diagnostic development from the dx perspective...the policies or endorsement of hologic inc. ......

Diagnostic Development From the Dx Perspective

Dr Paul Docherty– Relationship and Alliance Manager

Disclaimer

• This presentation contains my personal views and research and does not necessarily reflect

the policies or endorsement of Hologic Inc.

• This presentation contains forward-looking information that involves risks and uncertainties,

including statements that are based upon assumptions made by market research which are

subject to known and unknown risks and uncertainties that could cause actual results to

differ materially from those anticipated.

2

Hologic Service Overview

Services Summary

• DNA, RNA and miRNA

extraction

• Genomics – RUO and GCP

• Biomarker discovery,

verification and validation

• LDT/CTA development and

testing

• IVD CDx development and

testing

What do Hologic also believe is

important?

Simple business models

• Flexible, no hedging costs, no termination

charges

Full disclosure – no black box, access to

information

Ability to deliver to timelines

Drop in drop out ‘full’ service

Commercial experience

Post Market Support

Validation and

Launch Prep

Develop-ment and

Verification

Product Definition

and Planning

Concept and

Feasibility

Hologic’s Biomarker, LDT & CDx Service

4

• IVD manufacturing

• Post Launch

Surveillance

• Technical Support

• Customer Support

• Reimbursement

• Bridging studies

Post Market Support

Validation and Launch Prep

Development and

Verification

Product Definition and

Planning

Concept and Feasibility

• Biomarker discovery

and POC studies

• Assay development

• Regulatory

assessment of

clinical trial design

• Define Product

Requirements

• IPP&S

• FAS

• Design Control

• Assay formulation

• Development lots

• IUO pilot lots

• Regulatory

preparation

• Analytical Validation

• Clinical Validation

(with drug)

• Regulatory

Submission

Why so few biomarkers make it to the clinic?

False Discovery. Janet Woodcock, FDA estimates “as much as 75 per cent of published

biomarker associations are not replicable”

– These are not genuine biomarkers – fail validation/not reproducible

– Study design limitations, e.g. small sample numbers

– Poor study execution, e.g. no sample randomisation

– Inappropriate Bioinformatics analysis

True Discovery. These are biologically meaningful markers that fail to reach the clinic:

– Clinical evidence, e.g. NPV/PPV, sensitivity/specificity

– Clinical utility, e.g. cost effectiveness for Payers

– Technical factors, e.g. platform accessibility in clinical setting

– Competing tests

– Information not necessary for clinical decision- making

“Traditional” IVD Test Development

Workflow

Pre-Clinical Phase I Phase II Phase III Launch

Biomarker Discovery and VerificationCompanion Diagnostic

Development

‘Reality’ situation for most personalised

medicines

• Investment decision mid/late Ph II

• No efficacy data before Phase II – 2/3 fail

• Pharma need to move to Phase III quickly

• IUO development timelines 12-18 months

• IVD CDx investment required before efficacy is proven

• Compresses timelines for Diagnostic partner

IVD Investment


IUO Assay

Drug Efficacy

Drug Investment

IVD CDx Development

Smooth Transition from LDT to IVD

Same Instrument

Same Reagents

Same Software

Panther Fusion is under development and not currently for sale.

IVD CDx

LDT GCP


LDT

LDT

5. HOLX defines

thresholds, cutoffs, etc.

and “locks” completed

LDT protocol

3. Run LDT on Fusion

2. Protocol is “unlocked”

during optimization

1.HOLX creates protocol

with LDT software

LDT Protocol Creation and Validation

Workflow


ABCB1 CYP2C19 FADS1 KIT SLCO1B1

ABCB11 CYP2C8 FGFR1 KRAS STK11

ABCG2 CYP2C9 FMO3 LEP TM6SF2

ABL1 CYP2D6 GSTM1 MTRR TMC4

ANGPT2 CYP3A4 HFE NR1I2 TNF

APOE CYP3A5 HGF NRAS

TNFRSF1

B

BRAF EGFR IGF2 OPRM1 TP53

CD74 ERCC1 IL6 PDGFRA UGT1A1

CFH ERCC3 JAK2 PIK3CA VEGFA

4. Results evaluated

Our Biomarker, LDT & CDx Service

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Post Market Support


Development and

Verification


Planning


+ + +

+++ ++ ++ ++ ++

+++ +++ +++ +++ +++

LDT

FDA

CE


11

• IVD manufacturing

• Post Launch

Surveillance



• Reimbursement


Post Market Support


Development and

Verification


Planning


• Biomarker discovery

and POC studies

• Assay development

• Regulatory

assessment of

clinical trial design

• Define Product

Requirements

• IPP&S

• FAS

• Design Control

• Assay formulation

• Development lots

• IUO pilot lots

• Regulatory

preparation



(with drug)

• Regulatory

Submission

12

Assay

HW

SW

MFG

OTS

OTS Eng

Materials

Facilities

QE

QC

Clinical

Reg

Technology

Selection


HW VerificationSystem

Architecture

Design &

Definition

Risk Management

Assay Reagent and Oligo Development

Assay VerificationAssay Procedure

Development

Procedure & Formulation

Optimization

System characterization / Development Testing

Detailed Design

Industrial Design

Instrument Development

Detailed Design Code / Unit Test

Instrument

Validation

System

Validation

Vendor ID & Qualification

(SQMT)

Input / Output Testing

SW Verification & Validation

Develop Packaging, Labeling, & Shipping

Dev Lots

with R&D/Ops

RUO/PEO

label

Equip IQ/OQ

Pilot Lots (CBER Conformance,

Export Sales)

IUO/PEO

label

Equip PQ

Manufacturing Lots

IVD

label

Facility / Cleaning Validation

Process Validation

Finalize Packaging, Labeling, & Shipping

Oligo,Transcripts

Cells, Plasmids

Formulation

Process

Quality

& Spec

QC Method & Spec Development QC Method & Spec Validation

Ext. Clinical Preparation

Regulatory PreparationRegulatory

Review

Ext. Clinical Trials

Final Test Methods & Specs

Phase or Design Review 1: Product Definition & Planning | Phase or Design Review 2: External Clinical Trial Readiness, if needed | Phase or Design Review 3: Launch Readiness

Approval

Phase Review Design ReviewTransfer Review

2 2

11

33

Start of Design Control Product Definition &

Planning Development & Verification Validation and Launch Prep

The Reality – FDA

Master Service

Agreement

Post Market Support

End up here


13

Decisions that are made here• Product and Technology choices

• Legal & IP

• Regulatory

• Market research


Development and

Verification


Planning


Our Companion Diagnostic Development Service

14


• Driven by Pharma and Dx company - multiple stop/go’s before design control:

– Biomarker discovery and proof of concept studies

– R&D assay development

– Platform/technology choice

– Legal agreements and IP searches

– Regulatory assessment of clinical trial design

– Market research

– Risk analysis

– Define Product Requirements – this feeds directly into the product design


15

Pharmaceutical CompanyDiagnostic Company - Kit and HardwarePayerTesting LabPatient

Product Requirements

• Key to the success of a CDx development product – multi stage process

• As much information as possible is required - as early as possible

• Gathered from multiple sources and stakeholders by both Pharma and Dx companies

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Physician

Product Requirements

17

User

Business

Regulatory

Intended Use

Hardware Platform

Assay Technology

Intended Use

Specimen Type

Specimen Stability

Specimen Collection Device

Specimen Transport Device

Specimen Volume

Specimen Dilution

External Controls

Internal Controls

Calibrators

Specimen Processing

Reagent Use

Software Platform

Throughput

Turnaround time

Hands on time

Interference performance

Cross reaction performance

Regulatory requirements

Proposed workflow

Inhibition performance

Kit vs Centralised

Analytical Performance

LOD

Specificity

Sensitivity

Range of Quantification

Precision

Clinical Performance

NPV/PPV

Testing numbers

Kit format

Kit size

Kit shelf life

Kit storage

Kit shipping conditions

Operator Expertise

Pricing

Language requirements

Instructions for Use

Package Insert

Labelling

Cost of Correcting a Requirements Error

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Concept andFeasibility

Product Definition andPlanning

Product Developmentand Verification

Validation Post Launch

Repeat Design – Pre Market Bridging Studies – Post Market Bridging Studies


19


Planning


Project Plan and Schedule

• High level project plan covering the whole development process

• Identifies processes, deliverables, milestones and timelines

• Product Scope (from Product Requirements)

• Project Team and Responsibilities

• Supplemented by individual plans from each functional area:

20

Dx Team Leader

R&D Operations Clinical Regulatory Quality QC BD/Marketing

Drug Development

Biomarker Development

Clinical Regulatory QualityAssay

DevelopmentBD/Marketing

Pharma Team Leader

• Design Control is a formal documentation procedure applied to product development

• It is an FDA requirement for medical devices

• Runs alongside and throughout the product development process

Design Control

21

Requirements

Design Input

(What?)

Design

Process

Design Outputs

(How?)

ProductValidation

Design Review

Verification


22

Development and

Verification


Planning


Development and Verification

• Implementation of product design and the systems required to manufacture them

• Verification testing to ensure all components of the product are ready for validation

23

Assay Hardware Software

Instrument

System

FDACE

Development and Verification

• QC method development and validation

• Manufacturing:

– Vendor identification and qualification

– Manufacturing equipment IQ/OQ/PQ

– Packaging, manuals, labelling and shipping

– Assay formulation

– Development lots – small scale

– IUO pilot lots – large scale

• Regulatory preparation

• Clinical Trial preparation

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Ready for Validation

Design Input

(What?)

Design

Process

Design Outputs

(How?)Verification

FDACE


25


Development and

Verification


Planning


Need a locked down IUO assay for validation – Phase III

Validation and Regulatory Submission


– Carried out prior to clinical validation

– Demonstrate the fitness of the assay (e.g. repeatability, reproducibility)


– Clinical utility of both the IUO CDx test and the drug

– The sooner you engage with a Dx partner the sooner we can look at the your trial design

• Regulatory Submission

– Regulatory guidance is required throughout the entire product development process

– Timelines and requirements vary depending on factors including; 510k/PMA/CE, US/ex-US

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LDT FDACE

FDA

Timelines

27

Approval ProcessNumber of Products on

the MarketExamples

Development

Times

LDT n/a Multiple 1-6 months

CE-Mark 54 APTIMA® HPV and PROGENSA® PCA3 8-12 months

PMA 8 Aptima HPV 16 18/45 genotype assay 2 years+

LDT

FDA

CE

Regulatory Approval!

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Post Market Support


29


Development and

Verification


Planning


Post Approval

• cGMP full scale IVD manufacturing production lots

• Post Launch Surveillance

• Marketing

• Manuals and IFU



• Reimbursement


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Dx development from a Dx perspective

31

‘Start with the end in mind’


Commercialisation

CDx Development

Biomarker Studies

Start with the End in Mind….

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• Speak to diagnostic partner as soon as possible

• What is your biomarker for?

• What does the end product look like?

• Gather as much information as you can, as soon as you can

• Collect samples throughout the drug discovery process

• Dx development timelines are critical – the Dx can never delay the

therapeutic

• The diagnostic must succeed every time – the therapeutic will not

Thank you

001375© 2017 Hologic, Inc. All rights reserved. Hologic, The Science of Sure, Aptima, Invader, InvaderPlus, Panther, Panther Fusion, ThinPrep,

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other countries. This information is intended for medical professionals and is not intended as a product solicitation or promotion where such

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diagnostic development from the dx perspective...the policies or endorsement of hologic inc. ......

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