Direct-to-consumer advertising for Roche/Gilead's Tamiflu should emphasize the importance of influenza vaccination, FDA Antiviral Drug Products Division Director Heidi Jolson, MD, said in a memo explaining FDA's rationale for approving the flu treatment.

DTC advertising for Tamiflu (oseltamivir) and the other FDA-approved neuraminidase inhibitor, Glaxo Wellcome's Relenza (zanamivir) "should contain information regarding the importance of vaccination [and] the reminder that not all viral illness is caused by influenza virus," Jolson suggested in her Oct. 25 "Division Director Memorandum."

Labeling for Tamiflu and Relenza emphasizes the importance of receiving an annual flu shot according to guidelines on immunization practices, and notes that the products are not indicated for prophylaxis.

Tamiflu received FDA approval Oct. 27, becoming the second neuraminidase inhibitor approved in the U.S. and the first available in pill form. Relenza, approved July 27, is inhaled. Both therapies will be available for the upcoming U.S. flu season and are indicated for the treatment of uncomplicated acute illness in adults who have been symptomatic for no more than two days.

Emphasizing the importance of flu vaccines is a part of recently announced partnerships from both Glaxo and Roche.

Glaxo is working with the American Lung Association on a three-year educational campaign, set to debut in early November. National radio public service announcements will run throughout the 1999/2000 flu season.

The educational message will focus on the importance of vaccination and on treatments available, should infection occur.

The National Women's Health Resource Center and the American Pharmaceutical Association each issued statements Oct. 28 hailing the approval of Tamiflu.

APhA is planning to issue a "New Product Bulletin on Tamiflu and other educational resources for pharmacists to use in educating themselves about the new flu treatment options." The pharmacy association suggested that pharmacists may be the first health care contact flu sufferers have when looking to treat flu symptoms with over-the-counter medication.

"When a patient comes into a pharmacy looking for relief from their cold or flu, the pharmacist can triage the patient and can possibly determine if they have a cold or the flu," APhA said. The pharmacist "can recommend the most appropriate treatment to attack the virus and provide symptomatic relief."

The National Women's Health Resource Center will be running nationwide televised public service announcements on influenza. The PSAs, set to begin airing in early November, will provide a hotline to call to receive an eight page "National Women's Health Report" on influenza, funded by an unrestricted educational grant from Roche. The PSAs will not carry the Roche name.

The NWHRC report will be released in December, and will include information on the flu vaccine and questions for women to ask a health care professional before vaccination. The report will discuss flu treatments as an alternative, and list the four antivirals available for the flu.

In addition to Relenza and Tamiflu, two flu therapies, Forest's Flumadine (rimantadine) and Endo's Symmetrel (amantadine), are available. Both are labeled for treatment and prophylaxis, but are only indicated for influenza A.

The women's health group is also adding an influenza content area on its web site, with an interactive feature for consumers to follow flu outbreaks and get flu information and advice specific to their region.

Following Relenza's approval, several managed care plans have begun their own influenza educational campaigns. The companies are encouraging members to get the flu vaccine in an attempt to hold down expected high costs for the neuraminidase inhibitors, particularly in the face of expected heavy DTC promotion (¹ Also see "WellPoint Hopes To Curb Relenza Costs By Pushing Flu Vaccination" - Pink Sheet, 18 October, 1999.).

Partnerships with consumer and professional groups may provide the comapies with alternate avenues for reaching potential patients and possibly overcoming managed care resistance.

Roche maintains that based on "positive" discussions with several managed care groups, it "does not anticipate hurdles" to reimbursement.

In addition to health plan opposition in the U.S., Relenza has encountered problems overseas: the U.K National Health Service will not cover Relenza for the 2000-2001 flu season (² Also see "NICE Should Revise Assessment Process After Relenza Review, ABPI Says" - Pink Sheet, 18 October, 1999.).

Roche is planning DTC advertising for Tamiflu and has initiated unbranded ads targeted at physicians.

Although Tamiflu is only approved for flu treatment, Roche could disseminate reprints of recent studies in The New England Journal of Medicine and Journal of the American Medical Association to educate physicians on the drug's potential role in flu prevention.

The Oct. 28 NEJM paper, published the day following Tamiflu's approval, reports 74% protective efficacy overall for oseltamivir in flu prevention when 75 mg was administered to healthy adults once or twice daily for six weeks. Tamiflu also was effective in treating and preventing experimentally-induced influenza in 88 healthy adult volunteers, according to the Oct. 6 JAMA.

Jolson emphasized in her memo that consumer promotion for the flu treatments should include information on "the likely modest treatment benefit" that patients should expect.

Tamiflu trials WV15671 and WV15670 each demonstrated a 1.3 day reduction in the median time until symptom improvement (defined as the time when 7 major symptoms were reported as either absent or mild). The two trials enrolled a total of 1,358 patients.

"These consistent results, both between studies and between dose groups, suggest that the observed finding is reproducible," Jolson's memo states.

Relenza labeling also reports a modest benefit of between 1 and 1.5 days, as measured by a similar endpoint defined by an absence of fever and self-assessment of four symptoms. Labeling, however, notes inconsistencies in efficacy results and a statistically insignificant finding in the largest trial.

"The clinical relevance of the modest treatment benefit is a highly subjective question," Jolson acknowledged. "It is my opinion that a one-day reduction in the duration of moderate-to-severe symptoms, including fever, is likely to be of clinical importance to many individuals."

However, "because influenza symptoms are self-limited in the majority of individuals," she continued, "it is anticipated that many persons with influenza will neither require, nor desire, treatment with antiviral medication."

Jolson suggested that studies demonstrating influenza prophylaxis, a reduction in complications or mortality, or pharmacoeconomic gain due to illness shortening would provide "more definitive demonstration of clinical or public health relevance with the neuraminidase inhibitors."

As part of its Phase IV commitments, Roche will evaluate cross-resistance between oseltamivir and zanamivir, the safety and efficacy of re-treatment with oseltamivir, and will provide additional information on oseltamivir's efficacy against influenza B.

Influenza B patients comprised only about 3% of the treated population in Tamiflu trials. Similarly, Relenza was studied primarily in influenza A, due to the low occurrence of influenza B in the flu seasons studied.

Roche is also completing ongoing studies, including two treatment studies: WV15812 (151 patients with chronic pulmonary or cardiac disease) and WV15819 (77 patients aged 65 and older).

A pediatric supplement for Tamiflu is expected to be submitted in the first quarter of 2000, FDA indicated, although the agency is deferring its deadline for pediatric data until Dec. 2, 2000. The pediatric data is based on a liquid formulation of Tamiflu.

Under additional Phase IV commitments, Roche will provide pharmacokinetic and safety information on Tamiflu use in patients with hepatic impairment and those with end-stage renal disease.

Recommended dosing for Tamiflu is 75 mg twice-daily for five days, with a suggested dose adjustment to 75 mg once-daily for five days in patients with a creatanine clearance of less than 30 mL/min.

The most common adverse events in Tamiflu trials were nausea and vomiting, present in 9.9% and 9.4% of Tamiflu patients, respectively, versus in 5.6% and 2.9% of patients receiving placebo.

Roche submitted NDA 21-087 for Tamiflu April 29, and received a priority review. Tamiflu was approved in Switzerland Sept. 21.

Tamiflu DTC Ads Should Encourage Flu Vaccination, FDA's Jolson Suggests

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