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FDA Embroiled in New Controversies

Contract Pharma, March 2008

Last Year's Big Bill a Bust?

By Stephen Barlas

The year 2008 was suppose to be the start of a New Era for the Food and Drug Administration given congressional passage last September of the biggest FDA reform bill in decades. The Food and Drug Administration Amendments Act (FDAAA) of 2007 was suppose to correct some of the regulatory shortcomings which hamstrung the FDA in responding convincingly to allegations about the safety of drugs such as Vioxx, Ketek, Avandia and many others. When the FDAAA passed the House and Senate in September 2007 by overwhelming margins, key sponsor Sen. Edward Kennedy (D-Mass.) called it a “strong and comprehensive measure.”

But in at least a couple important instances, that bill is turning out to be a bust. Democrats have already stymied implementation of some important provisions, including the Reagan-Udall Foundation, which was suppose to funnel private sector funding to contractors who would speed up the development of scientific methodologies the FDA could use to accelerate drug approvals and more accurately determine the safety of new drugs. For companies looking for pharmaceutical contracting opportunities, the RUF would be a gold mine; it is suppose to raise and spend only private money so that the 76 Critical Path Initiative projects the FDA has identified as needing funding can be begun. Only four have gotten off the ground since 2004, when the CPI was established, because of lack of FDA funding. “Our bill recognizes that innovation is the key to medical progress by establishing a new center, the Reagan-Udall Foundation, to develop new research methods to accelerate the search for medical breakthroughs,” Kennedy had said last September.

But Rep. Rosa DeLauro (D-Conn.), chairman of the House Appropriations subcommittee with responsibility for the FDA budget, refused to allow federal funding in 2008 for the RUF’s start up—things like paper clips, envelopes and a modest staff-- which the FDAAA authorized. Steven Walker, co-founder and chief advisor to the Abigail Alliance, a patient advocacy group, says, “The Reagan Udall Foundation, given the lack of congressional funding, is a foundation with a mission and nowhere to go. It is obviously crippled.” Mark McClellan, the chairman of the RUF and a former FDA commissioner, did not respond to numerous voice and e-mail messages asking for a progress report on the RUF. Nor would any of the board members contacted individually, via phone and e-mail, agree to be interviewed.

At the same time FDAAA provisions such as the RUF seem to be limping out of the starting gate, it is becoming clearer that the bill—lauded in September by Kennedy and others—may not even have addressed some major drug safety problems. That was evident when two members of the FDA Science Board, an advisory group composed of outside academics and industry scientists, appeared before the House Energy & Commerce Committee on January 29. They were part of the subcommittee formed in early 2007 when FDA Commissioner Andrew von Eschenbach asked for a report on whether FDA’s current science and technology can support the agency’s statutory mandate to protect the nation’s food and drug supply. The report, “FDA Science and Mission at Risk,” was published in November 2007. On January 29, 2008, before the House committee, Gail H. Cassell, vice president for scientific affairs at Eli Lilly, and chair of the Science Board subcommittee which wrote the report, said, “It became rapidly apparent that the FDA suffers from serious scientific deficiencies and is not positioned to meet current or emerging regulatory responsibilities.”

Of course, the FDAAA had a regulatory focus, not a scientific one, except for the Reagan-Udall Foundation. But even the big bill’s regulatory reforms seem thin now measured against such 2008 controversies such as the ruckus over Vytorin, marketed by Schering-Plough Corp. and Merck & Co. There, allegations are rife that the two co-marketers of Vytorin voluntarily conducted a clinical trial of the drug after it was approved by the FDA but first fudged the results, then failed to report them when they showed Vytorin was no more effective in than Zocor, a generic, in lowering the risk of heart disease and stroke. Here, it was Vytorin’s efficacy, not its safety, which is at issue.

The FDAAA does give the FDA new authority with regard to clinical trials, but only with regard to reporting the pre-approval results when a drug is first approved, and with regard to ordering post-approval trials (which Merck and Schering did voluntarily). The new law says nothing about how those studies—pre-approval or post-approval-- should be conducted or when the post-approval results should be reported. Again, the FDAAA addresses reporting of clinical trials at the time a drug is first approved. So, for example, it requires companies to post, for the first time, the results of Stage II, III and IV clinical trials once the drug is approved. In addition, that post-approval information must include links to FDA reviews of the clinical trials and to medical journal articles in which the trials are discussed. That must be done within 90 days of the FDA approving a new drug. The bill allows the FDA to levy those $250,000/$ 1 million civil penalties against recalcitrant companies.

As important as those clinical trial reporting requirements were for many patient advocacy groups, the provisions were not among those billed as major drug safety advances; ones that, for example, would give the agency more leverage to force companies to change the labeling of a drug when adverse reaction data became available. That was the issue with Vioxx, whose labeling Merck balked at changing, and which the FDA was powerless to force the company to do. Previously, all the agency could do if a company refused to make a label change was pull the drug off the market, which could have widespread and deleterious ramifications for the people taking it. The FDAAA sets up a new expedited pathway for making label changes, where the company and the FDA move quickly through a process of proposals and counterproposals and, if there is no agreement, there is a time certain for ending the company’s appeals and forcing it to make FDA-dictated changes. Normally, these negotiations will last no longer than 120 days and maybe substantially less.

But the ink on that provision was barely dry before congressional Democrats began charging the FDA with perverting the intent of those labeling changes. On January 23 Democrats in the House and Senate, including Ted Kennedy, sent an angry letter to FDA Commissioner Andrew von Eschenbach complaining a proposed rule the FDA issued on January 15 makes “a glaring omission in its description of congressional intent with respect to FDAAA’s labeling change authority.”

One of the signatories to that January 23 letter was DeLauro, the Reagan-Udall Foundation villain. She also has had a hand in neutering another FDAAA provision; one which allowed the FDA to charge drug companies user fees which would be used for FDA review of direct-to-consumer (DTC) television advertisements. The FDA reviews TV ads now, but very slowly. The fees would have allowed the FDA to hire additional ad review staffers and give companies quick feedback so they promptly received some assurance that marketing campaigns would not be derailed at some later date by slow-developing FDA objections. The program was to have been funded at $11.25 million in 2008; some of that coming from the FDA budget, some of it from user fees. But DeLauro only allocated $4 million and, to make matters worse, refused to allow the agency to even raise additional funds via user fees. DeLauro’s press secretary failed to return both phone calls and e-mails asking for DeLauro’s rational with regard to both the RUF and the user fees for TV ad review.

Pharmaceutical Research and Manufacturers of America (PhRMA) Senior Vice President Ken Johnson says, “The DTC user fee program was an important component of the drug safety enhancements that Congress passed through FDAAA. We urge Congress to act quickly and to provide the appropriate authority for the FDA to operate this vital program.”

None of these problems were foreseen, of course, when both the House and Senate passed FDAAA by overwhelming votes last September. The House passed the bill by a vote of 405-7 on September 19. The Senate followed the next day by unanimous consent. The FDAAA weighed in at over 400 pages of very technical verbiage and contains, according to the FDA’s von Eschenbach, at least 200 specific provisions, many of which have implementation timelines. There were essentially two parts to the bill: the drug safety provisions and the increase in user fees paid by the pharmaceutical companies, the revenue from which would pay the salaries of additional FDA staffers who would implement the drug safety provisions.

In fiscal 2008, according to Alan Goldhammer, deputy vice president, regulatory affairs, PhRMA, companies will pay a total of $459 million in drug approval user fees. Those fees will account for 62 percent of the budget of the FDA’s Center for Drug Evaluation and Research. The $459 million is an increase of nearly 50 percent over the $305 million the companies paid in 2007. That $459 million will increase in each of the next four years over the five year term of the reauthorization. Most of that money has been, and will continue to be, used for the review of new drugs. But the bill sets aside $54 million for drug safety activities in fiscal 2008, most of that in the area of post-marketing. That figure will also increase steadily over the next five years. Much of that $54 million will be used to hire staff in the area of post marketing surveillance.

But even the huge increase in user fees required under FDAAA turns out to be far short of what is actually needed. On January 29, members of the FDA Science Board described a report first issued last November which scathingly described the FDA’s scientific shortcomings, many of them the result of insufficient resources. In their appearances before the House committee on January 29, Cassell and Garret FitzGerald, a second member of the subcommittee and professor of medicine, chair of pharmacology at the University of Pennsylvania, decried the systematic funding shortfalls at the FDA and other bureaucratic problems.

“These include the politicization and instability of leadership, attrition of manpower, poor morale, structural and organizational inadequacies, depleted infrastructure and – most importantly- critical gaps in scientific expertise and technology as emphasized in our Science Board report,” said FitzGerald. “These factors – many, but not all reflecting a serious erosion of necessary resource - compound to undermine seriously the science base of the Agency and its ability to fulfill its mandate.”

After those hearings, Democratic leaders on FDA issues, instead of committing to increased FDA funding in the 2009 appropriations bill, did what politicians do when they try to avoid making tough decisions: call for a report. Rep. Henry Waxman (D-Calif.), a senior member of the House Energy & Commerce Committee, and Sen. Kennedy, sent a joint letter to the Government Accountability Office requesting an examination of the staffing, information technology, and other resources necessary for the FDA to successfully carry out its oversight of foods, drugs, biologics, and medical devices.

This question of inadequate resources also raises questions about the viability and completion of another important initiative authorized by the FDAAA: the new “active post-market risk identification” network. Here the FDA will create a master database of sorts linking databases currently established by the Department of Veterans Affairs, the Centers for Medicare and Medicaid Services and those of private health insurers. This new network will supersede MedWatch, the current adverse reaction reporting system, which is close to useless. MedWatch depends on reports from health care providers and individuals, and frequently duplicate reports are filed.

The idea behind this new surveillance network is that as soon as information on adverse effects of a new drug becomes available, at the point-of-care as a result of a physician visit, it comes to the FDA immediately as the physician enters the data on a patient’s electronic medical record. There is no need for anyone to fill out a separate report. Plus, the FDA can then do retrospective searches of this master data base when it gets an inkling that there may be a problem with a new drug, i.e. inputting that drug’s name into the master file and seeing if there are adverse event reports in the system. The bill gives the agency two years to develop the data sources for this new risk identification system. But by July 1, 2010 there have to be at least 25 million patients in the data base. That number must increase to 100 million two years after that.

Getting this gigantic surveillance network up and running should result, as with the Reagan-Udall Foundation, in the letting of numerous contracts to private sector entities. Barbara Rudolph, director of leaps and measures at the Leapfrog Group, a group of large companies concerned about health care quality, spoke at a meeting at the FDA in March 2007 which was held to help the FDA get insights into what a new surveillance network might look like. That meeting helped seed the provision in the FDAAA. Rudolph says she has not heard a peep out of the FDA on the surveillance network since the FDAAA’s passage.