Long Tail of the Law

Drug products are evolving long tails and they are going to carry costs for firms well into the future.

Drug safety commitments in the US and in Europe are developing into regulatory requirements that will stretch out for years, requiring time and resources from companies even after the products may have lost all commercial viability.

Two recent examples demonstrate this quirk of regulatory evolution.

Pfizer’s inhaled insulin, Exubera, was pulled from the market a year ago in October 2007; but a year later, FDA is imposing a formal Risk Evaluation & Mitigation Strategy on the product. That’s the authority that the agency received for controlling products in the post-market from the FDA Amendments Act in September 2007.

An article in “The Pink Sheet” (October 13) delves into the reasons for FDA’s belated regulatory requirements on the discontinued product. FDA says it expects Pfizer to undertake a supplemental NDA filing for Exubera to develop a medication guide and a communications plan to set a precedent for future inhaled insulin products that might try to come to market citing Exubera as a reference.

The legacy regulatory requirement is going to likely to cost Pfizer time and effort and stretch well past the commercial demise of Exubera.

FDA is also using its new legislated authority to further require Pfizer to submit data from Phase IV commitments. When Exubera was approved, the Phase IV commitments were part of an agreement reached by the company with FDA to conduct seven studies on 85,000 patients. FDA is converting that agreement into a mandatory requirement for six of the studies.

Pfizer says the studies have been terminated. FDA explains that it added the beyond-the-commercial-grave requirement to assure that any data that was collected by the sponsor would be submitted. As FDA says, “while the completion of the trials was not a mandate, the submission of data was.”

Shire also has had a recent experience with a withdrawn product that demonstrates the lingering costs and obligations even after a product is off the market.

At mid-year, Shire said it was discontinuing its overseas erythropoietin product, Dynepo, as a result of lower prices for the EPO class due to the introduction of biosimilars at prices 20-30% below branded levels. The company did not mention the general troubles in the ESA class from declining indications but that could not have helped the commercial prospects.

For commercial reasons, Shire decided to call it quits. But for regulatory reasons, the product will have lingering costs.

According to a late July briefing by the company on first half results, Dynepo will cost Shire about $6.5 million to warp up previous post-market study requirements. The company explains that “the costs are part of the commitments made to participants, centers, doctors, and clinical staff.” Like Pfizer, the company does not plan to finish the studies, but costs remain.

The situation of continued studies after market withdrawal is not new. With the post-market becoming more heavily regulated and with FDA having authority to require work (not just request it), companies should be prepared for long tails dragging behind dead products and holding back operating results.

Avandia Warning Letter: A Sign of Things to Come

You don't have to have finely honed news instincts to realize that if GlaxoSmithKline failed to disclose everything it knew about Avandia to the Food & Drug Administration, you are sure to have a big story.

So you will probably be reading a lot about the warning letter issued by FDA to GSK after inspecting the firm's post-market adverse event reporting procedures.

Many in industry may be tempted to dismiss the letter as just the latest in a series of woes for GSK and its once-blockbuster type 2 diabetes therapy, just more piling on to a bad news story that is almost exactly a year old.

That would be a mistake. The warning letter should be a must read for all biopharma companies with products on the market (and all companies who hope to be so lucky as to have products some day). The letter does indeed add to GSK's headaches, but for the rest of industry it should serve as notice that the agency is likely to do a lot more enforcement of post-marketing study reporting requirements in the months and years ahead.

Congress, remember, has just handed FDA new enforcement authority over post-marketing trials, in the form of the ability to mandate Phase IV studies--and fine sponsors who fail to live up to their commitments.

The violations FDA cited in the letter to GSK predate enactment of the FDA Amendments Act in 2007, but the agency is sending an unambiguous message: there is no excuse for failing to comply with basic reporting requirements that already existed in law.

According to FDA, the agency found that GSK failed to include updates on as many as 18 different post-marketing trials in its annual reports to the agency on Avandia. GSK notes that the missing reports were inadvertent and disclosed to the agency before the final safety labeling update on Avandia in November. FDA doesn't dispute that this is a case of mistakes rather than deliberate concealment. That, in fact is the point.

Here is the key part of the letter:

FDA's inspection revealed that your firm lacked appropriate knowledge of the studies associated with Avandia, resulting in the reporting deficiencies noted. Absent a clear explanation of the extent and cause of these deficiencies and an adequate plan to correct them, we are concerned that similar deficiencies in the postmarket reporting for your firm's other FDA-approved drugs may exist . We expect that your corrective actions will include a comprehensive evaluation of your firm's reporting of postmarketing studies for all drug products for which your firm holds an approved application.

In other words, it is not that GSK hid the data from FDA, it is that GSK did not have an appropriately rigorous process to ensure that it reported all the right data to FDA. In the new world of post-marketing oversight and regulation, expect the agency to make sure that every company gets that message loud and clear.

And in case you haven't read our analysis before, executives at all levels should bear in mind that the FD&C Act is a "strict liability" statute, meaning that top executives--starting with the CEO--can be held criminally accountable for violations they knew nothing about. (Indeed, as is FDA's policy, the letter to GSK is addressed to the CEO, JP Garnier.)

At this point, GSK is saying all the right things. “We take these findings seriously, and corrective steps to make sure we file periodic reports completely and promptly have been taken or are underway,” the company says in a statement. The company notes that many of the trials were in fact disclosed to FDA anyway, just not in the annual report as the agency says they should have been. And, the company adds, many of the studies were also publicly disclosed on the government's ClinicalTrials.gov website and through GSK's own on-line trial registry.

"GSK is committed to taking the appropriate steps to address the concerns raised by the FDA." The rest of the industry would do well to do the same.