MEETING THE CHALLENGES FOR

DRUG DEVELOPMENT IN THE 21st CENTURY

Jan S. Rosenbaum, Ph.D.CincyTech

Jan S. Rosenbaum, Ph.D.

Rosenbaum holds a Ph.D. in pharmaceutical chemistry from the University of California at San Francisco and a postdoctoral fellowship in clinical pharmacology from Stanford University. She is the author of more than 50 original papers, short communications and abstracts in peer reviewed journals and has been an invited speaker at numerous international meetings.

She holds an adjunct professor appointment in the Department of Pharmacology at The Ohio State University where she lectures in Pharmacogenomics, and a Visiting Scholar appointment in the Department of Pharmacology at the University of Cincinnati, where she co-developed a graduate course in New Drug Discovery-Preclinical Development, for those individuals seeking to understand process in the context of current global market forces and

Jan S. Rosenbaum, Ph.D., is a director of life sciences for CincyTech and founder of BRK-1 Technical Advisors Inc. a pharmacology and technical due-diligence consulting services practice supporting the pharmaceuticals and biotechnology communities.

To learn more about Dr. Rosenbaum, click here.

the drug development opportunities.

Objectives

What has happened to the Pharma

industry?

What is “Innovation” and where do we look

for it?

What does it mean to be second to the

market?

How does this affect me as a

Pharmacologist?

Productivity in the last 60 years

b

• Productivity has remained flat despite increased R&D spending

Source: a: B. Munos, Nat Rev Drug Disc 8:959-968 (2009)b: KI Kaitin, Clin Pharmacol Ther 87(3): 356-361 (2010)

Can This Trend Continue?

Let’s examine the various pressures that have converged on the Industry R&D output/What happens as we hit the Patent

Cliff?

The rising cost of healthcare in the US and

world-wide

The US Regulatory environment

“Business as Usual” is No Longer an Option for the Industry

The Patent Cliff is a problem36 blockbuster drugs (annual sales > $1B) saw patents expire

between 2009-2012WW sales for these products exceed $112B

Third party payers are demanding demonstration of therapeutic and/or economic advantages over ALL competitive products (including non-therapeutic options)This is increasingly challenging in the ex-US market

Improvement in safety profile is no longer sufficient to get on the market

The bar has been raised for Regulatory approval in the USGreater focus on pre-approval safety as well as post-marketing

surveillance in the post-Vioxx era

What is Innovation?

Innovation means different things to different people

Scientists

Patent attorneys

Consumers/Customers

Third Party Payers

Research vs. Innovation

Research: Transforming knowledge into information

Innovation: Transforming knowledge into products to create value for the consumer Medicinal Product Innovation: Chemistry

(structure/drug class), Method of Synthesis (process), Formulation, PK/PD, Pharmacogenetic

The Consumer: Patient, Physician, Third Party Payer (health-care systems, government)

Innovation-NoveltyNovelty and “Newness” are distinct concepts

“Newness” implies a new creation (i.e. a new chemical entity)

Novelty can be a NCE or it can be a new use for a known compound, or a new method, formulation, etc. From a patent standpoint, it must be something

that is “non-obvious” to someone skilled in the Art

Novelty/Newness is a key component of Innovation

Innovation-UsefulnessUnless an invention is useful, it is not innovative

Utility depends on the perspective of the userSource: JK Aronson et. al. Nat Rev Drug Discovery 11:253-254 (2012)

What do Physicians Consider Novel?

Survey of 184 expert physicians across 15 medical specialties and 30 US academic centersImproved efficacy (55%)Novel mechanism of action-first in class (37%)Impact on practice in field (24%)Less ImportantImproved safety, ease of patient use, re-

application potential, scientific merit (7-15%)

Why Are There Me-Toos?

If you are working on a new MOA, someone else is tooFor new drug classes approved since 1990,

>80% of the follow-on drugs were in clinical trials before approval of the first-in-class drug

For new drug classes where the first-in-class was approved since 1990, >70% of the follow-on drugs were in Phase II, and > 60% were in Phase III

Source: DiMasi JA and Faden LB Nat Rev Drug Disc 10:23-27 (2011)

Is It Important To Be

First-To-Market?

Source: Schultz U and Ringel M Nat Rev Drug Disc 12: 419-420 (2013)

Va

lue

Source: Schultz U and Ringel M Nat Rev Drug Disc 12: 419-420 (2013)

Va

lue

How Quick To Market Do You Have to Be?

Achieving Commercial Success With a Me-Too

Differentiating characteristics in a subgroup of patients-unique unmet need

Distinctive mechanistic class dynamicsRight drug for the right patient requires

cycling through multiple drugs with the same MOA

Sales force can drive market adoption

Why Do Drugs Fail?

Source: Khana I DDT 17: 1088-1102 (2012)

Commercial Failure = Strategic, lack of discrimination vs. competition, efficacy & economic risk/benefit ratio

Where Do Drugs Fail?

The majority of drugs fail in Phase II

Source: Khana I DDT 17: 1088-1102 (2012)

What is Pharma Doing?

M&A between major & mid-size Pharma was an attempt to address the Patent Cliff issue Short-term “fix” that led to massive layoffs in the

industry without an increase in R&D efficiencyPharma is looking to develop drugs for rare

diseases, on the assumption that the orphan drug can be reapplied to the treatment of a more common disease

Pharma is looking to Biotech and Academia to provide a portion of their pipeline

The Orphan Drug Approach

Requires disease pathology understanding Companion diagnostics to select patient

populations and streamline clinical trials Provides priority drug status and shorter timelines

for clinical development Has tax incentives for development Potential upside to capture multiple markets after

demonstration of safety & efficacy in initial orphan market

Increased Effort to Develop Orphan Drugs

Source: FDA Law Blog Feb 13, 2013 http://www.fdalawblog.net/fda_law_blog_hyman_phelps/orphan-drugs/

Source: I. Melnikova, Nat Rev Drug Discovery 11: 267-268 (2012)

Where Are Orphan Drugs Successful?

Developing New

Drugs/Targets

Everyone is a player at the Discovery Stage

Only Biotech/Pharma have the capacity to get to NDA/BLABiotech continues to be the primary

source for development and marketing of biologics

Why Worry About Cost?

Source: SM Paul et. al. Nat Rev Drug Disc 9:203-214 (2010)

Understanding the Cost of Clinical Trials

• Approval phase is shorter for orphan drugs because of priority status• For standard NMEs, Clinical phase and Approval phase length varies by therapeutic classSource: KI Kaitin & JA DiMasi, Clin Pharmacol Ther 89 (2): 183- 188 (2011)

Not All Trials Are Created Equal

Source: SM Paul et. al. Nat Rev Drug Disc 9:203-214 (2010)

Move to the “Fail Fast” Model in Clinical Trial

Design

A New Model of Pharmaceutical

Innovation

Pharma simply cannot afford to do it alone!Source: KI Kaitin, Clin Pharmacol Ther 87(3): 356-361 (2010)

Then vs. NowBlockbuster Model

Large patient population with high sales potential Crowded markets, difficult to differentiate Difficult to demonstrate enhanced value

The evolving modelTargeted therapies for specialized markets

Biomarkers & companion diagnostics inform clinical trial design & streamline patient selection

Pharmacoeconomic endpoints incorporated into trial design

Enhanced post-marketing surveillance Dependence on CROs

What Does This Mean For the Discovery

Pharmacologist?• In order to be successful in today’s

Pharmaceutical marketplace, it is no longer sufficient to demonstrate a drug is safe and effective

• The NME must also be offer significant economic and therapeutic value– Disruptive technology-only distinctive “me toos”– The clinical trial setting and patient population must be

considered at target selection– The Discovery program must be designed to meet both

customer (unmet medical) and third-party payer objectives

• If the drug does not add value, no one will reimburse it!

Pharmacologists are Ideally Suited to Guide

the Transition Rational target selection and target validation to

meet the unmet need

Development of biomarkers and functional imaging tools to assess efficacy and inform dose selection in preclinical, proof-of-concept, and later-phase trials

Development of modeling & simulation and resource-sparing adaptive trial design strategies.

Are YOU Ready To Meet the Challenges That The Industry Faces?

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