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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
Citation preview
OPTIMIZING PRECLINICAL PROOFOF CONCEPT
Presenter:
Wendy Hill, M.Sc., Gap Strategies Inc.
Presentation - May 13th, 2008
Slide 1OPTIMIZING PRECLINICAL PROOF OF CONCEPT
Drug Development Timeline
Discovery /Preclinical Phase 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%
Slide 2OPTIMIZING PRECLINICAL PROOF OF CONCEPT
Yearly Drug Development Costs
Discovery/Discovery/PreclinicalPreclinical
Phase Phase I/III/II Phase Phase IIIIII
55
MillionsMillionsofofdollarsdollars
5050
Slide 3OPTIMIZING PRECLINICAL PROOF OF CONCEPT
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
Slide 4OPTIMIZING PRECLINICAL PROOF OF CONCEPT
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
Slide 5OPTIMIZING PRECLINICAL PROOF OF CONCEPT
Indication Selection
Early on must have some idea of potential indication for drug ordevice 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 developmentpathway, strategy for development…)
Slide 6OPTIMIZING PRECLINICAL PROOF OF CONCEPT
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 intopreclinical POC (prophylaxis vs. treatment models)
Return to this plan to ensure consistency in development process
Should form part of your Business Plan
Slide 7OPTIMIZING PRECLINICAL PROOF OF CONCEPT
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 diseaseprocesses that differ from the human
Difficult to recreate the human disease condition in an animal
Animals that more closely resemble the human condition areexpensive and difficult to work with (primates)
WHAT STRATEGIES CAN BEEMPLOYED TO….
Slide 9OPTIMIZING PRECLINICAL PROOF OF CONCEPT
… Learn More about MOA and TargetIndication 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 ofthese compounds as positive control
Design protocols that mimic the course of disease and the application of theintervention (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
Slide 10OPTIMIZING PRECLINICAL PROOF OF CONCEPT
… 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 animaltoxicity studies
Animal safety and toxicity studies are usually performed on “normal” animals that maynot 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 onStrategies to Identify and Mitigate Risks for First-In-Human Clinical Trials withInvestigational Medicinal Products - July 19 2007
FDA Guidance for Industry: Estimating the Maximum Safe Starting Dose in InitialClinical Trials for Therapeutics in Adult Healthy Volunteers - July 2005
Slide 11OPTIMIZING PRECLINICAL PROOF OF CONCEPT
Selection of the Maximum RecommendedStarting Dose (MRSD)
No observed adverse effectlevels (NOAEL) OR
pharmacologically active dose(PAD)/minimal anticipated
biological effect level (MABEL)
Conversions of selected doseto human equivalent dose
(HED)
Determine MRSD based onHED and safety factors
Slide 12OPTIMIZING PRECLINICAL PROOF OF CONCEPT
… 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 humanapplication and human physiology Look at in vitro binding studies and choose species that is similar to
humans
Slide 13OPTIMIZING PRECLINICAL PROOF OF CONCEPT
… 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 tothis
Choose established CRO or academic collaborators that work under“GLP-like” standards
Slide 14OPTIMIZING PRECLINICAL PROOF OF CONCEPT
… Support Commercialization
Slide 15OPTIMIZING PRECLINICAL PROOF OF CONCEPT
Size of Potential Early Alliances
Slide 16OPTIMIZING PRECLINICAL PROOF OF CONCEPT
… 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 preclinicalmodels – What do they need to see to be convinced of animalefficacy?
Slide 17OPTIMIZING PRECLINICAL PROOF OF CONCEPT
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 strategysupports this plan
In the absence of funding seek out academic collaborations (ex. NIHintramural 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
Slide 18OPTIMIZING PRECLINICAL PROOF OF CONCEPT
Slide 19OPTIMIZING PRECLINICAL PROOF OF CONCEPT
Summary
Establish your development plan BEFORE embarking on preclinicaldevelopment
Make sure you understand the physiology of your targeted disease and yourcompound and design your nonclinical POC and studies accordingly
Seek advice from those who have experience