Organon, Inc.: Gepirone hydrochloride

Therefore, the application is not approvable under section 505(d) of the Act and 21 CFR 314.125(b).

You have still not, in our view, provided substantial evidence of the effectiveness of gepirone ER in the short-term or longer-term treatment of major depressive disorder (MDD).

We indicated that, if study 134004 were robustly positive, you would have sufficient efficacy data for filing the application.

We noted that part of the difficulty was a preponderance of negative studies for gepirone in the application, making the overall program very weak indeed.

Both analyses were based on a modified intent-to-treat sample, i.e., all patients randomized who received at least 1 dose of assigned treatment and who had at least 1 post baseline efficacy evaluation.

According to your analysis, the results on the primary endpoint, rate of relapse at study end, favored gepirone:

The results for gepirone are actually numerically worse than placebo, while the results for fluoxetine are numerically superior to placebo, and the p-value for the fluoxetine/gepirone contrast on the rimary outcome (HAMD-25) is strongly trending toward statistical significance (p=0.068).

In summary, you have not provided substantial evidence that gepirone ER is effective in the treatment of MDD.

Office of Clinical Pharmacology and Biopharmaceutics in our March 15, 2002 action letter.

Reference is also made to an Agency letter dated November 30, 1999, refusing to file this application, and to your resubmission of the above referenced NDA dated May 18, 2001.

The critical deficiency that is the basis of this nonapproval action is the lack of adequate efficacy data to support a claim in major depressive disorder as well as the inadequate amount of long-term safety data.

You have not provided substantial evidence of effectiveness for the claim of short-term efficacy for gepirone ER in major depressive disorder (MDD).

Although none of the 6 definitions would have been rejected as unreasonable primary endpoints, their post-facto identification, together with failure to show an effect on the primary endpoints, leaves Study 03A7-002 unable to provide primary support for the claim of efficacy of gepirone IR in MDD.

The 4 studies that you have proposed as positive in support of the efficacy claim arise from a total of 18 short-term placebo-controlled trials in depression.

We agree with the explanations proposed to explain the negative findings for many of these studies, in particular, the dose likely being too low, and an active control arm that also failed to beat placebo.

The additional study should be a dose-response study.

There is at present little data pertinent to the question of dose response.

However, it would be highly preferable to have the finding of lack of effect below 40 mg/day come from the same study in which doses above 40 mg/day were shown to be effective, i.e., a dose response study, as well as to explore the effective dose range.

While we have concluded that you have not provided substantial evidence of effectiveness for any dose, it is likely that, if the drug is effective, the effective dose is likely to be at least 40 mg/day.

At a minimum, you will need to augment this safety database to meet the ICH guidelines for longterm safety data exposure at clinically effective doses as described above.

In any resubmission of this NDA, please propose a section for vital signs in labeling.

The data in the cited appendix in support of your proposed labeling statement regarding weight changes address only the changes in the BMS development program.

The data pertaining to sexual function that support your proposed labeling statement regarding sexual function appear to come from AEs reported in the placebo controlled depression trials.

In order to more thoroughly identify patients whose symptoms may have represented an allergic reaction or hypersensitivity syndrome, we ask that you develop a case definition for allergic reaction/hypersensitivity syndrome, taking into account the multiple symptoms that may be part of such a syndrome.

Using this case definition, you should identify patients whose AE profile fits that of an allergic reaction/ hypersensitivity syndrome.

You should provide a dose response analysis using all reported treatment-emergent AEs.

4. The specifications for the drug product do not include a specification for the | content.

6. You indicate on page 167 of volume 1.10 in the table pertaining to the package insert that the requirements for the dimension and shipment marking are "conforms to specification" however it is not clear what these specifications are.

2. In the food effect study, the data showed that food has a significant effect on gepirone bioavailability (increase in Cmax approximately of 62%).

5. Prior to resubmitting this application, we recommend that you conduct an in vivo drug-drug interaction study with a potent CYP2D6 inhibitor to assess its effects on the pharmacokinetics of gepirone and its metabolites.