Lecture 57 – clinical evaluation of drugs Flashcards
Drug regulation policy’s
o Australia = TGA
o USA = FDA
o Europe = EMA (UK = MHRA)
o Regulates the manufacture, sale and advertising of medicines
Biologics control act, 1902
o St Louis USA
o 10 children died
o Received injections of diphtheria-anti-toxin contaminated with live tetanus bacilli
o Subsequent act to ensure “good manufacturing” of drugs
The federal food, drug and cosmetic (FDC) act, 1938
o Kansas City 1937
o 107 people died from renal failure after ingesting sulphanilamide diluted with diethylene glycol
o Subsequent act to ensure safety of drugs
Birth defects from Thalidomide – Kefauver-Harris amendments
o Sydney, 1961
o Dr William McBride described 3 children with phocomelia
o Thalidomide identified as cause of this “unusual” birth defect
o Subsequent act to ensure “efficacy” of drugs
Drug regulation overview
o Efficacy
o Safety
o Manufacturing
o GMP – good manufacturing practice
o GLP – good laboratory practice
o GCP – goof clinical practice
o Main role is to detect and prevent FRAUD
FDA process of drug development
o Step 1 = discovery and development
o Step 2 = preclinical research
o Step 3 = clinical research
o Step 4 = FDA review
o Step 5 = FDA post-market safety monitoring
Phase 1
o Study participants: 20-100 healthy volunteers or people with condition/disease
o Length of study: several months
o Purpose: safety and dosage
o Approximately 70% of drugs move to next phase
phase 2
o Study participants: up to several hundred people with the disease/condition
o Length of study: several months to 2 years
o Purpose: efficacy and side effects
o Approximately 33% of drugs move to next phase
phase 3
o Study participants: 300 to 3000 volunteers who have the disease or condition
o Length of study: 1 to 4 years
o Purpose: efficacy and monitoring of adverse reactions
o Approximately 25-30% of drugs move to next phase
Phase 4 (post-marketing)
o Study participants: several thousand volunteers who have the disease/condition
o Purpose: safety and efficacy
drug evaluation
o FDA
Application of NDA
Product IND
o Europe
Application of CHMP
o Australia
Application of ACPM (follow submission and report in EU format)
Post-evaluation
o PI = product information (label)
o CMI = consumer medicines information
o Registered or listed on ARTG
o Funding
Types of trial designs
o Parallel trial design
o Crossover trial design
o Matched pair trial design
o Withdrawal or enrichment trial design
o Factorial trial design (double dummy)
Factorial trial design
o Two pairs 2X and 2Y
o One X gets active treatment, one X gets placebo
o One Y gets active treatment, one Y gets placebo
Withdrawal or enrichment trial design
After the first specified period of time has elapsed, participants are randomised into two groups, one of which receives a placebo instead of continuing to receive the active treatment
Matched pair trial design
After screening, participants are matched into pairs. Within each pair, one participant is randomised into treatment A whilst the other is randomised into treatment B
Crossover trial design
o Patient X and Y are randomised into two different treatment arms Patient X receives treatment A during the first period of th study; patient Y receives treat B. after the first period is over, there is a washout period. Patient X then receives treatment B for the second period of the study while patient Y receives treatment A.
Parallel trail design
o After screening, patients are randomised into separate treatment groups. They remain in these treatment arms for the duration of the trial, analysis and follow-up activities.
Orphan drug act
Drug/biologic may be “designated” as an “orphan drug” if it is to prevent, treat or diagnose a disease/condition that occurs in <200,000 patients in US
Dosage in children depends on:
Pharmacodynamics, pharmacokinetics, therapeutic window, idiosyncrasy
Adverse events (AEs)
o During drug development:
SAEs (serious adverse event)
SUSARS (suspected unexpected serious adverse reaction)
o Post marketing
ADRs (adverse drug reactions)
Boxed warning (draw attention to the most serious of safety issues)
