Gaining Value from your Partner for Biomarker Research and ......Case Studies 1. Risk assessment for...

Copyright ©2015 Q2 Solutions. All rights reserved.

COMPANY CONFIDENTIAL

Yaozhou Shi, PhD

General Manager, Quest Diagnostics Clinical Trials China

Q2 Solutions, a Quintiles Quest Joint Venture

Gaining Value from your Partner for Biomarker Research

and Companion Diagnostics Development

Asian Regional Drug Development Summit | September 9, 2015

2 COMPANY CONFIDENTIAL

AGENDA

• Evaluating the trends and challenges in drug development across

complex trials

• Reviewing the importance of biomarkers and companion

diagnostics (CDx) in drug development

• Highlighting key biomarker and CDx case studies that demonstrate

risk mitigation in drug development across various therapeutic

areas.

• China CDx related regulatory


Personalized Medicine - the 4 Rs:

Company Confidential

Right Patient

Right Test

Right Drug

Right Treatment


The challenge is controlling rising drug development costs

Sources J.A. DiMasi and H.G. Grabowski. "The Cost of Biopharmaceutical R&D: Is Biotech Different?" Managerial and Decision Economics 2007; 28:

469–479; More recent estimates range from $1.5 billion to more than $1.8 billion. See J. Mestre-Ferrandiz, J. Sussex, and A. Towse. “The R&D Cost of

a New Medicine.” London: Office of Health Economics, 2012; S.M. Paul, et al. “How to Improve R&D Productivity: The Pharmaceutical Industry’s Grand

Challenge.” Nature Reviews Drug Discovery 2010; 9: 203–214; J.A. DiMasi, et al. “The Price of Innovation: New Estimates of Drug Development Costs.”

Journal of Health Economics 2003; 22: 151–185. Study findings originally reported in 2005 dollars. Based on correspondence with the study author,

these figures were adjusted to 2000 dollars.

The Average Cost to Develop One New Approved Drug – Including the Cost of Failures

Opportunity to reduce cost of failures through biomarkers

mid‐1970s mid‐1980s late 1990s early 2000s

$1.4 $1.2 $1.0 $0.8 $0.6 $0.4

$0.2

$0.0

Bill

ion

s (C

on

stan

t D

olla

rs, Y

ear

20

00

)

$140M

$320M

$800M

$1.2B


Challenges in Oncology Complexity of cancer pathways

Understanding the biology of the tumor is

paving the way for new therapies

Source: Hallmarks of cancer (Hannahan and Weinberg 2011)


Drug Development Paradigm Shift

Source: Igor Astsaturov, MD, PhD is Assistant Professor, Fox Chase Cancer Center, The Shifting Paradigm in Clinical Trial Design for Anti-cancer

Drugs, March 10, 2014; Applied Clinical Trials; http://www.appliedclinicaltrialsonline.com/shifting-paradigm-clinical-trial-design-anti-cancer-drugs

One-drug-for-all clinical trial design Mechanism-matched clinical trial design


Pharma is Focusing Efforts on Personalized Medicine

Situation: One drug does not fit

all… • Patient’s response to drug vs

population based on genomic/

proteomic differences.

• Patients need to be selected correctly

for placement on clinical trials to

increase likelihood of success.

Solution:

• Which drug works?

• Why does it work?

• For whom does it work?

• How this knowledge can be applied to

improve patient outcomes?

Approximately 46% of all new therapies in Phase III R&D

could benefit from a personalized medicine strategy (Source:

Diaceutics 2011 Report)


Evolving Trends in Clinical Trial Designs

• Phase-2 randomized studies

• Adaptive study designs

involving surrogate end points

• Prospective biomarker based

patient selection strategies

Need to partner with collaborative and consultative CRO

Source: Getz KA. Improving protocol design feasibility to drive drug development economics and performance.

International Journal of Environmental Research and Public Health. 2014;11(5):5069-5080.

Design Characteristics

(All values are Means)

2002 2012

Total number of endpoints 7 13

Total number of procedures 106 167

Total number of eligibility criteria 31 50

Total number of countries 11 34

Total number of investigator sites 124 196

Total number of patient randomized 729 597


Importance of Biomarkers and CDx in Drug Development

Demand for biomarkers and CDx in drug

development is rising: • Co-development of drugs and biomarkers is ideal

due to rising costs and attrition rates during clinical

trials

• FDA increasingly expects to see biomarker data

supporting NME applications

• Number of NME approvals has gone down over time,

while R&D spend has increased industry-wide

Biomarker can decrease costs, improve

time-to-market, and increase PTS • Incorporating a biomarker-based patient selection

criteria allows for smaller and lower cost trials that

get products on the marker faster

• Biomarker trials generate improved therapeutic

efficacy and tolerability, increasing probability of

regulatory success and stronger labels

Global biomarker market (in $B) is

growing and is dominated by oncology

Source: “Biomarkers market – Global Trends and Forecasts”, market research , 2014

“Cancer/Tumor Profiling Market”, markets and markets, 2013

12

30 6

11

18.5%

2018 2013

CAGR

Other

Oncology


Biomarkers Adoption Across Therapeutic Areas

• Inform Dose

• Select Patients in Early Clinical Trials

• Demonstrate Early Clinical Responses

• Drive Efficacious Combination Therapies

• Serves as a Companion Diagnostic

Source: Biomarkers In Clinical Trials: 80% Are Used In Two Or More

Therapeutic Areas, June18, 2014 John Audette; http://www.biomarker-

trends.com/tag/biomarkers-in-clinical-trials/


Importance of Biomarkers and Companion Diagnostics

Patients with the same diagnosis Patients likely to have toxic reaction

Patients likely to respond

Right patient, Right drug at the Right dose


The challenge is controlling rising drug development costs

Sources J.A. DiMasi and H.G. Grabowski. "The Cost of Biopharmaceutical R&D: Is Biotech Different?" Managerial and Decision Economics 2007; 28:

469–479; More recent estimates range from $1.5 billion to more than $1.8 billion. See J. Mestre-Ferrandiz, J. Sussex, and A. Towse. “The R&D Cost of

a New Medicine.” London: Office of Health Economics, 2012; S.M. Paul, et al. “How to Improve R&D Productivity: The Pharmaceutical Industry’s Grand

Challenge.” Nature Reviews Drug Discovery 2010; 9: 203–214; J.A. DiMasi, et al. “The Price of Innovation: New Estimates of Drug Development Costs.”

Journal of Health Economics 2003; 22: 151–185. Study findings originally reported in 2005 dollars. Based on correspondence with the study author,

these figures were adjusted to 2000 dollars.

The Average Cost to Develop One New Approved Drug – Including the Cost of Failures

Opportunity to reduce cost of failures through biomarkers

mid‐1970s mid‐1980s late 1990s early 2000s

$1.4 $1.2 $1.0 $0.8 $0.6 $0.4

$0.2

$0.0

Bill

ion

s (C

on

stan

t D

olla

rs, Y

ear

20

00

)

$140M

$320M

$800M

$1.2B


Drug Development Paradigm Shift

Source: Igor Astsaturov, MD, PhD is Assistant Professor, Fox Chase Cancer Center, The Shifting Paradigm in Clinical Trial Design for Anti-cancer

Drugs, March 10, 2014; Applied Clinical Trials; http://www.appliedclinicaltrialsonline.com/shifting-paradigm-clinical-trial-design-anti-cancer-drugs

One-drug-for-all clinical trial design Mechanism-matched clinical trial design


Pharma is Focusing Efforts on Personalized Medicine

Situation: One drug does not fit

all… • Patient’s response to drug vs

population based on genomic/

proteomic differences.

• Patients need to be selected correctly

for placement on clinical trials to

increase likelihood of success.

Solution:

• Which drug works?

• Why does it work?

• For whom does it work?

• How this knowledge can be applied to

improve patient outcomes?

Approximately 46% of all new therapies in Phase III R&D

could benefit from a personalized medicine strategy (Source:

Diaceutics 2011 Report)


Case Studies

1. Risk assessment for Companion Diagnostics -

Phase III oncology case study

2. Empowering personalized medicine with diagnostic

insights - an infectious disease case study

3. Accelerating medical research with diagnostic

biomarker insights for clinical trial recruitment - a

diabetes case study


Risk assessment for Companion

Diagnostics - Phase III oncology

case study

1 1


Case Study: Global DLBCL Oncology (CDx) Clinical Trial Phase III oncology case study

Date: 2014 to present

Company: Top Pharma Company (Phase 3 Randomized, Double-blind, Placebo Controlled, Multicenter Study to

Compare the Efficacy and Safety of Drug X Plus R-CHOP Chemotherapy (R2-CHOP) Versus Placebo

Plus R-CHOP Chemotherapy.)

Situation: Client is conducting DLBCL diagnostic trials (ABC sub type) globally with very high risk cancer patients.

Looking for central lab to coordinate specimens testing with a very specific 3 day TAT including week

ends, expert confirmatory pathology diagnosis support, Genomics CDx, communications and project/data

management.

Quest Central Laboratory and AP lab

Lab Testing & Spec/Data Management

Submission Timelines

Pharma Sponsor

Quest Dbase

Regulatory Compliance

Quest PM


Case Study: Biomarker Strategy for Phase III DLBCL Trial

Analysis to be performed prior to randamization-3 day turnaround including week ends in US and EU

Patient Enrollment-

Immediate analysis

Biomarker analysis-

Retrospective analysis

MRD-Batched Analysis Analysis to be performed

at time-TBD


NanoString DLBCL Assay

• Top 8 genes being overexpressed in activated B-cell-like DLBCL (ABC)

• The middle 5 genes being “housekeeping” genes

• The lower 7 genes being over-expressed in germinal center B-cell-like DLBCL

(GCB)

Source: Blood First Edition Paper, DOI 10.1182/blood-2013-11-536433


CDx as Regulated Biomarkers for Drug Development

Biomarker

Discovery

And Assay

Development

Clinical Trial and

CLIA Service

Development

Companion &

Complementary

Dx Kits & Services

Commercial

Launch

Authorized,

510k, de novo,

PMA, CE

Platforms

Manufacturing

Global Reach

Patient Access

Reimbursement

Promotion

Physician Sales

HCIT

Bioinformatics

Statistics

Platforms

Design & Analysis

Global Deployment

Test Validation

CAP/CLIA Testing

Medical Information

Clinical Insights

Scientific Insights

IVD /

FDA Cleared LDT LDT

Approval &

Launch

Phase II Phase III

Discovery Pre - Specified Pre - Clinical &

Phase I / II Aftermarket


2 2 Empowering personalized

medicine with diagnostic

insights - an infectious disease

case study


Empowering Personalized Medicine with Diagnostic Insights

An Infectious Disease Case Study

Structure Date: January 2012 to 2014 Company: Top Pharma Company Situation: Client is conducting HPV diagnostic trials globally . Looking for central lab to coordinate specimens testing, expert central pathology diagnosis support. communications and project/data management: • Establish and execute efficient 2-way

communications and planning . • Address critical issues such as data reporting,

budget planning and regulatory compliance. • Meet quality and timeline requirements suitable

for timely regulatory submission.

1. Leverage AP assay development, test performance and pathology expertise in Q2 Solutions laboratory

2. Quest central planning and risk mitigation to address issues across study and partners

3. Shorten timelines for communications, operations and outcomes

4. Reduced expenses including transportation costs

Q2 Solutions Central Lab and AP lab

Lab Testing & Spec/Data Management

Submission Timelines

Pharma Sponsor

Q2 Solutions PM

Q2 Solutions Dbase

Regulatory Compliance

Background

Benefits to Client


2 3

Accelerating medical research with

diagnostic insights for efficient

clinical trial recruitment - a diabetes

case study


Accelerating Medical Research With Diagnostic Insights for Clinical Trial Recruitment A Diabetes Case Study

Confidential – Do not copy or distribute

187 Q2 Solutions Physicians with 10+

highly relevant and precise cases

17,500 Q2 Solutions Physicians

with highly relevant patients

250 – 300k Physicians with

potentially relevant patients

Situation:

• Phase III Pharma POC study for diabetics w/ albuminuria with a complex protocol

• Involved a complex algorithm for patients with dual condition, i.e. diabetes and kidney disorder.

• Inclusion criteria: adult (age 18 to 80 years); diabetes fasting glucose ≥126 mg/dL, or 2 hbA1c

tests > 6.5%); history of albuminuria and eGFR.

• Exclusion criteria: hbA1c > 11%; Type 1 diabetes active cardiovascular diseases: ischemic

heart disease, cerebral vascular disease, and atherosclerotic peripheral artery disease; renal

transplant, acute renal dialysis, acute kidney injury, long QT syndrome hypothyroidism

Solution:

• Identified 17,500 Physicians that treated patients that met highly-specific inclusion criteria

• 187 of the Physicians identified saw 10 or more patients, providing extremely precise targeting

information

• Provided an efficient clinical trial recruitment strategy for a complex Phase III protocol via our data

warehousing and informatics


Q2 Solutions

Operational excellence

(PM/DM and Logistics)

CDx/LDT/

Biomarker Testing & Assay

Development including

commercialization

Central lab, Esoteric and

Specialty testing,

Specialized Central Lab Services

Esoteric and specialty Assay Development Labs

General Central Lab Services

Phases 1 2 3 4

Comprehensive “End-to-End” Lab Solutions for Pharma Pipeline

Biomarker

assay

development

Labs and CDx

development

Innovating in drug development and personalized medicine and

providing cutting edge science and increased value to Pharma pipeline

Informatics


• Medical Device Administration Regulation

• IVD Administration Regulation

• Clinical Trials Technical Guidance for IVD Product Registration

• Clinical Trials Technical Guidance for IHC Antibody/Kit Registration

• Clinical Trials Technical Guidance for PCR based Gene Mutation Detection kit

on Oncology Personalized Medicine

• Explanation and Interpretation of CMDE on CDx Product

CDx Related regulatory (No specific CDx regulation)

CDx Approval

Imported CDx product MUST be approved by FDA/CE

CFDA only allows hospital labs (certified) to conduct

CDx trials, no commercial lab allowed

Specific requirements

on enrollments and positive

cases


Regulation Critical information and interpretation

Medical Device

Administration Regulation

• NO clinical trial required for class I

• Class II and III require clinical trials but some types are waived for clinical trials, CFDA keeps

maintain the waived list, such as QPCR machine, Auto-Immuno Instrument

IVD Administration

Regulation

• Local Authorization approval (i.e FDA, CE etc) has to be obtained prior to China CFDA

registration for imported IVD product

• Class II and III IVD require clinical trials and clinical trials have to be conducted in three hospital

sites (for Class III) and two hospital sites (Class II)

• Class III- high –complexity tests, such as Pathogen Ag/Ab detection, Nucleic Acid detection,

ABO typing, HLA typing, Gene detection, Genetic Disease related

Clinical Trials Technical

Guidance for IVD Product

Registration

• New concept product (no approved similar product in the market) have to do “blind “ study

with “golden standard” , and for IVD product of early diagnostics, treatment monitor or prediction

of treatment, subjects enrolled should be visited and medical review will be provided

• IVD product with approved similar product, only requires comparison study with approved

product, discrepancies should be verified by “golden standard” method

• Class III product registration study requires 1000 cases except specially defined in other

regulations (PCR based pathogen detection requires 500 case, FLOW requires 500 cases, IHC

primary marker requires 1000 cases, complementary marker require 500 cases)


Guidance for IHC

Antibody/Kit Registration

• Class A and Class B for IHC IVD, Class A defines the treatment directly related ,such as

Her2,ER/PR,ALK, CD20, CMET,EGFR. Class B is defined as complementary marker for

diagnosis, monitoring and prediction, such as Ki67

• Analytical validation information: Immunogenicity on 30 types of normal tissues (3 cases per

type), claimed tumor tissues , precision, QC evaluation and stability.

• Clinical trials requirements: Class A >1000 cases with >300 positive cases. Class B >500

cases with >150 positive cases. For rare positive biomarkers, pre-communication and

agreement with CMDE is highly recommended

• TMA (Tissue microarray ) could be used for evaluation

Critical points and interpretations


Critical points and interpretations (Cont.)

Regulation Critical information and interpretation


Guidance for PCR based

Gene Mutation Detection

kit on Oncology

Personalized Medicine

• This guidance only applicable for PCR based method, Not applicable for Sanger Sequencing,

FISH, Kyrotyping

• Analytical validation: sample purification and recovery, precision, sensitivity, specificity,

interfering, RR and stability

• Clinical Trials: if there is no similar approved products or no sufficient study information

between the test and treatment, clinical trail can not jst do method comparison, clinical trial has

to do together with drug trial, evaluation should be based on the clinical treatment and overall

sustain

• Reference study: if there is no similar product for comparison, could use Sequence product OR

FISH/IHC given the evidence the correlation between gene amplification and FISH/IHC

Explanation and

Interpretation of CMDE on

CDx Product

• CDx in China usually not linked to drug in the drug label, only will recommend to use approved

and validated CDx product

• If there is link to specific drug on the label, and only claim the certain biomarker measurement,

retrospective study strategy could be used for CDx study

• If the CDx is linked to specific drug, CDx study has to be part of drug study and evaluation

based on the whole clinical trial with OS

• To follow IVD administration regulation, CDx registration study has to do in three hospital sites

• Clinical trial for CDx with similar product: comparison study with similar approved product,

recommend the comparison study based on clinical evaluation of patient

• Clinical trial for CDx without similar product: Can not only conduct comparison study but need to

do clinical trial together with the drug study, the evaluation should be based on the patient

treatment and validity of treatment.


Appendix – Neurology Case

Study


2 4 Early engagement for improving

patient enrollment to support

successful outcomes - a neurology

case study


Improving Patient Enrollment - A Neurology Case Study

Confidential – Do not copy or distribute

Situation: A major Pharma company having challenges with identifying the right patients for a rare

disease clinical trial involving neurology arena in Amyotrophic Lateral Sclerosis (ALS).

Solution: Developed a lab-based database to identify patients based on clinical, pathological and

biomarker information to improve patient recruitment.

The Clinical Trial Goals: • Improve treatment decisions

• Reduce barriers to adoption

• Improve compliance

• Demonstrate improved outcomes

Identify patients that would benefit from biomarker centric therapies

Gaining Value from your Partner for Biomarker Research and ......Case Studies 1. Risk assessment for...

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