Speaker: Wendy Hill, Gap Strategies. Part of the MaRS Best Practices Series.This session, led by seasoned industry experts, will explore how to effectively set up your pre-clinical POC studies, address pre-clinical safety requirements and issues, and give you an overview of the manufacturing standards required for Phase I studies More information: http://www.marsdd.com/Events/Event-Calendar/Best-Practices-Series/ind-05132008.html

1. OPTIMIZING PRECLINICAL PROOF
OF CONCEPT
Presentation - May 13th, 2008
Presenter:
Wendy Hill, M.Sc.,
Gap Strategies Inc.

2. Drug Development Timeline
Years
6 1 2 3 1-2
Discovery / Review /
Phase I Phase II Phase III
Preclinical Approval
< 1% 30% 70% 70% 80%
% Success Rate
Overall success rate: <10% for products entering Phase 1
OPTIMIZING PRECLINICAL PROOF OF CONCEPT
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3. Yearly Drug Development Costs
50
Millions
of
dollars
5
Discovery/ Phase I/II Phase III
Preclinical
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4. Why do drugs fail?
 Toxicity (49%)
 long term safety is still totally unpredictable
 Bioavailability and half life (15%)
 half life cannot be predicted, only guessed
 Metabolism (3%)
 drug/drug interactions; parent or metabolite
 Man (33%)
 understanding of pathophysiology is faulty
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5. Early Animal Models
 Follow-on to in-vitro testing
 Used for target validation (transgenic knock-outs or knock-ins)
 Used for the establishment of biomarkers (physiological, imaging …)
to carry through clinical development
 Used to select most promising development if multiple opportunities
 Elucidate mechanism of action
 Can be used for clinical dose determination
 Provide preliminary toxicity finding in a disease model
 Provide “Proof of Concept” for drug or device
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6. Indication Selection
 Early on must have some idea of potential indication for drug or
device for this will direct preclinical development plan
 Based on the manifestation of target in a disease process(es) select
indication(s)
 Mechanism of Action
 Iterative process (medical need, market potential, ease of development
pathway, strategy for development…)
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7. Development Plan
 Work backwards
 Develop your plan or strategy through to approval
 Costs, timelines, strategies, clinical trial designs
 Important that the preclinical programme supports later development
ex. incorporation of potential clinical trial design into
preclinical POC (prophylaxis vs. treatment models)
 Return to this plan to ensure consistency in development process
 Should form part of your Business Plan
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8. Issues with Animal Models
 Not always predictive of human efficacy
 Not always predictive of human drug metabolism
 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)
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9. WHAT STRATEGIES CAN BE
EMPLOYED TO….

10. … Learn More about MOA and Target
Indication
 If target is widely applicable, study it in several different disease models (body of
evidence)
 Choose well-established models
 Choose relevant species models (ex. pig for coagulation, dog for electrophysiology)
 Choose models that have been predictive for other compounds and select one of
these compounds as positive control
 Design protocols that mimic the course of disease and the application of the
intervention (is it treatment or prophylaxis?)
 Develop validated assays for measurement of biomarkers collected during each study
 Can be done as academic collaborations (NIH) not GLP
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11. … Support IND Filing
 For certain compounds like targeted biologics - you may realize a physiological effect
(efficacy) at doses far lower than those determined to be dose limiting in animal
toxicity studies
 Animal safety and toxicity studies are usually performed on “normal” animals that may
not express a disease target
 Toxicities may be quite different in an “expressing” animal model
 For these reasons both the FDA and EMEA have issued guidance documents
 Committee for Medicinal Products for Human Use (CMPH): Guideline on
Strategies to Identify and Mitigate Risks for First-In-Human Clinical Trials with
Investigational Medicinal Products - July 19 2007
 FDA Guidance for Industry: Estimating the Maximum Safe Starting Dose in Initial
Clinical Trials for Therapeutics in Adult Healthy Volunteers - July 2005
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12. Selection of the Maximum Recommended
Starting Dose (MRSD)
No observed adverse effect
levels (NOAEL) OR
pharmacologically active dose
(PAD)/minimal anticipated
biological effect level (MABEL)
Conversions of selected dose
to human equivalent dose
(HED)
Determine MRSD based on
HED and safety factors
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13. … Support IND Filing
 Include dose-finding and limited pharmacokinetic sampling
 Include measures of toxicity
 Bridge to preclinical safety species
 Use drug that is as close to final GMP formulation as possible
 Choose animal species that most closely resembles human
application and human physiology
 Look at in vitro binding studies and choose species that is similar to
humans
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14. … Ensure Quality of the Data and Results
 Include a negative control as well
 If possible “blind” the evaluation
 Develop protocol for each study prospectively and try to adhere to
this
 Choose established CRO or academic collaborators that work under
“GLP-like” standards
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15. … Support Commercialization
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16. Size of Potential Early Alliances
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17. … Support Commercialization
 Choose comparators that are relevant in the current market place
 Protect or enhance patent position – time publications carefully
 Engage potential partners or licensors in discussions of preclinical
models – What do they need to see to be convinced of animal
efficacy?
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18. The Last Word
 Utilize your animals to learn as much as possible for about your compound
 Establish a Development Plan in order to ensure the preclinical strategy
supports this plan
 In the absence of funding seek out academic collaborations (ex. NIH
intramural scientists)
 Understand what will be required to enhance your financing opportunities
 Protect your IP position (publications/contracts)
 If you proceed to clinical continue parallel preclinical development
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19. OPTIMIZING PRECLINICAL PROOF OF CONCEPT
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20. Summary
 Establish your development plan BEFORE embarking on preclinical
development
 Make sure you understand the physiology of your targeted disease and your
compound and design your nonclinical POC and studies accordingly
 Seek advice from those who have experience
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