Study design for laboratory developed tests (LDT) and in vitro diagnostics (IVD) can make or break product and business success. This top-down description of how to pick the right study design was delivered at the 5th Clinical Affairs & Regulatory Approvals For Diagnostics, October 27-29, 2014, in Alexandria, Virginia.
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The Power of Study Design for Diagnostic Success
1. The Power of Study Design
5th Clinical Affairs & Regulatory Approvals For Diagnostics
October 27-29 2014 – Alexandria, VA
Lyssa Friedman
1October 27, 2014 Lyssa Friedman
2. October 27, 2014 Lyssa Friedman 2
Golden Gate National Recreation Area
3. Key Points
Study design:
Things to consider
FDA regulation of LDTs:
Keep doing what you’re doing well
Publication success
Case Study
Successes and lessons learned
October 27, 2014 Lyssa Friedman 3
4. Study goals = company goals
Successful product launch
On time
In scope
Revenues
Reimbursement
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5. Start with the goal and work backward
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Business goals
Patient population
Regulatory requirements
Test requirements
Study design
Publication strategy
6. • Business strategy
• Unmet clinical need
• Target customer(s)
• Market and market size
• Messaging strategy
• Geography
– States (CLIA)
– US/global
• Reimbursement plan
• Revenue goals
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Business goals
7. • Disease/health condition
• Unmet clinical need
• Gold standard
• Current landscape
– Diagnostic tools
– Best practices
– Clinical guidelines
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Patient population
8. • Risk classification
• LDT regulated by CLIA
• IVD
– 510(k)
– PMA
– de novo
– HDE
• Companion diagnostic
• Kit manufacturing
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Regulatory requirements
9. • Performance characteristics
– Sensitivity
– Specificity
– Negative predictive value
– Positive predictive value
• Test results
– Continuous score
– Discrete result
• Clinical significance
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Test
requirements
12. Health Economics
• Payer modeling
• Verify unmet need
• Verify market
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Study
design
Why commercialize? What business benefit?
13. Health Economics:
Consider the payer
Market
Payer landscape
Target price
Revenue targets
Product positioning
COGS
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14. Analytic Validation
• Verify assay robustness
• Commercial readiness
• CLIA registration
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Study
design
Will the assay work? Is it submission-ready?
15. Analytic Validation
Consider the customer
Variability in handling at point of collection
Interruptions in current practice flow
Requisition form design
Patient report design
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16. Clinical Validation
Diagnostic Clinical Performance
• Establish test performance
• Gold standard
• Intended use
• Support
• FDA submission
• CLIA registration (some states)
• Publication plan
• Physician adoption
• Guideline acceptance
• Payer adoption
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Study
design
Will the data be published? Will physicians order the test?
Will it withstand regulatory scrutiny? Will payers reimburse?
17. Clinical Validation/Diagnostic Performance
Consider the business and regulatory needs
Engage agency prior to initiating study
Clarify intended use
Identify a reference (gold) standard
Consistent with practice
Recognized by community/literature
Enroll subjects that represent target patients
Select sites that support intended use
Pre-specify
Sample collection/handling procedures
Analysis methods
Use of archived samples (if needed)
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18. Clinical Outcomes
Clinical Utility
• Patient outcome based on test use and
results
• Randomized control trial
• Changes in physician behavior
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Study
design
What difference does it make to patient outcomes?
What difference does it make to healthcare costs?
19. Clinical Outcomes/Clinical Utility
Consider the payer
Consider the patient
Effect on patient outcomes
Ethics of randomized controlled trial
when marketed test available
Effect on healthcare costs
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21. 21
• ACCE Evaluation Process for
Genetic Testing
• Analytic validity
• Clinical validity
• Clinical utility
• Ethical/legal/social
• Publications in these areas
build the reimbursement case
Centers for Disease Control (CDC) Office of Public Health Genomics
Evaluation of Genomic Applications in Practice and Prevention (EGAPP™) Initiative
Publication strategy
October 27, 2014 Lyssa Friedman
23. FDA regulation of LDTs
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IVD LDT
• CLIA (if LDT)
• FDA
• CLIA
• Physician adoption
• Reimbursement
• FDA
• Physician adoption
• Reimbursement
• Quality system
• SOPs
• Quality for CLIA
• SOPs
• Physician adoption
• Economic modeling
• Clinical utility studies
• FDA
• Physician adoption
• Economic modeling
• Clinical utility studies
Analytic validation
Clinical validation
Documentation
Intended use
24. Keep doing what you’re doing well
Well-designed studies
Clean samples and clinical annotation
Clearly defined gold standard
SOPs and pre-specified protocols
Culture of design review
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26. Site Selection
What are the goals?
Study completion
Accrual numbers
Adherence to Good Clinical Practices
Pristine samples
Verifiable data
Strategic relationship building
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Key opinion
leader
Collaborator Influencer
Geographic
significance
27. Case Study
• 142 genes, microarray
• Gold standard: histopathology (central panel)
• Optimized for sensitivity/NPV – safe to avoid surgery
• Company launched 2008 (IVDMIA) – design control implemented
• Product launched as LDT 2011
• Key publications
– 2010: first clinical validation
– 2011: economic model/cost effectiveness (replacement for surgery)
– 2012: second clinical validation, clinical utility (change in recommendation for
surgery)
– 2013: second clinical utility, limits of gold standard
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Thyroid
nodule
Fine needle
aspirate
biopsy
Cytology
Indeterminate
15-30%
Diagnostic
surgery
Benign >50%
Afirma GEC
94% NPV
28. Case Study: Success/Challenges
Things that worked
• Funded on business plan – agnostic
regarding clinical platform
• All-hands focus on rapid first product
to market
• Aggressive publication plan – never
missed an abstract deadline!
• Small niche market – close
relationship with major KOLs and
influencers, who were clinical sites,
early customers, authors/speakers
• “Boutique” approach to managing
clinical sites, even if challenging
• Two clinical validation studies using
one amended clinical sample
collection protocol
• IVDMIA era – design control
Lessons learned
• “Tarnished” gold standard required
publication, customer education
• NPV as key message – refuted
based on practice variations in
malignancy prevalence
significantly
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29. What does success look like?
Design a business plan that drives R&D and product development
Build early relationships with KOLs and influencers
Strategize cross-functionally from the beginning
Stick to a long-term strategic publication plan
Commit to a quality system (LDTs)
Create a culture of design review with external reviewers (LDTs)
Adhere to a milestone-based plan aligned with corporate goals
Maintain relationships with strategic sites – even if challenging
Never miss an abstract submission deadline
Partner with marketing/sales group to transition sites to early customers
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30. What are lessons learned?
Be willing to change thinking quickly and flexibly
Challenge market research assumptions when
clinical operations offers counter-intel
Don’t underestimate the competition and the
naysayers
Stress test the product messaging with regard to
test performance
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As VP clinical operations at Veracyte, I helped bring the company’s beachhead product to market
As an independent consultant, I help early-stage diagnostic companies design a roadmap for the product development lifecycle. This includes developing reimbursement and publication strategies, and designing studies to help achieve goals quickly and efficiently.
The companies I work with have developed or are developing LDTs, and we are navigating the shifting landscape regarding FDA oversight of LDTs
My point of view is supporting startup LDTs who have traditionally been regulated under CLIA only, and for the most part my comments are focused on a US market
HDE: Humanitarian Device Exemption
example: urine test
Needed:
SOPs
pre-specified protocols and plans
Recommend culture of design or phase review – avoid drinking the Kool-aid
Keep doing what you’re doing well
Clinical and medical affairs milestones that tracked both cross-functionally and upward to company goals
Clinical operations guiding principles:
Clinical operations is the brand
These sites will be our customers in about 5 minutes
Handheld strategic sites to maximize their success
Anticipate what others will say and publish about the space
Veracyte based marketing on high NPV, which had very high number. This was in an environment where clinicians assumed the gold standard, histopathology, was 100%, though our data showed (and was later published) that pathology concordance was 96-97% This was criticized at meetings and in publications as being too dependent on disease prevalence in specific clinical environment. perhaps a sensitivity message could have had more sustained power, despite the fact that it was slightly lower (92%)