The Business of Genomic Testing by James Crawford

The Business of Genomic Testing: A Survey of Early Adopters

James M Crawford, MD, PhD [email protected]

Executive Director and Senior Vice President for Laboratory Services North Shore-LIJ Health System

Chair, Department of Pathology and Laboratory Medicine Hofstra North Shore-LIJ School of Medicine

Manhasset, NY

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Biomedical Research Alliance of New York (BRANY)** 2009- Vice Chair, Managing Committee

*uncompensated **CRO for Clinical Trials

Disclosure*

College of American Pathologists Personalized Healthcare Committee Business Working Group (2011-2013) James M Crawford, MD, PhD (Chair) [email protected] Lynn Bry, MD, PhD John Pfeifer, MD, PhD Sam Caughron, MD Stephen Black-Schaffer, MD Jeffrey A Cant, MD, PhD Jill H Kauffman, PhD

Business Aspects of Genomic Testing: Why Do It?

4 © 2012 College of American Pathologists. All rights reserved.

2014 Jul 10. doi: 10.1038/gim.2014.60.

•  Massively parallel sequencing (Next-Gen, NGS) –  Not SNP Microarray for screening/detection

•  Clinical applications (2005 ff….) –  Medical Genetics –  Cancer Genomics* –  Pharmacogenomics* –  Infectious Disease Diagnostics

•  *Question 1: “in extremis” or “ab initio”? •  Question 2: By Whom?

“Precision Medicine” (Genomic Testing)


•  “Genomic” laboratories: Business argument stands –  In support of integrated health systems? –  In support of independent providers?

•  Independent reference laboratories: access to market •  Private pathology practices: not yet in market •  Integrated health systems: the focus of this study

–  Predominantly Academic –  For the moment, these are the “providers” of Precision

Medicine

The Decision to bring Genomics into an Institution


•  Selection of Participants (“or”): –  Having members on the CAP Personalized

Healthcare Committee –  Performing NGS testing under a CLIA license –  Record of peer-review publications in this area –  Institutional announcement of NGS implementation

•  Survey: –  Standardized 1 hour interview by one Interviewer –  10 questions; follow-on questions as needed

A Survey of “Early Adopters”


•  Choice of Genomic Analysis Tests for Clinical Use •  Drivers and Barriers •  Reimbursement considerations •  Lessons Learned from Early Adopters •  CAP resources for Adoption

Topics addressed in the survey


•  Complete Interview transcripts: redacted •  Parse text into responses to each core question •  “Qualitative Response Analysis”

–  Identify specific [Units of Measure] (n=94) –  Develop lexicon of Common terms –  Group into [Categories] –  Compile Participants’ use of [Units] –  Analyze on basis of [Categories]

Data Compilation and Analysis


•  13 Institutions interviewed, in 10 different states and 1 Canadian Province

•  In their persons, during 2011-2012 the Interviewees had 93 publications relevant to Genes/Diagnosis

•  Research and Clinical applications including: –  Next Generation Sequencing/Targeted Sequencing –  Bioinformatics Pipeline –  Molecular Surgical Pathology –  Digital Molecular Imaging

•  2 of them CLIA-certified laboratories for NGS

Survey metrics


1. Why did your institution decide to adopt NGS? 2. How did you implement NGS? 3. What clinical applications did you choose for NGS? 4. How did you decide between in-house or send-out? 5. How did you obtain funding for NGS? 6. What are your plans for engaging payers? 7. Are NGS services considered a competitive advantage? 8. What lessons learned can you share? 9. How will you measure successful outcomes? 10. What can the CAP do to assist NGS adopters?

Survey Questions


Institutional Cumulative Word Count

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Pathologists. All rights reserved.

Words per Question

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Why?

How?

Apps?

In/Out?

$$$?

Payers?

>>>?

Lessons?

Metrics?

CAP?

© 2012 College of American Pathologists. All rights reserved.

•  Cancer Genomics 10 institutions –  CLIA certification 1 institution –  Secondary intent 8 institutions

•  Medical Genetics 3 institutions –  CLIA certification 1 institution –  Secondary intent 3 institutions

Intended applications for NGS


•  Demand from Clinical Colleagues 13 •  Anticipated efficiency 12 •  Acquisition of institutional expertise 9 •  Advancing clinical applications of PM 7 •  Requisite for institutional stature 5 •  Value for Research 5 •  Improved TAT in Molecular Diagnostics 4 •  Gaining expertise before NGS is commoditized 3 •  Desire to provide Leadership 2 •  Competitive market advantage 2 •  Reduction in overall cost of clinical care 2

Reasons to Adopt NGS


•  Demonstration of clinical utility will provide a competitive advantage. •  In-house bioinformatics, analytics ,and reporting provide an added

value to our clinicians •  Position pathology in the center of individualized treatment plans,

instead of just a reporting-of-values type of service. •  Provides strategic advantage with the hospital, since alignment with

the clinician base tends to get the hospital’s attention •  There is the question of how do you bring NGS into the everyday

world when there is so much pressure on price, when the technology is so complicated, and when many clinicians don’t understand this except in a very big picture way

Competitive Advantage of NGS: Institution X’s View

© 2012 College of American Pathologists. All rights reserved. 17

•  Will enable pathology as a discipline to demonstrate to our clinical colleagues: –  we own this, this is what we do. –  we’re preparing our trainees to do this –  we’ll take care of it, we’ll explain it to you –  leave it to us, we’ve got it covered.

•  It will only be a competitive advantage for a couple of years before most institutions are doing it

Competitive Advantage of NGS: Institution Y’s View


•  Very expensive. •  Time and effort needed to implement and maintain vs.

using other types of testing that would currently provide the same information.

•  We don’t know how to interpret most of the variants in an exome or genome.

•  Complex – both technically and for the IT/bioinformatics and computational infrastructure needed.

•  How to manage/store the data, from the IT, medical, ethical and legal standpoints.

Cons


•  Scarcity of Informatics expertise 7 •  Need to develop staff/professional expertise 5 •  Rapidly changing nature of technologies 4 •  Validation of clinical testing protocols 3 •  Expense of implementation 3 •  Amount of data to curate 2 •  Difficulty in getting first application deployed 2 •  Ethics of reporting findings (the “reveal”) 2 •  Lack of institutional support for training 2 •  Uncertainty of clinical utility 1 •  Uncertainty of reimbursement from Payers 1

Barriers to Implementation of NGS


•  Per institutional funding and infrastructure, many sites prefer to keep in house if possible. –  Control of pipelines, discovery activities.

•  At a minimum, keep some sequencing in house for targeted assays or confirmation.

•  Many see that sequencing is commodity and there are benefits to out-sourcing while the technology is currently expensive and complicated to manage.

•  Focus local resources on content development and interpretation

In house vs out-source aspects of Genomic Analysis


•  University President 1 •  Hospital Chief Executive Officer 5 •  Hospital Chief Operating Officer 3 •  Hospital Chief Financial Officer 2 •  Hospital Capital Committee 1 •  Dean, College of Medicine 2 •  Cancer Center Director 1 •  Chair, Department of Pathology 3

Institutional Decision-Making Process


Key issues that need to be addressed when seeking the resources to set up an NGS lab:

•  Define the clinical need (leverage institutional expertise) •  Define the business plan •  Determine the cost-benefit ratio of bringing NGS testing

in-house (does it support existing programs, what is being spent on send outs, what’s the return on investment)

Approval process


•  Hospital 100% 5 •  Pathology 100% 5 •  Pathology:Cancer Institute 50%:50% 1 •  Government 100% 1 •  Outsourced: no funding 1

Funding


•  Unanticipated OJT of Technologists 8 •  Unanticipated OJT of Pathologists/Scientists 5 •  Additional effort in Informatics 5 •  Requirement for a Project Manager 2 •  Need for support from Information Services 1 •  Need to establish multidisciplinary Governance 1

Additional Institutional Requirements


•  Need to demonstrate value to payors beyond currently methods (panels versus single gene tests)

•  Until reimbursement hurdle sorts itself out within your payor mix, it’s probably wise to limit the NGS test menu initially

•  Reimbursement for NGS will doubtless follow the rules of the marketplace: payors will reimburse, but will make deals with labs to do this testing at the lowest price

•  Conversations with payors can be more productive if you enlist clinical colleagues to be part of the discussion

Reimbursement


•  More complicated and took longer 4 •  Need a more complete multidisciplinary team 4 •  Need to start with proven applications 4 •  Need to understand market and testing load 2 •  Need to play to institutional strengths 2 •  Need to verify adequacy of Informatics 2 •  Need to be adequately capitalized at start 2 •  Need to have a local research partner 1 •  Need for multistakeholder advisory group 1 •  Need to specify patient selection for NGS 1

Lessons Learned


•  Small institutions might want to wait for: –  the platforms and informatics and reporting to be worked out –  the clinical utility is firmly established in the literature

•  It’s a trade-off: Is it better to get NGS in two years when things are pre-packaged, or be a leader in the field?

•  NGS is a much bigger and more complicated endeavor than you expect

•  Success depends on adequate resources (money and people); the technology and bioinformatics are not plug-and-play

•  Do you have the required informatics? It’s a lot easier to generate the data than to interpret it; you really have to adequately resource the informatics function for interpretation

•  Will the clinical load support an NGS lab?

Lessons Learned From Early Adopters: Institution A


•  It’s important to be adequately capitalized when you start off •  It’s important to be adequately staffed when you start off •  It’s possible to go from zero to a customized panel in under a year;

many labs will soon be doing NGS since it will become a requisite for oncology practice

•  Embrace change; it’s a brave new world, and NGS will enhance our medical practice as pathologists

•  Must work very closely with your oncologists and hematologists because you don’t want to offer something that they’re not going to feel is useful in their practice

•  Start simple to build the expertise; start with a small sequencer. •  Bioinformatics will be key

Lessons Learned From Early Adopters: Institution B


•  Put together an interdisciplinary group that can help you select the gene panel

•  “Get your feet wet” means start small; build your volume gradually so you keep your quality up

•  The amount of data is huge, so if you can’t manage that, you are very quickly going to find yourself incapable of keeping up with the information and the clinical demands for your services

•  Match your platform with the testing you want to do •  A whole exome can actually be a quicker and cheaper way to

develop panels than customized capture probes •  Regulatory issues arise (for example, you can’t force people to order

a panel)

Lessons Learned From Early Adopters: Institution C


•  Know the politics of your institution •  Carefully consider the additional work to do a customized panel as

opposed to use of a commercially available kit

Lessons Learned From Early Adopters: Institution D


•  Better management of patients 5 •  Growth in test volume 4 •  Expansion in test menu 2 •  Earlier clinical diagnosis 2 •  Achievement of self-sustaining finances 2 •  Elimination of other laboratory testing 1 •  Support of Education and Research 1 •  Successful redeployment of staff 1 •  Physician/client satisfaction 1 •  Patient satisfaction 1 •  Expansion of patient options for treatment 1

Measures of Outcomes


•  The expectation is that each panel will become easer (build infrastructure, develop staff, develop reporting.)

•  we spend a lot of time thru current clinical trials that are out there to identify drugs that are on clinical trials, the target specific genes that will be completed probably within the next year or so. And so we have built those genes into our next panel, so we’ll validate a panel of 120 genes or so

•  **Expect that in the future the exome test will become a sort of a universal assay and you pull out what you're interested I; at metabolized drugs that are used for cancer - so the universal assay idea is kind of nice rather than having to setup however many, different assays for different genes

Expectations, Next Steps


•  Educational programming 7 •  Testing standards, Checklists, Validation SOP 6 •  Proficiency Testing 5 •  Info about Coding, Billing, Reimbursement 3 •  Info about Natl Data Networks, Databases 2 •  Accreditation of laboratories 1 •  Advocacy 1 •  Peer Networks 1 •  Literature resources 1

Recommendations for the College of American Pathologists


Iden.fy clinical need

Examine ins.tu.onal strengths

Clinical programming Research programs Informa.cs

Establish Business Plan

Examine Ins.tu.onal Priori.es

Clinical Programming Research and Educa.on Market & Stature

Ins.tu.onal Resourcing

Unan.cipated Resources

Reimbursement Strategies Research Resources

Priori.ze Ini.al Clinical Applica.ons

Timeline and Monitors Governance* Outcomes Measures Develop Project Plan

Obtain Ins.tu.onal Approval

Implement

Monitor

Flow Chart

PCR-‐based tes.ng

NGS tes.ng for same purposes

NGS tes.ng commercial applica.ons

Expanded test menus

Custom NGS panels for specific applica.ons

NGS tes.ng Expanded test menus

Implementa%on Pathways

Pathway 1 Pathway 2 Pathway 3

NGS tes.ng Expanded test menus

Targeted NGS panels (5 to >100 genes)

Exome sequencing (and beyond)

?

Outsourcing

Pathway 4

Informa.cs

Technical

Academic Industry

Outsourced In-‐house

•  Amount of data that has to be curated •  Need to catalogue clinically actionable variants •  Limited consensus on what variants are relevant •  Lack of reimbursement for genomically-driven clinical

interventions •  Burden to Providers and Patients in following up on

genomically-driven clinical interventions

*Manolio TA et al., Genet Med 2013; 15: 258-267

Beyond the Laboratory*


•  Opportunity for advancing Patient Care •  Imperatives for developing Knowledge, Expertise •  Development of an Evidence Base for NGS use •  Need to provide Leadership •  Institutional Prestige

Key Concepts


•  This study does not touch on the issue of appropriateness of implementation of NGS. (This makes) discussion of implementing NGS difficult.

•  The authors should comment on (whether) desire for ‘recognition’ is a good reason to implement NGS.

•  Broader issues concerning the implementing of these technologies are only tangentially addressed.

•  We need more information on the business case for doing this testing. What is the anticipated ROI?

•  We need more information on how this technology might drive problems. How much will the technologies be used when they add little or no value?

•  What is the clinical utility? What is being done to assess the clinical utility? Is the technology driving more efficient care? Better outcomes?

Peer Review of manuscript

39

2014 Jul 10. doi: 10.1038/gim.2014.71.

•  Whatever the rationale for the study, the survey neglected to first assess central and difficult issues – these leaders’ perceptions of the clinical utility of NGS and their reasons for being early adopters.

•  Was it to be perceived as scientific leaders? If so, then NGS should have been introduced as a research tool.

•  Was it to be perceived as a market leader? If so, then the primary reason for adoption of this technology is responding to economic incentives…without sufficient concern about utility or costs.

•  Was it merely because NGS is now considered “affordable” and competitive with specific genetic tests of demonstrated value? If so, then it is important to consider the downstream medical and financial consequences of testing.

Editorial

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•  Analytic validity and clinical validity are necessary but not sufficient conditions for use. Without demonstrated utility, the potential for waste and harms outweights hypothetical benefits.

•  Evaluations such as this one… have great potential to inform the thoughtful introduction of whole-genome sequencing and other diagnostic tools, but they need to ask and answer the right questions, the important questions, not just the practical and business ones.

Editorial

42

•  This is precisely the conundrum: –  Other than dramatic case reports and series, the clinical

utility of NGS has not yet been demonstrated. –  Nevertheless, there are compelling reasons for

institutions deciding to implement NGS and “Genomic Medicine.”

•  This study examined the decision-making process, not whether these were the right decisions to make.

•  Only careful future study (with or without randomized clinical trials) can answer the question of clinical utility.

Conclusion

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[email protected]

Health & Medicine

The Business of Genomic Testing by James Crawford