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Next Wave Molecular Meets Point of Care Business & Financial Strategies for Molecular Diagnostics 2009 Conference 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

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Next wave molecular meets point of care l.jpg

Next WaveMolecular Meets Point of Care

Business & Financial Strategies for Molecular Diagnostics

2009 Conference


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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


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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


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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)


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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


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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


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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


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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


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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


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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


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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


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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


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Quidel vs. fluID vs. PCRPreclinical lot (Dev lot 4)

Decreasing viral titer



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Common Approaches

Integrated Sample Processing

Rapid PCR Amplification using miniaturized “thermocycler” approaches

Scalable equipment configurations to fit specific testing situations


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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


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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


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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


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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


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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.


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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


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55-95 C Developing World

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


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Rapid Inductive PCR Amplification Developing World

  • 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


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Rapid Inductive PCR Developing World

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


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Rapid Inductive PCR - “RIP” Developing World

  • 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


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Summary Developing World

  • 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


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THANK YOU Developing World


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