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The Pistoia Alliance is examining the challenges of the Faster Safe Companion Diagnostics (CDx) by Aligning Discovery & Clinical Data in the Regulatory Domain.
The slides discuss whether the data standards used in the research environment be aligned better with the data standards used in the regulated environment? If so, the time and cost of the development of NGS-based CDx could be reduced.

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  1. 1. Faster Safe Companion Diagnostics (CDx) by Aligning Discovery & Clinical Data in the Regulatory Domain 6th March 2018
  2. 2. This webinar is being recorded
  3. 3. ©PistoiaAlliance Speaker Biographies Keith Nangle: formerly Head, Genetic Data Sciences at GlaxoSmithKline Inc. Keith has also served as European Community Manager for the tranSMART Foundation before working with the Pistoia Alliance on the use of NGS in regulated areas of drug development. Mike Furness: is the MD and Founder of TheFirstNuomics and has spent over 30 years working in genomics and bioinformatics, developing and applying new technologies to understanding disease and drug R&D. He has previously worked for Life Technologies, Cancer Research UK, Pfizer, Incyte Genomics, DNAnexus and Congenica, as well as consulting widely for pharmaceutical and technology companies and investors. Stephen Lee: 30 years experience of in vitro diagnostic medical devices. Chair of European Commission's IVD Working Group. Now focused on implementation of IVDR (2017/746): performance evaluation; companion diagnostics; software / bioinformatics; classification; health institution exemption; conformity assessment; reference labs; etc. A lifelong learner adapted to working in a constantly changing environment. Chartered Scientist, Fellow of the Institute of Biomedical Science.
  4. 4. ©PistoiaAlliance Overview The growth and challenges of NGS in research and the regulated domain Keith Nangle (Pistoia Alliance) An overview of the regulations around CDx and the new changes coming Stephen Lee (Senior Regulatory Policy Manager – IVD Devices Division MHRA) How can bringing together discovery and clinical data standards reduce time and cost to generate safe CDx? Mike Furness (Pistoia Alliance)
  5. 5. ©PistoiaAlliance The growth and challenges of NGS in research and the regulated domain Keith Nangle Pistoia Alliance
  6. 6. ©PistoiaAlliance Question 1 • How much experience have you had with NGS for regulated purposes? – None – None but we expect to – Some experience, but not in a regulatory submission – We have successfully used NGS data in a regulatory submission 26 March 2018
  7. 7. ©PistoiaAlliance Next Generation Sequencing (NGS) • Refers to sequencing technology in which millions of short reads (100- 200 bases) are generated per sample, aligned to a reference genome, and genetic variants identified with respect to that reference genome. • While the technique is reliable and costs are low, the computational complexities of QC, mapping, and variant calling makes it difficult to get exact reproducible results. • This is a challenge for use of NGS in a regulated environment, such as diagnostic development, but the value of the technology makes it important that we work with regulators to establish effective guidelines and standards. • Reproducibility is just one of several challenges that come together during CDx development; others include the fact that many sequencing efforts have been done on large heterogeneous populations for purposes of discovery, and we would like to be able to use those data as well.
  8. 8. ©PistoiaAlliance Cost of Sequencing Wetterstrand KA. DNA Sequencing Costs: Data from the NHGRI Genome Sequencing Program (GSP) Available at: Accessed 22-Feb-2018.
  9. 9. ©PistoiaAlliance Growth of Large Genome Projects
  10. 10. ©PistoiaAlliance From Research to Clinical Genetic and Genomic tests, like other types of diagnostic tests, can be evaluated and regulated on the following three criteria: * Analytical Validity: Refers to how well the test predicts the presence or absence of a particular gene or genetic change. Can the test consistently and accurately detect whether a specific genetic variant is present or absent? Clinical Validity: Refers to how well the genetic variant(s) being analyzed is related to the presence, absence, or risk of a specific disease. Has having a specific genetic variant been conclusively shown to increase the risk or likelihood of having a disease or eventually developing a disease? Clinical Utility: Refers to whether the test can provide information about diagnosis, treatment, management, or prevention of a disease that will be helpful to patients and their providers. Will use of the test lead to improved health outcomes?  Definitions are adapted from the National Library of Medicine's Genetics Home Reference.
  11. 11. ©PistoiaAlliance The Reproducibility Challenge
  12. 12. ©PistoiaAlliance Typical NGS Analysis Workflow
  13. 13. ©PistoiaAlliance Reproducibility results
  14. 14. ©PistoiaAlliance Standards and guidelines Arch Pathol Lab Med. 2017 Jun;141(6):787-797. doi: 10.5858/arpa.2016-0517-RA. Epub 2017 Mar 21. J Mol Diagn. 2017 Jan; 19(1): 4–23. doi: 10.1016/j.jmoldx.2016.10.002
  15. 15. ©PistoiaAlliance Other regulatory guidance and resources • ICH guideline E18 on genomic sampling and management of genomic data - First version (Adopted Oct 2017) • EMA Concept paper on development and lifecycle of personalised medicines and companion diagnostics (Jul 2017) • Overview of FDA Precision Medicine and NGS Guidance Documents (Feb 2018) • EMA Guideline on good pharmacogenomic practice (Draft, Apr 2016) • FDA Principles for Codevelopment of an In Vitro Companion Diagnostic Device with a Therapeutic Product (Draft, Jul 2016) • List of Cleared or Approved Companion Diagnostic Devices (In Vitro and Imaging Tools) (Jan 2018) • List of Nucleic Acid Based Tests (Nov 2017) • IMI SAFE-T (Safer and Faster Evidence-based Translation)
  16. 16. ©PistoiaAlliance Technologies PDA J Pharm Sci Technol. 2017 ; 71(2): 136–146. doi:10.5731/pdajpst.2016.006734 bioRxiv 203554; doi:
  17. 17. ©PistoiaAlliance Technology/data initiatives and platforms • PrecisionFDA • NIH BD2K • The Human Variome Project • Global Alliance for Genomics and Health • Global Biological Standards Institute • The Common Workflow Language (CWL) • BioCompute Objects • Genome in a Bottle • Platinum Genomes • • BioSharing/FAIR Sharing • Reproducible Bioinformatics Project
  18. 18. ©PistoiaAlliance An overview of the regulations around CDx and the new changes coming Stephen Lee Senior Regulatory Policy Manager – IVD Devices Division MHRA
  19. 19. Regulation of companion diagnostic IVDs
  20. 20. ©PistoiaAlliance Overview of CDx regulation • IVDR basics • Clinical evidence requirements • Development models • Assessment of performance studies
  21. 21. ©PistoiaAlliance Health Warning! These views on the interpretation of the Regulations represent my own best judgement based on the information currently available. MHRA would always advise you to seek the views of your own professional advisers.
  22. 22. ©PistoiaAlliance Question 2 • What quality system are you currently using when analysing samples? – GxP – ISO 17025 – ISO 15189 – Something else? – What’s a quality system? 26 March 2018
  23. 23. ©PistoiaAlliance
  24. 24. ©PistoiaAlliance The Regulations entered into force on 25th May 2017. However, most requirements will not fully apply until 26th May 2020 for Medical Devices, and 26th May 2022 for In Vitro Diagnostic Medical Devices.
  25. 25. ©PistoiaAlliance IVD Development Device for performance evaluation Performance evaluation study NB assessment CE mark Clinical Use MHRA assessment EMA assessment Scientific Validity Analytical performance Clinical performance Interventionalstudy Companion Diagnostic Health Institution
  26. 26. ©PistoiaAlliance Clinical evidence is … • based on performance studies • used to demonstrate compliance with the regulations • updated through the lifecycle of the product
  27. 27. ©PistoiaAlliance Performance evaluation Performance study
  28. 28. ©PistoiaAlliance Performance indicators for IVDs
  29. 29. ©PistoiaAlliance General requirements for all IVD performance studies • the health and safety of patients, users and other subjects • the circumstances of the study • rights, safety, dignity and well-being of the subjects in the study • studies involving left over samples • data generated by the study data generated are going to be scientifically valid, reliable and robust
  30. 30. ©PistoiaAlliance Additional requirements may apply • Prior authorisation by a Member State(s) • Review by an independent ethics committee • Protection of vulnerable subjects • Management of risks and benefits to the subject • Informed consent and not exerting undue influence • Demonstrating analytical performance and scientific validity • Qualifications of those involved in the study • Study facilities
  31. 31. ©PistoiaAlliance 'companion diagnostic' • a device which is essential for the safe and effective use of a corresponding medicinal product to: • identify, before and/or during treatment, patients who are most likely to benefit from the corresponding medicinal product; or • identify, before and/or during treatment, patients likely to be at increased risk of serious adverse reactions as a result of treatment with the corresponding medicinal product • *This includes devices used in clinical trials to stratify patients for inclusion/exclusion in the trial or stratified to a cohort within a trial.
  32. 32. ©PistoiaAlliance Performance indicators of IVDs
  33. 33. ©PistoiaAlliance Companion Diagnostics: conformity assessment Phase I trial Phase II/III trial Marketing Authorisation Analytical performance/ Scientific validity Devices Authority review/notification Clinical performance study CE mark (Companion Diagnostic) Medicines Authority opinion Notified Body review Medicines legislation Devices Regulation Medicines Authority review Medicines Authority review
  34. 34. ©PistoiaAlliance “Follow-on” development Data?
  35. 35. ©PistoiaAlliance Stage 1. Application and coordination Stage 2. Verification Stage 3. Assessment Stage 5. Performance study report Stage 4. Running the trial Application process for Competent Authority assessment of companion diagnostic IVD performance evaluation studies 1a Trial sponsor notifies application 1b Commission assigns SIN via electronic system 2a Coordinating member state verifies application 2b In scope and complete? 2c Return to sponsor 2d In scope and complete? 2e Rejected 2f Member State appeals process 1d Trial sponsor submits changes 3a Member State opinion 4c Substantial modification 4d Member State opinion 4a Study begins 4b Study continues (with modification or corrective measures - if needed) 4e Refusal 4f Corrective measures needed 4g Sponsor opinion 4i Authorisation withdrawn 4h Member state opinion 5a Study ended, suspended, or terminated early by sponsor 5b Performance study report submitted 5c Performance study report publicly accessible 1c Agree coordinating Member State and inform sponsor 10 days from receipt with clock stops 10 days (extendable to 20+5 days) Within 1 week of the change 5 days from receipt of comments (extendable by 5 days) with clock stops 45 days (extendable by 20 days) 38 days (extendable by 7 days) 7 days 24 hours for early termination or suspension 15 days for end of study 3 months for early termination 1 year for end of study Immediately (if study terminated early) On registration (if study ended) Within one year (if study ended but device not registered) 6 days + 6 days
  36. 36. ©PistoiaAlliance Summary of CDx regulation • IVDR basics • Clinical evidence requirements • Development models • Assessment of performance studies • Anything else to cover?
  37. 37. ©PistoiaAlliance Thank you 020 3080 7309
  38. 38. ©PistoiaAlliance How can bringing together discovery and clinical data standards reduce time and cost to generate safe CDx? Mike Furness Pistoia Alliance
  39. 39. ©PistoiaAlliance Question 3 • How much experience have you had with NGS Companion Diagnostics? – Worked, or working, on one or more companion diagnostics brought successfully to market – Worked, or working, on companion diagnostics in development – Planning to work with companion diagnostics – Interested in finding out more about companion diagnostics 26 March 2018
  40. 40. ©PistoiaAlliance CDx - Companion vs Complementary Jan Trøst Jørgensen – Trends in Cancer vol. 2, pp706-712
  41. 41. ©PistoiaAlliance “… a survey by McKinsey in 2007 indicated that, on average, 30 to 50 percent of drugs in development have an associated biomarker program, and suggested this number was likely to increase…. while the most aggressive players have biomarker programs for 100 percent and companion diagnostics for 30 percent or more of their compounds, the average company has far fewer (30 to 50 percent and less than 10 percent respectively…” Invention reinvented – McKinsey 2010
  42. 42. ©PistoiaAlliance Growth of CDx usage Pharmgenomics Pers Med. 2015; 8: 99–110
  43. 43. ©PistoiaAlliance Precision Medicine Growth Areas Frost & Sullivan - Precision Medicine- Growth Opportunities for Genomics Technologies
  44. 44. ©PistoiaAlliance Companion Diagnostics for Cancer ……. AstraZeneca has collaborated with Roche to develop the cobas® EGFR Mutation Test v2 as the companion diagnostic for AZD9291.… ….ZD9291 is an EGFR-TKI, a targeted cancer therapy, designed to inhibit both the activating, sensitising mutations (EGFRm), and T790M, a genetic mutation responsible for EGFR-TKI treatment resistance. Nearly two-thirds of NSCLC patients who are EGFR mutation-positive and experience disease progression after being treated with an EGFR-TKI develop the T790M resistance mutation, for which there have been limited treatment options…..
  45. 45. ©PistoiaAlliance Companion Diagnostics by Therapeutic Area Pharmgenomics Pers Med. 2015; 8: 99–110
  46. 46. ©PistoiaAlliance Drug Discovery & Development – NGS & Omics
  47. 47. ©PistoiaAlliance Prospectively Stratify participants entering drug trial stratify trial Sub-population with target phenotype and/or genotype
  48. 48. ©PistoiaAlliance Clinical Research – Scaling up
  49. 49. ©PistoiaAlliance Stratify participants in Biobank stratify Trial 1 Trial 2
  50. 50. ©PistoiaAlliance Retrospectively Stratify participants after drug trial trial stratify 80% response with marker 20% response without marker 30% response FAIL PASS with CDx
  51. 51. ©PistoiaAlliance Front. Oncol., 16 May 2014 Companion Diagnostics (CDx) for Therapeutics
  52. 52. ©PistoiaAlliance References: Companion diagnostics for targeted cancer drugs - clinical and regulatory aspects. Olsen D, Jørgensen JT. - Front Oncol. 2014 May 16;4:105. doi: 10.3389/fonc.2014.00105. The current and future state of companion diagnostics. Agarwal A, Ressler D, Snyder G. - Pharmgenomics Pers Med. 2015 Mar 31;8:99-110. doi: 10.2147/PGPM.S49493 Frost & Sullivan - Precision Medicine- Growth Opportunities for Genomics Technologies genomics-technologies Invention Reinvented: McKinsey perspectives on pharmaceutical R&D al%20products/pmp%20new/pdfs/773771%20invention%20reinvented.ashx Companion and Complementary Diagnostics: Clinical and Regulatory Perspectives. Jørgensen JT. - Trends Cancer. 2016 Dec;2(12):706-712. doi: 10.1016/j.trecan.2016.10.013
  53. 53. ©PistoiaAlliance 11th April 2018 Workshop at Royal Soc Chemistry Morning Session Afternoon Session 09:00 Registration and Coffee 14:00 Industry Regulatory – Perspectives Challenges of NGS Companion Diagnostics Development (Stewart McWilliams, VP Quality & Regulatory Affairs, Almac) 10:00 Overview of the day and planned outcomes (Pistoia Alliance) 14:30 Cross-Expertise Delegate Breakout Groups to discuss: > What benefits could aligning the data requirements and standards bring? > What needs to be achieved to facilitate this? > Identify possible next steps 10:30 Overview of current large-scale NGS data projects (John Whittaker, VP Target Discovery, GSK) 11:00 Coffee 15:15 Coffee 11:30 What are CDx and the regulatory requirements around them? (Stephen Lee, Senior Regulatory Policy Manager – IVD Devices Division, MHRA) 15:45 Plenary session: Collect ideas, identify next steps and define targeted outcomes 12:00 How good is your next generation sequencing? (Simon Patton, Director, European Molecular Genetics Quality Network) 16:30 Networking Reception 12:30 Notified Body – Perspectives (Elizabeth Harrison, Technical Team Manager - IVD, BSI Group - tbc) 17:30 Close of Workshop 13:00 Lunch Register for workshop at
  54. 54. ©PistoiaAlliance More information Please see the problem statement on the Pistoia Alliance Interactive Project Portfolio Platform at: To explore this challenge, the Pistoia Alliance has created a short questionnaire that only takes a few minutes to complete. We would be very grateful if you would complete the questionnaire. It can be found at: The Pistoia Alliance will also hold a workshop at the Royal Society of Chemistry, Piccadilly, London on Wednesday 11th April 2018. To register your interest in attending the workshop please follow the link: