`
`
`
`
`
`
`
`
`CENTER FOR DRUG EVALUATION AND
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`
`
`APPLICATION NUMBER:
`22-272
`22-272
`
`
`STATISTICAL REVIEW(S)
`STATISTICAL REVIEW! S}
`
`
`

`

`STATISTICAL REVIEW AND EVALUATION
`
`Biometrics Division: VI (HFD-705)
`
`
`
`
`
`
`
`
`NDA NO.:
`SERIAL NO.:
`DATE RECEIVED BY THE CENTER:
`DRUG NAME:
`
`22-272
`S_000
`May 13, 2008, June 15, 2009
`Oxycodone HCL 10, 15, 20, 30, 40, 60, and 80 mg
`TR
`Tablets
`DOSAGE FORM:
`Pain management
`INDICATION:
`Purdue Pharma, L.P.
`SPONSOR:
`Electronic Copy Dated May 13, 2008, June 15, 2009
`DOCUMENTS REVIEWED:
`NAME OF STATISTICAL REVIEWER: Meiyu Shen, Ph.D. (HFD-705)
`Craig M. Bertha, Ph.D.
`NAME OF CHEMISTRY REVIEWER:
`
`
` ________________________
`
` Meiyu Shen, Mathematical Statistician
`
`
`
`Concur: ______________________
`
` Yi Tsong, Ph.D.
`
` Deputy Director, DBVI
`
`
`
`Distribution:
`
`
`
`
`
`
`
`
`
`------------------------------------
`
`
` Stella G. Machado Ph.D.
`
`
`Division Director, DBVI
`
`NDA 22-272
`HFD-705/Y. Tsong, Ph.D.
`HFD-705/S.Machado Ph.D.
`HFD-710/Roswitha Kelly, M.S.
`ONDQA/DPE1/Craig M. Bertha, Ph.D.
`
`

`

`Statistical Review of NDA22272 Oxycodone HCL
`
`
`
`
`
`
`
`2
`
`TABLE OF CONTENTS
`
`EXECUTIVE SUMMARY OF STATISTICAL FINDINGS ....................................................... 3
`1.1
`Conclusions and Recommendations.........................................................................................3
`1.2
`Overview of the Submission......................................................................................................3
`1.3
`Principal Findings .....................................................................................................................4
`1.3.1
`Sponsor’s Results and Conclusions .......................................................................................................4
`1.3.2 Reviewers’ Results and Conclusions .....................................................................................................5
`1.3.3
`Statistical Issues.....................................................................................................................................6
`STATISTICAL REVIEW AND EVALUATION OF EVIDENCE...................................... 6
`2.1
`Introduction and Background..................................................................................................6
`2.2
`Overview of the Stability Program and Studies Reviewed ....................................................6
`2.3
`Data Analyzed and Sources ......................................................................................................6
`2.4
`Stability Study............................................................................................................................6
`2.4.1 Data........................................................................................................................................................6
`2.4.2
`Sponsor’s Analysis, Results and Conclusions .......................................................................................7
`2.4.3 Reviewers' Analysis, Results and Conclusions......................................................................................7
`2.5
`Statistical and Technical Issues................................................................................................9
`2.6
`Statistical Evaluation of Collective Evidence..........................................................................9
`2.7
`Conclusions and Recommendation ..........................................................................................9
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
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`Page 2 of 8
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`

`

`Statistical Review of NDA22272 Oxycodone HCL
`
`
`
`
`
` Conclusions and Recommendations
`
`EXECUTIVE SUMMARY OF STATISTICAL FINDINGS
`
`1.1
`
` count bottles of Oxycodone
` 100,
`The sponsor submitted a 24-month stability studies for
`HCL 10, 15, 20, 30 and 40 mg TR Tablets with the request for an extrapolated shelf life of 24
`months on May 13, 2009. The sponsor also submitted a 24-month stability studies for
`
`count bottles for the 60 mg and 80 mg TR Tablets with the request for an extrapolated shelf life
`of 24 months on June 15, 2009.
`
`
`.
`
`
`The original and revised dissolution specification limits for Oxycodone HCL 10, 15, 20, 30, 40,
`60, and 80 are listed in the Table 1.
`Product
`Dissolution Time
`
`Specification
`Original
`
`12-month update
`
`24-month update
`
`10, 15, and 20
`mg
`
`30 and 40 mg
`
`60 mg
`
`80 mg
`
`1st hour
`4th hour
`12th hour
`1st hour
`4th hour
`12th hour
`1st hour
`4th hour
`12th hour
`1st hour
`4th hour
`12th hour
`
`NLT
`
`NLT
`
`
`
`
`
`
`
`NLT
`
`NLT
`
`
`
`
`
`
`
`NLT
`
`NLT
`
`NLT
`
`NLT
`
`
`When the revised specification is used, based on these analyses and evaluations of Oxycodone
`data, the product is expected to remain within specifications through 24 months for 10, 15, 20,
`30, 40, 60, and 80 mg TR tablets. The analysis showed that 24-month expiration was established
`for 10, 15, 20, 30, 40, 60, and 80 mg TR tablets. However, because there is no data for 60 and 80
`mg with 100 counts per package, the shelf-life for 60 and 80 mg with 100 counts per package are
`not established.
`
`1.2 Overview of the Submission
`
` count bottles of Oxycodone
`, 100,
`The sponsor submitted a 24-month stability studies for
`HCL 10, 15, 20, 30 and 40 mg TR Tablets with the request for an extrapolated shelf life of 24
`months on May 13, 2009. The sponsor also submitted a 24-month stability studies for
`
`count bottles for the 60 mg and 80 mg TR Tablets with the request for an extrapolated shelf life
`
`
`
`Page 3 of 8
`
`
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b)
`(4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`Statistical Review of NDA22272 Oxycodone HCL
`
`
`
`
`
`of 24 months on June 15, 2009. One batch per strength was used in stability studies. Each batch
`was split into
` package counts, such as
`, 100,
` counts per package.
`
`The statistical analyses were not performed for the assay data or the dissolution data at 1 hour, 4
`hours, or 12 hours of Oxycodone. The statistical analyses were not performed for degradation
`data because nearly all of the reported values except a few observations were reported as NMT
`
`
`1.3 Principal Findings
`
`1.3.1 Sponsor’s Results and Conclusions
`
`(I) Stability analysis for Oxycodone HCL 10, 15, 20, 30 and 40 mg TR Tablets
`
`In the submission on May 13, 2009, the sponsor tabulated long term stability data up to 24
`months for Oxycodone HCL 10, 15, 20, 30 and 40 mg TR Tablets. The sponsor’s conclusions
`were based on the eye-balling the results and specifications:
`
`1. Assay of Oxycodone HCl: all assay results were within the current proposed specification
`label claim) for the long-term 24-month stability data.
`
`
`2. Degradation products:
`
`: observed values were <0.1%.
`2) Individual unknown degradation product
`All individual unknown degradation products were within the specification limit of NMT
`From samples at all testing intervals, there were only four cases where the unknown
`degradation products were observed in levels at or above
` as listed below:
` in 20 mg, 100 count at 1 month room temperature
` in 40 mg, 100 count at 1 month room temperature
` in 30 mg,
` count at 12 months room temperature
` in 10 mg,
` count at 24 months room temperature
`To provide additional information of the unknown in the 30 mg stability sample and to confirm
`the original data of
` for this unknown, two additional sample solutions of the 30 mg,
`
`count, 12 months, room temperature stability sample were prepared and analyzed. This
`unknown in the two retested samples were below the LOD limit of 0.05%.
`
`3). Total degradation Products
`The results at all testing intervals (through 24 months at long-term stability) were within the
`specification (NMT
`) and the values ranged from NMT
`
`
`From samples at all testing intervals, there was only one case where the total degradation
`products was observed at a level above
` The total degradation products result was
`the 30 mg,
` count, 12 months room temperature stability sample.
`
`4). Dissolution
`All dissolution results from long-term stability data through 24 months met the proposed
`specifications in Table 1.
`
`
`.
`
` in
`
`
`
`Page 4 of 8
`
`
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b)
`(4)
`
`(b)
`(4)
`
`(b)
`(4)
`
`(b)
`(4)
`
`(b) (4)
`
`(b)
`(4)
`
`(b
`)
`(4)
`
`(b) (4)
`
`

`

`Statistical Review of NDA22272 Oxycodone HCL
`
`
`
`
`
`
`
`
`
` label claim) for the long-
`
`
`(II) Stability analysis for Oxycodone HCL 60 and 80 mg TR Tablets
`
`In the submission on June 15, 2009, the sponsor tabulated long term stability data up to 24
`months for Oxycodone HCL 60 and 80 mg TR Tablets. The sponsor’s conclusions were based
`on the eye-balling the results and specifications:
`1. Assay
`
`All assay results are within the current proposed specification
`term stability samples tested through 24 months.
`
`2. Degradation Products
`
`1) Known Degradation Product:
` count bottles)
`All
` results from long-term stability data (through 24 months in
`were within the current proposed specification limit of NMT
`, and all values were
`
`2) Individual Unknown Degradation Product
` count bottles), there was only
`From all long-term stability data (through 24 months in
`one incidence where unknown degradation products were observed in levels at or above
`;
`two unknowns in amounts of
` were observed in the 60 mg initial sample. It
`should be noted that these two unknowns were not seen in the later stability samples of the
`same batch.
`
`Except for these two unknowns in the 60 mg initial sample; all unknowns, if observed, were
` All individual unknown degradation products were within the proposed specification limit
`of NMT
`.
`
`3) Total degradation Products
`The total degradation products at all testing intervals (through 24 months long-term stability)
`were within the proposed specification (NMT
`) and the values ranged from < LOQ (0.10%)
`to
`. From samples at all storage conditions and test intervals, except for the 60 mg initial
`sample where the total degradation products was
` all values were
`
`
`4) Dissolution
`All dissolution results from long-term stability data (through 24 months in
`bottles), met the current proposed specifications in Table 1.
`
`The sponsor asked the proposed shelf-life of 24 months for all
`
`
`
`
`
`
`
` count
`
` package
`
`
`
`
`
`1.3.2 Reviewers’ Results and Conclusions
`
`The reviewer performed the standard Office of Biostatistics (OB) stability analyses for the assay
`data and the dissolution data at 1 hour, 4 hours, and 12 hours of Oxycodone. In this fashion one
`can determine whether the data are internally consistent (with pooled slopes and pooled
`
`
`
`Page 5 of 8
`
`
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b)
`(4)
`
`(b) (4)
`
`(b) (4)
`
`(b)
`(4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`Statistical Review of NDA22272 Oxycodone HCL
`
`
`
`
`
`intercepts) and whether each product characteristic supports an extrapolated shelf life of 24
`months. Based on these analyses and evaluations of Oxycodone data, the product is expected to
`remain within specifications through 24 months when the revised specification is used.
`
`1.3.3 Statistical Issues
`
`The sponsor eye-ball method for comparing the results and specification was not accepted.
`
` 2
`
` STATISTICAL REVIEW AND EVALUATION OF EVIDENCE
`
`Introduction and Background
`
`
`2.1
`
` count bottles of Oxycodone
`, 100,
`The sponsor submitted a 24-month stability studies for
`HCL 10, 15, 20, 30 and 40 mg TR Tablets with the request for an extrapolated shelf life of 24
`months on May 13, 2009. The sponsor also submitted a 24-month stability studies for
`
`count bottles for the 60 mg and 80 mg TR Tablets with the request for an extrapolated shelf life
`of 24 months on June 15, 2009. One batch per strength was used in stability studies. Each batch
`was split into
` package counts, such as
` 100,
`counts per package.
`
`The statistical analyses were not performed for the assay data or the dissolution data at 1 hour, 4
`hours, or 12 hours of Oxycodone. The statistical analyses were not performed for degradation
`data because nearly all of the reported values except a few observations were reported as NMT
`.
`
`
`2.2 Overview of the Stability Program and Studies Reviewed
`
`,
`The assay data of Oxycodone, the assay data of degradation products (
`unknown degradation, and total degradation), the dissolution data at 1 hour, 4 hours, and 12
`hours for Oxycodone were submitted under 250C/60% RH condition in SAS transport format.
`
`The statistical analyses were performed for the assay data and the dissolution data at 1 hour, 4
`hours, and 12 hours of Oxycodone. However, the statistical analyses were not performed for
`degradation data because nearly all of reported values except a few observations were below
`LOQ level (0.1%).
`
`2.3
` Data Analyzed and Sources
`The sponsor submitted the data in electronic format on May 13 and June 15, 2009. The data are
`located in the EDR at the following link: \\cdsesub1\n22272\S 00.
`
`2.4 Stability Study
`2.4.1 Data
`,
`The assay data of Oxycodone, the assay data of degradation products
`unknown degradation, and total degradation), the dissolution data at 1 hour, 4 hours, and 12
`hours for Oxycodone were submitted under 250C/60% RH condition in SAS transport format.
`
`
`
`
`Page 6 of 8
`
`
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b)
`(4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b
`)
`(4)
`
`

`

`Statistical Review of NDA22272 Oxycodone HCL
`
`
`
`
`
`2.4.2 Sponsor’s Analysis, Results and Conclusions
`In the submission on May 13, 2009, the sponsor tabulated long term stability data up to 24
`months for Oxycodone HCL 10, 15, 20, 30 and 40 mg TR Tablets.
`
`In the submission on June 15, 2009, the sponsor tabulated long term stability data up to 24
`months for Oxycodone HCL 60 and 80 mg TR Tablets.
`
`In both submissions, the sponsor’s conclusions were based on the eye-balling the results and
`specifications.
`
`The sponsor’s conclusions are listed below:
`1. The sponsor concluded the 24-month shelf-life was supported for all Oxycodone HCl 10, 15,
`20, 30 and 40 mg TR tablets can be supported.
`
`
`2.4.3 Reviewers' Analysis, Results and Conclusions
`The reviewer performed the standard Office of Biostatistics (OB) stability analyses for the assay
`data and the dissolution data at 1 hour, 4 hours, and 12 hours of Oxycodone. In this fashion one
`can determine whether the data are internally consistent (pooled slopes and pooled intercepts)
`and whether each product characteristic supports an extrapolated shelf life of 24 months. In the
`analysis, the initial value was repeatedly added to each of
` packages. Data was deleted when
`package=0. This is one of alternative approaches favor to the sponsor because it assumes the
`same initial value for each package when package variability is ignored.
`
`The analysis results are listed in Table 2. The specifications in Table 1 are used according to the
`sponsor’s updates. Based on these analyses and evaluations of Oxycodone data, the product is
`expected to remain within specifications through 24 months. The analysis showed that 24-month
`expiration was established for 60 and 80 mg with
` counts per package. However,
`because there is no data for 60 and 80 mg with 100 counts per package, the shelf-life for 60 and
`80 mg with 100 counts per package are not established.
`
`
`
`
`
`
`
`
`
`
`
`
`Page 7 of 8
`
`
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`Table 2: Analysis of Oxycodone HCL assay and its dissolution up to 24 months stability
`data for 10, 15, 20, 30, 40, 60, and 80 mg TR tablets using the revised specification
`Strength Parameter
`Final model
`Estimated shelf
`
`Estimated shelf
`h
`
`10 mg
`
`Dissolution at 1 hr
`
`Dissolution at 4 hr
`
`Dissolution at 12 hr
`
`Oxycodone HCL Assay
`
`15 mg
`
`Dissolution at 1 hr
`
`Dissolution at 4 hr
`
`Dissolution at 12 hr
`
`Oxycodone HCL Assay
`
`20 mg
`
`Dissolution at 1 hr
`
`Dissolution at 4 hr
`
`Dissolution at 12 hr
`
`Oxycodone HCL Assay
`
`30 mg
`
`Dissolution at 1 hr
`
`Dissolution at 4 hr
`
`Dissolution at 12 hr
`
`Oxycodone HCL Assay
`
`40 mg
`
`Dissolution at 1 hr
`
`Dissolution at 4 hr
`
`Dissolution at 12 hr
`
`Oxycodone HCL Assay
`
`60 mg
`
`Dissolution at 1 hr
`
`Dissolution at 4 hr
`
`Dissolution at 12 hr
`
`Oxycodone HCL Assay
`
`80 mg
`
`Dissolution at 1 hr
`
`Dissolution at 4 hr
`
`Dissolution at 12 hr
`
`Oxycodone HCL Assay
`
`
`
`(b) (4)
`
`

`

`2.5 Statistical and Technical Issues
`The sponsor’s conclusions were based on the eye-balling the results and specifications.
`
`2.6 Statistical Evaluation of Collective Evidence
`
`The reviewer performed the independent stability analyses for the assay data and the dissolution
`data at 1 hour, 4 hours, and 12 hours of Oxycodone. Based on these analyses and evaluations of
`Oxycodone data, the product is expected to remain within specifications through 24 months for
`10, 15, 20, 30, 40, 60, and 80 mg TR tablets when the revised specification is used. However,
`because there is no data for 60 and 80 mg with 100 counts per package, the shelf-life for 60 and
`80 mg with 100 counts per package are not established.
`
`2.7 Conclusions and Recommendation
`
`Based on this reviewer’s analyses and evaluations of Oxycodone data, the product is expected to
`remain within specifications through 24 months when the revised specification is used.
`
`The sponsor’s request for 24 month shelf life is established for 10, 15, 20, 30, 40, 60, and 80 mg
`TR tablets. However, because there is no data for 60 and 80 mg with 100 counts per package,
`the shelf-life for 60 and 80 mg with 100 counts per package are not established.
`
`
`
`

`

`---------------------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`---------------------------------------------------------------------------------------------------------------------
` /s/
`---------------------
`MeiYu Shen
`7/14/2009 01:15:05 PM
`BIOMETRICS
`
`Yi Tsong
`7/14/2009 01:21:01 PM
`BIOMETRICS
`
`Stella Machado
`7/17/2009 03:08:30 PM
`BIOMETRICS
`
`

`

`STATISTICAL REVIEW AND EVALUATION
`
`Biometrics Division: VI (HFD-705)
`
`
`
`
`
`
`
`
`NDA NO.:
`SERIAL NO.:
`DATE RECEIVED BY THE CENTER:
`DRUG NAME:
`DOSAGE FORM:
`INDICATION:
`SPONSOR:
`DOCUMENTS REVIEWED:
`
`22-272
`S_000
`Dec. 18, 2007, April 23, 2008
`Oxycodone HCL 10, 15, 20, 30, and 40 mg TR
`Tablets
`Pain management
`Purdue Pharma, L.P.
`Electronic Copy Dated Dec. 18, 2007, April 23,
`2008
`NAME OF STATISTICAL REVIEWER: Meiyu Shen, Ph.D. (HFD-705)
`Craig M. Bertha, Ph.D.
`NAME OF CHEMISTRY REVIEWER:
`
`
` ________________________
`
` Meiyu Shen, Mathematical Statistician
`
`
`
`Concur: ______________________
`
` Yi Tsong, Ph.D.
`
` Deputy Director, DBVI
`
`
`
`Distribution:
`
`
`
`
`
`
`
`
`
`------------------------------------
`
`
` Stella G. Machado Ph.D.
`
`
`Division Director, DBVI
`
`NDA 22-272
`HFD-705/Y. Tsong, Ph.D.
`HFD-705/S.Machado Ph.D.
`HFD-710/Roswitha Kelly, M.S.
`ONDQA/DPE1/Craig M. Bertha, Ph.D.
`
`

`

`Statistical Review of NDA22272 Oxycodone HCL
`
`
`
`
`
`
`
`2
`
`TABLE OF CONTENTS
`
`EXECUTIVE SUMMARY OF STATISTICAL FINDINGS ....................................................... 3
`1.1
`Conclusions and Recommendations.........................................................................................3
`1.2
`Overview of the Submission......................................................................................................3
`1.3
`Principal Findings .....................................................................................................................3
`1.3.1
`Sponsor’s Results and Conclusions .......................................................................................................3
`1.3.2 Reviewers’ Results and Conclusions .....................................................................................................4
`1.3.3
`Statistical Issues.....................................................................................................................................4
`STATISTICAL REVIEW AND EVALUATION OF EVIDENCE...................................... 5
`2.1
`Introduction and Background..................................................................................................5
`2.2
`Overview of the Stability Program and Studies Reviewed ....................................................5
`2.3
`Data Analyzed and Sources ......................................................................................................5
`2.4
`Stability Study............................................................................................................................6
`2.4.1 Data........................................................................................................................................................6
`2.4.2
`Sponsor’s Analysis, Results and Conclusions .......................................................................................6
`2.4.3 Reviewers' Analysis, Results and Conclusions......................................................................................6
`2.5
`Statistical and Technical Issues................................................................................................8
`2.6
`Statistical Evaluation of Collective Evidence..........................................................................8
`2.7
`Conclusions and Recommendation ..........................................................................................8
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Page 2 of 8
`
`
`
`

`

`Statistical Review of NDA22272 Oxycodone HCL
`
`
`
`
`
` Conclusions and Recommendations
`
`EXECUTIVE SUMMARY OF STATISTICAL FINDINGS
`
`1.1
`
`The sponsor submitted a 9 months stability studies for three package counts of Oxycodone HCL
`10, 15, 20, 30 and 40 mg TR Tablets with the request for an extrapolated shelf life of 24 months
`on Dec.18, 2007, updated the submission for the stability studies of 100 counts per package with
`12 months data on Feb 15, 2008, and tightened the 4 hour dissolution criteria on March 13, 2008.
`The sponsor updated the submission for the stability studies of
` 100,
` counts per package
`with 12 months data on April 23, 2008 and revised the 4 hour dissolution criteria from
` to
` for the 10, 15, and 20 mg strengths and
` to
` for the 30 and 40 mg
`strengths. One batch per strength was used in stability studies. Each batch was split into
`
`package counts, such as
`, 100,
` counts per package. When the revised specification is used,
`based on these analyses and evaluations of Oxycodone data, the product is expected to remain
`within specifications through
` months. The analysis showed that 24-month expiration was
`established.
`
`1.2 Overview of the Submission
`
`In the original submission, the sponsor provided 9 months drug product stability data for three
`package counts of Oxycodone HCL 10, 15, 20, 30 and 40 mg TR Tablets with the request for an
`extrapolated shelf life of 24 months on Dec.18, 2007, updated the submission for the stability
`studies of 100 counts per package with 12 months data on Feb 15, 2008, and tightened the 4 hour
`dissolution criteria on March 13, 2008. One batch per strength was used in stability studies. Each
`batch was split into
` package counts, such as
`, 100,
` counts per package. The sponsor
`updated the submission for the stability studies of
`, 100,
` counts per package with 12
`months data on April 23, 2008 and revised the 4 hour dissolution criteria from
` to
` for the 10, 15, and 20 mg strengths and
` to
` for the 30 and 40 mg strengths.
`
`
`The statistical analyses were performed for the assay data and the dissolution data at 1 hour, 4
`hours, and 12 hours of Oxycodone. However, the statistical analyses were not performed for
`degradation data because nearly all of the reported values except a few observations were below
`LOQ level (0.1%).
`
`1.3 Principal Findings
`
`1.3.1 Sponsor’s Results and Conclusions
`
`In the submission, the sponsor included the analysis of long term stability data up to 12 months
`for Oxycodone HCL 10, 15, 20, 30 and 40 mg TR Tablets conducted by
`
` The sponsor’s conclusions are listed below:
`
`
`1. Assay of Oxycodone HCl: The shortest calculated shelf-life for the long term condition was
`months for the 30 mg tablet strength from the analysis of the long-term stability data.
`
`
`
`
`Page 3 of 8
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`Statistical Review of NDA22272 Oxycodone HCL
`
`
`
`
`
`
`
`
`
`1st Hour:
`4th Hour:
`12th Hour: NLT
`
`
`
`2. Dissolution: The sponsor revised specification limits for the stability sample in the submission
`dated on April 23, 2008 as shown in Tables 1 were recommended. When the long term stability
`data were analyzed against the new specification limit, all calculated shelf lives were longer than
`the proposed 24-month shelf life, except for the 4-hour dissolution of the 40 mg strength, equal
`to 24 months.
`
`Table 1: Original and Revised Dissolution Specification Limits for Oxycodone HCl
`Original Specification Limit:
`Revised Specification Limit:
`Revised Specification Limit:
`10, 15, 20, 30, 40 mg TR
`10, 15 and 20 mg TR
`30 and 40 mg TR Tablet
`Tablets
`Tablet
`1st Hour:
`1st Hour:
`4th Hour:
`4th Hour:
`12th Hour: NLT
`12th Hour: NLT
`
`1.3.2 Reviewers’ Results and Conclusions
`
`The reviewer performed the standard Office of Biostatistics (OB) stability analyses for the assay
`data and the dissolution data at 1 hour, 4 hours, and 12 hours of Oxycodone. In this fashion one
`can determine whether the data are internally consistent (with pooled slopes and pooled
`intercepts) and whether each product characteristic supports an extrapolated shelf life of 24
`months. Based on these analyses and evaluations of Oxycodone data, the product is expected to
`remain within specifications through 24 months when the revised specification is used.
`
`1.3.3 Statistical Issues
`
`The sponsor’s approach was not accepted for the following reasons.
`
`
`1) Poolability test for package slope
`
`
` used the following strategy to test the poolability of slopes across packages at the 0.05 level
`of significance.
`
`Let us define y be the response variable, such as assay, or dissolution, and β0 be the intercept, βi
`be slope for the ith package (the 1st package is 0 counts per package, the 2nd package is
` counts
`per package, and the 3rd package is 100 counts per package, the 4th package is
` counts per
`package). The model is y= β0+ (β+βi)*Time, i=1, 2, 3, 4.
` proposed to test
`
`H0: β1 = β2= β3 = β4=β, reduced model (or pooling slopes)
`Ha: βi≠ βj, i≠j, full model
`
`The SAS codes used are:
`
`Proc glm;
`Class package; *package has 4 levels: 0,
`Model y=time Package*time;
`Run;
`
`, 100,
`
`counts per package;
`
`
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`Statistical Review of NDA22272 Oxycodone HCL
`
`
`
`
`
`
`If the p-value for term package*time in the full model was < 0.05, the NULL is rejected and
`OSC concluded that each package had a separate slope. Otherwise, they concluded that all
`package had the common slope.
`
`This statistical strategy is different from the OB standard poolability testing.
`
`2). The fact that the sponsor used the same initial observation as 0 package type is not acceptable
`because there is only one observation for 0 package type. Hence initial value of
` package
`types are treated as missing in the model and pooling slope is not really about pooling the slopes
`after initial of the three batches.
`
` 2
`
` STATISTICAL REVIEW AND EVALUATION OF EVIDENCE
`
`Introduction and Background
`
`
`2.1
`
` package counts of
`The sponsor provided 9 months drug product stability data for
`Oxycodone HCL 10, 15, 20, 30 and 40 mg TR Tablets with the request for an extrapolated shelf
`life of 24 months on Dec.18, 2007, updated the submission for the stability studies of 100 counts
`per package with 12 months data on Feb 15, 2008, and tightened the 4 hour dissolution criteria
`on March 13, 2008. The sponsor updated the submission for the stability studies of
`, 100,
`
`counts per package with 12 months data on April 23, 2008 and revised the 4 hour dissolution
`criteria from
` to
` for the 10, 15, and 20 mg strengths and
` to
` for
`the 30 and 40 mg strengths. One batch per strength was used in stability studies. Each batch was
`split into package counts, such as
` 100,
` counts per package. In addition, data through 6
`months storage at the 400C/75% RH were also submitted.
`
`2.2 Overview of the Stability Program and Studies Reviewed
`
`,
`The assay data of Oxycodone, the assay data of degradation products
`unknown degradation, and total degradation), the dissolution data at 1 hour, 4 hours, and 12
`hours for Oxycodone were submitted under 250C/60% RH condition in SAS transport format.
`The assay data of Oxycodone, the assay data of degradation products
`,
`unknown degradation, and total degradation), the dissolution data at 1 hour, 4 hours, and 12
`hours for Oxycodone were submitted under 400C/75% RH in pdf format.
`
`The statistical analyses were performed for the assay data and the dissolution data at 1 hour, 4
`hours, and 12 hours of Oxycodone. However, the statistical analyses were not performed for
`degradation data because nearly all of reported values except a few observations were below
`LOQ level (0.1%).
`
`2.3
` Data Analyzed and Sources
`The sponsor submitted the data in electronic format on December 18, 2007. The data are located
`in the EDR at the following link: \\cdsesub1\n22272\S_00.
`
`
`
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`

`Statistical Review of NDA22272 Oxycodone HCL
`
`
`
`
`
`2.4 Stability Study
`2.4.1 Data
`
`The assay data of Oxycodone, the assay data of degradation products (
`unknown degradation, and total degradation), the dissolution data at 1 hour, 4 hours, and 12
`hours for Oxycodone were submitted under 250C/60% RH condition in SAS transport format.
`
`2.4.2 Sponsor’s Analysis, Results and Conclusions
`In the submission, the sponsor included the analysis of long term stability data up to 12 months
`for Oxycodone HCL 10, 15, 20, 30 and 40 mg TR Tablets conducted by
`
` analysis result is listed in Table 2.
`
`
`Table 2 Estimated Shelf life from
`
`
`
`
`
`The sponsor’s conclusions are listed below:
`
`1. Assay of Oxycodone HCl: The shortest calculated shelf-life for the long term condition was 40
`months for the 30 mg tablet strength from the analysis of the long-term stability data.
`
`2. Dissolution: The sponsor revised the specification limits for the stability samples as shown in
`Table 1 were recommended. When the long term stability data were analyzed against the new
`specification limit, all calculated shelf lives were longer than the proposed 24-month shelf life,
`except for the 4-hour dissolution of the 40 mg strength, equal to 24 months.
`
`2.4.3 Reviewers' Analysis, Results and Conclusions
`The reviewer performed the standard Office of Biostatistics (OB) stability analyses for the assay
`data and the dissolution data at 1 hour, 4 hours, and 12 hours of Oxycodone. In this fashion one
`can determine whether the data are internally consistent (pooled slopes and pooled intercepts)
`and whether each product characteristic supports an extrapolated shelf life of 24 months. In the
`analysis, the initial value was repeatedly added to each of three packages. Data was deleted when
`package=0. This is one of alternative approaches favor to the sponsor because it assumes the
`same initial value for each package when package vari