Personalized Medicines…
Issues, challenges and points to consider in
developing a global regulatory strategy
Dr Georgios Amexis; RAC
Global Regulatory Lead - Oncology
Merck KGaA, Darmstadt, Germany
EBE / Brussels / March 2nd 2015
Personalized Medicines...is it worth the effort?
... ADR-related costs other than those caused by
hospitalization are estimated at €63.2 billion annually in
the EU. € 79 billion represents a reasonable estimate of
the total societal cost of ADRs occurring in the EU.
http://ec.europa.eu/smart-regulation/impact/ia_carried_out/docs/ia_2008/sec_2008_2670_en.pdf
Clinical and economic burden of adverse drug reactions; J Pharmacol Pharmacother. 2013 Dec; 4(Suppl1): S73–S77.
http://www.luminexcorp.com/prod/groups/public/documents/lmnxcorp/pgx-whitepaper.pdf
Questions related to biomarker development
and validation
Activity
Question being
addressed
Setting
Biomarker discovery and
development
Is there an informative marker that
correlates with a clinical state?
Laboratory
Analytical validation
Does the test measure the
biomarker reliably?
Laboratory
Clinical validation
Does the test predict the clinical
state?
Clinical research
Biomarker qualification
Does the test provide reliable
information?
Drug development
Clinical utility evaluation
Is the test worth doing?
Health care
Surrogate end-point evaluation
Does the test predict the desired
clinical response?
Drug development
Cost-effectiveness evaluation
Is the test worth paying for?
Reimbursement
Comparative effectiveness
evaluation
Is the test worth doing in the real
world, as compared with other
options?
Health care
Points to consider in developing a global
regulatory strategy
Target Product Profile should serve as
guiding principle to carve out regulatory
strategy
Align clinical development plan(s) with
business objectives
Provide guidance via periodic risk
assessments (ie choice of endpoints, doseselection, effect size, biomarkers/CDx,
number of supportive/pivotal trials, filingstrategy, life-cycle management, In/
exclusion with BMneg pts groups)
Provide routemap to development teams on
important decision points with key
stakeholders (planned key interactions with
regulatory agencies)
Monitor regulatory/policy/scientific
landscape to enable implementation of
novel approaches (Innovation Task
Force, Adaptive Licensing, HTA)
Reduce time-to-market and increase probability
of success
Reduce potential for Post-Market commitments
Regulatory overlaps/differences for Diagnostics
(EU/US)
EU
• 
• 
§ 
Diagnostic approval by
notified bodies and not
by regulatory agencies
No requirement to
demonstrate superior or
equivalent effectiveness
for predicate diagnostic
Patient treatment not
necessarily tied to a
specific companion
diagnostic
US
• 
IDE submission
obligatory
• 
Diagnostics intended
for marketing and
distribution must
submit a premarketing
approval to the FDA
EU + US
• 
Focus on safety and
performance
requirements (clinical
validity)
• 
No formal assessment
to establish clinical
utility (reimbursement)
Challenges in Developing Personalized Medicines
Co-development of drugs and companion diagnostics not trivial
Insufficient partnership between academia and industry (uncertainty to recover
investment)
Test Methods: Limited availability of consistent test methods
Evidence-based data: Bottleneck…insufficient data from clinical trials
Ethnic groups: insufficient prevalence data on genetic variants
Challenges in Developing Personalized Medicines
Bio-Banking: inadequate availability -quality of samples of defined phenotypes
resulting in difficulties to establish clinical relevance
Inconsistency of phenotype definitions and of testing methods (limited assays’
cross validation)
Missing Incentives (reimbursement low compared to drugs)
Intellectual property issues
Issue: Evidence Gap and Reimbursement
Fast-to-Market approach
•  Creates uncertainty for third-party payers due to evidence gap (limited
focus on clinical utility)
•  Creates hurdle for higher value, higher priced diagnostics (ie stand-alone
diagnostics)
Consequences of evidence cap...
•  Low investment in evidence generation
•  Increased clinical uncertainty
•  Reduced recommendations for use and poor reimbursement prospects
Reducing Uncertainty....Clinical Utility
•  Regulatory strategy should lead development process
to focus early in development on clinical utility.
•  Regulatory Strategy should identify viable
development approaches that reduce level of
uncertainty by allowing a rigorous evaluation of clinical
utility
•  Caveat: Reduced uncertainty at the payer/provider
level correlates with increased development costs
Main challenges...Summary
Codependency
Drug/Diagnostic
Reimbursement
Parallel diagnostic
and drug approvals
needed to ensure
successful market
entry
Diagnostic
reimbursement under
increasing payer
scrutiny (clinical
utility)
Difficult to
convince
diagnostic
manufactures to
engage in early
stages of
development
Region-specific
discrepancies in
payer requirements
Longer exclusivity
period
Advanced purchase
solutions
LDT / regulated
diagnostics
Significant uptake
in use of LDTs
due to lower cost
LDT compete
against regulated
diagnostics
(investment and
commercial risk)
Regulatory
Lack of regulatory
harmonisation
No requirements to
demonstrate clinical
utility
Fast-paced
technological changes
not reflected in
regulatory processes