Clinical Trials Study Documents

1. Type A - ADR's: Related to the drugs pharmacological action 2. Type B - ADR's: Unrelated to drugs pharmacological action 3. Type C - ADR's: Continuous reactions resulting from long term drug use (e.g., analgesic nephropathy) 4. Type D - ADR's: Delayed reactions - not observed until months/ years following drug use (e.g., alkylating agents leading to carcinogenicity) 5. Type E - ADR's: End of use reactions - leads to various withdrawal syndromes 6. Preclinical testing: - a number of lead compounds have been identified + initial screening tests have been conducted showing these compounds show potential - over 1-4 years more comprehensive preclinical testing 7. What do preclinical trials assess ?: Whether a drug is effective and safe from using in vitro and animal models 8. What does preclinical testing include?: - Basic laboratory investigations - In vitro testing - Evaluation in animal model (in vivo testing) 9. Preclinical testing: Basic laboratory investigations: - Physicochemical evaluation - Formulation studies 10. Preclinical testing: In Vitro testing: - Ames mutagenicity tests etc. 11. Preclinical testing: Evaluation in an animal model (in vivo testing): - initially using a single species, sex etc. - Progressing to more complex tests using multiple species, sexes, comparators, higher order species, etc. 12. Phase 1 clinical trials: - First administration and safety evaluation in humans - small number of healthy volunteers - determines safe and appropriate dose of the drug in humans 13. Phase 1a trials: - Explores the safety, tolerability and pharmacokinetic to support patient studies - uses healthy subjects , 40-60 - cost $200-400 - takes 6 months - uses escalating Single-dose, placebo-controlled, randomised, double blind Collects data on: - Adverse events - Pharmacokinetic parameters - Pharmacodynamic measures 14. Phase 1b trials:: - Explores the safety, tolerability and pharmacokinetic to support patient studies - uses healthy subjects , 30-50 1/5 - $200-400 - takes 6 months - uses escalating Repeat-dose, placebo-controlled, randomised, double blind Collects data on: - Adverse events - Pharmacokinetic parameters - Pharmacodynamic measures 15. Phase 2 clinical trials:: - Early exploratory and dose-finding studies in patients - evaluates the effectiveness of the drug and identifies any potential side effects 16. Phase 2a trials:: - Explores preliminary safety and efficacy to support go/no-go decisions - Uses patients , 50-200 - $500-1000 - takes 9 months - 2 years - uses intended clinical dose and regimen based on phase 1a & 1b results - Usually placebo-controlled, randomised, double blind + Sometimes open label (non-blinded) Collects data on: -Adverse events - PK parameters - Preliminary evidence of efficacy - Proof of concept 17. Phase 2b trials:: - It is confirmatory and aims to select doses to support registration - uses patients with 1 or more indications - uses 200-500 people - $2000-5000+ - takes 2-3 years - uses selected dose levels / regimens , is randomised and double blind Collects data on: - Statistically rigorous analysis of dose-response relationships - Confirmation of clinical dose and regimen for optimum efficacy, safety and tolerability 18. Phase 3 Trials: - Large-scale studies in patients - Evaluates the effectiveness of the drug compared to standard treatments Results from this stage: - Reported in peer-reviewed scientific journals + professional meetings 19. Phase 3 trials breakdown:: - It is confirmatory and has efficacy and safety data to support registration 2/5 - can include pharmacoeconomic evaluation - Uses patients with the target indication but included different groups e.g., age, ethnicity - uses 500-1000+ people - $2000-10,000+ - takes 2-5 + years - Uses Selected dose level, randomised and double bind. Collects data on: - Statistically rigorous measurements demonstrating safety and efficacy in comparison with placebo or existing therapies - it may include pharmacoeconomic analysis 20. Phase 4 Trials :: - Post marketing surveillance (safety monitoring) of patients (Pharmacovigilance) - serve to collect any info relating to safety concerns related to the use of a particular drug 21. Phase 4 trials breakdown:: - It is obligatory + post-marketing surveillance to reveal unexpected adverse effects or toxicity - Uses treated patients - Uses 10,000 + people - $10,000+ - takes 2-4+ years Collects data on: - Adverse events 22. Black Triangle Drugs:: - used on new medicines and vaccines that are under additional monitoring (high vigilance) - have an inverted black triangle symbol (¼) in package leaflet with summary of characteristics, together with a short sentence explaining what it means 23. Who is responsible for the maintaining of the list of black triangle products ?: European Medicines Agency (EMA) 24. What is trial design dependent on ?: The drug being considered and whether comparative treatments are available. 25. Comparative trials (controlled trials): Make use of a comparative treatment to yield a treatment group (taking the new drug) and a control group (given standard treatment or placebo). This approach allows you to evaluate if a new drug is superior to existing treatment. 26. Parallel groups: - a simple and commonly used clinical design which compares two treatments - usually seen when a test therapy is compared with a standard therapy in a comparative trial 3/5 27. Crossover trials: - involves the administration of two or more treatments to the sample patient group over a specific period of time - Randomisation is used to determine the order in which the patient receives each treatment i.e. treatment A first then B or vice versa. 28. What is an advantage of crossover trials ?: - It reduces the variability between patients as comparison of treatment A versus B is made on the same patient. 29. Randomised trials:: - Trial participants are placed randomly into one of the study groups e.g., trial, control etc. - this is to ensure each group contains a similar mix of participants 30. Advantages of Randomised Trials ?: - Removes investigator bias when allocating participants to treatment groups manually - Helps to guarantee the statistical validity of the study results. 31. Blinded Trials: People taking part in trial are not told which group they are placed into. 32. Double blind trials: Both participants & doctor do not know who is assigned to which study group - this avoids the doctor's expectations from being communicated to patients + influencing the trial results - all treatments are made to look as similar as possible 33. Type 1 Error: - The trial reports a difference between treatment A and B, where none actually exist = a false positive Probability of incurring error = significance of the result (e.g. p value < 0.05 indicates a significant result) 34. Type 2 Error: - No difference is found between treatment groups where one actually does exist = a false negative Probability of avoiding error = the power of the trial and a trial is usually designed to have a power of between 80-90% 35. Selection of trial: Important factors: Selecting an appropriate population of participants is important: - a group where benefit is expected - inclusion criteria e.g., age, organ dysfunction will be restricted at beginning of the clinical trials - sample size is critical 36. What tests must an individual undergo to asses their eligibility for clinical trials ?: - A full physical examination - Documented full medical history - ECG (12-lead) - Vital signs: BP., heart rate, respiratory rate and temperature - Height, weight and BMI 4/5 - Haematology, FBC and urine analysis - Hepatitis and HIV Screening - Urine screen for drugs of abuse - Alcohol breath-testing - Nicotine / cotinine testing (if only non-smokers must be recruited) 37. Describe Clinical trials ?: - Build on data already collected from pre-clinical studies - can assess both drug efficacy and safety - involve less than 10 up to many thousand of participants 38. What type of Data do Phase 1 trials aim to collect ?: Phase 1 trials collect data relating to adverse events, pharmacokinetics and pharmacodynamics. 39. What does a phase 1b clinical trial assess ?: - assesses more complex dosage patters (repeat dose) 40. What does it mean if the clinical trial is 'open labelled' ?: Both the clinical staff and participants know which trial group each participant is assigned to. 41. What is considered when designing a clinical trials ?: - Desired outcomes - Adequate representation of the intended patient population - Statistical validity - Ethics of placing patient with an illness on the placebo group of a trial 5/5