Lesson: Preclinical Phase 0-4 Flashcards
What happens in the pre-Clinical phase?
Under FDA GLP requirements a sponsor must first submit data showing that the drug is reasonably safety for use in initial small scale clinical studies.
What happens in the pre-clinical phase?
File IND with FDA to begin phase 1 Trail.
-Animal pharmacology and toxicology studies
-Manufacturing information
-Clinical protocol and investigators information
In vitro preclinical trials
Pharmacodynamic
-Needed for better characterisation by providing evidence for the desired biological effect of a drug
-Providing insight into potential toxicities to establish a human starting dose.
Pharmacokinetics The absorption tissue distribution, metabolism excretion, volume of distribution and half life of drug are quantified
What happen in phase 0 clinical trials?
-Exploratory IND study or First in human trial conducted with FDA 2006 guidance
-Know as Human Micro Dosing Studies
-Subject: 10-15 healthy volunteers
-gives no data on safety or efficacy being by definition a dose too low to cause any therapeutic effect. They are not mandatory are case to case based
Phase I vs phase 0
Phase I:
establish the recommended phase II DOSE
Determine safety and AE
18 or more patients
Multiple dosing
Phase 0:
Establish the dose for target modulation
Archive desired exposure for target modulation
Required pharmacodynamics assays integrated
8-10 subjects
One or limited dose
What is the goal of phase 1 clinical trials?
Safety( pharmacovigilance )
Tolerability
Pharmacokinetics
Pharmacodynamics
Determine the dose/dosing regimen that achieve target drug exposure in all relevant populations
What are favorable outcomes of a phase 1 drug (Absorption)
High absolute bioavailability with low variability
Exhibit linear, dose-proportional increase in Cmax
Cmax not significantly affected by concomitant food, pH-altering medication, grapefruits, alcohol etc
What are favorable outcomes of a phase 1 drug (Distribution)
Research the target sites of action immediately and at effective/ nontoxic concentration
Doesn’t accumulate in non-target organs
Not significantly bound to plasma protein
What are favorable outcomes of a phase 1 drug (metabolism/excretion)
Not a narrow therapeutic index drug
Does not prolong the QT internal
Not a significant inhibitors or inducer
Does not trigger formation of neutralizing anti drug antibodies or organ damaging immune complex (immunogenicity )
What do phase 1 clinical trials impacting on labeling?
-dosage and administration
-dosage forms and strengths
-contraindications
-warnings and precaution
-drug interaction
-use in specific populations
-overdosage
-clinical pharmacology
-patient counseling information
What happens in phase 2 clinical trials ?
-Once a dose or range of doses is determined, the next goal is to evaluate whether the drug has any biological activity or effects.
-Designed to assess how well the drug works as well as to continue phase I safety assessment
What happens in phase IIa ?
Goal: to determine the therapeutic efficacy
Pilot: dose response determination/ determination of target population
Trial design: open label or single/ double blind/ dose escalation/parallel dose response
What happens in phase 2b ?
Pivotal studies.
Objective: focus on aspects of phase IIa/ Blinded/Placebo or other concurrent control trial.
Subjects: similar to phase IIa
What happens in phase 3 ?
Randomized
Controlled
Multi center
# the patient are selected based on diseases/medical condition
How effective the drug is in comparison with the current gold standard treatment
What causes failure of phase 3 ?
Inadequate basic science
Flawed study design
Suboptimal dose selection
Flawed data collection and analysis
Problem with study operations
