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Executive Summary

The anti-endotoxin monoclonal antibodies, such as Centocor's Centoxin (HA-1A) and Xoma's E5, used for the treatment of gram- negative bacteremia in septic patients, will cost Riverside Methodist Hospital in Columbus, Ohio $ 1.4 mil. in their first year after FDA approvals, 10.7% of Riverside's annual pharmacy budget. Riverside's Associate Director of Pharmacy Gregory Wellman projected the first-year expenditures for sepsis treatments at the Dec. 8-12 midyear clinical meeting of the American Society of Hospital Pharmacists in New Orleans. Calculating a probable patient population similar to the current annual intensive care unit enrollment and a $ 4,000 per- treatment price for the new products, Wellman estimated that Riverside would have to devote 10.7% of its total drug budget in 1992 to the new sepsis products. Riverside is a 1,000-bed hospital with a $ 13 mil. per year pharmacy budget. Wellman's sepsis estimates indicate that the cost of the first sepsis drugs will quickly exceed some of the other large budget items at his hospital, such as thrombolytic agents, erythropoietin, and granulocyte colony stimulating factor. In one year, the sepsis drugs will require expenditures by Riverside equal to almost half of the hospital's current contrast media budget, Wellman pointed out. The Riverside projections jibe with wider industry predictions on the impact of the sepsis drugs. The hospital industry and third-party payers are watching the pre-marketing development of the sepsis products with keen attention. Hospital pharmacies are concerned that they will not be able to adjust to the use patterns and expenditures for the drugs after they are approved. Many hospitals are conducting pre-approval guideline reviews. A survey of 56 hospitals published in the October "Quality Review Bulletin" of the Journal of Quality Assurance found that the average hospital in that group believed that sepsis products would take up about 7.5% of the institution's drug budget. The survey was conducted on the member hospitals of the University Hospital Consortium (UHC). The ranges of impact varied widely from 3% of an institution's drug budget to 33%. The hospitals predicted an annual cost to their institutions ranging between $ 240,000 and $ 4 mil.; different hospitals estimated they would use the drugs between 100 and 1,000 times per year. One point of agreement among the UHC hospitals, however, was on the need for guidelines on the use of anti-endotoxin MAbs: 80% of the UHC-member hospitals reported they were working on such guidelines. In response, UHC began working on a set of general guidelines for the consortium for sepsis treatment. The guidelines currently are in draft form, the consortium reports. They have been distributed to UHC member hospitals, insurance associations, Centocor, Xoma, and Chiron (which, with the acquisition of Cetus, now has added a sepsis MAb to its pipeline). While UHC's expert panel has not completed its review yet, a spokesperson at one of the member hospitals said the current draft uses a modified version of the patient selection criteria used by Elizabeth Zeigler, MD, et al., in the clinical trial of Centocor's Centoxin published in the Feb. 14 issue of the New England Journal of Medicine. In that study, patients "with sepsis and suspected gram- negative infection" were treated. Sepsis was defined as fever or hypothermia (temperature greater than 101 degrees F or less than 96 degrees F); tachycardia (greater than 90 beats per minute in the absence of beta-blockade) and tachypnea (respiratory rate greater than 20 breaths per minute or the requirement of mechanical ventilation). Patients additionally were required to display either hypotension or two of the following six signs of systemic toxicity or peripheral hypoperfusion: unexplained metabolic acidosis; arterial hypoxemia; acute renal failure; elevated prothrombin or partial thromboplastin time or reduction of the platelet count to less than half the base-line value or less than 100,000 platelets per cubic millimeter; sudden decrease in mental acuity; and cardiac index of more than four liters per minute per square meter of body surface area with systemic vascular resistance of less than 800 dyn-sec-cm. The Centocor protocol excluded patients with a condition that is "clearly irreversible." The UHC guidelines will continue this exclusion and add several other conditions for treatment. To receive sepsis treatment with the monoclonals, UHC will suggest that the patient must be restricted to the intensive care unit, not have chemotherapy-induced neutropenia, and be on concurrent drug use evaluation (DUE). The monoclonal treatment must also be approved by an attending physician. The American Society of Hospital Pharmacists reports that a DUE analysis of anti-sepsis MAbs will appear in the March issue of its journal Clinical Pharmacology. That analysis will include treatment considerations. In the NEJM experiment, only 37% of the patients treated with Centoxin under these criteria later proved by blood culture to have gram-negative bacteremia -- an analysis which takes 48 hours to perform and therefore cannot be completed before a physician must make a treatment decision. The article notes: "No benefit of treatment with HA-1A was demonstrated in . . . patients with sepsis who did not prove to have gram-negative bacteremia." The NEJM article estimates about 400,000 cases of septicemia per year in the United States, about 30% of which are gram- negative bacteremic and could hope to benefit from Centoxin or, presumably, other anti-endotoxin MAbs. It appears that under UHC's draft guidelines, however, it is still this larger population that will receive the drug. The UHC survey assumes the price of a single dose of an anti- endotoxin MAb to be $ 3,750, based on the market price of Centoxin in Europe. Centocor has never declared a U.S. price. If correct, that price, when applied to the estimated 400,000 U.S. cases of sepsis per year, would create a $ 1.5 bil. per year market for the anti-endotoxin MAbs. That cost that will largely have to be absorbed by individual hospitals. Wellman told the ASHP meeting that he estimates that at Riverside "probably 65% of the cost of the monoclonals for us will be lost -- will not be reimbursed back to the institution." Similarly, the V-A hospitals recently have organized a subcommittee of their Executive Committee on Therapeutic Agents to develop guidelines for use of the anti-sepsis MAbs. A spokesperson for the V-A hospitals said that a panel of V-A experts and academic affiliates has already met and currently is developing an algorithm for use of the drugs. While the panel has not yet reached any conclusions, it is reportedly considering an exclusion for patients on "do not resuscitate" orders. UHC Technology Advancement Center associate director Peter Vlasses said the consortium's guidelines were intended to allow "local variation." University of California-Irvine drug information specialist Shelly Hayward told the ASHP meeting that her institution was formulating its own guidelines under the UHC umbrella. The UCal-Irvine guidelines will be "very strict," Hayward said, but they will "provide an out for using the drug." Hayward noted that during the hospital's internal discussion of guidelines a member of the hospital's pharmacy and therapeutics (P&T) committee asked if the institution simply could choose not to provide the drug. At this point, Hayward said, "the risk manager and the ethics person come into play and they say 'no you can't do that, you're liable to get sued.'" The UCal-Irvine guidelines have been sent to anti-sepsis drug manufacturers, Hayward noted. The hospital is attempting to advise the companies in advance of "what the experts of the medical center have established as appropriate use." Hayward noted that it is the "option" of each marketer "to detail the drugs as we've established their use should be in the medical center, or to counterdetail us."

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