Clinical Trials

• Type A adverse drug reactions: Adverse drug reactions that are predictable from the known pharmacology of the drug
• CTX: clinical trial exemption
• CTN: clinical trials notification
• MRSD: Maximum recommended starting dose
• NOAEL: No observed adverse effect level
• Stages to complete to move to clinical studies

  1. Pre-clinical analysis
  2. Safety analysis
  3. File full HREC application for conducting phase 1 study
• Pre-clinical analysis

  • Confirm good PK properties, few known drug-drug interactions
  • Confirm the mechanism of action in vitro and in vivo, and identify biomarkers of response
• Safety analysis

  • Full toxicological assessment in 2-3 animal species (most relevant species)
  • NOAEL calculations in 2-3 animal species
  • Determine safety factor based on the toxicity profile
  • Calculate the MRSD
• File full HREC application for conducting phase 1 study

  • CTN or CTX application with TGA
  • Register the trial with ANZCTR
• Purposes of Clinical Studies

  • Establish efficacy of the drug
  • Confirm the absence or limited nature of toxicity in humans
  • Identify type A adverse drug reactions
• Descriptive studies include case reports and studies, cohort studies
• Intervention studies involve Phase I, II, III, and IV studies
• Preventative intervention studies

  • Subjects are disease-free
  • Does the drug reduce the risk of developing the disease
• Therapeutic intervention studies

  • Subjects have the disease
  • Does the drug reduce the morbidity or mortality caused by the disease
• Phase I

  • Open label
  • Single arm study
  • Small sample size
• Open label: Health providers and patients are aware of the treatment being given
• Single arm study: Only one group of patients; no placebo group
• Main question of Phase I?

  Will it hurt the patient?
• Participants of phase I

  • Healthy volunteers or patients with the condition
  • 100 or less people
• Parameters of Phase I

  • Measuring toxicity experience in patients
  • Test multiple doses of the same drug and identify the dose that does not produce toxicity
  • Test PK to define the route of administration and frequency dosing interval
• Observations (vital signs, personal experiences) can inform toxicity experiences measured during Phase I
• Outcomes of Phase I

  • Pharmacokinetic-guided dosing information (Route of administration, frequency of dosing)
  • Mechanism of action (identify biomarkers to measure response)
• Phase II

  • Double blind
  • Randomised trial
  • Larger sample size
• Main question of Phase II?

  Will it be beneficial for the patient?
• Phase II is usually an open-label, single arm study, but can be double-blind, placebo studies
• Phase II involves up to 1000 people with the disease
• Parameters of Phase II

  • Measure treatment response based on the mechanism of action (Pre-clinical bioassays inform observed biomarkers)
  • Measure safety and toxicity in patients
• Outcomes of Phase II

  • Confirmed efficacy (MOA matches pre-clinical data)
  • Confirmed safety profile for the relevant population
• Phase III

  • Double blind
  • Randomised trial
  • Larger sample size
• Participants of Phase III

  • 1000-10000 people with the condition
  • Broader eligibility criteria, but still a clean population
• Main question of Phase III?

  Is it better than existing treatments?
• Phase III is conducted as a double-blind, randomised trial compared against the best drug or placebo drug
• Parameters of Phase III

  • Measure the drug's efficacy and safety in comparison to the best drug or placebo
• Outcomes of Phase III

  • Confirmed efficacy (MOA) matches Phase II data
  • Confirmed safety profile in the relevant population
  • Confirmed that the test drug is better than the best drug or placebo
• Phase IV main question?


  Does it work in the community?
• Phase IV usually takes place after the drug is approved
• Most systems for Phase IV require voluntary reporting
• More than 10000 people with the specific disease are involved in Phase IV
• Parameters of Phase IV

  • Further evaluation of the long-term safety and effectiveness of new treatments
• Why is Randomisation Good?

  • Reduces bias
  • Addresses population variability and random error
  • Ensures that the experimental and control groups are similar at baseline
  • Increases the chance that the only big difference between the groups is the drug intervention