overcoming challenges in drug development
TRANSCRIPT
1Charles Oo
OVERCOMING THE
CHALLENGES IN DRUG
DEVELOPMENT
Charles Oo, PharmD, PhD,
ABCP, FCP
2Charles Oo
Outlines Challenges in drug research and development
Complex problem requiring “multi-pronged” strategies:
Complete paradigm shift, and open innovation model
Marketing strategy: focus on ‘valued’ therapeutic classes and
personalized medicine
Biological complexity: balancing drug’s toxicity and safety
Scientific insight: pathophysiology, mechanism of actions, and
physicochemical profiles
Technology advances and biomarker utilization
Model-based drug development
Adaptive design
Bottom-line
Innovation is crucially needed for drug research and development, and
it can be developed with the right strategies
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Current Realities for Pharmaceutical Developers
Recent drug development process is long, risky,
expensive, and increasingly complex, after the low-
hanging fruits have been plucked
Growing regulatory hurdles and policy demands
stemming from implementation FDAAA and the Health
Care Reform law
Drug patents on many high revenue products are
expiring
Marketplace is highly competitive and reimbursement
environment is increasingly restrictive
Public support and image remain low.
Kaitin KI, Tufts Center for the Study of Drug Development ,2011: “Pharmaceutical Innovation in the 21st Century”
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Drug Research & Development is like:
http://blog.modernmechanix.com/mags/PopularScience/7-1939/needle_haystack.jpg
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Long & Expensive Drug Development
High Risk Process:
~15 Years, $1 B+
Preclinical Pharmacology
Preclinical Safety
Millions of
Compounds Screened
Idea Drug~ 15 Years
1 - 2
Products
Discovery Exploratory Development Full Development
Phase I Phase II Phase III
0 155 10
Clinical Pharmacology& Safety
Adapted from the slide of Lamattina, Pfizer
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Declining Trend in R&D Efficiency (Inflation-adjusted)
FURTHER INFORMATION
RCSB Protein Data Bank database: http://www.rcsb.org/pdb/statistics/holdings.do
SUPPLEMENTARY INFORMATION
See online article: S1 (table) | S2 (box) ALL LINKS ARE ACTIVE IN THE ONLINE PDF
Source: Scannell JW et al, Nat Rev Drug Dis 11:191-200, 2012
7Charles Oo Sources: Kaitin, Clin Pharmcol Ther, 2010;87:356-361; Medco; FDA Orange Book; MedAdNews; www.drugs.com/top200; Medco
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Pharma Leads in Drug Discovery but Not in
Innovation
• Of 252 drugs that the FDA approved between 1997 and 2008,
pharmaceutical companies discovered 58%, biotechnology firms
discovered 18% and universities discovered 24%, according to a
Nature Reviews Drug Discovery, November 2010
• However, pharma lagged on discovery of innovative drugs,
accounting for 46% of treatments designated for priority review and
44% of drugs with a novel mechanism or action
• Universities and biotechnology firms play bigger role in innovation.
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What Would Einstein Do?
Slide, Lesko LJ., 2007
Complex situations requires innovative approaches
to reduce R&D costs, clinical trial cycle time, and attrition rate
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What Types of Innovations Are Needed?
Scientific & operational models that reduce cycle time,
control costs, and ensure a high probability of success
Solutions that are differentiated and build durable patient-
centered relationship
Business models that create long-term value propositions
Market models that create new experiences in standard of
care
Open innovation that creates collaborative relationships
that allows increased insight and economic impact
Greater use of sophisticated portfolio management
techniques
Truman, Drug Development & Delivery, Jan 2010
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Complete Paradigm Shift is Needed
OLD -------------------> ‘NEW’
Sequential-----------> Parallel
Multiphase-----------> Adaptive
Milestone-led -------> Knowledge-led
Empirical -------------> Predictive
Hidden intuition ----> Transparent logic
Subjective ------------> Objective
‘New’
innovative
approaches
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Open Innovation Model
Source: modified from Chesbrough, H. 2003
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Collapse of the ‘Blockbuster Model’Shift to Targeted Niche of Personalized Medicines
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Fastest
growing
Areas
Therapeutic Areas in Terms of Market Size
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Biological ComplexityLinking Drug-effects and Biological Systems
Fliri TIPS 2010
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Balancing Efficacy and ToxicityMost of the clinical failures at late phase are due to wrong
dose
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Considerations for In-vivo Activities in Disease
Condition
Complexity of human systems in drug actions:
1. Few good animal models. Not readily predicted by
animal models;
2. Hugh difference between healthy and disease conditions;
3. Complex mechanism of action/target site/agonist-
antagonist/biological systems, as well as:
a) Important contributions from surrounding
microenviroment, as rarely a single tissue/pathway is
involved;
b) Genetic, epigenetic, and environmental interactions;
c) Perturbing homeostasis could lead to beneficial or
deleterious effects
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Reduce Attrition Rate by Ascertaining The
Relevant Mechanism of Action
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Considerations for Physicochemical Profile
of A New Molecular Entity
Permeability
pKa
Stability
Protein
bindingLog D
Polymorphism
Solubility
Integrity
ProfileLipophilicity
Adapted from KLE pharmacy, Belgium, 2009
Physicochemical profile of a new molecular entity represents the foundation
for building its efficacy and safety outcomes
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Technology Advance Leading to Greater Use of
Biomarkers
Slides, Pritchard F
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Increasing Use of BiomarkersCausal Path of Drug Effect: Better Explained by Intermediate
Measurements (Biomarkers) Than by Dose
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Model-based drug development (MBDD)
concept
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Logistics of MBDDRequire Close Collaboration between Nonclinical and Clinical Divisions
Iterative and Quantitative Application of All Available Information
S. R. B. Allerheiligen, AAPS 2006
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Decision Making in Using MBDD
Adapted from a slide by Benson N, Xenologiq.com, “Systems pharmacology in drug discovery; wrong but useful?”
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Adaptive Design in Drug Development
• A clinical trial design that uses accumulating data to decide how to modify
aspects of the study as it continues, without undermining the validity and
integrity of the trial
• FDA 2010 guidance – “a study that includes a prospectively planned
opportunity for modification of one or more specified aspects of the study
design and hypotheses ….
• Commonly accepted: - Phase 2: Response-adaptive randomization
- Phase 3: Early stopping for efficacy or futility
- Phase 3: Blinded sample size re-estimation
• Gradually being accepted: - Seamless phase 2/3 pivotal trials
- Unblinded sample size re-estimation
• Still very controversial: - Enrichment of subpopulations
- Change in choice of test statistic
- Change of primary hypothesis
- Change of primary endpoint
Sietsema, Kendle, 2010
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Example
Adaptive Clinical Trials for Phase II & III
Modified from Dr Jeff Maca, Novartis , Presenting at the PhRMA Adaptive Designs Workshop, Nov 2006
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Summary
Think Outside the Box….Innovation Is Needed
Achievable if the above strategies are adopted
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Questions and Comments?
Please forward to:
THANK YOU!!!