WARNER-LAMBERT LIPITOR NEWS RELEASE DRAWS FDA OBJECTION DUE TO HEAD-TO-HEAD COMPARISONS AND REFERENCE TO MORBIDITY/MORTALITY FINDINGS OF OTHER STATINS

A Warner-Lambert press release announcing FDA approval of Lipitor (atorvastatin) and referring to the results of other companies' large-scale statin trials is "misleading," FDA's Division of Drug Marketing, Advertising & Communications declared in a notice-of-violation letter to the company.

The release "implies that Lipitor will have a positive effect on cardiovascular morbidity and mortality. However, Warner-Lambert has failed to provide that the effect of Lipitor on cardiovascular morbidity and mortality has not been determined, as provided in Lipitor's approved labeling," DDMAC Regulatory Review Officer Russell Fleischer stated in the Dec. 27 letter.

In its Dec. 18 approval announcement, Warner-Lambert noted that "clinical data have established high LDL-cholesterol levels as a major risk factor for coronary heart disease and coronary death and have linked lowering elevated LDL-cholesterol to reducing the risk of these events." FDA remarked that this statement "is misleading because it misrepresents the source of the data. The conclusion that elevated LDL-cholesterol is associated with increased risks of cardiovascular morbidity and mortality was reached using epidemiological data."

Lipitor labeling does not include explicit claims describing an effect on mortality, claims which are included in labeling for Bristol-Myers Squibb's Pravachol (pravastatin) and Merck's Zocor (simvastatin). Warner-Lambert and its marketing partner Pfizer, however, are hoping that Lipitor sales will benefit from the results of large-scale mortality trials conducted with those other statins.

FDA's letter to Warner-Lambert reflects the agency's position against overt attempts to "piggyback" on research findings by competitors. The agency cited Merck and Sandoz in May for suggesting that results of the Bristol-sponsored Cholesterol and Recurrent Events (CARE) trial are applicable across the statin class ("The Pink Sheet" Nov. 25, 1996, p. 9).

FDA's ad division is watching the statin marketing wars closely. For example, DDMAC recently ordered Merck to discontinue a journal advertisement for Mevacor (lovastatin). The agency charged that the ad inaccurately implied that a comparative study of lovastatin versus pravastatin "supports a claim of clinical superiority for Mevacor over Pravachol."

"Specifically," DDMAC wrote in its Nov. 13, 1996 letter to the company, "Merck has selectively chosen the only statement from this study that suggests a positive result for Mevacor compared to Pravachol.... Merck has failed to adequately disclose the full results of the study, i.e., that `lovastatin and pravastatin were equally effective in improving the lipoprotein profile of patients.'"

DDMAC also ordered Merck to discontinue a second Mevacor ad for promotion of an off-label use. "The juxtaposition of the epidemiological data about first MIs with the data from the ACAPS study implies that Mevacor is effective for reducing the occurrence of first MIs. This is a use for which Mevacor is not indicated," the agency wrote. Both of the promotions were criticized for presenting study data without contextual information about the study design or its conduct.

In the agency's December correspondence to Warner-Lambert, FDA asserted that the company violated drug marketing regulations in its descriptions of head-to-head comparisons of Lipitor and other statins. "The statement -- `In head-to-head clinical trials comparing starting doses, Lipitor was superior to other statins...at reducing elevated total cholesterol, LDL-cholesterol and triglycerides' -- is misleading because it implies that Lipitor is clinically superior to the other statins, a claim that has not been adequately demonstrated," DDMAC charged.

According to trials presented in Lipitor labeling, atorvastatin 10 mg showed a statistically significant advantage in reducing total cholesterol, LDL-C and TG compared to starting doses of Pravachol 20 mg, Zocor 10 mg and Merck's Mevacor 20 mg ("The Pink Sheet" Dec. 23, 1996, p. 3).

Lipitor labeling adds that "the impact on clinical outcomes of the differences in lipid-altering effects between [statin] treatments...is not known. [These studies do] not contain data comparing the effects of atorvastatin 10 mg and higher doses of lovastatin, pravastatin and simvastatin. The drugs compared in the studies...are not necessarily interchangeable."

DDMAC also cited Warner-Lambert for failing to describe accurately the patient population for whom Lipitor is indicated. The assertion that Lipitor is "an excellent therapy as an adjunct to diet for a broad range of patients" is misleading, FDA maintained, "because it fails to provide the full indication for Lipitor and promotes Lipitor as being safe and effective for a larger and more diverse population of patients than it is approved for."

"Lipitor is only indicated," the agency noted, "for use in patients with primary hypercholesterolemia (heterozygous familial and nonfamilial) and mixed dyslipidemia (Frederickson Types IIa and IIb), and for patients with homozygous familial hypercholesterolemia as an adjunct to other lipid-lowering treatments or if such treatments are unavailable." The drug was classified "1P" by FDA and given a six-month user fee priority review. Other statins are approved only for "the reduction of elevated total and LDL cholesterol level in patients with primary hypercholesterolemia (Types IIa and IIb)."

The DDMAC NOV letter also referred to a quote in the Lipitor release, in which Pfizer CEO William Steere remarks that "strategically, Pfizer seeks those products that are either first in class or best in class." The quote "implies that Lipitor is clinically superior to all other statin products; a claim that is not supported by substantial evidence," DDMAC countered.

FDA added that the press release is misleading "because Warner-Lambert has failed to provide any contextual information about the studies, or the disclaimers that: (1) the impact on clinical outcomes of the differences in lipid-altering effects between treatments...is not known; (2) there are no data comparing the effects of the 10 mg dose of Lipitor with higher doses of the other statins; and (3) the drugs are not necessarily interchange-able, as provided in Lipitor's approved labeling" (emphasis FDA's).

DDMAC noted that "the press release is considered labeling for Lipitor. As such, it should have been disseminated with a copy of the full prescribing information."

The agency also charged that "the discussion of Lipitor's safety profile is lacking in fair balance because Warner-Lambert has failed to provide the bolded warning related to liver dysfunction and rhabdomyolysis associated with Lipitor, as provided in Lipitor's approved labeling." Lipitor labeling includes the warning that "HMG-CoA reductase inhibitors, like some other lipid-lowering therapies, have been associated with biochemical abnormalities of liver function." In a warnings section relating to skeletal muscle, labeling adds that "rhabdom-yolysis with acute renal failure secondary to myoglobinuria has been reported with other drugs in this class."

Warner-Lambert states that, compared to the cost of other statins at starting doses, Lipitor 10 mg will be available at a slight discount to Merck's Zocor 10 mg and Bristol's Pravachol 20 mg.

Lipitor is being introduced at a direct price of $136.80/10 mg 90s, $211.50/20 mg 90s and $254.70/40 mg 90s. AWP for Lipitor, the company states, is $164.16/10 mg 90s, $253.80/20 mg 90s and $305.64/40 mg 90s. The company is taking orders for Lipitor, and expects to complete the launch by the end of the first quarter. Bottles of 90 Pravachol tablets are available at a direct price of $138.37/10 mg, $148.98/20 mg and $251.85/40 mg. Zocor direct price is $128.21/5 mg 90s, $140.59/10 mg 90s, and $169.87 for both 20 mg/60s and 40 mg/60s, according to the December 1996 Red Book.

Novartis' Lescol will remain the least expensive agent in the class in terms of list prices. Lescol's AWP is $121.80 for 100 20 mg capsules. The introduction of Lescol has increased discounting by the other statin marketers.