Sandoz petitions FDA over requirements for generics of Advair Diskus

Generics/General | Posted 04/11/2016 post-comment0 Post your comment

Sandoz has asked the US Food and Drug Administration (FDA) not to approve generics of GlaxoSmithKline’s (GSK) chronic obstructive pulmonary disorder (COPD) treatment Advair Diskus (fluticasone/salmeterol), unless the generics applications contain the results of pharmacokinetic (PK) bioequivalence studies that ‘ensure the safety and efficacy’ of the products.

Inhaler MD002004 V13J25

In its citizen petition of 13 October 2016, Sandoz, which is developing an Advair Diskus generic, says FDA’s recommendations for the development of abbreviated new drug applications (ANDAs) referencing GSK’s product lack ‘the study design requirements that are necessary to address certain drug-specific characteristics’.

Sandoz’s AirFluSal Forspiro (fluticasone/salmeterol) is an innovative new inhaler for patients with asthma and COPD. It combines salmeterol (a long-acting inhaled β2-agonist) and fluticasone (an inhaled corticosteroid) in an innovative new inhalation device. The product is a generic of GSK’s Advair Diskus (fluticasone/salmeterol). Advair Diskus, which delivers two drugs to patients orally through an inhaler, is the world’s third-best selling drug with revenue of GBP 5 billion (US$8 billion) during 2012 and accounts for about a fifth of GSK’s annual sales.

Sandoz’s AirFluSal Forspiro was first approved in Denmark on 18 December 2013 [1], with subsequent marketing authorizations received in Belgium, Bulgaria, Germany, Hungary, Norway, Romania and Sweden [2].

GSK’s patent on Advair Diskus expired in the US on 23 August 2016 (with a six-month paediatric exclusivity). As yet there are no FDA-approved generics. However, Sandoz believes that FDA has accepted for review ANDAs that refer to Advair Diskus as the reference product.

FDA issued guidance on bioequivalence recommendations for generics of Advair Diskus in September 2013. Sandoz contends that these guidelines fail to address certain drug-specific characteristics of the Advair Diskus such as the batch-to-batch variability of the product and the blood absorption of the combination product’s active ingredients. Sandoz says that ‘based on its extensive in-house research’ the company ‘has a highly informed perspective on the development of generic versions of Advair Diskus’.

Sandoz also states that the PK batch-to-batch variability of orally inhaled drug products ‘has been a consistent concern for both regulators and industry in the context of generic development for several years’. The company is therefore asking that for ANDAs of generics of Advair Diskus at the low-strength of 100/50 FDA ensures that:

1. the Type I error rate is adequately controlled in PK bioequivalence testing, including accounting for Type I error rate inflation caused by batch-to-batch variability of the reference product;
2. the dose used in PK bioequivalence testing retains the necessary sensitivity to product differences existing at the marketed single inhalation dose of the reference product; and
3. the sampling schedule used in PK bioequivalence testing is robust and centered around the actual time to maximum plasma concentration of both active ingredients at the marketed dose of the reference product.

Sandoz concludes by saying that it ‘identified the emerging concerns’ ‘during its own development program[me]’. The company adds that ‘these issues could result in patient-relevant and recognizable differences among AB-rated generics’. It therefore believes that it is ‘critical that FDA address these PK bioequivalence concerns prior to approving any generic drug products for the treatment of asthma patients’.

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1. GaBI Online - Generics and Biosimilars Initiative. Sandoz gains Danish approval for innovative asthma inhaler []. Mol, Belgium: Pro Pharma Communications International; [cited 2016 Nov 4]. Available from:
2. GaBI Online - Generics and Biosimilars Initiative. Sandoz gains Belgian approval for generic inhalation device []. Mol, Belgium: Pro Pharma Communications International; [cited 2016 Nov 4]. Available from:

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Source: Sandoz Citizen’s Petition

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