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CALIFORNIA BIOEQUIVALENCE PANEL REJECTION OF NITROFURANTION FOR STATE MAC LEADS TO FDA REQUEST FOR UPDATED STUDIES, BENET TELLS SUBSTITUTION CONFERENCE

Executive Summary

Nitrofurantoin bioequivalence data are being updated on the request of FDA following decisions by several state drug utilization cmtes. not to place generic versions of the antibacterial on state formularies. At an Oct. 27-28 conference on drug substitution policy sponsored by Health Policy Internatl. in Princeton, NJ, Leslie Benet, PhD, chairman of California's Bioequivalence Advisory Panel (BAP), noted: "I think as a result of the California BAP recommendations and discussions with the FDA, the FDA has asked ]generic mfrs.[ to provide supplementary data." He added: "I think that data will prove nitrofurantoin is equivalent using modern analytical techniques." The California Bioequivalence Advisory Panel rejected all generic nitrofurantoin products for placement on that state's MAIC (Maximum Allowable Ingredient Cost) list at a meeting last spring. New Jersey Drug Utilization Review Council Executive Director Thomas Culkin, PharmD, pointed out that New Jersey also has not decided to list generic nitrofurantoin on the state formulary. While agreeing with Benet that nitrofurantoin is probably bioequivalent, Culkin declared: "We're getting poor data and it just doesn't prove that ]the generic product[ is equivalent." FDA Bioequivalence Div. Director Shrikant Dighe, PhD, confirmed that one generic mfr. is currently conducting updated bioequivalence tests with microcrystalline nitrofurantoin (the generic version of Norwich Eaton's Furadantin) using calorimetric and high pressure liquid chromatography (HPLC) assays. Dighe said that FDA is requesting new bioequivalency results because the studies used to base generic nitrofurantoin approvals were done in 1974 with assays inferior to those now available. Those 1974 bioequivalence studies, conducted for only 12 hours instead of 24 or 48 hours, showed urinary excretion for both test and reference products significantly below what had been reported in the medical literature, Dighe noted. FDA's bioequivalency ruling was not changed, however, because an FDA-contracted study in 1976 showed similar reduced excretion for both test and reference products. Dighe said that FDA would likely get better bioequivalence results from macrocrystalline nitrofurantoin ANDA submissions when Microdantin goes off patent due to the improved assay methods available today. In addition to nitrofurantoin, BAP will also reopen the record on its recommendations last spring for thioridazine and ibuprofen at the cmte.'s Nov. 4 meeting in San Francisco, Benet told the conference. The panel earlier recommended that generic ibuprofen be placed on the state's MAIC list while rejecting generic thioridazine. The panel will also address propranolol, diazepam, lorazepam, and metoclopramide at the upcoming meeting. In an informal survey of state substitution practices, presented at the conference, Culkin noted that thioridazine was second only to digoxin among the frequently-mentioned controversial products by the state pharmacy people that responded to the study. Phenytoin, furosemide, and theophylline extended-release were also cited, Culkin said. The conference, entitled "Scientific Basis of Drug Substitution Policy," was organized by Princeton-based Health Policy Internatl., and was sponsored by Ayerst, McNeil, Sandoz and Smith-Kline. The conference included presentations on state policy in substitution in elderly and pediatric populations, potential problems posed by excipients and additives, and substitution of psychotherapeutic, hormonal and cardiovascular drugs. Commenting on generic substitution in the elderly patient population, Peter Lamy, PhD, director of the Center for the Study of Pharmacy and Therapeutics for the Elderly at the University of Maryland, questioned whether FDA's plus or minus 20% bioequivalence standard is "tight enough to protect elderly patients who need drugs where action can be predicted." Lamy suggested that a list of "critical drugs" be developed for those diseases that are difficult to stabilize and, therefore, should not be eligible for substitution. Stephen Porter, PharmD, Likoff Cardiovascular Institute of Hahnemann University concurred with Lamy's recommendation of a "critical drugs" list that would require more extensive testing of a special category of generics before they could be approved for marketing. In his presentation, Porter also suggested that clinical trials should be required of a group of drugs with "first pass effect," including diltiazem, dobutamine, dopamine, epinephrine, hydralazine, nitroglycerin, propranolol, and verapamil. "These are drugs that do and will have problems with generic substitution primarily because these agents have significant first pass effects," Porter asserted. "When the proprietary agents on this list come off patent, I, for one, am taking the stand that they should have multiple dose, steady state clinical evaluation prior to approval and marketing." While acknowledging that most generic products are bioequivalent under the current regulatory process, Porter questioned whether the data were available to prove therapeutic equivalence. "I don't know if the data ever will exist under the current process," he said. "But I do have hope that is related to the information age and the use of computers in relation to getting up-to-date, valid information to the clinician, to an information network of adverse drug reactions, post-marketing surveillance, and computerized NDAs." In his presentation on cardiovascular substitution, Porter noted that bioavailability was not always important in showing therapeutic equivalence. In a comparison of Hoechst-Roussel's Lasix and Pharmadyne's generic furosemide, Porter noted that the generic furosemide pharmacokinetics reflected significantly lower maximum plasma concentration and urinary recovery, while pharmacodynamic differences were insignificant. "So here we have an example of significant problems with kinetic variability with outcome criteria that were not significant - urine output and sodium excretion," Porter pointed out. Another conference speaker, Natl. Institute of Child and Human Development Center of Research for Mothers and Children Director Sumner Yaffe, MD, also suggested that pharmacodynamics may be a better way of showing equivalence than pharmacokinetics. "If one can measure the drug effect, you don't need any of the other measurements," Yaffe said. He noted that with "more pharmacodynamic rather than pharmacokinetic studies" the "variability . . . with less bioavailable drugs" would not be a problem. However, Yaffe acknowledged: "We can't often measure the drug effect." In roundtable comments, Bolar exec Seymour Inkles questioned whether there were any "well controlled, meaningful studies" that could document evidence of adverse drug reactions from patients being switched to generic drugs. "It would seem to me an easy thing to do to prove that if people are switching from one (drug product) to another, so many percent came down with a, b, c, and d -- some problem that they did not have before," Inkles stated. "What have a great deal of credence to it is a well controlled study that says 'we switched to a generic drug and 49.2% came down with a, b, c, and d, and the patients did not have it before and the only new variable introduced was the generic drug.'" Several participants in the conference asserted that at issue was not the relative superiority or inferiority of brandname or generic products, but "indiscriminate switching" of patients from one product to another encouraged by state laws without the patient or physician's knowledge. Culkin noted that even with New Jersey's mandatory substitution law, physicians can still initial a second line on the Rx that would prevent substitution. According to 1982 survey data, "only 29% of them do it," Culkin said. In addition, physicians "either explicitly or tacitly allowed a substitution of 65% of all Rxs they wrote," he noted. However, the full impact of mandatory substitution of brands was softened, Culkin observed, because, as of 1982, parmacists did not substitute when required by law "on 40 of 100 Rxs." He noted that a new survey had just been started that would update this data "in the next six months."
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