Accessing New Drugs
Perspective from Pharma
Raphaël Rousseau, MD, PhD
Assoc. Group Medical Director
Global Development Team Leader, Pediatric Oncology Drug Development Program
Genentech, a member of the Roche group
South San Francisco, USA
Disclaimer
Some comments & views expressed in this presentation are mine and not
necessarily shared by Roche, Genentech or affiliated parties
A pediatrician’s atypical journey
from bench to bedside… to the pharmaceutical industry
identify pathways
“cure cancer in mice”
move to the clinic
< proof-of-concept
preclinical
sometimes up to phase 1
= funding
translational challenges
focus on one disease
obtain drugs from Pharma
collaborate with peers
generate a portfolio strategy
explore multiple diseases
collaborate w/ Academia, Regulators, Parent
at best
< confirmatory
phase 1, 2 trials
<
safety and efficacy
phase 3
registration if positive
=
challenging timelines
costs
attrition rate
access to patients
rarely phase 3
to industry’s portfolio
= access
resources for clinical research
beyond clinical research: registration
Symposium 2 – Saturday 13:50-15:20 - CARs on track in the clinic: are chimeric artificial receptors a true novel perspective for the cure of
resistant childhood leukaemias?
The complexity of industry workflows
integrating therapeutic & diagnostic R&Ds without delaying either of the
processes
compliance check(s)
Rx R&D process and decision points
Development ~8yrs
Research ~7yrs
New
Medicines
Proposal
Target
Validatio
n
Lead
Identificatio
n
Lead
Optimisation
Project
Initiation
EIH Enabling
Phase I
Pre-clinical
safety
Early clinical
safety
Clinical Candidate
Selection
Entry Into
Humans
Phase
IIa
Phase
IIb
Phase III
Proof
of
Concept
Early
clinical
efficacy
Key
registration
trials
Entry Into
Lifecycle
Management
pediatric plans submitted to EMA
Full Dev.
Decision
FDA
Registration
Filing Decision for
First Indication
approval needed
Dx development process and milestones
Pre-clinical assay development ~2yrs
Clinical Phase ~3yrs
Replication
Biomarker
Discovery
Confirm markers and reproducibility of
assay
Analytical Development
Translation of assay onto a clinical platform
BM Dx
candidate
identified
BM assay on clinical
platform
Non-clinical testperformance
Phase I
Phase II
Phase III
Sensitivity &
specificity
PPV and NPV
Clinical benefit
and economics
Clinical
validation
BM = Biomarker; EIH = Early In Humans; Rx = Therapeutic: Dx = Diagnostic; R&D = Research & Development
Clinical
utility
Registration
Clinical
impact
The costs of bringing new drugs to the market
portfolio prioritization becomes crucial
1000
average costs of R&D per drug: 1 billion USD over 10 years
patent expiry
800
market authorization
600
pediatric
reward
= 6 months
additional
exclusivity
400
Mio CHF
Phase 3 “go”
200
0
-200
-400
-600
-800
Sales indication 1
Sales indication 2
Sales indication 3
COGs
Total PP+FF
Cum DCF
COGs = Cost of Goods; DCF = Discounted Cash Flow
Total R+D
Only one success out of thirty-two
candidates
attrition rate, an additional challenge for pediatric• research
Biologics success rate
Benchmark on 14 pharmas
– 4x > small molecules
– but 8 mos longer cycle time
•
Therapeutic area success
– low ~2% (NS)
– high ~12% (virology)
• Pediatric preclinical tasks
– Juvenile toxicity = ~1 year
– Formulation = ~18 months
Challenges for portfolio selection
– increase return on investment
 first-in-class, best-in-class
– reduce costs of R&D
– must have “early kills”
Implications for academics
– time & efforts invested
ED: GLP Tox studies to start of phase 3 (5 yrs; 8% success)
– no carry-on mechanisms
LD: Start of phase 3 to market approval (3 yrs; 51% success)
NMEs entries to achieve 1 approval: PC 32.4; P1 20.5; P2 9.6; P3 2.2; registration 1.3 – time to study start
ED = Early Development; LD = Late Development; NME = New Molecular Entity; GLP = Good Laboratory Practices; PC = Pre Clinical; NS = neuroscience
Defining “early planning”
timing and outcome of Art. 7 PIP submissions
PIP agreed unchanged or with minor modifications
PIP agreed with major modifications
PIP agreed with suggestion to come back for later discussion in a "Modification of agreed PIP" procedure
PIP refused (negative PDCO opinion)
PIP withdrawn
15%
18%
50%
2%
4%
47%
15%
12%
4%
4%
20%
40%
12%
58%
39%
24%
50%
31%
18%
Before first human dose
in adults
End of Phase 1 in
adults
EFPIA/EMA Infoday - 23 May
2011
18%
19%
Following confirmation Following completion of After starting paediatric
of adult dose or proof of confirmatory clinical
trials
concept, but before the
trials in adults, but
start of paediatric trials
before the start of
paediatric trials
Pediatric Drug Development in Pharma
key success factors
1
Pediatric Expertise
Leverage & support current
internal pediatric expertise
Portfolio Strategy
2
Assess scientific, medical and
business opportunities with all
drugs
• consolidate past expertise into one cross-functional group
• facilitate internal awareness training, develop best
practices in pediatrics (ICF, template protocols)
• “one shop stop, one pediatric voice” internally and
externally
• interface between early & late development
• provide regulatory and pediatric expertise
• liaise with academic groups, regulators, patient advocates,
other pharma
Early planning & execution
3
Ensure early pediatric evaluation
of lead compounds & close
interactions between early & late
development teams
Ensure access to patients
4
Optimize access to patients to
ensure our societal role, inform
clinical development plan and
meet regulatory obligations
• inform clinical development plan early on potential
pediatric obligations & opportunities
• ensure smooth transition between early (design) and late
(execution) development teams
• ensure unmet pediatric needs are addressed proactively
• long-term commitment to pediatric cooperative groups:
proactive, early interactions, co-development/partnerships,
support to ISTs & educational programs
• support innovative trial design
Where pediatric opportunities defeat obligations
explore the pediatric oncology strategic framework
(2) MOLECULAR MAPPING &
SCIENTIFIC OPPORTUNITY:
Adequation to pediatric disease
pathways
(1) REGULATORY FIT:
focus on drugs “at
risk”
(4) CLINICAL BARRIERS TO ENTRY:
unmet medical needs vs. patient
access
(3) BUSINESS
OPPORTUNITY:
mid- and long-term potential
Oncology drug
opportunities
All parties (industry, academics, regulators, parents) should meet
regularly and agree on which drugs to prioritize within the existing
oncology portfolio
Prioritized
pediatric
oncology
drug
development
Improve access to new drugs for children
with high unmet medical needs
innovative trial design to reduce timelines & optimize patient accrual
Traditional early clinical trials in rare patient populations
Drug A
Drug B
Drug C
Additional clinical trials with
Drug C
years
Continual reassessment method (adaptive trial design)
Need to clarify
Drug A
Regulatory obligations
Incentive
Data protection
Patent legislation
Drug B
Drug C
Additional clinical trials with
Drug C
years
Partnership between Pharma & Academia
key success factors
Academia
Pharma
Innovative ideas
++
++
Great scientists
++
++
Research facilities
++
++
Manufacturing capacities
++
Direct patient access / network access
++
Medical expertise / disease-area expertise
++
Regulatory expertise / registration capacities
Quality control & quality insurance
++
+
Financial resources
Independence
+
++
++
++
+
Partnership between Pharma & Academia
evidence for complementarity
Academia
Pharma
Innovative ideas
++
++
Great scientists
++
++
Research facilities
++
++
Manufacturing capacities
++
Direct patient access / network access
++
Medical expertise / disease-area expertise
++
Regulatory expertise / registration capacities
Quality control & quality insurance
++
+
Financial resources
Independence
+
++
++
++
+
Partnership between Pharma & Academia
suggested improvements – a concerted effort
•
•
•
•
Industry
–
provide as-early-as-reasonably-can access to new drugs to Academia, provide funding for
preclinical testing
–
advocate internally and across industry for pediatric drug development
–
encourage cooperation between companies (pre competitive arena)
–
consider unmet medical needs in poor countries
Academia
–
avoid off-label use once drug is approved in adults, encourage accrual in available pediatric trials
–
provide feasibility data through real-world epidemiology
–
improve accrual capacity through networking or consolidation of current structures
–
increase awareness of drug development with pediatric trainees, encourage internships
Regulators
–
provide a regulatory pathway to allow for innovative trial designs (adaptive, combo, multicompany)
–
improve alignment between agencies (adolescent research), simplify procedures, rethink rewards
Parents
–
advocate for randomized, controlled trials
–
keep all of us under pressure!
Safety challenges in pediatric drug development
long-term commitment to best serve children
•
children are not small adults: toxicity assessment in adults
may not be predictive in children
•
monitoring for immediate toxicity is the norm but clearly
insufficient for children exposed at an early age
•
under reporting / off-label use by pediatricians
•
long-term follow up is needed for safety outcomes
–
An ethical and moral obligation
–
A logistical challenge
–
A concerted effort for all parties involved
•
ongoing discussions between US and EU regulators,
academic/cooperative groups and pharma
•
ultimately, will require physicians? patient/parents longterm
commitment
Regulators
Parents
Physicians
Pharma
Thank you
rousseau.raphael@gene.com