FDA Calls GlaxoSmithKline Professional Mailers For Tykerb “Misleading”

GSK shares FDA’s concerns, but says the promos were accompanied by full prescribing information, firm tells “The Pink Sheet” DAILY.

FDA asked GlaxoSmithKline to stop distributing professional mailers for Tykerb (lapatinib) tablets because they omit and minimize important risk factors. In addition, the promos over-represent the drug's efficacy by providing selective data from clinical trials, FDA said in warning letter posted on its Web site Nov. 26.

In the warning letter, FDA's Division of Drug Marketing, Advertising, and Communications told GSK that the promotional materials omitted key information about potential cardiac function problems that could result from use of Tykerb. DDMAC reviewed three "Dear Healthcare Practitioner" letters sent by GSK contractor P4Healthcare to doctors and oncology nurses during the product's launch in March.

GSK, however, told "The Pink Sheet" Daily that the three letters were accompanied by full prescribing information.

Tykerb was approved March 13 for use with Roche's Xeloda (capecitabine) to treat patients with advanced or metastatic HER2 positive breast cancer who have received prior therapy including Genentech's Herceptin (trastuzumab) (¹ (Also see "GSK Patient Assistance Program Will Cover Newly Approved Tykerb" - Pink Sheet, 13 Mar, 2007.)).

The drug has been found to decrease left ventricular ejection fraction in some patients, usually during the first nine weeks of administration. In its product labeling instructions to GSK, FDA said "LVEF should be evaluated in all patients prior to initiation of treatment." It added that monitoring of LVEF should continue during treatment to make sure function does not fall below normal limits.

Discontinuation of the drug is recommended for patients whose LVEF declines to Grade 2 or worse, but treatment may be restarted at a lower dose if LVEF recovers to normal levels and the patient is asymptomatic.

"The promotional pieces fail to convey the importance of the effect of Tykerb on cardiac function," DDMAC states. The mailers note that LVEF was monitored during clinical trials but do not provide detail on the seriousness of the related risk, nor the precautions called for by FDA.

Other warnings and precautions in FDA's product-labeling guidelines referred to patients with severe liver impairment and women who are pregnant. The agency also suggested language on proactive management with anti-diarrheal agents.

DDMAC said the mailers omit warnings for pregnant women and other precautions including severe liver impairment and QT prolongation. Warnings on diarrhea, a common side effect of Tykerb, lacked adequate coverage of the seriousness of and treatment considerations for such side effects, DDMAC said.

GSK's mailings also overstated the efficacy of Tykerb, based on clinical trials, according to DDMAC. The firm focused almost exclusively on results from a blinded independent review committee and mostly ignored data from an investigator assessment that produced less impressive findings.

Data from the IRC showed a 43 percent hazard-ratio reduction when Tykerb was used in tandem with capecitabine, compared with capecitabine alone. Median time to tumor progression (TTP) was increased from 18.6 weeks when capecitabine was used alone to 27.1 weeks for the combination of the two drugs.

However, the investigator assessment found a 28 percent hazard-ratio reduction and a 4.6-week increase in median TTP (23.9 weeks for the combination, 18.3 for single-drug therapy).

"The letters present only the more favorable analysis, thereby overstating the efficacy of the drug," DDMAC's letter states. Though the promos did state, "Differences between treatment groups based on unblinded investigator assessments were smaller but continued to be clinically and statistically significant," that statement "does not mitigate the misleading impression conveyed by the letters," DDMAC said.

DDMAC asked GSK to cease circulating the mailers immediately and to provide a written response by Dec. 6.

GSK told "The Pink Sheet" DAILY that the letters no longer are in circulation. The firm said it shares FDA's concerns and will comply with its request for a response by Dec. 6.

Glaxo said earlier this year that it was investigating whether Tykerb would have efficacy in patients who had not been treated with trastuzumab (² (Also see "GSK Exploring Tykerb Potential In Patients Not Previously Treated With Herceptin" - Pink Sheet, 4 Jun, 2007.).

-Joseph Haas ([email protected])