CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`22-192
`
`APPROVABLE LETTER
`
`

`

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`ii'a; —/C DEPARTMENTOFHEALTH&HUMANSERVICES PublicHealth Service
`Food and Drug Administration
`Rockville, MD 20857
`
`NDA 22-192
`
`Vanda Pharmaceuticals
`
`Attention: Paolo Baroldi, M.D., PhD
`Chief Medical Officer
`9605 Medical Center Drive
`Suite 300
`
`Rockville, MD 20850
`
`Dear Dr. Baroldi:
`
`Please refer to your new drug application (NDA) dated and received September 27, 2007,
`submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act for iloperidone
`tablets.
`
`' We acknowledge receipt of your submissions dated:
`
`November 27, 2007
`March 17, 2008
`May 1, 2008
`
`December 14, 2007
`April 2, 2008
`May 16, 2008
`
`January 28, 2008
`April 18, 2008
`June 13, 2008
`
`February 20, 2008
`April 25, 2008
`June 20, 2008
`
`This new drug application provides for the use of iloperidone for the treatment of schizophrenia.
`
`We completed our review and find the information presented is inadequate. Therefore, the
`application is not approvable under section 505(d) of the Act and 21 CFR 314.125(b). The
`deficiencies are summarized as follows:
`
`Non-Approvable Deficiencies
`
`There are two major deficiencies that are the basis for the non-approvable action.
`
`Lack of Sufficient Effectiveness Data
`
`We agree that study 3101 can be considered a positive study in support of the acute treatment of
`schizophrenia at a dose of 24 mg/day. We also note that this study had an active control group
`(ziprasidone 160 mg/day) and that iloperidone 24 mg/day had effectiveness similar to ziprasido'ne.
`We do not believe, however, that the other three controlled effectiveness studies in your program
`support the effectiveness of iloperidone.
`
`

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`NDA 22-192
`
`Page 2.
`
`The remaining three studies (3000, 3004, and 3005) included a mix of schizoaffective and
`schizophrenic patients. In our analyses, we have focused on the patients with schizophrenia. We
`consider schizoaffective disorder a distinct entity that would require a separate development
`program.
`'
`
`Study 3000: This study examined three fixed doses of iloperidone (4, 8, and 12 mg/day),
`haloperidol 15 mg/day, and placebo. The analysis plan for this study was to consider the entire
`randomized population (i.e., schizophrenic and schizoaffective) and to look first at the 8+12
`mg/day group vs placebo. Only if this contrast was positive would it be permissible to look at the
`other groups vs placebo. Whether one looks at the results for the total population or, as we
`preferred, the schizophrenic subgroup (69% of total sample), the p-value for the 8+12 mg/day
`group vs placebo is not significant. Therefore, we consider this a negative study for iloperidone,
`although there is some evidence of an effect at 12 mg.
`It is important to note, however, that the
`active control arm in this trial, i.e., haloperidol 15 mg/day, was highly statistically significantly
`superior to placebo.
`
`Study 3004: This study examined two dose ranges for iloperidone (4-8 mg/day and 10-16 mg/day),
`risperidone 4-8 mg/day, and placebo. The analysis plan for this study was to consider the entire
`randomized population (i.e., schizophrenic and schizoaffective) and to look first at the 10-16
`mg/day group vs placebo. Only if this contrast were positive would it be permissible to look at the
`4-8 mg/day group vs placebo. The initial contrast was significant (p=0.001), as was the 4-8 vs
`placebo contrast (p=0.012), but only for the entire randomized population. For the schizophrenic
`subgroup both iloperidone vs placebo contrasts are non-significant and we consider this a negative
`study for schizophrenia at the lower doses studied.
`It is important to note that the active control
`arm in this trial, i.e., risperidone 4 to 8 mg/day, was highly statistically significantly superior to
`placebo. Risperidone was also statistically significantly superior to iloperidone at both doses
`(p=0.006 vs iloperidone 4-8 mg/day and p=0.021 vs iloperidone 10-16 mg/day).
`
`Study 3005: This study examined two dose ranges for iloperidone (12-16 mg/day and 20-24
`mg/day), risperidone 6-8 mg/day, and placebo. The analysis plan for this study was to consider the
`entire population randomized (i.e., schizophrenic and schizoaffective) and to look first at the 12-16
`mg/day group vs placebo. Only if this contrast were positive would it be permissible to look at the
`20-24 mg/daygroup vs placebo.
`In fact, this initial contrast was not significant (p=0.09), so that
`the study could be considered a failed study. As noted, however, we made a decision, independent
`of the results of this study, to focus on the schizophrenic patients in this study (about 78% of the
`sample). If one takes this approach and looks first at 12—16 vs placebo, this contrast is significant
`(p=0.033). We feel this is an acceptable approach, even though it was not the protocol-specified
`_ approach. The next contrast, i.e., 20-24 vs placebo, is even more highly significant (p=0.005).
`
`Although this might be considered a positive study in support of the effectiveness of iloperidone in
`the treatment of schizophrenia in a dose range of 20-24 mg/day and possibly at 12-16 mg/day,
`there are two additional findings that complicate this interpretation. First, there is some evidence
`that iloperidone is substantially inferior to existing alternative treatments, although we do not
`consider this entirely established.
`The agency has,
`in the recent past,
`taken the relative
`effectiveness of new psychiatric drugs compared to currently available drugs into consideration
`when making overall risk benefit decisions about new psychiatric drugs. The overall principle is
`
`

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`NDA 22-192
`
`Page 3
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`that markedly inferior performance on the treatment of an acute schizophrenia episode presents a
`risk to patients.
`In the two previous instances where we have taken an action unfavorable to the
`new drug based on this type of analysis, the difference between the test drug and the standard
`treatment was significant at p<0.05. It is, therefore, worth noting that the contrast for risperidone
`vs iloperidone 12-16 mg/day is highly statistically significant in favor of risperidone (p=0.005).
`This indicates that, although iloperidone 12 to 16 mg/day was superior-to placebo in this trial, this
`dose range isclearly inferior to a standard dose of an active control agent. We believe this shows
`that iloperidone doses lower than 20 mg/day do not have a useful effect in the treatment of
`schizophrenia and could not be recommended for that use. Moreover, risperidone in this trial was
`considerably superior to the iloperidone 20-24 mg/day arm, although not at conventional levels of
`statistical significance (p=0.093) and we believe this represents a substantial concern. Second, in
`study 3005, the effect in both iloperidone groups is driven entirely by the non-U.S. population,
`with almost no effect in US. patients. We realize that cross-national differences in effect are not
`rare, but as study 3005 is one of only two studies supporting the 20-24 mg dose, this observation
`further weakens the degree of support it provides. We therefore have serious questions about the
`effectiveness of iloperidone relative to other available antipsychotic agents, and indeed about
`whether effectiveness is sufficiently established. We therefore ask that you design and conduct
`one additional
`trial
`to demonstrate the effectiveness of iloperidone in the treatment of
`schizophrenia. This trial should be placebo~controlled and should also include as an active control
`arm a robustly effectiVe antipsychotic agent, e.g., olanzapine or risperidone. We would be happy
`to discuss the design of such an additional trial with you.
`
`I should add that our concern with establishing a reasonable level of effectiveness is strengthened
`by the finding of a clear QT prolonging effect of iloperidone that would relegate the drug to what
`is, in effect, second line status.
`I note further that although the hypotensive effect of the drug is
`mitigated by the proposed daily titration, the need for this makes iloperidone a difficult drug to
`use.
`
`Lack of Sufficient Safety Data in a Relevant Dose Range
`
`At the doses for which you have some evidence of effectiveness and at least one study suggesting
`an effect similar to other antipsychotic agents (20 to 24 mg/day), you have not accumulated
`sufficient safety data. For this dose range of 20 to 24 mg/day, you have safety data for only 508
`patients, with only 64 treated for at least 6 months and only 22 for at least 1 year. These exposures
`are far below the minimum requirements for relevant doses according to ICH standards for a
`chronically used drug. Thus, we ask that you obtain additional exposures within this iloperidone
`dose range of 20-24 mg/day. You would need at least 1000 additional patients exposed, and the
`chronic use would need to meet the minimum standard of at least 300 for 6 months and at least 100
`for 1 year. We would be happy to discuss with you study designs to accumulate these additional
`data.
`
`Other Issues That Need to be Addressed
`
`Although not reasons for this not approvable action, you will also need to address the following
`items:
`
`

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`NDA 22-192
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`Page 4
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`Clinical
`
`It has come to our attention that there have been allegations of research misconduct by a clinical
`investigator named Dr. John Gilliam. We note that Dr. Gilliam participated in the iloperidone
`development program. It will be necessary, therefore, to assess whether or not findings from
`Dr. Gilliam’s site(s) had an important impact on the outcome of your development program for
`your above referenced NDA. As such, we are asking that you provide the following information:
`
`1. Determine whether Dr. Gilliam was an investigator in any of your pivotal efficacy studies.
`These would be the studies that are described in the labeling for the above referenced product
`as the basis for its claimed efficacy.
`
`2.
`
`If so, reanalyze the data for these studies, excluding the subjects from his study site(s) from the
`efficacy analysis with regard to all efficacy endpoints mentioned in labeling, and compare
`those results to the original analysis.
`
`3. Also assess the safety data from Dr. Gilliam’s research sites to determine if it is consistent with
`the safety data coming from other sites and consistent with what is currently in approved
`labeling. The safety assessment should include all studies in which Dr. Gilliam was an
`investigator (not limited to pivotal efficacy studies). If there are notable safety differences
`between Dr. Gilliaml’s data and what is described in the proposed labeling (e.g. in Adverse
`Events), please characterize thOSe differences.
`
`4. Please submit the requested information identifying each of the relevant studies, including
`study name/protocol number and date of submission.
`
`I Clinical Pharmacology
`1. Study CIL0522A0103, conducted in subjects with normal, mildly and moderately impaired
`hepatic function, was inconclusive because the exposure for mild subjects was greater than for
`moderately impaired subjects. We ask that you repeat the study in a moderately impaired
`group, comparing them to normals in the same study. The genotyping for the extensive
`metabolizers used in this study should be submitted to the Office of Clinical Pharmacology.
`
`2. You should conduct a study investigating the possible in vitro interaction of iloperidone and
`P-Gp as discussed in a prior communication.
`
`When you respond to the above deficiencies, include a Safety update as described at 21 CFR
`314.50(d)(5)(vi)(b). The safety update should include data from all non-clinical and clinical
`studies of the drug under consideration regardless of indication, dosage form, or dose level.
`
`1. Describe in detail any significant changes or findings in the safety profile.
`2. When assembling the sections describing discontinuations due to adverse events, serious
`adverse events, and common adverse events, incorporate new safety data as follows:
`a. Present new safety data from the studies for the proposed indication using the same format
`as the original NDA submission.
`b. Present tabulations of the new safety data combined with the original NDA data.
`
`

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`NDA 22- 192
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`Page 5
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`0. Include tables that compare frequencies of adverse events in the original NDA with the
`retabulated frequencies described in the bullet above.
`'
`d. For indications other than the proposed indication, provide separate tables for the
`frequencies of adverse events occurring in clinical trials.
`3. Present a retabulation of the reasons for premature study discontinuation by incorporating the
`drop-outs from the newly completed studies. Describe any new trends or patterns identified.
`4. Provide case report forms and narrative summaries for each patient who died during a clinical
`study or who did not complete a study because of an adverse event. In addition, provide
`narrative Summaries for serious adverse events.
`
`5. Describe any information that suggests a substantial change in the incidence of common, but
`less serious, adverse events between the new data and the original NDA data.
`6. Provide a summary of worldwide experience on the safety of this drug. Include an updated
`estimate of use for drug marketed in other countries.
`Provide English translations of current approved foreign labeling not previously submitted.
`When you have obtained the additional clinical data that are needed to support this application,
`we would be happy to meet with you to discuss the resubmission of the safety data for this
`program. There were a number of technical deficiencies in the application that would need to
`be addressed.
`
`9°.“
`
`Within 10 days after the date of this letter, you are required to amend the applications, notify us of
`your intent to file an amendment, or follow one of your other options under 21 CFR 314.120. If
`you do not follow one of these options, we will consider your lack of response a request to
`withdraw the application under 21 CFR 314.65. Any amendment should respond to all the
`deficiencies listed. We will not process a partial reply as a major amendment nor will the review
`clock be reactivated until all deficiencies have been addressed.
`
`Under 21 CFR 314.102(d), you may request a meeting or telephone conference with this division
`to discuss what steps need to be taken before the application may be approved.
`
`The drug product may not be legally marketed until you have been notified in writing that this
`application is approved.
`
`If you have any questions, contact Kimberly Updegraff, M.S., Regulatory Project Manager, at
`(301) 796—2201.
`‘
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Robert Temple, MD.
`Director
`
`Office of Drug Evaluation I
`Center for Drug Evaluation and Research
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Robert Temple
`7/25/2008 10:59:41 AM
`
`