Bydureon Bcise (exenatide synthetic): NDA 209210

Dr. Lau and his team leader Dr. Khurana recommend approval of this NDA. I agree that there are no clinical pharmacology issues precluding approval.

Recommendation: CDRH recommends approval based on review of the device constituent part of the combination product.

In study 120, EQWS was superior to placebo and was non-inferior to sitagliptin (pre-specified margin of 0.3%).

For study 120, sensitivity analyses also generally supported the robustness of the primary efficacy analysis shown above including the lack of demonstration of superiority of sitagliptin to placebo.

The following forest plots and data tables are from Dr. Kim's review and summarize the FDA treatment difference results using the aforementioned methodology9 for study 118 (first panel) and study 120. Note that the superiority of EQWS to sitagliptin was not demonstrated in any analysis using the ITT population.

With respect to the evaluation of Benefit, this review concludes that substantial evidence of clinical efficacy was met in this application.

The Applicant's claim for EQWS's noninferiority or superiority to sitagliptin is not clinically meaningful because of the failure to demonstrate a placebo-adjusted treatment effect for sitagliptin in study BCB120.

Applicant's claim for EQWS's noninferiority or superiority to sitagliptin is not clinically meaningful because of the failure to demonstrate a treatment effect for sitagliptin in study BCB120.

Reviewer Comment: I identified one subject in the Byetta group with the adverse event of hypoglycemia and unconsciousness requiring assistance and treated with oral glucose.

Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with BYDUREON BCISE.

Such monitoring may increase the risk of unnecessary procedures, due to the low specificity of serum calcitonin testing for MTC and a high background incidence of thyroid disease.

Gastrointestinal: nausea, vomiting, and/or diarrhea resulting in dehydration; abdominal distension, abdominal pain, eructation, constipation, flatulence, acute pancreatitis, hemorrhagic and necrotizing pancreatitis sometimes resulting in death [see Indications and Usage (1)].

Inform patients that the risk of hypoglycemia is increased when BYDUREON BCISE is used in combination with an agent that induces hypoglycemia, such as a sulfonylurea or insulin [see Warnings and Precautions (5.3)].

Nonetheless, these data do indicate the absence of any discernable novel MCT-related pancreatitis risk.

The Agency stated BCB109 may be listed as a PMR under EQWS for regulatory reasons; however determination of whether the postmarketing cardiovascular study BCB109 will fulfill the PMR will be a review issue.