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Clinical Trials Strategy: The Clinical Development Plan

Clinical Trials Strategy: The Clinical Development Plan



Part of the MaRS BioEntrepreneurship event series

Part of the MaRS BioEntrepreneurship event series
Speaker: Wendy Hill, Gap Strategies

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    Clinical Trials Strategy: The Clinical Development Plan Clinical Trials Strategy: The Clinical Development Plan Presentation Transcript

    • Clinical Trials Strategy Clinical Trials Strategy February 12th 2007 MaRS Discovery District
    • 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
    • The Clinical Development Plan Wendy Hill gap !!! strategies February 12th 2007
    • Yearly Drug Development Costs 50 Millions of dollars 5 Discovery Phase I/II Phase III
    • 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/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 !
    • 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 Health ! Products and Food Branch of Health Canada
    • 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
    • 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 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
    • 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)
    • 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 !
    • 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 too ! exclusionary – need to be able to generalize the results Clinically meaningful outcomes and prospectively ! defined “minimal clinical difference” Active controls can assist in pharmacoeconomic ! support 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 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
    • 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 ! 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 !