Optimizing Preclinical Proof of Concept

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Information about Optimizing Preclinical Proof of Concept

Published on May 14, 2008

Author: webgoddesscathy

Source: slideshare.net


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

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

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 Slide 1

Yearly Drug Development Costs 50 Millions of dollars 5 Discovery/ Phase I/II Phase III Preclinical OPTIMIZING PRECLINICAL PROOF OF CONCEPT Slide 2

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 OPTIMIZING PRECLINICAL PROOF OF CONCEPT Slide 3

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 OPTIMIZING PRECLINICAL PROOF OF CONCEPT Slide 4

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…) OPTIMIZING PRECLINICAL PROOF OF CONCEPT Slide 5

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 OPTIMIZING PRECLINICAL PROOF OF CONCEPT Slide 6

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) OPTIMIZING PRECLINICAL PROOF OF CONCEPT Slide 7


… 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 OPTIMIZING PRECLINICAL PROOF OF CONCEPT Slide 9

… 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 OPTIMIZING PRECLINICAL PROOF OF CONCEPT Slide 10

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 OPTIMIZING PRECLINICAL PROOF OF CONCEPT Slide 11

… 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 OPTIMIZING PRECLINICAL PROOF OF CONCEPT Slide 12

… 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 OPTIMIZING PRECLINICAL PROOF OF CONCEPT Slide 13

… Support Commercialization OPTIMIZING PRECLINICAL PROOF OF CONCEPT Slide 14

Size of Potential Early Alliances OPTIMIZING PRECLINICAL PROOF OF CONCEPT Slide 15

… 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? OPTIMIZING PRECLINICAL PROOF OF CONCEPT Slide 16

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 OPTIMIZING PRECLINICAL PROOF OF CONCEPT Slide 17


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 OPTIMIZING PRECLINICAL PROOF OF CONCEPT Slide 19

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