The Zyprexa Settlement and The Perils of Primary Care

We have been writing for some time about Big Pharma's primary care problem: the industry is built on an incredibly lucrative business model--selling oral medications for use by millions of patients with chronic conditions--that is going away before our eyes.

The primary care market is shrinking. The regulatory system is tilting towards smaller, niche market opportunities. The infrastructure built to support the blockbusters of yore is choking the industry. And the imperative to develop the next Lipitor is surely one reason behind the staggering lack of productivity in Big Pharma R&D.

Well, here's something you might not have realized. Apparently Big Pharma's incredible success in building massive primary care markets can now be painted as criminal conduct. That, at least, seems to be one implication from Lilly's record-setting $1.4 billion settlement agreement to resolve an investigation into its marketing of the antipsychotic Zyprexa. [UPDATE: of course records are meant to be broken, right? Pfizer's $2.3 billion Bextra settlement, astutely camoflaged by the Wyeth takeover, now takes that dubious honor.]

According to the government's memorandum supporting the entry of guilty plea by Lilly, a key element of the off-label promotion at issue was a decision by Lilly to "market Zyprexa to primary care physicians, even though there was almost no on-label use for Zyprexa in this market."

Here are some excerpts from the memo. (NB: These are described in the memo as facts that Lilly agrees would have been proven at trial.)

“Eli Lilly commissioned a report entitled ‘The Primary Care Opportunity’ from a nationally-known consulting firm. This report found that ‘larger competitors [eg. Merck, Pfizer, Bristol Myers] are migrating toward the primary care channel with drugs driven by profile improvements’ as compared to Eli Lilly, which was headed in the direction of providing drugs in specialty markets. The consulting firm advised Eli Lilly that ‘Primary care is a large opportunity that is likely to remain important. Lilly does not outperform its competitors in primary care and is leaving money on the able with current and pipeline products.’ The report identified Eli Lilly products, including Zyprexa, that if sold in the ‘primary care channel’ could significantly increase Eli Lilly's woridwide sales....

"The evidence would show that in October 2000, Eli Lilly began to detail Zyprexa to PCPs even though at least one internal Eli Lilly document acknowledged that there was virtually no on-label use for Zyprexa in the primary care market. The document, ‘ZYPREXA – Primary Care Strategy and Implementation Overview,’ provided that detailing PCPs was a major challenge because ‘Zyprexa's primary indications - schizophrenia and bipolar - are not viewed as PCP [primary care physician]-treated conditions, so there's not a specific indication for Lilly reps to promote in the PCP segment.'

"To get around the impediment that Zyprexa's indications - schizophrenia and bipolar mania - were not viewed as PCP-treated conditions, sales representatives were instructed to tout Zyprexa as a safe option for the treatment of a wide array of mood disorders commonly treated by PCPs....

"According to an internal newsletter, Eli Lilly USA Online, published on July 25, 2001, the launch of Zyprexa into primary care was a huge success."

While You Were Springing Forward

It certainly doesn't feel like spring at Windhover UK, but we'll take your word for it. Here are a few newsy things you may have missed over your abbreviated in-like-a-lion weekend.

• Lilly's Alaskan Zyprexa adventure rumbles along. The New York Times took a look on Saturday at Friday's testimony from Dr. John Gueriguian, a diabetes specialist and ex-FDA reviewer testifying on behalf of Alaska, whose bottom line is this: Lilly put “profit over concern of the consumer" by waiting too long to inform doctors of Zyprexa's links to severe weight gain and blood sugar changes.
  
• The WSJ interviews Amgen CEO Kevin Sharer, who talks about Amgen's recent tough times, its deal with Takeda, the difficulties of drug discovery and development, and some of the Big Biotech's new products, denosumab (D-Mab) and N-Plate, among other things. No word on why Amgen is giving all its product candidates these celeb-esque nicknames though.
  
• Hey, check it out. Free pharmaceuticals! (In your drinking water supply.) But just how will pharmacos charge for these freebies?
  
• More on this later, but for the moment allow us to get our Kent Brockman on to say we, for one, welcome our new insect corporate overlords.

The Windhover photo from flickr user greg.turner used under a creative commons license.

Zyprexa Depot: The Real Meaning of Delayed Release

FDA’s “non-approvable” decision on Eli Lilly’s long-acting olanzapine (Zyprexa) depot reiterates the reality of the new "Safety First" climate: product labeling and educational programs simply aren’t going to cut it as a comprehensive risk minimization program--especially if there are acceptable and well-understood alternatives on the market.

Going against the recommendations of its advisory committee, FDA declined to approve the long-acting olanzapine injection yesterday, stating that it needed “more information to better understand the risk and underlying cause of excessive sedation events.” In clinical trials, 1.2% of schizophrenia patients became profoundly sedated one to three hours after administration—to the point where some slipped into a coma.

Lilly presented FDA with a risk management plan to address the excessive sedation risk, including a bolded warning in Zyprexa labeling, a recommended post-injection observational period and a patient and physician education program. The company also said it would continue to monitor sedation events via a 5,000-patient observational study.

FDA’s Psychopharmacologic Drugs Advisory Committee bought into the program, agreeing with Lilly that with the appropriate labeling around the excessive sedation events, Zyprexa depot was effective and "acceptably safe" as a schizophrenia treatment in adults.

But FDA ultimately disagreed, pointing to a case in which a patient became excessively sedated three to five hours after the injection—a significantly later onset than what had been seen earlier in clinical trials. For FDA reviewers, that event no doubt called into question whether Lilly’s proposed risk management plan could adequately protect patients.

The Zyprexa non-approvable decision provides an early look into how FDA will view risk management in light of its new drug safety authorities under the 2007 FDA Amendments Act. Under the new law, sponsors are required to submit Risk Evaluation & Mitigation Strategies for all new drugs, or provide a justification to FDA for why one is not needed.

Risk management isn’t new: drug sponsors certainly have experience with designing programs to minimize the risk associated with new products. But Zyprexa demonstrates that the old rules no longer apply—especially for a line extension of an already-approved product. FDA is raising the bar, and industry would be wise to act accordingly.