Preclinical Development Planning for Emerging Pharma and Biotech Firms

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Accelerating Development Preclinical Development Planning for Emerging Pharma and Biotech Firms Valentia Lee-Brotherton, PhD May 13, 2008 MaRS Workshop: From Benchtop to IND

description

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: http://www.marsdd.com/Events/Event-Calendar/Best-Practices-Series/ind-05132008.html

Transcript of Preclinical Development Planning for Emerging Pharma and Biotech Firms

Page 1: Preclinical Development Planning for Emerging Pharma and Biotech Firms

Accelerating Development

Preclinical DevelopmentPlanning for Emerging Pharma

and Biotech Firms

Valentia Lee-Brotherton, PhD May 13, 2008

MaRS Workshop: From Benchtop to IND

Page 2: Preclinical Development Planning for Emerging Pharma and Biotech Firms

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)

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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

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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.)

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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)

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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

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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.)

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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

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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

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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)

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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

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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

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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

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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

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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.

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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.

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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

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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)

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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)

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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?

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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)

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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.)

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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

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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.

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THANK YOU !

Valentia Lee-Brotherton, PhD

Ashuren Health Sciences

www.ashuren.com