Global Learning and

Development, Corporate HR

Molecules to Markets

Autumn 2010
Ralph White John Faulkes
0

Who are we?

Ralph White

John Faulkes

www.ppmld.com
1
 Learning outcomes

■ You will be able to:

– Discuss current trends and challenges in the
industry
– Describe the Pharma Value Chain - from
molecules to markets
– Identify and share experiences
– Explain how Roche integrates these activities
and makes key decisions

How the course works

Input from us and visiting speakers on
– General industry trends / tasks
– Roche-specific content and processes
Team exercises - simulation
■ Sharing input / knowledge from you

3
Examples used on the Course

■ Tamiflu – What might

replace it?

■ Other products / projects of choice

raised by our expert visitors

Team introduction exercise

■ Introductory discussion at the
table….then present:

■ Who’s on your table? ?

■ Current range of knowledge -
– Less expert knowledge – you may want to
understand the whole process?
– More expert knowledge – you may want to
learn about some specific areas?
■ Specific questions? 5
 Roche Structure
Group functions ensuring cohesion and efficient services

Diversity Global Scale / Reach

gRED
Pharma

pRED
Partnering Pharma Medicines
Chugai
Diagn.

Business Business
Areas / Global
AreasFunctions Diagnostics
Business
Business Areas
Areas Regions
Diabetes Care
Group

Finance, IT, Legal, HR, Communications

Cohesion

Research Translational Medicine Clinical Development Strategic Marketing

TS CCS EIH LIP PND
Chemical / biochemical diversity Continuing research into the disease
and biological assay Therapeutic proteins Supply chain
Structure-activity relationships Quality assurance - GMP
Discovery Assessment of Transfer to primary and Distribution
Drug candidate selection developability to markets
secondary manufacture
Genomics, proteomics and Packaging
metabonomics - linking disease Development of synthesis / biosynthesis,
and biological target Formulation and means of production
Disease models Chemical / biotechnology research, Engineering Chemical manufacture
analytical methods and Pilot scale Biotech manufacture New formulations
Target tractability preliminary formulation Procurement Galenical manufacture
Technical Clinical Trials Materials
Carcinogenicity and
New
Short term Quality assurance - GLP teratogenicity tests
Medicines Non-clinical Phase 3B
toxicology
Longer term toxicology Phase 3A Peri-marketing New indications
Proposal
Biomarkers Pharmacokinetics / dynamics Efficacy, safety studies
Clinical and quality of life
Absorption, distribution, studies in patients Phase 4
metabolism and Phase 2A
Translational medicine PoC PoD Companion diagnostics Post-marketing
elimination studies and
Regulatory Data management Paediatric Investigational surveillance
Clinical pharmacology and biostatistics Plan
Regulatory strategy Quality assurance Further registrations
Commercial - GCP Phase 2B Promotional claims in new markets
Phase 0-1 Patient safety
Key value First time in humans studies Marketing Authorisation /
drivers Patents New Drug Applications
Clinical Trials Applications Draft Summary of
Competition Ethics approval Launch and Lifecycle
External research / Product Characteristics
Unmet needs Product optimisation Management
technology alliances
Differentiation Communications with
Acquisitions & strategic alliances customers - Pricing and reimbursement
Market sizing Licensing Key Opinion Leaders, Affiliate branding
Payor research Health Outcomes investigators and markets Market access plan

Targets Leads Phase 1 Phase 2 Phase 3 Phase 4

Years 1 2 3 4 5 6 7 7
 Research Translational Medicine Clinical Development Strategic Marketing
TS CCS EIH LIP PND
Chemical / biochemical diversity Continuing research into the disease
and biological assay Therapeutic proteins Supply chain
Also:
Also: Roche
Roche cross-
cross-
Structure-activity relationships Quality assurance - GMP
Discovery Assessment of Distribution
company
company Drug candidate selection developability Transfer to primary and
secondary manufacture to markets
Genomics, proteomics and Packaging
management
management and
and
metabonomics - linking disease Development of synthesis / biosynthesis,
Formulation and means of production
and biological target
decision
decision making
making Chemical manufacture
Disease models
Target tractability
Chemical / biotechnology research,
analytical methods and Main focus: Pharma
Engineering
Pilot scale Biotech manufacture New formulations
preliminary formulation Galenical manufacture
Technical functional activities
Procurement
Clinical Trials Materials
Carcinogenicity and
New
Short term Quality assurance - GLP teratogenicity tests
Medicines Non-clinical Phase 3B
toxicology
Longer term toxicology Phase 3A Peri-marketing New indications
Proposal
Biomarkers Pharmacokinetics / dynamics Efficacy, safety studies
Clinical and quality of life
Absorption, distribution, studies in patients Phase 4
metabolism and Phase 2A
Translational medicine PoC PoD Post-marketing
elimination Companion diagnostics studies and
Regulatory Data management Paediatric Investigational surveillance
Clinical pharmacology and biostatistics Plan
Regulatory strategy Quality assurance Further registrations
Commercial - GCP Phase 2B Promotional claims in new markets
Phase 0-1 Patient safety
First time in humans
Key value
drivers
Also:
Also: Diagnostics
Diagnostics relation
relation to
to studies Marketing Authorisation /
Patents Clinical Trials Applications New Drug Applications
Competition Pharma
Pharma ++ general
general Dia.
Ethics approval Dia. aspects
aspects Draft Summary of
Product Characteristics Launch and Lifecycle
Unmet needs External research /
technology alliances Product optimisation Management
Differentiation Communications with
Acquisitions & strategic alliances customers - Pricing and reimbursement
Market sizing Licensing Key Opinion Leaders, Affiliate branding
Payor research Health Outcomes investigators and markets Market access plan

Targets Leads Phase 1 Phase 2 Phase 3 Phase 4

Years 1 2 3 4 5 6 7
8

Research Translational Medicine Clinical Development Strategic Marketing

TS CCS EIH LIP PND

DISCOVERY MANUFACTURE
AND SUPPLY
SYNTHESIS AND FORMULATION

NON-CLINICAL TESTING
CLINICAL
EVALUATION

MARKETING
AUTHORISATION

SALES
COMMERCIALIZATION

Targets Leads Phase 1 Phase 2 Phase 3 Phase 4

Years 1 2 3 4 5 6 7
 Research Translational Medicine Clinical Development Strategic Marketing
TS CCS EIH LIP PND

DISCOVERY MANUFACTURE
AND SUPPLY
Section 1
SYNTHESIS AND FORMULATION
Research
Research
From
From vision
vision to
to clinical
clinical
NON-CLINICAL TESTING
candidate
candidate molecule
molecule
CLINICAL
EVALUATION

MARKETING
AUTHORISATION

SALES
COMMERCIALIZATION

Targets Leads Phase 1 Phase 2 Phase 3 Phase 4

Years 1 2 3 4 5 6 7

Research Translational Medicine Clinical Development Strategic Marketing

TS CCS EIH LIP PND

DISCOVERY MANUFACTURE
AND SUPPLY
SYNTHESIS AND FORMULATION Section 2
Translational
Translational
Medicine
Medicine
NON-CLINICAL TESTING
Identifying
CLINICAL a
Identifying a viable
viable
EVALUATION
medicine
medicine
MARKETING
AUTHORISATION

SALES
COMMERCIALIZATION

Targets Leads Phase 1 Phase 2 Phase 3 Phase 4

Years 1 2 3 4 5 6 7
 Research Translational Medicine Clinical Development Strategic Marketing
TS CCS EIH LIP PND

DISCOVERY MANUFACTURE
AND SUPPLY

Section 3AND FORMULATION

SYNTHESIS

Clinical
Clinical
Development
Development
NON-CLINICAL TESTING

Developing
Developing aa product
product of
of
CLINICAL
EVALUATION
value
value MARKETING
AUTHORISATION

SALES
COMMERCIALIZATION

Targets Leads Phase 1 Phase 2 Phase 3 Phase 4

Years 1 2 3 4 5 6 7

Research Translational Medicine Clinical Development Strategic Marketing

TS CCS EIH LIP PND

DISCOVERY MANUFACTURE
AND SUPPLY
SYNTHESIS AND FORMULATION
Section 4
Strategic
Strategic Marketing
Marketing
NON-CLINICAL TESTING
Maximising
Maximising profit
profit for
for the
CLINICAL the
life
life of
of the
the product
product
EVALUATION

MARKETING
AUTHORISATION

SALES
COMMERCIALIZATION

Targets Leads Phase 1 Phase 2 Phase 3 Phase 4

Years 1 2 3 4 5 6 7
Section 1: Research
■ Key goal: Foundation of a project to meet the
Vision for a new treatment
■ Key Outcome: Clinical Candidate Molecule(s)
■ Key elements of this section:
– Pressures on the industry
– Product vision, targets to leads
– Partnering to build our portfolio
– Patenting and licensing patents
– Optimizing leads – selecting a clinical candidate

14

Section 1: Research
Sub Section: Pressures on the industry
Healthcare environment and industry pressures –
external and internal

15
Exercise: Pressures on the Industry

16

The business environment is

increasingly difficult
ge
ma
Re

lic i

y
vit
la t

ct i
pub
Di rou

u
ed

od
ag p

Pri pr
G

c
ad
no s >

ep
Clin
ical res R&
D ost
sis

c
<B

tri al t su
re o w R &D
ran > L g
spa < sin
ren
c nc rea
y>
Is the <I
Safety
r equire Pharma
m
ents > scrutiny
Business < Marketing
still an
ti o n > attractive
substitu < Develop
Generic place to ing world
access
e t s > be in the <
bu d g I n crea
care > future? < I sing
d h ealth ns n d
licen
sing
it e t i o < u
Lim ti a M s t ry c cost
im
>

s l a rg o nso
rs

s
ce in lida
ila

Ac sq tion
im

ue
os

ez
Bi

17
e
The demand will never be satisfied
The Need For Pharmaceuticals Keeps Growing

More Patients Unmet Needs

Aging > < Non-Responders

Higher drug
consumption
Lifestyle > < Insufficient/Limited Response

New products
Environment > required < Evolving guidelines/
Treatment Targets

18

Demographics
More elderly, more medical needs, more spending
median age
millions % of annual income
- years
2,000 50 spent for healthcare
2.2
37.8 40
1,500

30
1,000
26.8 > 60
< 25
20
15
500
> 60 10
> 80

2000 2050
> 60
Median age

By 2050, 50 % of W Europe population will be > 60 19

 Incidence of cancer has doubled
over past 50 years
• Expected to grow further
Brain (2000-2020):
Mult Myeloma – > 25 % in Western World
Ovarian Incidence 2000 – > 60 % in ROW
Liver Incidence 2020
Leukemia • Main epidemiological factors:
Gastric – aging, lifestyle, diet
RCC • Slower rate of death vs.
NHL incidence:
Lung
– improvement in early detection
Bladder
Prostate – better treatments
ColoRectal
Breast
0 50 100150200250300350400
Thousands
Incidence chart for 5 major EU countries
20
Source : GLOBOCAN 2002 and Roche market research 2004

Obesity – The Epidemic Continues

Adult Prevalence Rates of Obesity (BMI ≥30)
in Countries Participating in the WHO-MONICA Study

21
Our industry has not responded well

53 New Molecular Entities (NMEs) $ 50 Bn

$ 17 Bn 24

1996 2008
R&D Spend
22

Key trend – segmentation of the industry

Transform
healthcare

Manage Cost
Innovative
Products
Technologies

Generics, OTC
Pharma Dia

Lower Risk High Risk

Lower Margins High Margins
23
The Roche response to win
■Maximise the value of our products (lifecycle
management)
■Leverage leadership in oncology
- Shape products and portfolio
- Shape the market
- Shape our organisation
■Build a position in key therapeutic areas of
the future
■Build differentiated products through an
Integrated Development &
Commercialization Plan (IDCP)
■Continuously adapt the Organisational
Structure to capture leadership opportunities 24

The vision driving all our changes

Driving personalised
healthcare

Leader in Leader in
Pharma Diagnostics

Early Patient
detection Diagnosis stratification Treatment Monitoring

25
Strategic challenges to developing
new products
■ Assessing whether new ideas are
‘developable’ as soon as possible
■ Cost ~ $1.7bn per product launched
– ‘1 in 4000’ reaches market, only 1 in 6
medicines re-coup cost of capital
■ Efficiency of product development
process - maximising patented period in
the market
■ Introduction of a clear customer focus at
all stages 26

Further information
(These will not be presented)

Many of these factors hit all industries –

not just Pharma

27
 External pressures – science

■ Inflation in cost of R&D

– Consistently outstrips the general economy
– Attrition
■ Reduced patent life and product lifecycle
■ Biotechnology
■ Human genome and Single Nucleotide
Polymorphisms (“SNPs”
– From blockbuster to personalised medicine and
smaller markets?
■ Regulatory harmonisation (ICH)
■ Harnessing the ‘e’ environment
28

External pressures – economics

■ Maintaining shareholder value
■ Increasing cost as % gross domestic product
■ Changing priorities
– Ageing population, Life style medicines
– Third world diseases, Drug resistance
■ Increased awareness and expectation
– Regulatory (patient groups) and Social
(activists) pressure
■ Value for money and the ‘4th hurdle’
– Evidence-based medicine
– Generics … and counterfeits
– Changing customer profiles 29
 Industry response – corporate
■ Mergers and acquisitions
■ Joint ventures and partnerships
■ In-licensing and out-licensing
■ Managing the value chain
■ Stripping out cost: manufacturing efficiency
– ‘Twice as much in half the time’
■ Concentrate on core skills
– ‘We do this …
■ Outsource non-core processes and functions
– … but we don’t do that’
30

Industry response – marketing

■ Measuring health outcomes and
pharmacoeconomics
■ Influencing managed care and disease
management concepts
■ New ways to sell medicines
■ Direct to Consumer (DTC)
■ Rapid access to key markets
– Sufficient size to make an impact
– Seeking increased market share
31
Section 1: Research
Sub Section: Product vision, Targets
and Leads

32

Summary of early Discovery

Disease Area
Understanding more and Reviews
more about diseases and
disease targets –
biomarkers and diagnostics
Continual review of
future healthcare needs
and market conditions

New Medicines
Proposal Leads – molecules that
may be potential
treatments
Research Project
33
 Key terms – diseases and targets
■ A disease is an incorrectly functioning
part or system of the body resulting from
the effect of genetic errors, infection,
poisons, nutritional deficiency, toxicity, or
unfavourable environmental factors
■ A target is a component within a given
biochemical pathway, such as a receptor
on a cell, an ion channel, an enzyme or a
transport system, that may be
responsible for causing a disease state.
34

Genetics - why in a pharmaceutical

company?
Healthcare Facts - We are different
■ We contract different diseases
■ We respond differently to medicines
Part of the answer lies in our genes
■ Diseases run in families
■ Disease-associated genes already
identified eg breast cancer -
Herceptin
■ Genes associated with medical
outcome identified eg cytochrome
P450
35
Disease to candidate medicine
– Why genetics research?
■ Genetics - addresses genetic
variations that predispose
certain people to certain
diseases
■ Genomics – identify role of
genes in diseases
■ Proteomics – study the
interaction between genes in
disorders such as cancers
■ Metabolomics – the
interaction between proteins
36

Potential targets in the body? (1)

The most fundamental – DNA transcription

Messenger RNA (mRNA) is

produced from DNA – a ‘template’
for subsequent protein production

37
Potential targets in the body? (2)
The next stage - DNA translation

Detail

38

Potential targets in the body? (3)

Completing assembly of Peptides - Termination

Peptides then ‘fold’ into

Proteins of varying
shape and composition
- which go to make
complex cell structures
39
Potential targets in the body? (4)
Proteins perform specific functions…..

40

Another type of Target – the Flu

virus

41
 The New Medicines Proposal
■ Is a new therapy feasible? N MP
– Why the Target should be
selected
– What is the potential mechanism
of drug action?
■ Is it commercially attractive?
– What is the future predicted value?
– What is the competitive environment?
■ Must be agreed and managed as it
evolves to maximise value and minimise
risk 42

The Project evolves

The Research Team starts to generate the
‘profile’ of the potential product

Generic Target Product TPP

Profile (TPP)

Outline, Asset-level TPP

We establish base criteria for a successful

medicine. More about the TPP later.
43
Validating the Target
■ Mass production of target proteins –
allowing us to screen for Leads
■ Developing assays to measure leads’
impact on the Target
■ Screening
– Compound
store
– 10,000’s of
compounds

Target
Identified
44

Small molecules …
■ Generally, agonists
or antagonists which
compete with natural
substrates for the
target
■ Detailed structure analysis and molecular
modelling – computational chemistry
■ Many iterations of modifying structures to
assess changed activity against target
■ Animal Proof of Mechanism studies
45
Beginning Lead Optimization
10,000s Lead Series
Identified 100s

Potency
Selectivity
Physiochemical Properties
Kinetics
Tissue penetration
In-vivo safety (e.g. mutagenicity)
Patentability

46

Compound selection and ‘NMP’

exercises

47
 Biologics

■ Very much larger molecules such as

therapeutic proteins and antibodies.
■ Paradoxically ‘easier’ to identify and develop
■ Generally interact with the target itself

– Target specificity,
humanized, BUT
expensive to manufacture
and must be delivered by
injection
48

Section 1: Research
Sub Section: Partnering
- To build our portfolio

Our Lead Molecules could come from

outside of Roche

49
Roche Pharma Partnering
What we are looking for
From opportunity to partnership

Want Find Get Manage

Strategic fit
Is this within our areas of expertise in R&D and commercialisation?
Does this complement our portfolio?

Scientific value
Will this result in an important, new medicine?

Business case
Will this bring value to both companies?
50

Cultural fit
Searching for people

Important for synergy in long-term relationships

• Clear vision • Solid management

• Strong motivation • Capacity for long-term
• Ambitious outlook growth
• Flexibility • Creative ideas
• Scientific rigor

51
Creative deal structures
Tailored to each partner
Expanded
Acquisition License Option Portfolio
Portfolio

Genentech
Memory
Boehringer Mannheim Synosia
ArQule
Syntex BioCryst Antisoma Chugai
Amira
Borean Maxygen
Evotec
Glycart

Roche Partner Products & technologies

52

Beyond the deal

Dedicated alliance management

Want Find Get Manage

One Global Alliance Director for each

partner
■ Interface between Roche and partner
■ Assigned early (before deal making)
■ Integrated into every level of decision making
■ Ensures partner is involved at every stage
53
 Further information
(These will not be presented)

54

Strategic and cultural fit

Case study: Plexxikon
Differentiated medicine
■First-in-class oral medicine
Strategic fit
■Oncology
■Validated discovery platform for novel
drugs; potential to expand collaboration
“With Roche we ■Potential for personalised medicine with
have a seat at parallel diagnostics collaboration
the development
table - that is Cultural fit
very important to ■Experienced management team
us.”
■Excellent collaboration during due
Kathy Glaub diligence
President, Plexxikon
■Open discussion of development
strategy
55
 Strategic and cultural fit
Case study: Transgene
Differentiated medicine
■Innovative therapeutic vaccine
Strategic fit
■Virology / oncology
■Late stage asset (phase 2 completed)
“A considerable
transforming event for
■Potential personalised medicine approach –
Transgene that we complementary with Roche Diagnostics’
anticipate will enable HPV detection assays
us to accelerate and Cultural fit
broaden the
development of our ■Pragmatic and balanced approach to
entire product partnering
portfolio.”
■Strong expertise in gene vaccines and
Philippe Archinard, Chief immunotherapies
Executive Officer,
Transgene ■Highly motivated team 56

Creative deal structures

Case study: Synosia
Innovative asset management
■Roche offers clinical phase CNS
compounds, deprioritised from
pipeline
■Synosia builds on safety data to fast
track search for new indications in
CNS
■Venture capitalists invest in promising
new development model

“Unlike the traditional licensing model, this deal shows how

venture capitalists and pharma can build partnerships with
biotech.”
Brad Bolzon, Managing Director, VersantVentures
57
Section 1: Research
Sub Section: Patenting and licensing
patents

58

Patentability
We can patent Molecules and Lead Series of
molecules if they are:
■ Novel
– Granted to first to invent (US) or first to file
(elsewhere)
■ Non-obvious
– An ‘inventive step’ by a skilled practitioner was
required
Patents are bought, sold and traded –
they are the basis of company market
value, and licensing agreements
between companies 59
What is a patent?
■ A contract between an inventor and the
state – conferring ‘monopoly’ for 20
years
■ No ‘world patent’, but multi-state (PCT)
applications can be made
■ Allows inventors to prevent others from
making, using and selling the invention.
■ In return the inventor must supply full
details of the invention - these are
published
60

Applying for Patents - illustration

Cost Example: Cost builds to
€40,000 for PCT
application to 8 EU states
Substantive
Foreign examination
Minimum Filings
details
Report, Appeals
published
Comments,
Preliminary Objections Grant
examination
Full
Application Search Publication
(‘Filing’)

1 11 6 18
Time (months)
61
Key patenting challenges

■ Secrecy
– Publication will invalidate patentablity
– We patent as soon as we establish
significant activity with Target
■ Challenges and Lawsuits
– Obviousness issues and similar work by
others will generate counter-challenges –
patent court actions are incredibly
expensive
62

Key patenting challenges (2)

■ Legal validity
– In theory – living organisms cannot be patented
– Inventions designed to harm are difficult to
patent
– Gene patenting is surrounded by controversy
■ Limited extensions to patent life
– Available for the Pharma industry – more
tomorrow

63
Gene patenting and screening
technology patent exercises

64

Further information
(These will not be presented)

65
Types of Intellectual Property

■ Automatic protection
– Copyright exists by default when an author (in
this case Roche) – has written a piece of text –
will apply to Patient Information Leaflets, etc.
■ Registering what something looks like
– Registered Designs (the shape and aesthetic
appeal of something – for instance a drug device
of a tablet shape)
– Trademarks (will be covered more tomorrow)
■ Registering how something works
– Patents (dealt with in this section)
66

Patent links

European Patent Office:

http://www.epo.org/patents.html

Swiss Federal Institute of Intellectual Property

http://www.ige.ch/e/patent/p1.shtm

Spanish Patent and Trademark Office

http://www.oepm.es/

67
Section 1: Research
Sub Section: Optimising
leads - selecting a
clinical candidate

68

Presentation to the Early Strategic

Portfolio Committee (ESPC)
■ Detailed biological rationale for 1-3
compounds
■ Viable budgeted route to next stage
PP
■ TPP with a basis for differentiation T

Clinical Lead
Selection
Request early supplies of drug materials and
increase in resources for early Tox. studies
Transfer to the early DB Project Team 69
Moving to Candidate Selection
■ What type of development is
this?
– Experimental?
ojec t Scope
– Clinical focus? Pr
– Technical focus?
– Fast focus? x plor atory
E
l
■ Roadmap to the Exploratory Clinica
Development goals - activities lo pm ent
needed to reach: Dev e
– Proof of Developability Plan
– Proof of Concept
70

The TPP is refined

Attributes are specified as

quantitatively as possible

71
Major presentation to the ESPC
■ Plans and TPP, together with Risk
assessment and the Integrated Project Plan
/ Budget
■ Request to form a full, cross-functional
Project Team

Clinical Candidate
Selection

■ Full investment into Entry Into Human

enabling activities
72

Section 2: Translational Medicine

■ Key goal: Identifying a Viable Medicine
■ Key Outcome: Passing the criteria for Lifecycle
Investment
■ Key elements of this section:
– Introduction – Criteria for Entry into Humans (EIH)
and LifeCycle Investment
– Developing Active Pharmaceutical Ingredient (API)
and Galenical
– Non Clinical Safety Assessment
– Early Business assessment – identifying market
value drivers
– Clinical Pharmacology and Proof of Concept
73
 Section 2: Translational Medicine
Sub Section: Introduction – criteria for
Entry into Humans (EIH) and
LifeCycle Investment

74

Decision making in Research and

Translational Medicine
Research Translational PoC Clinical Strategic Marketing
Medicine Development

Pharma Portfolio Executive Committee (PPEC)

gRED

DBA Oncology ESPC

Early
EarlyStage
StagePortfolio
Portfolio
DBA Inflammation ESPC
Committee
Committee(ESPC)
(ESPC)inin
each
eachDisease
DiseaseBiology
Biology
DBA Virology ESPC
Area
Area
DBA Metabolic ESPC

DBA CNS ESPC

75
Disease Biology Project Ops Team
Safety
Science
Discovery Leader Tox/DMPK
Leader Leader

CRED
Global Project Translational
Technical Medicine
Leader Leader
Leader
Project
Manager
Regulatory
Coordinator Clinical
Pharmacologist
CRED
Operations

Guiding activities toward Entry into Human,

and Lifecycle Investment Point
76

DBPT key responsibilities

te d D ev e lo pment Plan
t (LIP) Criteria
Integ ra
e s tm e nt P o in
■ Lifecycle Inv P ro o f o f Developability
c e p t/
(Proof of Con
uct Profile
■ Target Prod P)
roject Plan (IP
■ Integrated P ent
Risk Assessm
■ Budget and in ary business
riv e rs & p re lim
■ Key value d
case n
ry C li n ic a l D e velopment Pla
■ Explorato
(ECDP) s
th e r fun c ti o n -endorsed plan
■O 77
Section 2: Translational Medicine
Sub Section: Developing the active
pharmaceutical ingredient (API) and
galenical
Making a medicine from a molecule

78

API, Galenical - Manufacturing and

Quality
Chemical API
Development Manufacturing
Route and Process
BioPharm
Development
Formulation and Devices
Pharmaceutical Galenical
Development Manufacturing

Analytical Validated Assays Quality

Development Assurance

79
 6-step
6-step ROUTE,
ROUTE, using
using an
an optimized
optimized set
set of
of
PROCESSES
PROCESSES

80

Developing the process to make API:

small molecules
■ Determining salt form
■ Making progressively larger amounts of
the candidate drug substance – scale up
via the Pilot Plant - mg via Kilolab to
tonne
■ Finding quicker, simpler,
cheaper synthetic routes
■ Assessing hazardous
processes and emissions
■ Estimating cost of goods
■ Good Manufacturing Practice 81
 Drugs are seldom pure!
■ Organic impurities
– Arise during manufacture or storage
■ Inorganic impurities
– Result from the manufacturing process
■ Residual solvents
– Used as vehicles in the preparation of new drug
substances
■ Not considered impurities
– Extraneous contaminants resulting from GMP
issues
– Polymorphic forms
– Enantiomeric impurities
82

Developing the biopharmaceutical

process for large molecules
Genetic engineering of living cells –bacteria,
mammalian or insect cells, to produce large
quantities of specific complex molecules such
as terpenes, DNA, monoclonal antibodies or
other proteins
A further requirement
is to ‘humanize’ the
product to reduce
any adverse immune
reaction
83
 At the outset –
Proof of Developability
Developability is determining if a
candidate molecule can be turned into
a useful, commercially viable medicinal
product.

Developability encompasses very

practical issues that are important with
respect to cost-effective production and
delivery to the market of a safe and
effective medicine.
84

Case study – Tamiflu – moving from

chemistry to biotechnology

85
Manufacturing issues
■ The manufacture of Tamiflu is complex and
involves 10 main steps, some complicated
and hazardous(e.g. azide chemistry)

Takes approximately 6-8 months

once all the raw materials have been
sourced.
Roche’s assumption is that another
company starting now would take 2 to
3 years to produce Tamiflu. shikimic acid

86

Sourced from a natural product …

■ Starting material, shikimic

acid, is extracted from the
pods of the star anise.
■ Roche uses a specific
anise grown in south west
of China which provides a
higher purity and yield
than others grown
elsewhere.
■ 30 kg of anise yields 1 kg
of shikimic acid. 87
New way to make shikimic acid

■ Today, more is being made by fermentation.

■ Roche uses a special e-coli bacteria which,
when overfed glucose, produces shikimic
acid.
■ The bacteria need to be multiplied and
grown, and are transferred from small to
larger and larger fermenters.

88

Making the Product: Formulation

Secondary Manufacture
Processes to produce usable
medicines and packaging

89
 Evolving formulations
Making early Making formulations for
formulations toxicological evaluation

Making Clinical Trial Reliable to manufacture and

Formulation have an appropriate shelf life

Complex designs may increase

First launch sales, but may delay launch.
formulation Selecting and/or developing
devices

Line extensions - Can help extend the product

new opportunities life cycle
90

The challenge of pharmaceutical

formulation

■ Must deliver drug

acceptably -
maximise effect and
minimise toxicity

91
Developability and choice of
formulations exercises

92

Routes of administration
Intraarterial
injection

Rectal

93
Pharmaceutical formulation
Target organs can be systemic:
brain heart
tumours pancreas
kidney liver
peripheral circulation

Delivering the drug systemically:

oral
buccal
intestinal Injection
colonic
94

Pharmaceutical formulation

■ Target organs can be local:

eyes/nose drops, sprays
skin creams, ointments
lung inhalers
vagina creams, pessaries
rectum creams, suppositories

95
Pharmaceutical formulation

Local administration
can also be used to
gain systemic
exposure

intranasal
buccal
inhalation

rectal

96

Tablet products
■ Commercially attractive
– Carry logo, patient preference
– Many R&D ideas envisage oral
tablet
■ Aid safe effective use
■ Enable precise delivery of
product
■ Practically sized,
Transportable
■ Tamper evident (esp. OTC)
97
Sterile products

Ampoules

Pre-filled Syringes

Vials

Freeze Dried
Ophthalmics
98

Why make sterile products?

■ Bacteria Sensitive tissues

– e.g. - The eye - bacteria collect
and are difficult to clear
■ IV Routes
– Quickness of onset, speed of
response
■ Metabolism
– alteration of medicines by the gut
– low bioavailability compounds

99
Section 2: Translational Medicine
Sub Section: Non Clinical Safety
Assessment
Enabling human testing with confidence

100

Would you take this drug?

(assume it provides valuable therapeutic
effects for a distressing but not life-
threatening disease)

■ Causes mood alteration (generally

pleasant, but can induce irritability)
■ Is addictive
■ May cause sleep disturbance
■ Is a diuretic
■ Causes reversible genetic damage
■ Can induce paroxysmal atrial tachycardia
101
Why do we need non-clinical safety
assessment?

■ Drug Safety
– To ensure compound is safe enough for
volunteers, patients
■ Environmental safety
– Assess potential effects of large quantities on
manufacturing staff and general environment
■ To provide valid evidence at all stages to
regulatory authorities

102

Studies conducted
Research program
Safety
Pharmacology
Range finding Short term General Toxicology Long term

Genetic Toxicology
Reproductive Toxicology
Carcinogenicity
Absorption, Distribution, Increasing knowledge
Metabolism and Elimination about drug safety
(‘ADME’)

Clinical program

103
 Which species to use?

rat
Common

mouse rabbit
dog

Research Exploratory Confirmatory

non-human
primate cat
Rare

mini-pigs
guinea pig

104

Designing studies - for how long?

Depends
primarily on the
clinical plan.
More expensive
longer term
studies such as
carcinogenicity
will be delayed
until later in
development

Source: ICH M3
November 2000
105
Non-clinical safety - exercises

106

What safety margin is expected

today?

Therapeutic Index - Toxic Dose divided by

Clinical dose
■ 20 or more - a modern prescription
medicine?
■ 5 to 20 - an in-patient drug for life-
threatening disease - side effects accepted?
■ 3 to 4 - is there any medicine that is
acceptable at this level?

107
 Definitive GLP studies

■ Rodent and non rodent

■ Dosing usually by intended route and for
appropriate duration
– Usually oral or intravenous but can be others
– Low, medium and high doses with placebo control
– High dose should demonstrate limiting toxicity
– Recovery period

108

Standard toxicology study design

109
 Interpretation of results
■ Determine “Maximum Tolerated Dose” (MTD)
and “No Observed Adverse Effect Level”
(NOAEL)
– In all species tested
– May be different from “no effect level”
■ Convert to “human equivalent dose” on basis
of body surface area
■ Select most appropriate animal species
■ Apply safety factor
■ Result = Maximum recommended starting
dose for human studies 110

Studies in parallel with clinical

trials
■ Extended duration of repeat dose
– 3 months to “lifelong” duration
■ Reproduction toxicity studies
– Inclusion of women of childbearing potential
■ Carcinogenicity studies
– Depending on duration of drug treatment

111
 Drug metabolism
■ Adsorption (Bioavailability)
– How much got in? Define relationship between
systemic exposure and dose
■ Distribution (Pharmacokinetics)
– Where did it go and how long did it stay there?
■ Metabolism
– What happened to it? Determine if drug and
metabolites are eliminated or retained with
potential to accumulate.
■ Elimination
– Did it get out and if so, how? Identify the
routes.
112

Spectrum of consequences
of drug metabolism
■ Inactive products
■ Active metabolites
■ Similar to parent drug
■ More active than parent
■ New action
■ Toxic metabolites

Comparative metabolism

113
 Use of radiolabels
■ Whole body autoradiograph to visualise
distribution – in this case liver selectivity by
Pradefovir for treatment of Hepatitis C

114

What are the alternatives?

Human
Relevance

Intact Animals
Specifity

Perfused Organs
Isolated Cells
Subcellular Fractions
Purified Enzymes
The choice of alternative is a balance between relevance to
humans and specificity
115
 Animal studies - measured confidence
Interpreting data from animal studies and
predicting effects in humans remains the key

Negatives Positives
■ Small sample sizes ■ Vast knowledge base
■ Homogenous groups gives ~75-80%
vs. highly variable predictive confidence
human patient groups
■ Careful design
■ Specificity problems enables small
with Biotech
inexpensive early
compounds
studies
116

Reaching a drug safety decision

Expert opinion on
general toxic effects Start
Pathological examination Phase 1
from toxicity studies
(DP1)
Expert opinion on
(EIH)
metabolism profile
Continue to build Non Clinical package for
regulatory submission
One fundamental question: is it safe enough for humans?

117
Section 2: Translational Medicine
Sub Section: Early Business
assessment – identifying market value
drivers

118

Early commercial analysis

Review of:
■ unmet needs
■ market size and dynamics
■ differentiation
■ competition
■ pricing and reimbursement attributes
■ disease conjoint analysis

Key component of Proof of Developability

119
Market size and value
■ Total incidence/prevalence of
disease
■ People seeking medical advice
■ People receiving accurate diagnosis
■ People receiving drug prescription
■ People receiving your product

People receiving drug prescription x cost of

Market size prescription/day x number of days per year
Proportion of market value taken from
Market value competitors by the product

120

Key commercial deliverables at this

stage

Key components of the EBP: Early

ss
■ Conjoint analysis of asset Busine
ge
attributes/performance packa
parameter ranking
■ Top-down forecast /business case based
on agreed value drivers of the TPP and
conjoint analysis.

121
Payor research
ia l P a yor
Init
Value
es sm ent
A ss

■ Perceived level of unmet medical need

■ Minimum requirements for premium price v.
current gold standard
■ Potential barriers to reimbursement
■ Primary endpoints for the clinical programme
122

Section 2: Translational Medicine

Sub Section: Clinical pharmacology and
translational medicine

123
Would you join this volunteer study?
■ You will receive a thorough medical exam
■ You will be accommodated in a comfortable
unit for 5 days but you will not be allowed out
■ Great food, but no alcohol
■ Limited tea/coffee
■ You will able to watch satellite TV, use a
laptop and access the internet
– You will receive single, very small doses of new drug, or an
inactive placebo
– Mild side effects can be anticipated
– You will have an venous catheter in the back of your hand for
taking blood samples
– You will collect all urine and faecal samples during your stay.

124

'Bench to Bedside'

Despite unprecedented numbers of discovery

molecules:
■ Numbers surviving early clinical are falling
■ Safety requirements for traditional early studies
are higher
■ ‘Bench to Bedside’ time gap becoming ever longer
125
Problems with the traditional model:

Focuses on:
„ Simple, single-point causes of disease
„ Aspiration for super 'one size fits all' drugs

This model just does not work anymore!

126

'Trial and error' treatment

Switch Drug Again

Disease Severity

Switch Drug

Select Drug

Diagnosis

Time

127
The aim of translational medicine
• Forward translation
• Use bioinformatics, genomics in clinical
practice
• Develop biomarkers and molecular
imaging techniques for later stages Clinic
(including human studies) early in
process

• Reverse translation
• Bring measurements from the clinic into
early stages of research
Research • Faster measurement in humans by
micro-dosing testing
• Validating the biochemistry in target and
biomarker discovery
128

A 'network' of disease causation

Diseases may well

be caused by
changes at
multiple targets

129
 Biomarkers – fundamental to
genuine understanding
■ Substances in the body or aspects of
physiology that can be objectively measured
■ To connect disease processes and
treatments in a way we really understand
■ Can be Pharmacodynamic – measured
during drug therapy
■ Can be Predictive – hopefully, valid
predictors of likelihood of progression and
response to drugs
130

Supervised classification prognosis: breast cancer

van de Vijver, M. Oncologist 2005;10(Suppl 2):30-34

131
Copyright ©2005 AlphaMed Press
 A great vision..
..with massive challenges

132

Trial designs
■ Conventionally, the ‘holy grail’ is the
randomised double-blind placebo controlled
clinical trial
■ Undifferentiated mix of responders may
mean that a drug that for some may show
benefit, fails
% of
patients Biomarker
selected group
Undifferentiated
patients
Poor response Good response
133
Adaptive designs
■ Use accumulating data to decide how to
modify the study without undermining the
validity and integrity of the trial
– Should be adaptive by “design”, not remedy for
poor planning
■ More likely adaptations in Exploratory
Phases
– Allocation
– Add/drop treatment arms
– Sample size
■ Accelerate time to Proof of Concept
– Is the target correct?
134

First microdose clinical studies?

■ Human microdosing
– A fraction of the dose predicted to be of
therapeutic use - correspondingly reduced non-
clinical safety package
■ Ultrasensitive bioanalysis techniques:
– Positron Emission Tomography (PET)
– Accelerator Mass Spectroscopy (AMS)
■ But are PK results at low dose misleading??

135
Clinical Trials: Conventional Phase 1
■ First administration to humans ‘SAD/MAD’
– Single ascending dose in volunteers
– Multiple ascending dose studies
– Patient studies in certain circumstances

■ Key outputs
– Safety, tolerance, side-
effects
– Pharmacokinetics

136

Clinical Trials: Phase 2A

Start Phase 2
(DP2)

Safety evaluation still main aim

■ Side effect profile
■ Dose-response curve
■ Efficacy - possible but unlikely
■ Key information for Proof of Concept
137
Proof of Concept and the decision to
invest in full development

■ “Proof of Concept” means that there is

sufficient scientific, clinical and commercial
evidence that a drug candidate could be a
successful product to justify the expense of
completing its development

■ Clinical evidence can be collected at various

levels, depending how confident you are of
the predictive value
138

Proof of Concept - hierarchy

■ Drug administration to a patient results in a
series of outcomes, each essential for
ultimate success in achieving the Product
Profile Ultimate Outcome: The Product Profile
Efficacy / Safety: key benefits achieved
Surrogate: mechanistic activity leads to predictive effect
Activity: exposure leads to mechanism related effect
Exposure: acceptable PK profile consistent with dosage req’s

If equivalence or superiority to a competitor compound is

part of the Product Profile, that must be considered
relative to level of confidence in various PoC options
139
Proof of Concept and Value Drivers
exercises

140

Example of PoC hierarchy derived

from the Product Profile - Influenza
■ Resolution of symptoms within 24 h (Outcome)
■ No side effects such as nausea and vomiting
(Safety)
■ Effective when used up to 72 h from onset
(Efficacy)
■ Decreases elevated body temperature
(Surrogate)
■ Treatment decreases viral burden (Activity)
■ PK profile is consistent with once daily
treatment (Exposure)
141
 For adequate PoC, how much of
the Product Profile hypothesis do
you need to test?

You choose: depends how

confident you are of what
will happen in the next study 142

Reviewing the full package

■ Clear evidence that the Proof of Concept

(PoC) and Proof of Developability (PoD)
criteria have been met?
■ Can all potential indications be progressed?
■ Is there still strategic fit?
Lifecycle
Investment
Point
143
Background information
(These will not be presented)

144

Historical note - first “Clinical Trials”

■ Clinical Trials have a long history – even if

not acknowledged as Clinical trials
■ Formal record of clinical trials dates back
to the time of the “Trialists”:
– Dr. Lind’s, a ship surgeon, trial of oranges &
limes for scurvy [1747]

145
Core Components of Clinical Trials
■ Involve human subjects
■ Move forward in time
■ Most have a comparison CONTROL group
■ Must have method to measure intervention
■ Focus on unknowns: effect of medication
■ Must be done before medication is part of
standard of care
■ Conducted early in the development of
therapies
146

Core Components of Clinical

Trials
■ Must review existing scientific data &
build on that knowledge
■ Test a certain hypothesis
■ Study protocol must be built on sound &
ethical science
– Declaration of Helsinki
■ Control for any potential biases
■ Most study medications, procedures,
and/or other interventions
147
 Section 3: Clinical Development
■ Key goal: Developing a product of value
■ Key outcome: Regulatory Filing
■ Key elements of this section:
– Introduction – work towards the filing point
– Major Clinical Studies
– Set up of manufacturing
– Planning for commercial success
– Dealing with the Regulators

148

Section 3: Clinical Development

Sub Section: Introduction – work
towards the filing point

149
Decision making in Clinical
Development
Research Translational PoC Clinical Strategic Marketing
Medicine Development

Pharma Portfolio Executive Committee (PPEC)

gRED

DBA Oncology
Late
LateStage
StagePortfolio
Portfolio
DBA Inflammation Committee
Committee
South
SouthSan
SanFrancisco
Francisco
DBA Virology

DBA Metabolic Late

LateStage
StagePortfolio
Portfolio
Committee
Committee
DBA CNS Basel
Basel

150

LifecycleTeam
PreClinical International
Leader Business
International Leader
Economics
Strategy Leader

Global Lifecycle International

Technical Medical
Leader Leader
Leader
Project
Manager
Operations
Global Project
Regulatory Leader
Leader
Safety
Development Science
Subteam Leader
Leader

Guiding activities toward Full Development

Decision and Filing (PND) 151
Key responsibilities of Lifecycle Team
Life Cycle Strategic Plan

■ Farsighted vision
for the brand
■ May cover a franchise
of indications
■ Developed in first 3 months
of LCT with Affiliate input IDCP
See
See over
over
A key
component

152

Aligning all the players

Integrated Development and
Commercialisation Plan
■ Comprehensive plan for each indication
■ Generating common understanding of product
attributes for success
■ Seeking input from all to shape the Phase 3
program Components:
■ TPP, Integrated Project Plan
■ Clinical Development Plan
■ Technical Plan
■ Integrated Business Package
■ Key input from EU/US Affiliates 153
Section 3: Clinical Development
Sub Section: Major Clinical Studies

154

Key aspects of clinical studies

Good Clinical Practice Centre

Investigator

l
Clinica Clinical
pment Centre
Develo Research Investigator
Plan Organisation

Roche PD Regulatory Approval Centre

Investigator
Ethical Approval
Development
Sub-Team
Recruitment - Informed Consent
155
Key issues in major clinical work
What companies prefer What regulators demand
■ Carefully controlled
■ Representative patients
groups
■ Measures of actual disease
■ Quick measures -
surrogate markers ■ Competitor Value
comparisons
■ ‘Double blind / Placebo’
■ Personalized Health Care – Companion
Diagnostics
■ Increasing work in new territories – Brazil,
China, India, Mexico, Russia, South
Korea, Turkey (E7)
■ Assuring data integrity - fraud prevention
■ Genetic analysis of samples….. 156

Clinical Studies: Phase 2B

■ Safety evaluation still main aim
■ Side effect profile
■ Efficacy – possibly
■ Dose selection and dosing regimen for
Phase 3

157
Major operation – clinical supplies
■ Launch formulation must be used in Phase 3
■ Roche clinical supplies operations exceed
the whole commercial output of small
pharma companies!
■ Competitor product must be purchased and
disguised
■ Companion Diagnostic

158

Clinical trials exercises

159
Phase 2 complete

■ Phase 2B clinical studies confirm confidence

and readiness for Phase 3

Full
Development
Decision

■ (there are more aspects to FDD – but more

on Phase 3 first …) 160

Clinical Studies: Phase 3A

International multi-centre trials to
demonstrate
■ Efficacy and safety in large numbers of
patients
■ Therapeutic advantage
over competitors
■ Health economic value
■ Confirm therapeutic
profile
–indications, dosage, side
effects, contra-indications
161
Why do we need genetics in our
clinical trials?
■To identify populations of patients that
respond well to our compounds.
■To identify populations of patients that
may be susceptible to adverse
experiences
■To develop a better understanding of the
pathophysiology of disease
■To target therapy more accurately
162

The Ethical and Legal Aspects of

Genetic Research are Evolving
■ Ethical issues
–Risk of disclosure of information
–Identifiers & use of sample
■ Legal issues
–Privacy, ownership of research data
■ Variation between countries
–Legislation, policies vary

163
Background information
(These will not be presented)

164

Clinical trials Terminology

■ Retrospective: Refers to time of data

collection
■ Prospective: Refers to time of data
collection
■ Case Control Study: Persons w/ disease
& those w/out are compared
■ Cohort Study: Persons w/ and/or w/out
disease are followed over time
165
Terminology (Cont.)

■ Cross-sectional Study: Presence or

absence of exposure to possible risk
factor measured at one point in time.
Prevalence obtained.
■ Prevalence: The # of new cases and
existing cases during specified time
period.
■ Incidence: The # of NEW cases per unit
of a population at risk for disease
occurring during stated time period.
166

Types of trial …
■ Randomised:
Schemes used to ■ Blinded: Participants do
assign participant to not know if in
one group experimental or control
■ Nonrandomised: All group
with disease = cases; ■ Double Blinded:
others = controls
Participants AND staff
■ Protocol: Study do not know group
design – instructions
assignment
■ Adaptive
randomisation: ■ Placebo: Inactive pill
progress determined with no therapeutic
by emerging data value
167
Section 3: Clinical Development
Sub Section: Set up of manufacturing

168

Key issues in Manufacturing

■ Strategy – ensuring that supply matches
likely demand
■ Controlling physical properties
■ Engineering and new technology
■ Manufacturing processes - key challenges

169
Technical strategy
An educated gamble:
■ Do capacity projections meet
cal
market requirements? Techni
Plan
■ Can the Technical aspects of
differentiation be delivered?
■ Is Cost of Goods in line with
Target Product Profile?

Probability of Technical
Success (PTS)
170

Where to Manufacture?
■ New Product Introduction at certain sites –
first 1 to 2 years of manufacture
■ Global API sites – sometimes single
source – government incentives at certain
locations
■ Biotech API – at present often located
near technical centre
■ Regional Galenicals sites – close to major
markets

171
New product introduction - making
‘technical transfer’ work
■ Historically a major failure – now
manufacturing will typically be launched
at a specialist site
Key imperatives:
■ Manufacturing processes thoroughly
understood, controlled and ready
■ Close control of physical properties…….

172

Transfer into manufacturing – keeping

control over physical properties
Excipients

Drug
Equipment
Substance

Drug
Product

Scale Process
Parameters

Drug Delivery
System

ANY change to the materials or process conditions

can impact/change the final Drug Product. 173
Trends in quality requirements

Traditional Desired State Pharmaceutical

CMC Submission Quality Assessment System
Quality by Testing and Inspection Quality by Design – quality assured
by well designed product & process
Data intensive application – Knowledge rich submission –
disjointed information without “big supporting product & process
picture” design
Specifications based on process Specifications based on product
history performance requirements

“Frozen process” discouraging Flexible process within design

changes space allowing continuous
improvement
Focus on reproducibility – often Focus on robustness –
avoiding or ignoring variation understanding and controlling
variation

174

Engineering
■ Technology is constantly updating
■ New sites require construction and bringing
to readiness as fast as possible
■ Aggressive targets are set for gas emissions
and energy consumption

175
Engineering in practice
New biotech production centres in Basel and
Penzberg were both completed in record time

A new galenicals facility

in Shanghai features a
pioneering high
containment facility for
potent products, enabling
operators to wear only
normal protective
clothing

176

Manufacturing processes – video

clips

177
Further information
(These will not be presented)

178

Actives manufacture – small

molecules
■ Large scale chemistry
■ Major safety/
environment issues

■ Large external spend on expensive raw

materials

179
Manufacturing Large Molecules

180

Primer: Upstream processing

■ Vials of genetically engineered cells thawed
for growth in cell culture
■ Transferred to large fermentation vessels
■ Growth medium manipulated to maximise
production of the desired complex molecule

181
Primer: Downstream processing

■ Cells and debris separated from medium in

which the complex molecule has
accumulated
■ Chromatographic steps taken to
remove unwanted proteins, salts
and other components
■ Chemical modifications if
necessary
■ Filled off for clinical use
182

Inert
Materials Tabletting
Blending
process
Weighing & Dispensing

Active
Materials

Lubricant
Materials Blending
Compression

Granulation
Wet
Materials
Granulation

Film TABLET
Coating
Materials

COATED TABLET
Typical Batch Sizes Low Millions
183
Tablet Products
■ Despite some complex formulations –
technology is well understood
Controlled release

Film coatings, capsules

Shaped, coloured

184

Process of Steriles production

Supplied Actives Processing Formulations

Clean Sterile Sterile Solutions &

Liquids Filtration Filling Ointments

Mix

Powders Dissolution Freeze

Drying Freeze Dried

Sterile
Sterile powders Filling Powders

185
Sterile Products
Key challenge – sterility
■ Microscopic quantities of
contaminant particles
particularly dangerous if
injected
■ Highest regulatory standards
Key requirements –
■ Protect the product from the workers …
and the workers from the product!
■ The Cold Chain and Secure Supply
186

Liquids & Creams production

Manufacture Filling&Packing

Inert BULK
Materials LIQUID/CREAM
Mixing
Dispensing

Active
Bottle &
Materials Label/Tube

Water Carton
Batching
Circular
Bulk Volumes:
Misc.
Liquids - 2000 - 8000L Components
Creams - 500 - 2400kg
PACKAGED
BOTTLE/TUBE

187
Inhaled Products

■ Inhaled products use very low amounts of

active – accurate filling / powder mix is a
huge challenge – very small particle size
(less than 5 microns) to reach alveoli
■ Highly complex assembly

188

Case study continued - Tamiflu

189
Manufacturing strategy

■ More than a dozen manufacturing facilities

worldwide network for Tamiflu production,
more than half of which are with third party
manufacturers.

■ The different raw materials and excipients

needed for the manufacture of Tamiflu are
provided by about 50 external suppliers
today.
190

Increased production capacity

■ Roche has increased its production capacity
and is in a position to produce up to 400
million treatments of Tamiflu annually,
significantly exceeding all government
orders received to date.

191
Case study 2 - Herceptin

192

Manufacture of Herceptin - i
■ Herceptin (trastuzumab), a monoclonal
antibody (MAb), inhibits the ‘HER2 receptor’
over produced in breast cancer. Inhibition of
HER2 can reduce the spread of the disease
■ Earlier versions were derived in mice
(muMAbs) but these cause immune
responses in humans and are inactivated.
■ Genetic engineering enabled ‘humanisation’
of muMAbs - minimise immune response
■ Humanising muMAbs involves forcing cloned
cells to produce large amounts of mainly
‘human’ molecule retaining the active region.
193
Manufacture of Herceptin - ii
■ Substitute mouse portions of mAB with
human immunoglobulin structures using
recombinant DNA technology – to improve
specificity of immune response
■ Herceptin® is the recombinant human anti-
HER2 MAb derived from muMAb 4D5
■ Humanised MAb retains high-affinity HER2
recognition region of muMAb
■ Recombinant humanised anti-HER2 MAb
formulated into Herceptin® - IgG1 antibody
95% human and 5% murine 194

Section 3: Clinical Development

Sub Section: Planning for commercial
success

195
Product positioning in our industry
■ 70% of new products launched still have
same positioning as existing therapies
■ Much of the industry still relies on loose
positioning - suited to idealistic molecules
and huge promotional budgets
■ Simple and unique is best - e.g. HealthCare
physicians still associate high efficacy with
low safety - don’t position around both

196

Business responsibilities
Integrated Business
Package
ƒ Positioning and USPs
Strategic Value Concept
ƒ Competitor analysis ■ A product value ‘story’
ƒ Patient leverage points aimed at optimum
pricing,
ƒ Pricing, reimbursement
reimbursement,
ƒ Affiliate forecasts
market access
■ Based on TPP and
earlier pricing work

197
Does the Development Plan support
Claims? work
Ke y C l a i ms w
to r y and
Regula eykem a r keting
P
re that s in TP P
ƒ Ensu sement claim rted by
r o
reimbu ant and supp
v
are rele ns
l pla Clinical Deve
clinica lopment Plan
ƒ Ensure trials
support
requirements
of all stakeho
ƒ Draft comm lders
unications fo
professionals r all
ƒ Key safety
messages

198

Positioning in practice
Our Product’s
Attributes Market needs
What unique
(‘differentiated’)
space can our
Competition product occupy?

Starts in Phase 2
■ Enables concepts to be tested
■ Encourages clinical program to be designed
around commercial aims
■ Influences all communications
199
Product positioning and trade name
exercises

200

Positioning is not a trade secret!

■ Product positioning is obvious in ALL
communication to key stakeholders:
– Authorities responsible for assessing pricing and
reimbursement
– Key opinion leaders
– Editors of clinical journals
– Patient groups
■ Affiliates must be partners throughout

201
Mobilizing Global players to support
commercial aims
■ Develop agreed balance of regional
requirements within available budgets
■ Ensures Affiliate input into IDCP
■ NPP teams led by Affiliate Brand
Director
New
t
Produc
Plan
202

Section 3: Clinical Development

Sub Section: Dealing with the
Regulators

203
Drug disasters

■ 1937 "elixir of sulfanilamide”

■ 1962 thalidomide

■ 2004 … Vioxx
– “Merck to pay $4.8bn over arthritis drug cases”
Newspaper headline 10 November 2007
– $1.2bn paid out on litigation to date

204

Lessons from history

Tragedy

Public Response

Political
Intervention

New Regulatory
Authority
205
 Regulatory Review: Why do
governments regulate medicines?

■ For protection of the public from unsafe

medicines
■ Assessment of quality and efficacy
■ Promotion of better healthcare
■ The fourth hurdle – assessment of
Value
206

Regulatory Authorities (RAs) - How

they Regulate

■ Regulation of clinical research (Clinical Trial

Application CTA)
■ Review of risk:benefit for marketing
authorisation applications (MAA)
■ Compliance (GLP, GCP and GMP)
■ Post Licensing Commitments (Variations,
Renewals)

207
The International Regulatory Environment
‘Top down’ – agencies in Europe review
summary reports: look at raw data only if
necessary. Move to single pan-EU authorisation.
‘Bottom Up’ – they take all raw data and re-
analyse it. Process is public and open; fairly
collaborative.
Has been very secretive, closed and
bureaucratic process, now moving towards more
transparency and openness
Smaller countries’ agencies will grant with an
abbreviated submission, if already approved in
major markets – the CPP

ICH – International Conference on Harmonisation 208

Marketing Authorisation
■ Results in a licence to market a
pharmaceutical product in a particular
country or group of countries
– The NDA, the MAA
■ Defines the quality, permitted uses and
restrictions of use
■ Restricts the promotional claims which can
be made
■ Defines the packaging and labelling of the
product
209
Common Technical
Dossier (CTD)

NO
Tp
Format

art
of
Module 1

the
Regional

CT
Administrative

D
Information
1.0

CTD Table of Contents

2.1
2
le
du

CTD Introduction
Mo

2.2

Th
Nonclinical Clinical

eC
Quality Overview Overview

TD
Overall 2.4 2.5
Summary Nonclinical Clinical
2.3 Summary Summary
2.6 2.7

Module 3 Module 4 Module 5

Nonclinical Clinical
Quality Study Reports Study Reports
3.0 4.0 5.0 210

Challenges/Issues
■ Expansion of EU
■ Harmonisation of CT legislation in Europe
■ Implementation of CTD
■ Paediatric Investigational Plans
– Mandatory for new filings after 2009
■ More competitive marketplace
– Generics
– Pricing
– Parallel imports
– Counterfeiting
■ The move to proactive safety monitoring
■ Information exchange between RAs 211
Filing Process: How can we minimize
review time?

■ Recognize that RAs are risk-averse

■ Best quality dossier
■ Priority Review (6 month vs. 10 month)
where possible
– Post Approval Commitments
■ Minimize questions and issues during review
and ensuring rapid responses to questions
■ Managing the review process with the team
and the RAs
212

Post-Approval Commitments -
examples
Nearly all recent products!
■Tamiflu
– 2 x studies to look at immunocompromised
patients
■Pegasys
– Studies to further look at different populations,
different doses etc
■Mabthera
– Approx 40 clinical, safety and technical PACs
since approval 7 years ago
213
Post Licensing Activities
■ Variations
A change in the information provided to RAs, to:
– Maintain the product on the market
• site changes, safety issues
– Enhance the revenue from the product e.g.
• manufacturing changes to make it more efficiently,
cheaper
• add new indications, populations, formulations
■ Renewals
– valid for 5 years
– administrative exercise

214

Pharmacovigilance – an extremely
important activity. Why?
■ At the time of marketing approval, clinical
trial data are available on limited numbers of
patients for relatively short periods
■ At-risk patients and use of selected
concomitant meds are often not studied
■ Detection of rare adverse events (AEs) is
difficult if not impossible

A problem: under-reporting
215
EU requirement for Risk
Management Plan
■Pharmacovigilance plan
– Activities planned to extend knowledge of safety
– Routine PhV: ADR reports, ASR, PSUR
– More than just spontaneous reporting and PSURs
■Risk minimisation plan
– Measures to minimise known risks
– Need to be realistic and achievable in practice
– Need proposals for measuring success
– Specific to product, indication and lifecycle stage
– Should be operational by time of launch
– Identify potential risks and missing information 216

Approaching the filing point

■ Overall marketing costs l
Annua
■ Ongoing worldwide alignment ing
Market
■ Changes as product moves Plan
through lifecycle

ic
■ Informing all Affiliates of Strateg
product and priority/timelines Launch
pt
of indications Conce
■ Formally initiates planning of
Phase 3B and Phase 4 program
217
Final elements leading to PND
■ Updates to the Clinical Plan for
s
Phase 3B/4 Affiliate
■ Lead up to the dossier Market
submissions to Access
regulatory authorities Plan
■ Local health economics work
■ Key Opinion Leader development
Filing
■ Sales force/Education materials
Decision
(PND)
218

Clinical Studies: Phase 3B

■ Further international multi-centre trials

continue whilst the Regulatory Review is
conducted
■ Continued vigilance on adverse events
■ Special populations required by
Regulators (e.g. immunocompromised
patients, renal failure etc.
■ Health economic value evidence
gathering continues
219
Time to Filing and Approval –
■ Xeloda
– Breast Cancer: Accelerated approval
based on Phase 2 study and response
rate endpoints
– Full approval obtained with follow-up
Phase 3 study using survival (clinical
benefit) endpoints
■ Fuzeon
– Accelerated approval based on 24 weeks
data
– Full approval obtained with follow-up 48
week data 220

Background: strategic considerations

(These will not be presented)

221
Regulatory web sites …

International Conference on Harmonisation:

http://www.ich.org

European Medicines Agency

http://www.emea.europa.eu

US Food and Drug Administration

http://www.fda.gov

222

INDs and CTAs

■ Where - EU, US, RoW? When - Phase 1, 2 or 3?
■ Things to consider:
– US INDs are thought to be complex and in the
past may have been used later in the drug
development, however……
• IND provides opportunity for dialogue with FDA
• IND provides opportunity for critical evaluation of
study proposal and potential for input into next steps
in development
• Leaving to later can make more complex
– CTAs now provide a single system covering EU
• Has also increased the timeframes and complexity in
many countries
• carefully to ensure adequate timing 223
Marketing Authorisation Applications
■ Procedure
– Centralized or MRP/Decentralized Procedure
• For many products, choice is limited to Centralized
– Special Procedures
• Accelerated Assessment
• Conditional MA
• Approval under exceptional circumstances
• Oral explanation
– Post-Approval Commitments
■ Whom
– Choice of RMS:
• Someone who will:
– Be efficient in their review of the original dossier
– Be a good “manager” and of good support during the MRP process
– Choice of Rapporteur:
• Cannot choose anymore
• Rapporteur linked to area of expertise 224

New Drug Applications

■Fast Track
– Unmet medical need or significant benefit
– Provides for option of rolling submission
– Consider benefits and whether team can deliver
■Expedited Review
– Unmet medical need or significant benefit
– 6 month review

225
NDAs (contd.)
■Accelerated Approval
– Unmet medical need or significant benefit
– Approval based on surrogate endpoints likely to
predict clinical benefit
– Some restrictions need to be considered
– Use of 4 month safety update
– What will be included
– Can it be used to provide additional data during
review (i.e. use to assist in filing date)?
■Advisory Committee
– Plan ahead!
– Consider impact and outcome
– Post-Approval Commitments 226

Section 4: Strategic Marketing

■ Key goal: Maximising profit for the life of the
product
■ Key Outcome: Successful mature product
■ Key elements of this section:
– Introduction – market access, launch and sales
– Global supply chain
– Brand defence, generics and divestment,
– Roche in the future – Strategic Business Plan

227
 Section 4: Strategic Marketing
Sub Section: Introduction – market
access, launch and sales

228

Commercial goals throughout lifecycle

Maximise Patent expiry
profit
Divest?
+ Build sales
Net cash flow

rapidly
Launch
Peak sales
Timing
Break
even Time
Break even
point

Optimize product
-
Lifecycle Team Mature Product Team 229
Preparing for Launch
ic
Clear direction to Affiliates for Strateg
planning local introduction and Launch
Plan
marketing activities
■ Publication plans
■ Further market research
■ Medical education
■ Symposia
■ Trademark establishment …
■ Plans for Phase 4
230

Trademarks
■ Registered with national Intellectual
Property offices worldwide
Tamif
■ Indefinite life** lu ™
■ Can be words, colours, shapes, smells,
sounds associated with the product
■ Protect the brand – the customers’
perception of the product – and
guarantee source and quality
**Must be carefully used - adjective not noun
231
Product Trade name - exercise

M
derdrugT
Won

232

Clinical Studies: Phase 4

Studies on marketed products
■ Support specific Affiliate requirements
■ Trials to support marketing
■ Further comparative trials with
competitors
■ Trials to approve extended
indications
■ Trials to approve new formulations
■ Continued adverse event monitoring
233
Reimbursement and Pricing

■ A guide for Affiliates in

preparing and conducting price
and reimbursement
negotiations with payers. Global
Value
■ Pricing Policy – global r
Dossie
perspective giving Affiliates
rationale for setting local
margins

234

Customer perspectives exercises

235
What is Value for Money in
pharmaceuticals?
Address serious Increase
disease – Safety workplace
and Efficacy productivity
Medicines
with real value Pharmacoeconomics

Decrease
Increase length and/or utilisation of
quality of life health care resource
– Health Outcomes

236

Definition of Value for Money

Value = perceived benefits minus total costs
Value means different things to different people.

■ It is critical to identify the customer perspective

for the particular value proposition.
■ We try to define costs broadly, including adverse
events, long-term effects, lost work productivity,
etc.
■ Must have effective communication strategy for
resulting supportable value statements
237
Reimbursement exercises

238

Economic assessment
■ 'Quality of Life' measures – numerical
assessment of pain, mobility, ability to carry
out normal activities etc, using a Health
Assessment Questionnaire (e.g. EQ-5D)
-0.2 0.0 <x> 1.0
■ Quality Adjusted Life Years - QoL x Time
• Example: 6 months at a QoL of 0.6
QALY = 0.3
■ Cost/Utility Ratio
• Cost of treatment divided by QALYs
achieved 239
A realistic (and complex) example:

Comparison of two interventions:

Cost of Intervention B –
Cost / Utility Cost of Intervention A
Ratio =
No. of QALYs produced by intervention B –
No. of QALYs produced by Intervention A

240

Example of economic assessment

Liver Cancer Stage 2 – life expectancy 3 years
Regime Years QoL QALYs = Cost = Cost / QALY
expected Years x QoL €k gained €k
Intervention A
Standard of care 3.00 0.35 1.05 7.50

Intervention B
Drug 1 – adds 3 3.25 0.53 1.72 24.50 25.28
months
Drug 2 – adds 6 3.50 0.47 1.65 29.50 36.97
months

Health Authority Cost/QALY threshold = €30k

Therefore – Drug 2 rejected 241
Influencing healthcare professionals
Barriers to changing conservative attitudes:
■ Authority guidelines are always changing –
they are not developed locally enough
■ Healthcare professionals have too much
information
■ Patients don’t fit Pharma ‘boxes’
■ Detailed information on prescribing
behaviours is available – but some regions
are reacting against

242

‘Activating the Evidence’

■ Utilizing trial investigators to develop
treatment algorithms – and help with hands-
on implementation
■ Generate assessment and evaluation tools
for healthcare professionals
■ Generate prompts/reminder systems
■ Visits by specialists
■ Use patients to mediate interventions

243
What Doctors Want
■ Patient management advice
■ Education
■ Internet-based services

The big winners will be

those helping the
physician to use product
within the context of the
whole system of
processes and guidelines
244

Sales Executive’s Day - exercise

245
Sales – the future
■ Helping the Physician and the
Payer with the whole process of
health management
■ ‘Service’ as well as ‘Product’

Early Patient
detection Diagnosis Treatment Monitoring
stratification

The old way

246

Section 4: Strategic Marketing

Sub Section: Global supply chain

247
 FLEX – formulation line extensions
The market for a product can be expanded
by line extensions to maintain and increase
sales revenue after launch
Examples:

– New dosing regimens

– Route of administration
– New formulation
– Altered active ingredient
Considered at: FDD, Filing Point, and 10
years prior to patent expiry of drug substance
248

Roche manufacturing framework

excl. Genentech and Chugai

Mannheim
Clarecastle Penzberg
Nutley Fontenay
Boulder Basel
Leganés Segrate Chugai
Florence Shanghai
Genentech Karachi
Toluca

Rio
Isando
Montevideo

Manufacturing Sites
- Roche Primary ( = Chem. = Biotech.)
- Secondary ( )
249
Operational excellence

■ Continuous demand to reduce

variation and thus batch failure
■ Operators are best placed to
identify areas for improvement
■ Requires investment in people -
special training, time allocation
■ Essential to ensure that in-house
manufacturing is world-class

250

Quality assurance

■ All manufacturing processes, primary and

secondary, are subject to close regulatory
control
■ Also raw materials supplies, environmental
conditions, monitoring equipment, IT
systems for control and data recording
■ As pharma manufacturing becomes
increasingly global, adherence to standards
is more challenging
251
Cross-cultural Quality

Copegus - for HIV in

combination with Pegasys.
To supply in Japan, Roche
invited Chugai to help with
an in-depth understanding of
Japan requirements, to
facilitate successful
inspection of USA
manufacturing lines

252

Supply chain - exercises

253
Supply Chain - Definition

Flow of Information

Source Make Deliver

Supplier’s Chemical/ Galenical Warehouse/ Pharmacist

Supplier Wholesaler Patient
Supplier Biologic Plant DC /Hospital

Roche Supply
Chain Management

Flow of Goods

254

Factors influencing supply chain

performance Forecasts, complexity, visibility
Forecasts drive the supply chain.
¨ Key: Forecast accuracy

Complexity dramatically increases inventory

holding costs and negatively impacts production
efficiency
¨ Key: Avoid unnecessary complexity
Visibility creates transparency, enabling each
player in the supply chain to take informed
decisions.
¨ Key: Fact based decision-making and proactive
communication 255
 Forecasts
Key challenges
■ Marketing campaigns
– Impact usually hard to predict
– Not always known by all supply chain players
■ Life cycle management
– Earlier / delayed approvals
– Delayed market launch due to price negotiations
– Forecasting difficult for new products
– Patent expiration
■ Market dynamics
– Volatility of the market
– Slow moving products
■ Price changes
– Impact on sales volume 256

Dealing with complexity

12 PFS dose strengths x 35 country make-up’s 420
packs

257
Unnecessary complexity eats up margin
An illustrative example
Costs of products A and B

25%

Regulatory
20%
Costs in % of revenue

costs

Holding costs
15%
Text & artwork
10% costs

Setup costs
5%
Material &
labour costs
0%
Product A, 1 variant Product B, 13 variants
258

Section 4: Strategic Marketing

Sub Section: Brand defence, generics
and divestment

259
Transfer to Mature Product
■ When major central investments are no
longer justified
Transfer to
Mature Product

■ Class 1 – full central support still required

for single major brand – Mature Product
Team
■ Class 2 – partial central support
■ Class 3 – Affiliate completely empowered 260

Brand loyalty?
Drivers of loyalty:
■ Key pieces of evidence that continue to
make a clinical and business case PLUS
■ Association of a positive emotion with using
brand in the past

■ In reality – franchises of indications, new

indications and line extensions are what
helps
261
Something about generics
Generic companies required to:
■ Complete full Technical (CMC) regulatory
package
■ No Non-clinical or Clinical – just
bioequivalence studies

■ We have data exclusivity – no reference to

our regulatory dossier data allowed for 10
years after approval
■ We may have portfolio of patents…… 262

Why we may let generics operate

freely
■ Our manufacturing facilities are suited to
expensive processes
■ Generics companies are better at marketing
in a price-dominated situation than we are
■ Our energies are best suited to innovation
and new products
■ Governments very much encourage
generics companies

…but watch this space…. 263

 An IP portfolio around a product
Screening Gene
Drug substance
Formulation Patents
Intermediates
Manufacturing process
Indication
Delivery Device
Trademark Brand Name
Copyright Pack insert
Expiry year 2013 2014 2015 2016 2017 2018 2019
264

When we divest?

■ Where cost of central manufacturing is not

justified by current sales
■ Where generics are making inroads
■ Where third parties are interested

Divestment
Decision

265
Reminder: Learning outcomes

■ You will be able to:

– Discuss current trends and challenges in the
industry
– Describe the Pharma product development
process - from molecules to markets
– Identify and share experiences
– Explain how collaboration in Pharma is special,
different – and vital

266

Research Translational Medicine Clinical Development Strategic Marketing

TS CCS EIH LIP PND

DISCOVERY MANUFACTURE
AND SUPPLY
SYNTHESIS AND FORMULATION

NON-CLINICAL TESTING
CLINICAL
EVALUATION

MARKETING
AUTHORISATION
SALES
COMMERCIALIZATION

Targets Leads Phase 1 Phase 2 Phase 3 Phase 4

Years 1 2 3 4 5 6 267 7
Molecules to Markets

Thank you!
268