Preclinical Development Planning for Emerging Pharma and Biotech Firms

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Part of the MaRS Best Practices Series. Speaker: Valentia Lee-Brotherton, PhD, Ashuren. 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:

Transcript of Preclinical Development Planning for Emerging Pharma and Biotech Firms

  • Accelerating Development Preclinical Development Planning for Emerging Pharma and Biotech Firms Valentia Lee-Brotherton, PhD May 13, 2008 MaRS Workshop: From Benchtop to IND
  • Objective of Presentation To provide some points to consider when planning and conducting a preclinical development program to enable First-in-Human (FIH) studies Assumptions: Candidate selected (i.e. screening completed) Money in the bank (~3-4 $MM) Sufficient test article New Chemical Entity (not generic or reformulation)
  • Typical Timelines for Non-Clinical Testing Programs In-House Discovery and Candidate Selection Chemistry, Stability, (Bio) Analytical Development Nonclinical Toxicology, Pharmacokinetics, Safety Pharmacology Preparation of Regulatory Documentation Phase I Clinical Trial(s) 0 1 2 3 4 5 6 7 8 9 10 11 months
  • Challenges to the Emerging Biotech Company Lack of Resources Investor Pressure $ Meeting (realistic) timelines in the face of Experience in product issues (e.g., poor development candidate selection) Clearly Defined Vision Managing multiple Lack of clinical plan service providers Manufacturing/CMC Contract laboratories Issues (preclinical, analytical) Lack of test article Contract manufacturer (supply of test article) Formulation, scale-up issues Clinical CROs Consultants (clinical, nonclinical, manufacturing, regulatory affairs, biostatistics, etc.)
  • The IND Application: A Significant Effort What's Needed?: General Investigational Plan (clinical development plans overall) Investigators Brochure (IB) Proposed Clinical Trial Protocol(s) and Investigator Information Chemistry, Manufacturing, and Controls Information Pharmacology and Toxicology Information Previous Human Experience Preparation Time 3-4 people, 1 month How Big? Typically 10-15 volumes (2,500-4,500 pages)
  • Getting Started Product Development Strategy should incorporate: Manufacturing Preclinical Pharmacology and Toxicology Clinical Plans (from FIH to Phase II) Regulatory Remember that all aspects are inter-related Budget/Resource Management
  • Approaching the Nonclinical Safety Testing Program Toxicology studies should not be considered a box- checking exercise to simply satisfy Regulators Contributes to the understanding of the product Provides the supporting data to enable FIH studies (target organs, predict toxicology, reversibility, exposure levels, starting doses, etc.)
  • Perspective Preclinical development is an expensive investment for a small/emerging company that requires: A good plan/strategy that considers regulatory expectations and the Companys objectives (scientific/medical and business) Efficient and expedient implementation by experienced individuals Interpretation and positioning of results by experts If not designed, conducted, and/or interpreted correctly, preclinical studies can add considerable time and expense to a program
  • General Toxicology Program Considerations Regulatory expectation (21 CFR Part 312): Nonclinical safety studies should be conducted to determine the safety of proposed clinical trials Studies should be Conducted in accordance with Good Laboratory Practice (GLP) regulations/principles An international quality standard Its about the documentation! Covers personnel, facilities, equipment, operations, test article, data entry, reports, etc. Does not cover interpretation or evaluation of data Contributes to the timing and expense of studies Sponsor has obligations Ensuring the integrity of the data - monitoring the study
  • General Toxicology Program Considerations (contd) The preclinical development plan will depend on a number of factors, including: Product type and similarity to existing agents with known safety profiles Proposed indication in humans (i.e., cancer vs rheumatoid arthritis) Proposed duration of administration (i.e., short term vs chronic; dosing regimen) Target population (i.e., adults, infants, pregnant women, elderly, etc.) Proposed route(s) of administration Use pattern considerations (i.e., concomitant medications, adjuvant therapy)
  • General Toxicology Program Considerations (contd) Studies should be designed specifically for the drug under development Relevant animal species (i.e., pharmacologically active) Particularly for biologics / therapeutic proteins Knowledge of expected toxicities Dose range finding data and pilot studies Drug class effects (published literature, Freedom of Information, E.U. EPARs, scientific meetings, etc.) First principles Interaction with regulatory authorities
  • Objectives of Early Toxicology Studies Identify the target organs / systems of the drug Monitoring in clinical trials Gender differences Expected? (based on pharmacology) Characterize the dose-response curve No-Observed-Adverse-Effect Level (NOAEL) Important for Maximum Recommended Starting Dose (NCE) Maximum tolerated dose (MTD) Therapeutic Index
  • Objectives of Early Toxicology Studies (contd) Characterize the toxicity Reversible? Dose-dependent? Assess the systemic exposure Calculate pharmaco-/toxicokinetics (Tmax, Cl, Vd, t) Margins of safety relative to human exposures based on AUC and Cmax Aid in dose selection for further animal toxicology, FIH studies
  • Developing a Biologic is Different From a Drug Differences between small molecules and biologics a generalization Small Molecule Drug Biologic Low molecular weight High molecular weight Familiar antecedents Potentially unique Known impurities Unfamiliar impurities Often orally dosed Often parenteral, IV dosing Maximal tolerated dose Optimal biologic dose Meaningful chronic tox Uncertain chronic tox Species-independent Species-specific Biotransformed Degraded Not immunogenic Immunogenicity issues
  • Typical IND-Enabling Preclinical Safety Studies Species Duration of Studies Cost ($)* (Bio)analytical Assay development 1,000/day Validation (per species) 15,000-20,000 Running samples 70-100/sample Dose formulation Analyses $5K/time study Rat Single dose 29,000-75,000 7 day DRF 50,000-125,000 14 days 165,000-200,000 28 days 120,000-275,000 Dog Maximum tolerated dose (MTD) 30,000-65,000 7 day DRF 75,000-145,000 14 days 140,000-300,000 28 days 200,000-450,000 * Pricing will vary depending on the actual study design, route of administration, numbers of groups, numbers of animals, bioanalytical determinations, special tests required, etc.
  • Typical IND-Enabling Preclinical Safety Studies (contd) Species Type of Studies Cost ($)* Monkey MTD 75,000-125,000 7 day DRF 100,000-240,000 14 days 265,000-410,000 28 days