1Charles Oo

OVERCOMING THE

CHALLENGES IN DRUG

DEVELOPMENT

Charles Oo, PharmD, PhD,

ABCP, FCP

charlesoo@yahoo.com

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

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”

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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

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.

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

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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

12Charles Oo

Open Innovation Model

Source: modified from Chesbrough, H. 2003

13Charles Oo

Collapse of the ‘Blockbuster Model’Shift to Targeted Niche of Personalized Medicines

14Charles Oo

Fastest

growing

Areas

Therapeutic Areas in Terms of Market Size

15Charles Oo

Biological ComplexityLinking Drug-effects and Biological Systems

Fliri TIPS 2010

16Charles Oo

Balancing Efficacy and ToxicityMost of the clinical failures at late phase are due to wrong

dose

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

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Reduce Attrition Rate by Ascertaining The

Relevant Mechanism of Action

19Charles Oo

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?”

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

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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

27Charles Oo

Summary

Think Outside the Box….Innovation Is Needed

Achievable if the above strategies are adopted

28Charles Oo

Questions and Comments?

Please forward to:

charlesoo@yahoo.com

THANK YOU!!!