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FDA Oversteps its Bounds for Jazz Fibromyalgia Drug

BioWorld Perspectives Contributing Writer

Editor's note: This week's column is a special reprint from BioWorld Today columnist Karl Thiel. To make sure you receive all of his columns, subscribe to BioWorld Today or sign up for a free trial for 30 days. With a free trial, you'll also get access to our archives and the BioWorld Industry Snapshots database.

"The FDA has already done enormous harm to the health of the American public," economist and Nobel laureate Milton Friedman once wrote, "by greatly increasing the costs of pharmaceutical research, thereby reducing the supply of new and effective drugs, and by delaying the approval of such drugs as survive the tortuous FDA process."

Friedman was reacting to the Kefauver-Harris amendments of 1962, which made it part of FDA's mission to assess the effectiveness of new drugs before they could be sold in the U.S. Until this landmark change to the Food, Drug & Cosmetic Act of 1938, the agency had been tasked only with evaluating the safety of drugs. Just safety – period.

Relatively few people these days would go as far as Friedman in suggesting wholesale deregulation of the drug industry. But the simple calculus implicit in his point – that FDA does more to halt or delay beneficial innovations than it does to protect us from dangerous ones – raises some relevant issues about an agency that is increasingly flexing its authority to say "no" or give only a guarded "yes."

That came to mind after a joint meeting of the FDA's Arthritis and Drug Safety and Risk Management Advisory Committees, which convened on Aug. 20 to discuss Jazz Pharmaceuticals Inc.'s fibromyalgia treatment Rekinla (sodium oxybate). FDA's briefing documents circulated prior to the meeting seemed to suggest that the agency's reviewers were satisfied that the drug is safe in its intended audience. (See BioWorld Today, Aug. 19, 2010, Aug. 23, 2010, and Aug. 24, 2010.)

Indeed, its lower side-effect profile is the chief competitive advantage Jazz hopes to exploit as a potential fourth entrant to the market – and also that it is effective in improving fatigue and controlling pain associated with fibromyalgia. But sodium oxybate is a powerful sedative that has been used in "date rape" crimes, and the FDA wanted the panel to decide if the company's proposed risk evaluation and management strategy (REMS) was "sufficient to address the potential for misuse and abuse . . ."

And the panel voted no, 20-2.

Now, there are subtleties about the wording of the question and what each panel member may have meant by his or her vote, as well as the still-open question of what the FDA will ultimately do with that input. But the notion that FDA could theoretically reject a drug that it finds both safe and effective suggests it is in danger of overstepping its bounds.

FDA Power Expansion

Those bounds have been steadily expanded over the years. The Kefauver amendments were followed by authority to regulate certain patient information in 1976, and by RiskMAPs (risk minimization action plans) in the 1990s. This latter authority, limited to accelerated approvals and otherwise voluntary, was a precursor to the REMS authority, created under the Food and Drug Administration Amendments Act (FDAAA) of 2007 – the most sweeping change to the agency in decades.

The FDA, perhaps because of the generally high level of respect it commands among the public, Congress, and the judiciary, has always been given a huge amount of leeway in its ability to create rules and regulations that are sometimes, frankly, outside of its statutory authority. Consider the "Phase IV" post-marketing study, about which the agency made rules as far back as 1970, even making them mandatory for fast-tracked drugs, all without any specific statutory authority until Congress codified the process in the late 1990s.

Its system of warning letters provides no formal or timely system of appeal, while its rules on off-label promotion have always played fast and loose with the First Amendment. In short, the agency commonly takes a "by any means necessary" approach to fulfilling its mission without strict regard to statute.

And now it may extend its control beyond evaluating safety and efficacy to issues of access, distribution and dispensing that doctors, pharmacists, and other government agencies have traditionally controlled.

Not that this is exactly new. FDA has made these sorts of restrictions on a number of drugs over the years, often to the annoyance of health care providers who were shut out of the system because the drug could be obtained only through a single source.

But there's an issue of balance here, and the agency's decision on Rekinla will tell us a lot about where things are going. Is an acceptable REMS plan going to be a negotiated inevitability, like a product label, or is it going to be a potential roadblock, an issue that can make a drug unapprovable? I'm no lawyer, but as far as I can see the statute doesn't address this, which, if history is any guide, won't stop the FDA from going where it thinks it needs to.

A common sense understanding of REMS, however, leads one (OK, me) to expect that it is not a make-or-break part of an approval decision, but a post-marketing tool (that's post, as in after approval). After all, amassing compelling evidence of safety and efficacy is a scientific endeavor. While subjectivity will never be removed from the process, the goal is nevertheless the objective achievement of certain signals pre-agreed upon or spelled out in guidance documents.

A REMS, on the other hand, is a collaboration between the FDA and a sponsor with no clear empiric goal that can be reached prior to launch, just the need to "ensure that the benefits of the drug outweigh the risks of the drug," as the statutory language goes. Like coming up with acceptable labeling, it should be assumed that a safe and effective drug will achieve reasonable distribution.

In the past, the agency has shown it can balance the risks and benefits to a target population against a very different set of risks posed to a larger population in cases where the stakes were frankly higher than they are in the case of Rekinla. The 1998 approval Celgene Corp.'s Thalomid – the active ingredient of which is thalidomide, ironically the catalyst for the 1962 Kefauver amendments – is a prime example. It's worth noting, however, in that case the FDA was acting in part because it was trying to control an active black market in thalidomide, which was used by some AIDS patients, among others. And that was before REMS.

So the question is whether the agency will decide that drug scheduling, enforcement and competent doctors and pharmacists are all unequal to its latest tool. Keep watching.

Karl Thiel, an analyst for the Motley Fool, can be reached at kthiel@qwest.net. His opinions do not necessarily reflect those of BioWorld Today.

Published: August 30, 2010