This document outlines strategies for overcoming challenges in drug development. It discusses the current long and expensive drug development process, as well as growing regulatory hurdles. It argues that innovation is needed, including open innovation models, a shift to personalized medicine, balancing drug toxicity and safety, leveraging technological advances like biomarkers, and using adaptive clinical trial designs. The key message is that new approaches are required to reduce costs, cycle times, and failure rates in drug development.

1. 1Charles Oo
OVERCOMING THE
CHALLENGES IN DRUG
DEVELOPMENT
Charles Oo, PharmD, PhD,
ABCP, FCP
charlesoo@yahoo.com

2. 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

3. 3Charles Oo
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”

4. 4Charles Oo
Drug Research & Development is like:
http://blog.modernmechanix.com/mags/PopularScience/7-1939/needle_haystack.jpg

5. 5Charles Oo
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

6. 6Charles Oo
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

7. 7Charles Oo Sources: Kaitin, Clin Pharmcol Ther, 2010;87:356-361; Medco; FDA Orange Book; MedAdNews; www.drugs.com/top200; Medco

8. 8Charles Oo
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.

9. 9Charles Oo
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

10. 10Charles Oo
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

11. 11Charles Oo
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

12. 12Charles Oo
Open Innovation Model
Source: modified from Chesbrough, H. 2003

13. 13Charles Oo
Collapse of the ‘Blockbuster Model’
Shift to Targeted Niche of Personalized Medicines

14. 14Charles Oo
Fastest
growing
Areas
Therapeutic Areas in Terms of Market Size

15. 15Charles Oo
Biological Complexity
Linking Drug-effects and Biological Systems
Fliri TIPS 2010

16. 16Charles Oo
Balancing Efficacy and Toxicity
Most of the clinical failures at late phase are due to wrong
dose

17. 17Charles Oo
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

18. 18Charles Oo
Reduce Attrition Rate by Ascertaining The
Relevant Mechanism of Action

19. 19Charles Oo
Considerations for Physicochemical Profile
of A New Molecular Entity
Permeability
pKa
Stability
Protein
binding
Log D
Polymorphism
Solubility
Integrity
Profile
Lipophilicity
Adapted from KLE pharmacy, Belgium, 2009
Physicochemical profile of a new molecular entity represents the foundation
for building its efficacy and safety outcomes

20. 20Charles Oo
Technology Advance Leading to Greater Use of
Biomarkers
Slides, Pritchard F

21. 21Charles Oo
Increasing Use of Biomarkers
Causal Path of Drug Effect: Better Explained by Intermediate
Measurements (Biomarkers) Than by Dose

22. 22Charles Oo
Model-based drug development (MBDD)
concept

23. 23Charles Oo
Logistics of MBDD
Require Close Collaboration between Nonclinical and Clinical Divisions
Iterative and Quantitative Application of All Available Information
S. R. B. Allerheiligen, AAPS 2006

24. 24Charles Oo
Decision Making in Using MBDD
Adapted from a slide by Benson N, Xenologiq.com, “Systems pharmacology in drug discovery; wrong but useful?”

25. 25Charles Oo
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

26. 26Charles Oo
Example
Adaptive Clinical Trials for Phase II & III
Modified from Dr Jeff Maca, Novartis , Presenting at the PhRMA Adaptive Designs Workshop, Nov 2006

27. 27Charles Oo
Summary
Think Outside the Box….Innovation Is Needed
Achievable if the above strategies are adopted

28. 28Charles Oo
Questions and Comments?
Please forward to:
charlesoo@yahoo.com
THANK YOU!!!