clinical trials strategy: the clinical development plan
DESCRIPTION
Part of the MaRS BioEntrepreneurship event series Speaker: Wendy Hill, Gap Strategies This event is available as an audio file: http://www.marsdd.com/bioent/feb12TRANSCRIPT
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Clinical Trials Strategy
February 12th 2007
MaRS Discovery District
Clinical Trials StrategyClinical Trials Strategy
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MANAGING THE DRUG DEVELOPMENT GAP
Agenda
I. The Clinical Development Plan
II. Logistics and Practicalities of
Phase I Clinical Research
III. Beyond Traditional Designs in
Early Drug Development
IV. Estimating the Maximum Safe
Starting Dose for First-in-
Human Clinical Trials
V. Panel Discussion and
Questions
- Wendy Hill, gap strategies
- Sue Gilbert Evans, Ventana
Clinical Research
- Miklos Schultz, Scian Services
- Beatrice Setnik, Ventana Clinical
Research
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The Clinical Development Plan
Wendy Hill gap
!!! strategies
February 12th 2007
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Yearly Drug Development Costs
DiscoveryDiscovery Phase Phase I/III/II Phase Phase IIIIII
55
MillionsMillions
ofof
dollarsdollars
5050
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Why proceed into the clinic ?
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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
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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
! Project plan including development from preclinical to Phase III
(timelines and budgets)
! Could contain /Formulation/Manufacturing Plan
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Indication(s) Selection
“Multi-factorial Iterative Process”
! Based on MOA – Why should Drug/Device/Diagnosticwork?
! 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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Regulatory Strategy
! Orphan Drug
! Device/Diagnostic Class
! When to go to the FDA
– Timing of Pre-IND meeting
– End of Phase II meeting
! Prepare your questions carefully
! Consult with the appropriate bureau of HealthProducts and Food Branch of Health Canada
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Drug Development Timeline
Discovery /
PreclinicalPhase I Phase II Phase III
Review /
Approval
16 2 3 1-2
Years
30% 70% 70% 80%
Overall success rate: <10% for products entering Phase 1
% Success Rate
< 1%
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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
! Determine how a drug is absorbed, distributed,metabolized and excreted
! Determine the duration of action
! Cost of each trial $250,000 – 1.5 million
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Types of Phase I Studies
! Single Dose; Multiple Dose
! PK/PD; ADME
! Fed versus Fasted (oral)
! Select populations (gender, children, elderly)
! Drug Interactions
! Bioequivalence/bioavailability
! Abuse potential
! Formulation bridging studies
! Drug effect (efficacy and safety) - surrogate markers
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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
! Stay local
! 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
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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 Iexperienced a life-threatening incident of “Cytokine ReleaseSyndrome” 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 developerTeGenero hoped, TGN1412 induced a so called 'cytokinestorm'; the immune system was sent into overdrive andattacked healthy organs with tragic results.
– No further clinical testing of the compound is planned
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What we learned
! Design should incorporate a safe dosing strategy
! Healthy volunteers may not react like patients tointerventions
! Not all preclinical models are predictive of effects in humans
– Small animals have compressed “life line” with accelerated diseaseprocesses that differ from the human
– Difficult to recreate the human disease condition in an animal
– Animals that more closely resemble the human condition are expensiveand difficult to work with (primates)
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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-termtolerability and collect further data on optimum dose
! Look closely at the side effects in the targeted patientpopulation
! Sometimes use surrogate markers of efficacy
! Phase IIa (pilot/feasibility) and Phase IIb (well-controlledpivotal trial)
! Cost of each trial $2- 20 million
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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
! 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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Phase III
! Performed in indicated patient population
! Double-blind, randomized, placebo or standard therapy
controlled
! Usually involves 1,000 to 5,000 patients
! Must statistically confirm efficacy
! Must quantify adverse effects
! Must complete safety requirements
! Phase IIIa (filing trial) and Phase IIIb (post filing –
comparative, Q of L)
! Cost of each trial $20-100 million
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Optimizing Phase III Clinical Trials
! Ensure you have adequately powered studies
! Ensure eligibility criteria are selective but not tooexclusionary – need to be able to generalize theresults
! Clinically meaningful outcomes and prospectivelydefined “minimal clinical difference”
! Active controls can assist in pharmacoeconomicsupport for reimbursement
! Ensure long-term studies for safety
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CDP Outline
! Detailed protocol outlines
! Timelines
! Total Costs – CRO quotes
! Milestones
! Complimentary regulatory filing strategy
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Why do you need a CDP?
! Limit drug/device/diagnostic failures due to poorclinical design or strategy
! Enhance the potential of yourdrug/device/diagnostic with the addition of anefficient strategy of development
! Once a plan is in place it is easier to adjust the planif there are unexpected findings
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General Guidelines
! Establish a Clinical Development Plan with costsand timelines – even if an early alliance is planned
! Finance to meaningful milestones
! Stage development to meet company needs
! Validate and re-validate plan anddrug/device/diagnostic product
! Work with compatible CRO’s with a track record inthe therapeutic area of development – local ifpossible
! Establish a experienced Advisory Board