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Executive Summary

Rep. Dingell (D-Mich.) is suggesting that bioequivalence standards for generic versions of SmithKline Beecham's Dyazide be relaxed to facilitate approval of competing brands of the antihypertensive agent. In a Jan. 31 letter to Acting FDA Commissioner Benson, Dingell recommended that the agency "publish a special bioequivalence guideline for this drug [to] allow for [Dyazide's] apparent broad therapeutic range." One way the standards could be relaxed, the congressman suggested, would permit a finding of bioequivalence "if a generic producer could show that the rate and extent of the active moieties of its test lot fell within the range of two separate SmithKline lots." Dingell, whose House Energy & Commerce/Oversight Subcommittee investigations have led to accusations of lax FDA enforcement of the generic drug industry, offered his suggestion as one of a series of recommendations to facilitate the approval of generic copies of Dyazide. His letter was sent to the agency the same day Bolar recalled the last generic version of the product remaining on the market (see previous story). Bolar's having "finally agreed to recall and cease sale" of generic Dyazide leaves SmithKline Beecham "with no competition for one of the most widely prescribed drugs in the U.S.," the letter states. "Unfortunately the consumer stands to be the principal victim," Dingell contended. Noting that Dyazide labeling says that the product's triamterene component is "about 50%" bioavailable, the congressman said the component's bioavailability is actually "only about 30%," according to a study that SmithKline conducted late last summer and submitted to FDA and the subcommittee in "early January." Another SmithKline study, conducted earlier last year, rated the potassium-sparing component (triamterene) in Vitarine's and Bolar's marketed versions of the product at approximately 25%. The later study showed that "Dyazide did not even achieve its own revised labeling statement regarding the bioavailability of triamterene" and that the bioavailability of Dyazide's triamterene was "roughly comparable to the Bolar lot tested in the second study," Dingell said. Therefore, he contended, "it now appears that, using the agency's conventional +/-20% limits on rate and extent of dissolution in blood, Dyazide may not be bioequivalent to itself from lot to lot." The congressman noted that FDA's Center for Drug Evaluation and Research Director Carl Peck, MD, "repeatedly assured the public that despite the apparent fraud associated with the Bolar and Vitarine applications, their marketed copies of Dyazide posed no significant safety risk." A broader-than-usual bioequivalence standard for generic versions of Dyazide could be justified in light of "the record of safety and efficacy and Dr. Peck's apparent scientific judgment that even 25% bioavailability of the potassium retention agent is not cause for safety or efficacy concerns," Dingell remarked. As an alternative to loosening bioequivalence standards for the product, Dingell recommended that FDA consider a requirement that SmithKline reformulate Dyazide to make it more fully bioavailable. "Internal FDA memoranda indicate that the authority of the agency to protect the public health permits the FDA to insist on the reformulation of drugs despite a proven record of safety and efficacy," the congressman said. "Such a requirement would serve the public interest at least as much now as it would have 10 years ago," Dingell maintained. According to agency records, "FDA repeatedly goaded and threatened SmithKline regarding reformulation of Dyazide during the 1970s and early 1980s," he noted. "For a number of years, SmithKline had promised the FDA that it would reformulate its product. In fact, SmithKline markets a more bioavailable version of the drug outside the U.S.," the Michigan Democrat pointed out. "It is this poor formulation approved for the American market which has prevented generic competition, save for two companies [Vitarine and Bolar] apparently willing to engage in fraud to [obtain] agency acceptance of their bioequivalence studies." Under the congressman's third recommendation, FDA would urge physicians to prescribe less costly and more reliably bioavailable antihypertensive therapies, such as Mylan/Lederle's Maxzide. "If your agency judges that neither of the first two suggested courses of action is scientifically sound, there is certainly ample precedent for the agency to send out a 'Dear Doctor' letter explaining the pros and cons of the available treatments for hypertension," Dingell said. "There is a fully bioavailable alternative combination of hydrochlorothiazide and triamterene, Maxzide, which has substantial generic competition." FDA could also advise physicians to prescribe "hydrochlorothiazide alone as a diuretic to treat high blood pressure with any potassium loss compensated for by supplements or diet," Dingell said. "Finally, there exist treatments for hypertension that are not based on hydrochlorothiazide. These may be less expensive or may become so if SmithKline attempts to maximize its monopoly profits." He added that a voluntary price reduction by SmithKline would be "the simplest remedy."

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