Concerns about diabetes blockbuster Avandia have been addressed by the mass media, by FDA statements—and by the August 30, 2007, New England Journal of Medicine (NEJM). It’s not a surprise that the journal would have a negative view of the saga: its editors have recounted their perception of being mislead by industry on more than one occasion.

But the vehemence of the current NEJM article is noteworthy, in part because the journal has a pessimistic take on whether post-approval trials will provide significant insights into drug safety. “Disconcertingly, none of the several proposed analyses of the ongoing clinical trials is likely to define an absolute risk for myocardial ischemic events in patients with diabetes who are taking this drug,” writes Clifford Rosen, an endocrinologist at the Maine Center for Osteoporosis.

Back To Drawing Board

Rosen chaired the FDA advisory committee that decided to keep Avandia on the market. He’s no industry basher, having had grants from Lilly, Merck, and Novartis.

His article reviews what the advisory committee did, and his perspective has ramifications far beyond the Avandia story. For anyone hoping that Phase IV research will address the widely-acknowledged weaknesses of the current drug approval process, the article is a wet blanket.

Rosen briefly describes two observational studies that occurred after Avandia was approved. Neither had any connection to Glaxo or the FDA. But he and the advisory committee were disappointed in both sets of research data. “The indeterminacy of their results, due to the inevitable effects of the many confounding variables inherent in such studies, illustrates why this approach alone will neither solve the overriding problems of drug safety nor ultimately help a chronically underfunded federal agency,” Rosen writes. “There is no doubt that it will be costly to undertake true safety and efficacy studies of new drugs using clinical outcomes as primary measures, but in the long run, these efforts will save time, energy, and money.”

Frustration Factor

That paragraph may be aimed at Congress. Ordinary physicians are too busy or ill-informed about industry research and the FDA approval process to know which organization funded a particular trial, when the trial occurred during a drug’s life cycle or what the trial discovered.

As Rosen notes in his editorial, one of the observational studies of Avandia included 160,000 patients in the WellPoint database. On balance, the Avandia data, Rosen believes, “suggest that we urgently need to change the regulatory pathway for drugs for the treatment of type 2 diabetes to make clinical outcomes, not surrogates, the primary end points.”

Aiming At Washington?

The tone of the editorial appears to telegraph that whatever Washington decides to do about renewing the Prescription Drug User Fee Act (PDUFA), the academics at the NEJM won’t be placated. Indeed, there appears to be a new irritation at the NEJM with Congress and the FDA. As Rosen writes: “Without a regulatory sea change with regard to diabetes drugs, we are certain to be in the same position 5 years from now that we are in now: we will again find ourselves in possession of a new wonder drug that is designed to treat a devastating chronic disease but that may do more harm than good.”

The FDA, for the record, also contributed a response to Rosen’s article in the same issue of the NEJM. Those staffers, including the prominent Robert Temple, throw up their hands at the difficulty of designing better trials to tease out the cardiovascular risks of diabetes drugs. They write: “long-term trials will probably need to compare one drug within a multi-drug regimen with other available therapies, making demonstration of the effect of any single drug a formidable task.” That’s reasonable. But it’s also the sort of bland, safe utterance that will create the impression that the FDA is too friendly with the industry it regulates.

Three (Separate) Conversations

By our count, there are three conversations about drug safety. If you’re participating in one, you probably think the others are pointless. You probably will not be invited to the other two conversations.

One conversation is unfolding within industry, where there is a fairly advanced debate about a new paradigm for clinical research and regulatory approvals. Regulators and sponsors would release a drug to progressively wider circles of patients, gathering more data as they go. Lilly calls it “learn and confirm,” as we wrote here a few months ago, but it has other names. That’s a viable long-term solution to bringing even safer drugs to market.

Another conversation is proceeding within academia and nonprofit organizations. This is being lead by the NEJM and other journals. Here the pharmaceutical industry is being demonized as a sinister force that periodically, almost by accident, provides some minor benefit to science and society. This conversation has corroded the reputation of industry and the FDA, and promises to continue to do so. The industry has so far failed to engage its critics on their own terms.

A third dialogue is advancing inside Congress. That discussion concerns negligible funding and minor bureaucratic changes intended to create the appearance of improving the drug safety paradigm without angering anyone in the first two conversations. Connecting and reconciling these three conversations will be arduous. But it would be the first step toward reversing an ominous slide in the reputation of the industry and the regulatory agencies.