Essential Considerations for Your IND Submission:

Objectives and Pitfall Avoidance in Your Preclinical Program 

Darren Warren

Overview

Focus on objectives for preclinical arm of the IND package, highlighting concerns and potential pitfalls

Will assume some familiarity with IND requirements

Chemistry considerations - high level concerns

Assumptions for IND structure, mindfulness of:Clinical indication / Clinical plan

Chemical production plans

Strategies for satisfying applicable regulations, guidances, and agency expectations

Local / regional concerns

IND orientation is drug development, not drug discovery

Case Study – Concordia PharmaceuticalsClinical entry with a well characterized molecule

Outcome, Timelines, Resources:

Safety assessment supporting FIH Phase I trials

Commercially-viable prototype API process developed and demonstrated

IND filed 10 - 12 months after lead selection, barring any technical or safety issues. Requires parallel activities including IND preparation and clinical plan determination(15-18 months for biologics)

Total project cost = $ 2.5 – 4.0 million (biologics can be more)

A Successful IND Program

The Quote: “I want to file my IND by next July. When can we start dosing?”

Pitfall #1: Rush to the first dose

Chemistry precedes Biology. Allow adequate Chemistry / Production timelines. First dose may occur 40% of the way into the full development timeline. There is significant interconnection between CMC and Toxicology activities prior to first dose.

Credit: XKCD.com

Understanding of the Desired Target (Primary Pharmacology) and Off-Target Activity

Understanding candidate MOA and biology of the target

Confirmation of desired pharmacology in animal model(s) of human disease. In vivo pharmacology assessment in relevant animal model(s). Key for Biologics

Characterized dose & exposure responses, identify MED. Define PK/PD relationships

Model dose response and dose schedules

Prediction of clinically efficacious exposure as well as dose and exposure multiples

Pitfall #2: Inadequate modeling of clinical use schedules and exposures. These information are critical for an efficient IND program.

Research / Lead Optimization Yields

DMPK & Early Development

In Vitro MetabolismEx. Plasma & microsomal stability, Metabolism profiling, Protein binding, Species comparisons

Drug-Drug Interaction (DDI)Ex. CYP Assays (induction, inhibition, etc.), UGT enzyme inhibition

Cell Transport AssaysEx. Permeability / MDR (P-gp), Drug or Uptake transporters

Pharmacokinetics (PK) & Toxicokinetics (TK)Active drug profiles (AUC, Cmax/Cmin, Tmax, T1/2, Vd, & Cl)

Characterized over range of dosages, including expected clinical and toxicology dosages (1x-10x efficacious dosages)

Single & Repeat-dose PK profiling (3-7 days)

Metabolite kinetics if needed

DMPK & Early Development

Critical endpoints / models:

Non-clinical species selection / justification

Formulation selection

Bioavilability

Models for saturation of absorption, metabolism, clearance/excretion, accumulation, gender and species differences (rodent / non-rodent).

Defined metabolic pathway and major metabolites; metabolite structure elucidation

Prediction of human DMPK responses

Alerts for Drug-Drug Interactions of clinical concern

Pitfall #3: Proceeding to pivotal GLP studies without a solid DMPK foundation. Risks errant dose selection and inadequacy of IND to support clinical usage plan.

A Question on Species Selection

No, not always. Consideration for Rat vs. Mouse:DMPK considerations for relevance to humans

Selection typically based on in vitro metabolism and PK data

Major metabolites must be expressed in tox species (small), or pharmacology must be expressed (large)

Mice are small

Potential Pitfall: Ill-advised consistency in species usage. Utility of MED and IND information is for extrapolation to humans

“My efficacy model / MED information was developed in mice.

Is it prudent to continue with mice for my preclinical rodent species?”

Drug Safety

Pilot Toxicology Studies

Initial toxicity readouts (single and multiple dose)

Required in each species, non-GLP

Tolerability - define the Maximum Tolerated Dose (MTD): single dose; morbidity/mortality, GI distress, severe CNS effects, respiratory distress, immune reactions

Repeat Dose Range-Finding Toxicity: repeat dose 5-14 days; identify dose & exposure responses, target organ toxicity; major organ system pathology; dose-limiting toxicities; repeat-dose TK

A go/no-go decision often follows: Toxicity profile? PK profile? Dose limitations? Off target tox?

Toxicology Studies

Pitfall #4: not considering your formulations carefully

Pitfall #5: not conducting complete / robust pilot tox studies

Dose Administration & ScheduleShould be the same as intended clinical route & schedule Dose schedule: daily (or multiple daily) vs. cycle dosing

Characterize dose-response relationshipMinimum of 3 dosagesGood separation between dosages to avoid exposure overlapDose to toxic effect or maximum feasible limit

GLP vs non-GLPAny study can be conducted in accordance with GLPGLP incurs increased cost and timelinesGLP (only) required for extrapolation to humans

Toxicology & Safety Pharmacology Studies

Drug Safety

Pitfall #6: Insufficient Test Article characterization and demonstration of stability for GLP studies

Safety Pharmacology

Required: Respiratory, CNS, Cardiac (in vivo), hERG

Determine potential for untoward pharmacology

Single dose pharmacology study, top dose near MTD

Small molecule – commonly stand alone studies

Biological – incorporate endpoints into non-rodent tox study

Oncology (end stage) – waived

Genetic Toxicology

Hazard Identification for DNA damage (mutation or chromosomal)

Pre-IND requires 2 in vitro assays (AMES & Mammalian chromosomal aberration)

Registration requires additional in vivo Chrom Ab assay (Micronucleus Test)

Prudence in conducting all 3 assays pre-IND

Pivotal Drug Safety

IND-enabling (pivotal tox studies, 2 species)

Typically 14-28 day repeat dose studies specifically designed to support SAD & MAD Phase I clinical studies

Intended as survey studies. Expected to include endpoints relevant to molecular class, anticipated toxicity, PD identification

Augment with specific assessments Ex. Local tolerance (dose site), Biomarkers, Immunogenicity

Blood volume limitations for large animals

TA preferred same batch as Phase I

Pivotal Drug Safety

Pivotal tox study goals:

Identify target organ toxicity/pathology, translational predictive safety biomarkers, assess reversibility or progression, assess local tolerance, determine adverse effects with NOAEL & exposure ratios.

Provide a basis for selecting initial clinical doses & escalations

Pivotal Drug Safety

Recommendation: Maintain purity of purpose = IND enabling

Pitfall #7: Over reaching for data or over designing studies. Avoid discovery investigations and addition of unneeded endpoints.

Pitfall hit list (common sources of disappointment):

Rush to the first dose

Inadequate modeling of clinical use schedules and exposures

Proceeding to pivotal GLP studies without a solid DMPK foundation

Not adequately considering formulations used in tox studies

Not conducting complete / robust pilot tox studies

Insufficient Test Article characterization and demonstration of stability for GLP studies

Over designing pivotal studies

Summary

Questions