CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`203496Orig1s000
`
`OTHER ACTION LETTERS
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`

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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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`Food and Drug Administration
`Silver Spring MD 20993
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`NDA 203496
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`COMPLETE RESPONSE
`
`United Therapeutics Corp.
`Attention: Mr. Dean Bunce
`EVP, Regulatory Affairs & Compliance
`55 TW Alexander Drive
`P.O. Box 14186
`Research Triangle Park, NC 27709
`
`
`Dear Mr. Bunce:
`
`Please refer to your New Drug Application (NDA) dated December 24, 2011, received
`December 27, 2011, and resubmitted January 31, 2013 under section 505(b)(1) of the Federal
`Food, Drug, and Cosmetic Act, for treprostinil diolamine 0.125 mg, 0.25 mg, 1 mg, and 2.5 mg
`Tablets.
`
`We acknowledge receipt of your amendments dated February 14 and 15, 2013. Your submission
`of January 31, 2013 constituted a complete response to our October 23, 2012 action letter.
`
`We have completed our review of this application, as amended, and have determined that we
`cannot approve this application in its present form. We have described our reasons for this
`action below and, where possible, our recommendations to address these issues.
`
`Our first complete response letter for this application (23 October 2012) listed issues. We
`provide them again, summarize your response, and provide our current thinking.
`
`You were able to demonstrate an effect on 6-minute walk only in study 302. The effect
`in that study was quite small and of dubious clinical importance. The estimated mean
`effect probably exaggerates the true effect, as much of the effect seems to be attributable
`to how values are imputed to subjects missing week 12 data. (This appears to have been
`less of an issue with inhaled treprostinil. In addition, we note our disagreement about
`how some subjects in study 302 were categorized for the purposes of imputation.)
`
`You do not dispute the overall treatment effect size, but point out that it is similar to the effect of
`other formulations of treprostinil. This effect of oral treprostinil is achieved at peak (where
`plasma levels are 7 to 10 times levels at trough) with twice daily dosing. At trough, a statistically
`significant effect on oral treprostinil was not demonstrated, but the nominal effect was 13 m,
`about half the effect at peak. Therefore we do not agree that the effect of oral treprostinil is
`similar to that of treprostinil administered continuously or more frequently by other routes.
`
`
`
`
`Reference ID: 3281154
`
`

`

`NDA 203496
`Page 2
`
`
`In defense of the clinical significance of this effect, you say that, with a similar effect on 6-
`minute walk, subcutaneous treprostinil was able to avert clinical worsening in patients
`discontinuing Flolan. However, we are skeptical that oral treprostinil would recapitulate this
`benefit, as subcutaneous administration does not result in peak-trough excursions of 7- to 10-
`fold.
`
`You point out that survival in open label use of oral treprostinil is similar to that of subcutaneous
`treprostinil and that of bosentan and better than that seen in historical data. While this is
`somewhat reassuring from a safety perspective, neither subcutaneous treprostinil nor bosentan
`have mortality claims based on these open-label, historically controlled data, and there is no
`basis for attributing such good outcomes to oral treprostinil either.
`
`You note that in the long-term open-label study, only 19% of subjects add another vasodilator in
`the first year. We do not know how to interpret that observation, but we are skeptical that it
`reflects normalization of subjects’ symptoms on oral treprostinil.
`
`In the primary analysis of study 302, 21% of subjects on oral treprostinil and 14% of subjects on
`placebo had imputed values, with the imputation differences being among subjects assigned
`average placebo rank (4% on treprostinil vs. 0% on placebo) and those assigned last rank carried
`forward (8% on treprostinil vs. 1% on placebo).
`
`Clinical deterioration and death were similar on study drug and placebo. The differences that
`resulted in net better rank on oral treprostinil probably reflect its poorer tolerability. The effect
`on the ranked analysis is not large, but it does not accurately reflect an advantage to treatment.
`
`Pre-specified sensitivity analyses that (a) carry forward last rank for all missing data, (b) analyze
`completers only, or (c) use data obtained post-withdrawal, all show similar effect sizes and
`nominal p-values. Analyses based on the FDA reviewer’s opinion of cause for withdrawal or on
`Dr. Wittes’s “worst reasonable case” all retain a similar effect size and at least nominal statistical
`significance. Thus you show that the results are not highly sensitive to the imputation process,
`and we agree.
`
`You were unable to demonstrate an effect on time to clinical worsening in three phase
`3 studies.
`
`While this comment in the first Complete Response letter was intended to note merely that no
`benefit existed of greater clinical importance than the effect on 6-minute walk, you again remind
`us that subcutaneous treprostinil has the claim noted previously. Again, we are skeptical that this
`finding can be expected with the highly fluctuating plasma levels that accompany twice-daily
`dosing of oral treprostinil.
`
`You were unable to show an effect on 6-minute walk in two well-powered studies (301
`and 308) in which subjects were on background therapy with other, possibly more
`effective but certainly better tolerated vasodilators. Given the meager effect of treprostinil
`and its poor tolerability, it is difficult to name a clinical scenario in which use of oral
`treprostinil is appropriate.
`
`
`
`Reference ID: 3281154
`
`

`

`NDA 203496
`Page 3
`
`
`You do not refute the findings of studies 301 and 308, but you note that 40 and 45% of subjects
`in these studies were on both a PDE5 inhibitor and an endothelin receptor antagonist. We agree
`that this could have contributed to the difficulty in demonstrating an effect.
`
`In response to characterization of oral treprostinil as poorly tolerated, you note that 824 subjects
`have participated in open-label studies, of whom 641 remained on treatment at 1 year. Whether
`that constitutes good tolerability is a matter of perspective, but we concede that some people
`tolerate long-term use. We also agree that no novel toxicity was associated with the oral
`formulation, and that the oral formulation avoids formulation-specific problems with inhaled,
`intravenous, and subcutaneous administration.
`
`You responded to the challenge of naming a clinical scenario for use of oral treprostinil by again
`noting open-label, long-term use and the low uptake of additional therapy. We reiterate our
`skepticism that this is a reflection of benefit of oral treprostinil rather than a benefit of remaining
`in a study.
`
`You argue that oral treprostinil has been adequately shown to work in some definable setting,
`asserting that it should be approved for use in that setting (monotherapy). We disagree. When
`there were only a few such drugs, it made sense to approve them without concern about their
`interactions (or the small effect). Now there are multiple drugs in multiple classes. The
`symptomatic effect of any of them is so small as to be indiscernible by individual patients against
`the background of the day-to-day variability in symptoms; this is why it takes hundreds of
`subjects to detect a treatment effect. The magnitude of the effect matters here, and if a new
`product or new formulation cannot be shown to achieve a clinically important effect alone, it
`ought to be demonstrated to contribute to a meaningful effect; oral treprostinil has done neither.
`
`In summary, we concur that study 302 distinguishes the effects of oral treprostinil and placebo
`on 6-minute walk, but we find the effect observed to be too small to be clinically meaningful
`without demonstration that it contributes to a clinically meaningful effect of other vasodilator
`therapy.
`
`We recognize that oral treprostinil has a safety profile that should avoid some risks of treprostinil
`by other routes of administration, so we would hope that a pathway forward can be found. We
`strongly recommend a regimen with more than twice-daily dosing in any subsequent study. If
`you pursue a claim relating to 6-minute walk or dyspnea, a new study should be performed with
`a background of other vasodilator therapy, as in studies 301 and 308, but novel claims probably
`would not require this.
`
`LABELING
`
`We acknowledge your revisions to the package insert as well as to the carton and container
`labeling in your resubmission. However, we defer review of the labeling in your resubmission
`until the clinical issues identified above are resolved.
`
`
`
`
`
`
`Reference ID: 3281154
`
`

`

`NDA 203496
`Page 4
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`
`SAFETY UPDATE
`
`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 nonclinical and
`clinical studies/trials 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:
`
`
`
`• Present new safety data from the studies/clinical trials for the proposed indication
`using the same format as the original NDA submission.
`• Present tabulations of the new safety data combined with the original NDA data.
`•
`Include tables that compare frequencies of adverse events in the original NDA with
`the retabulated frequencies described in the bullet above.
`• 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 trial discontinuation by incorporating
`the drop-outs from the newly completed trials. Describe any new trends or patterns
`identified.
`
`4. Provide case report forms and narrative summaries for each patient who died during a
`clinical trial or who did not complete a trial 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 updated exposure information for the clinical studies/trials (e.g., number of
`subjects, person time).
`
`7. Provide a summary of worldwide experience on the safety of this drug. Include an
`updated estimate of use for drug marketed in other countries.
`
`
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`8. Provide English translations of current approved foreign labeling not previously
`submitted.
`
`
`OTHER
`
`Within one year after the date of this letter, you are required to resubmit or take other actions
`available under 21 CFR 314.110. If you do not take one of these actions, we may consider your
`lack of response a request to withdraw the application under 21 CFR 314.65. You may also
`request an extension of time in which to resubmit the application. A resubmission must fully
`
`
`
`Reference ID: 3281154
`
`

`

`NDA 203496
`Page 5
`
`
`address all the deficiencies listed. A partial response to this letter will not be processed as a
`resubmission and will not start a new review cycle.
`
`Under 21 CFR 314.102(d), you may request a meeting or telephone conference with us to
`discuss what steps you need to take before the application may be approved. If you wish to have
`such a meeting, submit your meeting request as described in the FDA’s “Guidance for Industry -
`Formal Meetings Between the FDA and Sponsors or Applicants,” May 2009 at
`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
`CM153222.pdf.
`
`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, please call Edward Fromm, RPh., RAC, Regulatory Project Manager,
`at (301)796-1072.
`
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Norman Stockbridge, M.D., Ph.D.
`Director
`Division of Cardiovascular and Renal Products
`Office of Drug Evaluation I
`Center for Drug Evaluation and Research
`
`
`
`
`
`
`
`
`Reference ID: 3281154
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`NORMAN L STOCKBRIDGE
`03/22/2013
`
`Reference ID: 3281154
`
`

`

`
`
`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`
`
`
`
`
`
`
`Food and Drug Administration
`Silver Spring MD 20993
`
`NDA 203496
`
`COMPLETE RESPONSE
`
`
`
`United Therapeutics Corp.
`Attention: Mr. Dean Bunce
`EVP, Regulatory Affairs & Compliance
`55 TW Alexander Drive
`P.O. Box 14186
`Research Triangle Park, NC 27709
`
`
`Dear Mr. Bunce:
`
`Please refer to your New Drug Application (NDA) dated December 24, 2011, received
`December 27, 2011, submitted under section 505(b)(1) of the Federal Food, Drug, and Cosmetic
`Act, for treprostinil diolamine 0.125 mg, 0.25 mg,
` 1 mg, and 2.5 mg tablets.
`
`We acknowledge receipt of your amendments dated January 13, 26, and 31, February 10, 27, and
`28, March 20, April 12 and 26, June 6 (two) and 25, August 3 and 10, September 11, 20, 21, 28,
`and October 16 and 18, 2012.
`
`We have completed our review of this application, as amended, and have determined that we
`cannot approve this application in its present form. We have described our reasons for this
`action below and, where possible, our recommendations to address these issues.
`
`
`You were able to demonstrate an effect on 6-minute walk only in study 302. The effect in
`that study was quite small and of dubious clinical importance. The estimated mean effect
`probably exaggerates the true effect, as much of the effect seems to be attributable to how
`values are imputed to subjects missing week 12 data. (This appears to have been less of an
`issue with inhaled treprostinil. In addition, we note our disagreement about how some
`subjects in study 302 were categorized for the purposes of imputation.)
`
`You were unable to demonstrate an effect on time to clinical worsening in three phase 3
`studies.
`
`You were unable to demonstrate an effect on 6-minute walk in two well-powered studies
`(301 and 308) in which subjects were on background therapy with other, possibly more
`effective but certainly better tolerated vasodilators. Given the meager effect of treprostinil
`and its poor tolerability, it is difficult to name a clinical scenario in which use of oral
`treprostinil is appropriate.
`
`We are unsure whether an additional clinical study can alter these impressions, but if you
`undertake an additional study, we advise you to consider
`
`Reference ID: 3207063
`
`(b) (4)
`
`

`

`NDA 203496
`
`Page 2
`
`0
`
`a fixed-dose design (titration to different target doses), so that you have the ability
`to generate data to support exposure-response analysis,
`
`0 more frequent dosing, to reduce the large peak-to—trough ratio you get with twice
`daily dosing and maybe reduce the impact of exposure-related tolerability issues,
`and
`
`0
`
`a setting in which you think you can defend the context of use as standalone
`therapy.
`
`LABELING
`
`Submit draft labeling that incorporates revisions in the attached labeling. In addition, submit
`updated content of labeling [21 CFR 314.50(l)(1)(i)] in structured product labeling (SPL)
`format and include CMC—specific DLDE tables for each strength as described at
`hm; ://www.fda . gov/ForIndusfl/DataStandards/StructuredProductLabelingzdefaulthtm.
`
`To facilitate review of your submission, provide a highlighted or marked—up copy that shows
`all changes, as well as a clean Microsofi Word version. The marked-up copy should include
`annotations that support any proposed changes.
`
`Please submit drafi carton and container labeling revised as follows:
`
`Container Labels
`
`1.
`
`be confusing
`
`(5) (4)
`
`This may
`“x"
`Therefore, we recommend removing this(we)
`
`. We acknowledge you have attempted to differentiate the gstrengths within your
`product line;
`
`M0
`Therefore, utilize an alternate color
`"m" strength to minimize the risk of
`
`for differentiation of the
`selection error.
`
`. Decrease the prominence of the “Rx Only” statement by debolding its font and
`relocating it away from the center to either side of the principal display panel to avoid
`crowding of important information.
`
`Decrease the prominence of the net quantity “100 Tablets” statement by debolding its
`font and relocating it away from the statement of strength.
`
`(m4) statement by
`Increase the prominence of the
`bolding its font and relocating it from the side panel to the bottom of the principal
`
`Reference ID: 3207063
`
`

`

`NDA 203496
`Page 3
`
`
`
`display panel. Consider relocating the manufacturer information from the principal
`display panel to the side panel to accommodate this change.
`
`
`6. Revise the storage statement to read: “Store at 25°C (77°F); excursions 15°C to 30°C
`(59°F to 86°F) [See USP controlled room temperature]. Keep out of reach of
`children.” We recommend dashes not be used in order to provide clarity and prevent
`the potential for misinterpretation of the “-” symbol as a negative sign, especially for
`a temperature designation.
`
`
`SAFETY UPDATE
`
`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 nonclinical and
`clinical studies/trials 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:
`
`
`
`• Present new safety data from the studies/clinical trials for the proposed indication
`using the same format as the original NDA submission.
`• Present tabulations of the new safety data combined with the original NDA data.
`•
`Include tables that compare frequencies of adverse events in the original NDA with
`the retabulated frequencies described in the bullet above.
`• 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 trial discontinuation by incorporating
`the drop-outs from the newly completed trials. Describe any new trends or patterns
`identified.
`
`4. Provide case report forms and narrative summaries for each patient who died during a
`clinical trial or who did not complete a trial 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 updated exposure information for the clinical studies/trials (e.g., number of
`subjects, person time).
`
`7. Provide a summary of worldwide experience on the safety of this drug. Include an
`updated estimate of use for drug marketed in other countries.
`
`Reference ID: 3207063
`
`

`

`NDA 203496
`Page 4
`
`
`
`
`8. Provide English translations of current approved foreign labeling not previously
`submitted.
`
`
`OTHER
`
`Within one year after the date of this letter, you are required to resubmit or take other actions
`available under 21 CFR 314.110. If you do not take one of these actions, we may consider your
`lack of response a request to withdraw the application under 21 CFR 314.65. You may also
`request an extension of time in which to resubmit the application. A resubmission must fully
`address all the deficiencies listed. A partial response to this letter will not be processed as a
`resubmission and will not start a new review cycle.
`
`Under 21 CFR 314.102(d), you may request a meeting or telephone conference with us to
`discuss what steps you need to take before the application may be approved. If you wish to have
`such a meeting, submit your meeting request as described in the FDA’s “Guidance for Industry -
`Formal Meetings Between the FDA and Sponsors or Applicants,” May 2009 at
`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
`CM153222.pdf.
`
`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, please call Dan Brum, Pharm.D., RAC, Regulatory Project Manager,
`at (301)796-0578.
`
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Norman Stockbridge, M.D., Ph.D.
`Director
`Division of Cardiovascular and Renal Products
`Office of Drug Evaluation I
`Center for Drug Evaluation and Research
`
`
`ENCLOSURE:
`Labeling
`
`
`
`Reference ID: 3207063
`
`29 Page(s) of Draft Labeling have been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`NORMAN L STOCKBRIDGE
`10/23/2012
`
`Reference ID: 3207063
`
`