Clinical Trials Strategy

February 12th 2007

MaRS Discovery District

Clinical Trials StrategyClinical Trials Strategy

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

The Clinical Development Plan

Wendy Hill gap

!!! strategies

February 12th 2007

Yearly Drug Development Costs

DiscoveryDiscovery Phase Phase I/III/II Phase Phase IIIIII

55

MillionsMillions

ofof

dollarsdollars

5050

Why proceed into the clinic ?

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

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

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

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

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%

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

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

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

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

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)

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

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

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

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

CDP Outline

! Detailed protocol outlines

! Timelines

! Total Costs – CRO quotes

! Milestones

! Complimentary regulatory filing strategy

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

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