/——--—-— identification test should be added to drug
`Dr. Srinivasachar said a
`product specifications. Dr. Simmons encouraged the firm to send any specific rotation data they
`have into the Division for review.
`
`Quota-£1925
`
`Dr. Advani said carton labels are nwded for all four strengths of Uniprost. The firm said they
`would supply these as artwork if that were acceptable to the Division. Dr. Advani said it was
`acceptable.
`
`How Supplied section
`
`Dr. Advani noted that the HOW SUPPLIED section of the draft labeling was incomplete (i.e., it did
`not include the storage statement and other information). The firm said they had inadvertently left
`out that information and would submit draft labeling correcting that omission.
`
`Conclusion
`
`
`
`of the manufacturing process of drug
`Dr. Simmons expressed concern that the ,
`substance were not covered by GMP guidelines. He said that the Division would contact the Office
`of Compliance. to review in detail, the completed FDAinspection of the manufacturing facility. He
`said that the Agency would set up a telecon with the sponsor to discuss the FDA inspection as well
`as other issues needing clarification pursuant to the meeting with the sponsor.
`
`Minutes Preparation:
`
`. ‘m .g 51
`
`Edward romm
`
`—-
`
`Concurrence Chair.
`
`Q,
`
`J
`
`Simmons, PhD.
`
`ef/lZ-l 1—00112-14-00/01-05-01
`
`Rd:
`
`cc:
`
`NNguyen-lZ/lZ/OO
`JVAdvani-12113IOO
`
`Ksrinivasachar-lZ/l 3/00
`
`NDA 21-272
`HFDJ 10
`HFD-l lO/EFromm/SMatthews
`
`

`

`. Minutes ofn Meeting between United Therapeutics and the FDA
`
`Date:
`
`November 15, 1999
`
`Applications:
`
`"""_‘
`UT-lS Injection
`
`Applicant:
`
`United Therapeutics
`
`Subject:
`
`Pre-NDA Meeting
`
`EDA Pam’cipangt:
`
`Robert R. Fenichel,‘ M.D., Ph.D., HFD—l 10, Deputy Division Director
`Douglas Throckmorton, M.D., HFD-l 10, Medical Officer
`James Hung, Ph.D., RFD-110, Statisticianfl‘earn Leader
`Xavier Joseph, DVM., HFD-l 10, Pharmacologist
`Nhi Nguyen, Pharm.D., HPD—860, Clinical Pharmacology and Biopharmaceutics
`Khin Maung U, M.D., Ph.D., Division of Scientific Investigations
`Karen Storms, RFD—45, Consumer Safety Officer, Division of Scientific Investigations
`Natalia Morgenstem, HFD-l 10, Chief, Project Management Staff (pre-meeting only)
`Edward Fromm, HFD-l 10, Consumer Safety Officer
`
`United Theramutics
`
`James Crow, Ph.D., President and Chief Scientific Officer
`Roger Jeff‘s, Ph.D., Director, Research, Development and Medical
`David Mottola, Ph.D., Director of Clinical and Scientific Affairs
`Shelmer Blackburn, Director of Operations
`Dean Bunce, ASSociate Director, Regulatory Affairs
`
`Consultants
`
`\
`
`Background
`
`UT-lS, a chemically stable tricyclic benzindene analog ofepoprostenol (prostacyclin), possesses
`potent pulmonary and systemic vasodilatory and platelet anti-aggregatory actions in vitro and in
`vivo. The ability ofUT-l 5 to reduce the loading condition ofthe right ventricle suggests that this
`agent may have utility in the treatment ofpulmonary hypertensiou. The acute hemodynamic profile
`of UT-l 5 in patients with pulmonary hypertension appears similar to that ofepoprostenol (Flolan),
`which is approved to treat pulmonary hypertension. Unlike epoprostenol, however, which must be
`delivered by continuous intravenous infusion, UT—l 5 has sufficient chemical stability to allow for
`subcutaneous administration, offering patients and clinicians an altemative therapeutic route of
`administration.
`
`. ..
`
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`
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`

`

`UT-l 5 was designated an orphan drug for the indication of Pulmonary Arterial Hypertension
`(PAH), effective November 2, 1999. The firm plans to submit an NDA for UT-l 5 in June 2000 and
`is requesting the Division’s feedback on the format and content of the proposed package.
`
`Meeting
`
`The firm opened the meeting by giving a brief background of pulmonary hypertension (PH). The
`firm noted that they are now requesting a change in designation of pulmonary hypertension to
`pulmonary arterial hypertension (PAH), per the September 1998 World Symposium on Primary
`Pulmonary Hypertension. They added that they were primarily concerned with the vascular forms
`of PH, both primary (PPH) and secondary. United ~Therapeutics noted that about 3000 patients per
`year were diagnosed with (PPH), and about 3 times that amount for secondary forms of pulmonary
`hypertension.
`'
`
`Carcinogenicityfl‘oxicology §tudies
`
`The firm said that they had completed 6 month toxicology studies in rats and dogs but have not
`done carcinogenicity studies. Citing technical problemswith the 6 month rat study, they stated that
`standard two year rodent studies for evaluation of carcinogenic potential could not be done because
`of the increased mortality that would be expected with the required duration of continuous infusion.
`Dr. Throckmorton asked about the feasibility of doing a shorter term alternative assay for
`determining carcinogenic potential. The sponsor noted that such alternative assays, which are
`generally performed in mice, were not feasible due to the difficulty of continuously infusing such a
`small animal for 6 months or longer. Dr. Fenichel stated that carcinogenicity studies might not be
`feasible or necessary now but that if the Carcinogenicity Assessment Committee (CAC) requests
`that the studies be done then the sponsor would have to begin these studies prior to filing the NDA.
`He indicated that the sponsor should submit additional information to the Division supporting its
`view that carcinogenicity studies are not necessary for this drug. These should include data on the
`mortality of patients with secondary forms of pulmonary hypertension.
`
`Pharmacokinetics
`
`Dr. Joseph asked the firm if there was any data on protein binding. The firm said that it has not been
`able to determine the protein binding of UT-l 5 because UT-lS is an extremely potent drug and
`because the C-14 label UT-l 5 synthesized had so much radioactivity that it was unstable (i.e., self-
`degraded) even at -70 degreesC. Dr. Nguyen asked the firm if there were difficulties conducting
`the C-14 mass balance study due to the instability of the radiolabeled UT-lS. The firm said that it
`will remount the GM study in December. All events will be synchronized to reduce the time the C-
`14 compound is stored, i.e., the preparation and sterilization ofthe GM UT-lS Injection, the start of
`the clinical phase (including obtaining IRB and radiation safety committee approval), and the
`analysis of various biological fluids. The excretion of radioactivity via both the biliary route and the
`renal route will be measured. Metabolites in the urine will also be examined. However, until the
`experiment is completed, it is unknown whether the metabolites have or have not been degraded due
`to the large amount ofradioactivity in the C-14 labeled compound.
`
`Dr. Nguyen asked ifthe firm had done pK analyses of the studies. The firm said that in P01 :04 and
`P01 :05, steady-state plasma samples were collected from individual patients during the weeks 6 and
`12 visits, at which time clinical assessments were also made. The plasma clearance levels will be
`determined from the steady-state plasma concentration (and UT-lS dose). The multivariate analysis
`will investigate 'whether various patient factors (i.e., demographics and concomitant medications)
`
`

`

`would explain some ofthe variabilityin UT-IS plasma clearance values. Dr. Nguyen indicated that
`this was acceptable.
`
`Dr. Nguyen inquired whether there had been an analysis ofdrug-drug interactions The firm said
`limited studies have been done.
`
`Safety/Efficacy
`
`Dr. Throckmorton inquired how many patients United Therapeutics would have at the time offiling
`of the NBA. The firm indicated that they will have 301 patients treated for the Efficacy population
`and is expecting and approximate total of 852 volunteers and patientsexposed for the Safety
`population. Dr. Throckmorton thought it would be beneficial to use confidence intervals when
`analyzing the mortality data. The firm said that it could calculate confidence intervals for relative
`risk ratio and risk difference for mortality and transplantation in the randomized, placebo controlled
`studies. Dr. Fenichel noted that the confidence intervals could have broad limits if needed.
`
`Dr. Fenichel said, if feasible, the firm should follow patient failures (e.g., those that went to Flolan)
`through the 12 week endpoint, to gather a combined endpoint of mortality, lung transplantation, and
`switch of therapy.
`
`Dr. Throckmorton noted that outlier analyses of safety parameters (e.g., ALT, AST) would be
`important with this drug. He said shift tables would be helpful in analyzing the safety information.
`Dr. Fenichel remarked that the small numbers of patients in the studies are conducive to using data-
`graphical displays to identify outliers.
`
`Dr. Throckmorton asked the firm if the ECG’s were abnormal in the patients studied. The firm said
`in the context of shifis fiorn “normal to abnormal” or “abnorrnal to a different type of abnormal”
`ECG, they did not notice anything significant. They also mentioned that they had not studied QT
`interval changes.
`
`Dr. Fenichel commented that approval guidelines contain three essential elements; that the drug is
`safe, is efi‘ective, and has reasonable instructions for use. He noted that there were no instructions
`for physicians on how to discontinue the drug. He was particularly concerned about rebound
`pulmonary hypertension as this event was associated with Flolan. The firm responded by saying that
`at least one subject died after withdrawal, but that the death occurred about 48 hours later and
`therefore did not appear to be attributable to a rebound worsening of pulmonary hypertension.
`United Therapeutics also noted that the half-life of Flolan was about 2 minutes whereas UT—lS had a
`much longer half-life. The firm was encouraged to include a discussion of ‘rebound’ in their NDA.
`
`Statistical
`
`Dr. Fenichel inquired about the analyses ofPAH and the subset analysis of PAH and whether the
`firm needed to accept a penalty for the two analyses. The firm explained that the primary analysis is
`a combined analysis of all patients in studies P01:04 and P01 :05. lfthe combined analysis is
`significant (two-sided p<0.049), that will serve as justification to look at each study separately. If
`each protocol has two-sided p<0.049, this would be considered acceptable; Ifone study is p<0.049
`and one study is p>0.049, then United Therapeutics will go back to the combined analysis to
`determine if it is clearly and robustly below p<0.0l . If combined study analysis is p5 0.01, this will
`be considered acceptable. lfnot, then the firm will look at the subset for PPH for significance (two-
`sided p<0.00]). Dr. Fenichel indicated that this approach did not need to have any penalties ofthe
`difl‘erent types of analyses.
`
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`The firm indicated that they would submit a detailed statistical plan to the Division towards the end
`of January 2000. They said that a data lock would be set for the end of March and asked if the
`Division could review the plan and provide feedback to the firm by the end of February. Dr. Hung
`said he would be able to this.
`
`m T
`
`he Division indicated that the following items should be submitted in electronic format:
`
`Annotated Case Report Forms (SAS files with SAS variables)
`Integrated Safety and Efficacy
`Key pK studies
`drafi labeling (4 or 5 copies on floppy disks)
`SAS data sets from clinical studies ’
`
`The firm asked if Word 2000 documents were compatible with the Division’s computers. Dr.
`Fenichel said that the Division used Word 97 now, but that Word 2000 was coming in, and that in
`any event this wouldn’t be a problem, since Word 2000 can save files in Word 97 format.
`
`Mr. Fromm asked the firm to include a pediatric section (i.e., how they plan to respond to the
`pediatric rule) in the NDA package.
`
`Conclusion
`
`The firm plans to submit this NBA in June of 2000. The firm plans on submitting a detailed
`statistical plan in January and the Division has promised a review of the plan by the end of February.
`
`Adam
`
`Dr. Nguyen noted that with regard to protein binding, the sponsor could determine protein binding by
`an in-vitro methodology that does not require a radiolabel.
`A
`0
`
`Minutes Preparation:
`
`Concurrence Chair:
`
`—
`
`.\ /S./
`v ..
`imam
`_
`- /
`RobertR; Fer/dingb., PhD.
`
`ef/1 1-1 7-99/1 l f26-99/12-6-99
`
`Rd:
`
`KMaug Ull l-l9o99
`DThrockmorton/l 1-29-99
`
`XJoseph/l 2- l —99
`NNguyen/l 2—1 -99
`JHung/12-3-99
`
`

`

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`RFD-110
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`

`Minutes of a Meeting between United Therapeutics and the FDA
`
`Date:
`
`November 8, I999
`
`.
`.
`Applications:
`
`'
`
`UT—l 5 Injection
`
`'
`’
`
`Applicant:
`
`United Therapeutics
`
`Subject:
`
`Pre-NDA Meeting (CMC)
`
`FDA Participants:
`
`Hasmukh Patel, Ph.D., Acting Deputy Director, Chemistry, Division ofNew Drug Chemistry I (HFD-81 0)
`‘ Kasturi Srinivasachar, Ph.D., Team Leader, Chemistry, Division ofNew Drug Chemistry I (HFD-810)
`Joseph Piechocki, Ph.D., RFD—810, Chemist
`Edward Fromm, HFD-l 10, Consumer Safety Officer
`
`United Theragutics
`
`James Crow, Ph.D., President and Chief Scientific Officer
`David Mottola, Ph.D., Director of Clinical and Scientific Affairs
`Shelmer Blackburn, Director of Operations
`Dean Bunce, Associate Director, Regulatory Affairs
`
`'
`
`i.
`
`Background
`
`UT—l 5 Injection is a chemically stable tricyclic benzindene analogue of prostacyclin (PGIz) with
`potent pulmonary and systemic vasodilatory and platelet anti-aggregatory actions in vitro and in
`' vivo. Unlike Flolan (epoprostenol), which must be delivered by continuous intravenous infusion,
`UT-l 5 has sufficient chemical stability to allow for subcutaneous administration, offering patients
`and clinicians an alternative therapeutic route of administration. United Therapeutics plans to
`submit this NDAIn the second quarter ofthe year 2000 andIS requesting the Division’s feedback
`on the format and content ofthe CMC section ofthe proposed package.
`
`Meeting
`
`Table of Contents
`
`Dr. Piechocki asked that CFN numbers be obtained for
`l) (Manufacturer of Drug Substance)
`all manufacturers that are working on this project.
`
`.
`
`._ - -_ 1—,”. _ ._. _—~____._._i __...._._-.....
`
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`
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`

`

`2)
`
`3)
`
`4)
`
`5)
`
`(Drug Substance Controls-Rationale for Specifications and Limits) Dr. Srinivasachar noted
`that is was important to look at each impurity and qualify it.
`(Method of Manufacture-Description of Process (Master Production Records) The firm
`indicated that they would include a sample fOr each strength.
`(Container-Closure System) The firm agreed to provide data to demonstrate suitability of the
`container-closure system to be used for the marketed drug product as per Dr. Patel’s request. It
`will include data on extractables from the container-closure system. Dr. Piechocki noted that a
`description ofthe .. "‘
`process used for the stoppers be included in the Container-
`Closure and Sterilization Process Validation sections of the NDA. The stoppers are ‘-
`after washing.-
`'
`(Stability of Drug Product-Stability Commitment and Expiration Date Statement) Dr.
`Piechocki said the Division needs executed batch records.
`
`6)
`7)
`
`'
`Dr. Patel noted that the carton label was also needed.
`(Labeling)
`(Drug Substance Reference Standard) The company was informed that submission of only
`COA for the reference standard is not adequate. lnforrnation on its synthesis, purification, and
`characterization should also be provided.
`(Batch Analysis Tables)
`Dr. Srinivasachar thought lnvestigational Formulations would be a
`more appropriate title for this section.
`(Environmental Assessment)
`Dr. Piechocki asked that the firm to send in a separate request
`for the environmental assessment exemption.
`10) (Sterilization Process Validation) Dr. Piechocki asked the firm to send this section in a
`separatejacket because microbiologists in another area review this section.
`
`8)
`
`9)
`
`Stabilig Assessment Section
`
`Dr. Piechocki noted that the stability data has positive slopes, which may indicate a packaging
`problem.
`
`Bracketing of primary studies for the 1.0 mg/ml, 2.5 mg/ml, and 5.0 mg/ml strengths is acceptable.
`Bracketing will include: ‘ ’
`‘
`’
`~—
`~
`Primary stability batches were manufactured according to the proposed
`commercial process and packaged in the proposed containemlosure system. Dr. Patel noted that
`shelf life expiration would be based on supportive and primary stability batches submitted in the
`NDA package.
`
`According to the Sponsor, the stability protocol submitted in the meeting was based on the
`recommendations from the Division received by them in the last meeting. The protocol discussed
`at that time included the 10 mg strength. The batches indicated in the stability protocol proposed in
`this meeting package have already been placed on stability. As it was previously agreed, the
`Division accepted the proposed stability protocol.
`
`-— of primary stability studies with the 10 mglml formulation.
`Dr. Patel asked the firm to do
`The firm said that they would have difficulty doing this because their clinical trials have not needed
`this strength yet. They noted that they have ~ stability data for s—\ and - data on
`another batch. Because of this, the original NDA will include data supporting a —-
`expiration date. Dr. Patel said
`‘-
`of primary stability data for the l0 mg/ml formulation
`were sufficient for now as it was agreed at the last meeting but asked the firm to send the .
`batch in when data is available. The firm indicated that additional 10 mg/ml stability data from the
`NDA batches will be filed to the NDA as an amendment during the review cycle. The stability data
`from a - 10 mg/ml batch will be submitted in an Annual Report to the NDA when available. It
`
`

`

`was agreed that amending the NDA for the additional stability data would not restart the review
`clock. However, the data may not be reviewed if submitted too late during the review process.
`I
`
`Dr. Patel stated that the bacterial endotoxin test should be added to the stability protocol at the end-
`of-shelf-life for designated batches of each strength (1, 2.5, 5 and 10 mg/ml). Dr. Srinivasachar
`asked why metacresol was used as a preservative. The firm said that metacresol was a microbial
`preservative and noted it was used in insulin pumps. Dr. Piechocki said he was concerned about
`degradation of metacresol and recommended that the firm do the Preservative Effectiveness Test at
`the last station of all stability test protocols.
`
`Photostability Section
`
`Dr. Srinivasachar asked if there were any formulation differences between the
`glass. The firm replied that there were no differences and mentioned also that the N glass was
`easily obtained.
`
`
`
`Use of \ glass for the commercial product is acceptable if data to demonstrate its suitability for
`the drug product and stability ofthe drug product are provided. The shelf life will be based on the
`quantity and quality of the data submitted for the
`glass vials. Supportive data may be used to
`determine the shelf life.
`
`Dr. Piechocki noted that the firm would need to justify the spectral power distribution of their UV
`lamps. He also stated that when doing forced degradation studies with light and heat that the
`degradation products need to be identified (per ICH guidelines) as to whether they resulted from
`heat or light or both.
`
`Impurities
`
`
`
`tests they had done with the drug product. The
`Dr. Srinivasachar asked what
`firm said they would user’s...»- ‘. to test forM~ Dr. Srinivasachar urged the firm
`to do a specific w test for the drug product. He added they would have to
`show justification if they decide not to do the test.
`
`Dr. Piechocki requested that the pH specification be tightened from 6.5 i l.0 to 6.5 :t 0.5. The
`analytical data will be examined to determine the final specification to be submitted in the NDA.
`
`Dr. Piechocki noted that the melting point range was a little wide.
`
`Proposed Drug Substance Smifications
`
`Dr. Srinivasachar stated that only one limit for Total Impurities was needed. Total Unidentified
`Impurities should be included within Total Related Substances. Dr. Srinivasachar noted that Total
`Volatiles could be deleted due to the assay being redundant with Water and Residual solvents.
`
`Conclusion
`
`The firm said that they plan to submit the NDA in June of 2000. They have agreed to send in
`stability information for the 10 mg/ml formulation as it becomes available.
`
`

`

`Minutes Preparation:
`
`Concurrence Chair:
`
`[ 3/
`Edward Fro s/
`
`'
`
`Hasmukh Patel, PhD.
`
`1217 l 1—19-99/1 1.24-99/12-8-99
`
`Rd:
`
`JPiechocki/l 1-23-99
`KSrinivasachar/ l l -23 -99
`
`cc:
`
`"*
`
`HFDol 10
`HFDJ lO/EFromm/SMatthews
`
`

`

`MEETING MlNUTES
`
`MAR I
`
`l
`
`[998
`
`Date: February 20, 1998
`
`Subj: WUT-15 (formerly 15AU81) for pulmonary hypertension
`End of Phase 2 Meeting
`
`Sponsor:
`
`United Therapeutics (formerly Lung Rx)
`
`Meeting Chair:
`Sponsor Lead:
`Recorder:
`
`’
`
`.
`
`Robert Temple, M.D.
`James Crow, PhD.
`Gary Buehler
`
`Attending:
`United Therapeutics
`James Crow, Ph.D.
`Shelmer Blackburn
`
`President
`Protect Leader
`
`FDA
`
`Director. ODE I, RFD-101
`Robert Temple. MD.
`Dir., Div. of Cardio-Renal Drug Prod., HFD-11O
`Raymond Lipicky, M.D.
`Medical Group Leader. HFD-110
`Shaw Chen, MD, Ph.D.
`Douglas Throckmorton, MD. Medical Reviewer. HFD-11O
`Xavier Joseph, DVM
`Pharmacology Reviewer. HFD‘-110
`Kooros Mahjoob, PhD.
`Statistical Reviewer. HFD-710
`Gary Buehler
`Project Manager, HFD.110
`
`BACKGROUND
`
`LIT-15, a chemically stable tricyclic benzindene analog of epoprostenol (prostacyciin),
`possesses potent pulmonary and systemic vasodilatory and platelet anti-aggregatory actions in
`vitro and in vivo. The ability of UT-15 to reduce the loading condition of the right ventricle
`suggests'that this agent may have utility in the treatment oi pulmonary hypertension. The acute
`hemodynamic profile of UT-15 in patients with pulmonary hypertension is similar to that of
`epoprostenol (Flolan); both drugs increase cardiac output and decrease pulmonary artery
`pressure and puirnonary vascular resistance. .Unlike epoprostenol, however, which must be
`delivered by continuous intravenous infusion. UT-15 has sufficient chemical stability to allow
`for subcutaneous administration. offering patients and clinicians an alternative therapeutic
`option.
`.
`*
`
`UT-15 was originally developed by the Burroughs Wellcome Co. as 15AU81 for CHF.
`
`‘ . _._._..... .__...-._.,— —.—_.__._—__...—-—-—-—._,._.——
`
`

`

`.
`
`,
`
`f
`
`\
`
`Sponsorship of the IND was transferred 'to Lung Rx on February 10, 1997. Lung Rx changed the
`name of the compound from 15AU81 to LRX-15. Lung Rx subsequently changed their name to
`United Therapeutics and changed the name of the compound to UT-15.
`
`mscussnort
`
`Pharmacology
`
`The firm was informed that if they completed the standard mutageniclty tests on the drug, it is
`highly probable that the Carcinogenicity Assessment Committee (CAC) would agree that
`carcinogenicity studies would not be required for-the approval of this drug.
`if the CAC does
`agree. the studies proposed in the pre~meeting package would be acceptable.
`
`The firm stated that they have completed a 90 day continuous subcutaneous infusion study in
`rats. and a similar study in dogs is planned. They propose to do a 6 month study of similar
`design in rats, but they are concerned about being able to complete it because of the difficulty in
`administering the drug 80 for that period of time. They were informed that the NDA would not
`be refused to file if they are not able to complete the study. They need, however. to attempt the
`trial.
`
`Number of Endpoints
`
`After establishing that the firm hopes that primary pulmonary hypertension patients (PPH)
`will make up about 1/3 of the total recruitment for their trial. the suggestion was made to
`consider two primary endpoints, one for the total enrollment and the second for PPH patients.
`Given only two endpoints, one of which is included in the other, it was estimated that the
`statistical penalty for doing this would result in testing both endpoints at the 0.035 level of
`significance. A second suggestion was to look at the two groups (PPH patients and non-PPH
`patients) separately, especially if the thought is that non-PPH patients may not respond as
`well. The correction in this case probably would be greater because the two endpoints
`(subsets) are completely independent. The alternative, to plan on analyzing all patients and
`going on to the ‘subset and having only one achieve significance without clear rules would be
`potentially troublesome.
`
`The firm asked what decision would result if the p value for the entire study was less than
`0.035, but the PH subgroup was significant at 0.035. The Agency responded that if there was
`not a lean in the right direction for the other patients, the indication would probably be
`narrowed to only PH patients.
`if there was a lean. it would require a iudgment.
`
`involving Other Sponsors
`
`The firm was approached about meeting with other sponsors who are studying PH. Because these
`patients are so rare, and the various proposed therapies, using different mechanisms of action.
`would be competing for these patients, it was thought that some type of joint effort could be
`attempted. Also, the possibility of finding that a combination of therapies was more effective
`\
`that any of the single entities would offer a significant benefit to the PH patients.
`
`The firm stated that they were a small company with limited resources. While they would
`probably not object to discussing a proposal. they would not want to have to delay their
`
`.
`
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`

`development program as a result of a cooperative effort.
`
`J
`
`NOTE: The firm called a few days after the meeting and agreed to discuss the above approach
`with other sponsors.
`
`Choice of Endpoint
`
`The firm was informed that the six minute walk test was an acceptable primary efficacy
`variable. The problem with it, however, is that it is not as convincing as a morbidity/mortality
`endpoint. The firm was encouraged to collect long-term data to determine if the therapy affects
`the overall morbidity and mortality of the patients. Hospitalizations, need for Floian,
`transplantation or decompensation would all be acceptable markers of morbidity.
`It was
`suggested that the results could be compared with outcome data compiled by NIH on PPH patients
`before and after the availability of Flolan. The firm said that they could do this, but they
`thought that they would only be able to do the comparison inPPH patients since comparative data
`do not exist for the non-PPH patients.
`
`Tolerance
`
`The firm was encouraged to investigate whether the need to adjust the dose upwards on the basis
`of need is a signal that tolerance is developing or simply a progression of the disease process.
`The firm said there appears to be a difference in the acute tolerance to the drug in normals vs.
`PPH patients. They therefore thought that animal models would be of limited use.
`it was
`suggested that they compare a dose that seems to behigher than is needed to their established
`top dose to determine if longoterm outcome improves.
`
`End of Therapy
`
`The firm explained that once a patient is started on therapy, it is very dangerous to abmptly
`discontinue the drug. They therefore requested that investigators be able to unmask the blind
`for the study when the 12 week double-blind period is over to safely continue the patients on
`appropriate therapy. This was perceived as a potential problem by Agency reviewers. To
`decrease the possibility that the investigators will know what patients are on active drug, it was
`suggested that the investigator not have access to the exercise or other efficacy data in the chart.
`All efforts should be made to preserve the blinding of the trial.
`
`Interim Looks
`
`The proposal for interim looks (3 for safety and 1 for efficacy) outlined in the pre-meeting
`package was considered acceptable.
`
`DECISIONS
`
`t. The proposal for not doing carcinogenicity testing for this drug and indication would be
`presented to the CAC for their decision.
`
`2. The firm was encouraged to include separate primary endpoints for either all patients and
`PPH patients or PPH patients and non—PPH patients.
`
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`
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`
`

`

`3. The firm will notify the Division if they would be willing to meet with other sponsors
`pursuing the pulmonary hypertension indication.
`
`4. The firm will attempt to compare the long~term outcomes from their trial with the
`historical data compiled by NIH on patients with PPH. They will not be able to do the
`comparison with non-PPH patients.
`
`5. The firm was encouraged to investigate, through animal studies or in their clinical trials, it
`tolerance is developed to UT-15.
`
`6. The firm was cautioned that all attempts should be made to preserve the blinding of their
`trial if it becomes necessary to unmask the treatment for each patient at the end of the 12 week
`trial period to determine the follow-on therapy.
`
`7. The method proposed by Dr. Koch lor interim looks tor safety and efficacy was acceptable.
`
`Minutes prepared by'
`
`/8/
`
`Gary Buehlen /
`Concurrence. Chair:
`/8/
`
`Robert TempleY M.D.
`
`K
`
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`HFD-t 10 SBenton
`
`RD:
`
`2 I 2 3/ 9 8
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`DThrockmorton‘
`2/ 2 3/ 9 8
`
`SChen
`XJoseph
`FlTemple
`
`2/ 2 3/9 8
`2/2 4/9 8
`3 / 3 / 9 8
`
`

`

`Minutes of a NDA Filing Meeting
`
`Date:
`
`November 3, 2000
`
`Application:
`
`NDA 21-272
`Uniprost (treprostinol sodium) Injection
`1.0, 2.5, 5.0, and lOmg/rnl
`
`Type:
`
`1P
`
`Applicant:
`
`United Therapeutics Corporation
`
`User Fee Goal Date:
`
`April 16, 2001
`
`Participants:
`
`Raymond Lipicky, M.D., HFD-l 10, Director, Division of Cardio-Renal Drug Products
`Norman Stockbridge, M.D.,Ph.D., HFD-l 10, Medical Team Leader
`Abraham Karkowsky, M.D., Ph.D., HFD-l 10, Medical Team Leader
`John Lawrence, Ph.D., HFD-l 10, Statistician
`
`Charles Resnick, Ph.D., HFD-l 10, Pharmacology Team Leader
`Xavier Joseph, D.V.M., HFD~110, Pharmacologist
`Kasturi Srinivasachar, Ph.D., Team Leader, Chemistry, Division of New Drug Chemistry I (HFD-810)
`Nhi Nguyen, Pharm.D., HFD—860, Biopharrnaceuticist
`Khin Maung U, M.D., RFD-45, DSI, Medical Officer
`Earl Butler, Ph.D., HFD.45, Pharmacologist
`Edward Fromm, RFD-110, Consumer Safety Officer
`
`Background
`
`United Therapeutics has submitted this NDA for treprostinol sodium, a prostacyclin (P612)
`analogue, for the treatment of pulmonary arterial hypertension. Studies for treprostinol sodium
`(formerly known as UT-IS) were conducted under _ ——
`
`Treprostinol sodium is related to Flolan (epoprostenol), a drug approved by the Agency on
`September 20, 1995 for primary pulmonary hypertension. Unlike Flolan which must be given
`through a central IV line, treprostinol is proposed to be given via a subcutaneous infusion pump.
`
`The firm is requesting orphan product designation (and an exclusion from user fee payment) for the
`indication of pulmonary arterial hypertension.
`
`An End-of—Phase 2 meeting was held on February 20, 1998 to discuss the design of phase 3 trials
`that would support filing of the NDA.
`
`A Pre-NDA meeting was held on November 15, 1999.
`
`Meeting
`
`Pharmacology
`
`Reviewer: Xavier Joseph, D.V.M.
`
`

`

`Dr. Joseph had no objections to filing the NDA. He expects his review to be completed by
`February 28, 2001
`
`Chemistry
`
`Reviewer: Javher Advani, Ph.D.
`
`Dr. Srinivasachar had no objections to filing the NDA. He said he expected Dr. Advani’s review to
`be completed by January 31. 2001.
`
`Facility inspections have been completed already.
`
`Biopharmaceutics
`
`Reviewer: Nhi Nguyen, PharmD.
`
`Dr. Nguyen had no objections to filing the NDA. Dr. Nguyen expects her review to be completed
`by January 2, 2001.
`
`Statistical
`
`Reviewer: John Lawrence, Ph.D.
`
`Dr. Lawrence had no objections to filing the NDA. The review is expected to be completed by
`January 2, 2001.
`
`Medical
`
`Medical Officers; Abraham Karkowsky, M.D., Ph.D.
`Douglas Throckmorton, M.D.
`Norman Stockbridge, M.D., Ph.D.
`
`Dr. Karkowsky will review the two pivotal efficacy studies POl:04 and P01 :05 while Dr. Throckmorton
`will review the remaining efficacy studies. Dr. Stockbridge will review safety. They expect their joint
`review to be completed by January 2, 2001.
`
`Secondary Medical Review
`
`Reviewer: Raymond Lipicky, MD.
`
`Dr. Lipicky expects to complete his review by January 15, 2001.
`
`Division of Scientific Investigations
`
`Dr. Lipicky and Karkowsky agreed that only 3 domestic sites would need inspection. Dr. U
`suggested inspections of the two pivotal studies sites based on high enrollments, relatively higher
`rates of dropouts and protocol deviations. Dr. Lipicky said this was acceptable.
`
`Dr. Ka