COVER STORY

OFF LIMITS

The growth of pharmaceuticals bearing restrictions has the profession and pharmacists worried

Once upon a time, the standard paradigm for approved drugs was unrestricted distribution through licensed pharmacies and a reliance on the drug's labeling to inform prescribers, pharmacists, and patients on the safe use of the medication. "We've learned in the past decade that for some drugs, that paradigm is not sufficient—that labeling in and of itself cannot always assure safe use in the sense of maximizing benefit and minimizing risk," said Murray Lumpkin, deputy director, Center for Drug Evaluation & Research, Food & Drug Administration .

Pushing the FDA to rely less on labeling is the fact that labeling and warning letters sent to physicians have been largely ineffective in preventing adverse drug reactions, said Anne Trontell, deputy director-FDA Office of Postmarketing Drug Risk Assessment. She told a conference of the Drug Information Association that Rezulin (troglitazone, Warner-Lambert) is a case in point. Warnings to physicians that regular blood tests were needed to monitor liver function were largely ignored. Because of liver failure among some patients, the antidiabetic was withdrawn from the market.

Also prompting the FDA to rely less on labeling is the fact that companies and researchers have gotten far better at developing drugs for diseases that couldn't be treated in the past. The biotech revolution, still in its infancy, promises to create many more such entities, but these drugs often bear higher risks for which labeling alone may be inadequate.

To deal with the situation, the FDA has adopted amendments to its old approval system so as to give the agency unmistakable authority to restrict distribution of a drug as a condition of approval, "if we think it's necessary to ensure that it's used in a safe manner," said Lumpkin. The restrictions pharmacists are seeing now come not only from the federal government but also from manufacturers.

Let's take the manufacturer-imposed restrictions first, starting with Fosamax 40 mg (alendronate, Merck). From pharmacy's viewpoint, the restriction on the medication, indicated for Paget's disease of the bone, is a hard pill to swallow. This dosage is available not through community pharmacies but exclusively through CVS ProCare. As a protesting Calvin Anthony, executive v.p.-National Community Pharmacists Association, recently wrote to Merck, "If specialty pharmacy distribution was indeed essential, why make that distribution exclusive to one specialty pharmacy in which Merck-Medco has a financial stake?"

The way the system works, physicians must submit prescriptions to ProCare by mail, fax, or phone, and the medication is then sent to the patient. Pharmacy insiders see no justification for the system and speak of the manufacturer's desire to maintain profit margins above those for other strengths of alendronate. However, Merck spokeswoman Donna Cary explained that Paget's disease "is relatively rare—affecting about 3,000 patients. We found that most drugstores didn't stock [the 40-mg strength], and patients could not get the product." Another factor was a desire to avoid confusion with the new once-a-week formulations of alendronate (35 mg and 70 mg). Paget's patients enroll in Merck's Patient Support Program, which includes refill reminders, 24-hour phone access to pharmacists to answer questions, and other services.

Another example of a restrictive program set up by manufacturers is the Bayer Direct program, which uses the Express Scripts mail-order pharmacy as the delivery vehicle. Initially, Bayer Direct was the exclusive provider of Bayer's antihemophilic agent Kogenate FS (recombinant factor VIII). The stated reason was to ensure "reserved inventory for enrolled patients, stable pricing," and access for patients with all types of insurance coverage. Nonetheless, the National Hemophilia Foundation strongly protested the Bayer Direct sole distribution system, and Bayer responded with "refinements." The amended system now allows distribution through hemophilia treatment centers, hospitals, and home health-care companies, as well as Bayer Direct.

Bayer Direct is also involved with Bayer's Prolastin (alpha-1 proteinase inhibitor) for panacinar emphysema. The service is the exclusive distributor of the product. More than a year ago, the American Pharmaceutical Association expressed its concern over the system's "disruption of pharmacist/ patient relationships, and the involvement of Bayer in patient care activities," but no change has been made in the program. Another drug on Bayer Direct's list is Gamimune N, 10%.

Years before these restrictions were adopted, the AIDS drug Crixivan (indinavir, Merck) was available only through Stadtlanders, a central fill pharmacy. Later, distribution was opened up. The drug had been approved early in the AIDS epidemic, before the facts on its efficacy were definitely known. Because the drug was desperately needed, the FDA approved it on a "surrogate" basis—that is, under the theory that if certain lab values were shown to improve, such as the change in the CD4 count on lymphocytes or the amount of viral RNA present—a clinical benefit could be expected. The manufacturer also had to agree to continue with clinical trials, and the clinical benefits were ultimately demonstrated.

Some time ago, the FDA required blood tests for schizophrenia patients taking Clozaril (clozapine, Sandoz), but the agency didn't mandate how this was to be carried out. Explained Lumpkin, "We said the company had to come up with a system whereby we could ensure patients had blood tests prior to getting the drug. We told the company that we did not believe the risk of this drug could be managed adequately simply by labeling, given that patients see different doctors, end up in emergency rooms, and don't have a common medical record that follows them wherever they go in the country." The system Sandoz (later merged into Novartis) adopted was to contract with Baxter Healthcare's Caremark Home Health Division to dispense the drug and take weekly blood samples, using Roche Biomedical to analyze the samples. This brought protests from the health-care community, including the Joint Commission of Pharmacy Practitioners, and an investigation by the Federal Trade Commission ensued. Later, the restrictive system was relaxed.

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