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Pharmaceutical Development

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  • 1. Accelerating Development Preclinical Development Planning for Emerging Pharma and Biotech Firms Valentia Lee-Brotherton, PhD May 13, 2008 MaRS Workshop: From Benchtop to IND
  • 2. 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)
  • 3. 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
  • 4. 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.)
  • 5. The IND Application: A Significant Effort • What's Needed?: – General Investigational Plan (clinical development plans overall) – Investigator’s 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)
  • 6. 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
  • 7. 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.)
  • 8. Perspective • Preclinical development is an expensive investment for a small/emerging company that requires: – A good plan/strategy that considers regulatory expectations and the Company’s 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
  • 9. 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 – It’s 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
  • 10. General Toxicology Program Considerations (cont’d) • 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)
  • 11. General Toxicology Program Considerations (cont’d) • 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
  • 12. 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
  • 13. Objectives of Early Toxicology Studies (cont’d) • Characterize the toxicity – Reversible? – Dose-dependent? • Assess the systemic exposure – Calculate pharmaco-/toxicokinetics (Tmax, Cl, Vd, t½) – Margins of safety relative to human exposures based on AUC and Cmax – Aid in dose selection for further animal toxicology, FIH studies
  • 14. 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
  • 15. 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 $5K/time study Rat Single dose 29,000-75,000 7 day DRF 50,000-125,000 14 days 165,000-200,000 28 days 120,000-275,000 Dog Maximum tolerated dose (MTD) 30,000-65,000 7 day DRF 75,000-145,000 14 days 140,000-300,000 28 days 200,000-450,000 * Pricing will vary depending on the actual study design, route of administration, numbers of groups, numbers of animals, bioanalytical determinations, special tests required, etc.
  • 16. Typical IND-Enabling Preclinical Safety Studies (cont’d) Species Type of Studies Cost ($)* Monkey MTD 75,000-125,000 7 day DRF 100,000-240,000 14 days 265,000-410,000 28 days 280,000-550,000 Genetox Bacterial mutagenicity 6,000-8,000 Chromosome aberration 20,000-27,000 Rodent micronucleus 25,000-35,000 Safety Pharm hERG inhibition (patch clamp) ~16,000 CNS rodent 25,000-35,000 Cardiovascular (telemetry) 75,000-120,000 Respiratory 25,000-35,000 * Pricing will vary depending on the actual study design, route of administration, numbers of groups, numbers of animals, bioanalytical determinations, special tests required, etc.
  • 17. Typical IND-Enabling Preclinical Safety Study Generalized design of a repeated-dose rodent toxicity study Treatment Dose Main (Terminal) Recovery Toxicokinetics* Group (mg/kg/day) Male Female Male Female Male Female Vehicle 0 10 10 5 5 0 0 Low Dose A 10 10 0 0 9 9 Mid Dose B 10 10 0 0 9 9 High Dose C 10 10 5 5 9 9 • Number of animals depends on blood volumes required, number of timepoints, etc. • GLP-compliance needed for a pivotal (clinical trial-supporting) study • Toxicokinetic evaluations • Standard AND drug- or disease-specific endpoints • Histopathology
  • 18. Example 1: (NCE, Cancer Indication) • Program – Abbreviated, in 2 species – Focus on repeat-dose studies (cycles of treatment) • Issues – Multiple salt forms (available at different times) – Dose selection in studies (cytotoxic NCE for cancer, so based on STD10, not NOAEL) – 2 very different routes of administration (mechanisms of action dependent on route)
  • 19. Example 2 (Biologic, Non-cancer Indication) • Program – Full program, 2 species – Molecular target (human) • Issues – Target down-regulated in healthy/normal animals/humans (toxicology program in healthy animals? Or disease models?) – Test material quality (research/pre-GMP/GMP) – Need to consider efficacy data when setting doses in humans (MABEL approach), not just toxicology data – Need to evaluate immunogenicity (toxicology program; method development)
  • 20. Strategies for Success • Desired: a successful preclinical development program that results in a high quality regulatory submission that anticipates the questions of the Regulator • Understand that the animal toxicology data impact the clinical trial design, but the trial design can also influence the toxicology program • Co-ordinate Toxicology and Manufacturing – Ensure that high-quality (ideally, GMP) product is available (quantity, timing, quality/identity/purity/stability is documented) • Have a regulatory strategy – Pre-IND/Pre-CTA consultation? – IND submission preparation co-ordinated with timing of toxicology program?
  • 21. Strategies for Success (cont’d) • Become “IND-Ready”, even at the preclinical stage of development: – Pharmacology studies: proper reports (report numbers, etc., and consider electronic filing) – Regulatory toxicology considerations (GLP compliance, etc.) – Anticipate types of data that will be needed – Manufacturing considerations (timing, logistics, stability data, characterization and release of API/product, with an eye to GMP product for trials)
  • 22. Strategies for Success (cont’d) • Present a high-quality submission: avoid Regulatory “Red Flags” and address reviewer’s expectations (content, format, quality of data to support the proposed trial, etc.)
  • 23. Help Needed! • Regulatory Agency guidelines (Canada, US, EU) • Regulatory Agency consultations (Pre-IND or Pre- CTA meetings) • Published commentaries, opinions, and guidance • Meetings, Conferences, Colleagues • Consultants
  • 24. FDA Guidance Related to Preclinical Safety Evaluation • FDA Regulatory Pharmacology and Toxicology homepage: • www.fda.gov/cder/pharmtox/default.htm – Links to all FDA guidance documents (draft and final) › ICH › FDA – Internal policies and procedures – Contact names of Pharm/Tox staff within CDER • Other sources (examples) – Oncology Drugs - DeGeorge, et al., 1998. Regulatory consideration for preclinical development of anticancer drugs. Cancer Chemother Pharmacol 41:173-185. – Inhalation Drugs - DeGeorge, et al., 1997. Considerations for toxicology studies of respiratory drug products. Regul Toxicol Pharmacol 25:189-193.
  • 25. THANK YOU ! Valentia Lee-Brotherton, PhD Ashuren Health Sciences www.ashuren.com