Emerging diagnostic technologies proving the clinical application through gold standard data 2014-03-25
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Next Generation Sequencing is an exciting new technology for diagnostics companies. But is it right for all products and for all companies? This presentation was delivered via Webinar for a IVD audience for Q1 Productions, March 25, 2014.
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Emerging diagnostic technologies proving the clinical application through gold standard data 2014-03-25
- 1. Emerging Diagnostic Technologies: Proving The Clinical Application Through Gold Standard Data Lyssa Friedman 1Lyssa Friedman3/25/14
- 2. Outline Asking the right questions: a stair-step approach to product development and selecting the right technical platform Focus on novel diagnostics Key components for success Case studies The role of clinical operations 3/25/14 Lyssa Friedman 2
- 3. Next Generation Sequencing: The right tool for the diagnostic job? 3/25/14 Lyssa Friedman 3
- 4. Next Generation Sequencing (NGS) 2013 4Lyssa Friedman3/25/14 Nho, K. et al. Whole-exome sequencing and imaging genetics identify functional variants for rate of change in hippocampal volume in mild cognitive impairment Braggio E, et al. Lessons from next- generation sequencing analysis in hematological malignancies Mille FA, et al. Testing personalized medicine: patient and physician expectations of next-generation genomic sequencing in late-stage cancer care
- 5. NGS in the news 3/25/14 Lyssa Friedman 5 Mar 17 2014 Mar 18 2014 Jan 14 2014 (Regeneron) Mar 8 2012 (Complete Genomics) Jan 26 2014 Oct 24 2013
- 6. NGS in the regulatory landscape 3/25/14 Lyssa Friedman 6 First high-throughput DNA sequencing analyzer to receive U.S. Food and Drug Administration (FDA) premarket clearance MiSeqDx Nov 2013 http://www.illumina.com
- 7. NGS in the clinic 3/25/14 Lyssa Friedman 7 • Indication: thyroid cancer • ThyroSeq – 12 genes • Ion AmpliSeq™ • Cystic fibrosis (CF), two products: • CF 139-Variant Assay – 139 variants • CF Clinical Sequencing Assay – additional variants • Prenatal testing: verifitest – 7 fetal chromosomal abnormalities • MiSeqDx • Two products/indications: • NeoTYPE MDS/CMML Profile – 16 genes, myelodysplastic syndrome/chronic myelomonocytic leukemia (MDS/CMML) • Solid tumor profile – 48 driver genes, multiple tumor types • 7 common KRAS mutations, multiple cancer types + Laboratory Developed Tests (LDTs) + New platform for existing clinical indication ± Lower cost of goods sold (COGS)
- 8. Back to basics: What is the right tool for the job? Honda Civic Jaguar XJ Does the job for the price ✚ ✚ Safe and compliant ✚ ✚ Sexy and stylish ✚ The next best thing ✚ Because I can afford it ✚ 3/25/14 Lyssa Friedman 8 Other technologies NGS ✖ Choose the technical platform that suits the business, clinical and performance needs
- 9. The tail wagging the dog Broad clinical question Target biomarkers Selected platform Business case Clinical need Reimbursement strategy Commercial strategy 3/25/14 Lyssa Friedman 9 Avoid retrofitting the business, clinical, reimbursement and commercial strategies to an early platform or assay decision
- 10. Instead, follow a stair-step approach 3/25/14 Lyssa Friedman 10 Business case Clinical assessment Biomarker discovery Risk assessment •Technical •Regulatory Technical platform and assay selection Product development Product launch
- 11. Setting the stage for successful product development and launch 3/25/14 Lyssa Friedman 11 Define • Market • Unmet clinical need • Gold standard Conduct early discussions • Regulatory strategy • Commercial strategy • Reimbursement strategy Stay focused • Clinical indication • Discovery or in-licensing plan Remain agnostic regarding technical platform and assay requirements – choose based on • Clinical and market needs • Test performance requirements • Regulatory risks • Technical risks • COGS Allow the chosen technical platform and assay to serve the clinical, business, commercial and reimbursement case
- 12. Consider these key components early Gold standard Regulatory strategy Study design Publication strategy Reimbursement strategy 3/25/14 Lyssa Friedman 12
- 13. LDT vs FDA 3/25/14 Lyssa Friedman 13 LDT FDA Companion diagnostics ✔ Kit for distribution ✔ Sole-source CLIA lab ✔ ✔
- 14. Define the gold standard • How do key stakeholders define the gold standard? – Physician community – Literature/guidelines – FDA – Payers • Is local diagnosis sufficient or is “expert” diagnosis needed? For expert diagnosis: – Individual vs. panel – Blinded vs. conference – Expert name recognition • Apply gold standard label early in the discovery process – avoid waiting for development phase – Risk that labels will change changes in performance 3/25/14 Lyssa Friedman 14
- 15. Publications drive reimbursement Well-designed studies with pre-defined • Samples • Clinical annotation • Gold standard label • Performance requirements High-impact peer- reviewed publications Positive coverage decisions 3/25/14 Lyssa Friedman 15
- 16. Studies Publications Reimbursement The ACCE Evaluation Process for Genetic Testing 3/25/14 Lyssa Friedman 16 http://www.cdc.gov/genomics/gtesting/EGAPP/index.htm http://www.cdc.gov/genomics/gtesting/ACCE/index.htm • ACCE Model Project: • Analytic validity • Clinical validity • Clinical utility • Ethical/legal/social • Publications in these areas help build the reimbursement case Centers for Disease Control (CDC) Office of Public Health Genomics Evaluation of Genomic Applications in Practice and Prevention (EGAPP™) Initiative
- 17. What does success look like? Case Studies 3/25/14 Lyssa Friedman 17
- 18. Three success stories 3/25/14 Lyssa Friedman 18 Publications LDT Multi- gene Novel/ licensed NGS? Clinical validation Analytic verification Clinical utility Cost effectiveness Genomic Health OncotypeDx ✔ ✔ Novel No ✔ ✔ ✔ ✔ Veracyte Afirma Thyroid FNA Analysis ✔ ✔ Novel No ✔ ✔ ✔ ✔ Illumina verifi prenatal test ✔ ✔ Licensed Yes ✔ ✔ ✔ ✔
- 19. Cancer assays Risk score (continuum) 3/25/14 Lyssa Friedman 19 •Samples: formalin-fixed paraffin-embedded tissue •Platform: Reverse transcription polymerase chain reaction (RT-PCR), mRNA •Gold standard: centralized pathology •Regulatory: CLIA LDT Breast cancer Risk of recurrence 21 genes Colon cancer Risk of recurrence 12 genes Prostate cancer Disease risk assessment 17 genes Bast RC & Hortobagyi. N Engl J Med 2004
- 20. Genomic Health Company Timeline 3/25/14 Lyssa Friedman 20 FFPE: formalin-fixed paraffin-embedded; RT-PCR: reverse transcription polymerase chain reaction; NSABP: National Surgical Adjuvant Breast and Bowel Project; NCI: National Cancer Institute; ASCO: American Society of Clinical Oncology; SABCS: San Antonio Breast Cancer Symposium; NEJM: New England Journal of Medicine; NCCN: National Comprehensive Cancer Network; DCIS: ductal carcinoma in situ • Series A • RNA extraction protocol • TaqMan (RT-PCR) • Proof of concept • Series B&C • Commercial strategy • Series D • ASCO, SABCS • Clinical validation • CLIA lab • Breast assay launch • Clinical validation publication (NEJM) • Economic/cost effectiveness publication • IPO • Medicare • Aetna • Colon assay development • United Healthcare • NCCN guidelines • Colon assay clinical validation • Breast assay clinical utility publications • Colon assay launch • Social media campaign • Prostate program • Smartphone app • Breast NGS data • DCIS test launch • Prostate clinical validation • NGS in development 2000 ‘01 ‘02 ‘03 ‘04 ‘05 ‘06 ‘07 ‘08 ‘09 ‘10 ‘11 ‘12 ‘13 • Prostate launch http://www.genomichealth.com, http://www.oncotypedx.com
- 21. Suspicious thyroid neoplasm Benign vs continued suspicious result 3/25/14 Lyssa Friedman 21 Thyroid neoplasm with indeterminate cytopathology 142 genes •Samples: RNA-preserved fine needle aspirate biopsy •Platform: Custom microarray (Affymetrix), mRNA •Gold standard: centralized pathology •Regulatory: CLIA LDT on FDA-cleared microarray platform Alexander EK, et al. N Engl J Med 2012
- 22. Veracyte Company Timeline 3/25/14 Lyssa Friedman 22 • Series A • RNA extraction protocol • Clinical validation data • Clinical validation publication • Series B • Thyroid benign classifier launch • Cost effectiveness publication • Clinical validation publication (NEJM) • Analytic verification publication • Clinical utility publication • Medicare • NCCN guidelines • 2nd clinical utility publication • Gene discovery IPF • United Healthcare • Aetna • IPO 2008 2009 2010 2011 2012 2013 2014 • Thyroid malignancy classifier launch NCCN: National Comprehensive Cancer Network; IPF: idiopathic pulmonary fibrosis http://veracyte.com, http://afirma.com
- 23. Fetal chromosomal abnormalities 3/25/14 Lyssa Friedman 23 (Verinata) Blood screen 7 fetal chromosomal abnormalities •Samples: maternal blood •Platform: massively parallel sequencing (MPS) of maternal plasma cell-free DNA (cfDNA) •Gold standard: previously existing and accepted prenatal aneuploidy screening •Regulatory: CLIA LDT on FDA-cleared DNA sequencing analyzer Bianchi DW, et al. N Engl J Med 2014
- 24. Verinata Company Timeline 3/25/14 Lyssa Friedman 24 • Stanford license • Clinical validation publication • Clinical utility publication • Name change (fr. Artemis Health) • Series C • Launch • Product expansion • Cost effectiveness publication • Fundraising • Series D • Acquisition (Illimuna) 2009 2011 2012 2013 2014 • Clinical validation publication (NEJM) http://www.illumina.com, http://www.verifitest.com
- 25. Poised for success: Stay laser-focused on goals Take a stair-step approach Novel diagnostics 3/25/14 Lyssa Friedman 25
- 26. Goals Staying on target is a continuous process 3/25/14 Lyssa Friedman 26 Clearly define •Success •Milestones •Timelines •Risks Stay •Focused •Flexible •Nimble Communicate with transparency •Speedbumps •Roadblocks •Brick walls Mitigate risk Question assumptions (avoid drinking the Kool-Aid) Learn quickly from failures
- 27. Successful companies choose the technical platform that suits business, clinical and test performance needs 3/25/14 Lyssa Friedman 27 Business case Clinical assessment Biomarker discovery Risk assessment •Technical •Regulatory Technical platform and assay selection Product development Product launch While managing many of these processes non-sequentially and simultaneously
- 28. 3/25/14 Lyssa Friedman 28 Business case • Market – Who are your key customers? – What is the clinical indication? – Where is your geographical target over the next 3 years? 5 years? 10 years? – What is the payer landscape? • Early consideration of risks – Who are your investors? – What return do your investors expect on their investment in 3 years? 5 years? 10 years? – Who are your competitors? – What is the regulatory landscape? Potential minefields? – What is the technical landscape? Potential minefields?
- 29. • Performance requirements and gold standard – What does the market need in order to trust the test • Equipment and reagents – How competitive is the space? FDA-cleared vs. research use only (RUO)? How will this affect • Supply agreements: cost, room to negotiate • Reagents: cost, availability, stability, need for verification • Software verification and validation (V&V) – What capital purchases and internal resources are needed? – How will V&V affect time and cost? 3/25/14 Lyssa Friedman 29 Business case, cont’d
- 30. • Unmet clinical need – What is the unmet clinical need? – What are the pain points? How can you ease your physician customer’s pain? – What is the current clinical workflow? How can you minimize disruption of that workflow? – What will it take to engender physician trust in your test? Performance? Gold standard? Publications? Guidelines? Influential KOLs? FDA-clearance? 3/25/14 Lyssa Friedman 30 Clinical assessment
- 31. • Gold standard – Is there label consistency from discovery through development? – Is there stakeholder buy-in for the gold standard? • Physician community • Literature/guidelines • FDA • Payers 3/25/14 Lyssa Friedman 31 Clinical assessment, cont’d
- 32. • Target sample: lessons learned from prospective sample collection – How are they collected and handled? – Where are they collected? Clinic, radiology, pathology? – What is the impact on sample collection on the patient? Special procedures, extra visits, discomfort, anesthesia? – How disruptive will collection and handling be to current workflow? – Will special training be needed? – Will special storage facilities be needed? – How many specialties will need to be involved? Clinic physician, radiology, pathology? 3/25/14 Lyssa Friedman 32 Clinical assessment, cont’d
- 33. • KOLs – how are they selected and engaged? – Protocol development – Development of key clinical questions – Publications – Guideline committees – Influence: US/ex-US – Study participation • Non-KOL investigators – Peer influence – Early adopters – Patient population – Clinic access - workflow 3/25/14 Lyssa Friedman 33 Clinical assessment, cont’d
- 34. • Clinical utility: so what? – Patient outcomes – Societal cost-effectiveness – Savings to payers • Performance requirements • Publication strategy • Reimbursement strategy 3/25/14 Lyssa Friedman 34 Clinical assessment, cont’d
- 35. Disease Test Present Absent Total Positive True positive A False positive B A + B Negative False negative C True negative D C + D Total A + C B + D A + B + C + D Sensitivity A A+C Probability test positive when disease present Specificity D B+D Probability test negative when disease not present Positive predictive value PPV A A+B Probability disease present when test positive Negative predictive value NPV D C+D Probability disease absent when test negative Prevalence A+C A+B+C+D Performance requirements: what type of test? 3/25/14 Lyssa Friedman 35
- 36. Performance requirements: things to think about • Will the test performance lead to actionable patient results? – What difference does the test make? • What performance will the community accept? – What are the barriers to uptake? How much education will the community need in order to understand test performance? • How well does the gold standard perform? – The test cannot outperform the gold standard 3/25/14 Lyssa Friedman 36
- 37. Publication and reimbursement strategy 3/25/14 Lyssa Friedman 37 Publications Protocol Clinical validation study Recognized gold standard Independent test set Clinical validity Analytic validity Clinical utility Clinical guidelines Positive coverage decisions
- 38. Samples Discovery Samples Study planning Samples Analytic testing Samples Validation 3/25/14 Lyssa Friedman 38 •Simultaneous and interdependent processes •Continuously re-assess risks and re-focus priorities throughout the continuum Processes are not sequential
- 39. • Use same gold standard from discovery through development – Changes can affect test performance • Continue other activities in parallel – Stability and kit testing – Planning: validation, product development, reimbursement, publication and commercial strategies • Ongoing and continuous risk assessment with focused and aggressive timelines – Building the bicycle while riding it (downhill at 60 mph!) 3/25/14 Lyssa Friedman 39 Biomarker discovery
- 40. • Will platform change from discovery to product development? If so, anticipate changes, with associated delays, to – Gene set – Equipment and reagents – Algorithm development – Test performance 3/25/14 Lyssa Friedman 40 Technical risk assessment
- 41. • LDT vs FDA clearance – LDT • CLIA lab: buy or build? • Equipment • Documentation • Staffing – FDA • Documentation – design control • Early meetings with agency • Kit and partnership strategies • Equipment and reagents – FDA-cleared vs RUO 3/25/14 Lyssa Friedman 41 Regulatory risk assessment
- 42. • Clearer platform decision at this stage with a stair-step approach – FDA-cleared vs. RUO – Reagents – Cost of goods – Regulatory pathway 3/25/14 Lyssa Friedman 42 Technical platform and assay selection
- 43. Technical platform: you get what you pay for 3/25/14 Lyssa Friedman 43 Data Development costs
- 44. What assay and technical platform? 3/25/14 Lyssa Friedman 44 RT-PCR: reverse transcriptase polymerase chain reaction; FISH: fluorescent in situ hybridization; SKI; spectral karyotype imaging; cDNA: complementary DNA Genomic information Indications PCR Multiple copies of targeted DNA sequence Large DNA targets RT-PCR Amplified RNA RNA viruses mRNA or large DNA translocations qPCR Real-time PCR Real-time quantification of multiple copies FISH Oligonucleotide probes attached to cDNA target Oncogene amplification, translocations Microarrays Thousands of transcripts and probes Gene expression “fingerprints” Single nucleotide polymorphisms (SNPs) Sequencing Precise order of nucleotides within DNA Molecular biology, evolutionary biology, metagenomiccosts Netto GJ, et al. Proc (Bayl Univ Med Cent) 2003
- 45. NGS: things to think about • Equipment is costly – can it be leveraged across projects in lab? • Computational challenges – Sequencing produces raw data requiring assembly into longer sequences – Sequences may not be assigned to specific chromosomes • When transferring existing assay to new platform full validation is needed – technology transfer not sufficient 3/25/14 Lyssa Friedman 45
- 46. • Transfer assay from R&D – conduct studies on platform to be used commercially • LDT: conduct studies in CLIA lab by approved personnel – Stability – collection, handling transport – Analytic sensitivity – input, dilution – Analytic specificity – interfering substances – Assay robustness – Reproducibility – Limits of detection – Quality control 3/25/14 Lyssa Friedman 46 Product development
- 47. • Clinical sites = early adopters • Partner with commercial group for knowledge transfer – Customer pain points and workflow – Nuances of patient population and physician specialty – Key contact people at customer sites 3/25/14 Lyssa Friedman 47 Product launch
- 48. Clinical operations: An integral part of the whole 3/25/14 Lyssa Friedman 48
- 49. Clinical operations: not just for accruing samples… Sample accrual Pristine annotation Gold standard labels Thorough data management and data auditing Prospective protocols conducted according to Good Clinical Practices 3/25/14 Lyssa Friedman 49
- 50. …We are the first ear to the voice of the customer and thus a key to success 50Lyssa Friedman3/25/14 • Articulate the clinical question – Unmet need – Pain points – Workflow challenges • Define the gold standard • Grow influential KOL relationship, which are critical to – Publications – Physician uptake – Guideline acceptance • Cultivate PI/site relationships: early commercial adopters • Develop critical protocols • Assess and mitigate risk • Define clinical utility • Publish abstracts and manuscripts that drive guideline and physician uptake and reimbursement
- 51. Questions? Lyssa Friedman lyssa.friedman@gmail.com / 415-250-8356