By the time a phase 3 trial is being designed, sufficient preclinical microbiology and in vivo pharmacology data should have been generated to support use of a drug in the targeted indications.

As outlined in the microbiological studies in advance of a phase 2 trial section, data should be available from:

  • In vitro microbiology studies focused on pathogens associated with the target indication.
  • Animal models of infection, including pharmacokinetic/pharmacodynamic (PK/PD) data and data on specific disease states.

As also relevant to phase 2 trials, prior studies will be needed on:

  • Drug–drug interactions (assessing the impact of co-dosing, for example through checkerboard studies testing drugs together at different concentrations).
  • Susceptibility testing methodologies: Establishing the methods to determine the susceptibility of isolates, for:
    • Minimum inhibitory concentration (MIC) testing, including any deviation from standard CLSI/EUCAST methodology.
    • Disk diffusion testing, placing antibiotic disks on pathogen cultures to assess antibacterial activity.
    • Establishing appropriate parameters for quality control studies.
  • Drug stability in frozen panels, to ensure the accuracy of data on stored samples.

These methodologies follow standards developed by the Clinical Laboratory Standards Institute (CLSI) and the European Committee on Antimicrobial Susceptibility Testing (EUCAST). Guidance can be found in CLSI document M23 and on the EUCAST website.

Some differences exist between CLSI and EUCAST methodologies, especially with regards to disk diffusion testing. Guidance from both CLSI and EUCAST should be consulted before MIC or disk testing methods are finalized.

Preparing for a clinical trial

A range of practical issues will need to be addressed in advance of a phase 3 trial. These include:

  • Supply of MIC panels (multi-well plates with specific concentrations of antibiotic) to the study’s central microbiology laboratory, and specification of comparator drugs.
  • Supply of disks for disk diffusion testing to clinical trial site laboratories.

It is also important that all microbiological procedures are carried out appropriately at clinical trial sites and the central microbiology laboratory. Key activities may include:

  • Ensuring sample collection from trial participants is performed correctly at clinical trial sites.
  • Carrying out a capability survey across clinical trial site laboratories.

Establishing a testing protocol with any contract research organization (CRO) conducting or contributing to a trial.