preclinical development planning for emerging pharma and biotech firms
Post on 17-Aug-2014
18.470 Views
Preview:
DESCRIPTION
TRANSCRIPT
Accelerating Development
Preclinical DevelopmentPlanning 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 planningand conducting a preclinical development programto 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 TestingPrograms
Preparation of Regulatory Documentation
Nonclinical Toxicology, Pharmacokinetics, Safety Pharmacology
In-House Discovery and Candidate Selection
Chemistry, Stability, (Bio) Analytical Development
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– $
– Experience in productdevelopment
• Clearly Defined Vision– Lack of clinical plan
• Manufacturing/CMCIssues– Lack of test article
– Formulation, scale-upissues
• Investor Pressure– Meeting (realistic)
timelines in the face ofissues (e.g., poorcandidate selection)
• Managing multipleservice providers– Contract laboratories
(preclinical, analytical)
– Contract manufacturer(supply of test article)
– 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)
– 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)
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 TestingProgram
• 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 (targetorgans, predict toxicology, reversibility, exposure levels,starting doses, etc.)
Perspective
• Preclinical development is an expensive investmentfor 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 experiencedindividuals
– Interpretation and positioning of results by experts
• If not designed, conducted, and/or interpretedcorrectly, preclinical studies can add considerabletime and expense to a program
General Toxicology Program Considerations
• Regulatory expectation (21 CFR Part 312): Nonclinicalsafety studies should be conducted to determine thesafety of proposed clinical trials
• Studies should be Conducted in accordance with GoodLaboratory 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
General Toxicology Program Considerations(cont’d)
• The preclinical development plan will depend on anumber of factors, including:– Product type and similarity to existing agents with known
safety profiles
– Proposed indication in humans (i.e., cancer vs rheumatoidarthritis)
– Proposed duration of administration (i.e., short term vschronic; 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(cont’d)
• Studies should be designed specifically for the drugunder 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 ofInformation, 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 (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 onAUC and Cmax
– Aid in dose selection for further animal toxicology, FIHstudies
Developing a Biologic is Different From a Drug
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
Differences between small molecules and biologics– a generalization
Typical IND-Enabling Preclinical Safety Studies
Species Duration of Studies Cost ($)*(Bio)analytical Assay development 1,000/day
Validation (per species) 15,000-20,000Running samples 70-100/sampleDose formulation Analyses $5K/time study
Rat Single dose 29,000-75,0007 day DRF 50,000-125,00014 days 165,000-200,00028 days 120,000-275,000
Dog Maximum tolerated dose (MTD) 30,000-65,0007 day DRF 75,000-145,00014 days 140,000-300,00028 days 200,000-450,000
* Pricing will vary depending on the actual study design, route of administration,numbers of groups, numbers of animals, bioanalytical determinations, specialtests required, etc.
Typical IND-Enabling Preclinical Safety Studies(cont’d)
Species Type of Studies Cost ($)*Monkey MTD 75,000-125,000
7 day DRF 100,000-240,00014 days 265,000-410,00028 days 280,000-550,000
Genetox Bacterial mutagenicity 6,000-8,000Chromosome aberration 20,000-27,000Rodent micronucleus 25,000-35,000
Safety Pharm hERG inhibition (patch clamp) ~16,000CNS rodent 25,000-35,000Cardiovascular (telemetry) 75,000-120,000Respiratory 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 testsrequired, etc.
Typical IND-Enabling Preclinical Safety Study
Generalized design of a repeated-dose rodent toxicity study
Treatment Dose
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
Toxicokinetics*RecoveryMain (Terminal)
• Number of animals depends on blood volumes required, numberof timepoints, etc.
• GLP-compliance needed for a pivotal (clinical trial-supporting)study
• Toxicokinetic evaluations
• Standard AND drug- or disease-specific endpoints
• Histopathology
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, sobased on STD10, not NOAEL)
– 2 very different routes of administration (mechanisms ofaction dependent on route)
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 diseasemodels?)
– Test material quality (research/pre-GMP/GMP)
– Need to consider efficacy data when setting doses inhumans (MABEL approach), not just toxicology data
– Need to evaluate immunogenicity (toxicology program;method development)
Strategies for Success
• Desired: a successful preclinical development programthat results in a high quality regulatory submission thatanticipates the questions of the Regulator
• Understand that the animal toxicology data impact theclinical trial design, but the trial design can alsoinfluence 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 oftoxicology program?
Strategies for Success (cont’d)
• Become “IND-Ready”, even at the preclinical stageof 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, stabilitydata, characterization and release of API/product, with aneye to GMP product for trials)
Strategies for Success (cont’d)
• Present a high-quality submission: avoidRegulatory “Red Flags” and address reviewer’sexpectations (content, format, quality of data tosupport the proposed trial, etc.)
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
FDA Guidance Related to Preclinical SafetyEvaluation
• FDA Regulatory Pharmacology and Toxicologyhomepage:
• 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 fortoxicology studies of respiratory drug products. Regul ToxicolPharmacol 25:189-193.
THANK YOU !
Valentia Lee-Brotherton, PhD
Ashuren Health Sciences
www.ashuren.com
top related