CENTER FOR DRUG EVALUATION AND RESEARCH APPLI CA I 0N NUMBER: 2061620rig1s000 OTHER SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED) I. GENERAL INFORMATION Device Generic Name: Germline Gene Mutation Test Device Trade Name: BRACAnalysis CDx™ Device Procode: PJG Applicant’s Name and Address: Myriad Genetic Laboratories, Inc. 320 Wakara Way Salt Lake City, UT 84108 Date(s) of Panel Recommendation: None Premarket Approval Application (PMA) Number: P140020 Date of FDA Notice of Approval: December 19, 2014 Priority Review: Granted priority review status on October 15, 2014, because BRACAnalysis CDx™ addresses an unmet medical need, as there is no approved alternative and as demonstrated by significant clinically meaningful advantage. II. INDICATIONS FOR USE BRACAnalysis CDx™ is an in vitro diagnostic device intended for the qualitative detection and classification of variants in the protein coding regions and intron/exon boundaries of the BRCA1 and BRCA2 genes using genomic DNA obtained from whole blood specimens collected in EDTA. Single nucleotide variants and small insertions and deletions (indels) are identified by polymerase chain reaction (PCR) and Sanger sequencing. Large deletions and duplications in BRCA1 and BRCA2 are detected using multiplex PCR. Results of the test are used as an aid in identifying ovarian cancer patients with deleterious or suspected deleterious germline BRCA variants eligible for treatment with Lynparza™ (olaparib). This assay is for professional use only and is to be performed only at Myriad Genetic Laboratories, a single laboratory site located at 320 Wakara Way, Salt Lake City, UT 84108. III. CONTRAINDICATIONS Patients who have undergone a previous allogeneic bone marrow transplant should not be tested with the BRACAnalysis CDx™. IV. WARNINGS AND PRECAUTIONS The warnings and precautions can be found in the BRACAnalysis CDx™ labeling. Reference ID: 3675977 V. DEVICE DESCRIPTION BRAC Analysis is an in vitro diagnostic device performed in a single laboratory, Myriad Genetic Laboratories, Inc. (Myriad), in Salt Lake City, UT. The test includes a sample collection kit, which is sent to ordering laboratories and healthcare providers. The collection kit contains the following components: 0 MonojectTM Blood Collection Tube (part no. 8881-311743); 0 Test Request Form; 0 Instructions for Sample Collection and Mailing; 0 Technical Information Summary. BRACAnalysis consists of the following two assays to detect sequence variants and large rearrangements in the BRCA1 and BRCA2 genes: 0 BRACAnalysis Sanger Sequencing; BRAC Analysis Large Rearrangement Test Dx). All reportable variants, including deleterious and suspected deleterious mutations, are con?rmed by repeat analysis with the BRACAnalysis Sanger Sequencing test or the Dx test, or by con?rmatory testing. Approximately 98% and 99% of all variants detected by the BRAC Analysis Sanger Sequencing test and the Dx tests, respectively, are confumed by repeat testing; the remaining variants (about 2% and respectively) require con?rmatory analysis by the following tests: 0 Alternate Primer Sequencing Con?rmatory PCR Analysis (CPA). BRAC Analysis is intended to be performed with serial nrunber-controlled instruments, as indicated in the table below. Instruments for Use with BRACAnalysis Instrument Serial umber(s) SP 14957 Tecan Freedom Evo 150 1310005128: 1402003965 Tecan In?nite F200 Pro Platereader 1309001987 5344 003700: 5344 009645: 5344 010536: 5344 010537: 5344 010530; 5344 010552: 5344 010572: 5344 026026: 5344 010613: 5344 010521: 5344 012323: 5344 009646: 6324CH718080: EP 6324CK418379: 6324C H018081: Pro 384 96 well 6324CK118382: 6324CK318376: 6324CH618076: 6324CK818381: 6324CK018387: 6324CK218385: 6324AR315529: 6324AR715518: 6324AR915513: 6324AR015528: 6324AR815510: Reference ID: 3675977 ABI 3730xl E-Gel iBase E-Gel Imaging System InGenius3 E-Gel Safe Imager Real-time Transilluminator 6321CP818805 1408-038; 16112-015; 18127-015; 25193-005; 24189-002; 24180-009; 25193-003; 1412-027 2113127 IG3/1219 12093074 Blood Collection and DNA Extraction Peripheral whole blood (~7 mL) is collected in a blood collection tube containing EDTA, and then the sample is mailed to Myriad at ambient temperature. At Myriad, the blood sample is accessioned, aliquoted, and then processed using an automated DNA extraction process. One aliquot (1 mL) per sample is loaded onto the QIASymphony SP instrument, which is configured for silica-based isolation and purification of genomic DNA using QIAGEN Software v4.0.1. When the extraction run is complete, the DNA is suspended in ~185 µL TE buffer. The DNA is then quantified and normalized using an automated robotic platform (Tecan Freedom EVO® 150 with Tecan EVOWare v2.4.8.7) and fluorometer (Tecan Infinite® F200 PRO with Magellan v7.0 Software). DNA samples are stored at 4°C until tested for variants in the BRCA genes. Detection of Sequence Variants Sequence analysis of the BRCA genes is conducted with the BRACAnalysis CDx™ Sanger Sequencing test. For BRCA1, full sequence determination of approximately 5,400 base pairs (bp) comprising 22 coding exons and approximately 750 adjacent bp in the non-coding intervening (intron) sequences is performed. Exons 1 and 4, which are noncoding, are not analyzed. For BRCA2, full sequence determination of approximately 10,200 bp comprising 26 coding exons and approximately 900 adjacent bp in the noncoding intervening sequences is performed. Exon 1 is non-coding, and therefore, is not analyzed. The intronic regions of BRCA1 and BRCA2 that are analyzed generally do not extend more than 20 bp proximal to the 5’ end and 10 bp distal to the 3’ end of each exon. The BRACAnalysis CDx™ Sanger Sequencing test uses primers that define specific base pair sequences to amplify each of the targeted regions by polymerase chain reaction (PCR). Each primer also contains an M13 tail on the 5’end to facilitate the downstream sequencing reactions. An automated robotic platform (Tecan Freedom EVO® 150 with Tecan EVOWare v2.4.8.7) is used to add the appropriate primers and DNA samples to the wells of 384-well PCR plates containing Sanger PCR MasterMix, which consists of pre-mixed reagents for the amplification reactions. Following inoculation, the PCR plates are centrifuged and then placed onto a thermocycler (Eppendorf MasterCycler EP or MasterCycler Pro 384) for PCR amplification. In total, 35 PCR reactions are carried out for BRCA1, and 49 PCR reactions for BRCA2. The amplified products are each directly sequenced in the forward and reverse directions using fluorescent dye-labeled sequencing primers. Fluorescently-labeled Sanger Reference ID: 3675977 sequencing fragments are generated using the Eppendorf MasterCycler thermocyclers, and then purified prior to sequencing on the Applied Biosystems (ABI) 3730xl. To evaluate the possibility of carryover throughout the procedure, each batch run includes two negative controls for the BRACAnalysis CDx™ Sanger Sequencing test: a No Genomic DNA Control and an M13 F+R Negative Control. In each control, no DNA template is added. The No Genomic DNA Control contains all PCR components and a PCR primer pair for one targeted amplicon. The M13 F+R Negative Control includes all PCR components in addition to the M13 forward and reverse primer pair. The controls must produce the expected results in order to evaluate the data from test samples. Chromatographic tracings of each amplicon are automatically generated with the ABI Sequence Analysis Software v5.3.1 and Gene Mapper v4.0, and subsequently analyzed using Myriad’s proprietary Alignment Software v1.7.4 and Mutation Calling Software v1.9.6 to identify possible sequence variants. The variant calling software numerically compares each base of the sequencing traces to consensus wild-type sequences, and any mismatches are flagged as potential variants. The flagged variants may then be routed for review by trained data analysts. In this case, two independent reviewers visually inspect the traces to confirm the variant calls. If the analysts do not agree, the results are reviewed by a supervisor for final determination. All reportable variants are independently confirmed by repeated PCR amplification of the indicated gene region(s) and subsequent sequencing. Detection of Large Rearrangements BRACAnalysis CDx™ Large Rearrangement Test (BART® CDx) is a multiplex PCR assay intended to detect large genomic rearrangements (e.g., deletions and duplications) across all coding regions, limited flanking intron regions, and the proximal promoter regions of the BRCA1 and BRCA2 genes. DNA is normalized to 2 ng/µL and then added to the wells of 384-well PCR plates containing pre-mixed reagents using the Tecan Freedom EVO® 15 automated robotic platform. The PCR plates are centrifuged, and then amplified products are generated using Eppendorf MasterCycler thermocyclers. During this process, fluorescently labeled primers are incorporated into the amplified DNA. In total, 11 multiplex PCR reactions are performed, and on average, there are 12 amplicons per multiplex with at least 2 amplicons per exon. The reactions are run in duplicate to obtain at least 4 data points for each region. The amplified products are purified using the AMPure® magnetic bead system and then loaded onto the Applied Biosystems (ABI) 3730xl for fragment analysis. Chromatographic traces are generated with the ABI Gene Mapper v4.0 software and analyzed for the presence of wild-type and variant fragments. The fragment data from separation of the PCR products are sized using an internal lane standard with fragments of known sizes. Myriad’s proprietary large rearrangement analysis software, MiniART Application v0.2, compares the relative peak intensities within a sample, and between samples run in the same batch, to generate statistical values and a gene dosage scatter plot. Briefly, each exon is represented by a minimum of 4 data points, so data from all amplicons of all samples in the same batch are normalized across the batch and then combined to yield one data point per sample per exon on the gene dosage scatter plot. Three housekeeping genes are used as additional copy number controls. The traces and scatter plot are reviewed by two independent trained analysts. Any sample flagged Reference ID: 3675977 during data review is reprocessed and reanalyzed. Any sample with a potential large rearrangement is reviewed by a trained supervisor to verify the result. In order to verify that the BART® CDx test can produce the expected results, two positive controls and one negative control are included in each run. The positive controls are two independent cell lines with defined BRCA large rearrangements. The negative control contains all of the components for the BART® CDx PCR reactions, with the exception of DNA template. If the controls produce the expected results, then the data from the test samples are assessed. Confirmatory Testing All reportable variants, including deleterious and suspected deleterious mutations, are confirmed by additional testing prior to result reporting. Approximately 98% of reportable sequence variants are confirmed by repeating the BRACAnalysis CDx™ Sanger Sequencing test for the indicated gene region(s), and about 99% of large rearrangements are confirmed by repeat BART® CDx testing. Certain variants that cannot be confirmed with repeat testing are subject to confirmatory analysis using Alternate Primer Sequencing (APS) or Confirmatory PCR Analysis (CPA). Approximately 2% of atypical variant results are confirmed using the APS test. APS is based on the same PCR and Sanger sequencing methods used in the BRACAnalysis CDx™ Sanger Sequencing test; however, PCR is conducted in 96-well PCR plates. The APS test is performed using alternative primer sequences, or primer combinations that flank the primer binding sites used in the BRACAnalysis CDx™ Sanger Sequencing assay, to allow for the identification of potential heterozygous base changes at primer binding sites that may have resulted in inefficient PCR amplification in the BRACAnalysis CDx™ Sanger Sequencing or BART® CDx tests. For example, a heterozygous base change could yield either unequal PCR amplification in the BRACAnalysis CDx™ Sanger Sequencing test or artifacts - such as apparent single exon deletions - in the BART® CDx test. The APS test is therefore used to confirm these types of rare results from the BRACAnalysis CDx™ Sanger Sequencing or BART® CDx tests. The CPA test is used for follow up testing for about 1% of atypical results, such as single exon deletions, from the BART® CDx test. Sequence-specific primers that span one or more exons are used to amplify breakpoint-specific genomic regions in a 96-well PCR plate format. The amplified products are evaluated using gel electrophoresis and subsequent imaging (E-Gel Imaging System InGenius3, Invitrogen E-Gel® Safe Imager and E-Gel® iBASE™ Power System with GENESys Gel Documentation System v1.4.0.0 software) and may be verified by sequencing. A size-based analysis of the PCR products is performed by comparing the PCR products from the sample of interest against wildtype PCR products. The confirmatory assays are generally performed as needed to confirm the presence of certain variants. Variant Classification Upon completion of testing at Myriad, a test report is sent to the ordering physician. The results of each test component, along with the classification of the germline variant(s) detected by the BRACAnalysis CDx™, are provided. Variant classification is conducted Reference ID: 3675977 according to a defmed classi?cation process by an in-house committee consisting of Laboratory Directors, the Chief Medical Of?cer, representatives ??om Medical Services, Genetic ormselors, and other trained professionals, including PhD-level scientists, board-certi?ed clinical molecular geneticists, or equivalent. Based on the classi?cation criteria, each identi?ed variant is classi?ed into one of ?ve categories. If multiple variants are detected with different classi?cations, the overall test interpretation is determined by the highest tiered variant classi?cation, as listed below. Variants determined to have a classi?cation of polymorphism are not included on the test report. Deleterious Mutation; Suspected Deleterious Mutation; Variant of Uncertain Signi?cance; Favor Polymorphism; Polymorphism (considered ?No Mutation Detected?). The BRACAnalysis is intended as an aid in selecting ovarian cancer patients with deleterious or suspected deleterious germline BRCA variants who may be eligible for treatment with LynparzaTM (olaparib). The majority 90%) of deleterious or suspected deleterious variants identi?ed by Myriad in BRCA1 and BRCA2 are classi?ed using objective criteria based on the type and genomic position of the variants, as described in the table below. Deleterious or suspected deleterious mutations classi?ed by other criteria that are based on available evidence may be subject to change. Objective Classi?cation Criteria for Deleterious and Suspected Deleterious Variants Classi?cation Variant Type Position? Tnmcates the reading ?ame at or before the most 3? known deleterious mutation Tnmcates the reading ?ame at or before the most 3? known deleterious mutation Deletion of an exon or exons predicted to disrupt the Deleterious reading ?ame or a critical functional domain Duplication of a non-tenninal exon or exons Large predicted to disrupt the reading frame or a critical Rearrangement functional domain Insertion of sequence that disrupts the reading or a critical domain Intronic variants that disrupt the consensus splice Splicing donor sites +2 intronic position) and splice acceptor sites (-1. -2 intronic position) There are exceptions that are classi?ed on a case-by-case basis. For example. a silent variant in exon 9 (C197C) in BRCAI has been reported to affect splicing (Miki et a1. 1994: Dosil et al.. 2010). Also. alternative splicing of exon 11 in BRCAI is partially functional (Thakur et al.. 1997: Kim et al.. 2006: Huber et al.. 2001). Nonsense Frameshift Suspected Deleterious Once the identi?ed variants are classi?ed, the completed dataset for each sample is reviewed and a report is sent to the designated physician. All mutations and genetic variants are named according to the convention of Beaudet and Tsui (1993). Nucleotide numbering starts at the ?rst transcribed base of BRCA1 and BRCA2 based on GenBank entries Ul4680 and U43 746, respectively. Reference ID: 3675977 VI. ALTERNATIVE PRACTICES AND PROCEDURES There are no FDA-cleared or -approved alternatives for BRCA mutation testing of DNA isolated from whole blood specimens for the selection of ovarian cancer patients who are eligible for treatment with Lynparza™ (olaparib). VII. MARKETING HISTORY Myriad Genetic Laboratories, Inc. initially designed and developed BRACAnalysis as a laboratory developed test, and the first commercial sample was tested in 1996. The BRACAnalysis test has been used to detect the presence of mutations within the BRCA1 or BRCA2 genes in the hereditary cancer predisposition setting. BRACAnalysis is not FDA-cleared or -approved. BRACAnalysis CDx™ has not been marketed in the United States or any foreign country. VIII. POTENTIAL ADVERSE EFFECTS OF THE DEVICE ON HEALTH Failure of the device to perform as expected or failure to correctly interpret test results may lead to incorrect BRCA test results, and subsequently, improper patient management decisions in ovarian cancer treatment. Patients with false positive results may undergo treatment with Lynparza™ (olaparib) without any clinical benefit, and may experience adverse reactions associated with olaparib therapy. Patients with false negative results may not be considered for treatment with Lynparza™ (olaparib), and therefore, may receive other treatment options. There is also a risk of delayed results, which may lead to a delay in treatment with Lynparza™ (olaparib). For the specific adverse events related to Lynparza™ (olaparib) that occurred in the clinical studies, please see Section X below. IX. SUMMARY OF PRECLINICAL STUDIES A. Laboratory Studies The specific performance characteristics of the BRACAnalysis CDx™ were determined by studies using samples from ovarian cancer patients, as well as samples from breast cancer patients and unaffected individuals from families with and without a high risk for Hereditary Breast and Ovarian Cancer. Samples were selected to represent a range of variants detected by the BRACAnalysis CDx™, as reflected in the device labeling. 1. Accuracy a. BRACAnalysis CDx™ Sanger Sequencing Test Accuracy of the BRACAnalysis CDx™ Sanger Sequencing test was verified by comparison against a validated next generation sequencing (NGS)-based Reference ID: 3675977 Reference ID: 3675977 assay. The two methods sequenced overlapping regions of the BRCA1 and BRCA2 genes (a total of 17,337 bases), and were used to independently evaluate a panel of 100 patient-derived specimens. All specimens were tested in a blinded manner. The specimens covered a range of variants, including single nucleotide variants, deletions 11p to 5 bp, and insertions up to 2 bp. After variant and non-variant calls (relative to wild-type sequences) were made for each test, the results were compared. From the set of samples tested, a total of 796 variant bases (representing 790 variants) and 1,732,907 non- van'ant bases were identi?ed by the NGS-based test. For each sample tested with the BRACAnalysis Sanger Sequencing test. successful calls were made for all amplicons that are part of the assay, and the no call rate was A11 variant and non-variant base calls between the two tests were concordant. The agreement analysis between the results from both tests demonstrated a positive percent agreement (PPA), negative percent agreement (NPA), and overall agreement of 100%. The lower bormds of the 95% con?dence intervals (CI) for PPA and NPA were 99.62% and 99.99%, respectively, which met the pre-speci?ed acceptance criteria for the study. The results are summarized in the table below. BRACAnalysis Sanger Sequencing Test vs. NGS?Based Assay Results NGS Assay Sanger Assay Concordant Calls Variant Bases 796 796 796 Non?Variant Bases 1.732.907 1.732.907 1.732.907 Total Bases* 1.733.703 1.733.703 1.733.703 Positive Percent Agreement (PPA) 100% (95% CI: 99.62%. 100%) Negative Percent Agreement (NPA) 100% (95% CI: 99.99%. 100%) Overall Agreement 100% (95% CI: 99.99%. 100%) *There were 3 one-base insertions in this sample set. . BRACAnalysis Large Rearrangement Test CDX) The performance of the Dx test was evaluated by comparing it to a validated microarray-based test. A set of 100 samples was processed in a blinded manner using the Dx and the microarray tests. The types of large rearrangements evaluated in this study were as follows: single exon and multi-exon deletion and duplication, the Portuguese formder mutation, and multi-exon triplication. Accuracy of the results from the Dx test was demonstrated by comparison against the positive and negative calls from the validated microarray test. Based on the microarray results, 26 samples were positive for a large rearrangement in BRCA genes, and 74 samples were negative. For the Dx test, 95 samples yielded valid results and 5 samples had invalid results, or no calls. Among the 95 samples with callable results, 94 samples had results that matched those ??om the microarray assay, while one did not. The rniscalled, or discordant, variant was identi?ed as a multi-exon duplication by the Dx test while the microarray test detected a multi-exon triplication. Although both tests detected an increase in dosage of Reference ID: 3675977 the same region, the Dx test is not designed to differentiate between duplications and triplications, and therefore, this is a limitation of the test. Based on the results, PPA was 84.6% (95% CI: 65.1% - 95.6%) and the NPA was 97.3% (95% CI: 90.6% - The overall agreement was 94% (95% I: 87.4% - The results are summarized in the table below. BARTC Test vs. Microarray Assay Variant Type Array Results Status Results Concordant Miscall No Call Single exon deletion 7 5 0 2 Single exon duplication 3 2 0 1 Multi-exon deletion 11 11 0 0 Positive Multi-exon duplication 3 3 0 0 Multi-exon triplication 1 0 1 0 Portuguese formder 1 1 0 mutation TOTAL 26 22 1 3 Negative 74 72 0 2 TOTAL 100 94 1 5 Large Rearrangement No Mutation Detected 2. Analytical Sensitivity DNA Input a. BRACAnalysis Sanger Sequencing Test PC Ampli?cation is the critical step in the BRAC Analysis Sanger Sequencing test for generating high levels of speci?c amplicons for the sequencing reactions. To assess the acceptable range of genomic DNA input to achieve the PC performance requirements of the test, DNA extracted ??om ?ve clinical specimens were each diluted to evaluate six DNA input concentrations (0ng, and 100 ng) per PCR reaction. The specimens carried variant types, such as single nucleotide variant and small deletion 11p to 5 bp. Each sample was tested for eight representative amplicons in duplicate. The amplicons were selected to represent the range of amplicon sizes, GC-content, and coverage applicable to the BRAC Analysis Sanger Sequencing test, as indicated in the table below. The rate of successful calls at each DNA input level was assessed, in addition to the concordance between the replicates per amplicon. Amplicon Characteristics . Amplicon Description Gene Amplicon Length (bp) GC Coverage 1 496 41 Bi-directional BR CA 1 2 506? 42 Bi-directional 3 292 42 Br-drrectronal 4 279 55c Bi-directional 5 82b 29 Uni-directional" 6 257 36 Bi-directional 7 445 36 Bi-directional 8 290 27d Bi-directional a Longest amplicon in the assay. b Shortest amplicon in the assay. c Most GC-rich amplicon in the assay. d Least GC-rich amplicon in the assay. e The presence of a homopolymer track renders one sequencing direction unreadable. BRCA2 The optimal DNA input concentration for PCR amplification is 20 ng, as specified in the protocol for the BRACAnalysis CDx™. At this level, all of the results for each sample met the quality criteria and generated callable results. The duplicate results for each amplicon were fully concordant for all of the variant and non-variant calls. For input levels at 100 ng and 40 ng, the no call rate was 0%, and all results were fully concordant. At 4 ng, the no call rate was 1%, and all callable results were concordant. At 1 ng, the no call rate was 4% and no miscalls were observed. At 0.2 ng, although the callable results were concordant, the no call rate was 44%, and therefore the acceptance criteria were not met for this input level. The DNA input level of 20 ng, which is specified in the standard protocol, is within the tolerated range of tested DNA input concentrations from 1 ng to 100 ng. b. BRACAnalysis CDx™ Large Rearrangement Test (BART® CDx) The BART® CDx test is a multiplex PCR assay that amplifies specific regions in the BRCA1 and BRCA2 genes. To evaluate the DNA input range for the PCR step, DNA concentrations higher and lower than the optimal DNA input amount of 8 ng, which is specified in the assay protocol, were evaluated. DNA samples from five patient specimens were each diluted and tested at seven different DNA input levels: 2 ng, 4, ng, 6 ng, 8 ng, 10 ng, 12 ng, and 14 ng. Samples with and without large rearrangements (e.g., multi-exon deletions) were included. The rate of successful calls for each sample per DNA input level was assessed, as well as the concordance across DNA concentrations. DNA input levels ranging from 2 ng to 12 ng produced callable results for all samples tested, and the results were fully concordant. At 14 ng, one sample did not yield callable results and, therefore, failed to meet the acceptance criteria of the study. The results demonstrate that DNA input levels from 2 ng to 12 ng generate similar results to those at 8ng, which is the DNA concentration specified for the BART® CDx test. 3. Analytical Specificity – Cross Reactivity a. BRACAnalysis CDx™ Sanger Sequencing Test The ability of the BRACAnalysis CDx™ Sanger Sequencing test to detect sequence variants is highly dependent upon the specificity of the primers for PCR amplification. To assess the potential for amplification of non-specific products from human genomic DNA, in silico analysis of the PCR primers Reference ID: 3675977 used in the assay was performed. Non-standard primer combinations were not evaluated since the assay consists of only singleplex PCR reactions. No nonspecific products were predicted for any of primer pair combinations. b. BRACAnalysis CDx™ Large Rearrangement Test (BART® CDx) A specificity analysis was conducted to determine if the PCR primers used in the BART® CDx test have the potential to amplify non-target sequences in the human genome. A bioinformatics program was used to align primer pairs against genomic sequence to predict if there may be any non-specific amplicons. Every possible primer pair combination per multiplex reaction was evaluated. In total, 3,016 combinations were assessed. Non-specific products were not predicted for any of the potentially cross-reactive primer pairs in any of the BART® CDx multiplex PCR reactions. 4. Interference To evaluate how potential interfering substances may impact the performance of the BRACAnalysis CDx™, the effects of three classes of substances were assessed: 1) endogenous substances normally present in human whole blood (i.e., hemoglobin, Albumin, IgG, and bilirubin); 2) an exogenous substance (i.e., K3EDTA); and 3) substances used in the standard process of the device (i.e., ethanol and bleach). Three whole blood samples from healthy subjects carrying a total of 30 different BRCA variants were evaluated. The types of variants included single nucleotide variant and small deletion up to 2 bp. The endogenous and exogenous substances were spiked into each blood sample, and then the samples were processed, along with a corresponding set of unspiked blood samples. The concentrations tested for some of the endogenous substances were based on the CLSI guideline document EP7-A2. In accordance with standard protocol for the assay, the method-specific substances - ethanol and bleach - were added to genomic DNA samples after the DNA quantification step. All of the samples were tested with the BRACAnalysis CDx™ Sanger Sequencing test and the BART® CDx test. The variant and non-variant calls were compared across the spiked and unspiked samples to determine if the potential interferents may lead to alterations in the test results. All non-spiked blood specimens yielded 100% callable and concordant results that passed the acceptance criteria for both the BRACAnalysis CDx™ Sanger Sequencing test and the BART® CDx test. Treatment with each potentially interfering substance at the maximum concentration tested, with the exception of IgG at 60 g/L, did not affect the performance of either test (i.e., hemoglobin at 20 g/dL, albumin at 50 g/L, conjugated bilirubin at 5 mg/dL, K3EDTA at 5%, ethanol at 12.75%, and 10% bleach at 0.5%). Samples with IgG at 60 g/L yielded a no call rate of 33%, which failed to meet the acceptance criteria for the BART® CDx test and demonstrated that IgG concentrations at 60 g/L interfere with the assay performance. At an IgG concentration of 9.5 g/L, which is near the average level typically detected in blood, all samples generated callable results that matched those of the corresponding unspiked samples. Thus, at 9.5 g/L of IgG, the acceptance criteria were met. Reference ID: 3675977 5. Reproducibility and Repeatability a. Combined Reproducibility Reproducibility of the BRACAnalysis CDx™ was assessed by testing a set of 20 patient-derived samples over three independent runs using two or three instruments of each type, three reagent lots, and three operators for each manual processing step. The three runs were conducted over non-consecutive days using the BRACAnalysis CDx™ Sanger Sequencing test and the BART® CDx test. The confirmatory assays were also performed, in accordance with the standard protocols. Across all tested samples, sequencing variants (single nucleotide variants and deletions up to 5 bp) and large rearrangements (single exon deletion, single exon duplication, and multi-exon deletion) were represented. For both tests, the no call rate was 0%, since all runs produced successful calls for all samples. For each sample, all calls were consistent across all runs. The positive percent agreement (PPA), negative percent agreement (NPA), and overall agreement were all 100%, which met the acceptance criteria for the study. b. Intra-Run Repeatability i. BRACAnalysis CDx™ Sanger Sequencing Test To determine if the BRACAnalysis CDx™ Sanger Sequencing test is reproducible across replicates of the same sample within a single batch run, three blood samples were tested in triplicate using ten amplicons of the test. The amplicons were selected to represent the range of genomic regions that are evaluated in the BRACAnalysis CDx™ Sanger Sequencing test. These include the longest amplicon, the shortest amplicon, the most GC-rich amplicon, and the least GC-rich amplicon. Regions for which the presence of a homopolymer track renders only one sequencing direction readable were also included. The amplicons were tested in two batches, such that 9 amplicons were run in one batch and 1 amplicon in another. For the batch with 9 amplicons, all of the replicates for each sample produced 100% callable and concordant results. For the batch with only one amplicon, 8 of 9 reactions were callable and the callable results were concordant within each sample. ii. BRACAnalysis CDx™ Large Rearrangement Test (BART® CDx) To demonstrate that the BART® CDx test can generate repeatable results across replicates of the same samples within a single batch run, ten specimens were processed in triplicate within one run. Variants of the following types were represented in the study: single exon duplication and multi-exon deletion. All replicates for each of the samples passed the Reference ID: 3675977 quality criteria and therefore produced callable results, all of which were fully concordant. 6. Guardbanding a. BRACAnalysis CDx™ Sanger Sequencing Test Guardbanding studies were performed to evaluate if the performance of the BRACAnalysis CDx™ Sanger Sequencing test is robust to withstand process variations around two key parameters: PCR annealing temperature, and sequencing annealing temperature. Five samples were tested in duplicate per tested condition, and variant types included single nucleotide variant and small deletion (up to 5 bp). i. PCR Annealing Temperature The thermal cycling profile was guardbanded by varying the PCR annealing temperature by ±1°C, ±2°C and ±3°C. The expected call for each sample was defined by the results obtained under the PCR annealing temperature specified in the standard protocol. The results from each test condition were compared to the expected calls. For three test conditions (+1°C, -2°C and -3°C), all replicates for each amplicon tested per sample yielded callable results that matched the expected call. Similar results were observed for the other test conditions (-1°C, +2°C and +3°C), with the exception that only one replicate of one of the tested amplicons for one sample generated no call. Overall, the acceptance criteria were met, and all test conditions were tolerated. ii. Sequencing Reaction Annealing Temperature The annealing temperature for the sequencing reaction was challenged by varying the temperature by ±1°C, ±2°C and ±3°C. The expected call for each sample was defined by the results obtained under the PCR annealing temperature specified in the standard protocol. The results from each test condition were compared to the expected calls. For three test conditions (1°C, +2°C and -3°C), all replicates for each amplicon tested per sample yielded callable results that were in agreement with the expected call. For the other test conditions (+1°C, -2°C and +3°C), one replicate for one of the tested amplicons for one sample generated no call, while all other replicates generated results that matched the expected call. Overall, the acceptance criteria were met, and all test conditions were tolerated. b. BRACAnalysis CDx™ Large Rearrangement Test (BART® CDx) The robustness of two critical parameters of the BART® CDx test was assessed: PCR annealing temperature and injection time of the PCR product input for capillary electrophoresis. In both cases, the same set of 28 unique samples was assessed and analyzed, of which two were run in duplicate. Two samples were positive for multi-exon deletions. Reference ID: 3675977 i. PCR Annealing Temperature The PCR annealing temperature was varied by ±1°C, ±2°C, and ±3°C. The expected call for each sample was defined by the results obtained under the PCR annealing temperature specified in the standard protocol. The results from each test condition were compared to the expected calls. Four test conditions (±1°C, -2°C, and -3°C) yielded reportable and concordant calls for all samples. At the two other conditions (+2°C and +3°C), one sample yielded a miscalled deletion result. Upon confirmatory testing, a variant in one of the BART® CDx PCR primer annealing sites was identified to be the cause for the decreased primer binding efficiency at the two elevated temperatures, leading to the miscall result. ii. Injection Time Different levels of PCR product injected onto the ABI 3730xl platform were assessed by altering the injection time of the PCR product. The injection time was set at 2, 4, 5, 6, 7, 10, or 20 seconds, while the voltage was held constant (2 kV), resulting in 4, 8, 10, 12, 14, 20 or 40 kV·s, respectively. Results obtained under optimal conditions (i.e., 12 kV·s) were used to compare results obtained under the test conditions. All conditions, except 40 kV·s, resulted in callable, concordant results for all samples. At 40 kV·s, calls of acceptable quality were not obtained for any sample, indicating that this setting falls outside of the linear detection range of the capillary electrophoresis instrument. Thus, the optimal condition of 12 kV·s is within the acceptable PCR input injection conditions from 4 kV·s to 20 kV·s. 7. Cross Contamination The potential for crossover contamination within a run and between runs was evaluated for three processes of the BRACAnalysis CDx™: 1) DNA extraction from whole blood specimens, 2) the BRACAnalysis CDx™ Sanger Sequencing test, and 3) the BART® CDx test. Specimens with different BRCA genotypes (for sequence variants and large rearrangements) were processed adjacent to each other in microtiter plate formats to maximize the potential for carryover between wells within a plate and between plates in separate batch runs. Two sequential batches were evaluated for inter-run carryover, and each run was evaluated separately for intra-run carryover. a. DNA Extraction DNA extraction from whole blood samples is an automated process using the QIASymphony robotic platform. Four blood samples were processed in triplicate from DNA extraction to data review. After isolation of genomic DNA, two samples were processed through the BRACAnalysis CDx™ Sanger Sequencing test and all four samples went through the BART® CDx test. For all samples in all batches, callable results were generated. All replicates were Reference ID: 3675977 fully concordant within each run and between runs. Thus, sample crossover events were not detected. b. BRACAnalysis CDx™ Sanger Sequencing test Two samples with unique BRCA sequence variants were set up within one PCR plate in a checkerboard pattern at alternating high (20ng for the first sample) and low (4 ng for the second sample) DNA input levels. In the first run, there were 84/90 (93%) reportable calls and 6/90 no calls for the two samples tested. All callable results were concordant. In the second run, there were 89/90 (99%) reportable calls, all of which were concordant. Although the no call rate was higher than observed in some other analytical studies, no miscall results were generated. c. BRACAnalysis CDx™ Large Rearrangement Test (BART® CDx) For the BART® CDx test, a total of ten samples were evaluated. In each batch, eight unique samples without BRCA large rearrangements were included with two samples with a large rearrangement. The two samples that were positive for a large rearrangement were tested in triplicate per run, while the samples that did not carry a large rearrangement were tested in six replicates per run. In the first run, two pairs of samples were set up in triplicate at high (12 ng for the large rearrangement negative samples) and low (4 ng for the samples with large rearrangements) DNA input levels. For all replicates of all samples in each batch, callable results were generated and were fully concordant with the expected results. Carryover events leading to miscall results were not observed. 8. Stability a. Specimen Stability To define the storage conditions and evaluate the stability of whole blood specimens for use with the BRACAnalysis CDx™, blood samples stored at defined temperatures and durations were assessed. Blood samples (25-30 mL) from five individuals were collected in EDTA tubes, aliquoted, and immediately tested (time point T0) or stored at two temperatures, 4°C (storage temperature specified in the standard protocol) and 30°C, for some specified amounts of time. Blood samples were stored at 4°C for 14 days, 30 days, and 37 days. At 30°C, samples were stored for 3 days, 5 days, and 7 days. At each time point, duplicate aliquots per sample were processed and analyzed with the BRACAnalysis CDx™ Sanger Sequencing test and the BART® CDx test. No large rearrangements were detected in the samples, and sequence variants included single nucleotide variants. Results from each time point were compared to those from time point T0 to determine if the same results may be obtained from stored samples. For all indicated time points at 4°C and 30°C, all replicates per sample yielded callable results that matched the results from T0. These data support that whole blood Reference ID: 3675977 Reference ID: 3675977 specimens are stable for 11p to 30 days when stored at and 11p to 5 days at . . Reagent Stability The storage and stability conditions for a de?ned set of reagents used in the BRAC Analysis were evaluated. Three lots of each set of reagents were stored under speci?ed temperature conditions and then tested at de?ned time points. Critical reagents used in three processes were evaluated: the BRAC Analysis Sanger Sequencing test, the test, and DNA quanti?cation and normalization. Under all of the test conditions, results from each time point were compared against those from time point To. The parameters tested for each reagent are listed in the table below. Reagent Stability Storage Conditions . . . Time Points Assay Step Reagent Temp Exprr atron Tested -20 0 mo** PCR 1 a 30 2411: 0. 12. 24. 36hr Sanger Oli 0 late -80 0 mo** sequencing 4 30 0. 30 7d 0.4.7.11d plate -20 TBD 0 mo** PCR -80 TBD 0 moQuantr?catron Standards Determined, Real-time stability studies are rmderway. For the BRAC Analysis Sanger Sequencing test, three reagent sets were assessed: PC plates with pre-mixed reagents (excluding DNA template and PC primers), Oligo plates which contain the PC primers, and plates which contain the components of the PC reaction for sequencing. A set of ?ve specimens with single nucleotide variants or deletions 11p to 2 bp were tested. For all time points and storage conditions tested for each reagent, variant and non-variant calls were successfully generated and concordant with the corresponding results ??om To. Expiration dating for each reagent is shown in the table above. Real-time stability testing for some reagents is ongoing. For the Dx test, PC plates with pre-mixed reagents (except for DNA template) were evaluated using a different set of ?ve samples. A multi-exon deletion was detected in one sample, while the others did not contain a large rearrangement. Stability testing for the Dx PC plate at is ongoing. For the DNA quanti?cation and normalization process, the stability of the standards used for quanti?cation was tested. Duplicate calibration curves were generated for the three lots at each time point, and the concentrations of two control DNA samples were then calculated. Across all tested time points, Reference ID: 3675977 minimal variation was observed for the calculated concentrations of the control DNA samples, supporting the expiration dating of 30 days at for the quanti?cation standards. Control Stability The stability of eight assay controls used in the BRACAnalysis was evaluated. Three lots of each control used in the BRACAnalysis Sanger Sequencing test and test were produced and assessed. For the CPA assay, two lots of each control were evaluated. If three lots were tested, ?ve replicates of each control lot were tested at each time point, for a total of 15 replicates. If two lots were available, the 15 replicates of each control were also tested, where eight replicates were tested with one lot and seven replicates with the second lot. For the positive controls, testing to the observable positive control endpoint was evaluated. For the negative controls, two testing endpoints were defmed; the ?st test observed the expected negative outcome of each control, and the second test was designed to yield a positive outcome by spiking the samples with ampli?able DNA template to demonstrate that the expected negative outcome in the ?rst test was not due to defective PC reagents or a processing error. The controls and storage conditions for this study are listed in the table below. Control Stability Storage Conditions - . - Time Points Assay Control Temp Expn atron Tested M13 - - 5 Sanger Negative Control - 6 TBD 0 1110 Cell Line Positive Quanti?ed. Control normalized 2 mo 0, 1, 2, 3 1110 at 4 ?9 . BART Alternate Positive Quanti?ed. Control normalized 1 mo 0. 1. 2? 3 1110 at 4 Amplicon Negative Control '20 TBD 0 1110 PCR Quanti?ed. Ampli?cation normalized 2 1110 0, 1, 2, 3 1110 Control 1 at 4 PCR Quanti?ed. CPA Ampli?cation normalized 2 mo 0, 1, 2. 31110 Control 2 at 4 No Genomic DNA Control 1 '20 TBD 0 1110 No Genomic DNA Control 2 20 TBD 0 1110 To Be Determined Real-time stability studies are underway. Results from each time point for the stored controls were compared to the corresponding To results. At To, all replicates for each control, except one, Reference ID: 3675977 yielded callable, concordant results. The one exception was the M13 Negative Control that was spiked with an M13-tailed PC amplicon. In this case, one replicate resulted in no call for one lot. As a result, there was a total of 14/15 successful calls for the spiked M13 Negative Control, and all calls were concordant. Time points for the following controls are complete: the Cell Line Positive and Alternative Positive Controls (1, 2, and 3 mo), and the CPA PC Ampli?cation Controls 1 and 2 (1 and 2 mo). For the Cell Line Positive Control, all tested time points met the acceptance criteria. For example, all replicates at 1 month and 3 months produced callable results that were fully concordant, and at the 2 month time point, there was one no call for one lot, while all other replicates had reportable and concordant results. Thus, the 2 month expiration for the Cell Line Positive Control was supported. For the Alternative Positive Control, all replicates at 1 month and 3 months produced callable results that were fully concordant; however, the 2 month time point failed to meet the acceptance criteria, as there were three no call results. For the CPA PCR Ampli?cation Controls 1 and 2, all replicates at the 1 and 2 month time points generated reportable results that completely corresponded to the To results. Taken together, the results support a current expiration of less than 1 month for the Alternative Positive Control, and less than 2 months for the CPA PCR Ampli?cation Controls 1 and 2. Additional real-time testing is ongoing for the CPA PC Ampli?cation Controls 1 and 2, as well as the M13 Negative Control, the Amplicon Negative Control, and the CPA No Genomic DNA Controls 1 and 2. . Intermediate Product Stability The stability of intermediate products of the BRACAnalysis was evaluated under speci?c storage conditions. Intermediate products generated from each of ?ve samples were tested in duplicate. Three samples contained sequence variants including single nucleotide variants and a deletion 11p to 19 bp; one sample had a large rearrangement. In all of the stability evaluations, the results of the tested time points were compared to the initial To results for successful calls and concordance. The intermediate products and storage conditions that were tested are listed in the table below. Intermediate Product Storage Conditions . . Time Points Assay Int. Product Temp Stability Tested 384-well plates anger PCR in 96-well plates inoculated plates 18-B. Reference ID: 3675977 . 7d 0.4.710d POSt'Elunon 18-Ambient temperature in the laboratory For the BRACAnalysis Sanger Sequencing test, all results at T0 produced callable results that were fully concordant. The results for all test conditions, except the PC intermediate product in 96-well plates stored at 4 for 4 days, produced successful sequencing calls. Although the acceptance criteria were also met for the PC intermediate product in 96-well plates stored at 4 for 4 days, one replicate for one amplicon in one sample failed to yield a callable result. All of the variant and non-variant calls for all time points were concordant with the results from To. For the test, all results at T0 generated calls, which were concordant for each of the 5 samples. For all time points tested for the two intermediate products, all samples produced successful Dx positive and negative calls that matched the To results. No nriscalls were detected. For the con?rmatory CPA assay, the post-PC intermediate product from one sample with a large rearrangement (as detected by Dx) was evaluated, in accordance with the standard protocol. All tested conditions generated results that were fully concordant with the To result. The results support the stability results shown in the table above. Animal Studies None . Additional Studies Variant Classi?cation Study To evaluate the robustness and reliability of the variant classi?cation process, a set of 262 unique BRCA variants was subjected to classi?cation as if they were new variant observations. The variants were classi?ed in a blinded manner according to de?ned classi?cation criteria. The resulting classi?cations for each variant were compared to the existing classi?cations in Myriad?s database, and the concordance rate was determined. One variant that was not previously observed at Myriad - and therefore was not previously classi?ed - was excluded from the study. The majority of variants (185/262) were identi?ed from clinical studies for LynparzaTM (olaparib), and the remaining variants (77/262) were selected for inclusion into the study in order to adequately cover the spectnun of variant types for classi?cation. The results are summarized in the tables below. Classi?cation Results Previous New Classr?catlon Classi?cation Classi?cation Deleterious (DM) 130 126 Suspected Deleterious (SD) 7 11 Uncertain Signi?cance WU S) 34 32 Favor Polymorphism (FP) 9 17 Polymorphism (PM) 81 75 Excluded from study 1 1 TOTAL 262 262 Discordant Results by Classi?cation Previous New Discordant Results Classification Classi?cation Classi?cation Treatment TOTAL 16 2 Comparison of the new classi?cations to the previous classi?cations resulted in agreement for 245 variants 95% CI: 90.2% - There were 16 variants that had inconsistent results; treatment eligibility for LynparzaTM (olaparib) would not be affected by 14 of the inconsistent classi?cations, but the different classi?cations for two variants would affect patient selection. Of the two, one is a missense variant classi?ed as suspected deleterious (SD), while the previous classi?cation was a variant of imcertain signi?cance (VU S). The change in classi?cation resulted from structural and evidence, which recently became available, to support the SD classi?cation. The other inconsistent result was an intronic splicing variant classi?ed as VUS in this study, but previously was SD. Again, the change in classi?cation was due to recently available evidence. Upon comparison of the two separate and independent variant classi?cations leading to the same eligibility status for treatment with Lynpar?zaTM (olaparib), the concordance rate was 99.2% (259/261, 95% CI: 97.2% - X. SUMNIARY OF PRINIARY CLINICAL STUDY Reference ID: 3675977 The clinical bene?t of the BRAC Analysis was demonstrated in a retrospective analysis of ef?cacy and safety data obtained ??om the open-label, non-randomized study to assess the safety and ef?cacy of olaparib treatment in patients with ovarian cancer who have a deleterious or suspected deleterious germlirre BRCA mutation and who have been previously treated with at least three lines of prior chemotherapy. Patients were em?olled from 13 centers in six c01mtries, including the United States. Local test results for BRCA status were used to assess patient eligibility for the trial. Samples ?'om a subset of em?olled patients ??om the intended population were retrospectively evaluated at one laboratory, Myriad (Salt Lake City, UT), using the BRACAnalysis DXTM, in a clinical bridging study. In the bridging study, there were two objectives: 1) agreement between the BRAC Analysis and the local test results for detection, and 2) the clinical outcomes ORR and for the patients with ovarian cancer who had received three or more prior lines of chemotherapy, who had measurable disease, and who were positive for deleterious or suspected deleterious germline BRCA mutations, as identi?ed by the BRACAnalysis CDx™. Lynparza™ (olaparib) demonstrated a robust overall response rate with a clinically meaningful duration of response in gBRCAm patients with ovarian cancer who had received three or more prior lines of chemotherapy. The magnitude of response in the subset tested with the BRACAnalysis CDx™ was comparable to that in the locally tested gBRCAm study population. These results were also supported by additional robustness analyses. Data from this bridging study were used to support PMA approval. A. Study Design The major effectiveness study was a single-arm, open-label, multi-center study to assess the safety and efficacy of olaparib treatment in patients with advanced cancers who have a deleterious or suspected deleterious germline BRCA mutation (gBRCAm). Patients were treated with 400 mg olaparib twice daily until disease progression or intolerance to study treatment. After starting study treatment, patients attended periodic clinic visits for assessment of safety and efficacy until confirmed objective disease progression. The primary objective of the study was to assess the efficacy of oral olaparib in patients with advanced cancers who have a confirmed genetic BRCA1 and/or BRCA2 mutation by assessment of tumor response. Other objectives were to assess the efficacy of oral olaparib in patients with advanced cancers who have a confirmed genetic BRCA1 and/or BRCA2 mutation, by assessment of objective response rate (ORR), progression-free survival (PFS), overall survival (OS), duration of response (DoR), and disease control rate (DCR). Safety information was collected throughout the study. To support approval of Lynparza™ (olaparib), the efficacy evaluation was performed in patients with deleterious or suspected deleterious germline BRCA mutation (gBRCAm)-associated ovarian cancer who had received three or more prior lines of chemotherapy and who had measurable disease based on ORR and DoR. The results of this clinical study are described in NDA 206162. To demonstrate clinical utility of the BRACAnalysis CDx™, a bridging study was conducted. Archived samples were available from a subset of patients with ovarian cancer enrolled in the open-label, non-randomized trial for retrospective analysis of gBRCAm status with the BRACAnalysis CDx™. The samples were tested in a blinded manner at Myriad (Salt Lake City, UT). The clinical utility of the BRACAnalysis CDx™ was established by comparing the mutation results and the associated clinical outcomes for the locally tested gBRCAm population to those for the subset of patients with confirmed gBRCA status upon retrospective testing with the BRACAnalysis CDx™. Additional robustness analyses were also performed. 1. Clinical Inclusion and Exclusion Criteria Enrollment in the clinical study was limited to patients who met the following inclusion criteria: 1. Provision of fully informed consent prior to any study-specific procedures. 2. Patients must be > 18 years of age. 3. Confirmed documented deleterious or suspected deleterious BRCA mutation. (The presence of a loss-of-function germline mutation in the BRCA1 and/or BRCA2 gene must be confirmed prior to consent according to local practice). Reference ID: 3675977 4. Histologically or, where appropriate, cytologically confirmed malignant solid tumour refractory to standard therapy and for which no suitable effective standard therapy exists. Haematological malignancies will be considered if there is a component of disease that can be assessed and followed for response by RECIST v1.1. 5. For the breast cancer setting, patients must have failed at least three previous lines of chemotherapy (not including tyrosine kinase inhibitors and hormonal treatments) in the metastatic/advanced setting. Patients who are hormone receptor positive must have also failed prior hormonal therapy. Patients who are HER2 receptor-positive must have failed prior trastuzumab. 6. For the ovarian cancer setting patients must have documented progressive or recurrent disease according to either RECIST v1.1 or Gynecologic Cancer Intergroup (GCIG) criteria either during or within 6 months of completion of their most recent platinum-based chemotherapy regimen OR greater than 6 months from completion of most recent platinum-based chemotherapy, but not suitable for further platinum therapy. This should be discussed with the AstraZeneca Study Physician prior to obtaining consent. Note that in the ovarian cancer setting, eligibility also includes patients who have developed recurrent ovarian cancer with macroscopic peritoneal metastases outside the pelvis or distant metastases. In addition, patients with primary peritoneal carcinoma or Fallopian tube carcinoma may be considered for the study. 7. For pancreatic cancer setting, patients must have failed systematic chemotherapy in the advanced or metastatic setting. 8. For the prostate cancer setting, patients must have: • hormone-refractory disease, defined as a testosterone value in the castration range • at least 2 consecutive rising PSA values above their nadir and measured at least two weeks apart • at least 6 weeks from discontinuation of anti-androgen therapy. • must have failed at least one systemic therapy for metastatic hormonerefractory disease. 9. Patients must have normal organ and bone marrow function measured within 28 days prior to administration of study treatment as defined below: Reference ID: 3675977 • Hemoglobin ≥9.0 g/dL • Absolute neutrophil count (ANC) ≥1.5 x 109/L • White blood cells (WBC) >3 x 109/L • Platelet count ≥100 x 109/L • Total bilirubin ≤1.5 x institutional upper limit of normal (ULN). • Aspartate transaminase (AST) (SGOT)/ALT (SGPT) ≤2.5 x institutional upper limit of normal unless liver metastases are present in which case it must be ≤ 5x ULN • Serum creatinine ≤1.5 x institutional upper limit of normal (ULN) 10. ECOG performance status ≤2 11. Patients must have a life expectancy ≥12 weeks 12. Evidence of non-childbearing status for women of childbearing potential, or postmenopausal status: negative urine or serum pregnancy test within 28 days of study treatment, confirmed prior to treatment on day 1. Postmenopausal is defined as: • Amenorrheic for 1 year or more following cessation of exogenous hormonal treatments • Luteinizing hormone and follicle-stimulating hormone levels in the postmenopausal range for women under 50 • radiation-induced oophorectomy with last menses >1 year ago • chemotherapy-induced menopause with >1 year interval since last menses • or surgical sterilization (bilateral oophorectomy or hysterectomy). 13. Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations. 14. At least one lesion (measurable and/or non-measurable) at baseline that can be accurately assessed by CT/MRI and is suitable for repeated assessment at follow-up visits. Patients were not permitted to enroll in the study if they met any of the following exclusion criteria: 1. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site) 2. Any previous treatment with a PARP inhibitor, including olaparib. 3. Patient with any other malignancy which has been active or treated within the previous 5 years, with the exception of a second suspected BRCA-related malignancy, adequately treated cone-biopsied in situ carcinoma of the cervix uteri, endometrial carcinoma stage 1A or 1, or non-melanoma skin lesions. 4. Patients receiving any systemic chemotherapy, radiotherapy (except for palliative reasons), within 2 weeks from the last dose prior to study treatment (or a longer period depending on the defined characteristics of the agents used). The patient can receive a stable dose of bisphosphonates for bone metastases, before and during the study as long as these were started at least 4 weeks prior to treatment. Prostate cancer patients may also continue to receive Luteinizing Hormone-Releasing Hormone (LHRH). 5. Patients receiving the following classes of inhibitors of CYP3A4 Reference ID: 3675977 • Azole antifungals • Macrolide antibiotics • Protease inhibitors 6. Persistent toxicities (>CTCAE grade 2), excluding alopecia, caused by previous cancer therapy. 7. Patients with symptomatic uncontrolled brain metastases. A scan to confirm the absence of brain metastases is not required. The patient can receive a stable dose of corticosteroids before and during the study as long as these were started at least 4 weeks prior to treatment. 8. Patients with spinal cord compression, unless they have received definitive treatment for this and have evidence of clinically stable disease for at least 28 days prior to study entry 9. Major surgery within 2 weeks of starting study treatment and patients must have recovered from any effects of any major surgery. 10. Patients considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, or any psychiatric disorder that prohibits obtaining informed consent. 11. Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication. 12. Breast-feeding women. 13. Immunocompromised patients, e.g., patients who are known to be serologically positive for human immunodeficiency virus. 14. Patients with known active hepatic disease (i.e., Hepatitis B or C). 15. Patients with a known hypersensitivity to olaparib or any of the excipients of the product. 16. Patients with uncontrolled seizures. 17. Previous enrollment in the present study. 18. Treatment with any investigational product during the last 14 days (or a longer period depending on the defined characteristics of the agents used). 2. Follow-up Schedule Tumor assessments were performed at baseline and at regular intervals thereafter (every 8 weeks + 1 week) until objective disease progression or up to 6 months after starting study treatment. If a patient had not progressed after 6 months, the tumor assessments were performed at extended intervals (12 weeks) until disease progression. Following confirmed disease progression, patients discontinued olaparib treatment, and were continued to be contacted to assess survival status Reference ID: 3675977 until death or the data cutoff for the primary analysis. 3. Clinical Endpoints With regard to safety, information about adverse events was collected from time of signed informed consent throughout the treatment period and up to and including 30 days after the patient discontinues olaparib treatment. With regard to effectiveness, the efficacy evaluation was performed in patients with deleterious or suspected deleterious germline BRCA mutation (gBRCAm)associated ovarian cancer who had received three or more prior lines of chemotherapy and who had measurable disease. The efficacy variables used to assess clinical benefit were objective response rate (ORR) and duration of response (DoR). The analyses were based on the assessment of response based on RECIST 1.1. For the clinical bridging study, there were two objectives: 1) agreement between the BRACAnalysis CDx™ and the local test results for gBRCAm detection, and 2) the clinical outcomes (i.e., ORR and DoR) for the patients with ovarian cancer who had received three or more prior lines of chemotherapy, who had measurable disease, and who were positive for deleterious or suspected deleterious germline BRCA mutations, as identified by the BRACAnalysis CDx™. B. Accountability of PMA Cohort Based on local test results, a total of 317 patients with advanced cancers were enrolled in the study. There were 193 patients with deleterious or suspected deleterious germline BRCA mutation (gBRCAm)-associated ovarian cancer, among whom 137 had measurable disease and had received three or more lines of prior chemotherapy. Out of the 137 patients, specimens from 61 patients were available for retrospective testing with the BRACAnalysis CDx™ in the clinical bridging study. C. Study Population Demographics and Baseline Parameters Study enrollment occurred at 13 centers in six countries (Australia, Germany, Spain, Israel, Sweden, and United States). Among the 137 gBRCAm patients with ovarian cancer who had received three or more lines of chemotherapy, 40 patients (29%) were enrolled in the US. Baseline demographic characteristics and tumor information for the 137 gBRCAm patients with ovarian cancer who had measurable disease and who had received three or more lines of chemotherapy are provided in the table below. Also shown are the characteristics for the subset of 59 patients with confirmed gBRCAm results with the BRACAnalysis CDx™ and for 78 patients who were not tested with the BRACAnalysis CDx™ test (due to unavailability of archived specimens). In general, the demographics for patients with and without a BRACAnalysis CDx™ test result are similar, apart from the ECOG Performance status for which there was a higher proportion of patients with a performance status of 0 in the subgroup with a BRACAnalysis CDx™ test result. Reference ID: 3675977 Demographic characteristics for patients with ovarian cancer, 3 or more prior lines of chemotherapy and measurable disease at baseline All patients (n=137) Patients with BRACAnalysis CDx™ result (n=59) Patients without BRACAnalysis CDx™ result (n=78) n (%) n (%) n (%) Mean (SD) 57.5 (9.02) 56.4 (7.89) 58.3 (9.75) Median (range) 58.0 (35-79) 56.0 (36-75) 59 (35-79) <50 26 (19.0) 11 (18.6) 15 (19.2) ≥50 to <65 83 (60.6) 39 (66.1) 44 (56.4) ≥65 28 (20.4) 9 (15.3) 19 (24.4) 137 (100) 59 (100) 78 (100) 129 (94.2) 56 (94.9) 73 (93.6) 1 (0.7) 1 (1.7) 0 (0) Asian 6 (4.4) 2 (3.4) 4 (5.1) Other 1 (0.7) 0 (0) 1 (1.3) 0 76 (55.5) 41 (69.5) 35 (44.9) 1 52 (38.0) 17 (28.8) 35 (44.9) 2 8 (5.8) 1 (1.7) 7 (9.0) Missing 1 (0.7) 0 (0) 1 (1.3) 125 (91.2) 55 (93.2) 70 (89.7) Fallopian tube 3 (2.2) 1 (1.7) 2 (2.6) Peritoneum 7 (5.1) 3 (5.1) 4 (5.1) Primary peritoneal 2 (1.5) 0 (0) 2 (2.6) Characteristic Age (years) Age group (years) Sex Female Race White Black/African-American ECOG performance status Site of tumour Ovary Due to rounding of % values, some groups may sum to greater than 100.0%. An assessment of the distribution of BRCA mutations between the patients with and without a BRACAnalysis CDx™ test result who had measurable disease and who received at least three lines of prior chemotherapy are summarized in the table below. The distributions of the mutations are generally similar between the groups. Reference ID: 3675977 BRCA mutation characteristics for patients with ovarian cancer, 3 or more prior lines of chemotherapy and measurable disease at baseline Characteristic All patients (n=137) Patients with BRACAnalysis CDx™ result (n=59) Patients without BRACAnalysis CDx™ result (n=78) n (%) n (%) n (%) BRCA1 variants 106 (77.4) 41 (69.5) 65 (83.3) BRCA2 variants 30 (21.9) 18 (30.5) 12 (15.4) 1 (0.7) 0 (0) Frameshift 102 (74.5) 39 (66.1) 63 (80.8) Nonsense 18 (13.1) 11 (18.6) 7 (9.0) Missense 7 (5.1) 4 (6.8) 3 (3.8) Splice site 4 (2.9) 2 (3.4) 2 (2.6) Large rearrangement 2 (1.5) 1 (1.7) 1 (1.3) Synonymous variant 1 (0.7) 1 (1.7) 0 (0.0) In-frame deletion 2 (1.5) 1 (1.7) 1 (1.3) Intronic variant 1 (0.7) 0 (0) 1 (1.3) BRCA1 & BRCA2 variants 1 (1.3) Due to rounding of % values, some groups may sum to greater than 100.0%. D. Safety and Effectiveness Results 1. Safety Results The safety, with respect to treatment with Lynparza™ (olaparib), will not be addressed in detail in the SSED for the BRACAnalysis CDx™. Adverse event information was obtained from multiple clinical studies. Major safety considerations related to the drug include the potential for an increased risk for the development of myelodysplastic syndrome/Acute Myeloid Leukemia (MDS/AML) and the risk of non-infectious pneumonitis. The most common adverse reactions (≥20%) in clinical trials were anemia, nausea, fatigue (including asthenia), vomiting, diarrhea, dyspepsia, headache, decreased appetite, nasopharyngitis/URI, arthralgia/musculoskeletal pain, myalgia, back pain, dermatitis/rash and upper abdominal pain. Refer to the drug label for more information. 2. Effectiveness Results The analysis of efficacy analysis was based on objective response rate (ORR) and duration of response (DoR) observed in 137 patients with deleterious or suspected deleterious germline BRCA mutation (gBRCAm)-associated ovarian cancer who had received three or more prior lines of chemotherapy and who had measurable disease. In this cohort, the ORR was 34% (95% CI: 26% - 42%) with a median Reference ID: 3675977 DoR of 7.9 months. The observed ORR represents an improvement over existing therapies and is reasonably likely to predict clinical benefit in the indicated population. The results are listed in the table below. The effectiveness analysis for the BRACAnalysis CDx™ was based on a subset of 61 gBRCAm patients with ovarian cancer who had received three or more prior lines of chemotherapy, who had measurable disease, and for whom specimens were available for retesting with the BRACAnalysis CDx™. The level of concordance between the local test results, as reported in the Case Report Form, and the results from the BRACAnalysis CDx™ was determined to be 96.7% (59/61, 95% CI: 88.7% - 99.6%). Among the discordant results, one sample did not yield a callable result with the BRACAnalysis CDx™, and another sample had different classification results between the local test and the BRACAnalysis CDx™ (deleterious vs. variant of unknown significance, respectively), although the specific variant that was detected by both tests matched. The clinical outcome data for the 59 patients with confirmed gBRCAm status was as follows: ORR was 41% (95% CI: 28% - 54%), and median DoR was 8.0 months. Taken together, the results in the subset of gBRCAm patients tested with the BRACAnalysis CDx™ were comparable to those observed in the cohort of 137 patients, which supports effectiveness of the device. The results are summarized in the table below. Clinical Study Results Median 95% CI DoR (months) Subset* Total Subjects n Subjects with Response n (%) ORR 95% CI Progressed n (%) All 137 46 (33.6) 0.34 (0.26, 0.42) 30 (65.2) 7.9 (5.6, 9.6) With BRACAnalysis CDx™ result 59 24 (40.7) 0.41 (0.28, 0.54) 14 (58.3) 8.0 (3.8, NC) No BRACAnalysis CDx™ result 78 22 (28.2) 0.28 (0.19, 0.40) 16 (72.7) 7.9 (6.0, 9.6) *Ovarian cancer patients with measurable disease who received at least three lines of prior chemotherapy 3. Subgroup Analyses Additional robustness analyses were conducted to consider the potential impact of missing data arising from patients with a positive BRACAnalysis CDx™ test result, but who may have been negative by the local test. Patients with such test results are part of the intended use population of the BRACAnalysis CDx™; however, they were excluded from the clinical trial due to negative results upon local test screening. To account for this missing data, the efficacy of olaparib treatment in patients with positive results from the BRACAnalysis CDx™ was estimated assuming different combinations for the following parameters: • The objective response rate (ORR) among patients with positive results with both the BRACAnalysis CDx™ and local tests was fixed at 41%, which was observed from the trial. Reference ID: 3675977 • • • The missing ORR among patients with positive BRACAnalysis CDx™ and negative local test results was assumed to be 5%, 10%, 15%, 20%, 25%, 30%, 35%, or 40% to exhaust all possibilities that do not exceed the ORR estimated from patients with positive results with both the BRACAnalysis CDx™ and local tests. The proportion of cases with negative local test results are assumed to be 5%, 10%, 15%, 20%, 25%, or 30%. Based on published literature, the germline BRCA mutation rate in unselected ovarian cancers is from 11% to 15% (Hennessy, et al. 2010; Pal, et al. 2005). The negative percent agreement (NPA) of the two tests (i.e., negative results by both tests) was fixed at 0.988 (159/161), as was observed from multiple clinical studies as well as literature (Kurian et al. 2014). Combining all of the above assumed parameter values, the ORR modeled for the BRACAnalysis CDx™ test-positive population, including those who may have tested negative by local tests, was calculated. The confidence intervals are calculated based on the imputed ORR from the subset of 137 patients with deleterious or suspected deleterious germline BRCA mutation (gBRCAm)-associated ovarian cancer who had received three or more prior lines of chemotherapy and who had measurable disease in the study. The smallest ORR value estimated for the BRACAnalysis CDx™ testpositive population, including those who may have tested negative by local tests, is 34% (95% CI: 26% - 43%), which is not significantly different from that observed for the overall subpopulation of 137 patients who had measurable disease and who had received 3 or more lines of prior chemotherapy (34%, 95% CI: 26% - 42%). The results are listed in the table below. Estimated ORR for the BRACAnalysis CDx™-Positive Population Assumed ORR for BRACAnalysis CDx™-positive and Local Test-Negative Assumed Prevalence Local Test-Negative 5% 10% 15% 20% 25% 30% 5% % (95%CI) 10% % (95%CI) 15% % (95%CI) 20% % (95%CI) 25% % (95%CI) 30% % (95%CI) 35% % (95%CI) 40% % (95%CI) 34% (26, 43) 37% (29, 46) 38% (30, 47) 39% (30, 47) 39% (30, 47) 40% (32, 49) 35% (27, 44) 38% (30, 47) 39% (30, 47) 39% (30, 47) 40% (32, 49) 40% (32, 49) 36% (28, 44) 38% (30, 47) 39% (30, 47) 39% (30, 47) 40% (32, 49) 40% (32, 49) 37% (29, 46) 39% (30, 47) 39% (30, 47) 40% (32, 49) 40% (32, 49) 40% (32, 49) 38% (30, 47) 39% (30, 47) 40% (32, 49) 40% (32, 49) 40% (32, 49) 40% (32, 49) 39% (30, 47) 40% (32, 49) 40% (32, 49) 40% (32, 49) 40% (32, 49) 40% (32, 49) 40% (32, 49) 40% (32, 49) 40% (32, 49) 40% (32, 49) 40% (32, 49) 41% (33, 50) 41% (33, 50) 41% (33, 50) 41% (33, 50) 41% (33, 50) 41% (33, 50) 41% (33, 50) E. Financial Disclosure The Financial Disclosure by Clinical Investigators regulation (21 CFR 54) requires applicants who submit a marketing application to include certain information concerning the compensation to, and financial interests and arrangement of, any Reference ID: 3675977 clinical investigator conducting clinical studies covered by the regulation. The pivotal clinical study was supplemented by retrospective testing at one site. None of the clinical investigators had disclosable financial interests/arrangements as defined in sections 54.2(a), (b), (c), and (f). The information provided does not raise any questions about the reliability of the data. XI. PANEL MEETING RECOMMENDATION AND FDA’S POST-PANEL ACTION In accordance with the provisions of section 515(c)(2) of the act as amended by the Safe Medical Devices Act of 1990, this PMA was not referred to the Molecular and Clinical Genetics Panel, an FDA advisory committee, for review and recommendation. XII. CONCLUSIONS DRAWN FROM PRECLINICAL AND CLINICAL STUDIES A. Effectiveness Conclusions The clinical benefit of the BRACAnalysis CDx™ was demonstrated in a retrospective analysis of efficacy and safety data obtained from the open-label, non-randomized study in which Lynparza™ (olaparib) demonstrated a robust overall response rate with a clinically meaningful duration of response in patients with deleterious or suspected deleterious germline BRCA mutation (gBRCAm)-associated ovarian cancer who had received three or more prior lines of chemotherapy. Results from local testing for gBRCAm were used to determine patient eligibility for the clinical study. The study enrolled 193 gBRCAm ovarian cancer patients, among whom 137 had received at least three lines of prior chemotherapy with measurable disease at baseline. Of the 137 patients, specimens from 61 patients were available for retrospective confirmation of gBRCAm status using the BRACAnalysis CDx™. After testing, 59 cases (96.7%) were verified to have deleterious or suspected deleterious germline BRCA mutations. Analysis of the subset of 59 patients revealed that the response rate was 41% (95% CI: 28% - 54%) and the median duration of response was 8.0 months. The results are similar to those observed in the overall population of 137 patients, for which the response rate was 34% (95% CI: 26% 42%) and the median duration of response was 7.9 months. Additional robustness and worst case scenario analyses to include missing results supported an improvement in response rate in gBRCAm ovarian cancer patients. The performance of the BRACAnalysis CDx™ was also supported by the analytical validation studies. As demonstrated in the analytical specificity study, the assay is highly specific for all targeted regions in the BRCA1 and BRCA2 genes. The device also demonstrated consistent performance to detect specific sequence variants and large rearrangements in the BRCA genes. Further, sequencing and large rearrangement results from the BRACAnalysis CDx™ correlated with results obtained from validated comparator methods. B. Safety Conclusions The BRACAnalysis CDx™ is an in vitro diagnostic device, which involves testing whole blood specimens collected from patients with ovarian cancer. The risks of the device are based on data collected in the clinical study conducted to support PMA Reference ID: 3675977 approval as described above. Risks of the BRACAnalysis CDx™ are associated with failure of the device to perform as expected or failure to correctly interpret test results. If incorrect, or false, results are reported, then ovarian cancer patients may not receive the proper treatment. Patients with false positive results may undergo treatment with Lynparza™ (olaparib) without any clinical benefit, and may experience adverse reactions associated with olaparib therapy. Patients with false negative results may not be considered for treatment with Lynparza™ (olaparib), and therefore, may receive other treatment options. There is also a risk of delayed results, which may lead to a delay in treatment with Lynparza™ (olaparib). C. Benefit-Risk Conclusions The probable benefits of the device are based on data collected in the clinical study, which were used to support PMA approval as described above. The clinical benefit of the BRACAnalysis CDx™ was demonstrated in a retrospective analysis of efficacy and safety data obtained from the open-label, non-randomized study in which Lynparza™ (olaparib) demonstrated a robust overall response rate with a clinically meaningful duration of response in patients with deleterious or suspected deleterious germline BRCA mutation (gBRCAm)-associated ovarian cancer who had received three or more prior lines of chemotherapy. Patients were enrolled into the clinical study based on local testing results for gBRCAm. Samples from a subset of enrolled patients with measurable disease who had received at least three lines of prior chemotherapy were subsequently tested with the BRACAnalysis CDx™ to verify gBRCAm status. The overall concordance rate between the local test results and those from BRACAnalysis CDx™ was 96.7% (95% CI: 88.7% - 99.6%). The observed clinical benefit in the subset of confirmed gBRCAm patients was comparable to that observed in the overall population. In the overall population of gBRCAm patients with previously treated ovarian cancer, the response rate was 34% (95% CI: 26% 42%) and the median duration of response was 7.9 months. These results were also supported by additional robustness analyses. Overall, the response rate in patients with gBRCAm-associated ovarian cancer is better than what would be expected of available therapy and represents an improvement on a surrogate endpoint that is reasonably likely to predict clinical benefit. Additional factors to be considered in determining probable risks and benefits for the BRACAnalysis CDx™ included: analytical performance of the device, representation of variants in the major effectiveness study, and the availability of alternative tests. First, the primary risks associated with the BRACAnalysis CDx™ are the possibility of inaccurate, or false, results that may lead to mismanagement of patient treatment. The performance of the device is supported by analytical validation studies, and additional analytical testing will be conducted in the post-approval setting. Second, a limited range of variant types were included in the clinical bridging study. Confirmatory clinical studies are being conducted to verify the results of the major effectiveness study, and additional variant types will likely be represented. Third, there is currently no FDA-approved or -cleared device for the selection of gBRCAm patients with previously treated ovarian cancer for treatment with Lynparza™ (olaparib). Reference ID: 3675977 In conclusion, given the available information above, the data support the use of the BRACAnalysis CDx™ as an aid in identifying ovarian cancer patients with deleterious or suspected deleterious germline BRCA mutations for fourth-line treatment with Lynparza™ (olaparib), and the probable benefits outweigh the probable risks. D. Overall Conclusions The data in this application support the reasonable assurance of safety and effectiveness of this device when used in accordance with the indications for use. Data from the open-label, non-randomized clinical study and the associated bridging study support the utility of the BRACAnalysis CDx™ as an aid in selecting patients with previously treated ovarian cancer who may be eligible for treatment with Lynparza™ (olaparib). Lynparza™ (olaparib) demonstrated improvement in objective response rate and duration of response in ovarian cancer patients who have been previously treated with at least three lines of prior chemotherapy and who have deleterious or suspected deleterious germline BRCA mutations, as identified with the BRACAnalysis CDx™. XIII. CDRH DECISION CDRH issued an approval order on December 19, 2014. The final conditions of approval cited in the approval order are described below. 1. As reflected in the labeling for BRACAnalysis CDx™, a limited range of variant types was included in some of the analytical validation studies. Additional testing of samples is required to establish the analytical performance characteristics of the BRACAnalysis CDx™ for all variant types that may be detected. Samples that adequately cover the range of small deletions, small insertions, and large rearrangements detected by the device, should be included, with consideration to variant lengths and genomic contexts. The results from these studies should be included in the labeling, and the results should be submitted within 7 months from the date of the approval order. 2. Since a limited range of variant types were included in the clinical validation study, results from the ongoing clinical trials (Study D0816C00002 and Study D0816C00010) using the BRACAnalysis CDx™ should be provided upon completion of the trials. If patients were enrolled based on results from a clinical trial assay (CTA), a bridging study between the CTA and BRACAnalysis CDx™ will be required. The results from these studies should be reflected in the labeling. 3. Defined criteria are used to classify variants detected by BRACAnalysis CDx™. Variant classifications may be subject to change over time based on newly available evidence that is evaluated in your classification process. To monitor the robustness of the variant classification process, continued evaluation of the process will be needed. When samples are received to be tested with BRACAnalysis CDx™, all variants that are detected should be treated as new variants and classified according to the current classification criteria. The current classification results should then be compared to the penultimate classifications (if variants were previously identified), with tabulation of agreement between the two classification results. A summary of the results should Reference ID: 3675977 be provided annually. The following should be included: the variants detected, the agreement between the previous and current classifications per category, the numbers of variants that changed per classification category, description(s) of the classification changes, and the criteria used for each classification (e.g., the criteria used for the previous classification, the criteria used for the current classification, and the rationale for any differences or changes to the classification criteria). The results from these studies could lead to labeling changes. 4. There was limited representation of deleterious and suspected deleterious germline BRCA1 and BRCA2 variants in the registrational clinical study. As treatment outcome data (e.g., literature) becomes available with broader representation of variants, the sponsor should assess and report on whether or not the variant classification criteria are in line with the drug efficacy results. 5. The BRACAnalysis CDx™ is intended to be used with EDTA blood collection tubes. The sponsor should track and report on the results from samples provided in K2EDTA and K3EDTA collection tubes. If the results from these studies lead to labeling changes, then a future PMA supplement would be required. The applicant’s manufacturing facilities have been inspected and found to be in compliance with the device Quality System (QS) regulation (21 CFR 820). XIV. APPROVAL SPECIFICATIONS Directions for use: See device labeling. Hazards to Health from Use of the Device: See Indications, Contraindications, Warnings, Precautions, and Adverse Events in the device labeling. Refer to drug label for Lynparza™ (olaparib) for additional information related to use of the drug. Post-approval Requirements and Restrictions: See approval order. XV. REFERENCES Beaudet AL and Tsui LC. (1993). A suggested nomenclature for designating mutations. Hum Mutat 2(4): 245-248. Dosil V, et al. (2010). Alternative splicing and molecular characterization of splice site variant: BRCA1 c.519C>T as a case study. Clin Chem 56(1):53-61. Hennessey BTJ, et al. (2010). Somatic mutations in BRCA1 and BRCA2 could expand the number of patients that benefit from poly (ADP Ribose) polymerase inhibitors in ovarian cancer. J Clin Oncol 28(22):3570-3576. Huber LJ, et al. (2001). Impaired DNA damage response in cells expressing an exon 11deleted murine Brca1 variant that localizes to nuclear foci. Mol Cell Biol 21(12):40054015. Reference ID: 3675977 Kim SS, et al. (2006). Hyperplasia and spontaneous tumor development in the gynecologic system in mice lacking the BRCA1-∆11 isoform. Mol Cell Biol 26(18):6983-6992. Kurian AW, et al. (2014). Clinical evaluation of a multiple-gene sequencing panel for hereditary cancer risk assessment. J Clin Oncol 32(19): 2001-2009. Miki Y, et al. (1994). A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 266(5182):66-71. Pal T, et al. (2010). BRCA1 and BRCA2 mutations account for a large proportion of ovarian carcinoma cases. Cancer 104(12):2807-2816. Thakur S, et al. (1997). Localization of BRCA1 and a splice variant identified the nuclear localization signal. Mol Cell Biol 17(1): 444-452. Reference ID: 3675977 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------EUNICE Y LEE 12/19/2014 Reference ID: 3675977 PMR/PMC Development Template This template should be completed by the PMR/PMC Development Coordinator and included for each PMR/PMC in the Action Package. NDA# Product Name: 206162 Lynparza (Olapraib) 50 mg Capsules PMR 2824-1 Description: Submit the progression free survival (PFS) and overall survival (OS) analyses with datasets from clinical trial D0818C00002, SOLO-2, the ongoing randomized double-blind, placebo-controlled, multi-center trial to assess the efficacy of olaparib maintenance monotherapy in relapsed high grade serous ovarian cancer (HGSOC) patients (including patients with primary peritoneal and / or fallopian tube cancer) or high grade endometrioid cancer with BRCA mutations (documented mutation in BRCA1 or BRCA2 that is predicted to be deleterious or suspected deleterious (known or predicted to be detrimental/lead to loss of function)) who have responded following platinum based chemotherapy. PMR Schedule Milestones: Interim Report (PFS analysis) Trial Completion Date: Final Report Submission (OS analysis): 02/2016 12/2018 03/2019 1. During application review, explain why this issue is appropriate for a PMR/PMC instead of a pre-approval requirement. Check type below and describe. Unmet need Life-threatening condition Long-term data needed Only feasible to conduct post-approval Prior clinical experience indicates safety Small subpopulation affected Theoretical concern Other Olaparib is being approved under subpart H (accelerated approval); therefore confirmatory trials are needed to confirm safety and efficacy in the proposed population: advanced, relapsed gBRCAm associated ovarian cancer. These patients have a serious and life-threatening condition with an unmet need for better therapies. 2. Describe the particular review issue and the goal of the study/clinical trial. If the study/clinical trial is a FDAAA PMR, describe the risk. If the FDAAA PMR is created post-approval, describe the “new safety information.” N/A PMR/PMC Development Template Reference ID: 3670063 Last Updated 12/9/2014 Page 1 of 3 3. If the study/clinical trial is a PMR, check the applicable regulation. If not a PMR, skip to 4. - Which regulation? Accelerated Approval (subpart H/E) Animal Efficacy Rule Pediatric Research Equity Act FDAAA required safety study/clinical trial - If the PMR is a FDAAA safety study/clinical trial, does it: (check all that apply) Assess a known serious risk related to the use of the drug? Assess signals of serious risk related to the use of the drug? Identify an unexpected serious risk when available data indicate the potential for a serious risk? - If the PMR is a FDAAA safety study/clinical trial, will it be conducted as: Analysis of spontaneous postmarketing adverse events? Do not select the above study/clinical trial type if: such an analysis will not be sufficient to assess or identify a serious risk Analysis using pharmacovigilance system? Do not select the above study/clinical trial type if: the new pharmacovigilance system that the FDA is required to establish under section 505(k)(3) has not yet been established and is thus not sufficient to assess this known serious risk, or has been established but is nevertheless not sufficient to assess or identify a serious risk Study: all other investigations, such as investigations in humans that are not clinical trials as defined below (e.g., observational epidemiologic studies), animal studies, and laboratory experiments? Do not select the above study type if: a study will not be sufficient to identify or assess a serious risk Clinical trial: any prospective investigation in which the sponsor or investigator determines the method of assigning investigational product or other interventions to one or more human subjects? 4. What type of study or clinical trial is required or agreed upon (describe and check type below)? If the study or trial will be performed in a subpopulation, list here. Randomized double-blind, placebo-controlled, multi-center study to assess the efficacy of olaparib maintenance monotherapy in relapsed high grade serous ovarian cancer (HGSOC) patients (including patients with primary peritoneal and / or fallopian tube cancer) or high grade endometrioid cancer with BRCA mutations (documented mutation in BRCA1 or BRCA2 that is predicted to be deleterious or suspected deleterious (known or predicted to be detrimental/lead to loss of function)) who have responded following platinum based chemotherapy (Study D0818C00002, SOLO-2). Required (PMRs) Observational pharmacoepidemiologic study Registry studies Primary safety study or clinical trial Pharmacogenetic or pharmacogenomic study or clinical trial if required to further assess safety Thorough Q-T clinical trial Nonclinical (animal) safety study (e.g., carcinogenicity, reproductive toxicology) Nonclinical study (laboratory resistance, receptor affinity, quality study related to safety) PMR/PMC Development Template Reference ID: 3670063 Last Updated 12/9/2014 Page 2 of 3 Pharmacokinetic studies or clinical trials Drug interaction or bioavailability studies or clinical trials Dosing trials Continuation of Question 4 Additional data or analysis required for a previously submitted or expected study/clinical trial (provide explanation) Meta-analysis or pooled analysis of previous studies/clinical trials Immunogenicity as a marker of safety Other (provide explanation) Agreed upon (PMCs): Quality study without a safety endpoint (e.g., manufacturing, stability) Pharmacoepidemiologic study not related to safe drug use (e.g., natural history of disease, background rates of adverse events) Clinical trials primarily designed to further define efficacy (e.g., in another condition, different disease severity, or subgroup) that are NOT required under Subpart H/E Dose-response study or clinical trial performed for effectiveness Nonclinical study, not safety-related (specify) Other 5. Is the PMR/PMC clear, feasible, and appropriate? Does the study/clinical trial meet criteria for PMRs or PMCs? Are the objectives clear from the description of the PMR/PMC? Has the applicant adequately justified the choice of schedule milestone dates? Has the applicant had sufficient time to review the PMRs/PMCs, ask questions, determine feasibility, and contribute to the development process? Check if this form describes a FDAAA PMR that is a randomized controlled clinical trial If so, does the clinical trial meet the following criteria? There is a significant question about the public health risks of an approved drug There is not enough existing information to assess these risks Information cannot be gained through a different kind of investigation The trial will be appropriately designed to answer question about a drug’s efficacy and safety, and The trial will emphasize risk minimization for participants as the protocol is developed PMR/PMC Development Coordinator: This PMR/PMC has been reviewed for clarity and consistency, and is necessary to further refine the safety, efficacy, or optimal use of a drug, or to ensure consistency and reliability of drug quality. _______________________________________ (signature line for BLAs) PMR/PMC Development Template Reference ID: 3670063 Last Updated 12/9/2014 Page 3 of 3 PMR/PMC Development Template This template should be completed by the PMR/PMC Development Coordinator and included for each PMR/PMC in the Action Package. NDA# Product Name: 206162 Lynparza (Olapraib) 50 mg Capsules PMR 2824-2 Description: Submit the progression free survival (PFS) and overall survival (OS) analyses with datasets from clinical trial D0816C00010, a randomized trial establishing the superiority of olaparib over physician’s choice single agent chemotherapy in the treatment of platinum sensitive relapsed ovarian cancer in patients carrying deleterious or suspected deleterious germline BRCA1/2 mutations. PMR Schedule Milestones: Interim Report (PFS analysis) Trial Completion Date: Final Report Submission (OS analysis): 06/2018 03/2020 06/2020 1. During application review, explain why this issue is appropriate for a PMR/PMC instead of a pre-approval requirement. Check type below and describe. Unmet need Life-threatening condition Long-term data needed Only feasible to conduct post-approval Prior clinical experience indicates safety Small subpopulation affected Theoretical concern Other Olaparib is being approved under subpart H (accelerated approval); therefore confirmatory trials are needed to confirm safety and efficacy in the proposed population: advanced, relapsed gBRCAm associated ovarian cancer. These patients have a serious and life-threatening condition with an unmet need for better therapies. 2. Describe the particular review issue and the goal of the study/clinical trial. If the study/clinical trial is a FDAAA PMR, describe the risk. If the FDAAA PMR is created post-approval, describe the “new safety information.” N/A PMR/PMC Development Template Reference ID: 3670063 Last Updated 12/9/2014 Page 1 of 3 3. If the study/clinical trial is a PMR, check the applicable regulation. If not a PMR, skip to 4. - Which regulation? Accelerated Approval (subpart H/E) Animal Efficacy Rule Pediatric Research Equity Act FDAAA required safety study/clinical trial - If the PMR is a FDAAA safety study/clinical trial, does it: (check all that apply) Assess a known serious risk related to the use of the drug? Assess signals of serious risk related to the use of the drug? Identify an unexpected serious risk when available data indicate the potential for a serious risk? - If the PMR is a FDAAA safety study/clinical trial, will it be conducted as: Analysis of spontaneous postmarketing adverse events? Do not select the above study/clinical trial type if: such an analysis will not be sufficient to assess or identify a serious risk Analysis using pharmacovigilance system? Do not select the above study/clinical trial type if: the new pharmacovigilance system that the FDA is required to establish under section 505(k)(3) has not yet been established and is thus not sufficient to assess this known serious risk, or has been established but is nevertheless not sufficient to assess or identify a serious risk Study: all other investigations, such as investigations in humans that are not clinical trials as defined below (e.g., observational epidemiologic studies), animal studies, and laboratory experiments? Do not select the above study type if: a study will not be sufficient to identify or assess a serious risk Clinical trial: any prospective investigation in which the sponsor or investigator determines the method of assigning investigational product or other interventions to one or more human subjects? 4. What type of study or clinical trial is required or agreed upon (describe and check type below)? If the study or trial will be performed in a subpopulation, list here. Randomized study establishing the superiority of olaparib over physician’s choice single agent chemotherapy in the treatment of platinum sensitive relapsed ovarian cancer in patients carrying deleterious or suspected deleterious germline BRCA1/2 mutations (Study D0816C00010) Required (PMRs) Observational pharmacoepidemiologic study Registry studies Primary safety study or clinical trial Pharmacogenetic or pharmacogenomic study or clinical trial if required to further assess safety Thorough Q-T clinical trial Nonclinical (animal) safety study (e.g., carcinogenicity, reproductive toxicology) Nonclinical study (laboratory resistance, receptor affinity, quality study related to safety) Pharmacokinetic studies or clinical trials Drug interaction or bioavailability studies or clinical trials Dosing trials PMR/PMC Development Template Reference ID: 3670063 Last Updated 12/9/2014 Page 2 of 3 Continuation of Question 4 Additional data or analysis required for a previously submitted or expected study/clinical trial (provide explanation) Meta-analysis or pooled analysis of previous studies/clinical trials Immunogenicity as a marker of safety Other (provide explanation) Agreed upon (PMCs): Quality study without a safety endpoint (e.g., manufacturing, stability) Pharmacoepidemiologic study not related to safe drug use (e.g., natural history of disease, background rates of adverse events) Clinical trials primarily designed to further define efficacy (e.g., in another condition, different disease severity, or subgroup) that are NOT required under Subpart H/E Dose-response study or clinical trial performed for effectiveness Nonclinical study, not safety-related (specify) Other 5. Is the PMR/PMC clear, feasible, and appropriate? Does the study/clinical trial meet criteria for PMRs or PMCs? Are the objectives clear from the description of the PMR/PMC? Has the applicant adequately justified the choice of schedule milestone dates? Has the applicant had sufficient time to review the PMRs/PMCs, ask questions, determine feasibility, and contribute to the development process? Check if this form describes a FDAAA PMR that is a randomized controlled clinical trial If so, does the clinical trial meet the following criteria? There is a significant question about the public health risks of an approved drug There is not enough existing information to assess these risks Information cannot be gained through a different kind of investigation The trial will be appropriately designed to answer question about a drug’s efficacy and safety, and The trial will emphasize risk minimization for participants as the protocol is developed PMR/PMC Development Coordinator: This PMR/PMC has been reviewed for clarity and consistency, and is necessary to further refine the safety, efficacy, or optimal use of a drug, or to ensure consistency and reliability of drug quality. _______________________________________ (signature line for BLAs) PMR/PMC Development Template Reference ID: 3670063 Last Updated 12/9/2014 Page 3 of 3 PMR/PMC Development Template This template should be completed by the PMR/PMC Development Coordinator and included for each PMR/PMC in the Action Package. NDA# Product Name: 206162 Lynparza (Olapraib) 50 mg Capsules PMR 2824-3 Description: Collect and analyze all cases of Acute Myelogenous Leukemia / Myelodysplastic Syndrome identified in patients treated with Lynparza (olaparib) on an annual basis. These interim reports should summarize all cases identified up until that reporting date (new cases and those reported in previous years), and should include patients treated with Lynparza on clinical trials and outside of clinical trials (including spontaneous safety reports) to provide an accurate assessment of the long-term incidence and risk of AML/MDS. PMR Schedule Milestones: Final Report Submission: Other: Interim Report #1 Interim Report #2 Interim Report #3 Interim Report #4 Interim Report #5 06/2020 12/2015 12/2016 12/2017 12/2018 12/2019 1. During application review, explain why this issue is appropriate for a PMR/PMC instead of a pre-approval requirement. Check type below and describe. Unmet need Life-threatening condition Long-term data needed Only feasible to conduct post-approval Prior clinical experience indicates safety Small subpopulation affected Theoretical concern Other There have been 21 confirmed cases of AML or MDS in the submitted Lynparza (olaparib) database, to date. However, the risk for the development of these events persists for years, even after discontinuation of olaparib therapy. We propose that the Sponsor submits annual updates to the NDA, summarizing new cases of AML or MDS, for 5 years after NDA approval. Each update should include detailed descriptions of each new patient diagnosed with MDS/AML, including the underlying cancer for which they received olaparib, previous chemotherapy and radiation therapy received, dose and regimen of olaparib received, duration of therapy with olaparib, exact timing of the diagnosis with regard to olaparib therapy (eg, if during therapy or after discontinuation). Details on bone marrow cytology, blast percent, cytogenetics, and flow cytometry should also be given. Finally, the Sponsor should describe any therapy administered to each patient for the treatment of MDS/AML, and should report the ultimate outcome for each patient (eg, event ongoing at the time of the report or death, including the exact date and cause of death). PMR/PMC Development Template Reference ID: 3670063 Last Updated 12/9/2014 Page 1 of 4 2. Describe the particular review issue and the goal of the study/clinical trial. If the study/clinical trial is a FDAAA PMR, describe the risk. If the FDAAA PMR is created post-approval, describe the “new safety information.” The goal of continued monitoring of all patients receiving olaparib therapy after NDA approval is to better understand the incidence of this adverse event (MDS/AML) in relation to olaparib therapy. It will also help to improve physicians’ ability to counsel their patients on the possibility of this event, as well as to effectively monitor patients for this event. 3. If the study/clinical trial is a PMR, check the applicable regulation. If not a PMR, skip to 4. - Which regulation? Accelerated Approval (subpart H/E) Animal Efficacy Rule Pediatric Research Equity Act FDAAA required safety study/clinical trial - If the PMR is a FDAAA safety study/clinical trial, does it: (check all that apply) Assess a known serious risk related to the use of the drug? Assess signals of serious risk related to the use of the drug? Identify an unexpected serious risk when available data indicate the potential for a serious risk? - If the PMR is a FDAAA safety study/clinical trial, will it be conducted as: Analysis of spontaneous postmarketing adverse events? Do not select the above study/clinical trial type if: such an analysis will not be sufficient to assess or identify a serious risk Analysis using pharmacovigilance system? Do not select the above study/clinical trial type if: the new pharmacovigilance system that the FDA is required to establish under section 505(k)(3) has not yet been established and is thus not sufficient to assess this known serious risk, or has been established but is nevertheless not sufficient to assess or identify a serious risk Study: all other investigations, such as investigations in humans that are not clinical trials as defined below (e.g., observational epidemiologic studies), animal studies, and laboratory experiments? Do not select the above study type if: a study will not be sufficient to identify or assess a serious risk Clinical trial: any prospective investigation in which the sponsor or investigator determines the method of assigning investigational product or other interventions to one or more human subjects? 4. What type of study or clinical trial is required or agreed upon (describe and check type below)? If the study or trial will be performed in a subpopulation, list here. The goal of continued monitoring of all patients receiving olaparib therapy after NDA approval is to better understand the incidence of this adverse event (MDS/AML) in relation to olaparib therapy. It will also help to improve physicians’ ability to counsel their patients on the possibility of this event, as well as to effectively monitor patients for this event. PMR/PMC Development Template Reference ID: 3670063 Last Updated 12/9/2014 Page 2 of 4 Required (PMRs) Observational pharmacoepidemiologic study Registry studies Primary safety study or clinical trial Pharmacogenetic or pharmacogenomic study or clinical trial if required to further assess safety Thorough Q-T clinical trial Nonclinical (animal) safety study (e.g., carcinogenicity, reproductive toxicology) Nonclinical study (laboratory resistance, receptor affinity, quality study related to safety) Pharmacokinetic studies or clinical trials Drug interaction or bioavailability studies or clinical trials Dosing trials Continuation of Question 4 Additional data or analysis required for a previously submitted or expected study/clinical trial (provide explanation) The annual updates should include analyses of patients treated in all new, ongoing, and completed trials with olaparib, as well as patients receiving olaparib outside of clinical trials. Meta-analysis or pooled analysis of previous studies/clinical trials Immunogenicity as a marker of safety Other (provide explanation) Agreed upon (PMCs): Quality study without a safety endpoint (e.g., manufacturing, stability) Pharmacoepidemiologic study not related to safe drug use (e.g., natural history of disease, background rates of adverse events) Clinical trials primarily designed to further define efficacy (e.g., in another condition, different disease severity, or subgroup) that are NOT required under Subpart H/E Dose-response study or clinical trial performed for effectiveness Nonclinical study, not safety-related (specify) Other 5. Is the PMR/PMC clear, feasible, and appropriate? Does the clinical trial meet criteria for PMRs or PMCs? Are the objectives clear from the description of the PMR/PMC? Has the applicant adequately justified the choice of schedule milestone dates? Has the applicant had sufficient time to review the PMRs/PMCs, ask questions, determine feasibility, and contribute to the development process? Check if this form describes a FDAAA PMR that is a randomized controlled clinical trial If so, does the clinical trial meet the following criteria? There is a significant question about the public health risks of an approved drug There is not enough existing information to assess these risks Information cannot be gained through a different kind of investigation The trial will be appropriately designed to answer question about a drug’s efficacy and safety, and PMR/PMC Development Template Reference ID: 3670063 Last Updated 12/9/2014 Page 3 of 4 The trial will emphasize risk minimization for participants as the protocol is developed PMR/PMC Development Coordinator: This PMR/PMC has been reviewed for clarity and consistency, and is necessary to further refine the safety, efficacy, or optimal use of a drug, or to ensure consistency and reliability of drug quality. _______________________________________ (signature line for BLAs) PMR/PMC Development Template Reference ID: 3670063 Last Updated 12/9/2014 Page 4 of 4 PMR/PMC Development Template This template should be completed by the PMR/PMC Development Coordinator and included for each PMR/PMC in the Action Package. NDA# Product Name: 206162 PMR 2824-4 Description: Submit the final report for trial D0816C00006 entitled, “An Open-label, Nonrandomized, Multicenter, Comparative, and Phase I Study of the Pharmacokinetics, Safety and Tolerability of Olaparib Following a Single Oral 300 mg Dose to Patients with Advanced Solid Tumors and Normal Renal Function or Renal Impairment”. LYNPARZA, Olaparib capsules,50 mg PMR Schedule Milestones: Interim report (planned primary PK analysis): Trial Completion: Final Report Submission: Other: 09/2015 08/2016 11/2016 1. During application review, explain why this issue is appropriate for a PMR/PMC instead of a pre-approval requirement. Check type below and describe. Unmet need Life-threatening condition Long-term data needed Only feasible to conduct post-approval Prior clinical experience indicates safety Small subpopulation affected Theoretical concern Other About 44% of olaparib (15% unchanged) is eliminated in urine. Increased olaparib exposures (plasma concentrations) may be seen in patients with renal impairment. A clinical trial evaluating olaparib in patients with varying levels of renal impairment is currently ongoing. The final report is required to allow for informative labeling recommendations including possible dose adjustments in patients with varying levels of renal impairment. 2. Describe the particular review issue and the goal of the study/clinical trial. If the study/clinical trial is a FDAAA PMR, describe the risk. If the FDAAA PMR is created post-approval, describe the “new safety information.” Increased olaparib exposures may be seen in patients with renal impairment. Increased olaparib exposure would likely result in increases in toxicities such as anemia and fatigue. Results of the renal impairment trial will allow for informative labeling recommendations including possible dose adjustments in patients with varying levels of renal impairment. PMR/PMC Development Template Reference ID: 3670063 Last Updated 12/11/2014 Page 1 of 3 3. If the study/clinical trial is a PMR, check the applicable regulation. If not a PMR, skip to 4. - Which regulation? Accelerated Approval (subpart H/E) Animal Efficacy Rule Pediatric Research Equity Act FDAAA required safety study/clinical trial - If the PMR is a FDAAA safety study/clinical trial, does it: (check all that apply) Assess a known serious risk related to the use of the drug? Assess signals of serious risk related to the use of the drug? Identify an unexpected serious risk when available data indicate the potential for a serious risk? - If the PMR is a FDAAA safety study/clinical trial, will it be conducted as: Analysis of spontaneous postmarketing adverse events? Do not select the above study/clinical trial type if: such an analysis will not be sufficient to assess or identify a serious risk Analysis using pharmacovigilance system? Do not select the above study/clinical trial type if: the new pharmacovigilance system that the FDA is required to establish under section 505(k)(3) has not yet been established and is thus not sufficient to assess this known serious risk, or has been established but is nevertheless not sufficient to assess or identify a serious risk Study: all other investigations, such as investigations in humans that are not clinical trials as defined below (e.g., observational epidemiologic studies), animal studies, and laboratory experiments? Do not select the above study type if: a study will not be sufficient to identify or assess a serious risk Clinical trial: any prospective investigation in which the sponsor or investigator determines the method of assigning investigational product or other interventions to one or more human subjects? 4. What type of study or clinical trial is required or agreed upon (describe and check type below)? If the study or trial will be performed in a subpopulation, list here. This trial is an open-label, non-randomized, multicenter, comparative, phase 1 trial to determine the pharmacokinetics of olaparib in patients with advanced solid tumors and normal renal function or mild or moderate renal impairment. Required Observational pharmacoepidemiologic study Registry studies Primary safety study or clinical trial Pharmacogenetic or pharmacogenomic study or clinical trial if required to further assess safety Thorough Q-T clinical trial Nonclinical (animal) safety study (e.g., carcinogenicity, reproductive toxicology) Nonclinical study (laboratory resistance, receptor affinity, quality study related to safety) Pharmacokinetic studies or clinical trials Drug interaction or bioavailability studies or clinical trials Dosing trials PMR/PMC Development Template Reference ID: 3670063 Last Updated 12/11/2014 Page 2 of 3 Continuation of Question 4 Additional data or analysis required for a previously submitted or expected study/clinical trial (provide explanation) Meta-analysis or pooled analysis of previous studies/clinical trials Immunogenicity as a marker of safety Other (provide explanation) Agreed upon: Quality study without a safety endpoint (e.g., manufacturing, stability) Pharmacoepidemiologic study not related to safe drug use (e.g., natural history of disease, background rates of adverse events) Clinical trials primarily designed to further define efficacy (e.g., in another condition, different disease severity, or subgroup) that are NOT required under Subpart H/E Dose-response study or clinical trial performed for effectiveness Nonclinical study, not safety-related (specify) Other 5. Is the PMR/PMC clear, feasible, and appropriate? Does the study/clinical trial meet criteria for PMRs or PMCs? Are the objectives clear from the description of the PMR/PMC? Has the applicant adequately justified the choice of schedule milestone dates? Has the applicant had sufficient time to review the PMRs/PMCs, ask questions, determine feasibility, and contribute to the development process? Check if this form describes a FDAAA PMR that is a randomized controlled clinical trial If so, does the clinical trial meet the following criteria? There is a significant question about the public health risks of an approved drug There is not enough existing information to assess these risks Information cannot be gained through a different kind of investigation The trial will be appropriately designed to answer question about a drug’s efficacy and safety, and The trial will emphasize risk minimization for participants as the protocol is developed PMR/PMC Development Coordinator: This PMR/PMC has been reviewed for clarity and consistency, and is necessary to further refine the safety, efficacy, or optimal use of a drug, or to ensure consistency and reliability of drug quality. _______________________________________ (signature line for BLAs) PMR/PMC Development Template Reference ID: 3670063 Last Updated 12/11/2014 Page 3 of 3 PMR/PMC Development Template This template should be completed by the PMR/PMC Development Coordinator and included for each PMR/PMC in the Action Package. NDA# Product Name: 206162 PMR 2824-5 Description: Submit the final report for trial D0816C00005 entitled, “An Open-label, Nonrandomized, Multicenter, Comparative, Phase I Study to Determine the Pharmacokinetics, Safety and Tolerability of Olaparib Following a Single Oral 300 mg Dose to Patients with Advanced Solid Tumors and Normal Hepatic Function or Mild or Moderate Hepatic Impairment.” LYNPARZA, Olaparib capsules,50 mg PMR Schedule Milestones: Interim report (planned primary PK analysis): Trial Completion: Final Report Submission: Other: 09/2015 08/2016 11/2016 1. During application review, explain why this issue is appropriate for a PMR/PMC instead of a pre-approval requirement. Check type below and describe. Unmet need Life-threatening condition Long-term data needed Only feasible to conduct post-approval Prior clinical experience indicates safety Small subpopulation affected Theoretical concern Other Olaparib is extensively metabolized in the liver. Increased olaparib exposures (plasma concentrations) are likely to be seen in patients with hepatic impairment. A clinical trial evaluating olaparib in patients with varying levels of hepatic impairment is currently ongoing. The final report is required to allow for informative labeling recommendations including possible dose adjustments in patients with varying levels of hepatic impairment. 2. Describe the particular review issue and the goal of the study/clinical trial. If the study/clinical trial is a FDAAA PMR, describe the risk. If the FDAAA PMR is created post-approval, describe the “new safety information.” Increased olaparib exposures are likely to be seen in patients with hepatic impairment. Increased olaparib exposure would likely result in increases in toxicities such as anemia and fatigue. Results of the hepatic impairment trial will allow for informative labeling recommendations including possible dose adjustments in patients with varying levels of hepatic impairment. PMR/PMC Development Template Reference ID: 3670063 Last Updated 12/11/2014 Page 1 of 3 3. If the study/clinical trial is a PMR, check the applicable regulation. If not a PMR, skip to 4. - Which regulation? Accelerated Approval (subpart H/E) Animal Efficacy Rule Pediatric Research Equity Act FDAAA required safety study/clinical trial - If the PMR is a FDAAA safety study/clinical trial, does it: (check all that apply) Assess a known serious risk related to the use of the drug? Assess signals of serious risk related to the use of the drug? Identify an unexpected serious risk when available data indicate the potential for a serious risk? - If the PMR is a FDAAA safety study/clinical trial, will it be conducted as: Analysis of spontaneous postmarketing adverse events? Do not select the above study/clinical trial type if: such an analysis will not be sufficient to assess or identify a serious risk Analysis using pharmacovigilance system? Do not select the above study/clinical trial type if: the new pharmacovigilance system that the FDA is required to establish under section 505(k)(3) has not yet been established and is thus not sufficient to assess this known serious risk, or has been established but is nevertheless not sufficient to assess or identify a serious risk Study: all other investigations, such as investigations in humans that are not clinical trials as defined below (e.g., observational epidemiologic studies), animal studies, and laboratory experiments? Do not select the above study type if: a study will not be sufficient to identify or assess a serious risk Clinical trial: any prospective investigation in which the sponsor or investigator determines the method of assigning investigational product or other interventions to one or more human subjects? 4. What type of study or clinical trial is required or agreed upon (describe and check type below)? If the study or trial will be performed in a subpopulation, list here. This trial is an open-label, non-randomized, multicenter, comparative, phase 1 study to determine the pharmacokinetics of olaparib in patients with advanced solid tumors and normal hepatic function or mild or moderate hepatic impairment. Required Observational pharmacoepidemiologic study Registry studies Primary safety study or clinical trial Pharmacogenetic or pharmacogenomic study or clinical trial if required to further assess safety Thorough Q-T clinical trial Nonclinical (animal) safety study (e.g., carcinogenicity, reproductive toxicology) Nonclinical study (laboratory resistance, receptor affinity, quality study related to safety) Pharmacokinetic studies or clinical trials Drug interaction or bioavailability studies or clinical trials Dosing trials PMR/PMC Development Template Reference ID: 3670063 Last Updated 12/11/2014 Page 2 of 3 Continuation of Question 4 Additional data or analysis required for a previously submitted or expected study/clinical trial (provide explanation) Meta-analysis or pooled analysis of previous studies/clinical trials Immunogenicity as a marker of safety Other (provide explanation) Agreed upon: Quality study without a safety endpoint (e.g., manufacturing, stability) Pharmacoepidemiologic study not related to safe drug use (e.g., natural history of disease, background rates of adverse events) Clinical trials primarily designed to further define efficacy (e.g., in another condition, different disease severity, or subgroup) that are NOT required under Subpart H/E Dose-response study or clinical trial performed for effectiveness Nonclinical study, not safety-related (specify) Other 5. Is the PMR/PMC clear, feasible, and appropriate? Does the study/clinical trial meet criteria for PMRs or PMCs? Are the objectives clear from the description of the PMR/PMC? Has the applicant adequately justified the choice of schedule milestone dates? Has the applicant had sufficient time to review the PMRs/PMCs, ask questions, determine feasibility, and contribute to the development process? Check if this form describes a FDAAA PMR that is a randomized controlled clinical trial If so, does the clinical trial meet the following criteria? There is a significant question about the public health risks of an approved drug There is not enough existing information to assess these risks Information cannot be gained through a different kind of investigation The trial will be appropriately designed to answer question about a drug’s efficacy and safety, and The trial will emphasize risk minimization for participants as the protocol is developed PMR/PMC Development Coordinator: This PMR/PMC has been reviewed for clarity and consistency, and is necessary to further refine the safety, efficacy, or optimal use of a drug, or to ensure consistency and reliability of drug quality. _______________________________________ (signature line for BLAs) PMR/PMC Development Template Reference ID: 3670063 Last Updated 12/11/2014 Page 3 of 3 PMR/PMC Development Template This template should be completed by the PMR/PMC Development Coordinator and included for each PMR/PMC in the Action Package. NDA# Product Name: 206162 Lynparza (Olapraib) 50 mg Capsules PMC 2824-6 Description: Conduct a stability study with the process validation batches (minimum of 3): ICH primary stability testing to the submitted NDA specifications (acceptance (b) (4) criteria, analytical method) for the commercial product, including up to end of expiry. PMC Schedule Milestones: Study Completion: Final Report Submission: Other: First Interim Report (includes 6 months of data) Second Interim Report (includes 12 months of data) 02/2017 04/2017 11/2015 05/2016 1. During application review, explain why this issue is appropriate for a PMR/PMC instead of a pre-approval requirement. Check type below and describe. Unmet need Life-threatening condition Long-term data needed Only feasible to conduct post-approval Prior clinical experience indicates safety Small subpopulation affected Theoretical concern Other The applicant provided insufficient data in the NDA to confirm stability to the end of expiry for the (b) (4) attribute of in the drug product. 2. Describe the particular review issue and the goal of the study/clinical trial. If the study/clinical trial is a FDAAA PMR, describe the risk. If the FDAAA PMR is created post-approval, describe the “new safety information.” (b) (4) Review issue: Insufficient characterization of in the drug product to demonstrate stability to ensure that the efficacy in the commercial product is comparable to that observed in the clinical product. Goal of study: Provide stability data, through to end of expiry, from a controlled ICH primary stability (b) (4) study conducted on the commercial product to demonstrate stability of in olaparib capsules. PMR/PMC Development Template Reference ID: 3670063 Last Updated 12/11/2014 Page 1 of 3 3. If the study/clinical trial is a PMR, check the applicable regulation. If not a PMR, skip to 4. - Which regulation? Accelerated Approval (subpart H/E) Animal Efficacy Rule Pediatric Research Equity Act FDAAA required safety study/clinical trial - If the PMR is a FDAAA safety study/clinical trial, does it: (check all that apply) Assess a known serious risk related to the use of the drug? Assess signals of serious risk related to the use of the drug? Identify an unexpected serious risk when available data indicate the potential for a serious risk? - If the PMR is a FDAAA safety study/clinical trial, will it be conducted as: Analysis of spontaneous postmarketing adverse events? Do not select the above study/clinical trial type if: such an analysis will not be sufficient to assess or identify a serious risk Analysis using pharmacovigilance system? Do not select the above study/clinical trial type if: the new pharmacovigilance system that the FDA is required to establish under section 505(k)(3) has not yet been established and is thus not sufficient to assess this known serious risk, or has been established but is nevertheless not sufficient to assess or identify a serious risk Study: all other investigations, such as investigations in humans that are not clinical trials as defined below (e.g., observational epidemiologic studies), animal studies, and laboratory experiments? Do not select the above study type if: a study will not be sufficient to identify or assess a serious risk Clinical trial: any prospective investigation in which the sponsor or investigator determines the method of assigning investigational product or other interventions to one or more human subjects? 4. What type of study or clinical trial is required or agreed upon (describe and check type below)? If the study or trial will be performed in a subpopulation, list here. A stability study with the process validation batches (minimum of 3): specifically, ICH primary stability testing to the submitted NDA specifications (acceptance criteria, analytical method) for (b) (4) the commercial product, including up to end of expiry. Required (PMRs) Observational pharmacoepidemiologic study Registry studies Primary safety study or clinical trial Pharmacogenetic or pharmacogenomic study or clinical trial if required to further assess safety Thorough Q-T clinical trial Nonclinical (animal) safety study (e.g., carcinogenicity, reproductive toxicology) Nonclinical study (laboratory resistance, receptor affinity, quality study related to safety) Pharmacokinetic studies or clinical trials Drug interaction or bioavailability studies or clinical trials Dosing trials PMR/PMC Development Template Reference ID: 3670063 Last Updated 12/11/2014 Page 2 of 3 Continuation of Question 4 Additional data or analysis required for a previously submitted or expected study/clinical trial (provide explanation) Meta-analysis or pooled analysis of previous studies/clinical trials Immunogenicity as a marker of safety Other (provide explanation) Agreed upon (PMCs): Quality study without a safety endpoint (e.g., manufacturing, stability) Pharmacoepidemiologic study not related to safe drug use (e.g., natural history of disease, background rates of adverse events) Clinical trials primarily designed to further define efficacy (e.g., in another condition, different disease severity, or subgroup) that are NOT required under Subpart H/E Dose-response study or clinical trial performed for effectiveness Nonclinical study, not safety-related (specify) Other 5. Is the PMR/PMC clear, feasible, and appropriate? Does the study/clinical trial meet criteria for PMRs or PMCs? Are the objectives clear from the description of the PMR/PMC? Has the applicant adequately justified the choice of schedule milestone dates? Has the applicant had sufficient time to review the PMRs/PMCs, ask questions, determine feasibility, and contribute to the development process? Check if this form describes a FDAAA PMR that is a randomized controlled clinical trial If so, does the clinical trial meet the following criteria? There is a significant question about the public health risks of an approved drug There is not enough existing information to assess these risks Information cannot be gained through a different kind of investigation The trial will be appropriately designed to answer question about a drug’s efficacy and safety, and The trial will emphasize risk minimization for participants as the protocol is developed PMR/PMC Development Coordinator: This PMR/PMC has been reviewed for clarity and consistency, and is necessary to further refine the safety, efficacy, or optimal use of a drug, or to ensure consistency and reliability of drug quality. _______________________________________ (signature line for BLAs) PMR/PMC Development Template Reference ID: 3670063 Last Updated 12/11/2014 Page 3 of 3 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------SUSAN JENNEY 12/11/2014 KATHERINE M FEDENKO 12/11/2014 Reference ID: 3670063 Interdisciplinary Review Team for QT Studies Consultation: Thorough QT Study Review NDA 206162 Brand Name To be determined Generic Name Olaparib Sponsor AstraZeneca Indication Ovarian cancer Dosage Form Capsules (50 mg) Drug Class PARP (poly ADP ribose polymerase) inhibitor Therapeutic Dosing Regimen 400 mg bd (capsule formulation) (eight 50 mg capsules) Duration of Therapeutic Use Chronic Maximum Tolerated Dose 400 mg bd (capsule formulation) Submission Number and Date SDN 041 / 2014 01 31 Review Division Division of Oncology Products 1 Note: Any text in the review with a light background should be inferred as copied from the sponsor’s document. 1 SUMMARY 1.1 OVERALL SUMMARY OF FINDINGS The sponsor submitted pooled QT/CTc data from two studies, namely, D0816C00004 and D0816C00007, which investigated the effect of food and itraconazole on the pharmacokinetics of olaparib. No large change (i.e., > 20 ms) in the QTc interval was detected when olaparib was administered up to 300 mg b.i.d. The study did not include positive control (moxifloxacin) arms. Both studies consisted of Part A and Part B. Part A of D0816C00004 is a randomized, open-label, two-treatment, two-period crossover study whereas Part A of D0816C00007 is a randomized, open-label study. Part B is an open-label study in the patients who completed in Part A. In Part A, study D0816C00004 received a single oral dose of olaparib tablets 300 mg in each of the two treatment periods (once in the overnight fasted state and once immediately following a high-fat meal) and study D0816C00007 received a single oral dose of olaparib 100 mg and a single oral dose of olaparib 100 mg administered concomitantly with itraconazole. In Part B, subjects received olaparib 300 mg twice daily (bd) in 2 studies. 1 Reference ID: 3658957 A total of 119 subjects (60 and 59 in studies D0816C00004 and D0816C00007, respectively) completed in part A and a total of 109 subjects (56 and 53 in studies D0816C00004 and D0816C00007, respectively) completed in Part B. Overall summary of findings are presented in Table 1. Table 1: The Point Estimates and the 90% CIs Corresponding to the Largest Upper Bounds for Olaparib up to 300 mg BID (FDA Analysis) Study Treatment D0816C00004 D0816C00007 Time (hour) Mean Std Dev 90% CI (ms) Olaparib 300 mg + (Fasted) (Part A) 2 3.1 10.8 (0.8, 5.5) Olaparib 300 mg + (High Fat) (Part A) 8 2.2 11.9 (-0.5, 4.8) Olaparib 300 mg BID (Part B) 4 -0.4 13.3 (-3.5, 2.7) Olaparib 100 mg + Fasted (Part A) 3 3.1 13.7 (0.1, 6.2) Olaparib 100 mg + Itraconazole (Part A) 4 4.1 15.9 (0.6, 7.7) Olaparib 300 mg BID (Part B) 1.5 0.8 14.5 (-2.7, 4.3) The mean drug concentration-time profile is illustrated in Figure 2. The PK results are presented in Table 25. Observed Cmax in this study (following administration of 300 bid [tablet]) is expected to be higher than following the intended clinical dose of 400 mg bid (capsule). Sponsor does, however, not disclose how much higher. Co-administration with itraconazole increased mean Cmax by about 40%. It is not known if the exposure following 300-mg tablets bid will result in lower or higher exposure compared to what is expected following itraconazole and 400 mg bid (capsules) coadministration. Hepatic impairment may decrease olaparib clearance. However, exposure data in patients with hepatic impairment is not available. Although it is possible that patients with hepatic impairment and or concomitant CYP3A4 inhibitors will be exposed to higher olaparib concentrations than those studied here, considering the indication; this reviewer agrees with applicant’s conclusion that no clinically relevant effect of olaparib on the QT interval after multiple dosing of 300 mg is observed. 2 PROPOSED LABEL The sponsor did propose any labelling language related to clinical QT assessment. 2 Reference ID: 3658957 QT-IRT’s proposed labeling language is a suggestion only. We defer final labeling decisions to the Division. 12.6 Cardiac Electrophysiology The effect of Tradename on the QTc interval was evaluated in a pooled study in 119 patients with solid tumors. No large changes in the mean QT interval (i.e., >20 ms) were detected in the study at the therapeutic drug exposure. 3 BACKGROUND 3.1 PRODUCT INFORMATION Olaparib is a novel oral PARP inhibitor that exploits deficiencies in DNA repair pathways to preferentially kill cancer cells. An orphan drug designation was granted by the FDA for ovarian cancer on 16 October, 2013. 3.2 MARKET APPROVAL STATUS Olaparib is not approved for marketing in any country. 3.3 PRECLINICAL INFORMATION The effect of olaparib on the hERG-encoded potassium channel was investigated in hERG-expressing Chinese Hamster Ovary (CHO) cells. In this assay, olaparib had an IC50 of 226 μM (95% confidence interval 193 to 266). Source: Nonclinical Written Summary – Pharmacology, page 24 Intravenous administration of the test article KU0059436, at doses of 1.5 and 5 mg/kg appeared to have no noticeable effects on the cardiovascular or respiratory parameters of anaesthetized dogs when compared with a vehicle control group. A higher dose of the test article (15 mg/kg) elicited a slight increase in heart rate. However, this increase in heart rate was not statistically significant compared with the vehicle treated group. Source: Study report for 2229/053, page 29 3 Reference ID: 3658957 3.4 PREVIOUS CLINICAL EXPERIENCE Table 2 summarizes the estimated number of subjects treated with the proposed product and the proposed regiment in sponsor’s studies. Table 2: Number of patients exposed to olaparib 400 mg bd monotherapy Source: Summary of clinical safety, Table 1, page 36 3.5 CLINICAL PHARMACOLOGY Appendix 6.1 summarizes the key features of olaparib’s clinical pharmacology. 4 SPONSOR’S SUBMISSION 4.1 OVERVIEW The QT-IRT reviewed the protocol prior to conducting this study under IND 75918. The sponsor submitted pooled QT/CTc data from two studies (Studies D0816C00004 and 4 Reference ID: 3658957 D0816C00007) . The sponsor submitted the study report for olaparib, including electronic datasets and waveforms to the ECG warehouse. 4.2 TQT STUDY 4.2.1 Title Final report on the Statistical Analysis of the pooled QT/QTc data from Studies D0816C00004 and D0816C00007 4.2.2 Protocol Number D0816C00007 and D0816C00004 4.2.3 Study Dates The last patients in studies D0816C00004 and D0816C00007 completed Part B on 01 April 2014 and 26 April 2014 respectively 4.2.4 Objectives D0816C00004 Part A To determine the effect of food on the pharmacokinetics of olaparib and the effect of olaparib on QT interval following a single oral dose of olaparib tablets. Part B To determine the effect of olaparib on the QT interval following multiple oral dosing of olaparib tablets. Part C To provided additional safety data collection. D0816C00007 Part A To assess the effect of itraconazole, a cytochrome P450 3A4 (CYP3A4) inhibitor, on the PK parameters of olaparib and determine the effect of olaparib on the QT interval following single oral dosing Part B To determine the effect of olaparib on the QT Interval following multiple oral dosing. Part C To provided additional safety data collection. 4.2.5 Study Description 4.2.5.1 Design 5 Reference ID: 3658957 D0816C00004 Part A This was a randomised, open-label, two-treatment period crossover design. Each patient received a single oral dose of olaparib tablets 300 mg in each of the two treatment periods (once in the overnight fasted state and once immediately following a high-fat meal), with at least 5 and no more than 14 days (washout) between doses. D0816C00007 Part A This was a non-randomised, open-label, two-treatment design. Patients received the following 2 study treatments: a single oral dose of olaparib alone (tablet formulation), and a single oral dose of olaparib administered concomitantly with itraconazole. A lower 100 mg single dose of olaparib was chosen for this study to protect the patients against higher exposures of olaparib due to the anticipated inhibitory effect of itraconazole. D0816C00004 and D0816C00007 Part B Part B in both studies was an open-label study in the same patients who participated in Part A. Upon completion of Part A, providing the patient continued to meet the study inclusion and exclusion criteria, and following a washout period of at least 7 days (5 days in Study D0816C00004) and no more than 14 days between the last dose in Part A and Day -1 of Part B), each patient received olaparib 300 mg twice daily (bd) for 5 days. 4.2.5.2 Controls No placebo or positive (moxifloxacin) control arms. 4.2.5.3 Blinding All arms and were open label. 4.2.6 Treatment Regimen 4.2.6.1 Treatment Arms D0816C00004    Olaparib 300 mg + (Fasted) (Part A) Olaparib 300 mg + (High Fat) (Part A) Olaparib 300 mg bid (Part B) D0816C00007    Olaparib 100 mg + fasted (Part A) Olaparib 100 mg + itraconazole (Part A) Olaparib 300 mg bid (Part B) 4.2.6.2 Sponsor’s Justification for Doses A lower 100mg single dose of olaparib was chosen for this study to protect the patients against higher exposures of olaparib due to the anticipated inhibitory effect of itraconazole. 6 Reference ID: 3658957 The 300mg bd dose was selected to assess the effect of multiple doses on the QT effect because this is the maximum tolerated dose (MTD) for the tablet formulation and is also the Phase III tablet dose. Reviewer’s Comment: The dose and formulation in this trial (300-mg tablets) is not the same as the proposed to be marketed dose and formulation (400-mg capsules). However, the applicant claims in their clinical overview (section 3.3.2 page 49) that the 300-mg bid tablet results in mean steady state exposures higher than those following a 400-mg bid capsule. Considering the indication, this reviewer agrees with applicant’s dose justification. 4.2.6.3 Instructions with Regard to Meals Data was obtained following both fasted and fed administration. Reviewer’s Comment: This is acceptable. 4.2.6.4 ECG and PK Assessments Pharmacokinetic samples were collected as defined in Table 3 while ECG was collected as defined in Table 4. Reviewer’s Comment: Acceptable. The sampling schedule is able to capture the effect at the peak concentrations and potential delayed effect up to 24 hours. 7 Reference ID: 3658957 Table 3: PK Schedule, Study D0816C00004 (upper) D0816C00007 (lower) Sourse: C-QT pharmacometric report 5.3.5.3. Tables 1 and 2. 8 Reference ID: 3658957 Table 4: dECG Schedule, Study D0816C00004 (upper) D0816C00007 (lower) Sourse: C-QT pharmacometric report 5.3.5.3. Tables 3 and 4. 4.2.6.5 Baseline Baseline is defined as the pre-dose measurement taken on the same day that the post-dose measurements are taken. 4.2.7 ECG Collection Intensive 12-Lead Holter monitoring will be used to obtain digital ECGs. Standard 12Lead ECGs will be obtained while subjects are recumbent. 4.2.8 Sponsor’s Results 4.2.8.1 Study Subjects There were 80 patients enrolled into study D0816C00004 where 60 patients were dosed and completed Part A and 56 patients completed Part B. Study D0816C00007 had enrolled 83 patients with 59 patients dosed and completed Part A and 53 completed Part B. This brings a total of 119 patients in the pooled data for QT/QTc analysis for Part A and 109 patients for Part B. 9 Reference ID: 3658957 4.2.8.2 Statistical Analyses 4.2.8.2.1 Primary Analysis The primary endpoints for both studies were changes from baseline in QTcF. D0816C00004: For Part A (fed), the highest mean increase from baseline in QTcF (mean [SD]) was 0.8 (10.38) ms which occurred at 30 minutes post-dose . A mean increase was also noted at 2 hours post-dose (0.6 [9.73) ms). For Part A (fasted), mean increases from baseline in QTcF were observed at 30 minutes, 1 hour, 1 hour 30 minutes, 2 hours, 3 hours, 4 hours, and 12 hours post-dose, with the maximum mean increase for the fasted treatment condition occurring at 1 hour and 30 minutes post-dose (7.3 [9.84] ms). For Part B, mean increases from baseline in QTcF were observed at 1 hour, 1 hour 30 minutes, 2 hours, 3 hours, and 4 hours post-dose, with the maximum mean increases occurring at 1 hour and 30 minutes post-dose (4.1 [8.83] ms), and 3 hours post-dose (4.1 [10.88] ms). Table 5: Summary of descriptive statistics for change from baseline for ECG variables: QTcF (D0816C00004) 10 Reference ID: 3658957 Frideriea?s Correction Formula (ms) Result Change (postibaseline) Treatment Time point [1 Mean SD Min Median Max [1 Mean SD Min Median Max 4 Hour Post Dose 56 413.5 14.67 386 413.0 465 55 -0.8 9.30 -27 0.0 19 6Hour Post Dose 56 411.1 16.70 360 413.0 463 55 -2.0 10.60 -26 0.0 21 8 Hour Post Dose 56 411.0 18.96 344 413.5 478 55 -2.0 11.14 -29 -3.0 31 12 Hour Post Dose 56 410.1 18.43 349 409.0 471 55 -3.5 10.09 -34 -3.0 17 24 Hour Post Dose 43 406.7 19.08 361 406.0 476 42 -4.9 11.97 44 -3.5 16 Tasted (A) Pre-dose 59 413.2 19.60 352 413.0 455 30 mins Post Dose 59 416.3 18.02 377 414.0 473 59 3.1 11.03 -16 2.0 36 1 Hour Post Dose 58 418.7 19.29 355 416.5 477 58 5.8 9.70 -14 5.0 32 1 Hour 30 mins Post 59 420.5 19.35 348 419.0 471 59 7.3 9.84 -14 5.0 27 Dose 2 Hour Post Dose 59 419.8 18.18 363 420.0 474 59 6.7 10.63 -16 6.0 32 3 Hour Post Dose 57 418.9 17.80 360 419.0 474 57 5.9 9.89 -22 5.0 32 4Hour Post Dose 57 418.3 18.13 369 419.0 470 57 5.3 13.37 -41 5.0 41 6 Hour Post Dose 56 411.9 17.69 376 411.5 486 56 -0.8 14.62 -24 -1.0 34 8 Hour Post Dose 55 409.7 16.47 371 410.0 462 55 -2.6 12.77 -35 -3.0 27 12 Hour Post Dose 53 413.6 19.50 363 412.0 478 53 0.7 11.98 -26 2.0 30 24 Hour Post Dose 47 410.0 18.56 370 412.0 470 47 -3.5 13.67 42 -3.0 26 Total: SD standard deviation. For each treatment. baseline (pie-dose) was de?ned as the pre-dose 111eas1u?e111e11t taken on the same day that the post-dose 111easure111e11ts were taken. Only scheduled time points are Frideriea?s Correction Formula (ms) Result Change [post?baseline) Treatment Time point [1 Mean SD Min Median Max [1 Mean SD Min Median Max Day-1 (B) Pre-dose 54 414.6 18.50 357 412.5 476 1 Hour Post Dose 53 418.1 17.23 378 417.0 480 53 3.8 9.42 -13 3.0 28 1 Hour 30 mins Post 53 417.9 17.31 385 416.0 486 53 3.6 9.34 -12 3.0 28 Dose 2 Hour Post Dose 53 417.9 17.25 375 416.0 476 53 3.6 9.83 -25 4.0 26 3 Hour Post Dose 53 416.4 17.95 353 415.0 483 53 2.1 8.73 -15 1.0 20 4 Hour Post Dose 53 416.0 19.09 363 415.0 483 53 1.7 9.51 -27 2.0 22 6 Hour Post Dose 54 411.0 18.92 348 408.0 482 54 -3.6 9.93 -33 -4.0 16 8 Hour Post Dose 54 409.5 18.76 337 409.0 471 54 -5.1 10.09 -26 -5.0 26 12 Hour Post Dose 49 412.5 19.76 345 413.0 472 49 -2.8 12.48 -23 -4.0 40 Olaparib Pre-dose 54 412.7 18.30 349 414Hour Post Dose 54 414.7 20.48 356 414.0 475 54 2.0 8.06 -17 3.0 24 1 Hour 30 mins Post 54 416.8 21.30 342 415.5 474 54 4.1 8.83 -22 3.5 23 Dose 2 Hour Post Dose 54 416.4 20.71 338 414.0 472 54 3.6 9.89 -23 5.0 23 3 Hour Post Dose 54 416.9 20.90 344 418.5 475 54 4.1 10.88 -26 3.0 27 4 Hour Post Dose 54 416.6 20.01 339 414.5 475 54 3.9 10.10 -18 2.0 27 6 Hour Post Dose 53 408.0 17.31 348 408.0 435 53 -4.0 8.73 -19 -5.0 14 11 Reference ID: 3658957 D0816C00007: For study D0816C00007, all patients who had at least 1 evaluable time-matched QT/QTc interval value at a scheduled time point, time-matched between Day -1 (baseline) and Day 1, and Day -1 (baseline) and Day 9 for Part A, and time matched between Day -1 (baseline) and Day 5 for Part B. For the olaparib alone dosing period of Part A, a mean increase from baseline in QTcF (mean [SD]) of 2.3 (7.31) ms occurred at 2 hours post-dose (Table 24). Smaller increases were also noted at 1 hour, 1 hour and thirty minutes, 3 hours and 4 hours post-dose. For the olaparib + itraconazole dosing period of Part A, mean increases from baseline in QTcF were observed at 30 minutes, 1 hour, 1 hour and thirty minutes, 2 hours, 3 hours, and 4 hours post-dose, with the maximum mean increase occurring at 2 hours post-dose (2.8 [7.20] ms). For Part B, mean increases from baseline in QTcF were observed at 1 hour, 1 hour and 30 minutes, 2 hours, and 3 hours post-dose, with the maximum mean increase occurring at 1 hour and 30 minutes post-dose (3.1 [8.90] ms). 12 Reference ID: 3658957 Table 6: Summary of descriptive statistics for change from baseline for ECG variables: QTcF (D0816C00007) 13 Reference ID: 3658957 Fridel'ica?s Correction Formula (ms) Result Change (post?baseline) Treatment Time point Mean SD Min Median Max 11 Mean SD Min Median Max 4 Hour Post Dose 5? 418.? 1?.63 368 418.0 456 5? 0.1 9.94 -29 1.0 1? 6 Hour Post Dose 5? 414.3 16.61 3?2 414.0 458 5? -4.3 11.69 -35 -3.0 18 8 Hour Post Dose 5? 412.5 1?.36 3?0 410.0 451 5? -6.1 10.42 -6.0 14 12 Hour Post Dose 5? 416.? 15.92 366 418.0 451 5? -1.9 10.08 -30 -3.0 1? 24 Hour Post Dose 50 412.1 16.58 3?1 413.5 44? 50 -6.9 11.90 -28 -5.0 19 Olaparib Pre-dose 5? 419.2 18.46 3?3 420.0 459 Itraconazole (A) 30 111i11s Post Dose 5? 420.1 18.20 3?1 420.0 45? 56 0.5 6.0? -19 0.0 14 1 Hour Post Dose 5.8 420.9 18.?8 36? 421.0 463 5? 6.58 -14 2.0 1? 1 Hour 30 1111115 5? 421.9 19.18 3?5 422.0 465 56 2.1 ".50 -19 2.5 19 Post Dose 2 Hour Post Dose 5? 422 2 18.50 3?4 422.0 468 56 2.8 ?.20 -11 2.5 22 3 Hour Post Dose 58 421.0 19.?9 362 422.0 454 5? 8.9? 2.0 21 4 Hour Post Dose 58 420.0 19.6? 3?5 421.0 463 5? 9.01 -19 .0 19 6 Hour Post Dose 5? 412." 18.39 365 414.0 463 56 -6.2 10.29 -30 -55 22 8 Hour Post Dose 5? 412.4 19.?3 360 414.0 460 56 -6.4 10.06 -30 -5.0 15 12 Hour Post Dose 56 415.1 19.55 363 415 5 45? 55 -4.8 10.34 -29 -5.0 21 24 Hour Post Dose 51 413 3 1?.94 3?3 411 0 445 50 10.28 -31 -8.0 16 14 Reference ID: 3658957 Reviewer’s Comments: We will provide our independent analysis evaluating different heart rate corrections and provide statistical analysis results in Section 5.2. 4.2.8.2.2 Assay Sensitivity No assay sensitivity established because no moxifloxacin positive treatment arm provided. 4.2.8.2.3 Categorical Analysis Categorical analysis was used to summarize in the categories of QTc ≤450 ms, between 450 ms and 480 ms, between 480 ms and 500 ms, and >500 ms, and changes from baseline QTc ≤30 ms, between 30 and 60 ms, and >60 ms. No subject’s absolute QTc > 500 ms and ΔQTc >60 ms. 15 Reference ID: 3658957 Table 7: Summary of QT and QTcF changes from baseline to last/any observation on treatment (D0816C00004) 16 Reference ID: 3658957 Table 8: Summary of QT and QTcF changes from baseline to last/any observation on treatment (D0816C00007) 4.2.8.3 Safety Analysis In study D0816C00004, a total of 52 (86.7%) patients in Part A, and 41 (68.3%) patients in Part B experienced at least 1 AE, the majority of which were gastrointestinal in origin and of CTCAE grade 2 or lower. In Part A, 6 (10.0%) patients reported CTCAE grade 3 AEs, and 1 (1.7%) of these was an SAE. In Part B, 1 (1.7%) patient reported CTCAE grade 3 AEs and no serious adverse events (SAEs) were reported. There were no AEs leading to olaparib discontinuation during Parts A or B of the study. In study D0816C00007, a total of 42 (71.2%) patients in Part A and 34 (57.6%) of patients in Part B experienced at least 1 AE, again, the majority of which were gastrointestinal in origin and of CTCAE grade 2 or lower. In Part A, 7 (11.9%) patients reported CTCAE grade 3 AEs (2 (3.4%) in the olaparib alone treatment period and 5 (8.5%) in olaparib+itraconazole treatment period). There were 7 (11.9%) patients who reported SAEs (1 [1.7%] patient in olaparib alone and 6 [10.2%] in olaparib+itraconazole treatment periods respectively). In addition, 1 patient experienced an AE leading to discontinuation from the study. In Part B, 2 patients reported CTCAE grade 3 AEs, 2 SAEs were reported and 2 patients experienced an AE leading to discontinuation from the study. 17 Reference ID: 3658957 In study D0816C00004, there was one cardiovascular AE and in study D0816C00007, four cardiovascular AEs were reported:  Patient E2841005, a 60 year old male, reported an AE of grade 1 tachycardia during the fasted treatment period and not considered related to olaparib.  Patient E2071003, a 61 year old female, reported an AE of grade 3 atrial fibrillation from Day 3 to Day 4 of Part B of the study. The event was resolved after treatment with digoxin. The dose was not interrupted or changed and the AE was not considered by the investigator to be related to olaparib.  Patient E2875009, a 68 year old female, reported an AE of grade 1 tachycardia during Part B of the study, 29 days from the first dose of olaparib in Part A. The event was ongoing and not considered by the investigator to be related to olaparib. This patient discontinued the study drug due to an AE of grade 3 INR increase (from 1.1 at baseline to 4.8 on Day 5 of Part B) which was not considered by the investigator to be related to olaparib. At the highest INR level, the patient had received 2 single doses of olaparib and 1 week of itraconazole (completed Part A). The patient was on tinzaparin since the beginning of the trial for past history of pulmonary embolus. The INR increase was considered related to the disease under progression in addition to anticoagulant medication from baseline. The patient did not finish continuous dosing on Part B Day 1 due to anaemia and increased INR. The tachycardia and increased INR happened as part of the same illness (urinary tract infection), and the patient reported AEs of dehydration, pyrexia, hypokalaemia and hyponatreamia during this period as well.  Patient E2875010, a 57 year old female, reported an AE of grade 1 first degree atrioventricular block as well as grade 1 sinus bradycardia on Day 10 of the olaparib + itraconazole dosing period of Part A. These events were not considered by the investigator to be related to olaparib.  Patient E5071003, a 71 year old female, reported an AE of grade 3 cardiac failure on Day 29 during Part B which was not recovered/resolved and led to discontinuation of olaparib. The patient also reported an SAE of pneumonia on Day 21 during Part B of the study that resulted in hospitalization, and interruption of olaparib. Dyspnoea persisted in spite of treatment with antibiotics, and a decreased left ventricular ejection fraction (35%) was observed on an echocardiogram. Olaparib causality could not be ruled out, and therefore these events were considered by the investigator to be related to olaparib. 4.2.8.4 Clinical Pharmacology 4.2.8.4.1 Pharmacokinetic Analysis 18 Reference ID: 3658957 The sponsor has not submitted PK results from the two submitted studies. A tabulated summary of selected exposure parameters and a figure of the concentration-time profiles are shown in reviewer’s analysis. 4.2.8.4.2 Exposure-Response Analysis The applicant has submitted a separate exposure response analysis report (C-QT pharmacomtetric report). The data was analysed as an overall pool and separately for the two individual studies. Analyses of Study 4 or Study 7 individually demonstrated no direct effect of olapari b on ΔQTcF and on ΔQTcI. In the pooled analysis of ΔQTcF, the relationship with olaparib plasma concentration was best described by a linear model with a coefficient of 0.238, indicating only a small change in Fridericia corrected interval for every μg/ml change in olaparib plasma concentration. In the pooled analysis of ΔQTcI, the relationship with olaparib plasma concentration was best described by the baseline value and a log-linear model of the olaparib plasma concentration with a value of 0.86 for the rate of change in QTcI as the natural logarithm of the olaparib concentration increased. Sponsor concludes that ΔQTcF and ΔQTcI does not increase to a clinically significant level, Table 9. Table 9: Prediction of ΔQTcF (upper) and ΔQTcI (lower) at the geometric mean Cmax 19 Reference ID: 3658957 Sourse C-QT pharmacometric report, page 7 and 8. Reviewer’s comments: Sponsor’s analysis is appropriate and the reviewer agrees with the conclusions. An independent analysis is presented below. 5 REVIEWERS’ ASSESSMENT 5.1 EVALUATION OF THE QT/RR CORRECTION METHOD We used the criterion of Mean Sum of Squared Slopes (MSSS) from individual regressions of QTc versus RR. The smaller this value is, the better the correction. Based on the results listed in Table 10, it appears that QTcI is better than QTcB and QTcF. To be consistent with the sponsor’s analyses, this reviewer used QTcF for the primary statistical analysis. Table 10: Average of Sum of Squared Slopes for Different QT-RR Correction Methods Study D0816C00004 QTcB Treatment Group QTcF QTcI N MSSS N MSSS N MSSS Olaparib 300 mg + (Fasted) (Part A) 59 0.00491 59 0.00614 59 0.00416 Olaparib 300 mg + (High Fat) (Part A) 59 0.00861 59 0.00519 59 0.00485 Olaparib 300 mg BID (Part B) 54 0.00521 54 0.00924 54 0.00535 All 60 0.00433 60 0.00547 60 0.00319 20 Reference ID: 3658957 Table 11: Average of Sum of Squared Slopes for Different QT-RR Correction Methods Study D0816C00007 QTcB QTcF QTcI Treatment Group N MSSS N MSSS N MSSS Olaparib 100 mg + Fasted (Part A) 58 0.00536 58 0.00452 58 0.00452 Olaparib 100 mg + Itraconazole (Part A) 58 0.00510 58 0.00670 58 0.00541 Olaparib 300 mg bd (Part B) 50 0.00651 50 0.00812 50 0.00694 All 59 0.00779 59 0.00915 59 0.00660 The relationship between different correction methods and RR is presented in Figure 1. Figure 1: QT, QTcB, QTcF, and QTcI vs. RR (Each Subject’s Data Points are Connected with a Line) 5.2 STATISTICAL ASSESSMENTS 5.2.1 QTc Analysis 5.2.1.1 The Primary Analysis for the Study Drug The primary endpoint is change from the baseline of QTcF. The descriptive statistics are listed in Table 12 and Table 13. For study D0816C00004, the largest upper bounds of the 2-sided 90% CI for the mean differences for olaparib 300 mg + fasted, olaparib 300 mg + high fat, and olaparib 300 mg b.i.d. are 5.5 ms, 4.8 ms and 2.7 ms, respectively. 21 Reference ID: 3658957 For study D0816C00007, the largest upper b01mds of the 2-sided 90% CI for the mean differences for olaparib 100 mg fasted, olaparib 100 mg itraconazole and olaparib 300 mg b.i.d. are 6.2 ms, 7.7 ms and 4.3 ms, respectively. Table 12: Analysis Results of for Olaparib 300 mg BID Study D0816C00004 90% CI for Treatment Time Mean Dev Mean Olaparib 300 mg+(Fasted) (Pan A) 0.5 59 -0.5 11.9 (-3.1.2.1) 1 57 1.4 11.2 (-1.1. 3.9) 1.5 59 2.2 10.9 (-0.2. 4.6) 59 3.1 10.8 (0.8. 5.5) 2 3 57 1.7 11.2 (08.42) 4 57 2.2 11.6 (-0.4.4.7) 6 8 54 1.2 12.0 3.9) 54 1.4 12.9 4.3) 12 52 -1.8 9.9 (-4.1. 0.5) 24 47 -1.1 12.0 (-4.0. 1.8) Olapan'b 300 mg (High Fat) (Part A) 0.5 56 -2.8 12.1 (-5.5. -0.1) 1 54 -5.0 10.7 (-7.5. -2.6) 1.5 57 -8.4 10.7 (-10.8. -6.0) 2 56 -3.1 12.4 (-5.9. -0.3) 3 56 -5.0 11.6 (-7.6. -2.4) 4 56 -3.5 10.6 (-5.8. -1.1) 6 8 55 0.0 10.3 (-2.3. 2.4) 56 2.2 11.9 (-0.5. 4.8) 12 55 -4.5 10.6 (-6.9. -2.1) 24 42 -2.2 13.4 (-5.6. 1.3) Olaparib 300 mg BID (Part B) 1 52 45 11.6 (-7.2. -1.8) 1.5 52 -2.0 12.3 (-4.8. 0.9) 2 52 -2.3 11.9 (-5.1. 0.5) 3 52 -0.6 11.1 (-3.2. 2.0) 4 52 -0.4 13.3 (-3.5. 2.7) 6 8 52 -1.9 11.3 (-4.5. 0.7) 52 -3.1 10.1 (-5.5. -0.8) 12 48 -6.1 8.6 (-8.2. -4.0) Reference ID: 3658957 Table 13: Analysis Results of of olaparib 300 mg BID Study D0816C00007 90% CI for Treatment Time Mean Dev Mean Olaparib 100 mg Fasted(Pa11 A) 0.5 57 -1.3 9.6 (-3.5. 0.8) 1 57 0.6 13.2 (-2.3. 3.6) 1.5 56 0.8 11.4 3.3) 2 56 2.7 10.0 (0.5.5.0) 3 56 3.1 13.7 (0.1. 6.2) 4 56 2.9 12.1 (0.2.5.6) 6 54 1.1 10.6 (-1.3. 3.5) 8 54 0.3 10.3 (-2.1. 2.6) 12 52 -0.1 11.0 (-2.6. 2.5) 24 49 -4.5 10.9 (-7.1. -1.9) Olaparib 100 mg Itraconazole (Part A) 0.5 56 0.3 10.4 (-2.0. 2.6) 1 57 1.9 12.3 (-0.8. 4.7) 1.5 56 2.8 11.7 (0.2. 5.4) 2 56 3.3 10.7 (1.0. 5.7) 3 57 3.9 14.5 (0.7. 7.1) 4 57 4.1 15.9 (0.6. 7.7) 6 54 0.1 12.3 (-2.7. 2.9) 8 54 0.5 14.2 (-2.8. 3.7) 12 50 -2.0 15.0 (-5.5. 1.6) 24 50 -5.1 12.0 (-8.0. -2.3) Olaparib 300 mg BID (Part B) 1 48 -1.1 14.6 (-4.6. 2.5) 1.5 48 0.8 14.5 (-2.7. 4.3) 2 49 0.6 13.8 (-2.7. 3.9) 3 48 0.4 13.9 (-3.0. 3.8) 4 49 0.2 14.7 (-3.3. 3.7) 6 49 0.5 12.2 (-2.5. 3.4) 8 48 -4.1 12.7 (-7.2. -1.1) 12 38 -0.5 9.8 (-3.2. 2.1) 5.2.1.1 Assay Sensitivity Analysis No assay sensitivity analysis established because no positive control aim included in the study. Reference ID: 3658957 23 5.2.1.2 Categorical Analysis Table 14 lists the nlunber of subjects as well as the nlunber of observations whose values are 450 ms, between 450 ms and 480 m, and between 480 ms and 500 ms. No subject?s is above 500 ms. Table 14: Categorical Analysis for 450 ms100 Study Treatment Group D0816C00004 Olaparib 300 mg (Fasted) (Part A) 59 51 8 Olaparib 300 mg (High Fat) (Part A) 58 47 11 Olaparib 300 mg BID (Part B) 54 42 12 D0816C00007 Olaparib 100 mg Fasted (Part A) 59 42 17 Olaparib 100 mg Itraconazole (Part A) 58 49 9 Olaparib 300 mg BID (Pan B) 52 39 13 5.2.3 PR Analysis The primary endpoint is change from the baseline of PR. The descriptive statistics are listed in Table 19 and Table 20. For study D0816C00004, the largest upper bounds of the 2-sided 90% CI for the mean differences for olaparib 300 mg fasted, olaparib 300 mg high fat, and olaparib 300 mg b.i.d. are 5.1 ms, 4.9 ms and 5.4 ms, respectively. For study D0816C 00007, the largest upper b01u1ds of the 2-sided 90% CI for the mean differences for olaparib 100 mg fasted, olaparib 100 mg itraconazole and olaparib 300 mg b.i.d. are 5.7 ms, 6.8 ms and 4.7 ms, respectively. Table 21 presents the categorical analysis of PR. Eighteen subjects and thilty subjects who expelienced PR interval greater than 200 ms are in studies D0816C00004 and D0816C00007, respectively. Reference ID: 3658957 27 Reference ID: 3658957 Table 19: Analysis Results of APR of Olaparib 300 mg BID Study D0816C00004 90% CI Treatment Time Mean Dev for Mean Olapan'b 300 mg (Fasted) (Part A) 0.5 58 -0.1 12.3 (-2.8. 2.6) 1 56 0.9 9.9 3.1) 1.5 58 2.5 11.9 (-0.1. 5.1) 2 58 1.7 10.7 (-0.6. 4.1) 3 56 2.5 11.6 (-0.1. 5.1) 4 56 0.7 9.5 (-1.4. 2.8) 6 54 0.0 12.2 (-2.8. 2.8) 8 53 1.2 10.4 (-1.1. 3.6) 12 51 -0.1 10.8 (-2.6. 2.5) 24 46 -3.1 16.3 (-7.1. 0.9) Olaparib 300 mg (High Fat) (Part A) 0.5 55 -5.6 10.9 (-8.1. -3.1) 1 54 -2.7 9.7 (-4.9. -0.5) 1.5 56 -2.6 9.2 (-4.7. -0.5) 2 55 -0.7 9.8 (-2.9. 1.5) 3 55 -1.3 9.3 (-3.4. 0.8) 4 56 -2.7 10.6 (-5.0. -0.3) 6 55 -0.4 11.4 (-2.9. 2.2) 8 55 2.2 12.0 (-0.5. 4.9) 12 54 0.7 10.1 (-1.6. 3.0) 24 41 -0.4 10.8 (-3.2. 2.4) Olaparib 300 mg BID (Part B) 1 50 1.4 8.2 (-0.6. 3.3) 1.5 50 1.0 10.0 3.3) 2 50 -0.3 13.0 (-3.4. 2.8) 3 51 0.9 10.2 (-1.5. 3.3) 4 51 2.8 11.0 (0.3. 5.4) 6 51 -1.1 10.7 (-3.6. 1.4) 8 51 -1.6 11.6 (43.11) 12 47 -0.8 8.8 (-2.9. 1.4) 28 Reference ID: 3658957 Table 20: Analysis Results of APR of Olaparib 300 mg BID Study D0816C00007 90% CI Treatment Time Mean Dev for Mean Olaparib 100 mg Fasted (Part A) 0.5 57 0.2 9.8 (-2.0. 2.3) 1 57 -0.6 10.6 (-3.0. 1.7) 1.5 57 1.7 9.3 (-0.3. 3.8) 2 56 3.0 12.0 (0.4. 5.7) 3 56 -0.3 13.5 (-3.4. 2.7) 4 56 2.2 11.3 (-0.4. 4.7) 6 54 -1.2 8.7 (-3.2. 0.7) 8 54 -0.1 10.6 (-2.5. 2.4) 12 52 -0.6 9.7 (-2.9. 1.7) 24 49 -4.8 8.8 (-6.9. -2.7) Olaparib 100 mg Itraconazole (Part A) 0.5 57 2.1 9.6 (-0.0. 4.3) 1 57 -0.2 11.1 (-2.6. 2.3) 1.5 57 4.1 10.2 (1.9. 6.4) 2 57 3.8 13.7 (0.8. 6.8) 3 57 2.6 11.8 (-0.0. 5.2) 4 57 2.9 10.2 (0.6. 5.2) 6 54 -1.6 11.3 (-4.1. 1.0) 8 54 -1.6 10.5 (-4.0. 0.8) 12 50 -1.3 14.5 (-4.7. 2.1) 24 50 -4.1 12.1 (-7.0. -1.2) Olaparib 300 mg BID (Part B) 1 48 1.2 13.0 (-2.0. 4.3) 1.5 48 -0.1 13.0 (-3.3. 3.0) 2 49 1.1 11.5 (-1.7. 3.9) 3 48 -0.2 11.9 (-3.1. 2.6) 4 49 -0.5 10.4 (-3.0. 2.0) 6 49 -0.0 11.3 (-2.7. 2.7) 8 48 -0.2 9.8 (-2.5. 2.2) 12 38 1.4 12.1 (-1.9. 4.7) 29 Table 21: Categorical Analysis for PR Study Treatment Group PR 200 ms PR >200 ms D0816C00004 Olaparib 300 mg (Fasted) (Part A) 58 53 5 Olaparib 300 mg (High Fat) (Part A) 57 52 5 Olaparib 300 mg BID (Part B) 53 45 8 D0816C00007 Olaparib 100 mg Fasted (Part A) 59 49 10 Olaparib 100 mg Itraconazole (Part A) 58 48 10 Olaparib 300 mg BID (Part B) 52 42 10 5.2.4 QRS Analysis The primary endpoint is change from the baseline of QRS. The descriptive statistics are listed in Table 22 and Table 23. For study the largest upper bounds of the 2-sided 90% CI for the mean differences for olaparib 300 mg fasted, olaparib 300 mg high fat, and olaparib 300 mg b.i.d. are 2.6 ms, 1.6 ms and 1.4 ms, respectively. For study D0816C 00007, the largest upper b01mds of the 2-sided 90% I for the mean differences for olaparib 100 mg fasted, olaparib 100 mg itraconazole and olaparib 300 mg b.i.d. are 1.8 ms, 1.8 ms and 1.6 ms, respectively. Table 24 presents the categorical analysis of QRS. Six subjects and three subjects who experienced QRS interval greater than 110 ms are in studies D0816C00004 and D0816C00007, respectively. Reference ID: 3658957 30 Reference ID: 3658957 Table 22: Analysis Results of AQRS of Olaparib 300 mg BID Study D0816C00004 90% CI for Treatment Time Mean Dev Mean Olapan'b 300 mg (Fasted) (Pan A) 0.5 59 0.3 4.2 (-0.7. 1.2) 1 57 -0.2 3.7 (-1.0. 0.7) 1.5 59 0.5 3.4 (-0.2. 1.3) 2 59 -0.5 3.5 (-1.2. 0.3) 3 57 0.0 4.3 (-0.9. 1.0) 4 57 0.8 3.9 (-0.1. 1.7) 6 54 1.5 4.7 (0.4. 2.6) 8 54 0.6 3.3 (-0.2. 1.4) 12 52 -0.3 3.2 0.5) 24 47 0.5 4.6 (-0.6. 1.6) Olaparib 300 mg (High Fat) (Part A) 0.5 56 0.6 3.9 (-0.3. 1.5) 1 55 0.7 3.5 (-0.1. 1.4) 1.5 57 0.6 4.2 (-0.3. 1.5) 2 56 0.3 2.4 (-0.2. 0.9) 3 56 -0.4 3.4 (-1.2. 0.3) 4 56 0.8 3.8 (-0.1. 1.6) 6 55 0.0 3.4 (-0.7. 0.8) 8 56 0.2 3.8 (-0.7. 1.1) 12 55 0.5 3.5 (-0.3. 1.3) 24 42 0.4 4.4 (-0.7. 1.5) Olaparib 300 mg BID (Part B) 1 52 0.2 3.8 (-0.7. 1.1) 1.5 52 0.6 3.8 (-0.3. 1.4) 2 52 -0.6 3.8 (-1.4. 0.3) 3 52 0.0 4.1 (-0.9. 0.9) 4 52 0.0 4.0 (-0.9. 1.0) 6 52 -0.3 3.9 0.6) 8 52 -0.4 2.9 12 48 -0.8 3.4 (-1.6. 0.0) 31 Table 23: Analysis Results of AQRS of Olaparib 300 mg BID Study D0816C00007 90% CI Treatment Time Mean Dev for Mean Olaparib 100 mg Fasted (Part A) 0.5 57 1.0 3.7 (0.1. 1.8) 1 57 -0.4 3.7 (-1.2.0.4) 1.5 56 -0.2 3.4 (-1.0.0.5) 56 -0.2 3.6 (-1.0.0.6) 56 -0.7 3.2 (-1.4.-0.0) 54 0.2 3.1 (05.09) 2 3 4 56 0.2 3.2 (05.09) 6 8 54 0.2 3.5 (061.0) 12 52 -0.5 5.0 (-1.7.0.6) 24 49 0.2 3.7 (07.11) Olaparib 100 mg Itraconazole (Part A) 0.5 56 0.8 4.7 (-0.3. 1.8) 1 57 0.2 4.0 (07.11) 1.5 56 0.7 3.6 (01.15) 57 0.4 3.7 (04.1.3) 57 0.2 4.1 (07.12) 54 0.2 4.6 (-O.8.1.0.9 3.2 (0.1.1.6) 12 50 -0.9 4.2 (-1.9.0.1) 24 50 0.4 3.3 (031.2) Olaparib 300 mg BID (Part B) 1 48 -l.2 4.5 (-2.3. -0.1) 1.5 48 0.4 4.6 (07.1.5) 49 0.2 3.3 (-0.6.1.0) 48 -0.3 4.4 (-1.3.0.8) 49 -0.1 3.3 (-0.9. 0.7) 2 3 4 49 0.0 4.0 (-1.0.1.0) 6 8 48 0.2 3.6 (07.11) 12 38 0.8 2.9 (0.0.1.6) Reference ID: 3658957 Table 24: Categorical Analysis for QRS Total QRS 110 QRS >110 Study Treatment Group ms [115 D0816C00004 Olaparib 300 mg (Fasted) (Part A) 59 57 2 Olaparib 300 mg (High Fat) (Part A) 58 56 2 Olaparib 300 mg BID (Part B) 54 52 2 D0816C00007 Olaparib 100 mg Fasted (Pan A) 59 58 1 Olaparib 100 mg Itraconazole (Part A) 58 57 1 Olaparib 300 mg BID (Part B) 52 51 1 5.3 CLINICAL PHARMACOLOGY ASSESSMENTS The mean diug concentration-time pro?le is illustrated in Figlu?e 2. The PK results are presented in Table 25. Cmax is expected to be higher following administration of 300 bid (tablet) compared with the intended clinical dose of 400 mg bid (capsule). Mean Serum Concentrations of olaparib (pg/mL) Reference ID: 3658957 Figure 2: Mean olaparib concentration-time pro?les Scum: and qtpk0004 .- Olaparib 300 mg (Fasted) (Part A) Olaparib 300 mg (High Fat) (Part A) I Olaparib 300 mg BID (Part B) - OLAPARIB 100MG FASTED (PART A) OLAPARIB 100MG ITRACONAZOLE (PART A) 9-6 OLAPARIB 300MG BID (PART B) Table 25: Estimated exposure parameter 33 Subjects D0816C00004/E2041002, D0816C00007/E5074005, and D0816C00004/E0542001 were excluded from the analysis. All concentrations are in unit: μg/mL Source: reviewer generated from qtpk0007 and qtpk0004 The relationship between ∆QTcI and pooled olaparib concentrations is visualized in Figure 3 with no evident exposure-response relationship. A linear mixed effect model with subject ID as random effect on intercept and slope was chosen as the final model based on -2LL and AIC. Slope was estimated to 0.21 (95%CI: [-0.03:0.43]). Confidence interval included 0 and was based on a non-parametric bootstrap with 1000 samples with replacement. 34 Reference ID: 3658957 Figure 3: ∆QTcI vs. olaparib concentration 5.4 CLINICAL ASSESSMENTS 5.4.1 Safety assessments None of the events identified to be of clinical importance per the ICH E 14 guidelines i.e. syncope, seizure, significant ventricular arrhythmias or sudden cardiac death occurred in this study. 5.4.2 ECG assessments Overall ECG acquisition and interpretation in this study appears acceptable. 5.4.3 PR and QRS Interval There was no clinically relevant effect seen on PR or QRS. 35 Reference ID: 3658957 6 APPENDIX 6.1 HIGHLIGHTS OF CLINICAL PHARMACOLOGY Therapeutic dose As monotlrerapy: 400 bd (capsule formulation) 300 mg bd (tablet formulation) Maximum tolerated dose As monotherapy: 400 mg bd (capsule formulation) 400 mg bd (tablet formulation) Principal adverse events As of 02 October 2013. approximately 2103 patients have received treatment with olaparib across the dose range (approximatelv 1214 patients as monotherapv). The maioritv of patients to date have received the capsule formulation of olaparib (an estimated 1635 patients). Approximately 468 patients have received the tablet formulation to date. The recommended monotherapv capsule dose is 400 mg bd. The recommended olaparib monotherapv tablet dose is 300 mg bd. Based on data from Phase I Study D0810C00024. the Iolerability pro?le of the 300 mg bd tablet dose is considered similar to the 400 mg bd capsule dose. Administration of olaparib monotherapy has been associated with reports of the following laboratory findings and'or clinical diagnoses. generally of mild or inudeiale se\ eiily Grade 1 or 2) and generally not requiring treatment! discontinuation: haematological effects (anaemia. neutropenia. tlrrombocytopenia. mean corpuscular volume elevation). decreased appetite. nausea and vomiting. diarrhoea. dyspepsia. stomatitis. abdominal pain. dysgeusia. fatigue (including asthenia). increase in blood creatinine. headache and dizziness. In addition in a small number of patients. (MDS):acute myeloid leukaemia (AML) events in patients with extensive previous exposure to chemotherapy and pneunronitis events with no consistent clinical pattern have also been reported Maximum dose tested Single Dose 600 mg (capsule formulation); 450 mg (tablet formulation) Multiple Dose 600mg bd (capsule fomrulation) continuous dosing: 450 mg bd (tablet formulation) continuous dosing Exposures Achieved at Single Dose apsule?: Maximum Tested Dose Mean Cm? 10.5 itg?mL Mean 68.7 ugh-1111. (53?o) Tablet": Mean Cm 10.8 uglmL Mean 51.2 ugh mL 36 Reference ID: 3658957 Range of linear PK Accumulation at steady state Metabolites Absorption Distribution Elimination Multiple Dose Capsule formulation: Tablet formulation: Capsule*: Mean Cmax 11.5 ugx?nlL (42? 0): Mean (9 AUCMZ 86.8 pglir?mL Tablet**: Mean (0 Cmax 10.4 (36? 0): Mean (0 AUCMZ 64.7 ugh/inL (22? 0) Oral doses 11p to 2 100 mg* Oral doses up to at least 450 mg** 1.53 (35?90) 011 twice daily dosing of the capsule at 400 111g bd* Not reported for tablet dosing** Circulating metabolites: 3 Each representing ~10?'o of circulating radioactivity and due to a) hydroxylation and opening of cyclopropyl ring: b) hydroxylation of ?uorine containing ring: c) dehydrogenation of piperazine ring Phaimacological activity: uirently untested Bioavailability tmax 0 bound Route Terminal ti/z Not determined For parent (post 400 111g capsule dosing) median (range) 1.72 11 (1 to 4)i For parent (post 300 111g tablet dosing) median (range) 1.5 (0.5 to Metabolites: undetelmined (14C tmax was simultaneous with parent (hug) Mean (0 210 (69? 0) (400 mg capsule dose) i Mean (0 146 (97? 0) (300 mg tablet dose) it 91% across a concentration range of0.1 to 1 uglian 81.9% at a concentration of 10 ugt?mL 35-50% dose eliminated Via renal route as unchanged 12-60?o dose eliminated Via faecal route (6-1490 as unchanged Mean (0 18.4 11 (38? 0) (400 mg capsule dose)? Mean (0 12.2 11 (44? 6) for parent (300 mg tablet dose) it Not determined for metabolites Reference ID: 3658957 37 Lf'l: Intrinsic Factors Age Sex Race Hepatic Renal Impainnent Extrinsic Factors Drug interactions Food Effects Mean (0 7.92 L111 (400 mg capsule dose)t Mean 7.95 th (5300) (300 111g tablet dose?t No evidence from population analysis that clearance changes with age Predominantly female population studied Predominantly Caucasian population studied Not yet studied o?adnn'nistration with itraconazole increased mean 1.42-fold (90? 1.33 1.52) and increased mean AUC 2.70-fold (900 2.44 2.97) o-adininistration with rifampicin decreased mean Cmby 71?26 (90?rbCI: 0.24 -0.33) and decreased mean AUC by 8790 0.11 0.16) For the capsule formulation co?administration with a high fat meal delayed tmax by approx 2 11. did not affect Cmax (TR 1.00: 90? 0.92 1.09) and increased mean AUC by 1990 (900 1.08 1.31) For the tablet fonnulation co-administration with a high fat meal delayed tmax by approx 2.5 11. reduced Cmax by 21% 0.72 0.86) and had little impact ofinean 1.08: 1.01 1.16) it Expected High Clinical o-administration with potent YP3A4 inhibitors ands?or in patients with Exposure Scenario hepatic dysfunction data taken from D0810C00002: data taken from D0810C00024: data taken from D08 10C 00010 data taken from D081AC0001: tidata taken from Reference ID: 3658957 38 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------DINKO REKIC 11/18/2014 JIANG LIU 11/18/2014 MOH JEE NG 11/18/2014 QIANYU DANG 11/18/2014 MICHAEL Y LI 11/18/2014 NORMAN L STOCKBRIDGE 11/18/2014 Reference ID: 3658957 Agency Memorandum Date: October 30, 2014 To: Rajesh Venugopal, RPM From: Subject: MEMORANDUM FOOD AND DRUG ADMINISTRATION Center for Drug Evaluation and Research Office of Prescription Drug Promotion (OPDP) Division of Oncology Products 1 (DOP1) Office of Hematology Oncology Products (OHOP) Marybeth Toscano, PharmD, RAC, Regulatory Review Of?cer Office of Prescription Drug Promotion (OPDP) OPDP comments on draft product labeling for Lynparza (olaparib) NDA 206162 In response to your consult request dated March 11, 2014, OPDP has reviewed the proposed product labeling (PI) for Lynparza. comments are based on the proposed, substantially complete version of the PI, sent to OPDP on October 24, 2014, available at the following link: \\cdsnas\t1?ansfer\DDOP RPM\Ra'esh e11u 206162 Ola a1?ib\Labels\S onsors Post ODAC Updated Labels 08.15.14\Package Insert OPDP provided verbal comments at the October 20, 2014, labeling meeting, and additionally, has the following comments: Section 14 CLINICAL STUDIES Statement from draft Deleterious or suspected deleterious, germline BRCA mutation status was veri?ed retrospectively by the companion diagnostic BRACAnaIysis which is FDA approved for selection of patients for LYN PARZA treatment, (4) Comment Does the device name speci?cally need to be mentioned in the Pl (not including a speci?c name may potentially help with future logistical issues, not needing to update the PI every time a new diagnostic device is approved/cleared)? Inclusion of the device name may raise some issues with respect to potential ?co-promotion,? especially since devices do not have the pre- submission requirement for Reference ID: 3651100  promotional materials as do drugs. Perhaps consider removing the word “companion”? (This qualifier seems unnecessary and makes it more “promotional”) If you have any questions, please contact Marybeth Toscano at 6-2617 or at Marybeth.Toscano@fda.hhs.gov. Reference ID: 3651100 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------MARYBETH TOSCANO 10/30/2014 Reference ID: 3651100 Department of Health and Human Services Public Health Service Food and Drug Administration Center for Drug Evaluation and Research Office of Medical Policy PATIENT LABELING REVIEW Date: October 28, 2014 To: Amna Ibrahim, MD Acting Director Division of Oncology Products 1 (DOP1) Through: LaShawn Griffiths, MSHS-PH, BSN, RN Associate Director for Patient Labeling Division of Medical Policy Programs (DMPP) Barbara Fuller, RN, MSN, CWOCN Team Leader, Patient Labeling Division of Medical Policy Programs (DMPP) From: Morgan Walker, PharmD, MBA Patient Labeling Reviewer Division of Medical Policy Programs (DMPP) Marybeth Toscano, Pharm D, RAC Regulatory Review Officer Office of Prescription Drug Promotion (OPDP) Subject: Review of Patient Labeling: Medication Guide (MG) Drug Name (established name) LYNPARZA (olaparib) Dosage Form and Route: Capsules, Oral Application Type/Number: NDA 206162 Applicant: AstraZeneca Reference ID: 3649830 1 INTRODUCTION On January 31, 2014, AstraZeneca submitted for the Agency’s review a New Drug Application (NDA) 206162 for LYNPARZA (olaparib) capsules with the proposed indication as monotherapy for the maintenance treatment of adult patients with platinum-sensitive relapsed ovarian cancer (including fallopian tube or primary peritoneal) with germline BRCA (gBRCA) mutation as detected by an FDAapproved test, who are in response (complete response or partial response) to platinum-based chemotherapy. This collaborative review is written by the Division of Medical Policy Programs (DMPP) and the Office of Prescription Drug Promotion (OPDP) in response to a request by the Division of Oncology Products 1 (DOP1) on March 11, 2014, for DMPP and OPDP to review the Applicant’s proposed Medication Guide (MG) for LYNPARZA (olaparib) capsules. 2 3 MATERIAL REVIEWED • Draft LYNPARZA (olaparib) MG received on January 31, 2014, revised by the Review Division throughout the review cycle, and received by DMPP and OPDP on October 15, 2014. • Draft LYNPARZA (olaparib) Prescribing Information (PI) received on January 31, 2014, further revised by the Applicant, revised by the Review Division throughout the review cycle, and received by DMPP and OPDP on October 24, 2014. REVIEW METHODS To enhance patient comprehension, materials should be written at a 6th to 8th grade reading level, and have a reading ease score of at least 60%. A reading ease score of 60% corresponds to an 8th grade reading level. In our review of the MG the target reading level is at or below an 8th grade level. Additionally, in 2008 the American Society of Consultant Pharmacists Foundation (ASCP) in collaboration with the American Foundation for the Blind (AFB) published Guidelines for Prescription Labeling and Consumer Medication Information for People with Vision Loss. The ASCP and AFB recommended using fonts such as Verdana, Arial or APHont to make medical information more accessible for patients with vision loss. We have reformatted the MG document using the Verdana font, size 11. In our collaborative review of the MG we have: • simplified wording and clarified concepts where possible • ensured that the MG is consistent with the Prescribing Information (PI) • removed unnecessary or redundant information • ensured that the MG is free of promotional language or suggested revisions to ensure that it is free of promotional language Reference ID: 3649830 4 • ensured that the MG meets the Regulations as specified in 21 CFR 208.20 • ensured that the MG meets the criteria as specified in FDA’s Guidance for Useful Written Consumer Medication Information (published July 2006) CONCLUSIONS The MG is acceptable with our recommended changes. 5 RECOMMENDATIONS • Please send these comments to the Applicant and copy DMPP and OPDP on the correspondence. • Our collaborative review of the MG is appended to this memorandum. Consult DMPP and OPDP regarding any additional revisions made to the PI to determine if corresponding revisions need to be made to the MG. Please let us know if you have any questions. 8 Page(s) of Draft Labeling have been Withheld in Full as b4 (CCI/TS) immediately following this page Reference ID: 3649830 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------MORGAN A WALKER 10/28/2014 MARYBETH TOSCANO 10/28/2014 BARBARA A FULLER 10/28/2014 LASHAWN M GRIFFITHS 10/29/2014 Reference ID: 3649830 LABEL AND LABELING REVIEW Division of Medication Error Prevention and Analysis (DMEPA) Office of Medication Error Prevention and Risk Management (OMEPRM) Office of Surveillance and Epidemiology (OSE) Center for Drug Evaluation and Research (CDER) *** This document contains proprietary information that cannot be released to the public*** Date of This Review: October 21, 2014 Requesting Office or Division: Division of Oncology Products I (DOP1) Application Type and Number: NDA 206162 Product Name and Strength: Lynparza (Olaparib) Capsules, 50 mg Product Type: Single Strength Product Rx or OTC: Rx Applicant/Sponsor Name: AstraZenaca Submission Date: May 9, 2014 and August 28, 2014 OSE RCM #: 2014-343 DMEPA Primary Reviewer: Davis Mathew, PharmD DMEPA Team Leader: Chi-Ming (Alice) Tu, PharmD 1 Reference ID: 3646174 1 REASON FOR REVIEW This review evaluates the proposed container labels, carton labeling and Prescribing Information (PI) for Lynparza capsules (NDA 206162) for areas of vulnerability that could lead to medication errors. 2 MATERIALS REVIEWED We considered the materials listed in Table 1 for this review. The Appendices provide the methods and results for each material reviewed. Table 1. Materials Considered for this Label and Labeling Review Material Reviewed Appendix Section (for Methods and Results) Product Information/Prescribing Information A FDA Adverse Event Reporting System (FAERS) Previous DMEPA Reviews Human Factors Study ISMP Newsletters Other Labels and Labeling N/A=not applicable for this review 3 OVERALL ASSESSMENT OF THE MATERIALS REVIEWED We identified the following areas of vulnerability to errors with the proposed container label, carton labeling, and full prescribing information: A. Prescribing Information 1. Section 16 of the proposed PI is missing storage and temperature excursion data in how supplied/storage and handling. 2. We note that Olaparib is primarily metabolized via CYP3A4 but the proposed PI does not include any information on food drug interaction Grapefruit). Per Clinical Pharmacology, the inhibition of CYP3A4 from grapefruit and Seville oranges could result in an increase in plasma concentrations of Olaparib. Therefore, we note that section 17 should include a statement informing patients not to take Olaparib with grapefruit or Seville oranges. However, we defer to clinical pharmacology or the clinical team on this matter. Reference ID: 3646174 3. Section 2.2 of the proposed PI lacks important specific dose adjustment criteria information (e.g. grades of nausea) for dose adjustment. However, at the October 6, 2014 internal meeting, the Review Team conveyed that for this proposed product, the specific grades of toxicity are not necessarily warranted in section 2.2 for dose adjustment. Therefore, we’ll align to not requesting specific dose adjustment criteria for this proposed PI. B. Container Label and Carton Labeling 1. The dosage form does not immediately follow the active ingredient. The established name for drug products should include the finished dosage form.1 2. Currently the established name appears as “olaparib” rather than in parenthesis and immediately followed by the dosage form “(Olaparib) Capsules.” Per Chemistry, Manufacture and Control (CMC) at the October 8, 2014 internal meeting, the established name should appear as “(Olaparib) Capsules”. 3. Prominence of the net quantity statement outweighs the prominence of the strength statement on the principal display panel. 4 CONCLUSION & RECOMMENDATIONS DMEPA concludes that the proposed label and labeling can be improved to increase the readability and prominence of important information on the label to promote the safe use of the product. 4.1 COMMENTS TO THE DIVISION Prescribing Information 1. Due to the large quantity of capsules a patient must take for the recommended dose (eight capsules), there is the potential for a patient or caregiver to manipulate the capsules (e.g. open or break the capsules) if the patient has difficulty swallowing. We recommend including the statement “Swallow capsule whole. Do not chew, dissolve, or open capsule” in Section 2 Dosage and Administration and Section 17 Patient Counseling Information of the PI. 2. In Section 16, we note there is no excursion data relative to temperatures in the event the capsules are stored or transported in temperatures that deviates from the specified value of 30˚C as stated on the principle display panel. We defer to the Office of New Drug Quality Assessment in determining the appropriate storage and handling conditions. 1 Guidance for Industry: Safety considerations for container labels and carton labeling design to minimize medication errors (Draft). April 2013. Accessed October 20, 2014 online at http://www fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm349009.pdf 3 Reference ID: 3646174 3. We note that per Clinical Pharmacology, the inhibition of CYP3A4 from consuming grapefruit or Seville oranges could result in an increase in plasma concentrations of Olaparib. Therefore, we note that section 17 should include a statement informing patients not to take Olaparib with grapefruit or Seville oranges. However, we defer to clinical pharmacology or the clinical team on whether this increase in plasma concentration of Olaparib is clinically significant enough such that labeling statements should be added. 4.2 RECOMMENDATIONS FOR THE APPLICANT/SPONSOR Carton and Container labeling 1. The established name for drug products should include the finished dosage form.2 Relocate the dosage form statement so that it immediately follows the established name on the principal display panel (PDP) as such: Lynparza (Olaparib) Capsules 2. Increase the prominence of the strength statement on the principal display panel by removing the (b) (4) background highlighting the net quantity statement. As currently presented, the prominence of the net quantity statement outweighs the prominence of the strength statement on the PDP. Please note by removing the (b) (4) background highlighting the net quantity statement, the (b) (4) font color on the proposed light (b) (4) background may not provide adequate contrast for legibility. Consider revising the font color of the net quantity statement. 3. Due to the large quantity of capsules a patient must take for the recommended dose (eight capsules), there is the potential for a patient or caregiver to manipulate the capsules (e.g. open or break the capsules) if the patient has difficulty swallowing. We recommend, if space allows, adding the statement “Swallow capsule whole. Do not chew, dissolve or open capsule” on the side panel of the container labels, and on the PDP of the carton labeling. 2 Guidance for Industry: Safety considerations for container labels and carton labeling design to minimize medication errors (Draft). April 2013. Accessed October 20, 2014 online at http://www fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm349009.pdf 4 Reference ID: 3646174 APPENDICES: METHODS 81 RESULTS FOR EACH MATERIALS REVIEWED APPENDIX A. PRODUCT INFORMATION Table 2 presents relevant product information for Lynparza that AstraZeneca submitted on August 28, 2014. Table 2. Relevant Product Information for Active Ingredient Olaparib Indication Treatment as monotherapy in adult patients with deleterious or suspected deleterious germline BRCA mutation (as detected by an FDA-approved test) and who have had three or more prior lines of chemotherapy. Route of Administration Oral Dosage Form Capsule Strength 50 mg Dose and Frequency 400 mg (8 capsules) twice a day How Supplied Carton consists of four bottles. Each bottle consists of 112 capsules. Storage Not to be stored above (86 Container Closure High density polyethylene (HDPE) bottle Reference ID: 3646174 APPENDIX 6. LABELS AND LABELING 6.1 List of Labels and Labeling Reviewed We reviewed the following Lynparza labels and labeling submitted by AstraZeneca on May 9, 2014 and August 28, 2014. 0 Container label submitted on May 9, 2014 Carton labeling submitted on May 9, 2014 0 Full Prescribing Information submitted on August 28, 2014 6.2 Label and Labeling Images Reference ID: 3646174 Reference ID: 3646174 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------DAVIS MATHEW 10/21/2014 CHI-MING TU 10/21/2014 Reference ID: 3646174 MEMORANDUM DEPARTMENT OF HEALTH AND HUMAN SERVICES PUBLIC HEALTH SERVICE FOOD AND DRUG ADMINISTRATION CENTER FOR DRUG EVALUATION AND RESEARCH ____________________________________________________________________________ CLINICAL INSPECTION SUMMARY DATE: September 3, 2014 TO: Rajesh Venugopal, Regulatory Health Project Manager Geoffrey Kim, M.D., Medical Officer Gwynn Ison, M.D., Medical Officer Division of Oncology Products 1 FROM: Lauren Iacono-Connors, Ph.D. Good Clinical Practice Assessment Branch Division of Good Clinical Practice Compliance Office of Scientific Investigations THROUGH: Susan D. Thompson, M.D. Team Leader Good Clinical Practice Assessment Branch Division of Good Clinical Practice Compliance Office of Scientific Investigations Kassa Ayalew, M.D., M.P.H. Branch Chief Good Clinical Practice Assessment Branch Division of Good Clinical Practice Compliance Office of Scientific Investigations SUBJECT: Evaluation of Clinical Inspections NDA: 206162 APPLICANT: AstraZeneca Pharmaceuticals LP DRUG: Olaparib (Lynparza) NME: Yes THERAPEUTIC CLASSIFICATION: Reference ID: 3620988 Priority Page 2 NDA 206162 Clinical Inspection Summary: Olaparib (AZD2281, KU-0059436) INDICATION(S): monotherapy for the maintenance treatment of adult patients with platinum-sensitive relapsed ovarian cancer (including fallopian tube or primary peritoneal) with germline BRCA (gBRCA) mutation as detected by an FDA-approved test who are in response (complete response or partial response) to platinum-based therapy. CONSULTATION REQUEST DATE: February 12, 2014 INSPECTION SUMMARY GOAL DATE: Original: August 7, 2014; Major Amendment: November 15, 2014 DIVISION ACTION GOAL DATE: Original: October 3, 2014 Major Amendment: January 2, 2015 PDUFA DATE: Original: October 3, 2014 Major Amendment: January 2, 2015 I. BACKGROUND: Ovarian cancer is the fourth most common cancer in women. The disease often presents at a late stage (usually stage II-IV) and therefore has a poor prognosis. Treatment includes surgery and platinum based chemotherapy, but most women develop recurrent disease and die within five years of diagnosis. Carboplatin plus paclitaxel is the current standard regimen for advanced cancer in the first line setting. Despite therapy, the disease often recurs. Patients who continue to have platinum sensitive disease may be retreated with the same drugs, but again recurrence is common. Olaparib (AZD2281, KU-0059436) is an inhibitor of polyadenosine 5’-diphosphoribose [poly(ADP-ribose)] polymerization (PARP) 1. PARP is a unique post-translational modification of histones and other nuclear proteins that contributes to the survival of proliferating and nonproliferating cells following DNA damage. PARP 1 activation leads to DNA repair through the base excision repair (BER) pathway. While the ability to repair DNA is desirable in normal cells, following cancer therapy it may enable tumor cells to recover from chemotherapy thus preventing effective treatment. For both PARP 1 and PARP 2, inactivation and cleavage promotes apoptosis and is part of the apoptotic cascade. Olaparib is supplied as a white 50 mg capsule. The dose for this study is 200 mg (four 50 mg capsules) taken orally twice a day (BID). The key study supporting this application is study D0810C00019. The study is a randomized, double blind, multi-center study in patients with platinum sensitive serous ovarian cancer who have received two or more previous platinum containing regimens. Platinum sensitivity is defined as disease progression greater than 6 months after completion of their second last platinum regimen prior to enrolling in this study. The primary purpose of the study is to determine the efficacy of AZD2281 compared to placebo in serous ovarian cancer platinum sensitive patients and in a defined homologous recombination deficiency (HRD) subset. The study will compare progression free survival (PFS) between the two treatment groups and further characterize the safety and tolerability profile of AZD2281 compared to placebo. Secondary endpoints include overall survival (OS) and safety endpoints. Reference ID: 3620988 Page 3 NDA 206162 Clinical Inspection Summary: Olaparib (AZD2281, KU-0059436) Patients were randomized in a 1:1 ratio (olaparib:matching placebo) to receive either olaparib 400 mg twice daily capsules or olaparib matching placebo capsules. It was planned that 250 patients would be randomized (125 in each group). Subjects had advanced platinum-sensitive serous ovarian cancer, had received 3 or more previous platinum-containing regimens and demonstrated an objective stable maintained response in the last platinum regimen prior to enrolment on the study. Subjects also had an estimated life expectancy of at least 16 weeks and an Eastern Co-operative Oncology Group (ECOG) performance status (PS) of 0 to 2. Of the 326 patients enrolled into the study, 61 patients were not randomized due to screening failures. Of the 265 patients randomized into the study, all olaparib patients (136) and 128/129 placebo patients received study treatment. This was an international multicenter study conducted at 82 clinical centers in 16 countries: Australia (7), Belgium (2), Czech Republic (1), Estonia (1), Germany (8), Israel (7), Canada (3), France (5), Netherlands (1), Poland (7), Romania (3), Russia (6), Spain (5), Ukraine (7), U.K. (8), and U.S.A. (11). This study was conducted under IND 75918. Four clinical sites were chosen for inspection: Site 1801 and 1802 (Dr. Ursula Matulonis, Massachusetts General Hospital and Dana Farber Cancer Inst, respectively, Boston, Massachusetts), Site 1703 (Dr. Charlie Gourley, Edinburgh, UK), and Site 701 (Dr. Phillip Harter, Wiesbaden, Germany) based on enrollment of large numbers of study subjects and insufficient domestic site data. II. RESULTS (by Site): Name of CI or Sponsor/CRO, Location CI#1: Dr. Ursula Matulonis Massachusetts General Hospital 55 Fruit St. Boston, MA 02114 CI#2: Dr. Ursula Matulonis Dana Farber Cancer Institute 44 Binney St. Boston, MA 02115 Reference ID: 3620988 Protocol #, Site #, and # of Subjects Inspection Date Final Classification Protocol: D0810C00019 May 20-13, 2014 NAI April 10-24, 2014 VAI Site Number: 1801 Number of Subjects: 9 Protocol: D0810C00019 Site Number: 1802 Number of Subjects: 11 Page 4 NDA 206162 Clinical Inspection Summary: Olaparib (AZD2281, KU-0059436) Name of CI or Sponsor/CRO, Location CI#3: Dr. Charlie Gourley Western General Hospital (Lothian NHS board University hospitals division) Cancer Research Centre Western General Hospital Crewe Road South Edinburgh, NA EH4 2UX Great Britain CI#4: Dr.Tanya Neunhoffer (Current PI) Protocol #, Site #, and # of Subjects Inspection Date Final Classification Protocol: D0810C00019 April 28, 2014 – May 2, 2014 Pending Dr.Phillip Harter (Former PI) Number of Subjects: 14 Site Number: 1703 Interim classification: NAI Number of Subjects: 13 Protocol: D0810C00019 Site Number: 701 May 5-9, 2014 Pending Interim classification: NAI HSK, Dr. Horst Schmidt Klinik Department of Gynecology and Gynecologic Oncology Ludwig-Erhard-Strasse 100 Wiesbaden, NA 65199 Germany Key to Classifications NAI = No deviation from regulations. VAI = Deviation(s) from regulations. OAI = Significant deviations from regulations. Data unreliable. Pending = Preliminary classification based on information in 483 or preliminary communication with the field; EIR has not been received from the field, and complete review of EIR is pending. 1. CI#1: – Dr. Ursula Matulonis (Site 1801) Massachusetts General Hospital Boston, MA a. What was inspected: The site screened 12 subjects, and 9 subjects were enrolled. Of the nine enrolled subjects, all received study medication for one or more treatment cycle. At the time of this inspection all subjects were out of active treatment, one had withdrawn consent, and one remains in survival follow up. The study records of all 12 subjects were audited. The record audit was conducted in accordance with the clinical investigator compliance program, CP 7348.811. The record audit included comparison of source documentation to CRFs and data listings submitted to NDA 206162. All subject records were Reference ID: 3620988 Page 5 NDA 206162 Clinical Inspection Summary: Olaparib (AZD2281, KU-0059436) reviewed to verify the following: 1) the protocol was followed, 2) subject eligibility, 3) randomization, 4) protocol adherence for assessments performed and the timing of assessments, 5) administration of the investigational product or placebo, 6) concomitant medications, 7) the identification of key personnel involved in collecting and analyzing data at the site, 8) the condition of the subject at time of entry and throughout participation in the investigation, 9) adverse event detection and reporting, and 10) accuracy of data listings provided with the assignment compared to supporting source documentation. b. General observations/commentary: Generally, the investigator’s execution of the protocol was found to be adequate. Records were well maintained and available for review. Records included source documents of protocol required examinations, evaluations and processes and signed informed consent documents. All records were reviewed for signed informed consent documents and source documents of protocol required screening examinations. It was observed that informed consent was documented for all subjects who were screened to participate in the study. The inspection revealed no significant deficiencies. There was no evidence of underreporting of adverse events. The primary efficacy endpoints in the data listings provided with the assignment were compared to progression free survival results in the source documents, and no discrepancies were observed. Review of source documentation for eligibility, randomization, treatment regimens, study drug administration cycles and drug accountability found no discrepancies. No Form FDA 483 was issued. c. Assessment of data integrity: The data for Dr. Matulonis’ site (1801), associated with Study D0810C00019 submitted to the Agency in support of NDA 206162, appear reliable based on available information. 2. CI#2: – Dr. Ursula Matulonis (Site 1802) Dana Farber Cancer Institute Boston, MA a. What was inspected: The site screened 11 subjects, and 11 subjects were enrolled. Study records of all subjects were audited. Two subjects are still in active treatment, 6 were discontinued per protocol defined progressive disease, two were discontinued from treatment secondary to disease progression outside of protocol defined progressive disease (RECIST criteria), and one withdrew consent (though Dr. Matulonis reported this subject also had disease progression outside of protocol defined progressive disease at the time of her consent withdrawal). The record audit was conducted in accordance with the clinical investigator compliance program, CP 7348.811. The record audit included comparison of source documentation to CRFs and data listings submitted to NDA 206162. All subject records were reviewed to verify the Reference ID: 3620988 Page 6 NDA 206162 Clinical Inspection Summary: Olaparib (AZD2281, KU-0059436) following: 1) the protocol was followed, 2) subject eligibility, 3) randomization, 4) protocol adherence for assessments performed and the timing of assessments, 5) administration of the investigational product or placebo, 6) concomitant medications, 7) the identification of key personnel involved in collecting and analyzing data at the site, 8) the condition of the subject at time of entry and throughout participation in the investigation, 9) adverse event detection and reporting, and 10) accuracy of data listings provided with the assignment compared to supporting source documentation. b. General observations/commentary: Generally, the investigator’s execution of the protocol was found to be adequate. The inspection revealed no significant deficiencies. The primary efficacy endpoints in the data listings provided with the assignment were compared to progression free survival results in the source documents, and no discrepancies were observed. No evidence was observed of underreporting of adverse events or serious adverse events on the part of the investigator. Test article accountability records were reviewed and appeared adequate. The FDA field investigator contacted the CDER OSI Reviewer, Lauren IaconoConnors, on April 14, 2014 while the inspection was ongoing, to report an unusual discrepancy between AEs source documentation for Subject 1802003 and that reported in data listings submitted to the application. Briefly, when source documents were compared to the background information provided with the assignment non-serious AE reporting discrepancies were noted for subject 1802003. Site staff explained that when they started training on the study in fall 2013, they were instructed by the clinical research (b) (4) coordinator, who was leaving the site that the CRO, , told the site that the site should follow non-serious AEs as usual, but no longer needed to report them on the AE CRF. Because the new site staff found no documentation to verify that the site was told to stop collecting non-serious AE CRFs, the new (b) (4) site staff sent an e-mail to the Clinical Operations Leader at , looking for clarification on October 10, 2013. The site had not transcribed non-serious AEs to study CRFs since late 2010. This apparently only affected Subject 1802003. (b) (4) staff responded on October 24, 2013, confirming that the site did not need to complete non-serious AE CRFs. In December 2013 a new Clinical (b) (4) Operations Leader took over the study at . It was not until the new Clinical Operations Leader asked for this site to provide some AE information (b) (4) in a February 11, 2014 e-mail that it was found that staff had misinformed the site staff on AE reporting requirements. The site then implemented a corrective action plan that included going through the past few years of clinical notes to document the AEs on CRFs and submit them to the sponsor. Reference ID: 3620988 Page 7 NDA 206162 Clinical Inspection Summary: Olaparib (AZD2281, KU-0059436) OSI Reviewer Note: The general observation of underreporting non-serious AEs on study Subject 1802003 CRF was discussed with Medical Officer Geoffrey Kim in mid-April 2014. Shortly thereafter, an IR was sent to the sponsor requesting clarification on AE reporting practices and updates to the application as needed. The sponsor provided a response on April 18, 2014. See below. IR Question #4: “Please provide any information you may have on any safety data that was reported to the sponsor but is not included in the CSR.” Sponsor Response: “As directed in the Clinical Study Protocol (CSP), adverse events (AEs) were collected from time of signed informed consent throughout the treatment period and up to and including the 30-day follow-up period. In February 2014 however, it came to our attention through ongoing data monitoring that AEs relevant to NDA 206162 were apparently not recorded on case report forms (CRFs) for two ongoing patients at site 1802, patients 1802001 and 1802003. On 24 February 2014, the AEs were collected, processed and reviewed to confirm the AEs had no effect on the overall safety conclusions for NDA 206162. The AEs will be included in the analysis for the next safety data submission, the Four Month Safety Update.” SUBJECT AETEXT AE Start Date AE Serious? CTC Grade AE End Date E1802001 SINUS INFECTION 2011-12-07 No 1 2011-12-29 E1802001 ELEVATED CREATININE 2012-10-04 No 1 2012-11-05 E1802003 LEFT WRIST PAIN 2011-02-15 No 1 2011-02-23 E1802003 BACK PAIN 2012-03-21 No 1 2012-05-16 E1802003 SHOULDER PAIN 2011-02-23 No 1 2011-06-17 E1802003 ELEVATED TSH 2012-05-16 No 1 2012-07-11 (b) (6) No 1 Ongoing E1802003 SEIZURES “Any events with a start date after 26 November 2012 will be reported at the 4 Month Safety Update.” (b) (6) “In addition, on , Patient 1802003 was admitted to the hospital after experiencing a seizure (grade 2) and an episode of speech impairment (grade 3). These two events were reported to in a single SAE package (SAE (b) (4) due to hospitalization) to in on April 9, 2014 (and to Astra Zeneca on April 11, 2014). However, upon further review, the SAE of seizures and speech impairment were considered to be due to disease progression, brain metastasis. Therefore, with the agreement of the investigator the SAE will be Reference ID: 3620988 Page 8 NDA 206162 Clinical Inspection Summary: Olaparib (AZD2281, KU-0059436) downgraded. As of April 18, 2014, we are waiting for the investigator signature to confirm this was disease progression and therefore not an SAE.” A Form FDA 483, Inspectional Observations, was issued citing one inspection observation. Briefly, one subject was enrolled who did not meet the inclusion/exclusion criteria and not all subjects were re-consented as required by the IRB in a timely manner. Observation 1: An investigation was not conducted in accordance with the signed statement of investigator and investigational plan. Specifically, a. Subject 1802001 was enrolled who did not meet inclusion/exclusion criteria #3, “Female patients with histologically or cytologically diagnosed serous ovarian cancer or recurrent serous ovarian cancer”. Subject 1802001 had a diagnosis of clear cell ovarian cancer, not serous ovarian cancer, yet was enrolled in the study on March 18, 2009. OSI Reviewer Note: According to inspection report, and the clinical investigators written response, dated May 9, 2014, to the Form FDA 483, the PI recognized the subject should not have been enrolled in the study on May 22, 2009. This deviation was brought to the attention of the sponsor and the IRB on May 22, 2009, and a Major Deviation/Violation, Exception request was filed with the IRB on May 29, 2009. It was determined by the IRB that no further action was required and the sponsor allowed the subject to remain in the study at the discretion of the PI, Dr. Matulonis. Dr. Matulonis agreed this was a major deviation, and stated it was the first subject in the study and she was focused on the ovarian cancer diagnosis and missed the cytology aspect. She admitted she should have caught the error, but did not until after enrollment. This was an isolated major deviation for this site, and should not importantly impact study outcomes. However, the review division may consider whether the subjects’ data may be included in the study analyses or censored as appropriate. b. Not all subjects were re-consented as required by the IRB in a timely manner. c. Assessment of data integrity: The data for Dr. Matulonis’ site (1802), associated with Study D0810C00019 submitted to the Agency in support of NDA 206162, appear reliable based on available information. 3. CI#3: – Dr. Charlie Gourley (Site 1703) Edinburgh, Great Britain a. What was inspected: The site screened 16 subjects, and 13 subjects were enrolled. Out of the 13 subjects enrolled, 1 subject withdrew before RECIST Reference ID: 3620988 Page 9 NDA 206162 Clinical Inspection Summary: Olaparib (AZD2281, KU-0059436) progression, and at the time of this inspection there was one subject continuing to receive study drug and four subjects attending ongoing follow-up visits. The study records of all enrolled subjects were audited. The record audit was conducted in accordance with the clinical investigator compliance program, CP 7348.811. The record audit included comparison of source documentation to CRFs and data listings submitted to NDA 206162, with particular attention paid to inclusion/exclusion criteria compliance, adverse events, treatment regimens, and reporting of AEs in accordance with the protocol. The FDA investigator assessed all informed consent documents, patient histories, laboratory results, drug accountability, concomitant medications, sponsor correspondence, and progress notes. b. General observations/commentary: Generally, the investigator’s execution of the protocol was found to be adequate. Records were well maintained and available for review. Records included source documents of protocol required examinations, evaluations and processes and signed informed consent documents. All records were reviewed for signed informed consent documents and source documents of protocol required screening examinations. It was observed that informed consent was documented for all subjects who were screened to participate in the study. The inspection revealed no significant deficiencies. There was no evidence of underreporting of adverse events. The primary efficacy endpoints in the data listings provided with the assignment were compared to progression free survival results in the source documents, and no discrepancies were observed. Review of source documentation for eligibility, randomization, treatment regimens, study drug administration cycles and drug accountability found no discrepancies. No Form FDA 483 was issued. c. Assessment of data integrity: The data for Dr. Gourley’s site (1703), associated with Study D0810C00019 submitted to the Agency in support of NDA 206162, appear reliable based on available information. Note: The general observations and actions on inspection are based on preliminary review of the EIR. An inspection summary addendum will be generated if conclusions change upon final review of the EIR. 4. CI#4: – Dr. Tanya Neunhoffer (Current PI [Site 701]) Dr. Phillip Harter (Former PI) Wiesbaden, Germany a. What was inspected: The site screened 19 subjects, and 14 subjects were enrolled. Out of the 14 subjects enrolled, 1 subject moved to another study site (Subject #16), and at the time of this inspection there were 3 subjects attending ongoing follow-up visits. The study records of all enrolled subjects were audited. The record audit was conducted in accordance with the clinical Reference ID: 3620988 Page 10 NDA 206162 Clinical Inspection Summary: Olaparib (AZD2281, KU-0059436) investigator compliance program, CP 7348.811. The record audit included comparison of source documentation to CRFs and data listings submitted to NDA 206162, with particular attention paid to inclusion/exclusion criteria compliance, adverse events, treatment regimens, and reporting of AEs in accordance with the protocol. The FDA investigator assessed all informed consent documents, patient histories, laboratory results, drug accountability, concomitant medications, sponsor correspondence, and progress notes. b. General observations/commentary: Generally, the investigator’s execution of the protocol was found to be adequate. Records were well maintained and available for review. Records included source documents of protocol required examinations, evaluations and processes and signed informed consent documents. All records were reviewed for signed informed consent documents and source documents of protocol required screening examinations. It was observed that informed consent was documented for all subjects who were screened to participate in the study. The inspection revealed no significant deficiencies. There was no evidence of underreporting of adverse events. The primary efficacy endpoints in the data listings provided with the assignment were compared to progression free survival results in the source documents, and no discrepancies were observed. Review of source documentation for eligibility, randomization, treatment regimens, study drug administration cycles and drug accountability found no discrepancies. No Form FDA 483 was issued. c. Assessment of data integrity: The data for Dr. Neunhoffer’s site (1703), associated with Study D0810C00019 submitted to the Agency in support of NDA 206162, appear reliable based on available information. Note: The general observations and actions on inspection are based on preliminary review of the EIR. An inspection summary addendum will be generated if conclusions change upon final review of the EIR. III. OVERALL ASSESSMENT OF FINDINGS AND RECOMMENDATIONS Based on the review of inspectional findings for clinical investigators Dr. Ursula Matulonis (Sites 1801 and 1802), Dr. Charlie Gourley (Site 1703), and Dr. Tanya Neunhoffer (Site 701), the Study D0810C00019 data appear reliable based on available information. The preliminary classification for clinical investigator Dr. Ursula Matulonis (Site 1801), Dr. Charlie Gourley (Site 1703) and Dr. Tanya Neunhoffer (Site 701) is No Action Indicated (NAI). One clinical site inspected, Dr. Ursula Matulonis (Site 1802), was issued a Form FDA 483 citing inspectional observations and the classification for this inspection is Voluntary Action Indicated (VAI). Reference ID: 3620988 Page 11 NDA 206162 Clinical Inspection Summary: Olaparib (AZD2281, KU-0059436) Generally, the investigators execution of the protocol was found to be adequate. Records were well maintained and available for review. Audits of three clinical sites (Sites 1801, 1703 and 701) revealed nothing to indicate under-reporting of AEs/SAEs. In addition, the primary efficacy endpoint data were verifiable for all 4 inspected clinical sites. The inspection of Dr. Ursula Matulonis (Site 1802) found that there was an unusual discrepancy between non-serious AEs in source documentation for Subject 1802003 and that reported in data listings submitted to the application. Site staff explained that when they started training on the study in the Fall of 2013, they were instructed by the clinical research (b) (4) coordinator, who was leaving the site, that the CRO, , told the site that the site should follow non-serious AEs as usual, but no longer needed to report them on the AE CRF. Because the new site staff found no documentation to verify that the site was told to stop collecting non(b) (4) serious AE CRFs, the new site staff sent an e-mail to the Clinical Operations Leader at looking for clarification on October 10, 2013. The site had not transcribed non-serious AEs to study CRFs since late 2010. (b) (4) staff responded on October 24, 2013, confirming that the site did not need to complete non-serious AE CRFs. In December 2013 a new Clinical Operations Leader took over the (b) (4) study at . It was not until the new Clinical Operations Leader asked for this site to (b) (4) provide some AE information in a February 11, 2014 e-mail, that it was found that staff had misinformed the site staff on AE reporting requirements. The site then implemented a corrective action plan that included going through the past few years of clinical notes to document the AEs on CRFs and submit them to the sponsor. An IR was sent to the sponsor from DOP1 requesting clarification on AE reporting practices and updates to the application as needed. The sponsor provided a response on April 18, 2014. The validity and impact of this observation on overall safety data was assessed by the sponsor. The sponsor concurred with the inspection observation, and informed that they became aware of the flawed AE reporting practices for the site in February 2014. They subsequently collected all missing AEs from the site and planned to include the missing AEs in the analysis for the next safety data submission, the “Four Month Safety Update” for the application. The extent of missing AEs were limited to 2 subjects; E1802001 and E1802003, all 7 AEs were non-serious and CTC grade 1. The inspection of Dr. Ursula Matulonis (Site 1802) also found that there was one subject enrolled who did not meet the inclusion/exclusion criteria and not all subjects were reconsented as required by the IRB in a timely manner. Briefly, Subject 1802001 was enrolled who did not meet inclusion/exclusion criteria #3, “Female patients with histologically or cytologically diagnosed serous ovarian cancer or recurrent serous ovarian cancer”. Subject 1802001 had a diagnosis of clear cell ovarian cancer, not serous ovarian cancer, yet was enrolled in the study on March 18, 2009. This deviation was brought to the attention of the sponsor and the IRB on May 22, 2009, and a Major Deviation/Violation, Exception request was filed with the IRB on May 29, 2009. The sponsor allowed the subject to remain in the study at the discretion of the PI, Dr. Matulonis. This was an isolated major deviation for this site, and should not importantly impact study outcomes. Reference ID: 3620988 Page 12 NDA 206162 Clinical Inspection Summary: Olaparib (AZD2281, KU-0059436) However, the review division may consider whether the subjects’ data may be included in the study analyses or censored as appropriate. Although regulatory violations were noted as described above, they are unlikely to significantly impact primary safety and efficacy analyses. These observations were not systemic and do not represent a trend in compliance violations for the overall study. The overall data for Study D0810C00019 in support of this application may be considered reliable based on available information. Note: The general observations and actions on inspection for two of the clinical sites are based on preliminary review of the EIRs. An inspection summary addendum will be generated if conclusions change upon final review of the EIRs. {See appended electronic signature page} Lauren Iacono-Connors, Ph.D. Good Clinical Practice Assessment Branch Division of Good Clinical Practice Compliance Office of Scientific Investigations CONCURRENCE: {See appended electronic signature page} Susan D. Thompson, M.D. Team Leader Good Clinical Practice Assessment Branch Division of Good Clinical Practice Compliance Office of Scientific Investigations CONCURRENCE: {See appended electronic signature page} Kassa Ayalew, M.D., M.P.H. Branch Chief Good Clinical Practice Assessment Branch Division of Good Clinical Practice Compliance Office of Scientific Investigations Reference ID: 3620988 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------LAUREN C IACONO-CONNORS 09/03/2014 SUSAN D THOMPSON 09/03/2014 KASSA AYALEW 09/03/2014 Reference ID: 3620988 RPM FILING REVIEW (Including Memo of Filing Meeting) To be completed for all new NDAs, BLAs, and Efficacy Supplements [except SE8 (labeling change with clinical data) and SE9 (manufacturing change with clinical data] Application Information NDA # 206162 NDA Supplement #:SEfficacy Supplement Type SEBLA# BLA Supplement # (b) (4) Proposed Proprietary Name: Established/Proper Name: Olaparib Dosage Form: Capsules Strengths: 50 mg Applicant: AstraZeneca Agent for Applicant (if applicable): Date of Application: February 3, 2014 Date of Receipt: February 3, 2014 Date clock started after UN: N/A PDUFA Goal Date: October 3, 2014 Action Goal Date (if different): Filing Date: April 4, 2014 Date of Filing Meeting: March 10, 2014 Chemical Classification: (1,2,3 etc.) (original NDAs only) NME - 1 Proposed indication(s)/Proposed change(s): Ovarian cancer Type of Original NDA: NME AND (if applicable) Type of NDA Supplement: 505(b)(1) 505(b)(2) 505(b)(1) 505(b)(2) If 505(b)(2): Draft the “505(b)(2) Assessment” review found at: http://inside.fda.gov:9003/CDER/OfficeofNewDrugs/ImmediateOffice/UCM027499. Type of Original BLA 351(a) 351(k) If 351(k), notify the OND Therapeutic Biologics and Biosimilars Team Review Classification: Standard Priority If the application includes a complete response to pediatric WR, review classification is Priority. If a tropical disease priority review voucher or pediatric rare disease priority review voucher was submitted, review classification is Priority. Resubmission after withdrawal? Part 3 Combination Product? No but need CDRH consult to review the in vitro diagnostic used from myriad. If yes, contact the Office of Combination Products (OCP) and copy them on all Inter-Center consults Version: 1/21/2014 Reference ID: 3484524 Tropical Disease Priority Review Voucher submitted Pediatric Rare Disease Priority Review Voucher submitted Resubmission after refuse to file? Convenience kit/Co-package Pre-filled drug delivery device/system (syringe, patch, etc.) Pre-filled biologic delivery device/system (syringe, patch, etc.) Device coated/impregnated/combined with drug Device coated/impregnated/combined with biologic Separate products requiring cross-labeling Drug/Biologic Possible combination based on cross-labeling of separate products Other (drug/device/biological product) 1 Fast Track Designation Breakthrough Therapy Designation Rolling Review Orphan Designation Rx-to-OTC switch, Full Rx-to-OTC switch, Partial Direct-to-OTC PMC response PMR response: FDAAA [505(o)] PREA deferred pediatric studies [21 CFR 314.55(b)/21 CFR 601.27(b)] Accelerated approval confirmatory studies (21 CFR 314.510/21 CFR 601.41) Animal rule postmarketing studies to verify clinical benefit and safety (21 CFR 314.610/21 CFR 601.42) Other: Collaborative Review Division (if OTC product): List referenced IND Number(s): IND 075918 Goal Dates/Product Names/Classification Properties YES NO NA Comment YES NO NA Comment PDUFA and Action Goal dates correct in tracking system? If no, ask the document room staff to correct them immediately. These are the dates used for calculating inspection dates. Are the proprietary, established/proper, and applicant names correct in tracking system? If no, ask the document room staff to make the corrections. Also, ask the document room staff to add the established/proper name to the supporting IND(s) if not already entered into tracking system. Is the review priority (S or P) and all appropriate classifications/properties entered into tracking system (e.g., chemical classification, combination product classification, 505(b)(2), orphan drug)? For NDAs/NDA supplements, check the New Application and New Supplement Notification Checklists for a list of all classifications/properties at: http://inside.fda.gov:9003/CDER/OfficeofBusinessProcessSupport/ucm163969.ht m If no, ask the document room staff to make the appropriate entries. Application Integrity Policy Is the application affected by the Application Integrity Policy (AIP)? Check the AIP list at: http://www.fda.gov/ICECI/EnforcementActions/ApplicationIntegrityPolicy/default .htm If yes, explain in comment column. X If affected by AIP, has OC/OMPQ been notified of the submission? If yes, date notified: User Fees YES NO NA Comment Is Form 3397 (User Fee Cover Sheet) included with authorized signature? Version: 1/21/2014 Reference ID: 3484524 2 User Fee Status Payment for this application: If a user fee is required and it has not been paid (and it is not exempted or waived), the application is unacceptable for filing following a 5-day grace period. Review stops. Send Unacceptable for Filing (UN) letter and contact user fee staff. Paid Exempt (orphan, government) Waived (e.g., small business, public health) Not required Payment of other user fees: If the firm is in arrears for other fees (regardless of whether a user fee has been paid for this application), the application is unacceptable for filing (5-day grace period does not apply). Review stops. Send UN letter and contact the user fee staff. Not in arrears In arrears 505(b)(2) YES NO NA Comment (NDAs/NDA Efficacy Supplements only) Is the application for a duplicate of a listed drug and eligible for approval under section 505(j) as an ANDA? Is the application for a duplicate of a listed drug whose only difference is that the extent to which the active ingredient(s) is absorbed or otherwise made available to the site of action is less than that of the reference listed drug (RLD)? [see 21 CFR 314.54(b)(1)]. Is the application for a duplicate of a listed drug whose only difference is that the rate at which the proposed product’s active ingredient(s) is absorbed or made available to the site of action is unintentionally less than that of the listed drug [see 21 CFR 314.54(b)(2)]? If you answered yes to any of the above questions, the application may be refused for filing under 21 CFR 314.101(d)(9). Contact the 505(b)(2) review staff in the Immediate Office of New Drugs Is there unexpired exclusivity on any drug product containing the active moiety (e.g., 5-year, 3-year, orphan, or pediatric exclusivity)? Check the Electronic Orange Book at: http://www.accessdata.fda.gov/scripts/cder/ob/default.cfm If yes, please list below: Application No. Drug Name Exclusivity Code Exclusivity Expiration If there is unexpired, 5-year exclusivity remaining on the active moiety for the proposed drug product, a 505(b)(2) application cannot be submitted until the period of exclusivity expires (unless the applicant provides paragraph IV patent certification; then an application can be submitted four years after the date of approval.) Pediatric exclusivity will extend both of the timeframes in this provision by 6 months. 21 CFR 314.108(b)(2). Unexpired, 3year exclusivity may block the approval but not the submission of a 505(b)(2) application. Exclusivity YES NO NA Comment Does another product (same active moiety) have orphan exclusivity for the same indication? Check the Orphan Drug Version: 1/21/2014 Reference ID: 3484524 3 Designations and Approvals list at: http://www.accessdata.fda.gov/scripts/opdlisting/oopd/index.cfm If another product has orphan exclusivity, is the product considered to be the same product according to the orphan drug definition of sameness [see 21 CFR 316.3(b)(13)]? If yes, consult the Director, Division of Regulatory Policy II, Office of Regulatory Policy Has the applicant requested 5-year or 3-year Waxman-Hatch exclusivity? (NDAs/NDA efficacy supplements only) If yes, # years requested: 5 years Note: An applicant can receive exclusivity without requesting it; therefore, requesting exclusivity is not required. Is the proposed product a single enantiomer of a racemic drug previously approved for a different therapeutic use (NDAs only)? If yes, did the applicant: (a) elect to have the single enantiomer (contained as an active ingredient) not be considered the same active ingredient as that contained in an already approved racemic drug, and/or (b): request exclusivity pursuant to section 505(u) of the Act (per FDAAA Section 1113)? If yes, contact the Orange Book Staff (CDER-Orange Book Staff). Has the applicant requested 12-year exclusivity under section 351(k)(7) of the PHS Act? (Original 351(a)BLAs/BLA supplements only) If yes, notify Marlene Schultz-DePalo, OBP Biosimilars RPM Note: Exclusivity requests may be made for an original BLA submitted under Section 351(a) of the PHS Act (i.e., a biological reference product). A request may be located in Module 1.3.5.3 and/or other sections of the BLA and may be included in a supplement if exclusivity has not yet been granted. An applicant can receive exclusivity without requesting it; therefore, requesting exclusivity is not required. Format and Content Do not check mixed submission if the only electronic component is the content of labeling (COL). All paper (except for COL) All electronic Mixed (paper/electronic) CTD Non-CTD Mixed (CTD/non-CTD) If mixed (paper/electronic) submission, which parts of the application are submitted in electronic format? Version: 1/21/2014 Reference ID: 3484524 4 Overall Format/Content YES NO NA Comment If electronic submission, does it follow the eCTD guidance? 1 If not, explain (e.g., waiver granted). Index: Does the submission contain an accurate comprehensive index? Is the submission complete as required under 21 CFR 314.50 (NDAs/NDA efficacy supplements) or under 21 CFR 601.2 (BLAs/BLA efficacy supplements) including: legible English (or translated into English) pagination navigable hyperlinks (electronic submissions only) If no, explain. BLAs only: Companion application received if a shared or divided manufacturing arrangement? If yes, BLA # Forms and Certifications Electronic forms and certifications with electronic signatures (scanned, digital, or electronic – similar to DARRTS, e.g., /s/) are acceptable. Otherwise, paper forms and certifications with hand-written signatures must be included. Forms include: user fee cover sheet (3397), application form (356h), patent information (3542a), financial disclosure (3454/3455), and clinical trials (3674); Certifications include: debarment certification, patent certification(s), field copy certification, and pediatric certification. Application Form YES NO NA Comment YES NO NA Comment YES NO NA Comment Is form FDA 356h included with authorized signature per 21 CFR 314.50(a)? If foreign applicant, a U.S. agent must sign the form [see 21 CFR 314.50(a)(5)]. Are all establishments and their registration numbers listed on the form/attached to the form? Patent Information (NDAs/NDA efficacy supplements only) Is patent information submitted on form FDA 3542a per 21 CFR 314.53(c)? Financial Disclosure Are financial disclosure forms FDA 3454 and/or 3455 1 http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm072349. pdf Version: 1/21/2014 Reference ID: 3484524 5 included with authorized signature per 21 CFR 54.4(a)(1) and (3)? Forms must be signed by the APPLICANT, not an Agent [see 21 CFR 54.2(g)]. Note: Financial disclosure is required for bioequivalence studies that are the basis for approval. Clinical Trials Database YES NO NA Comment YES NO NA Comment YES NO NA Comment YES NO NA Comment Is form FDA 3674 included with authorized signature? If yes, ensure that the application is also coded with the supporting document category, “Form 3674.” If no, ensure that language requesting submission of the form is included in the acknowledgement letter sent to the applicant Debarment Certification Is a correctly worded Debarment Certification included with authorized signature? Certification is not required for supplements if submitted in the original application; If foreign applicant, both the applicant and the U.S. Agent must sign the certification [per Guidance for Industry: Submitting Debarment Certifications]. Note: Debarment Certification should use wording in FD&C Act Section 306(k)(1) i.e.,“[Name of applicant] hereby certifies that it did not and will not use in any capacity the services of any person debarred under section 306 of the Federal Food, Drug, and Cosmetic Act in connection with this application.” Applicant may not use wording such as, “To the best of my knowledge…” Field Copy Certification (NDAs/NDA efficacy supplements only) For paper submissions only: Is a Field Copy Certification (that it is a true copy of the CMC technical section) included? Field Copy Certification is not needed if there is no CMC technical section or if this is an electronic submission (the Field Office has access to the EDR) If maroon field copy jackets from foreign applicants are received, return them to CDR for delivery to the appropriate field office. Controlled Substance/Product with Abuse Potential For NMEs: Is an Abuse Liability Assessment, including a proposal for scheduling, submitted per 21 CFR 314.50(d)(5)(vii)? If yes, date consult sent to the Controlled Substance Staff: For non-NMEs: Date of consult sent to Controlled Substance Staff : Version: 1/21/2014 Reference ID: 3484524 6 Pediatrics YES NO NA Comment YES NO NA Comment YES NO NA Comment PREA Does the application trigger PREA? If yes, notify PeRC RPM (PeRC meeting is required) 2 Note: NDAs/BLAs/efficacy supplements for new active ingredients, new indications, new dosage forms, new dosing regimens, or new routes of administration trigger PREA. All waiver & deferral requests, pediatric plans, and pediatric assessment studies must be reviewed by PeRC prior to approval of the application/supplement. If the application triggers PREA, are the required pediatric assessment studies or a full waiver of pediatric studies included? If studies or full waiver not included, is a request for full waiver of pediatric studies OR a request for partial waiver and/or deferral with a pediatric plan included? If no, request in 74-day letter If a request for full waiver/partial waiver/deferral is included, does the application contain the certification(s) required by FDCA Section 505B(a)(3) and (4)? If no, request in 74-day letter BPCA (NDAs/NDA efficacy supplements only): Is this submission a complete response to a pediatric Written Request? If yes, notify Pediatric Exclusivity Board RPM (pediatric exclusivity determination is required) 3 Proprietary Name Is a proposed proprietary name submitted? If yes, ensure that the application is also coded with the supporting document category, “Proprietary Name/Request for Review.” REMS Is a REMS submitted? If yes, send consult to OSE/DRISK and notify OC/ OSI/DSC/PMSB via the CDER OSI RMP mailbox Prescription Labeling Check all types of labeling submitted. 2 3 Not applicable Package Insert (PI) Patient Package Insert (PPI) Instructions for Use (IFU) Medication Guide (MedGuide) http://inside.fda.gov:9003/CDER/OfficeofNewDrugs/PediatricandMaternalHealthStaff/ucm027829.htm http://inside.fda.gov:9003/CDER/OfficeofNewDrugs/PediatricandMaternalHealthStaff/ucm027837.htm Version: 1/21/2014 Reference ID: 3484524 7 Carton labels Immediate container labels Diluent Other (specify) YES NO NA Comment Is Electronic Content of Labeling (COL) submitted in SPL format? If no, request applicant to submit SPL before the filing date. Is the PI submitted in PLR format? 4 If PI not submitted in PLR format, was a waiver or deferral requested before the application was received or in the submission? If requested before application was submitted, what is the status of the request? If no waiver or deferral, request applicant to submit labeling in PLR format before the filing date. All labeling (PI, PPI, MedGuide, IFU, carton and immediate container labels) consulted to OPDP? MedGuide, PPI, IFU (plus PI) consulted to OSE/DRISK? (send WORD version if available) Carton and immediate container labels, PI, PPI sent to OSE/DMEPA and appropriate CMC review office (OBP or ONDQA)? OTC Labeling Check all types of labeling submitted. Not Applicable Outer carton label Immediate container label Blister card Blister backing label Consumer Information Leaflet (CIL) Physician sample Consumer sample Other (specify) YES Is electronic content of labeling (COL) submitted? NO NA Comment X If no, request in 74-day letter. Are annotated specifications submitted for all stock keeping units (SKUs)? If no, request in 74-day letter. If representative labeling is submitted, are all represented SKUs defined? 4 http://inside fda.gov:9003/CDER/OfficeofNewDrugs/StudyEndpointsandLabelingDevelopmentTeam/ucm0 25576.htm Version: 1/21/2014 Reference ID: 3484524 8 If no, request in 74-day letter. All labeling/packaging, and current approved Rx PI (if switch) sent to OSE/DMEPA? Other Consults YES NO NA If yes, specify consult(s) and date(s) sent: Meeting Minutes/SPAs Comment CDRH – 2.6.14 OSI Clinical Inspection - 2.12.14 OSE – 3.11.14 OPDP – 3.11.14 Patient Labeling – 3.11.14 QT/IRT – TBD once datasets from final study reports arrive in May/June Are additional consults needed? (e.g., IFU to CDRH; QT study report to QT Interdisciplinary Review Team) YES NO NA Comment End-of Phase 2 meeting(s)? Date(s): November 18, 2009 If yes, distribute minutes before filing meeting Pre-NDA/Pre-BLA/Pre-Supplement meeting(s)? Date(s): October 2, 2013 If yes, distribute minutes before filing meeting Any Special Protocol Assessments (SPAs)? Date(s): If yes, distribute letter and/or relevant minutes before filing meeting Version: 1/21/2014 Reference ID: 3484524 9 ATTACHMENT MEMO OF FILING MEETING DATE: March 10. 2014 NDA 206162 PROPRIETARY NAME (Proposed) NAME: Olaparib DOSAGE Capsule/50 mg APPLICANT: AstraZeneca PROPOSED Ovarian cancer BACKGROUND: Olaparib (AZD2281, KU-0059436) is a potent oral inhibitor of polyadenosine 5'-diphosphoribose polymerase (PARP). These PARP enzymes are required for the ef?cient repair of DNA single strand breaks. During the repair process PARP auto-modi?es itself and dissociates from the DNA to facilitate access for other repair enzymes. Olaparib inhibits the action of PARP by preventing this dissociation, trapping PARP on the DNA and blocking repair of the single strand break. The proposed indication is for use as monotherapy for the maintenance treatment of adult patients with platimun?sensitive relapsed ovarian cancer (including fallopian tube or primary peritoneal) with germline BRCA mutation as detected by an FDA- approved test who are in response (complete response or partial response) to platimun- based chemotherapy. This NDA was received on February 3, 2014. REVIEW TEAM: Discipline/Organization Names Present at ?ling meeting? (Y or N) Regulatory Project Management RPM: Raj esh Venugopal L: Clnisty Cottrell Cross-Discipline Team Leader (CDTL) Amy McKee Clinical Reviewer: Geoffrey Ison TL: Amy McKee Social Scientist Review (for OTC Reviewer: products) Version: 1/21/2014 10 Reference ID: 3484524 OTC Labeling Review (for OTC TL: N/A Reviewer: N/A TL: N/A Reviewer: N/A TL: N/A products) Clinical Microbiology (for antimicrobial products) Clinical Pharmacology Biostatistics Nonclinical (Pharmacology/Toxicology) Statistics (carcinogenicity) Reviewer: Elimika Pfuma Y TL: Qi Liu N Reviewer: Hui Zhang Y TL: Shenghui Tang Y Reviewer: Brian Chiu/Tiffany Ricks Y TL: Todd Palmby Y Reviewer: N/A TL: N/A Immunogenicity (assay/assay validation) (for BLAs/BLA efficacy supplements) Reviewer: N/A TL: N/A Product Quality (CMC) Reviewer: Quality Microbiology (for sterile products) CMC Labeling Review Facility Review/Inspection (Office of Compliance_) OSE/DMEPA (proprietary name) Version: 1/21/2014 Reference ID: 3484524 Y TL: Gaetan Ladouceur/ Anne Marie Russell Ali Al Hakim/Hari Sarker Reviewer: Erika Pfeiler N TL: Bryan Riley N Y Reviewer: N/A TL: N/A Reviewer: N/A TL: N/A Reviewer: Jibril Abdus-Samad Y TL: Alice Tu N 11 OSE/DRISK (REMS) OC/OSI/DSC/PMSB (REMS) Reviewer: Naomi Redd N TL: Cynthia LaCivita N Reviewer: Robert Wittorf Y TL: Bioresearch Monitoring (OSI) Controlled Substance Staff (CSS) Other reviewers Other attendees N/A Reviewer: Lauren Iacono-Connor Y TL: Janice Pohlman N Reviewer: N/A TL: N/A Abraham Tzou – CDRH Eunice Lee – CDRH Okpo Eradiri – Biopharm Hongshan Li – Pharmacometrics Liang Zhao - Pharmacometrics Richard Pazdur – OHOP Amana Ibrahim – DOP1 Susan Jenney – DOP1 Jenna Lyndley – OSE, DPV Tracy Salaam – OSE, DPV Y FILING MEETING DISCUSSION: GENERAL • 505(b)(2) filing issues: Not Applicable o Is the application for a duplicate of a listed drug and eligible for approval under section 505(j) as an ANDA? YES NO o Did the applicant provide a scientific “bridge” demonstrating the relationship between the proposed product and the referenced product(s)/published literature? YES NO Describe the scientific bridge (e.g., BA/BE studies): • Per reviewers, are all parts in English or English translation? YES NO If no, explain: Version: 1/21/2014 Reference ID: 3484524 12 • Electronic Submission comments Not Applicable List comments: CLINICAL Not Applicable FILE REFUSE TO FILE Comments: Review issues for 74-day letter • YES NO Clinical study site(s) inspections(s) needed? If no, explain: • Advisory Committee Meeting needed? Comments: If no, for an NME NDA or original BLA , include the reason. For example: o this drug/biologic is not the first in its class o the clinical study design was acceptable o the application did not raise significant safety or efficacy issues o the application did not raise significant public health questions on the role of the drug/biologic in the diagnosis, cure, mitigation, treatment or prevention of a disease • Abuse Liability/Potential YES Date if known: June 25/26, 2014 NO To be determined Reason: Not Applicable FILE REFUSE TO FILE Comments: Review issues for 74-day letter • Not Applicable YES NO If the application is affected by the AIP, has the division made a recommendation regarding whether or not an exception to the AIP should be granted to permit review based on medical necessity or public health significance? Comments: CLINICAL MICROBIOLOGY Not Applicable FILE REFUSE TO FILE Comments: Review issues for 74-day letter Version: 1/21/2014 Reference ID: 3484524 13 CLINICAL PHARMACOLOGY Not Applicable FILE REFUSE TO FILE Comments: • Clinical pharmacology study site(s) inspections(s) needed? Review issues for 74-day letter YES NO PHARMACOMETRICS Not Applicable FILE REFUSE TO FILE Comments: Review issues for 74-day letter Not Applicable FILE REFUSE TO FILE BIOSTATISTICS Comments: NONCLINICAL (PHARMACOLOGY/TOXICOLOGY) Review issues for 74-day letter Not Applicable FILE REFUSE TO FILE Review issues for 74-day letter Comments: IMMUNOGENICITY (BLAs/BLA efficacy supplements only) Not Applicable FILE REFUSE TO FILE Review issues for 74-day letter Comments: PRODUCT QUALITY (CMC) Not Applicable FILE REFUSE TO FILE Comments: Review issues for 74-day letter BIOPHARMACEUTICS Not Applicable FILE REFUSE TO FILE Comments: Review issues for 74-day letter Environmental Assessment • Categorical exclusion for environmental assessment Version: 1/21/2014 Reference ID: 3484524 YES 14 (EA) requested? NO If no, was a complete EA submitted? YES NO If EA submitted, consulted to EA officer (OPS)? YES NO Comments: Quality Microbiology (for sterile products) Not Applicable • YES NO Was the Microbiology Team consulted for validation of sterilization? (NDAs/NDA supplements only) Comments: Facility Inspection Not Applicable • Establishment(s) ready for inspection? YES NO  Establishment Evaluation Request (EER/TBP-EER) submitted to OMPQ? YES NO Comments: Facility/Microbiology Review (BLAs only) Not Applicable FILE REFUSE TO FILE Comments: Review issues for 74-day letter CMC Labeling Review Comments: No comments for the 74-day letter Review issues for 74-day letter Version: 1/21/2014 Reference ID: 3484524 15 APPLICATIONS IN THE PROGRAM (PDUFA V) (NME NDAs/Original BLAs) N/A • Were there agreements made at the application’s pre-submission meeting (and documented in the minutes) regarding certain late submission components that could be submitted within 30 days after receipt of the original application? YES NO • If so, were the late submission components all submitted within 30 days? YES NO N/A • What late submission components, if any, arrived after 30 days? The clinical pharmacology data will be submitted as an amendment within 120 days of February 3 submission of the original NDA. • Was the application otherwise complete upon submission, including those applications where there were no agreements regarding late submission components? • Is a comprehensive and readily located list of all clinical sites included or referenced in the application? • Is a comprehensive and readily located list of all manufacturing facilities included or referenced in the application? YES NO The application was not complete however, a Refuse to File letter will not be sent to the Sponsor as the Agency agreed to this at the Pre-NDA meeting due to the life-threatening nature of the disease. The office director has stated that the Agency would accept late items for a life threatening disease. YES NO YES NO REGULATORY PROJECT MANAGEMENT Signatory Authority: Richard Pazdur, MD Date of Mid-Cycle Meeting (for NME NDAs/BLAs in “the Program” PDUFA V): May 6, 2014 21st Century Review Milestones (see attached) (listing review milestones in this document is optional): Comments: Version: 1/21/2014 Reference ID: 3484524 16 REGULATORY CONCLUSIONS/DEFICIENCIES The application is unsuitable for filing. Explain why: The application, on its face, appears to be suitable for filing. Review Issues: No review issues have been identified for the 74-day letter. Review issues have been identified for the 74-day letter. List (optional): Review Classification: Standard Review Priority Review ACTIONS ITEMS How many labeling meetings - 8 meetings July-Aug? - Done Team meetings- 1 in April? - done Will this have a REMS - No #of REMS Meeting – None # of practices for AC (3 + 1 OHOP,2nd or 3rd meeting at Monday ohop, Pazdur to 2nd and 4th meeting) meeting in June)? - done Wrap-up meeting –yes - done Ensure that any updates to the review priority (S or P) and classifications/properties are entered into tracking system (e.g., chemical classification, combination product classification, 505(b)(2), orphan drug). If RTF, notify everybody who already received a consult request, OSE PM, and Product Quality PM (to cancel EER/TBP-EER). If filed, and the application is under AIP, prepare a letter either granting (for signature by Center Director) or denying (for signature by ODE Director) an exception for review. BLA/BLA supplements: If filed, send 60-day filing letter If priority review: • notify sponsor in writing by day 60 (For BLAs/BLA supplements: include in 60-day filing letter; For NDAs/NDA supplements: see CST for choices) • notify OMPQ (so facility inspections can be scheduled earlier) Send review issues/no review issues by day 74 Conduct a PLR format labeling review and include labeling issues in the 74-day letter Update the PDUFA V DARRTS page (for NME NDAs in the Program) BLA/BLA supplements: Send the Product Information Sheet to the product reviewer and Version: 1/21/2014 Reference ID: 3484524 17 the Facility Information Sheet to the facility reviewer for completion. Ensure that the completed forms are forwarded to the CDER RMS-BLA Superuser for data entry into RMS-BLA one month prior to taking an action [These sheets may be found in the CST eRoom at: http://eroom.fda.gov/eRoom/CDER2/CDERStandardLettersCommittee/0 1685f ] Other Version: 1/21/2014 Reference ID: 3484524 18 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------RAJESH VENUGOPAL 04/07/2014 CHRISTY L COTTRELL 04/08/2014 Reference ID: 3484524 REGULATORY PROJECT MANAGER PHYSICIAN’S LABELING RULE (PLR) FORMAT REVIEW OF THE PRESCRIBING INFORMATION Complete for all new NDAs, BLAs, Efficacy Supplements, and PLR Conversion Labeling Supplements Application: NDA 206162 Application Type: New NME NDA Name of Drug/Dosage Form: Olaparib 50 mg Capsules Applicant: AstraZeneca Receipt Date: February 3, 2014 Goal Date: October 3, 2014 1. Regulatory History and Applicant’s Main Proposals Olaparib is a PARP (poly ADP ribose polymerase) inhibitor indicated as monotherapy for the maintenance treatment of adult patients with platinum-sensitive relapsed ovarian cancer (including fallopian tube or primary peritoneal) with germline BRCA (gBRCA) mutation as detected by an FDAapproved test who are in response (complete response or partial response) to platinum-based chemotherapy. 2. Review of the Prescribing Information This review is based on the applicant’s submitted Word format of the prescribing information (PI). The applicant’s proposed PI was reviewed in accordance with the labeling format requirements listed in the “Selected Requirements for Prescribing Information (SRPI)” checklist (see the Appendix). 3. Conclusions/Recommendations SRPI format deficiencies were identified in the review of this PI. For a list of these deficiencies see the Appendix. Reference ID: 3483643 Selected Requirements of Prescribing Information Appendix The Selected Requirement of Prescribing Information (SRPI) is a 42-item, drop-down checklist of important format elements of the prescribing information (PI) based on labeling regulations (21 CFR 201.56 and 201.57) and guidances. Highlights See Appendix A for a sample tool illustrating the format for the Highlights. HIGHLIGHTS GENERAL FORMAT and HORIZONTAL LINES IN THE PI YES 1. Highlights (HL) must be in a minimum of 8-point font and should be in two-column format, with ½ inch margins on all sides and between columns. Comment: YES 2. The length of HL must be one-half page or less (the HL Boxed Warning does not count against the one-half page requirement) unless a waiver has been granted in a previous submission (e.g., the application being reviewed is an efficacy supplement). Instructions to complete this item: If the length of the HL is one-half page or less, then select “YES” in the drop-down menu because this item meets the requirement. However, if HL is longer than one-half page:  For the Filing Period: • For efficacy supplements: If a waiver was previously granted, select “YES” in the dropdown menu because this item meets the requirement. • For NDAs/BLAs and PLR conversions: Select “NO” because this item does not meet the requirement (deficiency). The RPM notifies the Cross-Discipline Team Leader (CDTL) of the excessive HL length and the CDTL determines if this deficiency is included in the 74day or advice letter to the applicant.  For the End-of-Cycle Period: • Select “YES” in the drop down menu if a waiver has been previously (or will be) granted by the review division in the approval letter and document that waiver was (or will be) granted. Comment: YES 3. A horizontal line must separate HL from the Table of Contents (TOC). A horizontal line must separate the TOC from the FPI. Comment: YES 4. All headings in HL must be bolded and presented in the center of a horizontal line (each horizontal line should extend over the entire width of the column as shown in Appendix A). The headings should be in UPPER CASE letters. SRPI version 3: October 2013 Reference ID: 3483643 Page 2 of 11 Selected Requirements of Prescribing Information Comment: NO YES NO 5. White space should be present before each major heading in HL. There must be no white space between the HL Heading and HL Limitation Statement. There must be no white space between the product title and Initial U.S. Approval. See Appendix A for a sample tool illustrating white space in HL. Comment: 6. Each summarized statement or topic in HL must reference the section(s) or subsection(s) of the Full Prescribing Information (FPI) that contain more detailed information. The preferred format is the numerical identifier in parenthesis [e.g., (1.1)] at the end of each summarized statement or topic. Comment: 7. Section headings must be presented in the following order in HL: Section Required/Optional Required • Highlights Heading Required • Highlights Limitation Statement Required • Product Title Required • Initial U.S. Approval Required if a BOXED WARNING is in the FPI • Boxed Warning Required for only certain changes to PI* • Recent Major Changes Required • Indications and Usage Required • Dosage and Administration Required • Dosage Forms and Strengths Required (if no contraindications must state “None.”) • Contraindications Not required by regulation, but should be present • Warnings and Precautions Required • Adverse Reactions Optional • Drug Interactions Optional • Use in Specific Populations • Patient Counseling Information Statement Required Required • Revision Date * RMC only applies to the BOXED WARNING, INDICATIONS AND USAGE, DOSAGE AND ADMINISTRATION, CONTRAINDICATIONS, and WARNINGS AND PRECAUTIONS sections. Comment: Contraindications not listed in HL. HIGHLIGHTS DETAILS Highlights Heading YES 8. At the beginning of HL, the following heading must be bolded and should appear in all UPPER CASE letters: “HIGHLIGHTS OF PRESCRIBING INFORMATION”. Comment: Highlights Limitation Statement YES SRPI version 3: October 2013 Reference ID: 3483643 Page 3 of 11 Selected Requirements of Prescribing Information 9. The bolded HL Limitation Statement must include the following verbatim statement: “These highlights do not include all the information needed to use (insert name of drug product) safely and effectively. See full prescribing information for (insert name of drug product).” The name of drug product should appear in UPPER CASE letters. Comment: Product Title in Highlights YES 10. Product title must be bolded. Comment: Initial U.S. Approval in Highlights N/A 11. Initial U.S. Approval in HL must be bolded, and include the verbatim statement “Initial U.S. Approval:” followed by the 4-digit year. Comment: N/A N/A Boxed Warning (BW) in Highlights 12. All text in the BW must be bolded. Comment: 13. The BW must have a heading in UPPER CASE, containing the word “WARNING” (even if more than one warning, the term, “WARNING” and not “WARNINGS” should be used) and other words to identify the subject of the warning (e.g., “WARNING: SERIOUS INFECTIONS and ACUTE HEPATIC FAILURE”). The BW heading should be centered. Comment: N/A 14. The BW must always have the verbatim statement “See full prescribing information for complete boxed warning.” This statement should be centered immediately beneath the heading and appear in italics. Comment: N/A 15. The BW must be limited in length to 20 lines (this includes white space but does not include the BW heading and the statement “See full prescribing information for complete boxed warning.”). Comment: N/A Recent Major Changes (RMC) in Highlights 16. RMC pertains to only the following five sections of the FPI: BOXED WARNING, INDICATIONS AND USAGE, DOSAGE AND ADMINISTRATION, CONTRAINDICATIONS, and WARNINGS AND PRECAUTIONS. RMC must be listed in the same order in HL as the modified text appears in FPI. SRPI version 3: October 2013 Reference ID: 3483643 Page 4 of 11 Selected Requirements of Prescribing Information Comment: N/A N/A YES N/A NO 17. The RMC must include the section heading(s) and, if appropriate, subsection heading(s) affected by the recent major change, together with each section’s identifying number and date (month/year format) on which the change was incorporated in the PI (supplement approval date). For example, “Warnings and Precautions, Acute Liver Failure (5.1) --- 9/2013”. Comment: 18. The RMC must list changes for at least one year after the supplement is approved and must be removed at the first printing subsequent to one year (e.g., no listing should be one year older than revision date). Comment: Indications and Usage in Highlights 19. If a product belongs to an established pharmacologic class, the following statement is required under the Indications and Usage heading in HL: “(Product) is a (name of established pharmacologic class) indicated for (indication)”. Comment: Dosage Forms and Strengths in Highlights 20. For a product that has several dosage forms (e.g., capsules, tablets, and injection), bulleted subheadings or tabular presentations of information should be used under the Dosage Forms and Strengths heading. Comment: Contraindications in Highlights 21. All contraindications listed in the FPI must also be listed in HL or must include the statement “None” if no contraindications are known. Each contraindication should be bulleted when there is more than one contraindication. Comment: YES Adverse Reactions in Highlights 22. For drug products other than vaccines, the verbatim bolded statement must be present: “To report SUSPECTED ADVERSE REACTIONS, contact (insert name of manufacturer) at (insert manufacturer’s U.S. phone number) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch”. Comment: Patient Counseling Information Statement in Highlights SRPI version 3: October 2013 Reference ID: 3483643 Page 5 of 11 Selected Requirements of Prescribing Information YES 23. The Patient Counseling Information statement must include one of the following three bolded verbatim statements that is most applicable: If a product does not have FDA-approved patient labeling: • “See 17 for PATIENT COUNSELING INFORMATION” If a product has FDA-approved patient labeling: • “See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling” • “See 17 for PATIENT COUNSELING INFORMATION and Medication Guide” Comment: YES Revision Date in Highlights 24. The revision date must be at the end of HL, and should be bolded and right justified (e.g., “Revised: 9/2013”). Comment: SRPI version 3: October 2013 Reference ID: 3483643 Page 6 of 11 Selected Requirements of Prescribing Information Contents: Table of Contents (TOC) See Appendix A for a sample tool illustrating the format for the Table of Contents. YES 25. The TOC should be in a two-column format. Comment: YES 26. The following heading must appear at the beginning of the TOC: “FULL PRESCRIBING INFORMATION: CONTENTS”. This heading should be in all UPPER CASE letters and bolded. Comment: N/A 27. The same heading for the BW that appears in HL and the FPI must also appear at the beginning of the TOC in UPPER CASE letters and bolded. Comment: YES 28. In the TOC, all section headings must be bolded and should be in UPPER CASE. Comment: NO 29. In the TOC, all subsection headings must be indented and not bolded. The headings should be in title case [first letter of all words are capitalized except first letter of prepositions (through), articles (a, an, and the), or conjunctions (for, and)]. Comment: YES 30. The section and subsection headings in the TOC must match the section and subsection headings in the FPI. Comment: YES 31. In the TOC, when a section or subsection is omitted, the numbering must not change. If a section or subsection from 201.56(d)(1) is omitted from the FPI and TOC, the heading “FULL PRESCRIBING INFORMATION: CONTENTS” must be followed by an asterisk and the following statement must appear at the end of TOC: “*Sections or subsections omitted from the full prescribing information are not listed.” Comment: SRPI version 3: October 2013 Reference ID: 3483643 Page 7 of 11 Selected Requirements of Prescribing Information Full Prescribing Information (FPI) FULL PRESCRIBING INFORMATION: GENERAL FORMAT YES 32. The bolded section and subsection headings in the FPI must be named and numbered in accordance with 21 CFR 201.56(d)(1) as noted below (section and subsection headings should be in UPPER CASE and title case, respectively). If a section/subsection required by regulation is omitted, the numbering must not change. Additional subsection headings (i.e., those not named by regulation) must also be bolded and numbered. BOXED WARNING 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 6 ADVERSE REACTIONS 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Labor and Delivery 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance 9.2 Abuse 9.3 Dependence 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 12.4 Microbiology (by guidance) 12.5 Pharmacogenomics (by guidance) 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 13.2 Animal Toxicology and/or Pharmacology 14 CLINICAL STUDIES 15 REFERENCES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION Comment: YES 33. The preferred presentation for cross-references in the FPI is the section (not subsection) heading followed by the numerical identifier. The entire cross-reference should be in italics and enclosed within brackets. For example, “[see Warnings and Precautions (5.2)]” or “[see Warnings and Precautions (5.2)]”. SRPI version 3: October 2013 Reference ID: 3483643 Page 8 of 11 Selected Requirements of Prescribing Information Comment: N/A 34. If RMCs are listed in HL, the corresponding new or modified text in the FPI sections or subsections must be marked with a vertical line on the left edge. Comment: FULL PRESCRIBING INFORMATION DETAILS FPI Heading YES 35. The following heading must be bolded and appear at the beginning of the FPI: “FULL PRESCRIBING INFORMATION”. This heading should be in UPPER CASE. Comment: N/A N/A BOXED WARNING Section in the FPI 36. In the BW, all text should be bolded. Comment: 37. The BW must have a heading in UPPER CASE, containing the word “WARNING” (even if more than one Warning, the term, “WARNING” and not “WARNINGS” should be used) and other words to identify the subject of the Warning (e.g., “WARNING: SERIOUS INFECTIONS and ACUTE HEPATIC FAILURE”). Comment: YES CONTRAINDICATIONS Section in the FPI 38. If no Contraindications are known, this section must state “None.” Comment: NO ADVERSE REACTIONS Section in the FPI 39. When clinical trials adverse reactions data are included (typically in the “Clinical Trials Experience” subsection of ADVERSE REACTIONS), the following verbatim statement or appropriate modification should precede the presentation of adverse reactions: “Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.” (b) (4) Comment: N/A 40. When postmarketing adverse reaction data are included (typically in the “Postmarketing Experience” subsection of ADVERSE REACTIONS), the following verbatim statement or appropriate modification should precede the presentation of adverse reactions: SRPI version 3: October 2013 Reference ID: 3483643 Page 9 of 11 Selected Requirements of Prescribing Information “The following adverse reactions have been identified during post-approval use of (insert drug name). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.” Comment: YES YES PATIENT COUNSELING INFORMATION Section in the FPI 41. Must reference any FDA-approved patient labeling in Section 17 (PATIENT COUNSELING INFORMATION section). The reference should appear at the beginning of Section 17 and include the type(s) of FDA-approved patient labeling (e.g., Patient Information, Medication Guide, Instructions for Use). Comment: 42. FDA-approved patient labeling (e.g., Medication Guide, Patient Information, or Instructions for Use) must not be included as a subsection under section 17 (PATIENT COUNSELING INFORMATION). All FDA-approved patient labeling must appear at the end of the PI upon approval. Comment: SRPI version 3: October 2013 Reference ID: 3483643 Page 10 of 11 Selected Requirements of Prescribing Information Appendix A: Format of the Highlights and Table of Contents SRPI version 3: October 2013 Reference ID: 3483643 Page 11 of 11 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------RAJESH VENUGOPAL 04/04/2014 CHRISTY L COTTRELL 04/04/2014 Reference ID: 3483643 DGCPC/OSI CONSULT: Request for Clinical Inspections Date: 2/12/2014 To: Ni Khin, Acting Division Director, DGCPC Kassa Ayalew, M.D., Acting Branch Chief, GCPAB Janice Pohlman, M.D., M.P.H., Team Leader GCPAB CDEROCDSIPMOs@fda.hhs.gov Lauren Iacono-Connor, Ph.D. Division of Good Clinical Practice Compliance Office of Scientific Investigations Office of Compliance/CDER Through: Geoffrey Kim/Gwynn Ison, DOP1 Amy McKee 9TL)/Amna Ibrahim (Dep. Dir.), DOP1 From: Rajesh Venugopal, DOP1 Subject: Request for Clinical Site Inspections I. General Information Application#: 206162 IND#:75918 Applicant: AstraZeneca Phone: Email: Regulatory Point of Contact: Darci Bertelsen, Regulatory Affairs Director Regulatory Point of Contact Phone: (302) 886-7355 Regulatory Point of Contact Email: darci.bertelsen@astrazeneca.com Drug Proprietary Name: pending Generic Drug Name: olaparib (AZD2281, KU-0059436) NME or Original BLA (Yes/No): Yes Review Priority (Standard or Priority): Priority Study Population includes < 17 years of age (Yes/No): No Is this for Pediatric Exclusivity (Yes/No): No Proposed New Indication(s): Indicated as monotherapy for the maintenance treatment of adult patients with platinum-sensitive relapsed ovarian cancer (including fallopian tube or primary peritoneal) with germline BRCA (gBRCA) mutation as detected by an FDA-approved test who are in response (complete response or partial response) to platinum-based therapy DGCPC/OSI Consult version: 09/28/2011 Reference ID: 3453140 Page 2-Request for Clinical Inspections PDUFA: October 3, 2014 Action Goal Date: October 3, 2014 Inspection Summary Goal Date: August 7, 2014 Reference ID: 3453140 Page 3-Request for Clinical Inspections II. Protocol/Site Identi?cation Include the Protocol Title or Protocol Number for all protocols to be audited. Complete the following table (Note: All items listed are required, to process inspection request. Failure to provide complete information will result in delay of inspection process). Number (Name,Address, Phone Site Protocol ID of Indication number, email, fax#) Subjects Gourley, Charlie Randomised, double blind, study Western General Hospital, on the ef?cacy of AZD2281 in Edinblu?gh (Lothian NHS the treatment of patients with board University hospitals platinum sensitive serous ovarian division) Cancer Research cancer following treatment with Centre, Westem General 2 01' more platinum containing Hospital, rewe Road South 1703 D0810C00019 13 regimens Edinburgh, NA EH4 2UX GBR Westeln Europe phone: (m4) fax: (4) email: an?) Halter, Phillip Randomised, double blind, study HSK, Dr. Horst Schmidt on the ef?cacy of AZD2281 in Klinik ,Depaltment of the treatment of patients with Gynecology Gynecologic platinum sensitive serous ovarian Oncology, Ludwig-Erhard? cancer following treatment with StraBe 100 2 or more platinum containing Wiesbaden, NA 65199 701 D0810C00019 14 regimens DEU Westeln Elu'ope phone: fax: email (m4) Matulonis, Ursula Randomised, double blind, study Dana Faber Cancer Institute, on the ef?cacy of AZD2281 in 44 Biimey St, LG1B15 the treatment of patients with Boston, MA 2115 platinum sensitive serous ovarian USA United States 1802 D0810C00019 1 1 cancer following treatment with phone: 2 01' more platinum containing fax: (m4) regimens email: (m4) Reference ID: 3453140 Page 4-Request for Clinical Inspections (N ame,Address, Phone number, email, fax#) Site Protocol ID Number of Subjects Indication Matulonis, Ursula Massachusetts General Hospital,55 Fruit St. Boston, MA 2114 USA United States 1801 D0810C00019 phone: fax: email: (4) w) H) (4) Randomised, double blind, study on the ef?cacy of AZD2281 in the treatment of patients with platimun sensitive serous ovarian cancer following treatment with 2 or more platinum containing regimens Site Selection/Rationale Site Information sruovz 130810000019 [1802 NAME Matulonis, Ursula ana Faber Cancer Institute, 44 Binney St, LG1B15 LOCATION Foston, MA, USA 21 15 PHONEIFAX EMAIL (mm 7 FINLDISC 0 COMPLAINT IT RISK 14.8 OAI 0 TSLI Reference ID: 3453140 Page 5-Request for Clinical Inspections Site Values vs. Overall Results EIROLL SITEEFE SCREI Max 14 1.00 1.00 9.00 2.00 100% Study Rate 3 0.58 0.22 1.88 032 86% Min 1 0.00 -100 0.00 4.14 33% Site 11 0.55 0.10 6.00 -0.60 100% NSAE SAE DEATH DISCONT PROTVIOL nos EXPEUBICE Max 25.0 2.7 100% 100% 2.0 4.0 21 Study Rate 9Site 12Site Memo Reference ID: 3453140 Page 6-Request for Clinical Inspections Site Information ISTUDY: 130810000019 h801 NAME Natulonis, Ursula assachusetts General Hospital,55 Fruit St. LOCATION oston, MA, USA 2114 PHONEIFAX EMAIL 0814) 5 FINLDISC 0 COMPLAINT 0 RISK 15.7 OAI 0 Tsu 3 Site Values vs. Overall Studv Results ENROLL TRTEFR SITEEFFE SCREEN Max 14 1.00 1.00 9.00 2.00 100% Study Rate 3 0.58 0.22 1.88 6.32 86% Min 1 0.00 -1.00 0.00 4.14 33% Site 9 0.78 033 7.00 ?2.00 75% NSAE SAE DEATH DISCONT PROTVIOL EXPERIENCE Max 25.0 2.7 100% 100% 2.0 4.0 21 Study Rate 9Site 7Site Memo Reference ID: 3453140 Page 7-Request for Clinical Inspections Site Information sru0vz p0810000019 h703 NAME pouney, Charlie estem General Hospital, Edinburgh (Lothian NHS board University hospitals ivision) Cancer Research Centre, Western General Hospital, Crewe Road South dinburgh, NA, GBR EH4 2UX PHONEIFAX (4) EMAIL (4) 2 FINLDISC 0 COMPLAINT 0 RISK 21.4 OAI 0 TSLI 3 Site Values vs. Overall Studv Results ENROLL TRTEFR SITEEFE SCREEN Max 14 1.00 1.00 9.00 2.00 100% Study Rate 3 0.58 022 1.88 032 86% Min 1 0.00 -1.00 0.00 414 33% Site 13 0.54 069 7.00 414 81% i NSAE SAE DEATH DISCONT PROTVIOL EXPERIENCE Max 25.0 2.7 100% 100% 2.0 4.0 21 Study Rate 9Site 16Site Memo Reference ID: 3453140 Page 8-Request for Clinical Inspections Site Information ISTUDY: p0810?00019 701 NAME hatter, Phillip SK, Dr. Horst Schmidt Klin ,Department of Gynecology Gynecologic Oncology, udwigErhard-Stralse 100 iesbaden, NA, DEU 65199 PHONEIFAX (4) EMAIL 00(4) 1 FINLDISC 625 COMPLAINT 0 RISK 23.7 OAI 0 Tsu 3 Site Values vs. Overall Studv Results ENROLL TRTEFR SITEEFE SCREEN Max 14 1.00 1.00 9.00 2.00 100% Study Rate 3 0.58 0.22 1.88 0.32 86% Min 1 0.00 -100 0.00 4.14 33% Site 14 0.50 016 7.00 0.78 74% . NSAE SAE DEATH DISCONT PROTVIOL EXPERIENCE Max 25.0 2.7 100% 100% 2.0 4.0 21 Study Rate 9Site 9Site Memo Reference ID: 3453140 Page 9-Request for Clinical Inspections Summarize the reason for requesting OSI consult and then complete the checklist that follows your rationale for site selection. Medical Officers may choose to consider the following in providing their summary for site selection. Rationale for OSI Audits  A specific safety concern at a particular site based on review of AEs, SAEs, deaths, or discontinuations  A specific efficacy concern based on review of site specific efficacy data  Specific concern for scientific misconduct at one or more particular sites based on review of financial disclosures, protocol violations, study discontinuations, safety and efficacy results See at end of consult template for OSI’s thoughts on things to consider in your decision making process Reference ID: 3453140 Page 10-Request for Clinical Inspections Domestic Inspections: Reasons for inspections (please check all that apply):  Enrollment of large numbers of study subjects High treatment responders (specify): Significant primary efficacy results pertinent to decision-making There is a serious issue to resolve, e.g., suspicion of fraud, scientific misconduct, significant human subject protection violations or adverse event profiles. Other (specify): International Inspections: Reasons for inspections (please check all that apply):  There are insufficient domestic data Only foreign data are submitted to support an application Domestic and foreign data show conflicting results pertinent to decision-making There is a serious issue to resolve, e.g., suspicion of fraud, scientific misconduct, or significant human subject protection violations. Other (specify) (Examples include: Enrollment of large numbers of study subjects and site specific protocol violations. This would be the first approval of this new drug and most of the limited experience with this drug has been at foreign sites, it would be desirable to include one foreign site in the DSI inspections to verify the quality of conduct of the study). Five or More Inspection Sites (delete this if it does not apply): We have requested these sites for inspection (international and/or domestic) because of the following reasons: state reason(s) and prioritize sites. Note: International inspection requests or requests for five or more inspections require sign-off by the OND Division Director and forwarding through the Director, DGCPC. IV. Tables of Specific Data to be Verified (if applicable) If you have specific data that needs to be verified, please provide a table for data verification, if applicable. Should you require any additional information, please contact 301-796. Concurrence: (as needed) Medical Team Leader Medical Reviewer Reference ID: 3453140 at 301-796- or at Page 11-Request for Clinical Inspections Division Director (for foreign inspection requests or requests for 5 or more sites only) Things to consider in decision to submit request for OSI Audit  Evaluate site specific efficacy. Note the sites with the greatest efficacy compared to active or placebo comparator. Are these sites driving the results?  Determine the sites with the largest number of subjects. Is the efficacy being driven by these sites?  Evaluate the financial disclosures. Do sites with investigators holding financial interest in the sponsor’s company show superior efficacy compared to other sites?  Are there concerns that the data may be fraudulent or inconsistent?  Efficacy looks too good to be true, based on knowledge of drug based on previous clinical studies and/or mechanism of action  Expected commonly reported AEs are not reported in the NDA  Evaluate the protocol violations. Are there a significant number of protocol violations reported at one or more particular sites? Are the types of protocol violations suspicious for clinical trial misconduct?  Is this a new molecular entity or original biological product?  Is the data gathered solely from foreign sites?  Were the NDA studies conducted under an IND? Reference ID: 3453140 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------RAJESH VENUGOPAL 02/12/2014 AMY E MCKEE 02/12/2014 AMNA IBRAHIM 02/12/2014 Reference ID: 3453140