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 Because of liver failure among some patients, the antidiabetic was withdrawn from the market.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.

For a second group of drugs, distribution restrictions come from the public sector. One medication that's been walled off in this way for decades is methadone. When used as treatment for narcotic addiction, methadone is dispensed from specially licensed clinics that must comply with complex federal and state regulations, while providers must be registered with the Drug Enforcement Administration. Many states don't allow methadone clinics at all, forcing patients to drive long distances to receive their daily dose.

Mainstream methadone?

Will these clinics monopolize methadone forever? Perhaps not. Salon, an on-line magazine, wrote a year ago (March 14, 2000), "If scientists at the forefront of federal research on drug treatment have their way, methadone and other drugs used to treat heroin addicts will move out of clinics and into doctors' offices and pharmacies." With heroin addiction sadly becoming more common among the middle class and in affluent suburbs, there's growing pressure to introduce methadone into regular channels of medical practice and distribution. How many community pharmacies would be willing to dispense methadone is, of course, a separate issue. Another stumbling block might be the fact that methadone itself is an addictive drug.

The principal government agency restricting distribution is the FDA. Its authority to control and limit distribution is clearly stated in Subsection H of the 1997 FDA Modernization Act, dealing with drugs receiving accelerated approval. In its final rule, the FDA rejected the contention that it lacks that authority, or that such restrictions "impermissibly interfere with the practice of medicine and pharmacy. There is no legal support for the theory that the FDA may only approve sponsors' drugs without restriction because physicians or pharmacists may wish to prescribe or dispense drugs in a certain way."

The agency takes note of comments from the organized pharmacy community recommending that "postmarketing restrictions on distribution or use" be developed by agency committees that include physicians and pharmacists. The FDA also mentions pharmacy criticism of a system "that allows manufacturers exclusively to deliver prescription drugs directly to patients." To the first comment, the agency answers that "it will usually seek the advice of outside expert consultants." To the second comment, the agency makes no reply.

Subpart H was adopted not because the prior system wasn't working well, but to make the system even better, particularly improving the ease with which FDA can withdraw a drug from the market "if the risk management plan doesn't seem to be working," said Lumpkin. The first drug restricted under Subpart H was thalidomide (Thalomid), newly introduced by Celgene Corp. As nearly everyone knows, it was taken off the market in the early 1960s because of its association with horrendous birth defects. In its second life, it's been approved—under drastic restrictions—for an inflammatory skin condition caused by Hansen's disease. Before thalidomide was approved, there was a black market for the drug among the HIV population and cancer patients, "people who feel that the drug provides them with certain benefits." On the black market, "you have no idea what you're getting. You're taking all kinds of risks," said Lumpkin, and that's an additional reason for FDA approval—"so people can get good-quality drugs."

Lumpkin explained that with some drugs the side effects are unknown at the time of approval because they may occur in only one in 50,000 cases. But with thalidomide, the risk was known, and the question became, "How are you going to manage that risk? The answer is that there be no fetal exposures," he said. The way that's done is to ensure, as far as possible, that the patient is not pregnant when treatment is initiated and does not become pregnant while under treatment. Under the system worked out between the FDA and Celgene, physicians prescribing the drug and patients and pharmacists dispensing it must register with Celgene's STEPS program. The system also involves pregnancy tests, an informed patient consent agreement, and agreement by female patients to use two methods of birth control. While Rxs for Hansen's patients are few in number, off-label uses—for HIV/AIDS, breast or prostate cancer, and tuberculosis—could generate substantial volume.

The most extreme usage/distribution restrictions (short of withdrawing a drug) apply to Mifeprex (mifepristone, Danco Pharmaceuticals), used with misoprostol to end early pregnancies. No pharmacy may sell it. It's confined to certain doctors who meet stringent requirements—including the ability to provide or arrange for any necessary surgery resulting from the combined drugs—and to ensure patients have access to emergency care. Doctors must also agree to dispense the FDA MedGuide to patients.

Although mifepristone, also known as RU-486, was under FDA safety review for at least a decade, it appears that it's slated for even more scrutiny. President George W. Bush's new secretary of the Department of Health & Human Services, Tommy G. Thompson, said at his confirmation hearing that he favors a new safety review and called the drug's approval contentious and controversial.

For at least one high-risk drug, fentanyl, the FDA is demonstrating that there are better ways to go than walling it off from pharmacies. Older versions of fentanyl were used only in hospitals. Then the Oralet transmucosal formulation came along, with an indication for cancer pain, and "having this particular drug form available only in a hospital didn't meet the needs of patients," said Lumpkin. The fear of sending it home was that it looks like a lollipop and a child could find it and start sucking on it. "There's enough medicine in there to kill a child," he said.

The FDA's goal was to relieve the cancer patient's pain at home but keep the drug from being used by other persons in the home, hospice, or nursing facility. The solution, arrived at under the agency's risk management program and in consultations with the drugmaker and the Consumer Protection Agency, was fentanyl Actiq (Cephalon), also a transmucosal. It comes with a welcome kit featuring a child-resistant lock for cabinet storage and other measures to foil children. Though many pharmacies do not stock Actiq, they may get orders for the drug. This is because this year, nursing homes and outpatient clinics are required by the Joint Commission on Accreditation of Healthcare Organizations to measure patients' pain and treat it appropriately.

When the FDA or a manufacturer does decide to place distribution restrictions on a drug, it runs afoul of the organized pharmacy community. Recently, Henri R. Manasse Jr. , executive v.p./CEO of ASHP, wrote to then-FDA commissioner Jane E. Henney, expressing "concern over pharmaceutical manufacturers' increasing reliance on restrictive systems to distribute their products." These restrictions, he noted, "often include individual hospital as well as community pharmacies.... The patient-pharmacist relationship should not be misinterpreted as merely a product distribution function. Overall, drug therapy surveillance and management, including all the drugs the patient uses ... is the pharmacist's role and goal." ASHP, in comments to the FDA, added that "the prospect of a landscape of many different special handling processes is a frightening picture for health-system pharmacists."

Manasse was particularly irritated over the restriction on Tikosyn (dofetilide, Pfizer), for atrial fibrillation/ flutter. Initially, it was available only to hospitals and prescribers who received appropriate dosing and treatment education. All Rxs were filled by Stadtlanders (recently bought by CVS ProCare). Manasse complained that the requirements were confusing. The most recent word from Pfizer is that it is committed to exploring ways to make dofetilide available through retail pharmacy. Anthony, at NCPA, said Pfizer's willingness to cooperate with community pharmacy "can serve as an example in the future."

APhA's Susan Winckler, group director-policy and advocacy, said there's a problem "when the FDA can make approval of a product contingent on the manufacturer's agreeing to restricted distribution." She added that she has not seen any evidence that distributing a product from a single pharmacy, and separating that therapy out from all the other drugs a patient gets, is somehow safer. Even when it comes to drugs with stability problems, "assuming that pharmacists can't deal with these products is wrong."

Let pharmacies decide

The remedy, APhA believes, is opening up access to all pharmacists who wish to participate in distributing a drug, provided they meet legitimate use and monitoring requirements. The ideal, said APhA executive v.p. John A. Gans, would be for the FDA, in cooperation with R.Ph.s and other health-care professionals, to create a standardized process to work with products identified as demanding special attention. This common system, he continued, would allow pharmacists to build special monitoring/ oversight services into their practices.

NCPA's position is similar. Todd Dankmeyer, spokesman for the group, said that if a drug is approved, "they've demonstrated that it's safe and effective, and it should be available to any licensed pharmacy." Still, he acknowledged, with the growth of very specialized high-tech products, some pharmacies "are going to self-select themselves out" when it comes to drugs with "sophisticated clinical ramifications" because they don't want to do the things needed to safely and effectively provide the drug. But the choice is theirs.

To simplify matters for pharmacies that want to participate in a drug's distribution, NCPA has created the Specialty Drugs Network in partnership with a firm called TheraCom. It puts pharmacies in a position where they can select product by product, said Dankmeyer. What NCPA is vehemently against is the manufacturer or the FDA unilaterally deciding to deny the vast majority of pharmacies access to a drug. He calls that "anticompetitive." The reasons often given for restricted distribution, he contends, are not the true ones. He believes the actual motives of the manufacturer are the desire to control the market and maximize profit.

Distribution restrictions on Enbrel Injection (etanercept, Immunex and Wyeth-Ayerst) are not of the drastic type that NCPA, APhA, and others condemn. Recently the comarketers required patients to join an enrollment program in order to be assigned an enrollment card and number and pharmacy NCPDP number. The antiarthritis medication is then drop-shipped to the pharmacy by its regular wholesaler. Etanercept's marketers say the program's objective is to help ensure that current patients "receive an uninterrupted supply of medicine."

New conditions have also been set up for the distribution of Accutane (isotretinoin), the Roche acne drug that has been associated with patient suicide. Pharmacists must give out a MedGuide warning to patients who must sign a consent form saying they understand the risk. Both documents were recently revised.

Another side effect of isotretinoin, severe fetal abnormalities, is being addressed as well. For some years, black-box label warnings on the drug specified that female patients should use two forms of contraception and be tested for pregnancy prior to treatment. Further, Roche has a voluntary patient registry. Still, the measures have not been enough: Some women have ignored the warnings, and 2,000 of them have become pregnant while on the medication.

In other cases, the drug has been prescribed for mild acne, not just the severe cystic type for which it is indicated. This has led the FDA's Dermatologic & Ophthalmic Advisory Committee to recommend that the patient registry be mandatory and that pharmacists verify whether the patient has had a negative pregnancy test—in other words, backstop the doctor. Even without an FDA mandate, however, under the standards of practice, R.Ph.s have "shared responsibility" with the prescriber to inquire whether the patient has had a pregnancy test, said David Brushwood, professor of pharmacy, University of Florida College of Pharmacy, Gainesville.

Like isotretinoin—only more so—Pfizer's Trovan (trovafloxacin) has had a history of increasing restrictions. The drug was originally distributed, in early 1998, through regular channels. But when it began to display very serious side effects, the FDA and Pfizer limited its distribution to inpatient health-care facilities. Community pharmacies were instructed to return their inventory to the manufacturer. Even under inpatient conditions, the antimicrobial must be used with extreme caution. The FDA calls its present status an interim recommendation and said it will "continue to assess the drug's benefit/risk profile."

The ultimate restriction, of course, is withdrawal of a drug from the market. If approved medications are later withdrawn because of risk, one wonders why they passed FDA muster in the first place? The answer, explains FDA's Task Force on Risk Management, is that drugs are approved when the agency decides the benefits "outweigh the risks for the intended population and use." Once the drug is on the market, though, responsibility for ensuring safety shifts to health-care providers and patients, who are "expected to use the labeling information to select and use products wisely, thereby minimizing adverse events." After all, said the report, most injuries and deaths from drugs "result from known side effects."

The weakness in this system is that, as Lumpkin explained, "given the world of HMOs, doctors who see 40 patients a day, and pharmacists who are overworked," the idea of long patient counseling sessions with the doctor or pharmacist" is just not a reality. Furthermore, because clinical trials are conducted in small groups of patients, relatively rare side effects may not show up until a larger population has used the drug.

In all, 10 Rx drugs have been pulled from the market or severely restricted since 1997. Propulsid (cisapride, Johnson & Johnson), a GERD medication, was withdrawn a year ago because of dangerous side effects. Propulsid is now available only from the company under a compassionate-use program—essentially reverting it to Investigational New Drug status. APhA's Winckler questions this method. "You have to ask, Is that distribution system substantially safer? Or would you be better off with a system under which the physician who seeks a product with IND status works with a pharmacist to get that medication to the patient?" Her answer, clearly, is to work with and through the pharmacist.

Comeback for Lotronex?

An interesting case is Lotronex (alosetron, GlaxoSmithKline), for female irritable bowel patients. After severe side effects showed up following marketing, the FDA's first step was to require a MedGuide for patients. Then, when the side effects continued, the agency gave GlaxoSmithKline the choice between accepting a stringent program that included distribution only through the manufacturer, thus bypassing pharmacies, or withdrawing the drug from the market. The company opted for yanking alosetron. This satisfied its opponents, such as the Public Citizen Health Research Group, but angered patients whose quality of life quickly deteriorated once the drug was no longer available. The latest news is that alosetron may be given IND status or subjected to severe marketing restrictions, including, probably, exclusion of pharmacies from distribution.

In the opinion of some in the medical community, a major contributor to alosetron's problems was inappropriate prescribing despite labeling warnings. Perhaps the redesigned and improved drug package inserts the FDA is now recommending would have helped to keep alosetron as well as cisapride on the market. It has been reported that in cisapride's case, black-box warnings and other measures failed to curb inappropriate prescribing.

Alosetron also showed that MedGuides are no panacea. These patient guides are now required for HIV drugs Trizivir (abacavir, lamivudine, and zidovudine, GlaxoSmithKline) and Ziagen (abacavir), as well as for mifepristone. Pharmacists Planning Service Inc. recently petitioned the FDA to mandate MedGuides for all prescription COX-II and nonsteroidal anti-inflammatory drugs, because of the risk of upper gastrointestinal bleeding.

Much as they dislike it, pharmacists are probably facing the prospect of more high-risk drugs coming to market with restrictions on their distribution, or with MedGuides and other special warnings. This reflects, in part, the fact that we are in the early stages of a pharmaceutical revolution, and while genetically engineered medications dangle miracles before patients, they also hold the threat of dangerous side effects. While the new era can undermine pharmacy, it also provides an opportunity for the profession to make and prove the case that the least risky way for the FDA and manufacturers to go is to take full advantage of pharmacists' expertise and oversight and thus enhance medication safety.

Martha Glaser

Martha Glaser. OFF LIMITS.

Drug Topics

2001;5:57.