The 2nd Clinical Data Management Training

Innovative Drug Research and Development (创新药品的研发过程）

Frank Shen （沈志华） , Ph.D.

Head of Biometrics and Clinical Management

生物统计数据和临床管理负责人罗氏药品开发中国中心

August 30, 2010

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My Objective is…

The Global The Global InnovativeInnovative Pharmaceutical Industry Pharmaceutical IndustryThe Complexity of Drug Development and The Complexity of Drug Development and

Clinical ResearchClinical ResearchThe Role of Data Manager played in Clinical The Role of Data Manager played in Clinical

ResearchResearchChallenges and Opportunities in ChinaChallenges and Opportunities in China

After this talk, you will have some good understandings about:

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Top Line, Bottom Line, Pipeline and Regulated Industry

Pharmaceutical Automobile

Sales 100 100

Cost of Sales 28 75

Marketing 30 7

R&D 10 3

Administration &Overhead

7 8

Net income before tax

25 7

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Drug Discovery to Drug Development: A Ten-Year Bet

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Drug Discovery: Finding A Right Target and Picking Winners

Identify a disease Identify a disease target:target:

Cell Biology Cell Biology

GenomicsGenomics

Mass-screening for Mass-screening for hits:hits:

High-Throughput High-Throughput Screening (HTS)Screening (HTS)

MiniaturizationMiniaturization

Identify a key:Identify a key:

Combinatorial Combinatorial chemistrychemistry

Natural ProductsNatural Products

Compound AcquisitionCompound Acquisition

Quantitative-Structure Quantitative-Structure Activity Relationship Activity Relationship (QSAR)(QSAR)

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Early Phase Development: Use Clinical Pharmacology (CP), Pharmacokinetics (PK) and Pharmacodynamics (PD) to find A Right Drug

Early Phase Development: Use Clinical Pharmacology (CP), Pharmacokinetics (PK) and Pharmacodynamics (PD) to find A Right Drug

PK: What the body does to the drug

PD: What the drug does to the body

0

2

4

6

8

10

12

0 0.5 1 2 3 4 6 8 10 14 18 24

Time (h)

Conc

cent

ratio

n (n

g/m

L)

AUC

Cmax

Tmax

Drug Exposure (DOSE)

Res

pons

e (E

ffec

t)

Max Effect

50% Effect

50% Effect Dose

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Process Development

Formulation/Stability

File IND Phase I Phase II

Clinical Trials

Phase III

File NDA

APPROVAL

Metabolism

Toxicology

Late Phase Development: Finding A Right Clinical Plan

Drug DiscoveryPreclinical

(II-B)(II A)

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““ If it were not for theIf it were not for the great variability among great variability among individualsindividuals,,medicine might as well medicine might as well be a science and not an be a science and not an art”art”

99

Dilemmas in Modern MedicineDilemmas in Modern Medicine

““ Every day, doctors diagnose Every day, doctors diagnose patients and prescribe the most patients and prescribe the most appropriate drug, and yet in many appropriate drug, and yet in many cases, the drug won’t work or will cases, the drug won’t work or will trigger miserable side effects”trigger miserable side effects”

- - The Wall Street JournalThe Wall Street Journal

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Relative signal/noise in drug studies due to inter-subject Relative signal/noise in drug studies due to inter-subject variability (noise)variability (noise)

Phase 1Phase 1 Phase 2Phase 2 Phase 3Phase 3

1111

Evidence-Based Medicine is a Statistical-Based Medicine

Populationsample Inferences

based on the sample

Extrapolate

e.g. patients with high cholesterol

e.g. 150 patients with high cholesterol in a clinical trial

e.g. statin reducescholesterol

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Hypothesis (Scientific belief)

Data Collection

Data Analysis

Interpretation

•Confirm/Reject

•Refine

Design of Scientific Experiments (e.g., Clinical Trial)

Objective (Signals/endpoints)

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Clinical Trials of New DrugsClinical Trials of New Drugs

A high-noise/low yield endeavor Requires great care in design and execution

for success Expectations often not realized 50% of phase III trials failed to show positive

results Investment needs to be protected Buy A Good Insurance Policy and

Execute with High Quality

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Four Elements of Clinical ResearchFour Elements of Clinical Research

Data and MonitoringPatient

Protocol

Biostatistics

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Protocol DesignStudy Setup & Conduct

Data Base Lock

Analysis & Report

Draft/Design

Review

CRF/Form Design

Signoff

FPFV

Database design & verification

LPLV

CRF Lock

Data Review, Query & Cleaning

Clinical Trial and Protocol Life

STAGE

TASKData Entry/ CRF Processing

Data Q&R

External Data

Statistical Analysis Plan

Data Review Plan

Data Presentation Plan

Medical Encoding

Clinician/Statistician CRA/DM Statistician/ClinicianDM/CRA/ClinicianRoles

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Drug Development in China

Due to the large volume of generics, regulators (sFDA) concentrate mostly on drug manufacturing quality

Minimal experience in true innovation-based R&D processes

Complex regulatory processes subject to frequent policy changes and political environment

2005 US FDA Chinese sFDA

# of New Drugs 20 1,113*

# of Generics 344 8,075

# of Reviewers 1,800 120

* Include formulation changes

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Preclinical

Phase I

Phase III

Phase II

Marketing Authorizati

on

Global

CTA Clinical Trial IDP

Chinese

Launch in

China

0 1 2 3 4 years

CPP

4 years behind!

Routine Registration Map in China (Imported Drugs)

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China’s Rapid Pharmaceutical Market Growth

Source: IMS Audit China Hospital Market 2010

• Projected to be 3rd largest market by 2013, 2nd largest by 2020

• CAGR +20% 2002 to 2011 driven by generics, branded generics and innovative medicines

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1919

There will be an increasing need for new medicines in ChinaChanging Demographics in China 1995 - 2030

1995 2010 2030 19

(166M) (342M)

2020

Great Opportunities for Professional Growth Come From

1. Outsourcing strategy from global companies and CRO to support global projects

2. R&D center from global companies focused on penetrating China’s high potential market

3. New Professions: Biostatistics, Programming (SAS and DBA), Data Management, Pharmacometrics, etc…

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We Innovate Healthcare

The 2nd Clinical Data Management Training

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