Chelsea Therapeutics, Inc.: NORTHERA

You submitted the results of 3 clinical trials (studies 301, 302, and 303) to support the efficacy of droxidopa for the treatment of neurogenic orthostatic hypotension (NOH).

Exploratory analyses showed positive results on the composite Orthostatic Hypotension Questionnaire (OHQ) endpoint, generating a new hypothesis, i.e., that droxidopa improves the composite OHQ score in patients with NOH.

Accordingly, the primary endpoint of study 301 was changed to the composite OHQ score.

Study 301 has many of the characteristics of a single adequate and well-controlled study that could make it adequate to support effectiveness.

The finding on the primary endpoint is statistically persuasive.

Despite the enrichment strategy used in studies 302 and 303 to select subjects who both respond to and tolerate the drug, neither study succeeded on its primary endpoint.

Prior to submission of the NDA, we advised you that it would be important to provide evidence of durability of droxidopa's treatment effect.

We also recommend that you consult with the Agency on the specific study design elements, including endpoint measures, to be used in future trials.

Lacking data on supine blood pressure, if the drug were to be approved at this time, labeling would likely have to include a boxed warning regarding supine hypertension.

We have provided draft recommendations to several sections of the labeling, but reserve comment on the remaining sections until the application is otherwise adequate.

Please submit draft labeling that incorporates revisions to the attached labeling.

We acknowledge receipt of your submission dated September 28, 2011 of a proposed risk evaluation and mitigation strategy (REMS).

We have determined that, at this time, a REMS is not necessary for droxidopa to ensure that its benefits outweigh its risks.

Once the complete response (CR) is submitted, we will notify you if we become aware of new safety information and make a determination that a REMS is necessary.

8. Provide English translations of current approved foreign labeling not previously submitted.