Why European and United States drug regulators are not speaking with one voice on anti-influenza drugs: regulatory review methodologies and the importance of ‘deep’ product reviews

Mulinari, Shai; Davis, Courtney

doi:10.1186/s12961-017-0259-8

Table 3 Relenza labelling in Sweden (SWE), European Union (EU) and United States (US), 1999–2017

From: Why European and United States drug regulators are not speaking with one voice on anti-influenza drugs: regulatory review methodologies and the importance of ‘deep’ product reviews

Label	SWE March 1999	EU June 1999	EU 2001	EU 2017	US 1999	US 2017
Efficacy in IP^a	Relenza shortens the time of illness with 1–2.5 days compared to placebo	Relenza alleviates the symptoms of influenza and reduces their median duration by 1.5 days (range 1.0–2.5 days)	Label updated to include pooled analysis showing 1.5 day (95% CI 1.0–2.0 days) of shortening of median time of symptoms	Similar statement	Trials in North America suggested up to 1 day of shortening of median time of symptoms compared with placebo, although statistical significance was not reached; in a study conducted in the Southern Hemisphere, a 1.5-day difference in median time to symptom improvement was observed; additional evidence of efficacy was provided by the European study	Similar statement
Efficacy in ITT^b	No mention	No mention	No mention	The difference in time to alleviation of symptoms was 1.0 day (95% CI 0.5–1.5) in the combined analysis of studies	No mention	No mention
Efficacy in HR groups^c	In some studies a more pronounced therapeutic effect has been seen in patients belonging to the high-risk groups of elderly patients (≤ 65 years) and patients with some chronic diseases of the heart and lungs, although only a limited number patient in these risk groups have been evaluated	A limited number of HR patients, i.e. elderly and patients with asthma, were included; data are therefore limited in these groups of patients	A limited number of elderly patients were included; data is therefore limited in this group Label updated with conclusive study (1.5 day difference) in IP patients with underlying respiratory diseases	Similar statement	No consistent treatment effect was demonstrated in patients with underlying chronic medical conditions, including respiratory or cardiovascular disease	Similar statement
Complications^d	No mention	No mention	Label updated with pooled analysis in the IP population showing significant reduction in incidence of complications and antibiotics use	Similar statement	No consistent differences in rate of development of complications were observed	Similar statement

^aEfficacy in IP population: United States labels have consistently been the most cautious. Furthermore, unlike European labels, the United States labels do not combine the results from trials, neither as an interval of expected effects, as in the original Swedish label (i.e. 1–2.5 days), nor by pooling studies, as in subsequent European Union labels
^bEfficacy in ITT population: Although the intended users are patients with influenza-like symptom (i.e. ITT subjects), labels consistently cite results in the IP group. The current Europe-wide label is the exception, reporting results from a pooled analysis in the ITT population; however, the emphasis in current European Union labelling is still on efficacy in IP subjects
^cEfficacy in HR-IP groups: The original Swedish label from March 1999 professed that Relenza could be more efficacious in the elderly and some other HR subgroups. This statement was promptly removed and it was not present in the first Europe-wide label from June 1999. However, in 2001, a statement was introduced in the European Union label that efficacy had been demonstrated in patients with mild to moderate chronic airways disease. In contrast, FDA has maintained that no effect has been demonstrated in HR-IP patients, including those with chronic airway disease
^dComplications: FDA has maintained that no consistent effect on the incidence of complications has been demonstrated. The original Swedish and European Union labels did not make any claims regarding effects on complications. However, since 2001, the Europe-wide label reports on a pooled analysis showing fewer complications with Relenza. Notably, Jefferson et al. [8] have pointed out the exact same contradictory claims in the labels for Tamiflu
CI confidence interval, HR high risk, IP influenza positive, ITT intention-to-treat

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ISSN: 1478-4505

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