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Next Wave Molecular Meets Point of Care

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  1. Next WaveMolecular Meets Point of Care Business & Financial Strategies for Molecular Diagnostics 2009 Conference

  2. Molecular POC Defined • Molecular Point of Care diagnostic testing is done outside of the traditional molecular laboratory • Dispersed testing inside a hospital • Critical care centers • Physician labs • Retail service centers • Home testing • Retains the sensitivity and precision of lab-based Molecular testing and moves it closer to the patient and physician • Testing may include • Infectious agents • STDs • Genetic conditions • Oncology • Encompasses sample capture and preparation, amplification, and detection steps

  3. Profile of the Future Molecular POC Solution • Low cost – < $20 per test • Small, portable or hand held instrument • Time to result of < 30 minutes • Single use, integrated, disposable test device • Single test or panels, where they make clinical sense • Routine sample capture • Invisible methodology; i.e. sample in – answer out • Automated, or operationally simple – handled by non-skilled personnel or even patients • Clear result without need for interpretation • LIS connectivity • HIPPA compliant

  4. Challenges for Molecular Dx in POC setting • Molecular Dx is still in the early stage of market development • Though molecular methods have been around for decades, there are comparatively few FDA cleared diagnostic assays • Limited number of laboratories do Molecular Dx • Real Time PCR is and will likely remain the standard • This requires the amplification step which is time consuming and complex • Typical amplification times for diagnostic tests are 2 hours • Big challenge to reduce time and complexity of PCR • Molecular methods are highly complex • Require trained/skilled technicians • Require precision equipment; significant capital cost • Space and cost of operation considerations due to multiple steps (extraction, amplification, detection) • Time to answer not “rapid” • Products and technology will diverge • Highly automated lab testing (high volume, cost sensitive, not time sensitive) and • Dispersed/POC testing (lower volume, specific clinical action that is time sensitive or where convenience is important)

  5. Drivers of Molecular POC • Time critical treatment • Triage • Needed to initiate treatment or prescribe therapeutic regimen • Surgical support (oncology) • Ease of use/practicality/convenience • Patient setting • 24/7 availability • Low cost, easy to use • Need for high level of accuracy, specificity, sensitivity in testing that is provided by Molecular testing • Clinical Value is at the point of testing; the situation requires rapid analysis Clinically Actionable Information

  6. Examples of Molecular Diagnostics POC Applications • Time to result essential to therapeutic approach • Hospital acquired infections • Sepsis • Meningitis • Operating Room feedback (oncology) • Convenience • Drug resistance or adverse drug response testing (PGx); ability to provide prescription at time of visit • STDs; getting the answer when the patient is tested addresses privacy issues and closes the loop in a patient population that may be hard to reach for follow up • Examples for single tests • Enterovirus for meningitis (but a panel may be more useful ) • MRSA • Group B strep • TB (cost is big consideration but rapid sensitive testing could make a difference in treatment) • Panels make sense when there is limited patient sample but multiple data points are needed in diagnosis • Respiratory Panel – Influenza  and similar viruses • STD (Chlamydia, Gonorrhea, HPV); increased sensitivity over current POC methods • Sepsis • HPV panel • Meningitis; quickly identify and differentiate viral from bacterial to determine treatment • PGx; prescribe therapeutics at time of visit • Atypical pneumonia • Diarrheal; combine testing methods into one POC format • Leukemia • Newborn screening

  7. Move to Molecular POC • Laboratory testing • Molecular lab does sample extraction, preparation, RT PCR, detection on thermocycler • Requires trained, skilled lab personnel, equipment, lab space • Centralized with increasing automation Enabling Technology Breakthroughs Required • Point of Care testing • Testing done in patient setting using simple sample capture • Sample transferred to POC system, attendant or patient runs system • Answer to physician via LIS or wireless connectivity in 30 minutes

  8. Integration at Low Cost is the Key Technology Consideration • Sample capture has to be easy and integrated • Administered by patient or attendant; swab, finger stick, etc. • Requires innovative packaging and processing • Limited amount of DNA in a sample means that there needs to be amplification or new direct detection technologies • Most approaches are using some form of rapid PCR • Some work on direct detection and non-PCR • Accomplish this at a very low cost with processing time of less than 30 minutes. Sample Acquisition Extraction and Isolation Amplification Detection Reporting and Interpretation Integrated and invisible to user Simple without critical steps

  9. Cepheid GeneXpert • GeneXpert is the first example of an evolutionary move toward Molecular POC • Targeted for medium complexity labs • Proven in multiple diagnostic settings • Easier to use and portable • Technical features • 1 to 16 site random access instrument • Integrated sample processing and PCR amplification • Multiplexing • Emphasis on controls • Software based result analysis • Results in 1 to 2.5 hours depending on application • Applications • Anthrax screening for the USPS • MRSA • EV • GBS • Drawbacks • Technical skills still required for sample preparation • High cost per test • Footprint Reagent cartridge Expandable system

  10. Regulatory and Quality Considerations • FDA sign off required on all tests • New, more difficult CLIA waiver guidelines raise the hurdle • PMAs may be required in many cases for infectious disease tests; drives higher costs • Clinical validation of approach in the hospital, POL or other testing site • Central lab control will remain important in hospital settings • Qualification of platform and test • Process control for testing • Correlation to laboratory testing methods • Software validation; ability to read the answer versus interpret the data • Assay controls are important to make sure the tests have been performed properly

  11. Non-Molecular POC Competition • Immunoassay POC testing is becoming routine • Proven, easy to use formats • Low cost approach • Volumes drive adoption, cost, usability, etc. • Immunoassays don’t require sample extraction and amplification, a significant advantage over Molecular tests • However, lateral flow approaches have lacked sensitivity and precision required for many tests • Technological improvements in lateral flow devices may provide a cost effective alternative to some MDx POC applications • New immunoassay technologies will be available to provide testing solutions not currently available including • Infectious disease identification • Influenza subtyping • TB • The key for patients and physicians is the application and the result, not the technology • Several companies are working on combined MDx/Immunoassay platforms to be used in POC applications

  12. NeXus • Multi-analyte immunoassay testing system utilizing a synthetic binding system • Immunoassay cost profile • Quantitative or qualitative answers • Less than 20 minutes from sample to answer • Uses a small, inexpensive reader • Integrated sample and reagent packaging contains all the elements of the assay • Highly sensitive, CVs of ~5% • CLIA waiver possible depending on sample acquisition method

  13. Quidel vs. fluID vs. PCRPreclinical lot (Dev lot 4) Decreasing viral titer

  14. Development Approaches

  15. Common Approaches Integrated Sample Processing Rapid PCR Amplification using miniaturized “thermocycler” approaches Scalable equipment configurations to fit specific testing situations

  16. Th. Control System Biochip Core Pathogen A Pathogen B Pathogen C Marker A Marker B Reader Software platform ST Micro -- In-checkTM platform: Main elements Biological Content From ST partners

  17. Application: The concept of a panelSepsis • Field • Hospital • Emergency Room • Add Value • Multiplexing • Fast responses • User friendly • Point of care Multiple bacteria can be diagnosed per single test

  18. Avian Flu (Flexible panel to accommodate Any kind of pandemic risk virus) Influenza A Influenza B Positive controls H5N1 H5N2 H5N3 H1 – H16 N1- N6 Sample extraction PCR control Hybridisation control Positive control Negative control Sample Application: Flu-chip to prvent panedemic risk • Field • Point-of-needs • Airport • Immigration centers • Food industry • Add Value • Multiplexing • Fast responses • User friendly • Content • Influenza A • Influenza B • Avian flu Swab Lysis Nucleic Acid Extraction Reverse Transcription PCR Detection of most of influenza A & B Virus Define H1-H16 and N1-N6 genotyping

  19. Atlas Genetics Ltd • Novel platform for ultra-rapid Point-Of-Care’ infectious disease tests • First products for rapidly growing STD market (30MM Chlamydia tests in 2007 for USA & W Europe) • Single use, single patient disposable plastic card with simple reader instrument • Molecular (advanced; high reimbursement) and immunoassay (in development; medium reimbursement) • Provides a single test instrument for all diagnostics; avoids user labs/offices requiring multiple instruments • Multiple tests per card (up to 1 plus controls); enhanced value to user • IP protected: core assay chemistry, specific tests, and fluidic disposable card • Key know-how for all high value elements of the product • Assay development • Assay chemistry • Reagent formulation and deposition • Disposable card design

  20. Card functions Card assembly The cartridge is comprised of the following components: hard plastic cover (pneumatic lines), TPE layer (valves & bellows), hard plastic backbone (fluidic elements), adhesive tape, blister foil, blister seal, and the electrode on a polymer foil.

  21. Real Time PCR and Immunoassay Diagnostic Products for the Developing WorldMeaslesMalaria (Pan)Flaviviruses (Dengue) Rickettsia (spotted fevers)InfluenzaTyphoid/para-typhoid feverGoals:1) 20 minutes blood to answer2) Sensitivity similar to instruments in the developed world Paul Yager UW, PI Immunoassays Patrick Stayton UW, Molecular Sys Walt Mahoney Epoch/Nanogen N.A. Assay Fred Battrell Micronics Sys integration Gonzalo Domingo PATH Sys testing Bill Hunter Invetech Instrument design Supported by the Bill and Melinda Gates Foundation

  22. 55-95 C 56 C 95 C 55 C PCR Implementation in the DxBox • Move sample through different containers held at fixed temperatures above ambient for –Reverse Transcriptase –PCR cycling –Fluorescence detection (before and after thermal ramp) • Moving small samples uses little power • Cooling the sample, not the instrument or card uses power efficiently

  23. Rapid Inductive PCR Amplification • Using a novel method for heating: contact-less – inductively induced heat transfer in a coil • Low mass • Very fast heating rates • Electronic control with fast switching • Rapid air cooling • Easy coupling and insertion of cartridge

  24. Rapid Inductive PCR Eddy current depth penetration PCR Reaction mix (50 mL) PP sample tube Coil AC source (~ 40 kHz) Outer Al tube Temperature sensor Cool Air Flow

  25. Rapid Inductive PCR - “RIP” • Short amplification times • Maximum heating rates (15-20 0C per s) • 40 PCR cycles < 10 min • Modular • 1 to 5+ Units • Amplification • Contained in tube • No loss of Taq activity • Denaturation: 95 oC • Extension: 72 oC • Annealing: 60 oC

  26. Summary • Molecular POC testing will fill an important healthcare need for rapid, highly sensitive testing • Development will be evolutionary • Products and technologies will follow current Molecular Diagnostics approaches • Initially the biggest opportunities will be in infectious disease testing • Immunoassay technologies will fill part of the market need but will not replace the need for Molecular POC testing

  27. THANK YOU