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Headline: Senate Rejects Medicare Drug Price Negotiations

Headline: Senate Committee Passes Drug User Fee Reauthorization

Headline: Breast Cancer Rates Decline After Hormone Use Declines

You don't have to be a political scientist to connect the dots. It's business as usual on Capitol Hill, even as evidence for the need for more thoroughgoing reform at the Food and Drug Administration continues to mount.

I attended the Senate mark-up hearing yesterday that passed the reauthorization of prescription drug user fee act. The full Senate will take it up in a few months.

The bill contains some improvements in the FDA's ability to protect the public from unsafe drugs. But it safety provisions are a far cry from the structural changes called for in last year's Institute of Medicine report. Nor does it include key changes demanded by insiders who've been blowing the whistle about failures at the agency.

Today's New England Journal of Medicine has an article documenting one such case -- the antibiotic Ketek -- by former FDA reviewer David Ross. Ketek, which causes severe liver injuries in some instances, was approved after a "non-inferiority" trial -- it was compared to a drug of only marginal effectiveness -- where some of the data was later exposed as fraudulent. The bad data was presented to an outside advisory committee AFTER the FDA knew about the possiblity that it was not accurate.

Summing up, Ross concluded the approval process was marked by:

. . . the use of fraudulent data, the substitution of uncontrolled postmarket safety reports for controlled clinical trial data, and the acceptance of trials that could not show efficacy. There was also overt internal pressure brought to bear on FDA reviewers to alter their conclusions.

The FDA response, also contained in NEJM, was hardly reassuring. "There was no intention to deceive the advisory committee," a slew of top officials wrote. The agency had referred one of the clinical trial sites for criminal investigation, but "the FDA did not discuss data-integrity issues at the second advisory committtee meeting to avoid compromising the ongoing investigations, recognizing that the FDA retained the ultimate decision authority."

Ross held out hope that the Ketek example and other recent slip-ups at the FDA will lead to reform. But the bill passed out of committee yesterday will do little to halt similar instances in the future. For instance, it doesn't create an independent safety department that can put its foot down when the new drugs division -- whose salaries come largely from industry user fees and whose guidelines are driven by the need for faster approvals -- passes out a questionable drug.

Nor does it contain provisions calling for total independence of outside advisers. Nearly a third of all FDA advisers on its 30 advisory committee have financial ties with drug and biotech firms, usually in the form of lucrative ocnsulting deals and speaking gigs.

Nor does it put a moratorium on direct-to-consumer (DTC) advertising for new drugs for the first three years on the market. This wise precaution would enable epidemiologists to determine if the drug was damaging patients in ways not forseen or only hinted at in the clinical trials submited to the FDA to gain approval. Marketing campaigns that include DTC advertising get millions of people using a new drug whose therapeutic advantages are often minimal compared to previous drugs. That can result in tens of thousands of people suffering side effects that were only hinted at in the relatively small clinical trials that led to the drug's approval. The ill-fated Vioxx is the classic example.

The committee's debate over DTC was a classic. Sen. Pat Roberts (R-KN) waived around a reporter's notebook (he's an editor and publisher in his hometown of Dodge City) while defending commercial freedom of speech. "This turns the FDA into an editorial review board," he fumed.

Sen. Ted Kennedy, chairman of the committee, responded that the legislation only gave the FDA the authority to hold back ads if a drug seemed problematic. "This is for that rare circumstance," he said. Sen. Tom Coburn, the Oklahoma Republican who is the only physician on the committee, wondered why the FDA would approve the drug in the first place if it thought it was problematic enough to forbid DTC advertising for its first few years on the market.

Not a bad point. How likely is it that the FDA will use its new authority? Not likely, as Kennedy said. The advertising sales managers at the newsweeklies and evening news shows, which depend on the largesse of the pharmaceutical industry, have nothing to fear from this bill.

How about the risk assessment plans required by the legislation, which are its centerpiece? Every time a new drug gets approved, its sponsor will have to show the FDA a plan for monitoring and assessing the ongoing risk as it gains wider use in the marketplace.

Here's an interesting thought experiment. Imagine such a law in place when Wyeth won approval of its estrogen hormones allowing pre-menopausal women to stay "forever female." Would it have prevented millions of women from taking the drugs and exposing themselves to an increased risk of breast cancer, documented by the latest epidemiological evidence in today's NEJM?

The user fees in the act would triple the size of the FDA staff conducting post-marketing surveillance, which will allow the agency to conduct more epidemiological studies of drugs' effects on large populations. But it's still a tiny fraction of the total staff committed to reviewing new drug applications. And the safety department still won't have the institutional clout represented by having its own chief and the power to withdraw drugs it deems unsafe.

The IOM report talked about a "culture" problem at the FDA. The heart of that problem is an attitude at the FDA that says approving new drugs, only some of which are really significant medical advances, is a more important goal than the FDA's stated mission of protecting the public from unsafe and ineffective drugs.

Before the day was over, the committee agreed to consider a couple of amendments to the legislation. None are key to improving safety. Sen. Sherrod Brown (D-OH) got Kennedy to agree to consider a limitation on citizens petitions when the "citizens" are pharmaceutical companies or their proxies and the petition is an attempt to delay the introduction of generic competition once a patent has expired.

Kennedy also agreed to consider an amendment from Sen. Orrin Hatch (R-UT), best known in this arena for his efforts to keep dietary supplements free from FDA regulation. His amendment would make it easier to approve new antibiotics; reauthorize and expand the orphan drug act; and give extra patent protection when a company brings a chemical derivative of an already-approved drug to market. This latter provision bears some scrutiny, since it could open a huge loophole for extra patent life for the most useless forms of me-too drugs.

Finally, Kennedy agreed to reconsider an earlier decision to exclude giving the FDA explicit authority to approve generic biologics, a provision pushed by Sen. Hillary Clinton (D-NY) in the Senate and Rep. Henry Waxman (D-CA) in the House. Last month, Kennedy told his hometown Boston Globe that he opposed any measure that would not require follow-on biologics to conduct the same clinical trials as the original patent owner, a move that would remove much of the financial benefit of follow-on biologics for consumers.

So, as the legislative calendar moves toward its September 30th deadline for PDUFA reauthorization, it is still possible that FDA reform and PDUFA reauthorization will turn into a Christmas tree for every drug and biologics issue. It will be a field day for Big PhRMA lobbyists, who already are the most ubiquitous presence on Capitol Hill.

As things stand now, the Kennedy-Enzi bill, which will be subject of intense behind the scenes meetings before it goes to the full Senate, will do very little to change the culture at the FDA. Let's hope the House bill, which had its first hearing this week, will do a better job.

Posted by gooznews at April 19, 2007 08:33 AM