Managing Risk in Early Drug Development Vice President, Drug

1
Managing Risk in Early Drug DevelopmentVice
President, Drug Development ProgramsYalePharma
2
10 Year Trends in US Biomedical Research Spending
More Spending Less Apparent Productivity and
Innovation?
10 Year Trends in Number of Approvals of New
Molecular Entities by US FDA
PAREXELs Pharmaceutical RD Statistical
Sourcebook 2002/2003
US FDA
3
Some Excuses for Poor Productivity

• The easy drug therapies have already been
  discovered and developed
• Genomics and proteomics many new targets that
  are not well understood yet
• High throughput screening too many highly
  selective drug candidates? - promise of selective
  therapy not yet realized
• Public expects absolute safety and promised
  efficacy
• Regulators demanding more evidence of safety and
  efficacy
• Regulators mandating tighter quality standards in
  manufacturing, analysis, data management, patient
  privacy
• Costs of drug development keep rising
• Business demands on return on investment not
  compatible with long-term investment in drug
  development
• Shortage of patients for some clinical trials
  extend timeframes

4
Key Questions

• Is there a difference between drug discovery
  and drug development?
• Why do we call drug development a process?
• What are the key success factors in drug
  development?
• What risks need to be considered during drug
  development?
• How does a decision-gate approach help manage
  risk?
• Does size matter in drug development?
• How can we make better choices in selecting
  subjects and dosing strategies during early
  clinical research?
• What about biomarkers how do they help optimize
  early phase drug development?
• What about using exploratory INDs to improve
  efficiency in drug development?

5
High Level Process Map Drug Development
Animal Studies
Studies of Disease Mechanisms
Molecular Studies
Target Identification
High Throughput Chemisty
Lead Optimization
Hits to Leads
Discovery
Drug Candidate Safety Testing
Development
Product Development
Human Safety/Tolerance PK
Human Proof of Concept and Dose Response
Registration and Approval for Marketing
Pivotal Efficacy and Safety
Postmarketing Surveillance and Product Lifecycle
6
The Brutal Facts - High Attrition Makes Drug
Development a Risky Business
Market Launch FDA Review
Post-Marketing Surveillance
1
15
Phase III Clinical Trials
Pivotal Efficacy Safety
2
Phase II Clinical Trials
POC, Dose Response
2 - 5
10
Phase I Clinical Trials
Safety/Tolerance PK
5 10
Preclinical Testing
DMPK,Safety Chemistry
10 - 20
5
Basic Research
Screening Synthesis
3,000 10,000
0
Number of Compounds
Years
Source PhRMA analysis of Tufts CSDD database
7
Success Factors - Drug Development

• Good Drug
• selective, safe, easy to administer
• meets an unmet medical need

• Effective Drug Development Team
• committed people with proper balance of expertise
• team leader who is champion for project

• Good Drug Development Plan
• based on a decision strategy
• risk is managed
• timeframes challenging but reasonable

• Good Execution of Plan
• work completed on time
• timely communication of results with full team

• Flexible Response
• rational adjustments to plan made quickly
• problems addressed openly and quickly

8
Early Drug Development Value Proposition
Value
30-100
Cost
Risk 13 to 110 make it
5
Cost or Value (000,000)
3
1
Developable?
Give to Humans?
Clinical Proof of Concept?
9
Developing a Plan

• Plan reflects a disciplined decision process
• Plan is strategic defines when to ask and
  answer key questions
• Plan should move between decision gates
• Each decision gate requires answers to key
  questions that cumulatively result in a Go No
  Go Decision

Questions
Questions
Experiments or Studies
Experiments or Studies
Decision Gate
Decision Gate
Answers
Answers
10
Decision Gates in Drug Development
J.F. Pritchard et al. Nature Reviews Drug
Development 2 542-553, 2003
11

Assessing Developability
Ames bacterial mutation
Mouse lymphoma assay
hERG K Conductance
In Vitro Metabolism Metabolic Stability in
Hepatocytes
Bioanalytical Method Development
MDCK and/or Caco-2 Cell Permeability
Single IV/Oral Dose Pharmacokinetics in Rat)
Crossvalidation Rat Plasma
Lead Identified
Single IV/Oral Dose Pharmacokinetics in Dog
Crossvalidation Dog Plasma
No
Is Lead Developable?
Single (acute) Dose in Mouse
Repeated Dose Range Finder Toxicokinetics in Dog
Yes
Single (acute) Dose in Rat
Repeat Dose Range Finder Toxicokinetics in Rat
Go to Flowchart 4
Pharmaceutical Development Assessment
Solubility, Stability, Synthesis
Identify New Lead Compound
12
Preclinical Studies For IND
Lead is Developable
Tissue Distribution Rat ?
Stop
ADME Rat
Preparation of Radiolabeled Drug
No
ADME Dog or Monkey
Plasma Protein RBC Binding
Is Lead Drug Safe to Give to Humans?
ID CYP450 Enzymes)
Inhibition of CYP450 Enzymes)
Formulation Optimization, Characterization
Testing
Yes
Formulation Development
28-Day Toxicity Assessment in Rats
Toxicokinetics
28-Day Toxicity Assessment in Dogs or Monkeys
Toxicokinetics
Go to Flowchart 5
Cardiovascular Safety / Telemetry in Conscious
Animals Rabbit Purkinje APD (if necessary)
Pulmonary Function in Rat
Irwin Test of Behavior and Body Temperature in Rat
Reproductive Toxicology Studies
13
Clinical Proof of Concept
Rising Single Dose Safety, Tolerance and
Pharmacokinetics in Healthy Subjects or Otherwise
Healthy Patients
Design First Protocol
Has Concept Been Proven?
No
Yes
Safety, Tolerance and Pharmacokinetics in Healthy
Subjects Following Multiple Doses
Stop
Dose Range Finding for Efficacy in Patients
File IND
Studies to Define Factors that Affect PK/PD
e.g. Food, Gender, Age, Probe Studies for Drug
Interactions
IND Accepted?
Design Phase IIIII Clinical Program Initiate
Long-Term Toxicology
14
At Each Decision Gate, Decide How to Decide
What process? directive, consensus,
democratic Who decides? Who consults? Who is
informed? - rights and responsibilities in each
role. What choices? - study scenarios What
criteria? TPP (Target Product Profiles) -
define minimum, meets and exceeds criteria
15
Drug Development Teams Manage the Process

• Core Team
• small group of critical experts (7-10 people)
• empowered to make day-to-day decisions
• advise sponsor on go-no go decisions
• sponsor representative champions project
  internally and secures funding
• team leader champions the project among all
  groups who will execute portions of the drug
  development plan
• program manager who will track details of
  logistics, timing, budgets, and manage
  communications
• Extended Drug Development Team
• readily add expertise as needed
• may serve as core team member for portion of
  program

16
Trust, Communications and Passion for the Product
are Essential

• Way of Working
• team members enthusiastic about drug
• clear understanding what everyone will do
• mutual respect for everyones contributions and
  perspectives work to understand cultural
  differences
• trust built over time by collectively solving
  problems and addressing issues
• OK to disagree but then commit
• minimal switching of personnel
• promises kept access to expertise, completed
  work, payments
• Communication Plan
• defines roles, responsibilities, timing of
  meetings, preferred ways of communicating
  what/when
• teleconferencing, eRooms, e-mail, Webex are all
  effective

17
Drug Development is a Risky Business

• Risk (possibility of loss or injury)
• depends on which stakeholder you ask
• Risk to Patient (Focus of Regulators, IRBs,
  Investigators)
• Drug must provide a good chance of net benefit to
  patient (efficacy and safety)
• Risk of Therapeutic Failure (Focus of
  Investigators, Investors)
• Drug must have promise in order to promote
  investigator interest and patient enrollment
• Development Risk (Focus of Managers, Owners and
  Investors)
• Drug must have a reasonable chance for return on
  investment.

All three types of risk need to be considered
when setting strategy for global drug development
18
Key Factors in Managing Risk
Partners
Safety
Expectations
Regulations
Drug Interactions
Development Risk
Risk to Patient

Novelity

Market
Efficacy
Risk of Therapeutic Failure
19
Assessing the Marketplace
Partners
Safety
Expectations
Regulations
Drug Interactions

• Who is your real customer?
• another partnering company
• government/3rd party payers
• doctors/patients

Development Risk
Risk to Patient

Novelity

Market
Efficacy
Risk of Therapeutic Failure

• What is the target claim(s)?
• - number of patients/duration of treatment
• competition with other therapies
• comparison with other treatments
• access to investigators/patients

• Is geography a factor?
• regional disease
• unmet treatment needs
• drug regulatory requirements clinical research
  / marketing

20
Success Rate Depends on Disease Target
I.Kola and J.Landis, Nature Reviews Drug
Discovery 3711-715, 2004
21
Regulations Focus on Risk to Patients First
15 years of work
Partners
Safety
Expectations
Regulations
Drug Interactions
Development Risk
Risk to Patient
There are approximately 30 ICH guidelines
relevant to Global Drug Development

Novelity

Market
Efficacy
Risk of Therapeutic Failure
There approximately 70 FDA guidelines relevant to
Clinical Research
There are 6 guidelines that support the EU
Clinical Trial Directive
22
Novelty of Product
Partners
Safety
Expectations
Regulations
Drug Interactions

• Does size matter in drug development?
• small vs. large molecules
• drugs are getting bigger
• large molecules cost more to manufacture

Development Risk
Risk to Patient

Novelity

Market
Efficacy
Risk of Therapeutic Failure
Is the product among first in class? - education
of regulators, investigators, IRBs, subjects -
safety uncertainties lead to caution - slower
dose escalation in phase I - more long-term
safety data in phase III
Is the product an improved version of existing
product? - catch-up regulatory requirements (e.g.
carcinogenicity) - 505(b)(2) approach in US is
not cheap - pharmacogenomics impact - leveraging
biomarkers for market advanatage
23
Large vs Small Drugs Different Risks
Small Molecule Drugs
Immunogenicity
Recombinant Proteins
Peptides
Antibodies
Vaccines
Antisense Oligo- nucleotides
Cell-based Therapies
Gene Therapies
Blood Products
Cellular toxicity
Production control
24
Large vs Small DrugsSame Basic Clinical
Questions
Large MoleculeBiologic
Small molecule
25
Risk and Design Considerations How to Dose?

• Dose escalation strategies
• Choice of starting dose affects number of
  escalations needed
• FDA has defined algorithms based on NOEAL in
  animals
• Stopping rules important
• Overlapping Studies when time is the key factor
• Start repeat dosing studies before single dosing
  completed in a staggered design
• Incorporating food-effect pilot study in phase I
  single dose escalation study
• Developing IV route before oral
• To prove concept works in clinic before starting
  expensive oral formulation development (e.g. oral
  oncology products, anti-infective agents,
  antihypertensives)

26
Risk and Design Considerations Who to Dose?

• Healthy volunteers vs patients. Healthy subjects
  provide
• Quicker enrollment and dose escalation
• Cleaner safety and PK data
• Enable optimal dose regimen for treatment of
  patients (ethically better than knowingly
  treating patients with sub-therapeutic doses)
• Using otherwise healthy patients
• e.g. mild hypertensives, diet-controlled mild
  diabetics, moderate obese subjects
• Future cancer patients in remission to study
  non-cytotoxic drugs (e.g. mAbs)?
• Females of child-bearing potential
• Single dose escalation OK for some investigators
  and IRBs if dosing in a confined clinic and serum
  pregnancy testing done when subject checks in and
  before leaves
• FDA encourages gathering data in women in early
  trials

27
Risk and Design Considerations Fast to Man
Approaches

• Investigator INDs
• Intended for academic research
• Clinical investigator manages all aspects of IND
• Must trust investigators administrative
  abilities
• Drug material obtained
• Clinical investigator in charge has power to
  change things
• FDA will insist on full sponsor IND once clear
  that a formal drug development program is
  occurring
• Used in past to build confidence in drug by
  investigators and investors not proven to be a
  very effective drug development strategy (too
  long, too messy)

28
Risk and Design Considerations Fast to Man
Approaches

• Exploratory IND, Subtherapeutic Dosing,
  Microdosing
• Limited tox required, single doses to small
  number of volunteers or patients
• Need sensitive bioanalytical assay methods
• Need accurate way to deliver low doses of drug
• Best to confirm PK information
• Low doses 70 predictive of higher therapeutic
  doses
• Does not provide safety/tolerance information
  except if drug very unsafe or if there is a
  sensitive biomarker of efficacy
• Will require full typical preclinical package
  anyway before more human testing can be done in
  end costs more and takes longer
• Useful if
• Bioavailability or half-life are critical
  information for go/no-go decision
• Mechanism of action can be demonstrated at low
  doses
• Financial milestone achieved by first-in-human
  dosing

29
Technology is Expanding the Biomarker Universe
Biochemical Assays Enzyme Assays Drug Assays/PK
Proteomics
Genomics
Imaging
30
Managing the Business Risk
Partners
Safety
Expectations
Regulations
Drug Interactions
Is there enough development money?
Development Risk
Risk to Patient

Novelity
How are decisions made? - clear process for
accountability for decisions - record of being
decisive

Market
Efficacy
Risk of Therapeutic Failure

• Do you have access to expertise?
• drug development experience
• experienced investigators
• leadership with accountability/responsibility
• regional offices, affiliates or partners

• What have/should you promised to
  investors/owners/senior managers?
• challenging but reasonable timelines
• real costs
• return on investment talk in terms of managing
  risk
• dont over promise contribution to
  medicine/health

31
Clinical POC Before Series B Financing
Pre-Clinical Toxicology Safety

• Traditional IND Application Exploratory IND
  Application
• US (000) Mos US (000) Mos
• Acute tox rat 13 2.5 Acute tox
  rat - -
• Acute tox dog 60 4.0 Acute tox
  dog - -
• 14-day tox rat 200 5 14-day tox
  rat 200 5
• 14-day tox dog 300 5 14-day tox
  dog 300 5
• PK rat 30 2.5 PK rat 30 2.5
• PK dog 50 2.5 PK dog 50 2.5
• Genetic toxicol 45 4 Genetic
  toxicol 45 4
• Safety Pharm 128 4 Safety
  Pharm 128 4
• 826 8 653 7

32
Clinical POC Before Series B Financing
CMC

• Traditional IND Application Exploratory IND
  Application
• US (000) Mos US (000) Mos
• Research syn 50 2 Research
  syn 50 2
• Analytical devel 100
  6 Analytical devel 75 4
• Pilot scale (10 g) 50 1 Pilot
  scale 50 1
• Batch scale (50g) 150 2 Batch
  scale 300 4
• Mfg scale (500 g) 500 5 Mfg
  scale - -
• Stability 150
  6 Stability 100 6
• Formulation 75 2 Formulation
  25 1
• Fill/finish 75
  1 Fill/Finish 75 1
• 1,150 12 675 8

33
Exploratory INDs Improve Efficiency?

• Exploratory IND studies enable faster, cheaper
  route to clinic - but not necessarily faster,
  cheaper route to market
• FDA may be more enthusiastic than industry
  (again)
• Microdose strategy has limitations, but popular
  in EU
• Sub-therapeutic dosing studies may provide more
  value - particularly for early-stage biotech
  companies

34
Global Clinical Strategy

• Where to do Phase I?
• Few advantages in Europe over US since
  initiation of EU Clinical Trial Directive
• - regulatory filing for all human studies
• - more CMC requirements now in EU
• Canada averaging 7-10 days review time (can be
  shorter than 30 days)
• Japanese subjects required for Japan

• Where to do Phase II?
• Fastest access to patients at affordable cost
• - Eastern Europe, India, South America new
  options
• - US most expensive sometimes best expertise
• - China unique access to patients restrict
  sample
• movement to inside China
• CRO partner needs regulatory/monitoring
  expertise in region

35
Global Clinical Strategy

• Where to do Phase III?
• At least one pivotal efficacy study plus safety
  data in each region
• - often no choice when comparator products
  differ by region
• Bridging studies are pivotal for Japan, maybe
  others
• Access to novel biomarker technology (e.g.
  imaging) may dictate choice
• Placebo-controlled trials easier in countries
  that cannot offer an alternative standard of care
  
• - always raises ethical issues
• No obvious regional advantages for specific
  indications
• - always driven by availability of patients,
  investigators and potential regional market.

36
Take Home Messages

• Understanding the drug development process and
• risk is key to making effective drug development
  decisions
• Risk is evaluated differently by each stakeholder
  in drug development
• Learning and communicating within a strong team
  culture are essential for success
• New biomarkers, new regulatory options
  (exploratory IND) and more global clinical study
  options may improve efficiency

Acknowledgements Malle Jurima-Romet, Ph.D. Ian
Dews, MRCP, FFPM Paul Chamberlain, MBIRA Guy
Chamberland, Ph.D. Bruce Morimoto,
Ph.D. Douglas Wight, M.Sc. Robert Powell,
Pharm.D. Robert Butz, Ph.D. Heimo Scheer,
Ph.D. Lynn Pritchard, Ph.D Nigel Brown,
Ph.D. Steve Pinder, Ph.D.