Teva Pharmaceuticals, Inc.: TVB-009

FDA identified deficiencies that were conveyed to the representative of the facility.

Assessment prior to your complete response to this letter.

Your complete response should include the date(s) of the facility's correspondence(s) to address these deficiencies.

FDA may need to perform an onsite pre-license inspection (PLI) before this application may be approved.

Please be aware that we will not initiate the PLI until your complete response is received.

Also incorporate relevant updates according to the most recently approved labeling for the reference product into your product labeling.

Section 505-1 of the Federal Food, Drug, and Cosmetic Act (FDCA) authorizes FDA to require the submission of a risk evaluation and mitigation strategy (REMS) if FDA determines that such a strategy is necessary to ensure that the benefits of the drug outweigh the risks [section 505-1 (a)].

In accordance with section 505-1 of the FDCA, we agree that a REMS will be necessary for TVB-009, if it is approved, to ensure that the benefits of the drug outweigh the risk of severe hypocalcemia in patients with advanced chronic kidney disease (CKD) including dialysis-dependent patients associated with TVB-009.

The REMS, should it be approved, will create enforceable obligations.

Cosmetic Act for Austedo (deutetrabenazine) Oral Tablets 6 mg, 9 mg, and 12 mg.

Your clinical pharmacology studies were not adequate to determine whether all major human metabolites of deutetrabenazine have been identified.

This information is needed to assess whether the bridge to the listed drug on which you are relying (Xenazine) is scientifically justified to address the toxicity of all major metabolites of deutetrabenazine.

Please note that the method you proposed in your April 8, 2016, amendment to this NDA to assess potential major metabolites is acceptable, on face, and pending demonstration of suitable stability.

The toxicokinetic analyses of metabolites in the pivotal nonclinical studies of deutetrabenazine are limited to quantitation of the primary metabolites of deutetrabenazine (i.e., alpha and betaDHTBZ).

3. Per 21 CFR 25.15(d), revise your claim for categorical exclusion to include a statement that, to the applicant's knowledge, no extraordinary circumstances exist.

We recommend you submit for FDA review your planned analyses for abuse potential and rebound.

For this purpose, first-cycle actions include approvals, complete responses, and withdrawals after filing.