FDA Grants, Denies BI Spiriva Petition

FDA has granted in part and denied in part a 10/17/2012 Boehringer Ingelheim (BI) petition asking that the agency adopt certain requirements for proposed generic and follow-on versions of Boehringer’s Spiriva Handihaler or any other BI orally inhaled product containing the active ingredient tiotropium bromide. The agency’s 6/16 response says the petition specifically asked that FDA not approve an ANDA referencing the Spiriva Handihaler or any BI oral inhalation product containing tiotropium bromide unless the generic applicant has:

• demonstrated bioequivalence by, at a minimum, developing well-defined protocols with established endpoints for comparative clinical studies, developing and validating in vitro correlations, establishing statistically justified criteria for declaring bioequivalence, and ensuring that the proposed generic product fully satisfies qualitative and quantitative sameness requirements; and
• demonstrated that the proposed generic product carries the same labeling and instructions for use as the reference-listed product, and that any deviation in design or operating principles or ergonomics does not change operating mechanics for the patient.

The petition also asked that FDA only accept a Section 505(j) filing that is a duplicate of the Spiriva Handihaler or a BI tiotropium product. Finally, it asked that FDA not approve any 505(b)(2) application for a proposed follow-on version of the products unless the applicant has:

• conducted a robust clinical program, including clinical studies, that fully addresses all safety and efficacy issues that may arise/appear because of any changes or differences in the follow-on product; and
• conducted clinical studies demonstrating the efficacy and safety of a proposed product for all indications without extrapolation of the conclusions from one indication to another.

In its response, FDA says it disagrees that additional science is needed before generic versions of orally inhaled products, including those containing tiotropium bromide, are approved. “We also disagree that certain ‘unanswered questions identified by the broader scientific community’ should be ‘fully resolved’ before FDA may grant approval to generic versions of Spiriva,” the agency says.

The agency also disagreed that generic products submitting an ANDA need to be qualitatively and quantitatively the same as the reference-listed product. However, as reflected in the current product-specific guidance for tiotropium bromide-containing products, FDA agrees with the petition to the extent that the agency recommends that the tiotropium bromide product by qualitatively and quantitatively the same as the reference-listed drug as part of the agency’s recommended bioequivalence approach.

Safety warnings to avoid anticholinergic drug contact with the eyes or about the risks of acute narrow-angle glaucoma are not unique to Spiriva or other BI tiotropium bromide products, the letter says. It says FDA generally expects that the labeling for a proposed generic referencing a BI tiotropium bromide-containing product would include the same safety/warning statements as those contained in the applicable reference-listed product.

On the question of device design differences, FDA says it intends to follow the established statutory and regulatory framework regarding filing and assessing the appropriate regulatory pathway for proposed tiotropium bromide products. “Consequently, we agree in part with your petition’s request,” it adds.

For 505(b)(2) applications, FDA says it declines to preemptively impose specific requirements on the types of studies or data necessary to support approval of a 505(b)(2) application referencing a BI tiotropium bromide-containing product in the abstract because whether such studies and/or data might be necessary to demonstrate that the product is safe and effective depends on the specifics of an individual 505(b)(2) NDA.