Clinical trials Flashcards
Requirements for First Time in Man clinical trials
2 negative in vivo toxicity studies
In vitro metabolic data
Results of safety pharmacology
Clinical trial protocol (methodology, safety, integrity)
Desirable
Exact composition
Effects on tissue inc. kidney, liver
Interactions with other drugs/foods
Determination of starting dose
NOAEL determined in 2 of most-sensitive species
Human Equivalent Dose (HED) calculated by Allometric scaling
-Best for drugs with low hepatic metabolism, low volume of distribution, excreted predominantly renally
Safety factor applied
High safety factor used if:
Novel therapeutic target
Variability in bioavailability/effective doses
Unmonitorable effects
Non-linear kinetics
Purpose of Phase 1 Clinical trials
Dosing/Safety
Small group of healthy males
Find Dose-limiting toxicity by upwards titration until reversible SEs
Phase 2 Clinical trials
500 patients over 1-2 years
Safety: identify most common early ADRs- rule of three
Efficacy: Proof of concept or follow on testing
Dose near MTD
Phase 2 clinical trial example
Baricitinib Phase 2b trial
Various doses compared to placebo in RA patients remaining on methotrexate/DMARDs
Observation for common SEs
Responsiveness against placebo on DAS28
Safety (meta analysis of P1-3 trials)
-no increase in deaths amongst 3500 patients
Phase 3 clinical trials
Clinical benefit vs. existing therapies
Large, multicentre populations e.g. Euro/Japan/USA
Expanded efficacy testing to account for genetic/environmental variability
Subject to ICH CGP guidelines
Phase 3 clinical trial example
Rituximab Phase 3 for RA (multicentre DB RCT)
Already approved for Non-Hodgkins Lymphoma
Strict inclusion criteria
-Inadequate response to infliximab/etanercept
-No other hx of rheumatic AI disease
Patient-reported, physician global-scored results
Groups balanced for age/sex/disease activity
Also measured RF as an outcome (not Anti-CCP)
Higher rates of ADRs in placebo group
Phase 4 clinical trials
Post marketing surveillance
Observe for rare SEs/ADRs (Types C,D,E)
Periodic safety update reports published
Phase 4 clinical trial example
Withdrawal of Gemtuzumab from market
Drug used to treat AML, licensed early 2000s
Ongoing trials identified increased mortality excessive myelosupression in treatment groups
Interesting
Most common type of ADR- features of it
Type B (Hypersensitivity) Induced by the hapten hypothesis
Hapten Hypothesis
Greater immune responses are seen with drugs of a higher Mr
Drugs bind to endogenous macromolecules; antigen processing and presentation induces immune response
Bioactivation may lead to an immune response
