PALONOSETRON
`
`CLINICAL REVIEW STUDY 99-03
`
`There were some weaknesses in the study. The exclusion criteria for this study
`excluded non-naive patients who had moderate to severe nausea with prior
`chemotherapy. This'could have led to bias with a more favorable response in the non-
`naive group. However, the results do not demonstrate such a bias. Ifa site only had one
`drug available, the patient was automatically enrolled in that treatment arm. This does not
`reflect true randomization. However, this only occurred in five patients (2 in each of the
`palonosetron arms, and I in the ondansetron arm) Although the palonosetron seems to
`demonstrate some efficacy at 120 hours, some factors need to be considered. The p-
`values were not adjusted for multiple endpoints. Since there were multiple secondary
`endpoints, there may be issues with multiplicity.
`In addition,'the comparator arm
`ondansetron is not indicated for prevention of CINV at 120 hours. Thus, what the results
`may be demonstrating is that the nausea from the chemotherapy is simply wearing off.
`
`B. Safety
`In general, the palonosetron was well tolerated in this study. There was a high rate of
`treatment adverse events in all three study arms. The rate was highest for the patients in
`the palonosetron 0.75 mg group. Cancer patients undergoing chemotherapy generally
`have a high rate ofcomplications and co-morbid illness so the high rate is not
`unexpected. The number of serious adverse events was equal in all groups.
`Adverse events of the blood and lymphatic system were most cormnon in all treatment
`groups. These were equally spread out in all treatment groups and were secondary to
`chemotherapy. Following the blood and lymphatic disorders, headache was the most
`frequently reported adverse event. This also was balanced in all treatment arms. The
`majority of adverse events in all treatment arms were of mild intensity. The rate of
`severe adverse events was slightly higher in the palonosetron groups compared to the
`ondansetron group. The body system most frequently involved for severe adverse events
`was neutropenia (2/187, 1.1%) for the 0.25 mg palonosetron group and leukopenia
`(2/188, 1.1%) for the 0.75 mg palonosetron group. All the serious adverse events in the
`palonosetron group were judged to be unrelated or unlikely to be related to the study
`drug. One patient in the 0.75 mg palonosetron arm had to withdraw from the study due
`to debility. This adverse event was described as severe was thought to be possibly related
`to the study drug. There were .4 deaths reported during the study. Three occurred in the
`palonosetron 0.75 mg group and 1 in the ondansetron group. All deaths were judged as
`either unlikely or unrelated to the study drug.
`‘
`No significant safety issues were seen in vital signs, blood, or urine laboratory
`parameters. The majority of patients had no change in ECG. The 0.25 mg palonosetron
`group had the least number of patients with worsening ECG’s. There were no significant
`differences seen between treatment groups on QTc. The 0.25 palonosetron group showed
`a slight decrease in QTc in some intervals when corrected with Bazett’s formula.
`Ondansetron arm had the highest QT/QTc mean maximum change in duration. A subset
`of patients had underwent Holter monitor. A similar percentage of abnormalities (15% vs
`14.3%) were seen in the 0.25 mg palonosetron group compared to the ondansetron group.
`
`63
`
`

`

`PALONOSETRON
`
`CLINICAL REVIEW STUDY 99—03
`
`APPEARS THIS WAY
`0N GRIGlHAl
`
`APPEARS THIS WAY
`0N GRlGlPéAL
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`,
`Narayan Nair
`7/2/03 12:04:52 PM
`MEDICAL OFFICER
`
`Joyce.Korvick
`7/2/03 12:53:00 PM
`MEDICAL OFFICER
`
`

`

`CLINlCAL REVIEW
`
`Medical Officer Review of NBA 21-372
`
`Palonosetron
`
`- Date Submitted:
`Date Received:
`Date Assigned:
`Date Completed:
`
`26 September 2002
`27 September 2002
`October 1 2002
`6 June 2003
`
`Applicant:
`
`Helsinn Healthcare SA
`Via Pian Scairolo
`
`6912 Pazzallo (Lugano) - Switzerland
`
`Drug:
`
`Generic Name —
`Molecular Weight -
`Molecular formula -
`Molecular structure —
`
`Palonosetron
`332.87
`C|9H24NZOHCI
`
`Drug Class:
`
`5-HT; antagonists
`
`Formulation:
`
`5—ml vial of palonosetron-injection contains 0.25 mg palonosetron base as
`hydrochloride, 207.5 mg mannitol, disodium edetate and citrate buffer in water
`
`Route of Administration:
`
`Intravenous
`
`

`

`CLINICAL REVIEW
`
`Table of Contents
`
`Table of Contents .................................................................................................... 2
`
`Executive Summary ................................................................................................ 5
`
`1.
`
`Recommendations .................................................................................................. 5
`
`A.
`
`B.
`
`Recommendation on Approvability ............................................................ 5
`
`Recommendation on Phase 4 Studies and/or Risk Management Steps ...... 5
`
`II.
`
`Summary of Clinical Findings ............................................................................. 6
`
`A.
`
`Brievaerview of Clinical Program ........................................................... 6
`
`B.
`
`C.
`
`D.
`
`E.
`
`Efficacy ....................................................................................................... 6
`
`Safety ........................................................................................................... 7
`
`Dosing ......................................................................................................... 7
`
`Special Populations ..................................................................................... 7
`
`Clinical Review ........................................................................................................ 9
`
`I.
`
`Introduction and Background ............................................................................. 9
`
`A.
`
`B.
`
`C.
`
`D.
`
`E.
`
`Drug Established and Proposed Trade Name, Drug Class, Sponsor’s
`Proposed Indication(s), Dose, Regimens, Age Groups ............................... 9
`
`State of Armamentarium for Indication(s) .................................................. 9
`
`Important Milestones in Product Development .................. : ....................... 9
`
`Other Relevant Information ...................................................................... 1 l
`
`Important Issues with Pharmacologically Related Agents ........................ l 1
`
`II.
`
`Clinically Relevant Findings From Chemistry, Animal Pharmacology and
`Toxicology, Microbiology, Biopharmaceutics, Statistics and/or Other
`Consultant Reviews ............................................................................................. 11
`
`Page 2
`
`

`

`CLINICAL REVIEW
`
`III.
`
`IV.
`
`Human Pharmacokinetics and Pharmacodynamics ........................................ 11
`
`A.
`
`B;
`
`Pharmacokinetics ...................................................................................... 1 1
`
`Pharmacodynamics .................................................................................... 12
`
`Description of Clinical Data and Sources ......................................................... 13
`
`A.
`
`Overall Data .............................................................................................. 13
`
`B.
`
`C.
`
`D.
`
`Tables Listing the Clinical Trials .............................................................. 13
`
`Postmarketing Experience ......................................................................... 15
`
`Literature Review ...................................................................................... 15
`
`Clinical Review Methods .................................................................................... 15
`
`A.
`
`B.
`
`C.
`
`D.
`
`E.
`
`How the Review was Conducted .............................................................. 15
`
`Overview of Materials Consulted in Review ............................................ 15
`
`Overview of Methods Used to Evaluate Data Quality and Integrity ........ 16
`
`Were Trials Conducted in Accordance with Accepted Ethical Standards 17
`
`Evaluation of Financial Disclosure ........................................................... 17
`
`VI.
`
`Integrated Review of Efficacy ............................................................................ 17
`
`A.
`
`Brief Statement of Conclusions ................................................................ 17
`
`B.
`
`C.
`
`D.
`
`General Approach to Review of the Efficacy of the Drug ........................ 18
`
`Detailed Review of Trials by Indication ................................................... 19
`
`Efficacy Conclusions........\
`
`............................................................ 21
`
`VII.
`
`Integrated Review of Safety ............................................................................... 57
`
`A.
`
`Brief Statement of Conclusions ................................................................ 57
`
`B.
`
`C.
`
`D.
`
`E.
`
`Description of Patient Exposure ................................................................ 58
`
`Methods and Specific Findings of Safety Review .................................... 60
`
`Adequacy of Safety Testing .....................................
`
`...................... 79
`
`Summary of Critical Safety Findings and Limitations of Data ................. 80
`
`Page 3
`
`

`

`CLINICAL REVIEW
`
`Vlll. Dosing, Regimen, and Administration lssues ................................................... 80
`
`1X.
`
`Use in Special Populations .................................................................................. 81
`
`A.
`
`B.
`
`C.
`
`D.
`
`Evaluation of Sponsor’s Gender Effects Analyses and Adequacy of
`Investigation .............................................................................................. 81
`
`Evaluation of Evidence for Age, Race, or Ethnicity Effects on Safety or
`Efficacy ..................................................................................................... 81
`
`Evaluation of Pediatric Program ............... .'............................................... 81
`
`Cements on Data Available or Needed in Other Populations ................ 81
`
`X.
`
`Conclusions and Recommendations .................................................................. 82
`
`A.
`
`B.
`
`Conclusions ............................................................................................... 82
`
`Recommendations ..................................................................................... 83
`
`XI.
`
`Appendix .............................................................................................................. 83
`
`A.
`
`B.
`
`Other Relevant Materials .......................................................................... 83
`
`Individual More Detailed Study Reviews (If performed) ......................... 84
`
`Page 4
`
`

`

` CLINICAL REVIEW
`
`Executive Summary Section
`
`Clinical Review for NBA 21-372
`
`Executive Summar_v
`1.
`Recommendations
`
`Recommendation on Approvability
`A.
`This medical officer recommends approval of palonosetron for the indication of
`prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of
`moderately emetogenic cancer chemotherapy. Approval is also recommended for prevention of
`acute nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer
`chemotherapy. Approval is not recommended for delayed prevention of nausea and vomiting
`associated of highly emetogenic cancer chemotherapy. This is a single dose regimen of 0.25 mg
`palonosetron administered intravenously which is being recommended for approval. .
`Helsinn Healthcare SA has submitted a New Drug Application (NDA) for the drug
`palonosetron. This new molecular entity is a member ofthe 5-HT; antagonists drug class. The
`applicant is requesting approval for the indications of the prevention of acute and delayed nausea
`and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy,
`including highly emetogenic chemotherapy.
`The applicant’s submission demonstrates a favorable risk/benefit profile for this
`indication. This is based on three pivotal and one supportive study which demonstrated efficacy,
`and safety review of 18 palonosetron clinical trials. The efficacy data demonstrates that
`palonosetron is not inferior to other FDA approved medications for the indication of preventing
`nausea and vomiting associated with chemotherapy. The side effect profile is acceptable and
`comparable to other drugs in this class.
`B.
`Recommendation on Phase 4 Studies and/or Risk Management Steps
`There are some limitations of the safety data. While these limitations do not necessitate
`non-approval, they may addressed in Phase 4 studies and/or a risk management program.
`Because of concerns of QTc prolongation, the agency requested that 300 patients undergo Holter
`monitoring for 72 hours. The applicant had difficulty in obtaining this number due the high
`number of cancer patients who refused to undergo Holter monitor secondary to reasons of
`discomfort and inconvenience. The applicant has provided Holter data on 193 subjects for 22
`hours. Although less than originally requested, this data is judged to be adequate to help establish
`safety. In addition, the applicant provided a retrospective analysis of ECGs obtained in Phase I,
`and 2 studies. However, as with any approved new molecular entity, if an adverse event has a
`low enough incidence a signal may not be apparent in the safety database. Thus, to further
`augment what is known about palonosetron’s cardiac safety profile, further
`pharmacokinetic/pharmacodynamic studies in which ECG and/or Holter parameters are assessed
`before and afler drug administration may be helpful.
`
`Page 5
`
`

`

`
`
`CLINICAL REVIEW
`
`Executive Summary Section
`
`II.
`
`Summary of Clinical Findings
`A.
`Brief Oveniew of Clinical Program
`Palonosetron clinical development program includes a variety of clinical trials held in the
`United States, Europe, Mexico, Russia, and Canada. There were total of 18 clinical trials
`including intravenous and oral administration to chemotherapy induced nausea and vomiting
`(CINV) and post-operative nausea and vomiting (PONV) patients or healthy volunteers, Phase 1
`trials were performed in Japan, the United States and Europe. Phase 2 and 3 trials were
`conducted in North America, Mexico and Europe. The Phase 1 and 2 trials were conducted from
`1993 to 1995 and administered by the manufacturer Syntex Laboratories. The Phase 3 trials were
`conducted by Helsinri and begun in 1999. ln all the studies a total of 2360 patients received
`palonosetron. This development package contains two pivotal trials for prevention of acute and
`delayed nausea and vomiting following moderately emetogenic chemotherapy and one pivotal
`plus one supportive trial in patients receiving highly emetogenic regimens.
`B.
`Efficacy
`Palonosetron 0.25 mg given as an intravenous bolus 30 minutes prior to chemotherapy is
`efficacious in preventing moderately, and highly emetogenic CINV in the acute (0-24 hours)
`setting. The applicant also demonstrated efficacy for preventing moderately emetogenic CINV in
`the delayed setting (24-120 hours). Efficacy was not established for delayed prevention of highly
`emetogenic CINV.
`‘
`Assessment of efficacy for moderately emetogenic chemotherapy is based on two adequate
`and well controlled pivotal Phase 3 efficacy trials, PALO-99-03 and PALO-99-O4, that used
`standard, accepted efficacy and safety endpoints, and FDA-approved active comparators. The
`primary efficacy parameter was complete response (defined as no emetic episode and no rescue
`medication) within the first 24 hours after chemotherapy. This endpoint has been used as the
`basis for approval of other medications for this indication. The results demonstrated the non-
`inferiority of both palonosetron 0.25 mg and 0.75 mg when compared to ondansetron and
`dolasetron. The lower limit of the 97.5% confidence interval for the difference in complete
`response rates between the ondansetron and the palonosetron groups during the first 24 hours
`after chemotherapy was above the preset 15% delta. These trials also demonstrated that
`palonosetron 0.25 mg was efficacious for delayed prevention (24-120 hours) of moderately
`emetogenic CINV.
`In regards to highly emetogenic chemotherapy, the assessment of efficacy is based on the
`adequate and well controlled pivotal Phase 3 efficacy trial PALO-99-05 and PALO-00-01( a
`Phase 2 supportive trial). PALO-99-05 used standard, accepted efficacy and safety endpoints,
`and FDA-approved active comparators..'.l'he trial design and endpoints were identical to PALO-
`99-03. The results demonstrated the non-inferiority of both palonosetron 0.25 mg and 0.75 mg
`when compared to ondansetron. Again, the lower limit of the 97.5% confidence interval for the
`difference in complete'reSponse rates between the ondansetron and the palonosetron groups
`during the first 24 hours after chemotherapy was above the preset 15% delta. However, these
`trials did not establish that palonosetron 0.25 mg was efficacious for delayed prevention (24-120
`- hours) of highly emetogenic CINV. While the results did show non-inferiority to the comparator
`arms, the comparator drug is not indicated for delayed prevention of ClNV. Thus, in order to
`show efficacy the study drug should demonstrate superiority to the comparator drug. It did not do
`so. There was no statistically significant difference between palonosetron and ondansetron for
`
`Page 6
`
`

`

`
`
`CLINICAL REVIEW
`
`Executive Summary Section
`
`delayed prevention of highly emetogenic CINV. The evidence the applicant has presented does
`not substantiate an efficacy claim for this indication.
`C.
`Safety
`The clinical Integrated Summary of Safety (188) ofthis NDA includes all safety data
`collected in 3137 unique subjects enrolled in the 18 palonosetron clinical trials of whom 2360
`received palonosetron. Review of this data demonstrates that palonosetron when given as single
`dose prior to chemotherapy was well tolerated. A wide dose range was studied (less than 0.25 mg
`to approximately 6 mg). No deaths occurred that were attributable to the study drug. An
`extensive review of cardiac safety was conducted which included analysis of ECG (performed in
`2172 subjects) and Holter tracings (143 subjects) using high-resolution methods and a
`centralized review by a blinded cardiologist. No dose response on QTc interval was observed.
`The cardiac safety profile for palonosetron is similar to that of other drugs in this class. No signal
`for adverse effects of the study drug on laboratory or vital signs was detected.
`The most common adverse reactions seen with palonosetron (2 2%) were constipation and
`headache. Incidences of these reactions were similar across all palonosetron dose groups and the
`active comparator 5-HT; receptor antagonists, ondansetron and dolasetron. All other adverse
`reactions were seen at incidences equal to or less than 1%. Nearly all episodes of constipation
`were self-limiting and not severe. However, two subjects who took palonosetron in Phase 2 trials
`suffered from constipation that required treatment in a hospital. The current package insert for
`another already approved 5-HT; antagonists ondansetron states that constipation occurred in
`1 1% of chemotherapy patients receiving multiday ondansetron. The package insert for
`dolasetron reports a 3.2% incidence of constipation in chemotherapy patients.
`The safety database is limited in several ways. Although the numbers of patients was
`relatively large, a signal could not have been detected for an adverse event that has a low
`incidence. The majority of subjects did not have an ECG performed at CMAX when cardiac
`changes may be most likely to occur. The applicant was unable to recruit the requested 300
`patients to undergo Holter monitoring. Despite these limitations, the applicant was able to
`demonstrate safety of palonosetron.
`D.
`Dosing
`The applicant proposes a dose of 0.25 mg palonosetron intravenously given over 30
`seconds, 30 minutes prior to chemotherapy being closed. This is based on the pivotal studies that
`demonstrated that the 0.25 mg dose of palonosetron was more efficacious than the 0.75 mg dose.
`Palonosetron is to be supplied as a single-use sterile, clear, colorless solution in glass 5 ml vials
`ready for intravenous injection.
`In Phase 1 and Phase 2 trials, palonosetron was shown to be well tolerated at 30-second
`IV bolus doses up to 90 ug/kg. The maximum dose tested was approximately 6 mg as a fixed
`dose. The selection of doses for Phase 3 trials was based primarily on efficacy data. Study 2330
`was a Phase 2 study in which subjects received one of the following doses of palonosetron: 0.3,
`1, 3, 10, and 30 jig/kg . Based on efficacy data from this study, the 3-ttg/kg and IO-ug/kg doses
`were selected as the doses to evaluate in Phase 3 trials. These were converted to the fixed doses
`
`of 0.25 mg and 0.75 mg in order to simplify dosing regimens in clinical practice.
`E.
`Special Populations
`_
`The applicant has adequately evaluated the effects of gender on efficacy and safety. For
`the Phase 3 studies the majority of subjects were female. Subgroup analyses by gender
`demonstrated that male subjects had a trend for greater complete response rates during the first
`
`Page 7
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`

`

`
`
`CLINICAL REVIEW
`
`Executive Summary Section
`
`24 hours after chemotherapy than female subjects. For the moderately emetogenic trials 90% of
`males had a complete response versus 67% for females. For the highly emetogenjc nial 67% of
`males had a complete response versus 52% ofthe females.
`In regards, to safety no relevant
`difference was seen in adverse events, severe adverse events, or deaths based on gender.
`Twenty three percent (316) of the 1374 adult cancer patients in clinical studies of
`palonosetron were over the age of 65 years. Review of this data reveals no overall differences in
`safety or effectiveness between these subjects and the younger subjects. There was a slightly
`increased incidence of selected cardiovascular AEs among older subjects than younger subjects
`but these AEs were not clearly related to the study drug. No alteration of the dose or special
`monitoring is required for geriatric patients.
`There was a relative paucity of Black and Asian subjects relative to the US. population.
`The Phase 3 trials consisted of the following races:
`65% Caucasian
`
`31% Hispanic
`1% Asian
`
`3% Black
`
`0.3% Other
`
`No relevant differences in safety or effectiveness were seen based on race.
`
`APPEARS THlS WAY
`0N ORIGINM
`
`Page 8
`
`

`

`
`
`CLINICAL REVIEW
`
`Executive Summary Section
`
`Clinical Review
`
`I.
`
`.
`
`Introduction and Background
`
`A.
`
`Drug Established and Proposed Trade Name, Drug Class, Sponsor’s
`Proposed Indication(s), Dose, Regimens, Age Groups
`The applicant Helsinn Healthcare SA has submitted a New Drug Application (NDA) for
`the new molecular entity palonosetron. It does nOt have trade name established as of yet.
`. Palonosetron is a new molecular entity that belongs to the drug class of 5-HT; antagonists. The
`applicant’s proposed indication is for prevention of acute and delayed nausea and vomiting
`associated'with initial and repeated courses of emetogenic cancer chemotherapy, including
`highly emetogenic chemotherapy. The proposed dose is a single 0.25 mg sterile injection
`administered intravenously. It is to be used in adults 18 years and older. Pediatric studies are
`still ongoing.
`State of Armamentarium for Indication(s)
`B.
`There are currently three 5-HT; antagonists approved for treatment of nausea and
`vomiting in the United States. Zofran (odansetron hydrochloride) was approved January 4,
`199] lt is currently indicated for prevention of nausea and vomiting associated with initial and
`repeat courses of emetogeznic cancer chemotherapy, including highly--emetogenic chemotherapy
`(cisplatin dose >50 mg/m2) lts label states that efficacy of the single dose beyond 24 hoursin
`these patients has not been established Anzemet (dolasetron mesylate monohydrate) was
`approved September 1 l, 1997. It is currently indicated for the prevention of nausea and
`vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy,
`including high dose cisplatin. Kytril (granisetron) was approved March 1 1, 1994. It is
`indicated for the prevention of nausea and vomiting associated with initial and repeat courses of
`emetogenic cancer therapy, including high—dose cisplatin. All three of these 5-HT; antagonists
`are available in injectable and oral formulations.
`C.
`Important Milestones in Product Development
`Palonosetron was initially develo ed b Syntex Laboratories Inc. The first Investigational
`New Drug (IND) clinical protocol (IN '
`1'
`1 was submitted to the FDA on June 2, 1992.
`This was a Phase I escalating dose tolerance study involving the intravenous formulation Of
`palonosetron. The target indication was “treatment of cancer chemotherapy induced nausea and
`emesis”. On July 15, 1992, the Agency placed a clinical hold on the initial filing of INDI ”in
`until additional preclinical hemodynamic and cardiac conduction data were provided. This data
`"
`was supplied by Syntex Laboratories on November 9, 1992, and on December 24, 1992, the
`Agency notified the sponsor by letter that the clinical hold had been lified. Please see the
`pharmacology/toxicology review for details.
`Syntex Laboratories also
`_
`
`
`-—--
`
`t In 1994, the
`Between 1992
`target indication was expanded to M
`and 1995 Syntex Laboratories conducted five Phase 1 clinical trials and five Phase 2 clinical
`trials for both the oral and intravenous formulation of palonosetron. The last of the Phase 2 trials
`was completed in 1995.
`
`jiINDt
`
`Page 9
`
`

`

`
`
`CLINICAL REVIEW
`
`Clinical Review Section
`
`,from S
`
`In 1998, Helsinn Healthcare SA (based in Lugano, Switzerland) acquired palonosetron
`tex Laboratories. On June 23, 1998, all rights and responsibilities related to IND’s
`IV palonosetron), and
`were transferred from Syntex Inc. to
`Helsinn Healthcare SA. This was conveyed to the FDA by letter on August 3,1998. Helsinn
`decided to focus development solely on the indication for chemotherapy induced nausea and
`vomiting (CINV) and on the intravenous formulation.
`On March 10, 1999, an End-of Phase 2 Meeting between Helsinn and the FDA was held
`with a follow-up teleconference held April 29, 1999. During the meeting the target indication
`V
`was changed from '
`_
`
`o“prevention of nausea and
`vomiting associated with initial and repeated courses of emetogenic cancer chemotherapy,
`including highly emetogenic chemotherapy. " The Agency and Helsinn agreed that the trials
`PALO-99-03 and PALO-99-04 (both involving moderately emetogenic chemotherapy) and
`PALO-99-05 (involving highly emetogenic chemotherapy), would serve as the pivotal Phase 3
`studies for efficacy. To support a claim for palonosetron in the prevention of nausea and
`vomiting due to highly emetogenic chemotherapy the Agency agreed with the applicant’s plan to
`use Study PALO-99-05 (a comparison of palonosetron to ondansetron and historical control) and
`Study 2330 (a Phase 2 efficacy, safety, pharmacokinetics trial). The FDA also deemed
`acceptable the use of historical controls with a 15 % delta for these non-inferiority studies. At
`the follow-up teleconference, it was agreed on the inclusion of both chemotherapy naive and
`non—naive patients in the efficacy trial. In addition, both parties agreed to the primary efficacy
`outcome measure.
`
`Another issues raised at the End of Phase 2 meeting was the concern whether
`palonosetron was metabolized to ,.——-
`:a metabolite with potential cardiovascular
`toxicity.) On November 8, 2001, a FDA Preclinical Cardiovascular Safety meeting was held. In
`response to these concerns, a series ofin vitro and in vivo metabolic studies were conducted by
`Helsinn which demonstrated that this metabolite was not present.
`In late 1-999, Helsinn submitted Pivotal efficacy protocols for Special Protocol
`Assessment. The FDA replied to these assessments in January 2000. The FDA’s response
`contained the following pertinent points:
`'
`o Agreed with the definition ofthe primary efficacy endpoint “complete response”
`0 Agreed to the uses of concomitant dexamethasone
`0
`Suggested a subset of patients should undergo Holter monitoring (the applicant agreed
`and conducted trials)
`A teleconference was convened October 18, 2001, to discuss statistical concems about
`the Special Protocol Assessment. There were no historical placebo complete response efficacy
`data for placebo use with dexamethosone for acute CINV. The applicant suggested using meta-
`analysis to predict the dexamethasone effect on historical placebo and the agency agreed this
`may be the best approach.
`A final Pre~NDA meeting was held Apnl 10,2002. At this meeting, the applicant
`submitted multiple questions relating to submission format as well as various chemistry,
`toxicology and clinical issues. Several pertinent clinical issues were discussed with the
`applicant. The Agency noted that although there was a response to delayed emesis this was a
`secondary and not a primary endpoint.
`It was also noted that one investigator from a single trial
`initially conducted by Syntex was disqualified by the FDA. This investigator had violations that
`
`Page 10
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`CLINICAL REVIEW
`
`Clinical Review Section
`
`did not affect data integrity. The Agency agreed with Helsinn’s approach to exclude the efficacy
`data from this investigator but to include the Safety data. The conclusion of the meeting was
`that the NDA was ready for submission. On September 27, 2002 the NDA was submitted to the
`FDA.
`
`D.
`
`Other Relevant Information
`
`It not
`Palonosetron is not approved in the United States for any other indication.
`approved in any foreign country for this or any other indication. It is currently under
`development for the European market.
`E.
`Important Issues with Pharmacologically Related Agents
`There are currently three approved 5HT3 receptor.antagonists approved for use in the
`United States. They consist of Zofran(ondansetron hydrochloride), Kytril(granisetron), and
`Anzemet (dolasetron mesylate monohydrate). This class of medications is widely used for CINV.
`As a class, they are well tolerated and in general, safe and efficacious. Although they have been
`shown to affect ventricular depolarization and repolarization, no significant safety concerns have
`been introduced regarding this phannacologic class since their introduction into the market.
`
`II.
`
`Clinically Relevant Findings From Chemistry, Animal Pharmacology
`and Toxicology, Microbiology, Biopharmaceutics, Statistics and/or
`Other Consultant Reviews
`
`The chemical review was conducted by Dr. Marie Kowblansky. She stated that from a
`chemistry standpoint this NDA could be approved pending completion of a satisfactory GMP
`inspection. In addition, she deferred to the toxicology reviewer a decision regarding whether the
`
`impurities
`_
`.
`~
`_
`qualified to be present at the of -— 3, as proposed by the applicant. The toxicology review was
`conducted by Dr. Yosh Chopra. He has stated in his review that the level of impurities was
`acceptable that there are no outstanding toxicological issues that interfere with approval.
`The statistics reviewer was Dr. Stella Grosser. The primary issue from a statistical
`standpoint was the minimization allocation procedure used for randomization in the pivotal
`studies. Although she cited several drawbacks to this method of allocation, she concludes there is
`sufficient evidence that palonosetron 0.25 mg is efficacious in the prevention of acute nausea and
`vomiting following moderately and highly emetogenic cancer chemotherapy. She also found that
`there is also sufficient evidence that it is efficacious in the prevention of delayed emesis
`following moderately (but not highly) emetogenic chemotherapy.
`
`are
`
`III. Human Pharmacokinetics and Pharmacodynamics
`A.
`Pharmacokinetics
`'
`'
`
`Information about the pharmacokinetics of palonosetron is based on 14 Phase 1 to 3
`clinical studies. Generally, this data follows a two compartment open model with first order
`elimination. After intravenous infusion of palonosetron, there is. an initial slow.,decline in plasma
`concentrations. Following this initial decline, several subjects had secondary peaks in drug levels
`two to four hours post-dosing. These were thought to be due to entero-hepatic re-circulation. The
`mean time to maximum plasma concentration (Tum) is three to four hours. The mean terminal
`elimination half-life of palonosetron was 37.4 hours. However, some patients had half-lives of
`over 100 hours. Area under the curve (AUC) was dose —proportional when given in standard
`
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` CLINICAL REVIEW
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`Clinical Review Section
`
`dosages. Palonosetron has a large volume of distribution with an estimated median volume ofthe
`central compartment of 632 liters (584 to 680 l