05 December 2018 Precision Medicine: Developing a CDx...

Precision Medicine: Developing a CDx Commercialization Strategy

NextLevel Access Leaders Forum

05 December 2018

© 2018 Boston Healthcare Associates, Inc. | 2

Personalized Medicine: Developing a Global CDx Commercialization Strategy

• Oncology CDx Landscape

• Building a Strategy

• Key Considerations


Cancer treatment has accelerated in its complexity over the last 20 years with the much of the growth driven by targeted and immunotherapies

2

1

4

6

3

2

1

CLL

Melanoma

Prostate Cancer

Lung Cancer

Breast Cancer

1996

Source: Drugs@FDA, Feb 2017; ARK R&D Intelligence, Feb 2017; QuintilesIMS Institute, Mar 2017, BHA analysis

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7

7

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2006

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8

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2016

Chemotherapy Hormonals Immunotherapy HER2 EGFR

Anti-CD Chemotherapy CDK BRAF Others

Number of Available Treatment Options over Time for Select Tumors (US)

The pace of development has been exceptionally fast in the last decade, and oncologists, particularly in the community setting, often fail to keep up with the range of treatment options

19 7635


Multiple treatment options exist for the same molecular target adding to the complexity

Biomarker Tumor Type Novel Agent ComparatorResults (Months)

Year of LaunchNovel Agent Comparator

First Line EGFR-MutNSCLC

Erlotinib Chemo PFS 10.4 PFS 5.2 2004

Afatinib Pemetrexed + Cisplatin

PFS 11.1 PFS 6.9 2013

Gefitinib Carboplatin + Paclitaxel

PFS 10.9 PFS 7.4 2015

Second Line NSCLC

Nivolumab Docetaxel OS 12.2 OS 9.4 2015

Pembrolizumab Docetaxel OS 17.3 OS 8.2 2015

Atezolizumab Docetaxel OS 13.8 OS 9.6 2016

First Line BRAF-Mut Melanoma

Dabrafenib + Trametinib

Dabrafenib OS 25 OS 18.7 2014

Vemurafenib + Cobimetinib

Vemurafenib OS 22.3 OS 17.4 2015

Source: Drugs@FDA, Feb 2017; QuintilesIMS Institute, Mar 2017, BHA analysis

Approval of these agents has improved survival compared to previously available agents, but has also increased complexity in treatment decision making, and clinicians often face challenges in selecting the right treatment for the right patient

EGFR

PD-1 / PD-L1

BRAF / MEK

Market Landscape


Guiding therapy selection: Accelerating development of Immuno-Oncology drugs is rapidly increasing the complexity of the cancer testing landscape

• Multiple drugs and combinations

• Multiple biomarkers- Multiple PD-L1 antibodies- MSI/MMR- Multiple TMB assays

• Different thresholds of PD-L1 positivity

• Emerging testing paradigms

• Layer on global differences in clinical and lab practice, funding, and policy development, and it gets complex quickly

pembrolizumab+

Melanoma

>1% >50% >5% ≥25% >10%

28-8

Liquid Biopsy

nivolumab+

durvalumab+atezolizumab+

avelumab+

NSCLCSCHNN

Bladder

Breast

Colorectal

Pan-tumor

22C3

SP263 SP142

DNA microarrays

FISHCTCs

Source: BHA analysis

Market Landscape


Oncologists: The pace of innovation, particularly in molecular testing and targeted medicines has resulted in information overload for clinicians

• Oncologists are satisfied with the comprehensiveness and actionability of test reports, but would like to see content overload reduced

Highest unmet need

Lowest unmet need

“Very wordy; quite honestly there is information that I am not sure how to use. I only read the first 2 pages that shows the highlights of what are the actionable mutations”

“We can trim it down. It’s so voluminous, wordy, and there is so much information I don’t need”

“There is a content overload with mutations that I have no idea about. There is no information on actionability”

Top Unmet Needs Among Oncologists

• Informationoverload

• Helpwithclinicalinterpretation

• Qualityofhowinformationisreportedbylabs

• Actionabilityofinformation

• Testingturnaroundtime

• Comprehensivenessofcontent

Source: BHA US Oncologist Primary Research 2018 (N = 20)


Pathologists: Drugs being considered are not typically communicated to the pathologist to inform test selection

• Pathologists identify several types of requisition forms- Form has generic “PD-L1 Testing” (across tumors) - No requisition required since done reflexively/automatically - General test requisition form (paper) - Several PD-L1 assays listed

• Order forms do not have multiple boxes for PD-L1 that include drug names

- Some requisition forms indicate which assay is to be used, however oncologists are not typically able to choose

• Oncologists are not specifying the drug being considered, antibody to be tested, or a particular scoring method (i.e. TC, IC)

• Pathologists do not routinely ask oncologists about which treatment is being considered

Source: BHA EU Pathologist Primary Research 2018 (N=30)

Freq

uenc

y

“We do not include drug names in the form. It is not possible to list ten to twenty drugs in such a request form, it just gets too confusing.”

EU Pathologist

“We do not ask about the intended treatment. We thought about doing that, proactively going back to clinician to ask them, but at the moment we do not.”

EU Pathologist


Informatics deployed to create genotypic and phenotypic profile of the patient

• Unique patient populations are tested with particular methods (e.g., KRAS for Erbitux)

• Limits on tissue availability make this single marker approach less sustainable long term

• Expense/complexity of unique testing may promote this approach

• NGS increasingly dominates other DNA methods (e.g., PCR, FISH)

• RNA-seq increasingly dominates RNA ISH

• May be indication-specific (e.g., all NSCLC get comprehensive panel while urothelial get select biomarkers)

Single Markers and Hotspot Panels

• Mix of different test methods gives best picture

• Possible reflex test patterns with some tests being prioritized because of their ease of use/affordable cost

• Some FDA approved / some LDTs

Multi-modality

Current Near-term Long-term

Broad NGS Testing

Oncology testing is evolving from primarily single-marker, tumor-specific testing to an increase in NGS testing to define the "genomic profile" of a patient’s cancer


Market Landscape


Positive reimbursement changes, accelerating CDx approvals, and availability of CDx kits will all increase use of targeted NGS panels and CGP

Centralized Tissue Service Distributed Tissue Kit Liquid Sample Type

• Decentralization of testing to hospital-based labs

• Quicker turnaround time• Ease of ordering and sample

transportation/ preservation

• Access to patients in which biopsy contraindicated

• Quantity-not-sufficient results• Progression on 1L treatment

Impact on Patient Access

Particularly in Europe, labs & oncologists strongly prefer testing at local labs (via distributed kit); continued transition to the kit model will drive overall CGP usage, and potentially shift testing from the independent lab to hospital lab

setting, particularly in community hospitals

Market Landscape

Developing a CDx Commercialization Strategy


Dx Commercialization Framework

Key Stakeholders: Oncologists, Laboratorians, Payers, Dx Companies, Specialty Societies, Quality Bodies

• Value Proposition

• Evidence Development

• Stakeholder Engagement

• Capabilities and Resources Needed to Execute

Strategic ImplicationsMarket Landscape

Sample Journey and Testing Network

Market Authorization

Test Quality

Health Technology Assessment and Policy

Funding / Reimbursement

Dx Commercialization Framework

Routine patient access to testing and appropriate

intervention

Results


Addressing Roadblocks in the Sample Journey

FFPE block preparation and histopathology

Pathologist/Lab analyzes tissue

Initial consultation and diagnosis

• Presentation of symptoms

• Imaging (X-ray and CT scan)

• Sputum cytology• Needle biopsy

(radiologist) or bronchoscopy (pulmonologist) or open biopsy (surgeon)

• EGFR and ALK testing are reflexive

• Panel may include other NCCN genes (e.g., RET, ROS1)

• Molecular testing likely to be sent out in community setting, while academic institutions retain testing in-house

Reporting and treatment decision

• Pathologist report sent to ONC

• Therapy selection based on report, genotype, preference, insurance coverage

Disease monitoring

• Monitor response to therapy

• If disease progression, ONC may order additional molecular tests for second-line treatment

• Sample quality evaluated

• FFPE blocks prepared for further testing

• Histological analysis• Further molecular

testing either ordered by ONC or reflexive

PCP, radiologist, pulmonol., surgeon Anatomical pathologist Molecular pathologist Oncologist Oncologist, pathologist

2 days to 3 weeks

Schematic: NSCLC Tissue Journey

While tissue availability for PD-L1 testing in NSCLC can be a challenge, other tumor types may be more challenging such as bladder, with no established practice of molecular testing

Sample Journey / Test Network


Establishing the Testing Network for IO Testing

What testing network is needed to align with market-specific access needs? How might the testing network change over time?

SoleSource

AMCs /Specialty

Labs

Regional Affiliates / IDNs

Large Scale Commercial Labs

Community Hospitals

Can sometimes service entire market if volume requirements are manageable. Often used by innovators of proprietary tests to maximize value capture

Can leverage specialty status and/or support of institution to secure favorable payment terms; testing access typically limited to patients treated within the AMC

Collective regionalization creates centralized laboratory centers that can take advantage of economics of scale; increasingly providing care similar to AMCs

Interested in broadening menu offerings but core business is based on economies of scale and volume discounting rather than innovation

Widely distributed testing could lead to variable quality/standardization; offering typically limited to basic pathology


Testing Network


Balancing Test Quality and Access

Reduced Lab to Lab Variability

Widespread Patient / Lab Availability

Allows for Ongoing Test Innovation

Robust Evidence to Support Quality

Payment Adequacy for Provider

Simultaneous Drug and Test Access

Quality Access

Stakeholders are seeking transparency and predictability-- driving quality, access, and innovation

How do we balance broad patient access with the need for test quality?

Test Quality


Quality imperative: In the LDT context, Pharma companies have been supportive of several test-specific quality and guidelines initiatives

• Lab-to-lab variability was well-documented in the clinical literature noting equivocal cases as difficult to interpret, even for highly experienced and validated laboratories, highlighting the need for quality-control procedures

• Genentech / Roche supported development of studies to demonstrate the need for quality standards and the eventual CAP/ASCO HER@ testing guidelines

• BCR-ABL1 measurements varied greatly between laboratories due to lab practice variability so WHO and others developed a reference standard

• Most laboratories using a time-consuming sample exchange process with reference laboratories for International Scale (IS) calibration

• Novartis has supported further development of robust BCR-ABL1 tests standardized to the IS

• AstraZeneca initiated the EGFR FASTnet program in Italy to facilitate the exchange of biological material, patient level data and diagnostic reports

• Includes oncologists, primary pathologists and referral laboratories / Care Team

• Activated through a dedicated website (www.egfrfastnet.it), a call center and a courier

• Features quality guidance citing supporting publications

HER2

BCR-ABL

EGFR

Test Quality


Lower

Large, multicenter RCTs

Meta-analysis of grouped data

Smaller, single-site RCTs

Randomized comparative trial

Prospective studies

Retrospective studies

Studies with historical controls

Case series or reports

Consensus / Expert opinion

Strength of Evidence

Com

plex

ity

/ T

ime

/ Ex

pens

e

Higher

Strength of Evidence vs. Complexity and Cost

Higher

Types of Clinical Evidence for Dx

• Range of study designs are available but innovators must balance strength of evidence with complexity and cost of evidence development

Source: Hayes GTA Program, BHA analysis

HTA & Policy


Four Basic CDx Funding and Reimbursement Models: Does our CDx Market Access Roadmap align with that of the drug?

Pharma Direct

Funding

Explicit Payer

Funding

Pharma Indirect Funding

Implicit Payer

Funding

• Spain: No coding or payment for CDx in place

• France: INCa / RHIN budget

• Germany: Permanent payment assuming positive coverage (EBM / GOA)

• Germany: Coding / Payment lag

• Japan: Coding / Payment lag • Japan: Permanent, payment assuming positive coverage (Shinryo Hoshu)

• US: Payer funding using non-specific coding

• UK: Cancer Research Fund (may need supplement)

• UK: Direct Funding of labs

• US: Fund testing if regulatory compliant

• UK: Tariffs, Block Contracts

• US: Positive coverage, novel analyte-specific coding

• Italy: Crosswalk to similar testing or Immediate new code (region dependent)

• Italy: Direct Funding of labs

• Italy: Potential for novel coding and payment

• Germany: Crosswalk to similar test or new code

Funding / Reimbursement


Commercialization Implications

Value Demonstration

Stakeholder Engagement

Partnering Approaches

Capability and Resource Needs

• Label impact? Guidelines timing?• Do we have the data needed to show test quality?• For indications where molecular testing is not the norm, how do

we show test value?

• New indications often mean new stakeholder types that require engagement

• Does my global partner have the platform footprint to meet demand? Commercial capabilities?

• What local partnerships will be needed to fill gaps or address market-specific conditions? Other Dx companies? Labs? Quality organizations?

• What capabilities do we need to fill gaps that partners cannot fill? What do we have to “own” to ensure success?

Boston Berlin ShanghaiI I

www.bostonhealthcare.com

Contact

Joseph [email protected]

05 December 2018 Precision Medicine: Developing a CDx...

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