1. Developing Biomarkers into Products: An Overview Bill Rodriguez, M.D.
30 January 2018
TBVI Annual Symposium
Les Diablerets, Switzerland

2. Disclosures Draper Richards Kaplan Managing Director Foundation
FIND Scientific Advisory Board
World Health Organization Expert Advisory Panel on Health Science and Technology Policy

3. Goals of this Presentation
Highlight what is required for a newly discovered biomarker to be (a) validated and (b) available “off-the-shelf” for use in vaccine (or related) studies
-- Protein / proteomic markers
-- Nucleic acid markers
-- T cells / T cell subsets / T cell responses / small molecules
What key issues should I be concerned with?
Where can I get help?

4. Technology Development and Adoption Technology and Adoption
February 2015
Dx in Resource-Limited Settings
Source: Getty Images

5. Overview of Product Development – Diagnostic Biomarkers
Technology and Adoption
Concept
Phase 0
Development
Phase 2
Validation
Phase 3
Access
Phase 4
Feasibility
Phase 1
Project
Opportunities
No Go
Redirect Go
Project Uncertainty
Project Resources
Phase 0 Review
Phase 1 Review
Phase 2 Review
Phase 3 Review
Phase 4 Review
DR1
DR2
DR3
DR4
Design Reviews
(DR)
Phase Reviews
(PR)
Design Input Review
Design output Review
Design Verification Review
Design
Validation Review
Biomarker
Candidates

6. Overview of Product Development – Diagnostic Biomarkers
Technology and Adoption
Concept
Phase 0
Development
Phase 2
Validation
Phase 3
Access
Phase 4
Feasibility
Phase 1
Project
Opportunities
No Go
Redirect Go
Project Uncertainty
Project Resources
Phase 0 Review
Phase 1 Review
Phase 2 Review
Phase 3 Review
Phase 4 Review
DR1
DR2
DR3
DR4
Design Reviews
(DR)
Phase Reviews
(PR)
Design Input Review
Design output Review
Design Verification Review
Design
Validation Review
“Hey. This just might work!”
“Could this work?”
“It works.”
Biomarker
Candidates
February 2015
Dx in Resource-Limited Settings

7. Overview of Product Development – Diagnostic Biomarkers
Technology and Adoption
$2M - $20M
Concept
Phase 0
Development
Phase 2
Validation
Phase 3
Access
Phase 4
Feasibility
Phase 1
Project
Opportunities
No Go
Redirect Go
Project Uncertainty
Project Resources
Phase 0 Review
Phase 1 Review
Phase 2 Review
Phase 3 Review
Phase 4 Review
DR1
DR2
DR3
DR4
Design Reviews
(DR)
Phase Reviews
(PR)
Design Input Review
Design output Review
Design Verification Review
Design
Validation Review
Biomarker
Candidates
February 2015
Dx in Resource-Limited Settings

8. Overview of Product Development – Diagnostic Biomarkers
Technology and Adoption
What happens at the end of the Feasibility phase is:
The reason so few TB biomarkers have been successfully developed to date;
The difference between a $2M and a $20M Development program;
Largely determined by the quality, case definition, and size of the Feasibility sample set tested; and
Ultimately, a scientific question, not a product development question.
$2M - $20M
Concept
Phase 0
Development
Phase 2
Validation
Phase 3
Access
Phase 4
Feasibility
Phase 1
Project
Opportunities
No Go
Redirect Go
Project Uncertainty
Project Resources
Phase 0 Review
Phase 1 Review
Phase 2 Review
Phase 3 Review
Phase 4 Review
DR1
DR2
DR3
DR4
Design Reviews
(DR)
Phase Reviews
(PR)
Design Input Review
Design output Review
Design Verification Review
Design
Validation Review
Biomarker
Candidates
February 2015
Dx in Resource-Limited Settings

9. Product Development Detail – Diagnostic Biomarkers
Technology and Adoption
February 2015
Dx in Resource-Limited Settings

10. Example 1: (*New and Improved*) LAM Technology and Adoption
LAM: Lipoarabinomannan
Previous LAM-based tests with antibodies that are low sensitivity and/or cross-react with oral bacteria
Modified from Treumann and Homans:

11. Example 1: (*New and Improved*) LAM Technology and Adoption
LAM: Lipoarabinomannan
Previous LAM-based tests with antibodies that are low sensitivity and/or cross-react with oral bacteria
Alere Determine™ TB LAM Ag test
Immunochromatography
Polyclonal antibodies
Use urine only (due to cross activity with oral bacteria)
Low sensitivity (higher sensitivity in TB-HIV co-infected patients)
Modified from Treumann and Homans:

12. Example 1: (*New and Improved*) LAM Technology and Adoption
LAM: Lipoarabinomannan
Previous LAM-based tests with antibodies that are low sensitivity and/or cross-react with oral bacteria
To validate a *New and improved* LAM in Feasibility Phase
Establish and validate a new sample processing protocol
Lab-based characterization of sensitivity and specificity using clinical samples of known provenance
2 clinical studies
LAM (ELISA format) vs. PCR (n= )
Direct from sputum (n=~300) in TB suspects, ill controls, healthy controls
Cross-contamination with oral flora
Limit of detection across target demographic groups
2 analytical studies

13. Project structure & status
TB Biomarkers as Diagnostics – Protein signature
Example 2: Proteomic signature
Project structure & status
Track 1: To transfer newly identified (host) markers to a Luminex assay
Validate the assay and determine the diagnostic performance in a large sample set
Establish final biomarker signature
Track 2: To identify 1-2 suitable "near patient testing" platforms and evaluate them with final markers
Source: FIND

14. Explosion in near-patient molecular platforms
Multiple platforms are available for molecular and protein diagnostic testing
Explosion in near-patient molecular platforms
Epistem
Great Basin
Veredus
PositiveID
Stat-Diagnostica
BioFire
Alere q
Molbio
PositiveID STATDiagnostica Great Basin Cepheid BioCartis IdahoTechnologies
BioFire Alere Veredus Epistem iCubate Osmetech
QuantumDx
Rheonix QuantumDx Spartan Fluidigm Qiagen Micronics
Curetis Roche Enigma Gentura Atlas Genetics Molbio 14

15. Example 3: Cepheid GeneXpert

16. Example 3: Cepheid GeneXpert
Project post-feasibility ran from
FIND Support:
Development/Validation: ~$10M
NIAID support:
Cartridge/Mfg: ~$4M
Key Collaborators:
David Alland, UMDNJ
Catherina Boehme, FIND
Mark Perkins, FIND 16

17. Diagnostic Biomarker Development - Failure Points
Overly optimistic transition to product development before sufficient Feasibility data are collected;
limited and biased assessment of biomarker data based on small-n exploratory studies
poorly characterized or incomplete sample sets;
lack of performance data measured on a field-deployable platform;
lack of well-designed validation and confirmation studies; and
lack of standards and frameworks for biomarker validation, such as geographic validation requirements, or evaluation of cross-contamination with non-tuberculous mycobacteria (NTMs).

18. Commercialization is Challenging
Commercialization is Challenging in Markets for Diseases of Poverty
Commercialization is Challenging
Many companies have diagnostic technologies in late-stage development or in limited commercial use for nucleic acid, IgG/IgM, and antigen detection, and have a stated willingness to develop a high-priority test
- More than 70 companies submitted product development plans for a near-patient Ebola diagnostic test during the course of the epidemic
- 3 years later, only 6 companies have Ebola tests that received Emergency Use Authorization (EUA) from US FDA or the equivalent designation from WHO Diagnostic Pre- Qualification (plus tests from US CDC and DoD)
- No diagnostic products have received regulatory clearance for Ebola through FDA or WHO PQ non-emergency mechanisms 18

19. Project structure & status
FIND TB Biomarker Program
TB Biomarkers as Diagnostics – Protein signature
Project structure & status
Source: FIND

20. Key Issues to Consider
Are your feasibility data telling you what you think they are?
Do you use standardized, validated protocols (esp. sample processing) to measure your biomarker?
Do you know what commercial testing platform(s) you want t use in the field, and is it the same one as you are using in your laboratory during feasibility testing?
Have you evaluated performance in multiple populations, including:
- confirmed TB cases of low- and high-burden?
- ill controls
- healthy subjects
Are there any IP issues?

21. Goals of this Presentation
Highlight what is required for a newly discovered biomarker to be (a) validated and (b) available “off-the-shelf” for use in vaccine trials
-- Protein / proteomic markers
-- Nucleic acid markers
-- T cell responses / small molecules
What key issues should I be concerned with?
Where can I get help?
Goals of this Presentation
Feasibility data
Standardized protocols
Platform selection
Clinical validation against reference testing in well-characterized populations
Analytic validation