Requirements for an IND

(Edward G. Spack, Vector BioSolutions, Fast Forward, LLC)

Definitions and concepts:

  • IND – investigational new drug
  • TPP – target product profile
  • NCE – new chemical entity
  • NDA – new drug application
  • CMC – chemistry, manufacturing, control
  • COA – certificate of analysis
  • GLP – good laboratory practices
  • GMP – good manufacturing practices

In drug discovery, time can be considered the most expensive “reagent”

  • Patent life is a very important consideration – there needs to be enough patent life to ensure commercialization
  • Also need to consider changes in the competitive landscape and/or business models over time

Begin with the end in mind (both the clinical and pre-clinical sides).

  • Clinical end: TPP to NDA to label – considerations:
    • Current drugs on the maket
    • Patient sub-populations
    • Duration of treatment
    • Bioavailability and dosing route
    • Patient compliance (e.g. oral administration better)
  • Pre-clinical end: IND application – considerations:
    • Toxicology studies to support the dosing regimen
    • Bioavailability shows target reached
    • Scalability of NCE production

Chemistry, manufacturing and control (CMC)

  • Initial hits and leads are not necessarily drugs.
  • Scaling up means more than just making more.
    • Maximize yield/purity of 1-2 analogs.
    • Define salt form or polymorph (focus on scalability and formulation).
    • Purity is essential (≥ 98%+), and impurities need to be defined and qualified.
      • Impurities ≥ 0.05% must be reported.
      • Impurities ≥ 0.1% must be qualified with toxicology studies.
    • Characterize stability.
    • Cost of manufacturing is a critical consideration (gram/kilogram quantities).
      • Simple steps, keep metals out
  • Certificate of Analysis (COA)
    • Identity – Structure elucidation
      • IR, UV, NMR, MS, elemental analysis, wet chemical
      • Color, taste, odor, texture, crystallinity
    • Strength - measure of therapeutic activity
      • Assay to measure potency; HPLC, biological activity
    • Quality – Measure of ingredient and manufacturing control
      • pH, optical rotation, specific gravity, viscosity, refractive index, dissolution, disintegration
    • Purity
      • Known impurities: Intermediates, reagents/catalysts
      • Known constituents: Moisture, organic volatile impurities, heavy metals, arsenic, lead, sulfate, chloride
      • Unknowns: Residue on ignition, readily carbonizable substances, loss on drying
      • Biological: Sterility, pyrogens, microorganisms
  • Issue of assay validation is very important at this point. Factors to consider:
    • Accuracy – Comparison of assay to existing measurements of analyte.
    • Precision – Agreement among individual test results (e.g. variance, standard deviation, coefficient of variation), including:
      • Repeatability- Intra-assay variability under the same operating conditions (same operator, same day).
      • Intermediate Precision- Intra-assay variability under varying conditions (different operator, different day).
      • Reproducibility - Variability of assays performed in different laboratories.
    • Specificity – Performance of an assay in actual biological matrix (e.g. serum, saliva) and in presence of potentially interfering agents.
    • Detection limit – Limit of detection (LOD) defined by spiking sample with a known quantity of analyte standard.
    • Quantification limit - Lower limit of quantitation (LLOQ) and upper limit of quantitation (ULOQ) of analyte that can be measured accurately.
    • Linearity and range – The range in which analyte concentration is proportional to assay readout.
    • Robustness - Effect of environmental variations (e.g. temperature, humidity) & performance variations (e.g. incubation times).
    • See RESOURCE – Guidance for Industry: Bioanalytical Method Validation
  • Considerations for CMC for biologics:
    • Monoclonal antibodies – Humanizing options with differing licensing fees and issues
    • Production cell line – Various cell lines with different production levels and licensing fees
    • Master cell bank – Need to maintain a high yield, well characterized, stable, clonal source of cells producing the biologic
    • Working cell bank – Aliquot from the master cell bank used for a production campaign
    • Characterization – Sterility, mycoplasma, endotoxin

Pharmacology and toxicology

  • Definitive GLP studies – IND-directed repeated dose toxicity studies
    • Documentation is critical (GLP/GMP).
    • Rodent and non-rodent (selected from range-finding studies).
    • Dosing strategy informed by intended route and frequency.
    • Recovery period (usually 2 weeks for a 28 day study).
    • Analysis
      • Clinical Observations, body weight, food consumption
      • Clinical pathology (clinical chemistry, hematology, coagulation)
      • Urinalysis, ophthalmology
      • Toxicokinetics (TK)
      • Determine drug profile and accumulation Day1 vs. Day 28
      • Histopathology (all tissues)
      • Identify MTD and No Observable Adverse Effect Level (NOAEL)
  • Genetic toxicology studies are generally required for all small molecule compounds.
    • Bacterial reversion assay – Salmonella/E.coli reverse mutation assay (Ames test)
    • In vitro mammalian cell assay – mouse lymphoma assay or CHO chromosomal aberrations)
    • Micronucleus assay (may be performed as part of GLP rodent toxicity study)
    • Second tier (in vivo) test may be required if a positive response in one of the above is observed – assays: transgenic mutagenesis, in vivo unscheduled DNA synthesis
    • Biologics exception - Biologics generally do not require the in vitro tests, but micronucleus may be requested as part of animal studies.
  • Additional safety testing for biologics
    • Tissue cross-reactivity panel – tests cross-binding of monoclonal antibody to non-target tissues expressing the same or related epitope
      • Generally > 30 tissue types analyzed from multiple healthy donors
      • Testing of binding to non-human tissues may no longer be required
    • Immunogenicity assay (not required at IND stage but should be taken into consideration)
      • The key issue is production of neutralizing antibodies
      • Generally, screening and confirmatory ELISAs are followed by a functional assay to confirm effect beyond binding.
      • Example: sub-populations of MS patients develop neutralizing antibody responses to beta-interferon
        • Preclinical development involves many components and steps (see FIG. 3)
  • It can take 2-3 years and more than $1 million for preclinical development (industry averages).
  • Team and project management is a key aspect for success.
  • Integrated preclinical development and early planning can help alleviate attrition down the line
    • Invest more in Phase 0 studies – Adds time, but generates more data to support hypothesis
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