2. ________________________________________
Definition
2
Companion diagnostic – A diagnostic test
used to predict the likely clinical
effectiveness and/or safety of a particular
therapeutic intervention for a specific
individual; the term is most often used to
describe a molecular diagnostic test that
stratifies a patient population with regard to
the likelihood of response to, or the safety
of, a pharmacologic therapy.
3. ________________________________________
An Ongoing Medical Revolution
• “Personalized medicine” / “Precision
Medicine”
– The right treatment (Tx)
– For the right patient
– In the right amount
– At the right time
• Diagnostic (Dx) is the key to Tx success
3
4. ________________________________________
Limits of Traditional Medicine
• Tx success is frequently probabilistic
– Protocols based on population-wide data
– Non-response rates are high
– Complication rates are high
– Determinants of success are poorly known
• Informed guessing yields
– Delays in identifying effective Tx
– Exposure to unnecessary risks
– Enormous financial, time and opportunity costs
4
5. ________________________________________
Pharma Has a Parallel Problem
• Lengthy and expensive product
development process
– Size and duration of clinical trials is a major
factor
• Painfully low yield rate on compounds
screened
• High failure rate in clinical trials
• Phase IV (and beyond) safety issues
5
7. ________________________________________
In the Clinic …
• Stratify patient population on the basis of
validated indicators of Tx effectiveness
and/or safety
– Increase response rates
– Decrease complication rates
• Better and safer drugs (Rx)
• Less time and money wasted
7
8. ________________________________________
In Drug Development …
• Targeted screening of compounds allows
better choices for clinical development
• Ability to recruit patients who are likely
responders yields smaller clinical trials with
higher probability of success
• Economics of process transformed (?)
– Development time and cost reduced
– Blockbuster model severely threatened
8
9. ________________________________________
For Society …
• Targeted Tx selection means higher return
on health care investment
– Less ineffective or unnecessary care
– Fewer complications and adverse events
– Healthier population
– Lower health insurance costs?
– Control of health care share of GDP?
9
10. ________________________________________
Success Ought to Follow
• All affected parties seem to benefit
• Essential enabling technologies are
advancing
– Pharmacogenomics and proteomics
– Bioinformatics
– Molecular pathology testing
– Health information technology / electronic
health records
10
11. ________________________________________
Many Positive Signs
• Drug and diagnostics companies are
deeply engaged
• Venture capital is being invested
– Diagnostics; Bioinformatics tools; HIT
• IPO window is open
• Regulatory agency (FDA) is on board
• A dominant business model has emerged
11
12. ________________________________________
DHHS Is Supportive
• Secretary’s Advisory Committee on
Genetics, Health and Society
– http://www4.od.nih.gov/oba/SACGHS.HTM
• Dedicated website
– http://www.hhs.gov/myhealthcare/
• “Personalized Health Care: Opportunities,
Pathways, Resources”, Sept. 2007
– http://www.hhs.gov/myhealthcare/news/preso
nalized-healthcare-9-2007.html
12
13. ________________________________________
FDA Resources for Industry
• Paving the Way for Personalized Medicine
(Oct. 2013)
– http://www.fda.gov/downloads/ScienceResearch/Sp
ecialTopics/PersonalizedMedicine/UCM372421.pdf
– Contains extensive list of FDA Guidances
pertaining to personalized medicine
• In Vitro Companion Diagnostic Devices Draft
Guidance, July 14, 2011
– http://www.fda.gov/MedicalDevices/DeviceRegulati
onandGuidance/GuidanceDocuments/ucm262292.
htm
• “Table of Valid Genomic Biomarkers”
http://www.fda.gov/drugs/scienceresearch/researchareas/pharm
acogenetics/ucm083378.htm
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14. ________________________________________
Pharmacogenomic Markers in Drug
Labeling
• Genomic biomarker information in labeling
may describe …
– Drug exposure and clinical response
variability
– Drug interactions
– Adverse event risk
– Genotype-specific dosing
– Mechanisms of action
– Polymorphic drug target and disposition
genes 14
16. ________________________________________
Progress is Nonetheless Slow
• A minority of cases show a definitive link
between genomic info and efficacy
– 45/158 provide some label guidance on
“Indications and usage”
• Other valuable information is provided –
– 28/158 provide guidance on “dosage”
– 10/158 provide guidance on
“contraindications”
– 35/ 158 provide guidance on “drug
interactions” 16
17. ________________________________________
Significant Rate-Limiting Factors
• Genomic and proteomic influence on Rx
efficacy is more complex than at first
envisioned
– 1/1 cases of effectiveness are rare
• Complexity of the regulatory pathway
remains an impediment
– Despite FDA clarification of guidance
• Dominant business model may not be
scientifically/clinically optimal
17
18. ________________________________________
The Regulatory Regime
• FDA has mandated “contemporaneous”
review of companion Dx components
– Requires separate but coordinated review by
CDRH and CDER/CBER
– Centers have different standards, review
processes, staffs, cultures
• Labs cannot rely on less costly CLIA
clearance process
– But test requirement on label is generic, not
proprietary
18
19. ________________________________________
Effective Regulatory Planning
• Requires coordination between regulatory
professionals with disparate expectations rooted
in practical experience
• To secure diagnostic IDE and therapeutic IND
approvals with a unified clinical trial design …
and subsequent …
• Simultaneous approval of a PMA and an NDA
• From FDA Centers with different competencies,
expectations and cultures
• With mutually agreed division of responsibility
and cost
19
20. ________________________________________
The Business Model Problem
• Regulatory framework and underlying business
requirements mandate Dx / Rx co-development
• Pharma and diagnostics have diverse, possibly
incompatible, business processes and cultures
– Product development timeframes and costs
– ROI expectations
– Regulatory and reimbursement regimes
– Workplace cultures
• Customer requirements are ill-defined and
evolving
20
21. ________________________________________
Structuring the CDx Effort
• Some Pharma tried to bring Dx
development capability in-house through
acquisition or internal startup
– Choice between immediate culture clash and
long incubation period
– Many internal operational / financial / political
issues
• Partnership for co-development dominates
– More fruitful and less traumatic
21
23. ________________________________________
Partnering Activity Remains High
• Dako, an Agilent Technologies company, announced today it has
entered into a master framework agreement with Merck to develop
companion diagnostic tests for oncology drugs currently in
Merck’s development pipeline Jan. 9, 2014.
• Foundation Medicine and Clovis Oncology Expand Collaboration
to Develop Novel Companion Diagnostic for Rucaparib in Ovarian
Cancer April 3, 2014
• Thermo Fisher Scientific Announces Agreement with
GlaxoSmithKline and Pfizer to Develop Oncology Companion
Diagnostics Using Next-Generation Sequencing (NGS) September
25, 2014
• QIAGEN N.V. … has entered into a master collaboration agreement
with … Novartis AG … development and commercialization of
companion diagnostics to be paired with existing Novartis
pharmaceutical products as well as compounds in its development
pipeline. November 11, 2014
23
24. ________________________________________
Dynamic Market Growth Projected*
• The global CDx market ($8.7 billion in 2014) will see CAGR
of 22.9% over the next ten years;
• > 10 million tests/year by 2024.
• Companion drugs generated estimated revenues of more
than $26 billion in 2013, with six drugs achieving
blockbuster status.
• Rich CDx pipeline - more than 75 drugs being co-
developed with predictive biomarkers.
• Partnership seems to be the most preferred model for
development; since January 2011, there have been more
than 90 collaborations between pharmaceutical and
diagnostic companies.
*Companion Diagnostic Market 2014-2024.Roots Analysis Private Ltd.,June 2014
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25. ________________________________________
The Reimbursement Regime
• In traditional fee-for-service settings, Dx
and Rx will be subject to separate
coverage and payment determinations,
often by different entities
– Will insurer pay for Dx required by PBM to
secure payment for Rx?
– Label requirement helps, but the payer
entities need to coordinate
• Capitation changes this dynamic
25
26. ________________________________________
Coding is Critical to Reimbursement
• Broken Molecular Pathology Coding System
has been Fixed
– Molecular diagnostic tests had been coded by
processes, not by analyte; a single test required
“stacking” of multiple processes and repetitions
– Prevented electronic claim processing
– Hard to identify test performed, analyze
utilization, etc.
• New codes effective Jan. 1, 2013 address the
problem
26
27. ________________________________________
Progress on Coding Continues
• New MolPath codes facilitate electronic
processing, utilization analysis, and test-specific
fee setting for some tests
– Tier 1 - Unique identifiers for 99 high volume tests
– Tier 2 – Nine resource intensity group codes
– CPT 81479 for Unlisted molecular pathology procedure
• NGS codes effective January 1, 2015 address
large scale multi-analyte sequencing procedures
• Payment uncertainty remains an impediment to
use
27
28. ________________________________________
Payer Coverage Status
• Generally aware of pharmacogenomic
developments
– Coverage for Dx/Rx pairs is case-by-case
– Traditional decision criteria have worked so far
– Limited experience no commitment to a model
– Critical mass not yet reached
• Great majority of 158 entries in FDA table are advisory only
• Some PBMs understand the issues well
– Uniquely positioned to evaluate and manage the
financial benefits of companions
– Report more receptivity from self-insured employers
than from third party insurers
28
29. ________________________________________
Priorities for Gaining Coverage
• Understand the traditional coverage
criteria
– “Reasonable and necessary” standard
• Integrate reimbursement planning into
clinical development plan
– Leverage FDA process and outcome
• Recognize the primacy of the therapeutic
goal
– Focus on clinical utility of Dx
29
30. ________________________________________
Leverage FDA Process For …
• Unequivocal confirmation of biomarker
validity – both analytic and clinical
• Demonstration of objective basis for
stratification of patient population
• Empirical evidence of clinical utility
– link between Dx status and Tx success
– Minimization of probabilistic element
• Dx/Rx tied by label indications
30
31. ________________________________________
Conclusions (1)
• The CDx value proposition is clear and
well understood
– Clinical value – efficacy and safety
– Cost-effectiveness
• Co-developed Dx/Rx pairings increase
probability of success and reduce total
costs
– Other Dx development models are financially
and operationally problematic up until now …
31
32. ________________________________________
Conclusions (2)
• Pharma and diagnostics developers need
further experience working together
– Close the expectations and culture gaps
– Gain positive experiences to build on
• Regulators and payers are moving – if
slowly – to adapt to and facilitate CDx
development and utilization
• CDx presence in clinical practice will
inexorably accelerate …
32
