Slide 1
Navigating the IND:
Planning for Success
Dr. Ba
y Rosenblatt, Ph.D.
SME Biotech Consulting
Target Identification
Candidate
Selection
Candidate Optimization
Pre-IND Evaluation
and Clinical Trials
Time
Conc
Biotech Process of Creating a Drug
t1/2
Target
Validation
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Why File an IND
A new biologic, drug, or device may not be entered into interstate commerce unless:
It is approved by the FDA as safe and effective
(biological license application [BLA], new drug application [NDA], pre-market approval [PMA], or other marketing approval)
OR …
An IND is in effect
(exempting the study from the premarketing approval requirements that are otherwise applicable)
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IND Checklist
Form FDA 1571
Table of Contents
Introductory statement and general investigational plan
Investigator’s
ochure
Protocols
Chemistry, manufacturing, and control data
Pharmacology and toxicology data
Previous human experience
Additional information
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The IND Goal?
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The IND Goal!
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Evaluate safety and explore efficacy and dose ranging
Obtain efficacy and safety data for approval
Post marketing commitments to monitor safety and efficacy
Evaluate safety and side effects
IND filing
BLA filing
Proof of concept, safety, potential toxicity, dosing strategy
Phase XXXXXXXXXXPhase XXXXXXXXXXPhase 3
Preclinical
Marketing
Phase 4
Getting to Market
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Drug Development is a Risky Business!
Longest R&D cycle of any industry
Increased investment has not decreased risk
Global development increases complexity
Tufts Institute estimates that the average cost to develop a new prescription drug is over $1B
Creativity and innovation must be joined by
Proficient Planning
Clear Thinking
Crisp Decision-making
Excellent Communication
Well-coordinated Teamwork
Efficient Execution
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The Duration of Drug Development
Keeps Increasing
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Comparability & Getting to Market
Specs?
Comparability?
Comparability?
Develop
Apply
Analyze
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Key Information Prior to First-in-Human Study (Small Molecules)
Pharmacologic Efficacy
Estimate of potency vs. efficacy, duration of action, and tolerance/ no tachyphylaxis
Full dose response relationship established
Minimally effective dose in at least one model of efficacy identified
Safety Toxicology (usually 28-day study in 2 species)
Viable therapeutic index/ exposure multiples, maximum tolerated dose identified
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Key Information Prior to First-in-Human Study (Small Molecules)
Pharmacokinetics/ Drug Metabolism
Human dose is estimated (via relevant pharmacologic models and allometric scaling) and practical
Predicted metabolic stability, bioavailability acceptable
In vitro hepatocytes, preclinical PK, toxicokinetic analysis
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Key Information Prior to First-in-Human Study (Small Molecules)
Chemistry, Manufacturing & Pharmaceutical Properties
Chemistry for large scale synthesis is feasible
Acceptable solubility, permeability and stability such that a human formulation supporting a 2-year shelf life can be developed
Initial Cost of Goods (COG’s) estimate provided
Additional Profiling of compound
Negative in Ames assay
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Preclinical Profiling Occurs in Parallel with Chemical Development
10 mg
25-50 mg
In vitro
screening
In vitro
profiling
XXXXXXXXXXmg
In vivo profiling
Acute toxicology studies
In vitro metabolism
1-2 kg
Chronic animal models
7-day dose ranging toxicology
Pre-Formulation Activities
GMP
10-15 kg
28-day chronic toxicology
Genotox panel, Safety pharm
Preclinical PK & metabolism
Clinical
Supply
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Information Related to Biopharmaceuticals
Species Cross-Reactivity Can Be A Major Issue
Many studies can only be conducted in non-human primate
Anti-drug antibodies can impact PK of protein
Safety Toxicology
Pharmacology studies have not shown unexpected safety risks
Tissue cross-reactivity screen has identified tox species
Manufacturing & Pharmaceutical Properties
Robust cell line; large scale manufacturing judged feasible
Initial formulation developed (lyo vs. liquid)
Acceptable solubility, permeability and stability for intended use in the clinic
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Section 4: General Investigational Plan
The FDA is Interested in:
Disease Target
Patient Population
Phase 1: Healthy Volunteers or Patients?
Monotherapy or Combination?
The Corporation is Also Interested in:
Development Strategy
Timeline
Year of Launch
Return on Investment
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One-third of Development Costs Spent By End of Phase 1
Molecule is safe at single and multiple doses; maximum tolerated dose established; key DDI’s, dose limiting adverse event profile known
Success rate still < 10%
Insufficient Exposure
Lack of Target Engagement
Unvalidated Targets
Polypharmacology
Safety
Best chance to manage risk is to have efficient Development Strategy to demonstrate POC
Studies should be designed to build a dataset that address key items needed to design pivotal studies
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Four Fundamental Questions for
a Development Strategy
Does the product profile address an unmet medical need, and how important a need?
Does the plan contain clear decision points that are linked to the most important aspects of the product profile?
Has the drug raised any questions during preclinical development that should be addressed in the strategy and are there clear decision points linked to those questions?
Is the speed of development appropriately aggressive?
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Drug Development
Timelines & Decision Points
Begin with the end in mind
key elements of label in Target Product Profile
plan clinical strategy to support claims
Develop clear criteria to enable crisp decisions
process requires prospective thinking
Reassess performance at predetermined intervals
have data changed your perspective
has competitive landscape changed
Update management as development proceeds
as probability of success increases, so does investment
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Target Product Profile
Clinical Indication
Patient Population
Projected number of patients CMC
Demographics
Juveniles? Preclinical/Tox
Child bearing age? Preclinical/Tox
Chronic vs acute Preclincal/Tox
Route of administration Preclinical/Tox
Dosage CMC/Preclinical
Con-combinant Medications? XXXXXXXXXXCMC/Preclinical
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Target Product Profile
Formulation (dependant on dose, route)
Concentration CMC/Preclinical
Liquid vs lyophilyzed CMC/Preclinical
Vial vs pre-filled syringe CMC/Preclinical
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Inter-relationship Between CMC and Preclincal/Tox
Characterization of Material used for Pre-clinical studies
Does it compare to material used for Phase I?
Same process?
Is it stable during the study?
Effects of degradants/contaminants on interpretation of study (i.e. aggregates in PK/PD)
Virological/microbiological profile
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Contents of the CMC section
Physical, chemical, and/or biological characteristics
Manufacturer(s)
Source and method of preparation
Removal of toxic reagents
Quality controls (e.g., identity, assay, purity, impurities profile)
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Contents of the CMC section
Description of testing and acceptable limits
Sterility (aseptic processing or sterilization process, sterility and endotoxin testing, etc.)
Linkage of pharmacological and/or toxicity batches to clinical trial batches
Stability information
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Contents of the CMC section
Source of material
Initial Construct
Banking system
Master Cell Bank (MCB)
Working Cell Bank (WCB)
Genetic Stability (EoP, CAL)
Description of Production Process
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Contents of the CMC section
Description of Purification Process
Analytic Characterization
Lot Release
Stability
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Effects of the TPP on the IND
Choice of Expression system:
Type of product (small protein vs large glycoprotein)
Level of expression needed
Choice of Production system
Scale
Batch vs Fed Batch vs Perfusion
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Effects of the TPP on the IND
Down Stream Process
Scale
Contaminant profile
i.e. High multidose requires better contaminant profile than low single dose
Formulation
Excipient safety profile
Stability
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Exercise
Your company: MUWBiotech has a new product in development: A recombinant humanized monoclonal targeting a receptor in the eye that is key in macular degradation. The drug must be injected inter-occularly to be effective. The patient population may include Juveniles. What other critical attributes may affect the TPP?
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Exercise: TPP Worksheet
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Sheet1
Target Product Profile Worksheet
Clinical Indication
Drug type Protein Nucleic acid Cellular Peptide Virus vecto
Mab DNA Stem cell Allegeneic Intact virus Strain
Cytokine RNA Adult VLP
Other hESC
Vaccine
Modified Yes/No
Type of modification Conjugated Differentiated in vitro?
Genetically modified?
Transient expression
Dosage Range weight adjusted?
Dosage Frequency Chronic Multiple Single
Daily
Weekly
Biweekly
Monthly
Semiannual
Annual
PRN
Route of administation i.v. i.p. s.c. p.o. i.n i.m
push
bolus
infusion
Formulation liquid lyophilized
target concentration
Sheet2
Sheet3
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Case Study
Use of PK studies to support Target Product Profile:
The PK studies were conducted in two animal species and used the final pegylated version of rBChE (human butyrylcholinesterase) for the first time. In general, the conjugation of proteins with polyethylene glycol (PEG) has been shown to decrease immunogenicity, increase circulating serum half-life and increase stability of recombinant proteins. The data from these studies confirm that the specific PEG chosen for conjugation to rBChE will significantly improve the half life of the protein in vivo.
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Case Study
The PK studies demonstrated that Protexia® had a half life of approximately four days in primates and three days in rodents when administered by intramuscular injection. These data compare favorably with what was predicted for the drug's PK profile in these animal species
"These results are very meaningful in that they show that Protexia® meets or exceeds our target product profile for use as a chemical nerve agent prophylaxis. The impressive half life data also confirm that the pegylation of rBChE as part of our manufacturing process achieved the goal of extending the half-life of the protein to one which makes it a feasible product for use in humans."
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Used for treatment of nerve gas (organophosphate) victims.
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Case Study
In this case, the TPP defined the need for development of a form of the drug that had an extended half-life.
This decision drove the CMC process to develop and characterize a PEGylated form of the drug
The PK data and the CMC data together allowed for continuation into the next phase.
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Biomarkers: New Tools for Drug Development
Provide Data on Pharmacological Effect in Human
Objective measurement
Enables decision-making, early termination of inferior compounds
Reduce Risk in Drug Safety and Efficacy
Identification/ Evaluation/ Validation Should Begin in Discovery
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Biomarkers: New Tools for Drug Development
Categories:
Target: does compound reach intended tissue?
Mechanism: does compound elicit biochemical change?
Clinical: does relevant aspect of disease state change?
Holy Grail: Su
ogate (Clinically Relevant) Endpoint
Requires extensive co
elation with clinical endpoint
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Proof of Concept
Demonstrate effect on short term clinical outcome
Ideally, enroll 200 or fewer patients for < 4 weeks
Longer studies require more extensive preclinical safety support
Not necessarily based on clinical efficacy
Biomarker panels, su
ogate markers can be used
May relate to demonstration of safety advantage
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Proof of Concept
Criteria should be well-defined in the Development Strategy in order to make clear Go/No Go decisions
Evaluate Emerging versus Target Product Profile(s); reassess risks
Do the data support the early commercial projections?
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Additional Considerations
Development in Asia considered, development plans consistent with local needs
Target product profile is viable for global markets
Global commercial assessment is available
Early Clinical Plan content and timing prepared
Invention Data Package filed, legal risk assessment provided
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Emerging versus Target Product Profile(s)
Refine Strategy, Define the Positioning and the
Phase 3 Program
key claims, key studies planned
decision on comparators for pivotal trials
manufacturing strategy
product positioning and pricing (global)