CENTER FOR DRUG EVALUATION AND RESEARCH
APPLICATION NUMBER:
213591Orig1s000
OTHER REVIEW(S) SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED)
I. GENERAL INFORMATION
Device Generic Name: Next generation sequencing oncology panel, somatic or germline variant detection system
Device Trade Name: FoundationOne®CDx (F1CDx)
Device Procode: PQP
Applicant’s Name and Address: Foundation Medicine, Inc. 150 Second Street Cambridge, MA 02141
Date(s) of Panel Recommendation: None
Premarket Approval Application (PMA) Number: P170019/S011
Date of FDA Notice of Approval: May 6, 2020
The original PMA (P170019) for FoundationOne®CDx (F1CDx) was approved on November 30, 2017 for the detection of genetic alterations in patients who may benefit from one of fifteen FDA-approved therapies for non-small cell lung cancer (NSCLC), melanoma, breast cancer, colorectal cancer, and ovarian cancer. Subsequently, six PMA supplements were approved for expanding the indications for use of F1CDx since its original approval. PMA supplement (P170019/S005) for adding genomic loss of heterozygosity (LOH) was approved on April 10, 2019. PMA supplement (P170019/S004) for adding an indication for LYNPARZA® (olaparib) in ovarian cancer patients with BRCA1/2 alterations was approved on July 1, 2019. PMA supplement (P170019/S008) for adding an indication for TAGRISSO® (osimertinib) in NSCLC patients with EGFR exon 19 deletions and EGFR exon 21 L858R alterations was approved on July 1, 2019. PMA supplement (P170019/S006) for adding an indication for PIQRAY® (alpelisib) in breast cancer patients with PIK3CA alterations was approved on December 3, 2019. PMA supplement (P170019/S010) for adding a second site in Research Triangle Park, NC, where the F1CDx assay will be performed was approved on December 16, 2019. PMA supplement (P170019/S013) for adding an indication for PEMZYRE® (pemigatinib) in cholangiocarinoma patients with FGFR2 fusions was approved on April 17, 2020.
The current supplement was submitted to expand the intended use of F1CDx to include a companion diagnostic indication for single nucleotide variants (SNVs) and indels that lead to MET exon 14 skipping in NSCLC patients who may benefit from treatment with TABRECTA® (capmatinib).
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Reference ID: 4604109
II. INDICATIONS FOR USE
FoundationOne®CDx (F1CDx) is a next generation sequencing based in vitro diagnostic device for detection of substitutions, insertion and deletion alterations (indels) and copy number alterations (CNAs) in 324 genes and select gene rearrangements, as well as genomic signatures including microsatellite instability (MSI) and tumor mutational burden (TMB) using DNA isolated from formalin-fixed paraffin embedded (FFPE) tumor tissue specimens. The test is intended as a companion diagnostic to identify patients who may benefit from treatment with the targeted therapies listed in Table 1 in accordance with the approved therapeutic product labeling. Additionally, F1CDx is intended to provide tumor mutation profiling to be used by qualified health care professionals in accordance with professional guidelines in oncology for cancer patients with solid malignant neoplasms. Genomic findings other than those listed in Table 1 are not prescriptive or conclusive for labeled use of any specific therapeutic product.
Table 1. Companion diagnostic indications Indication Biomarker Therapy Non-small cell lung EGFR exon 19 deletions and EGFR exon GILOTRIF® (afatinib), cancer (NSCLC) 21 L858R alterations IRESSA® (gefitinib), TAGRISSO® (osimertinib), or TARCEVA® (erlotinib) EGFR exon 20 T790M alterations TAGRISSO® (osimertinib) ALK rearrangements ALECENSA® (alectinib), XALKORI® (crizotinib), or ZYKADIA® (ceritinib) BRAF V600E TAFINLAR® (dabrafenib) in combination with MEKINIST® (trametinib) MET single nucleotide variants (SNVs) TABRECTA™ (capmatinib) and indels that lead to MET exon 14 skipping Melanoma BRAF V600E TAFINLAR® (dabrafenib) or ZELBORAF® (vemurafenib) BRAF V600E and V600K MEKINIST® (trametinib) or COTELLIC® (cobimetinib) in combination with ZELBORAF® (vemurafenib) Breast cancer ERBB2 (HER2) amplification HERCEPTIN® (trastuzumab), KADCYLA® (ado trastuzumab-emtansine), or PERJETA® (pertuzumab) PIK3CA C420R, E542K, E545A, E545D PIQRAY® (alpelisib) [1635G>T only], E545G, E545K, Q546E, Q546R, H1047L, H1047R, and H1047Y alterations
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Reference ID: 4604109 Indication Biomarker Therapy Colorectal cancer KRAS wild-type (absence of mutations in ERBITUX® (cetuximab) codons 12 and 13) KRAS wild-type (absence of mutations in VECTIBIX® (panitumumab) exons 2, 3, and 4) and NRAS wild-type (absence of mutations in exons 2, 3, and 4) Ovarian cancer BRCA1/2 alterations LYNPARZA® (olaparib) or RUBRACA® (rucaparib) Cholangiocarcinoma FGFR2 fusions and select rearrangements Pemazyre™ (pemigatinib)
The test is also used for detection of genomic loss of heterozygosity (LOH) from formalin-fixed, paraffin-embedded (FFPE) ovarian tumor tissue. Positive homologous recombination deficiency (HRD) status (F1CDx HRD defined as tBRCA-positive and/or LOH high) in ovarian cancer patients is associated with improved progression-free survival (PFS) from RUBRACA (rucaparib) maintenance therapy in accordance with the RUBRACA product label.
The F1CDx assay is be performed at Foundation Medicine, Inc. sites located in Cambridge, MA and Morrisville, NC.
III. CONTRAINDICATIONS
There are no known contraindications.
IV. WARNINGS AND PRECAUTIONS
The warnings and precautions can be found in the FoundationOne®CDx assay labeling.
V. DEVICE DESCRIPTION
FoundationOne®CDx (F1CDx) is performed at Foundation Medicine, Inc. sites located in Cambridge, MA and Morrisville, NC. The assay includes reagents, software, instruments and procedures for testing DNA extracted from formalin-fixed, paraffin- embedded (FFPE) tumor samples.
The assay employs a single DNA extraction method from routine FFPE biopsy or surgical resection specimens, 50-1000 ng of which undergoes whole-genome shotgun library construction and hybridization-based capture of all coding exons from 309 cancer-related genes, 1 promoter region, 1 non-coding RNA (ncRNA), and select intronic regions from 34 commonly rearranged genes, 21 of which also include the coding exons (refer to Table 2 and Table 3, below, for the complete list of genes included in F1CDx). In total, the assay therefore detects alterations in a total of 324 genes. Using the Illumina® HiSeq 4000 platform, hybrid-capture selected libraries will be sequenced to high uniform depth (targeting > 500X median coverage with > 99% of exons at coverage > 100X). Sequence data is processed using a customized analysis
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Reference ID: 4604109 pipeline designed to detect all classes of genomic alterations, including base substitutions, indels, copy number alterations (amplifications and homozygous deletions), and selected genomic rearrangements (e.g., gene fusions). Additionally, genomic signatures including microsatellite instability (MSI), tumor mutational burden (TMB), and positive homologous recombination deficiency (HRD) status (tBRCA positive and/or LOH high) will be reported.
Table 2. Genes with full coding exonic regions included in F1CDx for the detection of substitutions, insertions and deletions (indels), and copy number alterations (CNAs) ABL1 BRAF CDKN1A EPHA3 FGFR4 IKZF1 MCL1 NKX2-1 PMS2 RNF43 TET2 ACVR1B BRCA1 CDKN1B EPHB1 FH INPP4B MDM2 NOTCH1 POLD1 ROS1 TGFBR2 AKT1 BRCA2 CDKN2A EPHB4 FLCN IRF2 MDM4 NOTCH2 POLE RPTOR TIPARP AKT2 BRD4 CDKN2B ERBB2 FLT1 IRF4 MED12 NOTCH3 PPARG SDHA TNFAIP3 AKT3 BRIP1 CDKN2C ERBB3 FLT3 IRS2 MEF2B NPM1 PPP2R1A SDHB TNFRSF14 ALK BTG1 CEBPA ERBB4 FOXL2 JAK1 MEN1 NRAS PPP2R2A SDHC TP53 ALOX12B BTG2 CHEK1 ERCC4 FUBP1 JAK2 MERTK NT5C2 PRDM1 SDHD TSC1 AMER1 BTK CHEK2 ERG GABRA6 JAK3 MET NTRK1 PRKAR1A SETD2 TSC2 APC C11orf30 CIC ERRFI1 GATA3 JUN MITF NTRK2 PRKCI SF3B1 TYRO3 AR CALR CREBBP ESR1 GATA4 KDM5A MKNK1 NTRK3 PTCH1 SGK1 U2AF1 ARAF CARD11 CRKL EZH2 GATA6 KDM5C MLH1 P2RY8 PTEN SMAD2 VEGFA GID4 ARFRP1 CASP8 CSF1R FAM46C KDM6A MPL PALB2 PTPN11 SMAD4 VHL (C17orf39) SMARC ARID1A CBFB CSF3R FANCA GNA11 KDR MRE11A PARK2 PTPRO WHSC1 A4 SMARC ASXL1 CBL CTCF FANCC GNA13 KEAP1 MSH2 PARP1 QKI WHSC1L1 B1 ATM CCND1 CTNNA1 FANCG GNAQ KEL MSH3 PARP2 RAC1 SMO WT1 ATR CCND2 CTNNB1 FANCL GNAS KIT MSH6 PARP3 RAD21 SNCAIP XPO1 ATRX CCND3 CUL3 FAS GRM3 KLHL6 MST1R PAX5 RAD51 SOCS1 XRCC2 KMT2A AURKA CCNE1 CUL4A FBXW7 GSK3B MTAP PBRM1 RAD51B SOX2 ZNF217 (MLL) KMT2D AURKB CD22 CXCR4 FGF10 H3F3A MTOR PDCD1 RAD51C SOX9 ZNF703 (MLL2) PDCD1L AXIN1 CD274 CYP17A1 FGF12 HDAC1 KRAS MUTYH RAD51D SPEN G2 AXL CD70 DAXX FGF14 HGF LTK MYC PDGFRA RAD52 SPOP BAP1 CD79A DDR1 FGF19 HNF1A LYN MYCL PDGFRB RAD54L SRC BARD1 CD79B DDR2 FGF23 HRAS MAF MYCN PDK1 RAF1 STAG2 BCL2 CDC73 DIS3 FGF3 HSD3B1 MAP2K1 MYD88 PIK3C2B RARA STAT3 BCL2L1 CDH1 DNMT3A FGF4 ID3 MAP2K2 NBN PIK3C2G RB1 STK11 BCL2L2 CDK12 DOT1L FGF6 IDH1 MAP2K4 NF1 PIK3CA RBM10 SUFU BCL6 CDK4 EED FGFR1 IDH2 MAP3K1 NF2 PIK3CB REL SYK
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Reference ID: 4604109 BCOR CDK6 EGFR FGFR2 IGF1R MAP3K13 NFE2L2 PIK3R1 RET TBX3 BCORL1 CDK8 EP300 FGFR3 IKBKE MAPK1 NFKBIA PIM1 RICTOR TEK
Table 3. Genes with select intronic regions for the detection of gene rearrangements, a promoter region, and an ncRNA gene ALK BRCA1 ETV4 EZR KIT MYC NUTM1 RET SLC34A2 introns 18, introns 2, introns 5, introns 9- intron 16 intron 1 intron 1 introns 7 intron 4 19 7, 8, 12, 6 11 11 16, 19, 20 BCL2 BRCA2 ETV5 FGFR1 KMT2A NOTCH2 PDGFRA ROS1 TERC 3’UTR intron 2 introns 6, intron 1, 5, (MLL) intron 26 introns 7, introns 31 ncRNA 7 17 introns 6 9, 11 35 11 BCR CD74 ETV6 FGFR2 MSH2 NTRK1 RAF1 RSPO2 TERT introns 8, introns 6- introns 5, intron 1, intron 5 introns 8 introns 4-8 intron 1 Promoter 13, 14 8 6 17 10 BRAF EGFR EWSR1 FGFR3 MYB NTRK2 RARA SDC4 TMPRSS2 introns 7- introns 7, introns 7 intron 17 intron 14 Intron 12 intron 2 intron 2 introns 1- 10 15, 24-27 13 3
Test Output The output of the test includes:
Category 1: CDx Claims noted in Table 1 of the Intended Use
Category 2: Cancer Mutations with Evidence of Clinical Significance
Category 3: Cancer Mutations with Potential Clinical Significance
Genomic findings other than those listed in Table 1 of the intended use statement (i.e., Categories 2 and 3) are not prescriptive or conclusive for labeled use of any specific therapeutic product.
Test Kit Contents The test includes a sample shipping kit, which is sent to ordering laboratories. The shipping kit contains the following components: • Specimen Preparation Instructions • Shipping Instructions • Return Shipping Label
Instruments The F1CDx assay is intended to be performed with serial number-controlled instruments as indicated in Table 4, below. All instruments are qualified by Foundation Medicine, Inc. (FMI) under FMI’s Quality System.
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Reference ID: 4604109 Table 4. Instruments for use with the F1CDx assay Instrument Illumina HiSeq 4000 Illumina cBot Beckman Biomek NXP Span-8 Liquid Handler Thermo Scientific Kingfisher Flex DW 96 Covaris LE220
Test Process All assay reagents included in the F1CDx assay process are qualified by FMI and are compliant with the medical device Quality System Regulation (QSR).
A. Specimen Collection and Preparation Formalin-fixed, paraffin-embedded (FFPE) tumor specimens are collected and prepared following standard pathology practices. FFPE specimens may be received either as unstained slides or as an FFPE block.
Prior to starting the assay, a Hematoxylin and Eosin (H&E) stained slide is prepared, and then reviewed by a board-certified pathologist to confirm disease ontology and to ensure that adequate tissue (0.6 mm3), tumor content (≥ 20% tumor) and sufficient nucleated cells are present to proceed with the assay.
B. DNA Extraction Specimens passing pathology review are queued for DNA extraction which begins with lysis of cells from FFPE tissue by digestion with a proteinase K buffer followed by automated purification using the 96-well KingFisher™ FLEX Magnetic Particle Processor.
After completion of DNA extraction, double-stranded DNA (dsDNA) is quantified by the Quant-iT™ PicoGreen® fluorescence assay using the provided lambda DNA standards (Invitrogen) prior to Library Construction (LC). The sample must yield a minimum of 55 ng of genomic DNA to ensure sufficient DNA for quality control (QC) and to proceed with LC.
C. Library Construction Library Construction (LC) begins with the normalization of DNA to 50-1000 ng. The normalized DNA samples are randomly sheared (fragmented) to ~200 bp by adaptive focused acoustic sonication using the Covaris LE220 before purification with a 1.8X volume of AMPure® XP Beads (Agencourt®). Solid-phase reversible immobilization (SPRI) purification and subsequent library construction with the NEBNext® reagents (custom-filled kits by NEB), including mixes for end repair, dA addition and ligation, are performed in 96-well plates (Eppendorf) on the Bravo Benchbot (Agilent) using 1 the “with-bead” protocol to maximize reproducibility and library yield. Indexed (6 bp barcodes) sequencing libraries are PCR amplified with HiFi™ (Kapa) for 10 cycles and subsequently 1.8X SPRI purified. Purification and dilution for QC are performed.
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Reference ID: 4604109
Following LC, a QC procedure is performed by quantifying single-stranded DNA (ssDNA) from purified libraries using the Quant-iT™ OliGreen® ssDNA Assay Kit (Life Technologies) read on a Molecular Devices Multimode SpectraMax M2 plate Reader. Libraries yielding insufficient sequencing library are failed.
D. Hybrid Capture Hybrid Capture (HC) begins with normalization of each library to 500-2000 ng. Normalized samples then undergo solution hybridization which is performed using a > 50-fold molar excess of a pool of individually synthesized 5’-biotinylated DNA 120 bp oligonucleotides. The baits target ~1.8 Mb of the human genome including all coding exons of 309 cancer-related genes, introns or non-coding regions of 35 genes, plus > 3,500 single nucleotide polymorphisms (SNPs) located throughout the genome. Baits are designed by tiling overlapping 120 bp DNA sequence intervals covering target exons (60 bp overlap) and introns (20 bp overlap), with a minimum of three baits per target; SNP targets are allocated one bait each. Intronic baits are 2 filtered for repetitive elements as defined by the UCSC Genome RepeatMasker track.
After hybridization, the library-bait duplexes are captured on paramagnetic MyOne™ streptavidin beads (Invitrogen), and off-target material is removed by washing one time with 1X SSC at 25°C and four times with 0.25X SSC at 55°C. The PCR master mix is added to directly amplify (12 cycles) the captured library from the washed beads.3 After 12 cycles of amplification, the samples are 1.8X SPRI purified. Purification and dilution for QC are performed.
QC for HC is performed by measuring dsDNA yield using the Quant-iT™ PicoGreen® dsDNA Assay Kit (Life Technologies) read on a Molecular Devices Multimode SpectraMax M2 plate Reader. Captured libraries yielding less than 140 ng of sequencing library are failed.
E. Sequencing Sequencing is performed using off-board clustering on the Illumina cBot with patterned flow cell technology to generate monoclonal clusters from a single DNA template followed by sequencing using sequencing by synthesis (SBS) chemistry on the Illumina HiSeq 4000. Fluorescently labeled 3′-blocked dNTPs along with a polymerase are incorporated through the flow cell to create a growing nucleotide chain that is excited by a laser. A camera captures the emission color of the incorporated base and then is cleaved off. The terminator is then removed to allow the nucleotide to revert to its natural form and to allow the polymerase to add another base to the growing chain. A new pool of fluorescently labeled 3′-blocked dNTPs are added with each new sequencing cycle. The color changes for each new cycle as a new base is added to the growing chain. This method allows for millions of discrete clusters of clonal copies of DNA to be sequenced in parallel.
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Reference ID: 4604109 F. Sequence Analysis Sequence data are analyzed using proprietary software developed by FMI. Sequence data are mapped to the human genome (hg19) using Burrows-Wheeler Aligner (BWA) v0.5.9.4 PCR duplicate read removal and sequence metric collection are performed using Picard 1.47 (http://picard.sourceforge.net) and SAMtools 0.1.12a.5 Local alignment optimization is performed using Genome Analysis Toolkit (GATK) 1.0.4705.6 Variant calling is performed only in genomic regions targeted by the test.
Base substitution detection is performed using a Bayesian methodology, which allows for the detection of novel somatic alterations at low mutant allele frequency (MAF) and increased sensitivity for alterations at hotspot sites through the incorporation of tissue-specific prior expectations.7 Reads with low mapping (mapping quality < 25) or base calling quality (base calls with quality ≤ 2) are discarded. Final calls are made at MAF ≥ 5% (MAF ≥ 1% at hotspots).
To detect indels, de novo local assembly in each targeted exon is performed using the de-Bruijn approach.8 Key steps are: • Collecting all read-pairs for which at least one read maps to the target region. • Decomposing each read into constituent k-mers and constructing an enumerable graph representation (de-Bruijn) of all candidate non-reference haplotypes present. • Evaluating the support of each alternate haplotype with respect to the raw read data to generate mutational candidates. All reads are compared to each of the candidate haplotypes via ungapped alignment, and a read ‘vote’ for each read is assigned to the candidate with best match. Ties between candidates are resolved by splitting the read vote, weighted by the number of reads already supporting each haplotype. This process is iterated until a ‘winning’ haplotype is selected. • Aligning candidates against the reference genome to report alteration calls.
Filtering of indel candidates is carried out similarly to base substitutions, with an empirically increased allele frequency threshold at repeats and adjacent sequence quality metrics as implemented in GATK: % of neighboring bases mismatches < 25%, average neighboring base quality > 25, average number of supporting read mismatches ≤ 2. Final calls are made at MAF ≥ 5% (MAF ≥ 3% at hotspots).
Copy number alterations (CNAs) are detected using a comparative genomic hybridization (CGH)-like method. First, a log-ratio profile of the sample is acquired by normalizing the sequence coverage obtained at all exons and genome-wide SNPs (~3,500) against a process-matched normal control. This profile is segmented and interpreted using allele frequencies of sequenced SNPs to estimate tumor purity and copy number at each segment. Amplifications are called at segments with ≥ 6 copies (or ≥ 7 for triploid/≥ 8 for tetraploid tumors) and homozygous deletions at 0 copies, in samples with tumor purity ≥ 20%. Amplifications in ERBB2 are called positive at segments with ≥ 5 copies for diploid tumors.
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Reference ID: 4604109 Genomic rearrangements are identified by analyzing chimeric read pairs. Chimeric read pairs are defined as read pairs for which reads map to separate chromosomes, or at a distance of over 10 megabase (Mb). Pairs are clustered by genomic coordinate of the pairs, and clusters containing at least five chimeric pairs (three for known fusions) are identified as rearrangement candidates. Filtering of candidates is performed by mapping quality (average read mapping quality in the cluster must be 30 or above) and distribution of alignment positions. Rearrangements are annotated for predicted function (e.g., creation of fusion gene).
To determine microsatellite instability (MSI) status, 95 intronic homopolymer repeat loci (10-20 bp long in the human reference genome) with adequate coverage on the F1CDx assay are analyzed for length variability and compiled into an overall MSI score via principal components analysis (PCA). Using the 95 loci, for each sample the repeat length is calculated in each read that spans the locus. The means and variances of repeat lengths are recorded. PCA is used to project the 190-dimension data onto a single dimension (the first principal component) that maximizes the data separation, producing an MSI score. Each sample is assigned a qualitative status of MSI-High (MSI-H) or MSI-Stable (MSS); ranges of the MSI score are assigned MSI-H or MSS by manual unsupervised clustering. Samples with low coverage (< 250X median) are assigned a status of MSI-unknown.
Tumor mutational burden (TMB) is measured by counting all synonymous and non- synonymous variants present at 5% allele frequency or greater and filtering out potential germline variants according to published databases of known germline polymorphisms including Single Nucleotide Polymorphism database (dbSNP) and Exome Aggregation Consortium (ExAC). Additional germline alterations still present after database querying are assessed for potential germline status and filtered out using a somatic-germline/zygosity (SGZ) algorithm. Furthermore, known and likely driver mutations are filtered out to exclude bias of the data set. The resulting mutation number is then divided by the coding region corresponding to the number of total variants counted, or 793 kb. The resulting number is communicated as mutations per Mb unit (mut/Mb).
After completion of the Analysis Pipeline, variant data are displayed in the FMI custom-developed CATi software applications with sequence QC metrics. As part of data analysis QC for every sample, the F1CDx assay assesses cross-contamination through the use of a SNP profile algorithm, reducing the risk of false-positive calls that could occur as a result of an unexpected contamination event. Sequence data are reviewed by trained bioinformatics personnel. Samples failing any QC metrics are automatically held and not released.
G. Report Generation Approved results are annotated by automated software with CDx relevant information and are merged with patient demographic information and any additional information provided by FMI as a professional service prior to approval and release by the laboratory director or designee.
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Reference ID: 4604109
H. Internal Process Controls Related to the System Positive Control Each assay run includes a control sample run in duplicate. The control sample contains a pool of ten HapMap cell lines and is used as a positive mutation detection control. 100 different germline SNPs present across the entire targeted region are required to be detected by the analysis pipeline. If SNPs are not detected as expected, this results in a QC failure, as it indicates a potential processing error.
Sensitivity Control The HapMap control pool used as the positive control is prepared to contain variants at 5%-10% MAF which must be detected by the analysis pipeline to ensure the expected sensitivity for each run.
Negative Control Samples are barcoded molecularly at the LC stage. Only reads with a perfect molecular barcode sequence are incorporated into the analysis. The Analysis Pipeline includes an algorithm that analyzes the SNP profile of each specimen to identify potential contamination that may have occurred prior to molecular barcoding and can detect contamination lower than 1%.
Biomarker Rules for SNVs and indels that lead to MET exon 14 skipping A SNV or indel in MET shall be considered to result in skipping of exon 14 if one or more of the following criteria are met:
1. Deletions greater than or equal to 5 bp that affect positions -3 to -30 in the intronic region immediately adjacent to the splice acceptor site at the 5′ boundary of MET exon 14. 2. Indels affecting positions -1 or -2 at the splice acceptor site of the 5′ boundary of MET exon 14. 3. Base substitutions and indels affecting positions 0, +1, +2, or +3 at the splice donor site of the 3′ boundary of MET exon 14.
VI. ALTERNATIVE PRACTICES AND PROCEDURES
There are FDA-approved companion diagnostic (CDx) alternatives for the detection of genetic alterations using FFPE tumor specimens, as listed in Table 1 of the F1CDx intended use statement. The approved CDx tests are listed in Table 5, below; for additional details see FDA List of Cleared or Approved Companion Diagnostic Devices at: https://www.fda.gov/medical-devices/vitro-diagnostics/list-cleared-or-approved companion-diagnostic-devices-vitro-and-imaging-tools. Each alternative has its own advantages and disadvantages. Physicians should consider the best method that suits their patients and that best meets their expectations.
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Reference ID: 4604109 Table 5. List of FDA approved CDx assays for genes targeted by Fl CDx Device Company Technology Therapy Indication PathVysion HER-2 DNA Probe Kit Abbott Molecular, FISH HERCEPTIN Breast cancer Inc. (trastuzumab) PATHWAY Anti-HER-2/neu (4B5) Ventana Medical IHC HERCEPTIN Breast cancer Rabbit Monoclonal Prima1y Antibody Systems, Inc. ( trastuzumab) InSite HER-2/neu Kit Biogenex IHC HERCEPTIN Breast cancer Laborato1ies, Inc. (trastuzumab) SPOT-Light HER2 CISH Kit Life CISH HERCEPTIN Breast cancer Technologies, Inc. (trastuzumab) Bond Oracle HER2 IHC System Leica Biosystems IHC HERCEPTIN Breast cancer (trastuzumab) HER2 CISH pharmDx Kit Dako Denmark CISH HERCEPTIN Breast cancer :: AIS ( trastuzumab) .~.... a INFORM HER2 Dual ISH DNA Ventana Medical Dual ISH HERCEPTIN Breast cancer s Probe Cocktail Systems, Inc. ( trastuzumab) -...§- HercepTest Dako Denmark IHC HERCEPTIN Breast cancer 1 AIS ( trastuzumab) Gastric or "l PERJETA Gastroesophageal .~ (pertuzumab) junction ·~ KADCYLA adenocarcinoma (ado t:rastuzumab emtansine) HER2 FISH phannDx Kit Dako Denmark FISH HERCEPTIN Breast cancer AIS ( trastuzumab) Gastric or PERJETA Gastroesophageal (pertuzumab) junction KADCYLA adenocarcinoma (ado t:rastuzumab emtansine) ~ ~ THxID BRAF Kit bi0Me1ieux PCR MEKINIST Melanoma ~ (tramatenib) ~ cobas 4800 BRAF V600 Mutation Roche Molecular PCR ZELBORAF Melanoma ~ Test Systems, Inc. (vemurafenib) THxID BRAF Kit bi0Me1ieux PCR TAFINLAR Melanoma ( dabrafenib) Oncomine Dx Target Test Life NGS TAFINLAR NSCLC ~ ~ Technologies, Inc. ( dabrafenib) \0 MEKINIST ~ (trametinib) ~ therascreen BRAF V600E RGQ PCR QIAGEN PCR BRAFTOVI Colorectal cancer Kit (e ncorafenib) Erbitux (cetuximab)
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Reference ID 4604109 Device Company Technology Therapy Indication ~ Praxis Extended RAS Panel Illumina, Inc. NGS VECTIBIX Colorectal cancer ~ (panitumumab) cobas KRAS Mutation Test Roche PCR ERBITUX Colorectal cancer Molecular ( cetuximab) Systems, Inc. VECTIBIX (panitumumab) therascreen KRAS RGQ PCR Kit QIAGEN PCR ERBITUX Colorectal cancer ( cetuximab) ~ VECTIBIX (panitumumab) Praxis Extended RAS Panel Illumina, Inc. NGS VECTIBIX Colorectal cancer (panitumumab) Vysis ALK Break Apa1t FISH Probe Kit Abbott FISH XALKORI NSCLC 0= Molecular, ( c1izotinib) ·;;; .e Inc . I ~ ALK (DSF3) CDx Assay Ventana IHC XALKORI NSCLC ·~ Medical ( c1izotinib) Systems, Inc. cobas EGFR Mutation Test v2 Roche PCR TARCEVA NSCLC ~ Molecular ( erlotinib) "' Systems, Inc. TAGRISSO 0= ~ ( osimertinib) .... l£l =QC> therascreen EGFR RGQ PCR Kit QIAGEN PCR GILOTRIF NSCLC ~ ...:l (afatinib) ~ I IRESSA (gefitinib) <;,!:)~ Oncomine Dx Target Test Life NGS IRESSA NSCLC ~ Technologies, (gefitinib) Inc. r:: cobas EGFR Mutation Test v2 Roche PCR TAGRISSO NSCLC <;,!:) 0\~ Molecular ( osimertinib) ~~ Systems, Inc. ~ FoundationFocus CDXBRCA Foundation NGS RUBRACA Advanced ovarian ...... 0 Medicine, Inc. (mcaparib) cancer ~ therascreen PIK3CA RGQ PCR Kit QIAGEN PCR PIQRAY Breast cancer u ( alpelisib) ~ ·~
Abbreviations: FISH - fluorescence in situ hybridization; IHC - immunohistochemistiy; CISH chromogenic in situ hybridization; ISH - in situ hybridization; PCR - polymerase chain reaction; NGS - next generation sequencing.
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Reference ID 4604109
VII. MARKETING HISTORY
Foundation Medicine, Inc. initially designed and developed the FoundationOne® laboratory developed test (F1 LDT), and the first commercial sample was tested in 2012. The F1 LDT has been used to detect the presence of genomic alterations in FFPE tumor tissue specimens. The F1 LDT is not FDA-cleared or -approved.
The F1CDx Premarket Approval (PMA) was originally approved on November 30, 2017 by FDA (P170019) and is commercially available in the U.S. since March 30, 2018.
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 test results, and subsequently, inappropriate patient management decisions. Patients with false positive results may undergo treatment with one of the therapies listed in the above intended use statement without clinical benefit and may experience adverse reactions associated with the therapy. Patients with false negative results may not be considered for treatment with the indicated therapy. There is also a risk of delayed results, which may lead to delay of treatment with the indicated therapy. For the specific adverse events related to the approved therapeutics, please see the approved drug product labels.
IX. SUMMARY OF NONCLINICAL STUDIES
A. Laboratory Studies The evidence in support of the performance of F1CDx in detecting SNVs and indels that lead to MET exon 14 skipping was from the data presented using intended use specimens across all validation studies. Analytical accuracy/concordance study and precision studies at the limit of detection (LoD) were conducted to support the indication for SNVs and indels that lead to MET exon 14 skipping.
For F1CDx platform-level validation (P170019), performance characteristics were established using DNA derived from a wide range of FFPE tissue types; tissue types associated with CDx indications were included in each study. For information regarding the platform-level validation, please see Section IX.A.10, Table 24 in Summary of Safety and Effectiveness Data P170019).
1. Analytical Accuracy/Concordance a. Comparison to an Orthogonal Method for Detecting SNVs and Indels that lead to MET exon 14 Skipping An analytical accuracy study was performed to demonstrate the concordance between F1CDx and an externally validated NGS assay (evNGS) for the detection of SNVs and indels that lead to MET exon 14 skipping. This study evaluated a set of 168 NSCLC FFPE specimens, (50 patients positive for SNVs and indels that lead to MET exon 14 skipping and 118 patients negative
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Reference ID: 4604109 for SNVs and in de ls that lead to MET exo n 14 skipping) from NSCLC patients from archival specimens and from the GEOMETRY-mono 1 clinical trial (please see Section X.A for study details). Positive samples included 19 patients positive for SNVs and indels that lead to MET exon 14 skipping with sufficient remaining DNA from the GEOMETRY-mono 1 clinical trial. Due to the low prevalence ofsome SNVs and indels that lead to MET exon 14 skipping, samples from Foundation Medicine's clinical archive (3 1 samples positive for SNVs and indels that lead to METexon 14 skipping) were included to cover rare SNVs and in de ls that lead to MET exo n 14 skipping. 11 8 NSCLC samples without SNVs and indels that lead to METexon 14 skipping were leveraged from prior studies (please refer to Section IX.A. I .a of Summary of Safety and Effectiveness Data P 170019) and supplemented with archival specimens with remaining DNA ofsufficient quantity and quality in this study. Samples were selected by Fl CDx. A summa1y of positive percent agreement (PPA) and negative percent agreement (NPA) in reference to an externally validated NGS assay and coITesponding 95% two-sided exact confidence intervals (Cls) is provided in Table 6, below.
Table 6. Concordance summary for samples with SNVs and indels the lead to MET exon 14 Sk" IPPID . !?: Unad.justed Unad.justed Ad.justed Ad.justed FlCDx+/ FlCDx- FlCDx+ FlCDx- PPA NPA PPA NPA Variant evNGS+ /evNGS+ /evNGS /evNGS (950/oCI) (950/oCI) (950/oCI)* (950/oCI)* SNVs and in de ls 49 0 1 118 100.00% 99.2% 100% 99.94% that lead to MET (92.8%, (95.4%, (47.31%, (99.66%, exon 14 skipping 100.0%) 100.0%) 100%) 100%)
2. Analytical Sensitivity a. Limit ofDetection (LoD) The LoD of SNVs and indels that lead to MET exon 14 skipping was assessed by Fl CDx. A total of4 NSCLC specimens positive for SNVs or indels that lead to MET exon 14 skipping (all biomarker rnles were covered by the 4 samples) were tested to assess the mutant allele frequency (MAF) necessa1y for accmate detection and sensitivity of SNVs and indels that lead to MET exon 14 skipping. LoD was estimated using 5 levels ofMAF ranging from 2.5% to 20% (2.5%, 5%, 10%, 15% and 20%) with 10 replicates per level. The LoDs of SNVs and indels that lead to MET exon 14 skipping were detennined empiraclly and are summarized in Table 7, below.
Table 7. Summary ofLoD for SNVs and indels that lead to MET exon 14 s kiIPPID2 . LoD* Alteration Allele Fraction (%) MET Exon 14 substitutions 2.93% MET Exon 14 insertion and deletion 5.73%
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Reference ID 4604109 *LoD calculations for the CDx variants were based on the hit rate approach, as there were less than three levels with hit rate between 10% and 90% for all CDx variants. LoD from the hit rate approach is defined as the lowest level with 100% hit rate (worst scenario).
LoDs were confirmed by testing NSCLC samples near the established LoD in the Precision Study (See Section IX.A.8). See Section IX.A.2 of Summary of Safety and Effectiveness Data for P170019 for additional analytical sensitivity data.
3. Analytical Specificity See Section IX.A.3 of Summary of Safety and Effectiveness Data for P710019
4. Carryover/Cross-Contamination See Section IX.A.4 of Summary of Safety and Effectiveness Data for P170019
5. Precision and Reproducibility a. Intermediate Precision for SNVs and indels that lead to MET exon 14 skipping A precision study was conducted using eight NSCLC samples harboring SNVs or indels that lead to MET exon 14 skipping (four samples near LoD and four samples at 2-3x LoD) covering all of the biomarker rules. Repeatability including intra-run performance (run on the same plate under the same conditions) and reproducibility including inter-run performance (run on different plates under different conditions) were assessed and compared across three different sequencers and two different reagent lots, across multiple days (typical assay workflow spans 10 days) of performance by multiple operators. A full factorial design for this study was carried out with four replicates per reagent lot/sequencer combination for samples with 24 replicates. The previous precision studies for F1CDx (P170019) and FoundationFocus CDxBRCA (P160018) were conducted with 36 replicates using a full factorial study design and yielded high agreement rates; thus, 24 replicates per sample to demonstrate F1CDx precision for SNVs and indels that lead to MET exon 14 skipping were deemed acceptable to support this PMA supplement.
The results for the precision study for the NSCLC samples near LoD and at 2 3x LoD are summarized in Table 8, below. There were two replicates from two different samples that failed post-sequencing QC metrics due to low sequencing coverage. These replicates were excluded from the analysis. Among the remaining replicates, two replicates from two samples were discordant. Intra-run repeatability was evaluated across 12 duplicates per plate as percent agreement and two replicates exhibited discordances due to low allele frequency, which was below pipeline reporting thresholds. Inter-run reproducibility was evaluated across 24 replicates as percent agreement, which is the fraction of calls consistent with the majority call. Reproducibility and repeatability were 100% across six out of eight replicates. The
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Reference ID: 4604109 con esponding two-sided exact 95% Cls are provided for repeatability and reproducibility positive call rates.
T able 8 . P r ec1s1on resu l ts i or SNVs and ID. d es l t h at l ea d to MET ex on 14 SkiIPPIDI! Sample Target Alteration Mutant #Valid Reproducibility Repeatability Allele Results Positive Call Positive Call Fraction Rate Rate (MAF) (% ) (95% exact en (95% exact en 1 splice site 2888 7.0 24 100.0% 100.0% 10 291ldel34 (85.8, 100.00) (73 .5, 100.0) 2 splice site 2888 4. 1 23 95.8% 91.7% 37 2888 (78.9, 99.9) (61.5, 99.8) 30delCGTCTTTA 3 splice site 2888 11.0 23 100.0% 100.0% 18 2888-5del14 (85 .2, 100.0) (7 1. 5, 100.0) 4 D lOlON 3.0 23 95.8% 91.7% (78.9, 99.9) (6 1. 5, 99.8) 5 splice site 3028+2T>C 3.3 24 100.0% 100.0% (85.8, 100.0) (73 .5, 100.0) 6 splice site 4.2 24 100.0% 100.0% 2999 3028+4del34 (85.8, 100.0) (73 .5, 100.0) 7 splice site 3028+ 1 G> A 6.0 24 100.0% 100.0% (85.8, 100.0) (73 .5, 100.0) 8 splice site 10.5 23 100.0% 100.0% 3028 3028+2delGGT (85.8. 100.0) (7 1. 5. 100.0)
b. Site-to-site reproducibility (SNVs and indels that lead to MET exon 14 skipping) A reproducibility study to include the new second site in MoITisville, No1i h Carolina was not conducted. Site-to-site reproducibility is being provided as a post-market study.
6. Reagent Lot Interchangeability There were no changes to the reagents and specifications between FoundationFocus™ C D XBRCA assay and FlCDx. Therefore, for reagent lot interchangeability results, see Section IX.A g of Summary of Safety and Effectiveness Data for P1 6001 8.
B. Animal Studies No animal studies were conducted using the FlCDx assay.
C. Additional Studies No additional studies were conducted using the F l CDx assay.
X. SUMMARY OF PRIMARY CLINICAL STUDY
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Reference ID 4604109 The clinical performance of FoundationOne®CDx (F1CDx) for detecting SNVs and indels that lead to MET exon 14 skipping in NSCLC patients who may benefit from treatment with capmatinib (Table 1), was established with clinical data generated from the GEOMETRY-mono 1 study, and a clinical bridging study to demonstrate concordance between the enrollment assay and the F1CDx assay to establish the clinical efficacy of the F1CDx assay.
A. FoundationOne®CDx Clinical Bridging Study for SNVs and indels that lead to MET exon 14 skipping
The safety and effectiveness of F1CDx for detecting SNVs and indels that lead to MET exon 14 skipping in NSCLC patients who may benefit from treatment with capmatinib was demonstrated in a retrospective analysis of samples from patients enrolled in the GEOMETRY-mono 1 trial (CINC280A2201). A bridging study was conducted to assess the clinical efficacy of F1CDx in identifying patients positive for SNVs and indels that lead to MET exon 14 skipping for treatment with capmatinib and the concordance between SNVs and indels that lead to MET exon 14 skipping tested with the clinical trial assay (CTA) and F1CDx in the intent-to-test population. Retrospective testing with F1CDx was done for patients from the drug efficacy population Cohorts 4 and 5b, and a random selection of MET exon 14 skipping negative patients. The retrospective testing population consisted of 204 patients (78 patients positive for MET exon 14 skipping, and 126 patient samples negative for MET exon 14 skipping), originally tested by the MET exon 14 skipping CTA for patient selection.
1. Study Design GEOMETRY-mono 1 is a prospectively designed, multi-cohort, multicenter, non- randomized, open-label, Phase II trial of oral cMET inhibitor (capmatinib) in adult patients with EGFR wild-type (wt) metastatic NSCLC. The primary endpoint was to assess overall response rate (ORR) and the key secondary endpoint was duration of response (DOR) by a blinded independent review committee (BIRC) assessment according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 to determine the effectiveness of capmatinib in NSCLC patients. Patients were enrolled into multiple cohorts of the study, out of which the bridging study was focused on the fully-enrolled MET exon 14 skipping positive Cohorts 4 and 5b (efficacy population). Cohort 4 only enrolled pretreated (second and third line) MET exon 14 skipping patients and Cohort 5b only enrolled treatment-naïve MET exon 14 skipping patients. Patients were screened for enrollment in Cohorts 4 and 5b for MET exon 14 skipping status as detected using a MET exon 14 deletion reverse-transcriptase PCR (RT-PCR) CTA. After the initial patient screening, clinical samples were stored for retrospective testing. GEOMETRY-mono 1 is an ongoing trial that was initiated on June 11, 2015 with first patient first visit (FPFV). Patients receive 400 mg of capmatinib orally twice daily in tablet form. Dose adjustments for capmatinib are permitted for safety concerns. Efficacy is evaluated every six weeks from the first day of treatment until RECIST 1.1 disease progression. Safety and tolerability is evaluated in all
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Reference ID: 4604109 subjects who received at least one dose of capmatinib by assessment of incidence of adverse events (AEs) and serious adverse events (SAEs), change in vital signs, laboratory results, and electrocardiogram (ECG).
2. Bridging Study The aim of the bridging study was to determine the concordance between MET exon 14 skipping results from the enrolling CTA generated at the time of patient screening for GEOMETRY-mono 1 and the results of SNVs and indels that lead to MET exon 14 skipping using F1CDx. The study was also conducted to establish the clinical utility of F1CDx in identifying patients positive for SNVs and indels that lead to MET exon 14 skipping for treatment with capmatinib.
Retrospective testing with F1CDx was done for patients from Cohort 4 (previously treated) and Cohort 5b (treatment naïve) and a random selection of MET exon 14 skipping negative samples. The bridging study population consisted of 204 patients (78 MET exon 14 skipping positive patients, and 126 MET exon 14 skipping negative patient samples), originally tested by the MET exon 14 CTA for patient selection.
Concordance between F1CDx and the CTA was demonstrated with the companion diagnostic (CDx)-evaluable patient population from GEOMETRY- mono 1 trial that produced valid F1CDx results. Clinical utility of F1CDx was evaluated by estimation of clinical efficacy in the CTA-enrolled MET exon 14 skipping positive patient population as assessed by the primary objective of ORR by BIRC. Baseline demographic and disease characteristics were compared between the CDx-evaluable and CDx-unevaluable populations within all enrolled CTA-positive patients in Cohort 4 and Cohort 5b. All the covariates were well balanced between the two groups of patients (See Section X.B below).
B. Study Population Demographics and Baseline Parameters The demographics, disease characteristics and specimen characteristics for the CDx evaluable and CDx-unevaluable patients were similar for all of the CTA-enrolled patients in both the GEOMETRY-mono 1 MET exon 14 skipping positive Cohorts 4 and 5b (Table 9).
Table 9. Comparison of demographic and disease characteristics between CDx evaluable and CDx-unevaluable set for CTA-positive patients by cohort and CDx sample requirements for CDx samples that met the minimum sample requirements. Cohort 4 Cohort 5b ______CDx CDx CDx CDx Baseline evaluable unevaluable All evaluable unevaluable All characteristics N=53 N=16 N=69 N=20 N=8 N=28 Age (Years) N 53 16 69 20 8 28 Mean 71.8 68.2 71.0 71.4 75.1 72.4
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Reference ID: 4604109 Cohort 4 Cohort 5b
CDx CDx CDx CDx Baseline evaluable unevaluable All evaluable unevaluable All characteristics N=53 N=16 N=69 N=20 N=8 N=28 SD 8.97 4.90 8.32 6.40 8.18 7.02 Median 73.0 68.5 71.0 70.5 75.5 71.0 Min 49 59 49 57 60 57 Max 90 78 90 83 86 86 Sex - n (%) Female 29 (54.7) 11 (68.8) 40 (58.0) 11 (55.0) 7 (87.5) 18 (64.3) Male 24 (45.3) 5 (31.3) 29 (42.0) 9 (45.0) 1 (12.5) 10 (35.7) Race - n (%) Caucasian 36 (67.9) 13 (81.3) 49 (71.0) 16 (80.0) 8 (100) 24 (85.7) Black 0 0 0 0 0 0 Asian 16 (30.2) 3 (18.8) 19 (27.5) 4 (20.0) 0 4 (14.3) Native American 1 (1.9) 0 1 (1.4) 0 0 0 Other 0 0 0 0 0 0 Unknown 0 0 0 0 0 0 ECOG at baseline - n (%) 0 13 (24.5) 3 (18.8) 16 (23.2) 6 (30.0) 1 (12.5) 7 (25.0) 1 39 (73.6) 13 (81.3) 52 (75.4) 14 (70.0) 7 (87.5) 21 (75.0) 2 1 (1.9) 0 1 (1.4) 0 0 0 Histological grade - n (%) Well differentiated 5 (9.4) 0 5 (7.2) 2 (10.0) 2 (25.0) 4 (14.3) Moderately 8 (15.1) 1 (6.3) 9 (13.0) 1 (5.0) 1 (12.5) 2 (7.1) differentiated Poorly differentiated 12 (22.6) 7 (43.8) 19 (27.5) 5 (25.0) 1 (12.5) 6 (21.4) Undifferentiated 3 (5.7) 2 (12.5) 5 (7.2) 2 (10.0) 0 2 (7.1) Unknown 25 (47.2) 6 (37.5) 31 (44.9) 10 (50.0) 4 (50.0) 14 (50.0) Stage at study entry - n (%) IIIB 1 (1.9) 1 (6.3) 2 (2.9) 0 0 0 IV 52 (98.1) 15 (93.8) 67 (97.1) 20 (100) 8 (100) 28 (100) - All percentages calculated using N as denominator. - ECOG=Eastern Cooperative Oncology Group; SD=standard deviation.
C. Accountability of sPMA Cohort A total of 3,036 patients were screened for trial eligibility from 152 investigational sites across 25 countries. 2551 patients within the original 3,036 were screened for MET exon 14 skipping by RT-PCR CTA. Within that screened population, 2295 patients produced valid CTA results (positive and negative) by which the patient could be deemed eligible or ineligible for the trial. As of April 15, 2019, a total of 334
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Reference ID: 4604109 patients were enrolled into all available cohorts. Of the patients whose samples produced valid CTA results, 97 were enrolled in Cohorts 4 and 5b of the GEOMETRY-mono 1 trial, with 69 and 28 patients respectively. MET exon 14 skipping negative patients were not enrolled in the GEOMETRY- mono 1 trial. Available MET exon 14 skipping negative patients identified through screening for the GEOMETRY-mono 1 trial were evaluated for the clinical bridging study from which 130 CTA-negative patients were randomly selected. Out of the 130 CTA- negative samples, 93 were randomly assigned to Cohort 4 and 37 to Cohort 5b. Of the 227 positive and negative samples (97 positive and 130 negative), retrospective retesting with F1CDx was performed for 204 CTA tested patient samples that met F1CDx minimum sample testing criteria (78 of the MET exon 14 skipping positive enrolled patients and 126 MET exon 14 skipping negative not-enrolled patients). F1CDx testing yielded 198 CDx-evaluable results and six (6) invalid results which were used for the CDx and CTA concordance analysis.
Sensitivity analyses were conducted with all 227 samples from PAS-A (Primary Analysis Set-A: Cohort 4 69 positive samples and its randomly assigned 93 CTA- negative samples) and PAS-B (Primary Analysis Set-B: Cohort 5b 28 positive and its randomly assigned 37 CTA-negative samples) to determine the impact of missing F1CDx results on concordance and efficacy results. Standard F1CDx processing metrics require samples to have tissue volume ≥ 0.6 mm3, tumor content ≥ 20% and DNA yield ≥ 55 ng. To increase retention of clinical trial samples in the clinical bridging study, samples were also processed down to the minimum sample inputs (Tested with deviation). Samples meeting minimum sample inputs fell below the standard F1CDx requirements listed above, but no lower than tissue volume 0.1 mm3, tumor content ≥ 10% and DNA yield ≥ 22 ng. Nineteen (19) CTA-positive patient samples were not tested due to failing to meet the F1CDx minimum tissue input requirements (13 and 6 from Cohorts 4 and 5b, respectively). Full disposition of the patient samples from GEOMETRY-mono 1 and those used for the F1CDx bridging study is shown in Tables 10 and 11.
Table 10. Disposition of all screened subjects in the GEOMETRY mono-1 trial Actual Total Tested by patients CDx All screened (positive and negatives) 3036 227 Screened by CTA 2551 204 Prescreen failures (not enrolled) 2605 125 Patients with valid CTA results (positives and negatives) 2295 204 Total enrolled in GEOMETRY mono-1 (as at 04/15/19 DBL) 334 78 Tested as CTA-positive (enrolled only in C4 and C5b) 97 78 Enrolled in Cohort 4 69 56 Enrolled in Cohort 5b 28 22 Tested as CTA-negative (pre-screen failure; not enrolled) 1882 126 Randomized to Cohort 4 for bridging analysis 93 89 Randomized to Cohort 5b for bridging analysis 37 37 Tested as invalid per CDx 6 6 Not tested by CDx for positive and negative by CTA 23 0
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Reference ID: 4604109
Table 11. Disposition of bridging subjects for CDx and CTA (Primary analysis set, CTA-enrolled) CTA
Positive Negative CDx N=97* (%) N=130 (%) Tested without deviation Positive 44 (45.4) 0 (0) Negative 1 (1.0) 121 (93.1) Invalid 0 (0.0) 0 (0.0) Tested with deviation Positive 28 (28.9) 0 (0.00) Negative 0 (0.0) 4 (3.1) Invalid 5 (5.2) 1 (0.8) Not tested 19 (19.6) 4 (3.1) * One patient did not have any available sample for F1CDx retrospective testing
For concordance between F1CDx and CTA, the point estimates of PPA, NPA, and OPA are detailed in Tables 12 and 13 below.
D. Safety and Effectiveness 1. Safety Results The safety with respect to treatment with capmatinib was addressed during the review of the NDA and is not addressed in detail in this Summary of Safety and Effectiveness Data. The evaluation of safety was based on the analysis of adverse events (AEs), clinical laboratory evaluations, physical examinations, and vital signs. Please refer to Drugs@FDA for complete safety information on TABRECTA® (capmatinib).
The majority of adverse events (AEs) reported were grade 1 or 2. In addition, the safety findings in this study are consistent with the known safety profile of capmatinib and no new or unexpected safety signals were identified.
Most of the on-treatment deaths occurred in the context of disease progression. Serious AEs were reported in 169 subjects (50.6%), however, the incidence of specific individual serious adverse events (SAEs) was low (<5%; except for dyspnea occurring in 6.9% subjects). ILD/pneumonitis grouped AEs were infrequent (4.5% of subjects) and mostly of low severity. Hepatotoxicity grouped AEs were reported in 28.1% of subjects during treatment with capmatinib, and mainly consist of asymptomatic AST/ALT elevations which were reversible with dose adjustment or interruption. The AEs are manageable with medical therapies and/or dose modifications. Overall, the safety in Cohorts 4 and 5b which have longer exposure to study drug is similar to safety in other cohorts in which subjects have shorter exposure.
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Reference ID: 4604109 No adverse events were reported in connection with the bridging study used to support this PMA supplement, as the study was performed retrospectively using banked samples.
2. Effectiveness Results a. Concordance Results The primary concordance analysis was conducted on 204 (78 MET exon 14 skipping positive patients, and 126 MET exon 14 skipping negative patient samples) CDx-evaluable CTA-positive and CTA-negative population which included the patients that met the F1CDx standard and minimum testing criteria and yielded valid CDx results.
Agreement between F1CDx and the CTA was demonstrated. The point estimates of PPA, NPA, and OPA between F1CDx and the CTA for CDx samples that met that standard DNA input requirement (Table 12) and those using the minimum DNA input requirement (Table 13) were calculated with and without invalid CDx results, using the CTA results as reference for the CTA-enrolled patients. The concordance analysis was performed with and without treating samples that met minimum sample requirements as ascertained for CDx.
Table 12. Agreement between CDx and CTA based on CTA results in Cohorts 4 and 5b for samples that met the F1CDx standard sample requirements.
Without CDx "Invalid" With CDx "Invalid" Percent Percent Measure of agreement 95% CI agreement 95% CI agreement % (n/N) (1) % (n/N) (1) Cohort 4 PPA 98.1 ( 52/53) (89.9, 100) 92.9 ( 52/56) (82.7, 98.0) NPA 100 ( 88/88) (95.9, 100) 98.9 ( 88/89) (93.9, 100) OPA 99.3 (140/141) (96.1, 100) 96.6 (140/145) (92.1, 98.9) Cohort 5b PPA 100 ( 20/20) (83.2, 100) 90.9 ( 20/22) (70.8, 98.9) NPA 100 ( 37/37) (90.5, 100) 100 ( 37/37) (90.5, 100) OPA 100 ( 57/57) (93.7, 100) 96.6 ( 57/59) (88.3, 99.6) N: The total number of patients. It is the denominator for percentage (%) calculation. n: Number of patients with agreement between CTA and CDx. (1) The 95% CI calculated using Clopper-Pearson method
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Reference ID: 4604109
Table 13. Agreement between CDx and CTA based on CTA results in Cohorts 4 and 5b for samples that met the minimum F1CDx sample requirements. Without CDx "Invalid" With CDx "Invalid"
Percent Percent Measure of agreement 95% CI agreement 95% CI agreement % (n/N) (1) % (n/N) (1) Cohort 4 PPA 98.1 ( 52/ 53) (89.9, 100) 92.9 ( 52/ 56) (82.7, 98.0) NPA 100 ( 88/ 88) (95.9, 100) 98.9 ( 88/ 89) (93.9, 100) OPA 99.3 (140/141) (96.1, 100) 96.6 (140/145) (92.1, 98.9)
Cohort 5b PPA 100 ( 20/ 20) (83.2, 100) 90.9 ( 20/ 22) (70.8, 98.9) NPA 100 ( 37/ 37) (90.5, 100) 100 ( 37/ 37) (90.5, 100) OPA 100 ( 57/ 57) (93.7, 100) 96.6 ( 57/ 59) (88.3, 99.6) N: The total number of patients. It is the denominator for percentage (%) calculation. n: Number of patients with agreement between CTA and CDx. (1) The 95% CI calculated using Clopper-Pearson method
b. Clinical Efficacy Results in the GEOMETRY-mono 1 MET Exon 14 Skipping Cohort The GEOMETRY-mono 1 clinical trial met its primary objective of ORR as assessed by BIRC according to RECIST 1.1 in patients with MET exon 14 skipping positive tumors.
Capmatinib demonstrated an estimated 40.6% (95% CI 28.9 - 53.1%) best overall response rate (ORR) by CTA in the MET exon 14 skipping positive patients from Cohort 4. An estimated 67.9% (95% CI 47.6 - 84.1%) best overall response rate was calculated in the MET exon 14 skipping positive patients from Cohort 5b. The analyses by BIRC assessment were similar to the analyses by investigator assessment. (Tables 14 and 15). Treatment with capmatinib was considered efficacious under the standard testing requirements in both Cohort 4 (second and third line) and Cohort 5b (treatment-naive) (36.7% (95% CI: 19.9, 56.1) and 78.6% (95% CI: 49.2, 95.3), respectively) and under the minimum testing requirements for both Cohort 4 and Cohort 5b (44.2% (95% CI: 30.5, 58.7) and 70% (95% CI: 45.7, 88.1), respectively) as demonstrated by an ORR per BIRC.
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Reference ID: 4604109 Table 14. Overall response per BIRC assessment in (CTA-positive, CDx-positive) and CTA-positive patients by cohort and CDx sample requirements (Cohort 4) (CTA+, CDx+) CDx sample requirements ______Standard + Standard Minimum CTA+ N=30 N=52 N=69 95% CI 95% CI 95% CI n (%) (1) n (%) (1) n (%) (1) Overall Response Rate 11 (36.7) (19.9, 56.1) 23 (44.2) (30.5, 58.7) 28 (40.6) (28.9, 53.1) (ORR: CR + PR) (1) The 95% CI calculated with the Clopper-Pearson Exact method.
Table 15. Overall response per BIRC assessment in (CTA-positive, CDx-positive) and CTA-positive patients by cohort and CDx sample requirements (Cohort 5b). (CTA+, CDx+) CDx sample requirements
Standard + Standard Minimum CTA+ N=14 N=20 N=28 95% CI 95% CI 95% CI n (%) (1) n (%) (1) n (%) (1) Overall Response Rate 11 (78.6) (49.2, 95.3) 14 (70.0) (45.7, 88.1) 19 (67.9) (47.6, 84.1) (ORR: CR + PR) (1) The 95% CI calculated with the Clopper-Pearson Exact method.
c. Duration of Response For the CTA selected patients, the responses in treatment-naïve (Cohort 5) MET exon 14 skipping positive NSCLC patients were durable with 68.4% of patients having responses of 6 months or longer and 47.4% of patients having responses of 12 months or longer (median DOR of 12.58 months (95% CI: 5.55, 25.33)) by BIRC assessment. The responses in previously treated (Cohort 4) MET exon 14 skipping positive NSCLC patients were also durable with 64.3% of patients having responses of 6 months or longer and 32.1% of patients having responses of 12 months or longer (median DOR of 9.72 months (95% CI: 5.55, 12.98)) by BIRC assessment. In both MET exon 14 skipping positive cohorts, the onset of response occurred within 7 weeks of treatment in the majority of patients (68.4% of treatment-naïve patients and 82.1% of previously treated patients) as assessed by BIRC.
Duration of response (DOR) data are captured in Table 16 for (CTA+, CDx+) patients that experienced complete or partial response. The data captures DOR
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Reference ID: 4604109 per BIRC assessment for patients by cohort for both standard and standard + minimum sample requirements.
Table 16 Summary of duration of response (CR + PR) per BIRC assessment
Previously Treated Treatment-Naïve (Cohort 4) (Cohort 5b) Duration of Response (DOR) - CINC280A2201a Total number of patients with confirmed PR or N = 28 N = 19 CR Median (months) (95% CI)b 9.7 (5.5, 13.0) 12.6 (5.5, 25.3) Patients with DOR ≥ 12 months 32% 47%
Duration of Response (DOR) - CTA+/CDx+ population (Standard + Minimum) The total number of patients with confirmed N= 23 N= 14 PR or CR in (CTA+, CDx+) Median (months) (95% CI) b 9.72 (4.27, 12.98) 12.58 (5.55, 25.33) Patients with DOR > 12 months 34.8% 50.0%
Duration of Response (DOR) - CTA+/CDx+ population (Standard) The total number of patients with confirmed N= 11 N= 11 PR or CR in (CTA+, CDx+) Median (months) (95% CI) b 9.59 (4.27, 12.98) 12.58 (4.24, 25.33) Patients with DOR > 12 months 27.3% 45.5% a Based on capmatinib USPI. b Based on Kaplan-Meier estimate.
d. Clinical Efficacy Results in the CDx-positive Population In Tables 12 and 13, all patients who were found to be negative for MET exon 14 skipping by the CTA were also tested negative by the F1CDx (i.e., NPA = 100%) for Cohorts 4 and 5b. Therefore, the conditional probability of being CTA positive in the F1CDx positive population is 100% (i.e., Pr(CTA+|CDx+) = 100%), regardless of the prevalence of MET exon 14 skipping as determined by the CTA. Thus, the final estimated drug efficacy (ORR) for F1CDx positive patients in the intended use population equals to the estimated drug efficacy of the (CTA+ and CDx+) patients observed in the GEOMETRY-mono 1 clinical trial. Table 17 shows the efficacy results in F1CDx-positive patients for Cohorts 4 and Cohort 5b using standard and minimum DNA input requirements.
Table 17. Estimated Clinical efficacy results for F1CDx positives Cohort 4 ORR with 95% CI Cohort 5b ORR with 95% CI CDx (Standard) 36.7% (19.9 – 56.1%) 78.6% (49.2 –95.3%) CDx (Minimum) 44.2% (30.5 – 58.7%) 70% (45.7 – 88.1%)
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Reference ID: 4604109 Sensitivity analysis, using the multiple imputation methods was performed to evaluate the robustness of the clinical efficacy estimate against the 24 patients who tested positive by the CTA but were missing from the F1CDx results, which includes 19 patient samples that were not retested by F1CDx due to failing to meet the F1CDx minimum tissue sample requirements and/or due to lab error or also due to not meeting quality control metric, and five (5) patients who were tested by F1CDx but received invalid results.
Multivariate logistic regression analyses were performed to identify the clinically relevant covariates that are associated with the device outputs and clinical outcomes, respectively. Given that the sample size is limited in each cohort, a significance level of 0.2 was used as the criteria to select covariates in the logistic regression models. Any relevant covariates not identified in the analysis and considered to be clinically important were assessed for imbalance of distributions between CDx-evaluable and CDx-unevaluable sets within all enrolled CTA-positive patients. The distribution of the propensity scores among the group of patients with CDx results and the group without CDx results were assessed. Missing F1CDx results were imputed for Cohort 4 and Cohort 5b separately. The sensitivity analysis results demonstrated that the drug efficacy in F1CDx positive population is robust to missing F1CDx results.
3. Pediatric Extrapolation In this premarket application, existing clinical data was not leveraged to support approval of a pediatric population since it is not applicable for the NSCLC indication.
E. Financial Disclosure The bridging study was conducted retrospectively at a single testing site in Cambridge, MA and exempt from the requirements for Investigational Device Exemption as defined in Title 21 of the Code of Federal Regulations (21 CFR), 812.2(c)(3). The investigational product was not used in the diagnosis or treatment of patients. The information provided does not raise any questions about the reliability of the data.
XI. SUMMARY OF SUPPLEMENTAL CLINICAL INFORMATION
Not applicable.
XII. PANEL MEETING RECOMMENDATION AND FDA’S POST-PANEL ACTION
In accordance with the provisions of section 515(c)(3) of the act as amended by the Safe Medical Devices Act of 1990, this PMA supplement was not referred to the Molecular and Clinical Genetics Panel, an FDA advisory committee, for review and recommendation because the information in the PMA substantially duplicates information previously reviewed by this panel.
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Reference ID: 4604109 XIII. CONCLUSIONS DRAWN FROM PRECLINICAL AND CLINICAL STUDIES
A. Effectiveness Conclusions
For the intended use to identify SNVs and indels that lead to MET exon 14 skipping in NSCLC patients to be treated with capmatinib, the effectiveness of the F1CDx assay was demonstrated through a clinical bridging study using specimens from patients screened for enrollment into the GEOMETRY-mono 1 study. The data from the analytical validation and clinical bridging studies support the reasonable assurance of safety and effectiveness of the F1CDx assay when used in accordance with the indications for use. Data from the GEOMETRY-mono 1 study show that patients who had qualifying SNVs and indels that lead to MET exon 14 skipping received benefit from treatment with capmatinib and support the addition of the CDx indication to F1CDx.
B. Safety Conclusions
The risks of the device are based on data collected in the analytical studies conducted to support PMA approval as described above. The F1CDx assay is an in vitro diagnostic test, which involves testing of DNA extracted from FFPE tumor tissue. The assay can be performed using DNA extracted from existing (archival) tissue samples routinely collected as part of the diagnosis and patient care.
Failure of the device to perform as expected or failure to correctly interpret test results may lead to incorrect test results, and subsequently, inappropriate patient management decisions in cancer treatment. Patients with false positive results may undergo treatment with one of the therapies listed in Table 1 of the intended use statement without clinical benefit and may experience adverse reactions associated with the therapy. Patients with false negative results may not be considered for treatment with the indicated therapy. There is also a risk of delayed results, which may lead to delay of treatment with the indicated therapy.
C. Benefit-Risk Determination
GEOMETRY-mono 1 is a prospectively designed, multi-cohort, multicenter, non- randomized, open-label Phase II trial of oral cMET inhibitor (capmatinib) in adult patients with EGFR wild-type (wt), metastatic NSCLC. The primary endpoint was to assess overall response rate (ORR) and the key secondary endpoint was duration of response (DOR) by a blinded independent review committee (BIRC) assessment to determine the effectiveness of capmatinib in NSCLC patients. Patients have been enrolled into multiple cohorts of the study, out of which the bridging study was focused on the fully-enrolled MET exon 14 skipping positive Cohorts 4 and 5b. Cohort 4 only enrolled pretreated (second and third line) MET exon 14 skipping positive patients and Cohort 5b only enrolled treatment-naïve MET exon 14 skipping positive patients. Patients were screened for enrollment in Cohort 4 and 5b for MET exon 14 skipping status as detected using a MET exon 14 deletion a reverse-transcriptase PCR (RT-PCR)
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Reference ID: 4604109 CTA. After initial patient screening, clinical samples were stored for retrospective testing.
The GEOMETRY-mono 1 clinical trial met its primary objective demonstrating a statistically significant improvement in ORR by a blinded independent review committee (BIRC) in patients with MET exon 14 skipping positive tumors. Capmatinib demonstrated an estimated 40.6% (95% CI 28.9 - 53.1%) best overall response rate (ORR) by CTA in the MET exon 14 skipping positive patients from Cohort 4. An estimated 67.9% (95% CI 47.6 - 84.1%) best overall response rate was calculated in the MET exon 14 skipping positive patients from Cohort 5b.
The clinical utility of F1CDx based on patients with valid CDx results was demonstrated in the MET exon 14 skipping positive population for both the “Standard” and “Standard + Minimum” populations. For the double positive samples (CTA+, F1CDx+) that met “Standard + Minimum” sample requirements, ORR was determined as 44.2% by CDx with 95% CI (30.5 - 58.7%) for Cohort 4 and estimated 70% for Cohort 5b with 95% CI (45.7 -88.1%).
In terms of the bridging study, to determine the efficacy in the F1CDx positive population, it is important to note that all patients who were found to be negative for MET exon 14 skipping by the CTA also tested negative by the F1CDx (i.e., NPA = 100%) for Cohorts 4 and 5b. Therefore, the conditional probability of being CTA positive in the F1CDx positive population is 100% (i.e., Pr(CTA+|CDx+) = 100%), regardless of the prevalence of MET exon 14 skipping as determined by the CTA. Thus, the final estimated drug efficacy (ORR) for F1CDx positive patients in the intended use population equals the estimated drug efficacy for the double positives (CTA+, CDx+) observed in the GEOMETRY-mono 1 clinical trial, which maintains the efficacy in the ITT population. There is however, a degree of uncertainty regarding benefit due to the analytical studies for two site reproducibility, which will be performed as a conditions of approval.
There is potential risk associated with the use of this device, mainly due to 1) false positives, false negatives, and failure to provide a result and 2) incorrect interpretation of test results by the user. The performance of the accuracy study partially mitigates the risks associated with this device, however, there is a degree of uncertainty regarding risk due to the analytical studies for two site reproducibility, which were not performed pre market.
1. Patient Perspectives This submission did not include specific information on patient perspectives for this device.
Summary of Benefits Treatment with capmatinib provides meaningful clinical benefit to NSCLC patients with MET exon 14 skipping, as measured by ORR demonstrated in the GEOMETRY-mono 1 trial. Given the available information, the data supports the conclusion that
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Reference ID: 4604109 FoundationOne®CDx has probable benefit in selecting patients with SNVs and indels that lead to MET exon 14 skipping for treatment with capmatinib in patients with NSCLC.
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 clinical bridging study support the performance of F1CDx as an aid for the identification of SNVs and indels that lead to MET exon 14 skipping in NSCLC patients for whom TABRECTA® (capmatinib) may be indicated.
XIV. CDRH DECISION
CDRH issued an approval order on May 6, 2020. The final clinical conditions of approval cited in the approval order are described below.
The applicant will provide the following in a post-approval report: • Provide the results of a site-to-site reproducibility study to include the second laboratory site in Morrisville, North Carolina using the same representative approach with intended use specimens carrying MET exon 14 SNVs and indels that lead to MET exon 14 skipping, as was used in support of the Morrisville, North Carolina site approval (P170019/S010).
The applicant’s manufacturing facilities have been inspected and found to be in compliance with the device Quality System (QS) regulation (21 CFR 820).
XV. 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.
Post-approval Requirements and Restrictions: See approval order.
XVI. REFERENCES
1. Fisher S., Barry A., Abreu J., et al. A scalable, fully automated process for construction of sequence-ready human exome targeted capture libraries. Genome Biol 12, R1 (2011). 2. Karolchik, D., Hinrichs AS, Kent WJ., et al. The UCSC Table Browser data retrieval tool. Nucleic Acids Res 32, D493-496 (2004). 3. Gnirke A., Melnikov A., Maguire J., et al. Solution hybrid selection with ultra-long oligonucleotides for massively parallel targeted sequencing. Nat Biotechnol 27, 182 189 (2009).
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Reference ID: 4604109 4. Li H. & Durbin, R. Fast and accurate long-read alignment with Burrows-Wheeler transform. Bioinformatics 26, 589-595 (2010). 5. Li H., Handsaker B., Wysoker A., et al. The Sequence Alignment/Map format and SAMtools. Bioinformatics 25, 2078-2079 (2009). 6. DePristo MA., Banks E., Poplin R., et al. A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat Genet 43, 491-498 (2011). 7. Forbes SA, Bindal N., Bamford S., et al. COSMIC: mining complete cancer genomes in the Catalogue of Somatic Mutations in Cancer. Nucleic Acids Res 39, D945-950 (2011). 8. Compeau PE., Pevzner PA., Tesler, G. How to apply de Bruijn graphs to genome assembly. Nat Biotechnol 29, 987-991 (2011).
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Reference ID: 4604109 Signature Page 1 of 1 ------This is a representation of an electronic record that was signed electronically. Following this are manifestations of any and all electronic signatures for this electronic record. ------/s/ ------
KELIE M REECE 05/06/2020 11:03:44 AM Uploaded on behalf of Abde Abukhdeir
Reference ID: 4604109 MEMORANDUM REVIEW OF REVISED LABEL AND LABELING 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)
Date of This Memorandum: April 10, 2020 Requesting Office or Division: Division of Oncology 2 (DO2) Application Type and Number: NDA 213591 Product Name and Strength: Tabrecta (capmatinib) Tablets, 150 mg and 200 mg Applicant/Sponsor Name: Novartis Pharmaceuticals Corporation OSE RCM #: 2019-2114-1 DMEPA Safety Evaluator: Janine Stewart, PharmD DMEPA Team Leader: Chi-Ming (Alice) Tu, PharmD, BCPS
1 PURPOSE OF MEMORANDUM The Applicant submitted revised container labels received on April 6, 2020 for Tabrecta. Division of Oncology 2 (DO2) requested that we review the revised container labels for Tabrecta (Appendix A) to determine if it is acceptable from a medication error perspective. The revisions are in response to recommendations that we made during a previous label and labeling review.a
2 CONCLUSION The Applicant implemented all of our recommendations and we have no additional recommendations at this time.
APPENDIX A. IMAGES OF LABEL AND LABELING RECEIVED ON APRIL 6, 2020 Container Labels- Commercial
a Stewart J. Label and Labeling Review for Tabrecta (NDA 213591). Silver Spring (MD): FDA, CDER, OSE, DMEPA (US); 2020 MAR 26. RCM No.: 2019-2114. 1 2 Page(s) of Draft Labeling have been Withheld in Full as b4 (CCI/TS) immediately following this page
Reference ID: 4590575 Signature Page 1 of 1 ------This is a representation of an electronic record that was signed electronically. Following this are manifestations of any and all electronic signatures for this electronic record. ------/s/ ------
JANINE A STEWART 04/10/2020 05:07:13 PM
CHI-MING TU 04/11/2020 09:20:18 AM
Reference ID: 4590575 Clinical Inspection Smnmary NDA 213591 for capmatinib
Clinical Inspection Summary
Date 4/6/2020 From Yang-Min (Max) Ning, M.D., Ph.D. Kassa Ayalew, M.D., M.P.H. Good Clinical Practice Assessment Branch (GCPAB) Division of Clinical Compliance Evaluation (DCCE) Office of Scientific Investigations (OSI) To Luckson Mathieu, M.D. Erin Larkins, M.D. Harpreet Singh, M.D. Kelie Reece, RPM Division of Oncology 2 (D02) Office ofOncologic Diseases (OOD) NDA # 213591 Applicant Novaiiis Phaimaceuticals Corporation Dru2 Capmatinib (Tabrecta) NME (Yes/No) Yes Therapeutic Classification Tyrosine kinase inhibitor Proposed Indication Treatment ofpatients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with a mesenchymal-epithelial transition (MET) exon 14 skipping mutation as detected by an FDA-approved test Consultation Date December 10, 2019 Review Priority Priority Summary Goal Date April 10, 2020 Action Goal Date April 30, 2020 PDUFADate August 12, 2020
I. OVERALL ASSESSMENT OF FINDINGS AND RECOMMENDATIONS
Clinical data from two coho1is of an ongoing, single-aim trial (Study CINC280A2201) were subinitted to the Agency in suppo1i ofa New Drng Application (NDA) for capmatinib for the above proposed indication. Four clinical investigators, Dr. Rebecca Heist (Site 2508), Dr. Maja de Jonge (Site 1803), Dr. Egbert Smit (Site 1802), and Dr. Johan Vansteenkiste (Site 4100), were selected for clinical inspections.
The inspections ofDrs. Heist, de Jonge, and Smit were perfo1med, and the results showed that the Applicant's subinitted clinical data were verifiable with source records at these three investigator sites, with no evidence of unde1Tepo1iing of adverse events or insufficient protection ofstudy subjects. The scheduled inspection of Dr. V ansteenkiste in Belgium was
Reference ID 4587533 Page 2 Clinical Inspection Summary NDA 213591 for capmatinib
cancelled because of the COVID-19 pandemic (see additional information in the Results section of this summary).
Based on the results of the three completed inspections, the clinical data generated from these three investigator sites appear to be reliable and adequate in support of this NDA.
II. BACKGROUND
The Applicant, Novartis Pharmaceuticals Corporation, seeks accelerated approval of capmatinib for use in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) that tests positive for a mesenchymal-epithelial transition (MET) exon 14 skipping mutation. Capmatinib is an inhibitor of the MET receptor tyrosine kinase and its investigational name used under IND 124033 was INC280.
To support the proposed indication for capmatinib in this NDA, the Applicant submitted clinical data from Cohorts 4 and 5b of an ongoing, multicohort trial (Study CINC280A2201) titled “A phase II, multicenter, study of oral c-MET inhibitor INC280 in adult patients with EGFR wild-type (wt), advanced non-small cell lung cancer (NSCLC)”. Efficacy data of these two cohorts that targeted subjects with advanced NSCLC harboring MET mutations is the basis for this NDA.
This study (NCT02414139) is an open-label Phase 2 trial of capmatinib (INC280) in subjects with locally advanced or metastatic NSCLC harboring MET mutations and/or amplification. Subjects who signed the molecular pre-screening informed consent form had their tumor tissue or specimens tested for MET mutations and amplification in a sponsor- designated central laboratory. Based on their MET status and prior lines of therapy for NSCLC, subjects were enrolled into one of nine separate cohorts of the study. Subjects with MET mutations, regardless of MET amplification, were to be allocated to Cohorts 4 and 5b.
Subjects in Cohort 4 were required to have received 1 or 2 lines of prior systemic therapy for NSCLC and subjects in Cohort 5b to have had no prior systemic therapy for advanced NSCLC. In addition, subjects were required to have epidermal growth factor receptor (EGFR) wild-type status (e.g., absence of exon 19 deletions and exon 21 L858R substitution mutations) and to have no anaplastic lymphoma kinase (ALK) rearrangement. At study entry, subjects were required to have documented disease progression with at least one measurable lesion as per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1).
The primary endpoint was the confirmed objective response rate (ORR) as assessed by Blinded Independent Review Committee (BIRC).
Study subjects were scheduled to receive capmatinib 400 mg orally twice daily on a continuous dosing schedule, with every 21 days as a complete treatment cycle. Study treatment with capmatinib continued until disease progression, unacceptable toxicity, lost
Reference ID: 4587533 Page 3 Clinical Inspection Summary NDA 213591 for capmatinib
to follow-up, or at the discretion of the investigator.
Tumor assessments were to be performed with CT/MRI scans at baseline (Day -28 to Day 1 prior to Day 1 of Cycle 1) and then every 2 cycles (± 4 days) until disease progression as determined by investigator and confirmed by BIRC. All on-study scans, including baseline scans, were required to be submitted to the sponsor’s contracted BIRC (Bioclinica Inc.) for central review. For subjects who had disease progression as determined by the local investigator, the submitted scans underwent an expedited central review (within 5 business days from the time of the receipt of images) and the results were communicated to the study site. If the central review did not confirm disease progression, subjects continued receiving the study treatment unless there was a medical need (i.e., rapid progression or clinical deterioration) for an immediate change in therapy per the investigator’s clinical judgment.
From 06/11/2015 through 04/15/2019 (the data cutoff date for the interim analysis in this NDA), this study enrolled 334 subjects from 92 study sites across 20 countries. Ten percent of subjects were from the U.S. and 90% from 19 countries across Europe, Asia, and Latin America. Of the enrolled, 69 subjects were allocated to Cohort 4 and 28 to Cohort 5b. Subjects in these two MET-mutated cohorts tested positive for a MET exon 14 skipping mutation based on the molecular pre-screening results from the central laboratory ( (b) (4) ).
The review division DO2 and OSI selected four investigator sites, as listed in Section I, for clinical inspections, with a primary focus on subjects in Cohorts 4 and 5b of the study CINC280A2201. Relative to other investigator sites, these four sites had large numbers of subjects in the two cohorts and/or significant objective responders that are pertinent to assessments of this NDA. Dr. Heist’s site (Site 2508) had the highest enrollment among the sites in the United States (U.S.). The reason for selection of the three foreign sites was that 90% of study subjects were recruited from regions outside the U.S. None of the four investigators had a history of FDA inspections prior to this application.
III. RESULTS
1. Rebecca Heist, M.D. (Site 2508) Yawkey 7B, 55 Fruit Street Boston, MA 02114-2621
The clinical investigator was inspected from February 25 through March 3, 2020, as a data audit for Study CINC280A2201. This was the first FDA inspection of the investigator. The investigator site enrolled six subjects into the study, with one subject to Cohort 4, two to Cohort 5b, and three to other cohorts. As of the data cutoff, the subject (Subject (b) (6) ) in Cohort 4 was discontinued from study treatment due to adverse event (pneumonitis deemed to be related to study drug); In Cohort 5b, one (Subject (b) (6) ) remained on study treatment and the other (Subject (b) (6) ) was discontinued at the investigator’s discretion.
Reference ID: 4587533 Page4 Clinical Inspection Smnmary NDA 213591 for capmatinib
Source records for all enrolled subjects were reviewed during the inspection and were compared with the Applicant's submitted data listings for this site. The reviewed records included but were not limited to the infonned consent fo1m s (ICF), eligibility criteria, CT/MRI scans perfonned, laborato1y tests, adverse events (AEs) documented and assessed by the investigator with respect to severity and relationship to study treatment, concomitant medications, and electronic case repo1i fonns (CRFs). Regulato1y documents related to the conduct and oversight of the study were also reviewed, including the Institutional Review Board (IRB) approvals of the protocol/amendments, info1m ed consent, and associated communications, monitoring visits and communications with the sponsor, protocol deviations, study dmg accountability, and retention of study records.
The inspection found that the Applicant's submitted data listings were verifiable with source documentation at the site, with no objectional observation repo1ied. Tumor assessment scans were perfo1m ed and submitted to the sponsor's designated BICR. There was no undeITepo1iing ofadverse events.
At the conclusion of the inspection, no Fo1m FDA 483 was issued to the investigator. There was one discussion item regarding the use ofthe prescreening ICF that specifically lists the investigator's name, protocol number, title of the study, and study dmg, but did not list all potential risks contained in the main ICF. The investigator provided evidence showing that both ICFs were discussed with subjects at the same time, although only the prescreening ICF was signed for central dete1mination ofmolecular eligibility for the study. No trial procedures were caITied out before subject's consent to pa1i icipation in the study.
2. Maja de Jonge M.D. (Site 1803) Locatie Daniel den Hoed Depaiiment B0-060a Groene Hilledijk 301 Rotterdam, NA 3015 CE Netherlands
Dr. de Jonge was inspected on Mai·ch 2-6, 2020, as a data audit for Study CINC280A2201. This was the first FDA inspection of this investigator. The clinical site screened 9 subjects for the study and enrolled 5 into the study, with two su\)jects each in 6 Coho1i 4 and Cohort 5b. As ofthe date cutoff, one subject (Subject All enrolled subjects' source records were audited for the info1med consent, protocol adherence, scans perfo1med and investigator's tumor assessment documentation and submission to the BICR, adverse event repo1iing, and test aiiicle accountability. Other documents reviewed at the site included, but was not limited to, the investigator's agreement, protocol and amendments, local ethic committee's approvals, site training Reference ID 4587533 Page 5 Clinical Inspection Smnmary NDA 213591 for capmatinib logs, sponsor 's monitoring reports, site signature and responsibility logs. The inspection revealed that this investigator had followed the protocol and its required procedures and evaluation for this study. The submitted efficacy and safety data were verifiable with the reviewed source records. There was no evidence ofunden epo1i ing of adverse events as ofthe data cutoff. Overall, there were no significant objectionable observations identified or repo1ied. At the end of this inspection, no Fo1m FDA 483 was issued to the investigator. Ofnote, . (6)(6) . (b)(6J Subject m Coho1i 4 had the last treatment dose on (after the data cutoff date of 4/1 5/201 9) but did not have an End of Treatment (EOT) scan perfo1med within the protocol specified 7 days after last dose. The investigator agreed with this finding and stated that the scan should have been repeated for the EOT visit. A con ective action was indicated and discussed. 3. Egbert Smit M.D., Ph.D. (Site 1802) Plesmanlaan 121 Amsterdam, NA 1066 CX Netherlands This foreign clinical investigator was inspected on Febmaiy 24-28, 2020, as a data audit for Study CINC280A2201 . This was the first FDA clinical inspection for the investigator. The established inspection repo1i (EIR) is cmTently unavailable. Based on the prelimina1y summaiy provided by the inspector, the investigator site emolled 11 subjects into the study. As ofthe data cutoff, all 5 subjects in Coho1i 4 were .. 6 61 discontinued from study treatment due to disease rogression (Subjects < >< and (1>) (6) or adverse events (Subj. ects (1>) (6) (1>) (6) and (1>)(6) one of the two 6 ..Sl-1b'-~--e-_cts_in·' Coho1i 5b remained on study treatment (Subject Cb>< and the other was 5 discontinued due to adverse event (Subject Source records for all emolled subjects were reviewed during the inspection and were compai·ed with the subinitted data listings for the site. The reviewed records and regulato1y documents, per the preliminaiy summaiy, included the signed info1med consent fonns, eligibility dete1mination, primaiy endpoint assessments, adverse event repo1i ing, test aiiicle accountability, IRB's approvals, monitoring repo1is, responsibility logs, and site training logs. The inspection repo1ied that the subinitted data listings were verifiable with source records at the site. Note that the BICR measurements or results were not available at the site, but the scans and investigator's tumor assessments were confnmed with source documentation. All adverse events were found to have been reported through the data cutoff date. No Fo1m FDA 483 was issued to the investigator at the close of this inspection. Reviewer's Comments: An amendment to this clinical inspection summary will be Reference ID 4587533 Page 6 Clinical Inspection Summary NDA 213591 for capmatinib introduced if the EIR for Dr. Smit contains substantial differences that can alter the current assessment of inspectional findings. 4. Johan Vansteenkiste M.D. (Site 4100) Herestraat 49 Leuven, NA 3000 Belgium This clinical investigator was scheduled to be inspected in March 2020 by the Office of Regulatory Affairs (ORA), but was canceled due to the COVID-19 pandemic related travel restrictions. Following discussions between OSI and DO2, a decision was made by DO2 not to proceed with inspection of Dr. Vansteenkiste’s site in the current NDA review cycle. As a result, OSI is unable to provide a recommendation regarding the investigator’s study conduct related to data integrity and study subject protection at this site. Reviewer’s Comments: Given the change in the scheduled inspection of this investigator, OSI discussed with the review team about possible rescheduling the inspection when the COVID-19 pandemic situation improves and/or when the related travel restrictions get lifted. With the feedback obtained from the above three site inspections, the review team informed OSI to withhold this site inspection in the current NDA review cycle. If applicable, this site inspection may be revisited and/or considered in the future when data from confirmatory trial(s) are submitted to the Agency. Reference ID: 4587533 Page 7 Clinical Inspection Summary NDA 213591 for capmatinib {See appended electronic signature page} Yang-Min (Max) Ning, M.D., Ph.D. Good Clinical Practice Assessment Branch Division of Clinical Compliance Evaluation 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 Clinical Compliance Evaluation Office of Scientific Investigations cc: Central Doc. Rm. NDA 213591 for capmatinib Review Division /Division Director/H Singh Review Division /Medical Team Leader/E Larkins Review Division /Medical Officer/L Mathieu Review Division/Project Manager/K Reece OSI/Office Director/D Burrow OSI/DCCE/ Division Director/N Khin OSI/DCCE/Branch Chief/K Ayalew OSI/DCCE/GCP Reviewer/YM Ning OSI/ GCP Program Analysts/ Joseph Peacock/Yolanda Patague OSI/Database PM/Dana Walters Reference ID: 4587533 Signature Page 1 of 1 ------This is a representation of an electronic record that was signed electronically. Following this are manifestations of any and all electronic signatures for this electronic record. ------/s/ ------ YANGMIN NING 04/06/2020 03:37:27 PM KASSA AYALEW 04/06/2020 04:03:41 PM Reference ID: 4587533 Interdisciplinary Review Team for Cardiac Safety Studies QT Study Review Submission NDA 213591 Submission Number 002 Submission Date 12/10/2019 Date Consult Received 2/18/2020 Drug Name capmatinib Indication MET-mutated advanced non-small cell lung cancer (NSCLC) Therapeutic dose 400 mg orally twice daily with or without food Clinical Division DO2 Note: Any text in the review with a light background should be inferred as copied from the sponsor’s document. This review responds to your consult dated 2/18/2020 regarding the sponsor’s QT evaluation. We reviewed the following materials: Previous IRT reviews under IND 124033, dated 12/08/2014 and 01/23/2017 in DARRTS; QT Evaluation Checklist (Submission 0017); Concentration-QTc analysis report (Submission 0000); Clinical study reports for Study A2201 and Study A2108 (Submission 0000); Proposed label (Submission 0000); Investigator’s brochure (Submission 0145 under IND 124033); and Summary of clinical pharmacology (Highlight of Clinical Pharmacology and Cardiac Safety table in Appendix table 5-6) (Submission 0000). 1 SUMMARY No large mean increases (>20 msec) in the QTc interval were detected in this QT assessment of capmatinib 400 mg BID. Without a positive control or a large exposure margin, we are reluctant to conclude a lack of an effect (ICH E14 Q&A (R3) 6.1). The effect of capmatinib was evaluated in Phase 2 Study CINC280A2201 and Phase 1 Study CINC280A2108. The highest dose that was evaluated was 400 mg BID, which is the maximum recommended human dose. The data were analyzed using concentration- QTc analysis as the primary analysis, which did not suggest that capmatinib is associated with large mean increases in the QTc interval at 400 mg BID (refer to section 4.5) – see Table 1 for overall results. The findings of this analysis are further supported by the by- time analysis (section 4.3) and categorical analysis (section 4.4). 1 Reference ID: 4587319 Table 1: The Point Estimates and the 90% Cl s (FDA Analysis) ECG Treatment Concentration L'lQTcF 900/oCI parameter (ng/mL) (msec) QTc Capmatinib 400 mg BID 4386.6 0.8 (0.3, 1.8) For further details on the FDA analysis p lease see section 4. Capmatinib is extensively metabolized by CYP3A4 and aldehyde oxidase. The highest exposure scenario is 20% increase in subjects with low body weight (BW<60 kg vs. BW between 60 and 80 kg), or 42% increase in AUC with concomitant use of strong CYP3A inhibitor (no increase in Cmax). 1.1 RESPONSES TO QUE STIONS POSED BY SPONSOR Not applicable. 1.2 COMMENTS TO THE REVIEW DIVISION Not applicable. 2 RECOMMENDATIONS 2.1 ADDITIONAL S TUDIES Not applicable. 2.2 PROPOSED LABEL Below are proposed edits to the label submitted to Submission 0000 from the IRT. Our changes are highlighted (addition, deletion) and are for suggestion only. We defer final labeling decisions to the Division. 12.2 Pharmacodynamics Cardiac Electrophysiology I capmatinib does not cause a large .. _m__ean__,in_c__re--ase- C""'i.e--. >--20-ms....,..) ""'"in-thJ__e Q~T-c """in__te-_rva_l._. I (b>l4> (b)(4) 2 Reference ID 4587319 3 SPONSOR’S SUBMISSION 3.1 OVERVIEW 3.1.1 Clinical Capmatinib (also known as INC280) is a kinase inhibitor indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with a mesenchymal-epithelial transition (MET) exon 14 skipping mutation. The proposed dose is 400 mg orally twice daily with or without food. The product is available in 150 mg and 200 mg film-coated tablets. Previously the IRT agreed with the sponsor’s proposal to use PK/ECG data from Study CINC280A2201 to evaluate whether the proposed 400 mg BID dose is associated with large mean increases on the QT/QTc interval (IND 124033, 01/23/2017 in DARRTS). Specifically, the IRT recommended that “The sponsor should submit the data and analyses to the NDA for review and provide a by-time descriptive statistical analysis (mean and two-sided 90% confidence interval) of the ΔQTc for the 400 mg BID dose level. The concentration-QTc analysis should contain (1) appropriate exploratory plots to evaluate model assumptions (e.g., linearity, lack of PK/PD hysteresis) and (2) goodness-of-fit plots for the final model.” In the current submission, the sponsor conducted concentration-QTc analysis using pooled data from studies A2201 and A2108. Study CINC280A2108 is a multicenter, open label, Phase I dose escalation study in patients with cMET dysregulated advanced solid tumors. Capmatinib was given with food. Extensive time-matched PK and ECG profiles were collected in all subjects (n = 35) following single dose (Cycle 1 Day 1) and at the steady state (Cycle 1 Day 7) at 300 mg BID (n = 8) and 400 mg BID (n = 27) of capmatinib administration. Study CINC280A2201 is a Phase II, multicenter study in adult patients with EGFR wild-type advanced NSCLC. Capmetinib 400 mg BID was administered in a total of 334 subjects across all cohorts (Cohorts 1-6). Extensive time-matched PK and ECG profiles were collected from 58 subjects on Cycle 1 Day 1 and at the steady state (Cycle 1 Day 15), while sparse time-matched PK/ECG were collected from other subjects (N=180). All ECG data were obtained in triplicate and were reviewed centrally. The sponsor used QTcF as the primary endpoint and used concentration-QTc analysis as the primary analysis. The sponsor provided by-timepoint descriptive statistics and categorial analysis results in individual clinical study reports. 3.1.2 Nonclinical Safety Pharmacology Assessments The potential interaction of INC280 with the hERG channel was evaluated using voltage clamped human embryonic kidney cells (HEK293). INC280 inhibited hERG potassium current by 50% at 18.7 M (40X the human free-drug Cmax at the therapeutic dose of 400 mg BID). 3 Reference ID: 4587319 In vivo safety pharmacology studies demonstrated that INC280 had no significant effects on CNS and respiratory functions in rats, and no effects on cardiovascular function as measured by telemetric electrocardiography (ECG) in monkeys. 3.2 SPONSOR’S RESULTS 3.2.1 By Time Analysis The primary analysis for capmatinib was based on exposure-response analysis. Given the small sample size, by-time results in study CINC280A2108 was not interpretable; the sample size in study CINC280A2108 was reasonable. Reviewer’s comment: Sponsor’s descriptive analysis results of the mean change from baseline QTcF, HR, PR and QRS were similar to FDA reviewer’s analysis results for both studies. Please see section 4.3 for additional details. 3.2.1.1 Assay Sensitivity Not Applicable. 3.2.1.1.1 QT Bias Assessment Not applicable. 3.2.2 Categorical Analysis There were no significant outliers per the sponsor’s analysis for QTcF (i.e., > 500 msec) for both studies. One subject in study CINC280A2201 experienced ΔQTcF greater than 60 msec. Sponsor used different categories for HR, PR and QRS. Results were not directly comparable. Reviewer’s comment: FDA reviewer’s categorical analysis results for QTcF and ΔQTcF are similar to the sponsor’s results. A large number of subjects experienced HR >100 bpm in both studies. One subject in each study experienced PR >220 msec and 25% increase over baseline. Three subjects in study CINC280A2201 experienced QRS >120 msec and 25% increase over baseline. Please see section 4.4 for details. 3.2.3 Exposure-Response Analysis The sponsor applied linear mixed-effect modeling on time-matched (within 30 minutes) plasma capmatinib concentration and QTcF change from baseline, with QTcF as the response; capmatinib concentration, baseline QTcF as fixed effects; and subject as a random effect. To account for the potential impact of food conditions, the model tested study (A2201-Cohorts 1 to 5, fasted, versus A2108, fed) as a covariate. The analysis did not show statistical significance of food condition as a covariate and was thus removed from the final model. The analysis suggested a flat exposure-response relationship (slope and 95% CI: 0.62 [0.34, 0.9] ms/(ug/mL)). The predicted QTcF was 1.33 ms (90% CI: 0.090, 2.575) at the mean Cmax,ss at the 400 mg BID dose level (5447.9 ng/mL). Reviewer’s comment: The reviewer’s analysis results are similar to the sponsor’s. 4 Reference ID: 4587319 3.2.4 Safety Analysis Related to QTc Prolongation In Study A2201, 3.0% (10 subjects) had QTc interval prolongation-grouped AESis and the individual PTs were: syncope (1.5%; 5 subjects), ECG QT prolonged (0.9%; 3 subjects) and cardiac aiTest (0.6%; 2 subjects) (Table 2-21). Adverse events (all grades) that were suspected to be study drng-related were repo1ied in 3 subjects (0.9%): 2 5 subjects had grade 1 ECG QT prolonged on Day 15 (Subject A2201 · < > and 61 61 Subject A2201· < ) and 1 subject had a cardiac aITest (A2201- (b)( ). • Subject A2201· 5 Reference ID 4587319 Table 2-21 Incidence of adverse events of special interest - QTc interval prolongation (Safety set) A ll solid All NSCLC tumor Study A2201 subjects s ubjects N=334 N=419 N=541 n (%) n (%) n (%) Number of subjects with at least one event (95% Cl) 10 (3.0) 12 (2 9) 14 (2 6) (1.4, 5.4 ) (1.5, 5.0) (1.4, 4.3) Exposure-adjusted overall incidence, n (IR per 100 STM') 10 (0.5 ) 12 (0.5 ) 14 (0.5 ) Maximum grade Grade 3 AEs 1 (0.3) 2 (0.5) 2 (04) Grade 4 AEs 2 (0.6) 3 (0. 7) 3 (0.6) Grade 3/4 AEs 3 (0.9) 5 (1.2) 5 (0.9) Treatment-related A Es 3 (0.9) 3 (0.7 ) 3 (0.6) SAEs 2 (0.6) 3 (0. 7) 4 (0.7) Ac tio n taken Drug interrupted 0 0 1 (0.2) Dose not changed 9 (2.7) 9 (2.1) 10 (1.8) Not applicable 1 (0.3) 3 (0. 7) 3 (0.6) Numbers (n) represent counts of subjects. MedDRA version 22 0, CTCAE version 4.03, Case Retrieval Strategy version released 29-Jul-2019. *Incidence rate per 1DD subject-months Source: [SCS Appendix 1-Table 2.2 .5-4a) and [SCS Appendix 1-Table 2.2 .5-4b) Source: Table 2-21 in Summa1y ofClinical Safety Reviewer's comment: Without a control arm, the background incidence ofthese AEs are not known. Given that none ofthe subjects had QTcF >500 msec, only 1 subject had an increase from baseline QTcF >60 msec and the mean increase in QTcF detected by both exposure-response and by-time ana~yses were <20 msec, capmatinib does not appear to have large mean increases in QTc. 4 REVIEWERS' ASSESSMENT 4.1 EVALUATION OF THE QT/RR C ORRECTION METHOD The sponsor used QTcF for the primaiy analysis, which is acceptable as no large increases or decreases in heart rate (i.e. lmeanl < 10 bpm) were observed (see section 4.3.2). 4.2 E C G ASSESSMENTS 4.2.1 Overall Overall ECG acquisition and inte1pretation in these two studies appears acceptable. 4.2.2 QT Bias Assessment Not applicable. 4.3 BY-TIME ANALYSIS The analysis population used for the by-time analysis included all subjects with a baseline and at least one post-dose ECG. 6 Reference ID 4587319 The statistical reviewer evaluated the QTcF, HR, PR and QRS effects using parametric descriptive statistics. Two datasets were evaluated (CINC280A2108 and CINC280A2201). Number of subjects varied for different time points. Number of subjects in the respective time point is displayed in the following tables. Given the small sample size, by-time results in study CINC280A2108 was not interpretable; the sample size in study CINC280A2108 was reasonable. 4.3.1 QTc Figure 1 displays the time profile of ΔQTcF for different treatment groups. The maximum ΔQTcF values by treatment are shown in Table 2. Figure 1: Mean and 90% CI of ΔQTcF Time Course (unadjusted CIs). 7 Reference ID: 4587319 Table 2: The Point Estimates and the 90% Cls Corresponding to the Largest Upper Bounds for AQTcF Actual Treatment Study Identifier Period/Day N Time (hours) ~QTCF (msec) 90.0% Cl (msec) Capmatinib 300 mg BID CINC280A2108 1/ 1 8 4 -0.5 (-10.7 to 9.8) Capmatinib 400 mg BID CINC280A2108 3/1 12 0 0.6 (-5.8 to 7 0) Capmatinib 400 mg BID CINC280A2201 1/ 1 56 2 5.2 (3.0 to 7.5) 4.3.1.1 Assay sensitivity Not Applicable. 4.3.2 HR Figure 2 displays the time profile of ~HR for different treatment groups. Figure 2: Mean and 90% CI of AHR Time Course CI NC280A21 08 16 14 12 10 ------ 8 6 C3 '2 4 ~ .E 2 ~ -;n 0 +-:1:-'' 16 14 12 10 ------8 -10 ------ -12 -14 -16 ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ 0 ~ ~ ~ 0"' 0"' 0"' 0"' 0.$) 0.$) 0.$) 0... 0"' 0"' Time Actual Treatment -- Capmatinib 300 mg BID -- Capmatinib 400 mg BID 8 Reference ID 4587319 4.3.3 ΔPR Figure 3 displays the time profile of ΔPR for different treatment groups. Figure 3: Mean and 90% CI of ΔPR Time Course 4.3.4 ΔQRS Figure 4 displays the time profile of ΔQRS for different treatment groups of two studies. 9 Reference ID: 4587319 Figure 4: Mean and 90% CI of ΔQRS Time Course 4.4 CATEGORICAL ANALYSIS Categorical analysis were performed for different ECG measurements either using absolute values, change from baseline or a combination of both. The analysis was conducted using the safety population and includes both scheduled and unscheduled ECGs. In any of the following tables, if a category is omitted that means that no subjects had values in that category. 4.4.1 QTc Table 3 lists the number of subjects as well as the number of observations whose QTc values were ≤ 450 msec, between 450 and 480 msec, between 480 and 500 msec. In study 2201, capmatinib 400 mg BID group, 3 subjects out of 324 subjects experienced QTcF more than 480 msec. 10 Reference ID: 4587319 Table 3: Cate2orical Analysis for QTcF (maximum) Total (N) Value <= 450 msec 450 msec < Value 480 msec < Value Study Actual <=480 msec <= 500 msec Identifier Treatment # Subj. #Obs. # Subj . #Obs. # Subj. #Obs. # Subj. #Obs. Capmatinib 7 93 1 3 0 0 CINC280A2108 8 96 300 mg BID (87.5%) (96.9%) (12.5%) (3.1%) (0%) (0%) Capmatinib 27 320 0 0 0 0 CINC280A2108 27 320 400 mg BID (100.0%) (100.0%) (0%) (0%) (0%) (0%) Capmatinib 312 1217 9 28 3 11 CINC280A2201 324 1256 400 mg BID (96.3%) (96.9%) (28%) (2.2%) (09%) (09%) Table 4 lists the categorical analysis results for ~QTcF (less than 30 msec, between 30 and 60 and greater than 60 msec). In study CINC280A2201, capmatinib 400 mg BID group, one subject out of 324 subjects experienced ~QTcF more than 60 msec. Table 4: Categorical Analysis for AQTcF (maximum) 30 msec < Value <= Total (N) Value <= 30 msec Value > 60 msec Study Actual 60 msec Identifier Treatment # Subj. #Obs. # Subj. #Obs. # Subj. #Obs. # Subj. #Obs. Capmati nib 8 96 0 0 0 0 CINC280A2108 8 96 300 mg BID (100.0%) (100.0%) (0%) (0%) (0%) (0%) Capmati nib 26 319 1 1 0 0 CINC280A2108 27 320 400 mg BID (96.3%) (997%) (3.7%) (0.3%) (0%) (0%) Capmati nib 311 1236 12 19 1 1 CINC280A2201 324 1256 400 mg BID (96.0%) (984 %) (3.7%) (1.5%) (0.3%) (0.1%) 4.4.2 HR Table 5 lists the categorical analysis results for maximum HR ( <= 100 beats/min and >100 beats/min). In study CINC280A2108, there were 3 subjects in capmatinib 300 mg BID group and 10 subjects in capmatinib 400 mg BID group, who experienced HR greater than 100 beats/min. In study CINC280A2201 , 61 subjects experienced HR greater than 100 beats/min in capmatinib 400 mg BID group. Table 5: Cate2orical Analysis for HR (maximum) Study Actual Total (N) Value <= 100 beats/min Value > 100 beats/min Identifier Treatment # Subj. #Obs. # Subj. #Obs. # Subj. #Obs. Capmatinib 5 84 3 12 CINC280A2108 8 96 300 mg BID (625%) (875%) (375%) (12.5%) Capmatinib 17 279 10 41 CINC280A2108 27 320 400 mg BID (630%) (872%) (370%) (12.8%) Capmatinib 263 1131 61 125 CINC280A2201 324 1256 400 mg BID (812%) (90.0%) (188%) (10.0%) 4.4.3 PR Table 6 lists the categorical analysis results for PR (less than 200 msec; between 200 and 220 msec and above 220 msec with and without 25% increase over baseline). One subject in each study experienced PR greater than 220 msec and >= 25% increase from baseline. 11 Reference ID 4587319 Table 6. Cate2onca. 1 A nal 1yS I.S i or PR Value > 220 msec & Value > 220 msec & Total (N) Value <= 220 msec Study Actual < 25% >=25% Identifier Treatment #Subj. #Obs. #Subj. #Obs. # Subj. #Obs. #Subj. #Obs. Capmatinib 7 1 CINC280A2108 85 0 8 3 300 mg BID 8 96 (875%) (88.5%) (0%) (8.3%) (12.5%) (3 1%) Capmatinib 14 CINC280A2108 27 25 306 2 0 0 400 mg BID 320 (92.6%) (95.6%) (7.4%) (4.4%) (0%) (0%) Capmatinib 299 1147 13 50 1 1 CINC280A2201 313 400 mg BID 1198 (955%) (95.7%) (4.2%) (4.2%) (0.3%) (0 1%) 4.4.4 QRS Table 7 lists the categorical analysis results for QRS (less than 120 msec and above 120 msec with and without 25% increase over baseline). In study CINC280A2201, three subjects experienced QRS greater than 120 msec and >= 25% increase from baseline. Table 7. Cate2onca. 1 Ana1 1ys 1. s i or QRS Value > 120 msec & Value > 120 msec & Total (N) Value <= 120 msec Study Actual < 25% >=25% Identifier Treatment #Subj. #Obs. #Subj. #Obs. #Subj. #Obs. #Subj. #Obs. Capmatinib 6 70 2 26 0 0 CINC280A2108 8 96 300 mg BID (750%) (72.9%) (25.0%) (27 1%) (0%) (0%) Capmatinib 25 306 2 14 0 0 CINC280A2108 27 320 400 mg BID (92.6%) (95.6%) (7.4%) (4.4%) (0%) (0%) Capmatinib 1176 19 76 4 CINC280A2201 324 302 3 400 mg BID 1256 (932%) (93.6%) (5.9%) (6.1%) (0.9%) (03%) 4.5 EXPOSURE-RESPONSE ANALYSIS Exposure-response analysis was conducted using all subjects with baseline and at a least one post-baseline ECG with time-matched PK. 4.5.1 QTc Prior to evaluating the relationship between drng-concentration and QTc using a linear model, the three key assumptions ofthe model needs to be evaluated using explorato1y analysis: 1) absence ofsignificant changes in heait rate (more than a 10 bpm increase or decrease in mean HR); 2) delay between plasma concentration and ~QTc and 3) presence ofnon-lineai· relationship. • Figure 2 shows the time-course of ~HR and an absence ofsignificant ~HR changes. • Figure 5 evaluates the time-course ofmu g-concentration and ~QTc in each study. The PK profiles in studies A2201 and A2108 ai·e different. The geometric mean Cmax at the 400 mg BID dose level was calculated from patients who contributed to both 1-hr and 2-hr postdose samples on Day 15. The major metabolite is not phannacologically active. The PK profiles ofthe major metabolite resembles that of the pai·ent di11g, therefore, the effect ofmetabolite exposure on the QTc interval cannot be differentiated from the pai·ent diug. The figure does not appeai· to show significant hysteresis within each treatment/study. • Figure 6 shows the relationship between di11g concentration and ~QTc and suppo1ts the use ofa linear model on the pooled dataset. 12 Reference ID 4587319 Figure 5: Time course of drug concentration (top) and QTc (bottom) Figure 6: Assessment of linearity of concentration-QTc relationship Finally, the linear model was applied to the data and the goodness-of-fit plot is shown in Figure 7. The estimated slope [95% CI] is 0.65 [0.38, 0.93] ms/(ug/mL). The intercept is small but statistically significant (mean [95% CI]: -2.08 [-3.27, -0.89] ms). Predictions from the concentration-QTc model are provide in Table 1. Figure 7: Goodness-of-fit plot for QTc 13 Reference ID: 4587319 Approximately 10% data have an absolute time difference greater than 30 min between PK and ECG sampling. 75% of these samples were collected as predose samples. In a sensitivity analysis excluding these 10% data, results of the exposure-response analysis are similar to the primary analysis. Geometric mean Cmax in the PK/ECG dataset is slightly lower than that is reported from all patients who had evaluable full PK sampling for noncompartmental PK analysis (4780 ng/mL). However, the prediction at a concentration of 4780 ng/mL has a mean value less than 10 ms and does not change the conclusions from this QT assessment. 14 Reference ID: 4587319 Signature Page 1 of 1 ------This is a representation of an electronic record that was signed electronically. Following this are manifestations of any and all electronic signatures for this electronic record. ------/s/ ------ NAN ZHENG 04/06/2020 01:39:52 PM Hongshan Li is the primary clinical pharmacology reviewer. HONGSHAN LI 04/06/2020 02:12:17 PM FERDOUSE BEGUM 04/06/2020 02:14:21 PM YU YI HSU 04/06/2020 02:28:48 PM DALONG HUANG 04/06/2020 02:30:04 PM MICHAEL Y LI 04/06/2020 02:31:28 PM LARS JOHANNESEN 04/06/2020 02:52:45 PM CHRISTINE E GARNETT 04/06/2020 03:58:41 PM Reference ID: 4587319 FOOD AND DRUG ADMINISTRATION Center for Drug Evaluation and Research Office of Prescription Drug Promotion ****Pre-decisional Agency Information**** Memorandum Date: March 31, 2020 To: Kelie Reece, Regulatory Project Manager Division of Oncology (DO2) From: Nazia Fatima, Regulatory Review Officer Office of Prescription Drug Promotion (OPDP) CC: Brian Tran, Team Leader, OPDP Subject: OPDP Labeling Comments for TABRECTA® (capmatinib) tablets, for oral use NDA: 213591 In response to DO2’s consult request dated March 25, 2020, OPDP has reviewed the proposed product labeling (PI), patient package insert (PPI) and carton and container labeling for the original NDA submission for TABRECTA® (capmatinib) tablets, for oral use. OPDP’s comments on the proposed labeling are based on the draft PI and PPI received by electronic mail from DO2 (Kelie Reece) on March 25, 2020 and are provided below. A combined OPDP and Division of Medical Policy Programs (DMPP) review was completed, and comments on the proposed PPI were sent under separate cover on March 30, 2020. OPDP’s has reviewed the carton and container labeling submitted by the Sponsor and has no comments. Thank you for your consult. If you have any questions, please contact Nazia Fatima at 240- 402-5041 or [email protected]. 24 Page(s) of Draft Labeling have been Withheld in Full as B4 (CCI/TS) immediately following this page 1 Reference ID: 4584401 Signature Page 1 of 1 ------This is a representation of an electronic record that was signed electronically. Following this are manifestations of any and all electronic signatures for this electronic record. ------/s/ ------ NAZIA FATIMA 03/31/2020 05:10:41 PM Reference ID: 4584401 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: March 30, 2020 To: Kelie Reece, PhD Regulatory Project Manager Division of Oncology II (DO2) Through: LaShawn Griffiths, MSHS-PH, BSN, RN Associate Director for Patient Labeling Division of Medical Policy Programs (DMPP) Sharon R. Mills, BSN, RN, CCRP Senior Patient Labeling Reviewer Division of Medical Policy Programs (DMPP) From: Susan Redwood, MPH, BSN, RN Patient Labeling Reviewer Division of Medical Policy Programs (DMPP) Nazia Fatima, PharmD, MBA, RAC Regulatory Review Officer Office of Prescription Drug Promotion (OPDP) Subject: Review of Patient Labeling: Patient Package Insert (PPI) Drug Name (established TABRECTA (capmatinib) name): Dosage Form and tablets, for oral use Route: Application NDA 213591 Type/Number: Applicant: Novartis Pharmaceuticals Corporation Reference ID: 4583603 1 INTRODUCTION On December 10, 2019, Novartis Pharmaceuticals Corporation submitted for the Agency’s review an original New Drug Application (NDA) 213591 for TABRECTA (capmatinib) tablets, with a proposed indication for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with a MET exon 14 skipping mutation as detected by an FDA-approved test. 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 II (DO2) on February 7, 2020 and February 5, 2020, respectively, for DMPP and OPDP to review the Applicant’s proposed Patient Package Insert (PPI), for TABRECTA (capmatinib) tablets. 2 MATERIAL REVIEWED • Draft TABRECTA (capmatinib) PPI received on December 10, 2019, revised by the Review Division throughout the review cycle, and received by DMPP and OPDP on March 25, 2020. • Draft TABRECTA (capmatinib) tablets Prescribing Information (PI) received on December 10, 2019, revised by the Review Division throughout the review cycle, and received by DMPP and OPDP on March 25, 2020. 3 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. 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 reformatted the PPI document using the Arial font, size 10. In our collaborative review of the PPI we: • simplified wording and clarified concepts where possible • ensured that the PPI is consistent with the Prescribing Information (PI) • removed unnecessary or redundant information • ensured that the PPI is free of promotional language or suggested revisions to ensure that it is free of promotional language • ensured that the PPI meets the criteria as specified in FDA’s Guidance for Useful Written Consumer Medication Information (published July 2006) 4 CONCLUSIONS Reference ID: 4583603 The PPI 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 PPI 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 PPI. Please let us know if you have any questions. 5 Page(s) of Draft Labeling have been Withheld in Full as B4 (CCI/TS) immediately following this page Reference ID: 4583603 Signature Page 1 of 1 ------This is a representation of an electronic record that was signed electronically. Following this are manifestations of any and all electronic signatures for this electronic record. ------/s/ ------ SUSAN W REDWOOD 03/30/2020 04:20:53 PM NAZIA FATIMA 03/30/2020 04:22:00 PM SHARON R MILLS 03/30/2020 04:25:37 PM LASHAWN M GRIFFITHS 03/30/2020 04:29:40 PM Reference ID: 4583603 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: March 26, 2020 Requesting Office or Division: Division of Oncology 2 (DO2) Application Type and Number: NDA 213591 Product Name, Dosage Form, Tabrecta (capmatinib) Tablets, 150 mg and 200 mg and Strength: Product Type: Single Ingredient Product Rx or OTC: Prescription (Rx) Applicant Name: Novartis Pharmaceuticals Corporation FDA Received Date: October 15, 2019 , December 19, 2019, and February 19, 2020 OSE RCM #: 2019-2114 DMEPA Safety Evaluator: Janine Stewart, PharmD DMEPA Team Leader: Chi-Ming (Alice) Tu, PharmD, BCPS 1 Reference ID: 4581806 1 REASON FOR REVIEW As part of the NDA review process, this review evaluates the proposed Tabrecta (capmatinib) Tablets prescribing information (PI) and container labels 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 Previous DMEPA Reviews B– N/A Human Factors Study C– N/A ISMP Newsletters* D – N/A FDA Adverse Event Reporting System (FAERS)* E – N/A Other F– N/A Labels and Labeling G N/A=not applicable for this review *We do not typically search FAERS or ISMP Newsletters for our label and labeling reviews unless we are aware of medication errors through our routine postmarket safety surveillance 3 OVERALL ASSESSMENT OF THE MATERIALS REVIEWED The proposed labels and labeling provide instructions to dispense Tabrecta tablets in the original container. We communicated with OPQ via email on March 10, 2020 for verification of the necessity of the proposed statements (e.g., “Dispense in original package. Protect from moisture. Do not remove desiccant. Discard unused tablets after 6 weeks…”) that appear on the container label. OPQ clarified via email on March 11, 2020 that the product is (b) (4) Therefore, OPQ found that the proposed statements are necessary to promote the safe and effective use of this product. We considered that it may be necessary for pharmacies to dispense a quantity less than a full bottle (e.g., cash payers, vacation supply, or an emergency supply until patients can see the doctor for a new prescription). (b) (4) (b) (4) (b) (4) 2 Reference ID: 4581806 (b) (4) The Review Team expressed agreement with this approach. Our review of the proposed PI and container labels identified areas where the labels and labeling may be improved to promote the safe use of the product. Thus, we provide related recommendations below in Section 4. 4 CONCLUSION & RECOMMENDATIONS We conclude that the proposed PI and container label can be improved to increase clarity, readability, and the prominence of important information to promote the safe use of the product. We provide recommendations for the division in Section 4.1 and recommendations for Novartis Pharmaceuticals Corporation in Section 4.2 below. 4.1 RECOMMENDATIONS FOR DIVISION OF ONCOLOGY 2 (DO2) A. Prescribing Information 1. Dosage and Administration Section a. Consider revising (b) (4) statement (b) (4) (b) (4) to (b) (4) read “Swallow Tabrecta tablets whole. Do not break, crush, or chew.” 2. How Supplied/Storage and Handling Section a. To ensure stability, the proposed Tabrecta product should be dispensed in its original container with the desiccant. (b) (4) (b) (4) b. Revise section 16 from bulleted sentences to a table format to improve readability for example as follows: 3 Reference ID: 4581806 TABRECTA 150 mg and 200 mg tablets How Supplied Tablets Strength Description NDC Number per Bottle Pale orange brown, ovaloid, curved film-coated tablet with beveled edges, unscored, 150 mg 56 0078-XXXX-XX debossed with ‘DU’ on one side and ‘NVR’ on the other side. (b) (4) ovaloid, curved film-coated tablet with beveled edges, unscored, 200 mg (b) (4) 56 0078-XXXX-XX debossed with on one side and ‘NVR’ on the other side. c. Revise the storage condition in Section 16 to include the “Discard unused tablets 6 weeks after first opening.” Instruction, for example: Storage Dispense in the original package with the desiccant cartridge. Store at 20C to 25C (68F to 77F), excursions permitted between 15C and 30C (59F and 86F) [see USP Controlled Room Temperature]. Protect from moisture. Discard unused tablets 6 weeks after first opening. 4.2 RECOMMENDATIONS FOR NOVARTIS PHARMACEUTICALS CORPORATION We recommend the following be implemented prior to approval of this NDA: A. Container Labels (Commercial and Professional Sample Configurations) 1. As proposed, the NDC numbers are incomplete. The product code (middle 4 digits) and the package code (last 1-2 digits) are denoted by a placeholder (0078-XXXX-XX). Submit revised labels with the complete NDC numbers. a. Healthcare providers use the middle digits (product code) to help verify a product’s strength, dosage form, or formulation. The similarity of the product code numbers has led to selecting and dispensing of the wrong strength and wrong drug. Avoid assigning sequential product code numbers. 4 Reference ID: 4581806 b. If for some reason the middle digits cannot be revised, increase the prominence of the middle digits by increasing their size in comparison to the remaining digits in the NDC number or put them in bold type. For example: XXXX-XXXX-XX. 2. To ensure consistency with the Prescribing Information, revise the statement, (b) (4) to read “Recommended Dosage: See prescribing information.” 3. Ensure the linear barcode is surrounded by sufficient white space to allow scanners to correctly read the barcode in accordance with 21 CFR 201.25(c)(i). 4. In September 2018, FDA released draft guidance on product identifiers required under the Drug Supply Chain Security Act.1 The Act requires manufacturers and repackagers, respectively, to affix or imprint a product identifier to each package and homogenous case of a product intended to be introduced in a transaction in(to) commerce beginning November 27, 2017, and November 27, 2018, respectively. We note the presence of the human-readable product identification, however; the 2D data matrix barcode is omitted. We recommend that you review the draft guidance to determine if the product identifier requirements apply to your product’s labeling. The draft guidance is available from: https://www.fda.gov/ucm/groups/fdagov public/@fdagov-drugs-gen/documents/document/ucm621044.pdf 5. The proposed product has a different expiration date after the botte is first opened (i.e., 6 weeks after first opening). Revise the statement (b) (4) (b) (4) on the side panel to read “Discard unused tablets 6 weeks after opening.” (a shorter statement) to improve readability. In addition, consider changing the font color of this statement or use other methods to draw attention to this important information. 6. Add the statements “Attention: Dispense and store Tabrecta in original container with the desiccant to protect from moisture.” to the principal display panel (PDP) to alert pharmacist/dispensers to dispense Tabrecta in its original container. With this information added to the PDP, remove the statements (b) (4) from the side panel to improve readability of the remaining information by allowing more white space. 7. Relocate the equivalency statement, “Equivalent to…”, which appears on the PDP to appear on the side panel. 5 Reference ID: 4581806 8. Remove or relocate to the side panel the statements (b) (4) on the PDP to allow for adequate white space and to improve readability of the remaining important information. 9. Consider decreasing the size of the logo (to the upper right corner of the proprietary name TABRECTA) on the PDP to allow for adequate white space and to improve readability of the remaining important information. B. Container Labels (Professional Sample Configurations) 1. We note the professional sample container labels includes the reference to a Tabrecta website for more information about the proposed product. Given that we did not evaluate the website, we recommend revising the statement to: “For more information, call (b) (4) or visit www.TABRECTA.com. The website has not been evaluated or approved by the FDA.” 6 Reference ID: 4581806 APPENDICES: METHODS & RESULTS FOR EACH MATERIALS REVIEWED APPENDIX A. PRODUCT INFORMATION/PRESCRIBING INFORMATION Table 2 presents relevant product information for Tabrecta received on February 19, 2020 from Novartis Pharmaceuticals Corporation. Table 2. Relevant Product Information for Tabrecta Initial Approval Date N/A Active Ingredient capmatinib Indication For the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with a mesenchymal epithelial transition (MET) exon 14 skipping mutation as detected by an FDA-approved test. Route of Administration Oral Dosage Form Tablets Strength 150 mg and 200 mg Dose and Frequency Maximum daily dosage: 400 mg twice day (800 mg per day) Dose may be reduced to 300 mg twice a day or 200 mg twice a day for the management of adverse reactions based on individual safety and tolerability. How Supplied 150 mg: HDPE Bottles of 56 tablets 200 mg: HDPE Bottles of 56 tablets Storage Dispense in the original package with the desiccant cartridge. Store at 20℃ to 25℃ (68℉ to 77℉), excursions permitted between 15℃ to 30℃ (59℉ to 86℉). Protect from moisture. 7 Reference ID: 4581806 APPENDIX G. LABELS AND LABELING G.1 List of Labels and Labeling Reviewed Using t he principles of human factors and Fai lure Mode and Effects Analysis, a along with postmarket medication error data, we reviewed the following Tabrecta labels and labeling submitted by Novartis Pharmaceutica ls Corporation. • Container label received on October 15, 2019 • Professional Sample Container label received on October 15, 2019 • Prescribing Information (Image not shown) received on February 19, 2020, available from \\cdsesub1\evsprod\nda213591\0014\m1\us\proposed-clean.doc G.2 Label and Labeling Images Container Labels- Commercial (bf(4J •Institute for Healt hcare Improvement (IHI). Fa ilure Modes and Effects Analysis. Boston. IHl:2004. 1 Page(s) of Draft [ at>eling nas t>een Witnnela in Full as 84 (CCI/TS) immeaiately following tliis page 8 Reference ID 4581806 Signature Page 1 of 1 ------This is a representation of an electronic record that was signed electronically. Following this are manifestations of any and all electronic signatures for this electronic record. ------/s/ ------ JANINE A STEWART 03/26/2020 03:08:26 PM CHI-MING TU 03/26/2020 04:52:22 PM Reference ID: 4581806