Clinical Trials Flashcards
Pre-Clinical trial requirements
- General pharmacology (dynamics and kinetics)
- Acute toxicity (LD 50)
- Chronic toxicity (2 animal species)
- Reproductive toxicity
- Carcinogenic
- Mutagenic
- Chemical/ pharmaceutical data
Clinical Trial Start Requirements
*Written protocols
* Approval from Institutional Ethics Committees (IRB)
* Approval from MOH
Phase I Aims
AIMS:
* Open study to establish tolerability and safety in human
* Pharmacokinetics: dose range, maximum tolerated dose, adverse reactions, route of administration
- Safety
- Biological effects
- Pharmacological effects
Results:
* Safe Dosage Range + Optimal administration route
* Compared with preclinical studies
Phase I people involved
Who: Healthy volunteers or patients who suffer from the disorder for which the drug is intended
Selection of healthy volunteers/patients
* N=25-50
* 18-35 years or older
* Usually male
* Free of substance abuse
* No clinical or laboratory abnormalities
By Who: Investigators are pharmacologist or specialists in that particular disorder or any qualified person
Phase I investigation parameters
Investigations in HUMAN
* Vital Functions: Cardiovascular(CVS), Cognitive(CNS), Lung
* Blood & Urine: Sampling, Safety Tests, Determining Drug Concentration, etc
* Other Parameters: Weight, Height, Body Temperature, etc
Phase I facility
- Physical facilities : beds, equipment, Pharmacokinetics, laboratory
- SOPs: for all routine tasks, specific clinical trial procedures
- Trained clinical staff: medical, nursing, technicians
- Access to acute medical services
- In-patient clinic, with comprehensive medical surveillance, emergency and intensive care facilities
Hypersensitivity
Localised: rhinitis, asthma; rash, urticaria
Generalised (if it involes more than multiple systems): Anaphylactic shock
Toxic Epidermal Necrolysis
(TEN) : immune-complex mediated
Stevens-Johnson syndrome(SJS)- target lesions, mucosal involvement(conjunctivitis) : immune-complex–mediated
Dose Selection
Principle of Dose selection: Minimal risk of toxicity
1) Convert TOX studies to a human equivalent dose
2) Apply a safety factor (10-fold) to give Max. Recommended Starting Dose (MRSD)
3) MRSD adjusted on basis of predicted pharmacological action
Initial dose: 1/100 to 1/50
Max dose : 1/10 to 1/5
Dose Escalation / Dose Ranging:
* 2× previous dose at each increment
Phase I: Study designs
- Intra-individual: single dose, multiple doses
- Parallel group: compares two or more treatments.
Participants are randomly assigned to either group, treatments are administered, and then the results are compared
Phase II aims
Early studies if the drug is effective and safe in in patients with target disease
- Small/medium size studies (100-200 patients), in well defined disease categories
HOW: controlled trials, single centre, closely supervised by specialists, short/medium duration, determine dose range, PK data
Phase IIa
Phase IIa
* Pilot clinical trial to evaluate efficacy and safety in patients with target disease
* Selected patients
* Dose response, safety and efficacy endpoint
Phase IIb
Phase IIb
* Well controlled trial to evaluate efficacy and safety in patients with target disease
* Eg: placebo, active comparator, blinded, parallel group study, 150 patients for 8 weeks
Run-in period
- Run-in period is used in condition/disease that may alter
spontaneously with passage of time, e.g. HPT that settles down with rest, those with wax and wane diseases - To study compliance (allow subjects to decide before the randomization)
- To exclude those with high placebo effect
“Control” group
- Provides a reference for the results in the study
- To eliminate the effect of natural variability of the disease.
- No treatment (placebo) “placebo- control trial”
- For ethical reason: Subjects receive a know effective treatment can be a control group: “active-control trial”
Wash-out period
- When patients were on pre-trial medicine
- Before the trial or during cross-over design to ensure that the effects of the treatment is not carried over to next
