Essential Considerations for
Your IND Submission:
Objectives and Pitfall Avoidance
in Your Preclinical Program
Darren Warren
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
A Successful IND Program
Case Study – Concordia Pharmaceuticals
Clinical entry with a well characterized molecule
Outcome, Timelines, Resources:
Safety assessment supporting FIH Phase I trials
Commercially-viable prototype API process developed and
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)
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.
Research / Lead Optimization Yields
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.
DMPK & Early Development
In Vitro Metabolism
Ex. Plasma & microsomal stability, Metabolism profiling,
Protein binding, Species comparisons
Drug-Drug Interaction (DDI)
Ex. CYP Assays (induction, inhibition, etc.), UGT enzyme inhibition
Cell Transport Assays
Ex. 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
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
“My efficacy model / MED information
was developed in mice.
Is it prudent to continue with mice for
my preclinical rodent species?”
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
Drug Safety
Toxicology Studies
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?
Pitfall #4: not considering your formulations carefully
Pitfall #5: not conducting complete / robust pilot tox studies
Drug Safety
Toxicology & Safety Pharmacology Studies
Dose Administration & Schedule
Should be the same as intended clinical route & schedule
Dose schedule: daily (or multiple daily) vs. cycle dosing
Characterize dose-response relationship
Minimum of 3 dosages
Good separation between dosages to avoid exposure overlap
Dose to toxic effect or maximum feasible limit
GLP vs non-GLP
Any study can be conducted in accordance with GLP
GLP incurs increased cost and timelines
GLP (only) required for extrapolation to humans
Pitfall #6: Insufficient Test Article characterization and
demonstration of stability for GLP studies
Pivotal Drug Safety
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
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

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