer-reviewed and reflect "well-controlled" clinical studies. It would abandon the FDA's prior practice of pre-reviewing articles advocating the off-label use of drugs before they could be distributed by industry salesmen. Under this proposal, virtually all of Merck's ghost-written studies could have been distributed. As it was, the company bought nearly a million copies of the seminal study that led to the approval of Vioxx that had appeared in the New England Journal of Medicine.

The draft guidance has already drawn fire from Rep. Henry Waxman (D-CA), and I commented on it in this post, "FDA Proposes Lack-of-Evidence-Based Medicine Policy" when it first came out. Perhaps the best thing that readers of this blog can do at this point is to write to the FDA protesting these proposed guidelines, which you can do by going to the Regulations.gov website, putting in the docket number -- FDA-2008-D-0053 -- and hitting the "submit a comment" button.

Despite a New England Journal of Medicine commentary opposing the guidance last week, there were only 33 comments as of this morning, many of them from industry groups that support liberalizing the reprint policy. A patient and consumer coalition in which I take part plans to file comments before the deadline, which is next Monday. I hope to post those comments in this space later in the week.

You can read the study on ghost-writing here; and the re-analysis of the Merck Alzheimer trial here.

This issues raised by Drs. Bruce Psaty and Richard Kronmal in the Alzheimer's trial are especially disturbing since the company, which ran the trial, did not set up a data safety monitoring committee. Company officials and lawyers quoted in the stories said it wouldn't have made a difference. But Psaty, one of the nation's leading independent biostatisticians, said, "This was a huge safety signal. If this had been made public in a timely fashion, many fewer patients would have used Vioxx, and fewer might have been harmed by it."

The authors conclusions, which go far beyond the ghost-writing issue, are worth pondering:

For sponsors that conduct their own studies or use contract research organizations to conduct studies, it is not clear how transparency in the reporting of results can be achieved if a sponsor chooses to represent its products in the best possible light. The commercialization of clinical trials has neither improved the quality of the science nor enhanced the protection of human research participants.

The findings from this case study suggest that additional protections for human research participants, including new approaches for the conduct, oversight, and reporting of industry-sponsored trials, are necessary. A clinical trials system in which sponsors fund the trials that are conducted by independent investigators would provide additional protections.

Woodcock to Run CDER, Again

The Food and Drug Administration announced yesterday that deputy commissioner Janet Woodcock will return to her former post as head of the Center for Drug Evaluation and Research.

The Wall Street Journal noted this morning that she will be in charge of recruiting new staff to implement the recently enacted law beefing up the agency's post-market safety surveillance system. Let's hope her heart is in the task. She has been the primary architect within the agency of the Critical Path Initiative, whose mandate -- helping industry emerge from its innovation drought -- was institutionalized in the newly created Reagan-Udall Institute.

Will this new non-profit, chaired by former FDA commissioner Mark McClellan, get off the ground? Rep. Rosa DeLauro, D-CN, is holding up funding after raising questions about industry domination of its board and mission.

One of Woodcock's first tasks will be to reassure Congress that Reagan-Udall isn't just a think tank for implementing industry's wish list for speeding new drugs to market. She could do that by releasing her suggestions for the new non-profit's research priorities. Don't forget that the mission of Reagan-Udall is not just coming up with new tools for speeding new drugs to market, but developing better tools for evaluating the safety of new drugs once they're on the market.

FDA Proposes Lack-of-Evidence-Based Medicine Policy

The Food and Drug Administration today proposed giving drug industry detailers the right to hand physicians reprints of journal articles touting the off-label use of prescription drugs. The proposed guidance was immediately blasted by Rep. Henry Waxman (D-CA), chairman of the House Oversight and Reform Committee, who called it "terrible for the public health. It caters to the industry’s desire to market their products without adequate testing or review."

Last December, Waxman's staff uncovered minutes of a meeting between top FDA officials and Dan Troy (who was general counsel at FDA during President Bush's first term) and other drug industry lobbyists. The industry spokesmen "expressed concerns about Federal prosecutors pursuing distributors of (joumal reprints) for criminal misconduct," according to the minutes. "There is confusion about the rules, possibly an FDA guidance could clarify the rules."

Waxman demanded the agency hold off on issuing its guidance until Congress passed a law protecting physicians and the public from a new burst of off-labeling marketing that would surely result from liberalization of the rules. His efforts were backed by state attorneys general fighting to hold down costs in their Medicaid programs and trial lawyers suing drug companies over illegal marketing schemes (the use of journal reprints promoting off-label use was a major element in the Neurontin case).

So what was in today's proposed guidance? It pretty much gives industry everything it was looking for. It would allow drug salespersons to drop off article reprints as long as they came from a peer-reviewed journal that had a conflict-of-interest disclosure policy. Articles from industry-funded supplements would not be allowed.

The policy also said the reprint couldn't be marked up in any way to highlight specific points, and must include a copy of the approved FDA label for the drug or device. It also couldn't be accompanied by other promotional literature for the approved uses.

Note what isn't in the policy: It doesn't say that the studies of unapproved uses must be from randomized controlled clinical trials, which is the gold standard of medical research. All the proposed guidance says is that the studies should be "adequate and well-controlled clinical investigations that are considered scientifically sound by experts with scientific training."

This is an open door for the drug industry to conduct more so-called seeding trials that encourage off-label uses. Because of their small size and lack of a control group, these trials are almost always of limited value in judging the true benefit of the drug in that off-label use.

Unfortunately, there are lots of second-tier journals in every medical specialty that publish dozens of such trials every year. And they will be happier than ever to take them since, should this guidance get adopted, they are likely to see reprint requests from drug companies soar.

Moreover, in exchange for the right to distribute literature on off-label uses, the company won't even have to pledge to submit an application to the FDA seeking approval for that off-label use. Not now, not three years from now, not ever.

As the nation grapples with how to pay for skyrocketing health care costs and policy wonks grapple with how to get more physicians to follow evidence-based medical practices, the Bush administration's FDA (the guidance was written by Randall Lutter, who was at the American Enterprise Institute before taking over the agency's policy shop) has proposed opening the floodgates to wider promotion and use of unproven drugs.

There's a name for that kind of policy: Lack-of-Evidence-Based Medicine.

Institutional Conflicts of Interest

Nearly a decade ago, an 18-year-old student named Jesse Gelsinger died in a gene therapy experiment at the University of Pennsylvania. It was run by a physician-professor who had invented the technology; started a company to develop it with the university's financial support; and used the company's cash to finance the clinical trial, which was conducted at the university. The disclosure forms signed by the patient and his family did not adequately reveal the risks involved.

In the wake of that ethical fiasco, the U.S. Department of Health and Human Services issued guidance to academic medical centers to adopt policies governing the so-called institutional conflicts of interest that exist when universities have a proprietary interest in a technology under development in its labs and clinics. But a new survey published in the Journal of the American Medical Association today found that by 2006, just 38 percent of the nation's academic medical centers had adopted such policies (30 of the 86 institutions that responded; there are about 125 medical schools in the U.S.). Another 29 are working on them.

Even more disturbing was the limited scope of the policies that were put in place. Most of the policies had strict guidelines for top officials at the universities. They had to reveal institutional conflicts of interest. But to whom? The study's authors noted:

The 2004 U.S. Department of Health and Human Services guidance urges institutions to establish policies for conflict of interest committees to provide information, recommendations, and findings to Institutional Review Boards [or IRBs, which are required by law to oversee clinical trials to ensure they adhere to ethical standards]. Substantial gaps exist in informing institutional IRBs of potential institutional conflicts of interest in research projects under review, other than of those of its own members. This is a disturbing finding, may be contrary to federal guidance, and calls for prompt institutional attention.

Note the implicit assumption in the study's finding. It's okay for IRBs to be staffed by physicians or administrators with conflicts of interest.

This raises an important question. Does disclosure of conflicts of interest to members of an IRB -- whether they exist within the institution, the management of the institution, or within the IRB itself -- ensure that the trial under review adheres to the highest ethical standards? Isn't it possible that those conflicts will influence the review? And doesn't the mere presence on the IRB of someone with a stake in the outcome of that trial create the appearance that the conflict of interest may have influenced a decision?

Appearances matter. What if something goes wrong in the trial, like what happened in the Gelsinger case. Won't someone point to the presence of an IRB member with a conflict of interest and suggest that it was due to lax oversight? Would an IRB or its institution want to see that allegation spread across the front page of its local newspaper?

In my view, when it comes to IRBs, anyone with a conflict of interest that relates to a particular trial under review should recuse themselves from overseeing and making any decisions about the ethical validity of that trial. Surely universities can find people without conflicts of interest to sit on these IRBs, which are a crucial firewall for protecting the safety of participants.

Meanwhile, an accompanying editorial by David Rothman of Columbia University's Center on Medicine as a Profession ignored the weaknesses in the policies being adopted by the minority of institutions that have adopted them. Instead, he raised the specter of mandatory federal regulation if the slow-moving universities don't get off the dime and enact policies of their own.

"Will government regulation step in to fill the vacuum? Current federal and state interests in industry-academy relationships provide reason to believe so. Congressional hearings are addressing the implications of industry support for continuing medical education, gifts to clinicians, the sale of physician-prescribing data, and pharmaceutical company efforts to intimidate researchers critical of their products. Currently eight states and the District of Columbia have laws or resolutions affecting marketing of pharmaceuticals. Thus, it may not require another Gelsinger-type incident to bring about significant regulation and legislation."

It's not clear that Congress will pursue the issue. Just a few weeks ago, the HHS inspector general issued a report lambasting the National Institutes of Health for failing to oversee or even collect data on the conflict of interest policies that grant-receiving institutions are supposed to enact for investigators that get the NIH grants. The agency responded by rejecting the IG's suggestion that NIH collect conflict-of-interest disclosures from universities. It would appear you can lead the government agency to water, but you can't make it drink.

There is a solution, of course. Forget about "guidance." Congress could step in and pass a law that prohibits investigators or university officials with conflicts of interest from sitting on IRBs and requires NIH to collect conflict-of-interest disclosure data from grant recipients and post it on its grants database (it's known as the CRISP database). To enforce the law, NIH could cut off all federal grants to that institution if those policies aren't adopted by a date specified in the legislation.

That would get medical schools' attention, and provide institutions, IRBs, investigators, journal editors and the public with a useful tool for managing conflicts of interest.

Gov't. Scientists Whistling in the Dark

Top officials at the Centers for Disease Control are blocking publication of a 400-page, peer-reviewed report documenting toxic hot spots in the eight-state Great Lakes region after demoting the scientist who led the study, the Center for Public Integrity reported last week. The House Science and Technology committee is investigating.

In a letter sent last week to CDC director Julie Gerberding, Rep. Bart Gordon (D-TN) questioned the seven-month delay in issuing the report, and asked for details on “disturbing allegations about interference with the work of government scientists” at the CDC’s Agency for Toxic Substances and Disease Registry (ATSDR). The report, which warns that more than nine million people may face elevated health risks from exposure to dioxin, PCBs, pesticides, lead, mercury, or six other hazardous pollutants, was slated for release last July.

The study’s chief author was Christopher De Rosa, the director of ATSDR’s division of toxicology and environmental medicine and, according to the story, “a highly respected scientist with a strong international reputation from his 15 years in charge of the division.” Howard Frumkin, the chief of ATSDR, told him the Great Lakes study was “well below expectations” and removed him from his position. De Rosa is seeking reinstatement to his former position, claiming that Frumkin illegally retaliated against him. CDC officials refused to talk to the Center for Public Integrity.

In another case involving whistleblowers, the Food and Drug Administration is being asked to document all meetings between its staff and companies regulated by the agency. Sen. Charles Grassley (R-IA) called for the change last week in the wake of an investigation that found the agency blindly accepted conflict of interest charges leveled by a private company against one of its scientists. The Center for Veterinary Medicine removed adverse events coordinator Victoria Hampshire from her position in January 2005 after top officials at a Wyeth Pharmaceutical subsidiary lodged the complaint. At the time, Hampshire was preparing to go before an advisory committee where she planned to oppose reintroduction of the company’s ProHeart 6 canine heartworm drug, which triggered severe allergic reactions in some dogs.

At a private meeting two months prior to her reassignment, company officials gave then acting FDA Commissioner Lester Crawford and chief counsel Dan Troy numerous slides from a private investigator’s report that accused Hampshire of running a website that sold a competitor’s product. Grassley’s investigation found those allegations to be false. Moreover, the FDA’s Office of Internal Affairs used those documents, which Grassley called “rife with error” and easily refuted, to seek a criminal investigation of Hampshire. “Industry representatives ought to have a good working relationship with FDA,” he said, “but under no conditions should the scientific process be compromised by industry pressure.”

Meanwhile, whistleblower protection advocates are hoping the House and Senate will quickly reconcile and approve legislation that would protect scientists like De Rosa and Hampshire. Besides beefing up legal rights that have been largely eviscerated by the U.S. Court of Appeals for the Federal Circuit (it has rejected 179 of 180 whistleblower complaints), the House version would prevent federal agencies from retaliating against scientists who reveal when their superiors distort or suppress government science. The Bush administration has lobbied against both versions of the bill and threatened a veto.

A version of this story first appeared in Integrity in Science Watch, a publication of the Center for Science in the Public Interest.

Former FDA Insider Analyzes New Report on Agency's Flaws

Susan Wood, formerly head of the Food and Drug Administration's women's bureau, just posted an insightful analysis of a new report from the agency's Science Board calling for more resources for the agency. She focuses her attention on its proposals for beefing up the FDA's scientific capacity. Check it out over at The Pump Handle, a blog for the public health crowd.

Conflict-free Advisers Easily Found

When the original 2001 Vioxx study appeared in the New England Journal of Medicine, its industry-funded authors dismissed data showing the drug raised the risk of heart attack by suggesting the comparison drug in the trial had been cardio-protective. Last month, the Food and Drug Administration did something similar with a study of conflicts of interest on its advisory committees. The agency's press release said it would be difficult to create advisory committees free from conflicts of interest. The study, which cost taxpayers $60,000, according to FedSpending.org, also claimed the advisors granted conflict-of-interest waivers had greater expertise than those without conflicts serving on the committees.

In fact, a Center for Science in the Public Interest reanalysis of the data contained in the report revealed that the FDA and the report should have drawn the opposite conclusions. The report examined four committees created during 2006 that granted 17 waivers. It took just 88 person-hours to identify 30 independent experts with all the expertise needed to fill those slots. Each of the 30 affirmatively declared in the medical literature that they had no conflicts of interest. Moreover, the expertise of those potential candidates, according to the report's own methodology, was greater than either the conflicted or unconflicted experts chosen to serve on the committees.

In a letter sent today to Commissioner Andrew von Eschenbach, a coalition of consumer groups called on the FDA to reopen consideration of an agency proposal made last March that would forbid anyone who has financial ties with industry worth more than $50,000 from serving on advisory committees. It would also deny voting rights to advisers with lesser conflicts. "While the FDA's proposed guidance doesn't go far enough, this study shows that those barred or restricted under its limited provisions could be easily replaced," said Merrill Goozner, director of CSPI's Integrity in Science Project. Recently passed legislation only requires the agency to reduce total waivers by 20 percent over the next five years, which is well short of the total ban on conflicts of interest sought by consumer groups.

Reprinted from Integrity in Science Watch, a publication of the Center for Science in the Public Interest.

Did Bush Administration Muzzle FDA?

Near the end of his recap of the recently enacted Food and Drug Administration reform law, former deputy commissioner for policy William Schultz claims in today's New England Journal of Medicine that the Bush administration "blocked agency officials from . . . providing timely 'technical' assistance to ensure that legislation would be drafted to meet congressional goals."

Is this true? While it is perfectly logical that the FDA did not publicly support changes in the law -- I believe federal employees are prohibited from lobbying Congress -- it is crucial that they be allowed to advise Hill staff drafting proposed changes so Congress can work its will, or, conversely, insure that it doesn't inadvertently damage the ability of the agency to do its job. If someone stopped them from doing this during the yearlong debate over FDA reform, it should be exposed and condemned.

Loophole in New FDA Law: Reporting Failed Trials

Barry Meier of the New York Times has an eye-opening article this morning pointing out a major flaw in the recently passed Food and Drug Administration reform law. Clinical trials that are halted because their products will not meet the FDA's safety and efficacy standards probably won't have their results registered in the government's clinical trials database because the results are never compiled. The story cites a failed silicone breast implant trial by Inamed as one example. The trial's existence and protocols presumably were registered at ClinicalTrials.gov because the company usually wants a successful trial published in a medical journal, and most of the good ones conform to the International Committee of Medical Journal Editors guidelines that require registration of clinical trials before the first patient gets enrolled if the results are to be published.

But negative results? That's the blackhole in every field of science. And, as today's story points out, this black hole in the medical information system has very real and negative consequences for public health.

The Failure of FDA Reform

The Guardian (UK) just posted my analysis of the Food and Drug Administration reform bill that President Bush signed into law last week. You can read it on the Comment Is Free section of their website.

Most Important Drug-Safety Legislation in a Century?

The New England Journal of Medicine in an editorial this morning calls the Food and Drug Administration bill now moving through Congress "the most important drug-safety legislation in a century." More important than the 1938 law that ushered in the safety requirement? More important than the 1962 law that required drugs be effective?

The editorial's list of the essential ingredients that must be included in a successful reform bill also did not justify the hyperbole:

While it called for mandatory public registration of clinical trials, it did not call for mandatory public posting of their results.

While it called for stiff penalties for false advertising, it did not call for a ban on direct-to-consumer ads, which are deeply resented by most members of the medical profession not to mention a significant contributor to the distortion of medical priorities in this country.

The editorial makes no mention of tougher standards for approving and monitoring medical devices. Remember the brouhaha over drug-coated stents? Millions of Americans with heart disease had them inserted, but sales are now collapsing because outcomes are worse than patients who received the bare-metal variety. Yet the provisions on devices in this bill are so weak that the industry's trade association has admitted they "dodged a bullet" and offered warm support for the bill.

And, finally, the editorial did not mention ending or even limiting conflicts of interest on FDA advisory committees, which is contained in the House version of the bill.

While the editorial refers favorably to last year's Institute of Medicine report, it ignores one of the central messages of that report: that the FDA's culture has become warped in favor of industry because of its reliance on industry user fees, in place since passage of the 1992 Prescription Drug User Fee Act. The agency is now primarily oriented toward approving new drugs, not protecting the public from unsafe or ineffective drugs.

Instead of altering those incentives, this bill increases the agency's reliance on user fees. More will go to safety compliance, for sure. But a truly significant FDA reform bill would have cut the ties between the user fees and agency performance goals, which all involve speeding new drugs to market. Or, it would have eliminated user fees entirely and appropriated taxpayer resources to fund this critical agency. Can't the government find another half billion dollars a year? Heck, that's what we spend in Iraq in two days.

The greatest reform in a century? This editorial sends a clear message to Capitol Hill on the eve of its conference committee that as far as the medical profession is concerned, milquetoast reforms are enough.

FDA Reform Bill Goes to House Floor

The House Energy and Commerce Committee late today passed the Food and Drug Administration user fee reauthorization bill that slightly improves the ability of the agency to ensure new drugs are safe and well-monitored once on the market.

On the upside, the bill includes $225 million over the next five years for beefing up the agency's safety department. This was also included in the Senate-passed bill, and would enable the beleaguered safety department to conduct a lot more studies of problematic drugs once they've entered mass use.

The bill also includes a requirement to register all late stage clinical trials and their results. This is also in the Senate bill, and should help independent researchers and consumers -- not to mention the FDA's internal reviewers -- conduct many more meta-analyses of widely used drugs that may have safety problems.

While the bill gives the agency increased powers to levy fines for misleading ads, the Democratic-controlled House caved into the pharmaceutical and broadcast industry lobbies by refusing to give the agency the power to impose a three-year moratorium on direct-to-consumer ads.

On the conflict of interest front, the Republicans tried to repeal a clause that will limit the agency to appointing just one scientist with a conflict of interest onto any advisory committee. The FDA usually follows the advice of its outside advisory panels, but in recent years, nearly a quarter of all advisers (mostly academicians) have had ties to companies regulated by the agency.

Assuming the one-waiver-per-meeting clause stays intact through the full House vote, which is expected later this summer, expect a confrontation with the Senate in conference committee. The Senate bill has no limitation on the number of waivers the FDA can grant.

The bill also included an amendment offered by Bart Stupak (D-MI) that beefs up the adverse event reporting system and pushes the agency to require that companies complete clinical trials promised by companies at the time their new drugs get approved. About three-quarters of such promises never get fulfilled.

The bill also included a provision that all direct-to-consumer ads contain an 800 number where consumers can report adverse events.

All in all, it's a lot better than the Senate bill, and a lot better than the status quo. The action now shifts to the full House floor before it heads to conference. Look for a lot of behind the scenes lobbying by the pharmaceutical industry lobby to push the final outcome in the Senate's direction.

FDA Crisis Confab?

Where's the Food and Drug Administration's top managers? With the House Energy and Commerce Committee on the eve of marking up FDA reform legislation, all the top officials at the agency -- including Andrew von Eschenbach, Janet Woodcock and Randall Lutter -- didn't show up for work yesterday. The rumor that swept through headquarters was that they'd been summoned to a "crisis management" meeting by Health and Human Services Secretary Mike Leavitt.

Lutterly Lacking

There are two crucial Food and Drug Administration reforms that the House must insist upon as it reauthorizes of the Prescription Drug User Fee Act: First is giving the FDA the power to impose a two-year moratorium on direct-to-consumer advertising for newly approved drugs; the second is the right to insist that the company complete a post-approval clinical trial within a specified period of time or the drug gets withdrawn from the market.

This became clear to me as I listened to the various members of the health subcommittee of the House Energy and Commerce Committee attempt to elicit meaningful responses from Randall Lutter, the deputy commissioner who had been sent up to the Hill to testify. Lutter is a former fellow at the American Enterprise Institute, and has now taken over the reins of the FDA’s regulatory affairs office. He’s well versed in the many proposed guidances that have come pouring out of the FDA in recent months, including one involving conflicts of interest on FDA advisory committees.

Which, of course, is the other major provision that has to be inserted in to the House bill – a complete ban on appointing scientists with ties to industry, not the “one waiver per meeting” policy included in the current version of the bill. The committee also needs to insert a “look back” period for determining conflicts of interest that is at least three years long. There’s nothing on this question in the current bill, and it represents a huge loophole that will render any reform the House passes on this issue moot.

Lutter was woefully underprepared for the meeting. The most entertaining back-and-forth involved Rep. Diane DeGette (D-CO), who at a previous subcommittee meeting had asked the FDA for some data involving medical devices. They were supposed to have responded in writing within a few weeks of the hearing – a typical response at Congressional hearings when the witness can’t immediately put his hands on the information being requested. A month ago, DeGette wrote a follow-up letter asking "where's the data?" When she brought that letter to Lutter’s attention today, he admitted that he hadn’t read it because he hadn’t seen it. It was a graphic portrayal of an administration that is either totally incompetent or contemptuous of the Democrats who now control Congress. Maybe both.

The various Congress-folk took turns trying to pin Lutter down on the different elements of the reform package, which includes establishing risk management plans for new drugs, sending all new drugs to advisory committees, a mandatory clinical trial registry, including results, and smorgasbord of add-ons that run from extending extra patent term to companies that conduct pediatric clinical trials to establishing a new institute within the FDA (named, oddly, Reagan-Udall) that would develop new science to help the agency do its job of protecting the public from unsafe and ineffective drugs and medical devices.

In the Senate, a coalition of broadcast, print advertising and drug industry lobbyists – you know what you call that in Washington? Powerful – succeeded in stripping from the bill language that would have given the FDA the power to limit direct-to-consumer advertising during the first several years the drug is on the market. This is crucial when there are signals in the data at the time of approval that a drug may have harmful side effects. Those signals can only be tested by an appropriately designed clinical trial, and until the results are in, the drug should diffuse slowly, like in the old days before DTC was allowed.

The argument made by the lobbyist coalition that a lawfully imposed moratorium would violate commercial freedom of speech suggests the public’s interest in protecting the public from needless exposure to a potentially life-threatening events (heart attack and stroke in the cases of Vioxx and Avandia) is outweighed by the First Amendment. I was a reporter for 20 years. I don’t think so. Oliver Wendell Holmes understood that freedom of speech isn't absolute – the famous yelling fire in a crowded theater illustration. It seems to me that protecting public health is one of those situations where the rights of commercial speech do not hold sway.

The FDA also needs a new weapon to ensure the trials get done during this moratorium period. That's where the threat of losing the drug’s tentative approval comes in. Companies have failed to start or complete hundreds of trials that were ordered by the FDA. These post-marketing trials are supposed to test whether the hints of harm in the pre-approval trials was real or just a statistical fluke. If it is real and the risk outweighs the benefits of the drug (Vioxx was just another pain pill; and Avandia, the latest drug in the dock, is just another blood sugar lowering drug), then the drug can be withdrawn before too much harm had been done. And what if the signal turns out negative? Then it can begin marketing the drug to a mass audience, if that is part of the corporate strategy.

There’s a number of other pressing issues that should be included in the bill during the mark-up session, which takes place Thursday. For instance, scientists at the agency should be protected if they go public with safety concerns, and they should be given the right to publish and speak independently. Rep. Jan Schakowsky asked Lutter about the recent case involving the scientist who tried to issue a warning about Avandia a year ago, but was told by her higher-ups at the agency to sit down and shut up. Schakowsky also mentioned the case of David Ross, who recently departed for the Veterans Administration after blowing the whistle on Ketek, an antibiotic with dangerous side effects.

“We take these concerns very seriously,” Lutter said. “I am unfamiliar with their cases.” There was a lot he was unfamiliar with Tuesday.

Meanwhile, the Republicans pressed an opening handed to them by whoever stuck an anti-preemption clause into the bill. This would not allow companies to use, as a defense in drug safety suits, the excuse that they complied with all the FDA regulations. (The failure to warn is the essence of many if not all product liability cases.)

I’m not up on the intricacies of this issue, but I do know this: in more than a year of talking about, writing about, and lobbying for FDA reform, this never came up. Why now? If this has something to do with undoing the handiwork of Dan Troy, the drug industry corporate lawyer who ran the FDA’s legal counsel office early in the Bush administration, then those issues ought to be fully discussed. Something that has far-reaching implications shouldn’t be snuck into a bill at the last minute, which appears to have happened in this case.

One Day in Iraq

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

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

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

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

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

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

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

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

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

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

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

Durbin, Bingaman Push Conflicts Amendment

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

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

PhRMA Power II

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

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

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

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

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

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

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

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

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

Inadequate FDA Reform Bill Moving in Senate

The Senate's Health Education Labor and Pensions committee will hold a mark-up hearing Wednesday on FDA reform legislation that fails to adequately deal with many of the agency's flaws. Opinion pieces in the New England Journal of Medicine and the Boston Globe, widely circulated in committee chairman Ted Kennedy's home turf, have taken the bill to task.

Even the conflict of interest provisions fail to take into account recent proposed changes at the FDA (see this article from yesterday's Integrity in Science Watch from the Center for Science in the Public Interest, which I edit). The question becomes: Why are the Democrats in the Senate going along with this clearly inadequate bill?

FDA Reform by the Numbers

It's crunch time in the Senate on Food and Drug Administration reform. The Health Education Labor and Pensions committee, chaired by Sen. Ted Kennedy, will hold a mark-up hearing next week on a bill that lumps together safety, generic biologics, medical devices and pediatric drugs. Lobbyists will get to see the first draft of the bill later this morning.

I'll have more to say on its contents after I see it. But here's a few public opinion measuring points:

Will it give adequate new powers to the FDA to pull unsafe drugs off the market? According to a recent Consumer Reports poll, 58 percent of the American public are either "very concerned" or "concerned" about the safety of prescription drugs.

What new limits will it put on direct-to-consumer advertising? Just under 60 percent "strongly agree" that advertising should be prohibited if there are safety concerns about a drug. There is strong pushback from the drug industry lobby about limiting commercial "freedom of speech."

Will it require public disclosure of the results of all clinical trials, whether or not they were submitted to the agency for getting a new drug approved? Fully 68 percent of the public "strongly agree" to full disclosure.

Will companies be punished if they don't complete in a timely fashion follow-up trials ordered at the time of drug approval? Again, two-thirds of the public want those studies done.

And, finally, will it prohibit the FDA from hiring outside advisers who have financial ties to the companies (or their competitors) whose products are being evaluated? Two-thirds of the Consumer Reports poll expressed deep concern about these conflicts of interest, mirroring a Harris Interactive poll from last summer which showed that 70 percent of the public thought they ought to be banned.

Meanwhile, billions of dollars are at stake in the generic biologics portion of the bill. With three-quarters of the American public worried about the rising cost of drugs (despite the new Medicare prescription drug benefit), will the bill provide an easy pathway for firms seeking to bring generic versions of complex proteins to market once the original goes off patent?

According to lobbyists for generic manufacturers like Barr Laboratories, the science isn't as complex as Amgen, Gemzyme and Genetech (makers of Epogen, Cerezyme and Human Growth Hormone, respectively) have claimed. The FDA's top officers have testified before Congress that they have the technical expertise to determine that generic biologics are comparable to the original version without demanding the full range of human clinical trials.

It will be interesting to see how the Senate's HELP committee, now under Democratic leadership, resolves these questions. Will it side with the people, or will it bend over backwards to accommodate the drug and biotechnology industry lobbyists who are swarming over Capitol Hill?

Abigail Alliance v. FDA

Here's a copy of a column that appeared in February in the Bay Area Oncology News. Contractual obligations forbade me from publishing it here until now. If I could only figure out how to make this website pay . . .

In the wake of the Vioxx fiasco, the Food and Drug Administration has come under attack for failing to protect the public from unsafe drugs. An Institute of Medicine report released last fall blamed the agency’s internal culture, which emphasizes faster new drug approvals over monitoring the safety of drugs already on the market. Legislation to improve the nation's drug safety system is moving forward on Capitol Hill.

Given these heightened concerns about safety, you’d think the FDA would be extremely wary of opening the door to greater use of unproven drugs. But that’s precisely what the agency proposed in mid-December, largely in response to court rulings in a suit filed by the Abigail Alliance, a patient advocacy organization formed in 2001 by Virginian Frank Burroughs shortly after his 21-year-old daughter died of head and neck cancer.

Last May, a three-judge panel in the U.S. Court of Appeals for the District of Columbia ruled that terminal ill patients like Burroughs’ daughter have a constitutional right to unapproved drugs as long as the hoped for benefit exceeds the risk. When you’re talking about cancer drugs, that’s almost always the case. As a practical matter, the ruling opened the door for any critically ill patient to gain access to any drug that had passed the minimal testing characteristic of small-scale Phase I safety trials.

The FDA immediately appealed the ruling, since, as two attorneys writing in the Journal of the American Medical Association pointed out in early January, it threatens “the ability of the FDA to protect public health.” If the full appeals court refuses to overturn the ruling, the agency will probably appeal to the Supreme Court.

Given the libertarian leanings of the Bush administration’s most recent appointments to the high court, it’s not surprising that the agency has moved to head off the suit by widening its existing expanded access rules, which are sometimes called compassionate use rules. Community oncologists have a lot riding on the final disposition of this proposed regulation because it is going to increase pressure to find experimental medicines for dying patients, even if they are not enrolled in clinical trials.

The FDA first created expanded access rules in 1987 in the midst of the HIV/AIDS crisis. Dying patients demanded access to the handful of experimental drugs then in the pipeline. After numerous demonstrations by militants at FDA headquarters, the agency complied.

However, those regulations upheld the primacy of the scientific process over the patient’s right to experiment on themselves. The scientific evidence “taken as a whole” had to suggest the drug would work, and the company had to be actively seeking FDA approval through controlled clinical trials. The idea was to extend treatment to dying patients who might have been excluded from Phase III trials because they were too sick or in other ways didn’t meet the trial’s inclusion criteria.

The FDA estimates that in the succeeding two decades, more than 100,000 patients received investigational drugs under expanded access programs. But most were run through company programs under FDA-approved protocols. The rules did allow for individual patients and their physicians to seek out experimental drugs, but the very few did, largely because no criteria were spelled out for treating physicians.

The proposed rule opens the door wide for community physicians who want to go down that path. They will be able to obtain experimental drugs for their patients as long as they tell the FDA that the risk from the experimental drug is not greater than the risk from the disease being treated. They also must certify that the patient can’t get the drug from a company program like an ongoing clinical trial. At the end of the treatment, the physician must provide a written summary of the results, including any adverse effects. The rules allow both physicians and drug companies to get reimbursed for these “treatments.”

Note what’s missing from the criteria. There is no mention of the “weight of scientific evidence” to justify prescribing the drug. There’s also no requirement that these individual patients be organized into a systematic clinical trial, although the rule states the FDA “may ask the sponsor to submit an Investigative New Drug application or protocol for the use.”

There are huge risks in this approach. For drug companies, it’s going to make it much more difficult to recruit patients for legitimate clinical trials. Moreover, the medical literature will undoubtedly become flooded with case studies and small-scale observational trials of dubious quality or predictive power.

Doctors will come under enormous pressure from sub-cults of dying patients who exchange hot tips over the Internet about the latest “miracle” drugs. Those who are leery of participating may face lawsuits from surviving family members or dying patients who feel they were denied information about all their options. Even if doctors properly caution patients about how little is known about the drug, they may be accused of malpractice if the drug turns out to be dangerous.

The biggest risk of all may be to medical science. Most cancer drugs fail. It’s hard not to sympathize with patients who want to fight for their lives with every available weapon. But they doesn’t give them the right to drag down evidence-based medicine with them.

FDA Enforcement: A Story in Pictures

In the wake of 9/11 and the October 2001 anthrax attacks, the government beefed up its efforts to inspect the nation's food and drug supply. It was a logical move, since both represented potential focal points for terrorist activity. But like everything else the Bush adminsitration sought to do in its War on Terror, the effort flagged once the War in Iraq got underway and diverted government resources to that ill-conceived, poorly executied and, as we now see, ill-fated adventure.

Here's the latest statistics from the FDA's Office of Enforcement:

Show Chart

A similar fate has befallen the FDA's efforts to police quality. Here's the agency's record in admonishing manufacturers for poor performance:

Show Chart

FDA Reform Is in the Air

The Food and Drug Administation, responding to the scathing Institute of Medicine report issued last September, launched a preemptive strike on drug safety yesterday to forestall legislative changes. You can read the details in news accounts here, here and here, or look at the FDA's own documents here.

It's a start, was the generous consensus. "Small potatoes," said Consumers Union, a view generally in line with my own. When I asked the head of the Center for Drug Evaluation and Research whether the agency would force companies to conduct post-marketing safety trials (most of those requests, issued at the time of approval, are ignored by the companies), Steve Galson replied that it would be up to Congress to give the agency that authority. Yes, but that begs the question, Dr. Galson. Do you want that authority? Will the Bush administration you serve ask for it in the budget request released next week? And, if it is given, will you use it?

The agency was also dodgy in its response to the issue of prohibiting scientists and physicians with conflicts of interest from serving on its advisory committees, which play a powerful role in determining if marginally effective or mildly dangerous drugs (because of side effects) get to market. These are the risk-reward trade-off decisions that the agency is often called upon to make, the ones that are as much about human judgment as they are about science. They often turn to outside advisers for help in that process through a committee structure that has received withering criticism from consumer groups and some physicians as being overly biased toward approving new drugs. Getting rid of conflicted advisers -- even though their votes have been shown to not be all that different from advisers without conflicts of interest -- would open slots for creating more balanced panels.

Randy Lutter, who manages policy for the agency, did say that the agency planned to put more epidemiologists on these committees, which presumably would give them additional insights into how drugs affect large populations once on the market. But he refused to give a definitive answer to how they'll handle the conflict-of-interest issue. We'll have to await a guidance document, which will be released later this year.

Meanwhile, Sens. Chris Dodd (D-CT) and Charles Grassley (R-IA) told the New York Times that they plan to reintroduce their legislation calling for a legislative overhaul of the agency. Which brings me to the final curious comment in that story. Scott Gottlieb, who recently left his political appointment at the FDA to return to the conservative American Enterprise Institute, said that the real battle this year will be over FDA intrusion into the practice of medicine. “I think we need to give the agency the resources it needs to get information about drug risks quickly,” he said. “But we don’t need the government telling doctors and patients what to do.”

I can think of two reforms that would constitute such an intrusion. One would be a requirement that all new drugs coming before the agency get tested against existing therapies as part of their initial regulatory approval process. This would provide physicians with important information for determining if the new drug was any better, or worse, than what's already out there. This might be a blow to the marketing departments of major pharmaceutical firms, but a solid advance for evidence-based medicine.

The other reform would be further restrictions on physicians' ability to prescribe drugs for other than their FDA-approved use, so-called off-label prescribing. Many of the worse abuses of the drug marketers have come from their illegal promotion of off-label use of drugs.

If these are the issues Gottlieb referred to, I say, bring it on. These would be very valuable discussions to have in Capitol Hill hearings later this year, say around reauthorization of the Prescription Drug User Fee Act, which provides over half the funds for the FDA's new drug approval activities and expires next October.

Can Left, Right Unite on User Fees?

While drug safety dominates the news, the big battle brewing over at the Food and Drug Administration is next year's reauthorization of the Prescription Drug User Fee Act, which accounts for nearly half the funds that flow into the agency. Consumer groups oppose user fees because it makes the agency beholden to the very firms it regulates for staff salaries.

The answer, of course, is get Congress to properly fund the agency. If the mission of the FDA is to protect the health and safety of the American people, then the American people -- all of them -- should fund the agency, not predominantly the drug and device manufacturers.

That's a bit of background for today's news, which came in an interesting letter to the editor in the Wall Street Journal, (subscription required). Henry Miller, an associate at the ultra-conservative Hoover Institution and a former FDA employee, complains that industry fees are unfair! Here's what he had to say:

These kinds of user fees are, after all, nothing more than a discriminatory tax on a single industrial sector. You could at least have raised the possibility of appropriated funds substituting for user fees when Congress takes up the reauthorization of PDUFA next year.

This could make for some interesting coalition building next year.

Crawford Charged with Lying to FDA

Former Food and Drug Administration administrator Lester Crawford, who for a time was the Bush administration's pick to permanently lead the agency, was charged today with lying about stock he held in firms regulated by the agency. Here's the relevant paragraph from the Bloomberg account:

Crawford, who was acting or deputy FDA commissioner for more than three years, also served as chairman of the FDA's Obesity Working Group in 2003 and 2004 while owning shares of Sysco, a distributor of snack foods, and Pepsico Inc., the world's No. 2 soft drink maker, according to court papers. The panel was formed to study the link between weight and health in the U.S.

You couldn't make this stuff up.

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.