The document discusses key aspects of clinical trial strategy and design. It covers the different phases of clinical trials (Phase I, II, III) and provides guidance on optimizing trials at each phase. Phase I focuses on safety and dosing, Phase II evaluates efficacy and further safety, and Phase III confirms efficacy in a larger patient population. The document emphasizes establishing a detailed clinical development plan with timelines and costs to help guide development decisions and reduce risks.

1. Clinical Trials Strategy
Clinical Trials Strategy
February 12th 2007
MaRS Discovery District

2. Agenda
The Clinical Development Plan Wendy Hill, gap strategies
I. -
Logistics and Practicalities of
II.
Phase I Clinical Research Sue Gilbert Evans, Ventana
-
Clinical Research
Beyond Traditional Designs in
III.
Early Drug Development
Miklos Schultz, Scian Services
-
Estimating the Maximum Safe
IV.
Starting Dose for First-in-
Human Clinical Trials Beatrice Setnik, Ventana Clinical
-
Research
Panel Discussion and
V.
Questions
MANAGING THE DRUG DEVELOPMENT GAP

3. The Clinical Development Plan
Wendy Hill
gap
!!! strategies
February 12th 2007

4. Yearly Drug Development Costs
50
Millions
of
dollars
5
Discovery Phase I/II Phase III

5. Why proceed into the clinic ?

6. DEVELOPMENT RISK
References: “The Drug Discovery, Development and Approval Process,” Pharma New Medicine, (October 2004), page 43.
*p values from DiMasi (2001), Clinical Pharmacology & Therapeutics 69:5: 287-307

7. Clinical Development Plan (CDP)
Part of your Strategic Development Plan
!
Detailed evaluation of target indication(s) including unmet needs
!
Description of product with evidence or speculation of effect in
!
target indication
Analysis of market including competition and potential sales
!
Regulatory Strategy
!
“Mock” package insert
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Project plan including development from preclinical to Phase III
!
(timelines and budgets)
Could contain /Formulation/Manufacturing Plan
!

8. Indication(s) Selection
“Multi-factorial Iterative Process”
Based on MOA – Why should Drug/Device/Diagnostic
!
work?
Unmet medical need?
!
Market Analysis – market potential, competition,
!
products in development
Presence or absence of FDA guidelines
!
Co-morbidities in indicated patient population
!
Limitations of clinical trial outcomes
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9. Regulatory Strategy
Orphan Drug
!
Device/Diagnostic Class
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When to go to the FDA
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– Timing of Pre-IND meeting
– End of Phase II meeting
Prepare your questions carefully
!
Consult with the appropriate bureau of Health
!
Products and Food Branch of Health Canada

10. Drug Development Timeline
Years
6 1 2 3 1-2
Discovery / Review /
Phase I Phase II Phase III
Preclinical Approval
30% 70% 70% 80%
< 1%
% Success Rate
Overall success rate: <10% for products entering Phase 1

11. Phase I
Usually done in normal volunteers or refractory patients
!
Can be randomized, parallel or sequential
!
Involves 20 to 100 patients
!
First look at safety/ tolerability/dosing
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Determine how a drug is absorbed, distributed,
!
metabolized and excreted
Determine the duration of action
!
Cost of each trial $250,000 – 1.5 million
!

12. Types of Phase I Studies
Single Dose; Multiple Dose
!
PK/PD; ADME
!
Fed versus Fasted (oral)
!
Select populations (gender, children, elderly)
!
Drug Interactions
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Bioequivalence/bioavailability
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Abuse potential
!
Formulation bridging studies
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Drug effect (efficacy and safety) - surrogate markers
!

13. Optimizing Phase I Clinical Trials
Combine bioavailability studies in Phase I single dose
!
Consider patients in your Phase I study
!
Combine trial designs (ex. single, multiple, fed/fasted)
!
Use positive (commercial or development) controls
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Stay local
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Use same CRO for all Phase I studies
!
Measure surrogate markers that can be used in future
!
development
Ensure large enough sample size to accomplish your objective
!

14. When a Phase I goes wrong…
TeGenero TGN1412
!
– A fully humanized CD28-Mab which activates regulatory T-
cells (stimulatory) targeting inflammatory conditions
– On March 13, 2006 6 of 8 healthy volunteers in Phase I
experienced a life-threatening incident of “Cytokine Release
Syndrome” associated with T-cell activation
– Intense scrutiny of preclinical data by MRHA
• results in humans not predictable from preclinical
– Instead of subtly 're-tuning' the immune system, as developer
TeGenero hoped, TGN1412 induced a so called 'cytokine
storm'; the immune system was sent into overdrive and
attacked healthy organs with tragic results.
– No further clinical testing of the compound is planned

15. What we learned
Design should incorporate a safe dosing strategy
!
Healthy volunteers may not react like patients to
!
interventions
Not all preclinical models are predictive of effects in humans
!
– Small animals have compressed “life line” with accelerated disease
processes that differ from the human
– Difficult to recreate the human disease condition in an animal
– Animals that more closely resemble the human condition are expensive
and difficult to work with (primates)

16. Phase II
Sometimes done in refractory patients
!
DB or Open label but usually randomized and controlled
!
Usually involves 100 to 500 patients
!
Assess the effectiveness (efficacy) of the drug, shot-term
!
tolerability and collect further data on optimum dose
Look closely at the side effects in the targeted patient
!
population
Sometimes use surrogate markers of efficacy
!
Phase IIa (pilot/feasibility) and Phase IIb (well-controlled
!
pivotal trial)
Cost of each trial $2- 20 million
!

17. Optimizing Phase II Clinical Trials
Use control arm of current “popular” therapy when
!
possible
Can use subset patient population that are higher risk
!
Try to use “clinically meaningful” endpoint even if as
!
secondary outcome
Try to control for co-morbid conditions
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If concern over possible chronic toxicities or to build
!
safety database, use long-term follow-up
In some therapeutic areas can act as a pivotal filing trial
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18. Phase III
Performed in indicated patient population
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Double-blind, randomized, placebo or standard therapy
!
controlled
Usually involves 1,000 to 5,000 patients
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Must statistically confirm efficacy
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Must quantify adverse effects
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Must complete safety requirements
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Phase IIIa (filing trial) and Phase IIIb (post filing –
!
comparative, Q of L)
Cost of each trial $20-100 million
!

19. Optimizing Phase III Clinical Trials
Ensure you have adequately powered studies
!
Ensure eligibility criteria are selective but not too
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exclusionary – need to be able to generalize the
results
Clinically meaningful outcomes and prospectively
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defined “minimal clinical difference”
Active controls can assist in pharmacoeconomic
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support for reimbursement
Ensure long-term studies for safety
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20. CDP Outline
Detailed protocol outlines
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Timelines
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Total Costs – CRO quotes
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Milestones
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Complimentary regulatory filing strategy
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21. Why do you need a CDP?
Limit drug/device/diagnostic failures due to poor
!
clinical design or strategy
Enhance the potential of your
!
drug/device/diagnostic with the addition of an
efficient strategy of development
Once a plan is in place it is easier to adjust the plan
!
if there are unexpected findings

22. General Guidelines
Establish a Clinical Development Plan with costs
!
and timelines – even if an early alliance is planned
Finance to meaningful milestones
!
Stage development to meet company needs
!
Validate and re-validate plan and
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drug/device/diagnostic product
Work with compatible CRO’s with a track record in
!
the therapeutic area of development – local if
possible
Establish a experienced Advisory Board
!