Next Generation Molecular Diagnostics in Scotland. Dr Mark Drummond Haematologist, Beatson Cancer Centre

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1 Next Generation Molecular Diagnostics in Scotland Dr Mark Drummond Haematologist, Beatson Cancer Centre

2 Outline Precision Medicine Regulatory and Funding background in Scotland (briefly) The Gap in the system A solution to the Gap : Joint Working Patient Impact & Supporting SMC approvals Future directions

3 Precision Medicine Precision medicine is a medical model that proposes the customization of healthcare, with medical decisions, practices, and/or products being tailored to the individual patient. * Not new (e.g. CML): but scale & technologies involved are. *Wikipedia, November 2016

4 Precision Medicine (Simple version)

5 The Molecular Testing Governance Framework In NHS Scotland The Molecular Pathology services in Scotland are nationally commissioned through NSD: equity of access across Scotland Network of four laboratories to deliver service Molecular Pathology Evaluation Panel (MPEP) for test approval (Horizon Scanning / SMC) Molecular Pathology Steering Committee (MPSC, oversee how & where service is delivered) Governance framework in Scotland works well

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7 The Problem (2014) New Biomarkers in literature plus Clinical trials, Early Access Programmes and Licensed Drugs Imminent, many requiring target identification (inc Pre-Screening). Who will perform this R&D? Large scale investment into Academia (10 x HiSeq sequencers) Lack of dedicated R&D funding in NHS Molecular / Genetics labs Staff time Money & Equipment Academic partnerships are crucial but not the solution to NHS Service development

8 Why Focus on NHS R&D rather than Academic? Quality of Testing (National & Local QA, QM etc) Incorporation of testing into existing diagnostic pathways (i.e. not always extra, will displace existing tests): Molecular Testing does not exist in isolation. MDT input is mandatory. Reactive, accessible, equitable. Reporting and data management (inc storage): a huge issue / problem. The NHS will tackle this at a Regional & National level (e.g. RCPath). R&D is a core NHS responsibility

9 NHS GG&C Joint Working Project Objectives SMC/MPEP identified companion diagnostics Supporting EAP & clinical trials Development of diagnostic pathways Interaction with academia, pharma and biotech companies Introduction of Next Generation Sequencing and novel technologies

10 Joint Working Project Working with Industry Conference, Glasgow, June 2014

11 Joint Working: Checklist 1 Is the main benefit of the project focused on the patient? Yes 2 Will both the Pharmaceutical and NHS partners pool skills, knowledge and resources? Yes 3 Is there a proportionate contribution of overall resources (taking into account people, finance, equipment & time) from all parties involved? Yes Yes No 4 Is there a shared commitment to successful delivery of the project by all parties involved? 5 Will the project deliver benefits for all parties involved: for patients, industry and the NHS? 6 Are all partners committed to, and have in place, a medium via which a summary of the Joint Working agreement can be made public prior to implementation e.g. published on the organisation s website Yes Yes Yes 7 Will the patient outcomes of the project be measured and documented? Yes 8 Will the project be managed by a joint project team comprising NHS representation and pharmaceutical Industry? 9 Do all parties and their respective organisations; have appropriate skills and capabilities in place to manage the project thus enabling delivery of the outcomes? Yes Yes 10 Do all partner organisations have clear procedures in place for reviewing and approving Joint Working projects? Yes 11 Are all partners clear on the respective signatories for Joint Working agreements? Yes 12 Is there an agreed exit strategy/contingency arrangement? Yes

12 The GG&C MDPD Joint Working Project The partnership was established between NHS GG&C, Novartis and Celgene after initial discussions June The funding application was to support two service based (NHS band 7) research scientists for 3 years with new equipment To work on both solid tumour and haematological cancer testing within the NHS, bridging the gap between R&D and service delivery Equipment and consumables funded from other sources Illumina NGS Platform from WoSCAN Endowment Funds & Charitable Funding - White Lilly Fund, Beatson charity Digital PCR from core NHS funding Reagent Costs from other endowments Total Investment of around K. Steering Group oversight (Lab, Haem, Path, Oncologists, Academia, Pharma)

13 Patient Impact: Example 1: AML / Myeloid Malignancies

14 AML

15 Example 1, New Tests: Myeloid Malignancies (NGS panel testing) Current PCR testing JAK2 CALR MPL FLT3 ITD NPM1 Panel testing 6 Diagnostic 9 Therapeutic 15 Prognostic Others: send away Diagnostic Therapeutic Prognostic

16 MDS/AML panel testing: example 1 Previous results Normal Karyotype 4% Blasts R-IPSS Score 2 (Low Risk) MDS Age 55 Category Prognostic NGS Panel results Gene ASXL1, RUNX1, EZH2, STAG2, SRSF2 5 x Pathogenic / likely pathogenic variants Poor prognosis indicators

17 What is bioinformatics? Technology evaluation Bioinformatics Using computational methods to analyse and interpret biological data Big data storage/cloud, security/governance Complex analysis Solutions for diagnostic somatic sequencing in their infancy Need to develop acceptable analytic / data storage / reporting practices for an NHS lab.

18 AML panel testing NGS results Sequenced DNA from 18 research patients 238 variants detected and reviewed Current testing strategy detects 5 variants Polymorphism class I Likely Benign class II Variant of unknown significance class III Likely pathogenic class IV Pathogenic class V No of variants % of total variants % thought to be pathogenic *FLT3-ITD not investigated by NGS

19 Myeloid / AML Panel Testing of Live samples: Molecular MDT Design and issue reports Prospective validation between NHS labs Work towards some form of accreditation.

20 Patient Impact: Example 2

21 xample 2: Supporting SMC Approved Drug Introduction: SMC/MPEP identified companion diagnostics Olaparib new PARP inhibitor for treatment of ovarian cancer in patients with BRCA variants Approved by SMC Olaparib is suitable for patients with a germline or somatic pathogenic BRCA variant Currently only germline testing offered Olaparib Germline Somatic

22 Germline and somatic testing Germline Inherited Blood Blood sample Variants in ~50% sample Somatic Acquired Tumour FFPE formalin fixed paraffin embedded tissue Variants at any level

23 Somatic BRCA testing Existing germline test not suitable to detect somatic variants Compare options to perform test ahead of requirement Germline (currently available) Somatic Sample type Blood Biopsy FFPE Pre-processing none Cutting, potential dissection DNA quality High Variable Appropriate technology Sanger sequencing, NGS NGS Data processing routine Bioinformatic pipeline required Variant detection level ~50% >5%?

24 Somatic BRCA testing Summary Complete initial comparison of NGS options (3 kits compared) Choose kit for phase 2 validation Ahead of SMC outcomes: no delay to patients Benefits accrued: working with FFPE tissue

25 Sustainability At the end of year 2, we ve achieved most of the goals set out by the JWP This project has a 3 x 1 year rolling cycle of funding from Celgene and Novartis But what happens after this? How or who should be funding this type of work for NHS Scotland? Have already engaged with NSD & GG&C management: MPEP application in development. Health Economic analysis underway

26 Nicola Williams, Paul Westwood, Rachel Dakin, Claire McKeeve, Alan Winter (GG&C Mol Gen Lab) NHS, academic and industrial collaborations (in particular Maggie Clark, Novartis), Thanks & Collaborations