Clinical Trials Course Materials

- resulted from medical experiments that were conducted on thousands of concentration camp prisoners without their consent - first international document which adWhat is the Nuremberg Code (1947)? vocated voluntary participation and informed consent - start of ethics consideration within clinical trials - has 10 principles of the code what is clinical research? investigation into human disease using human subjects, it looks at: - causes and origin of disease - prevention of disease - diagnosis of disease - outcome of disease - treatment of disease What is a clinical trial? biomedical or health related research studies in humans that follow a pre-defined protocol What is the aim of a clinical trial? to prove the trial hypothesis and reject the null hypothesis (you might not be able to accept the trial hypothesis but you must be able to reject the null hypothesis) How many phases of clinical trials are there? 4, 1-3 occur prior to a licence being granted phase I studies - this is the 1st time the drug is being used in a human - uses healthy volunteers (usually 19-25 year old men, females not often used in case fertility is affected) - very small number of subjects 20-80 - collect safety data, tolerability, pharmacokinetics, pharmacodynamics - dose response relationship (usually low dose used) 1/9 can sometimes be conducted in severely ill subjects (e.g. cancer patients, no other treatment available and a last resort) phase II studies - subjects have the target disease - larger than phase I but still small number of subjects (100-300) for a limited period of time - data collected on pharmacological activity, dose requirement, short term safety, efficacy of the drug/procedure - placebos used - specialist investigators - regulatory approval - ethics approval phase III studies - pivotal stage -> mimic real life situation - subjects with target disease - larger scale trial (1000-3000) in multiple centres for longer periods of time (could take years) - regulatory + ethics approval mandatory - not 'very ill' or child-bearing subjects - test this current intervention compared to the current market lead (efficacy) - adverse effects monitored - specific safety data - start prelaunch what is stage IIIa before submission of a new drug application (NDA) what is stage IIIb period between submission for NDA and receipt of marketing authorisation phase IV studies - after a medicine is marketed, post marketing surveillance - very large numbers of subjects, actual patients taking the medication - provide additional details about the products long term safety, pharmacovig2/9 ilance (adverse effects) - continued monitoring of efficacy - clinical trial must be designed - institutional reviews are completed - true volunteers, free to leave trial - careful monitoring of safety What is needed for a clinical trial today? - informed consent - good manufacturing practice (GMP) - good clinical practice (GCP) guidelines - standard operating procedures (SOPs) What is clinical trial design? - a plan of each element of the trial that is to be undertaken - aim is to ensure the results obtained from the trial are valid - element of bias should be avoided + source of bias should be controlled what are the sources of bias? subject choice nature of the disease (stage of the disorder) choice of treatment for individual subjects choice and accuracy of clinical measurement subject choice and bias - patient population needs to be defined (avoid investigator specific population = selection bias) - subject population may change at different stages of the trial: phase I - healthy volunteers phase II - criteria restrictive phase III - samples the whole patient population so trial results should be general 3/9 recruitment criteria for a clinical trial factors that influence if the subject is a fit candidate: 1. do they have the target disorder 2. the stage of the disorder the subject is at 3. any concurrent disorders 4. use of other medication 5. age and sex of subject etc (clear instructions of the eligible criteria have to be defined so that bias is eliminated) nature of the disorder and bias - trial design should consider the type and nature of treated disorder - acute (sudden onset) or chronic (long developing) - influences duration of trial, subject population, design of trial etc - some disorders are cyclical, others are seasonal, trials have to take this into account to avoid inherently biased results choice of treatment and bias - most trials are controlled, a comparative treatment used - compared the effect of the investigated intervention against a standard - the purpose is to ensure that the difference in groups originates from the difference in treatments not something else - 3 main types of control : no treatment, treatment with placebo and treatment with active comparator what is a placebo? - no active ingredient present in the treatment - identical appearance to the test compound (bias) - used to determine efficacy of the active ingredient - ethical issues - practical issues, withdrawal, sample 4/9 size, subject selection - may show efficacious and/or adverse reactions what is an active comparator? - a different active ingredient present in the treatment - identical in appearance to the test compound (bias) - used to compare efficacy and safety of the trial active - usually lead market competitor compound is used - practical issues: countries, registration, dosing may be different to ensure the test/control groups are comparable what is the aim of randomisation? the test/control group and subject population must be considered what are the types of randomisation? - restricted simple randomisation - un-restricted sample randomisation - alternative randomisation - stratified randomisation - random permutated blocks (in reality trials use a combination of the different randomisation types) No. in group A = no. in group B what is restricted simple randomisation subjects are randomly allocated to the treatment groups in equal numbers no. in group A ` no. in group B numbers in each group are NOT equal what is un-restricted sample randomisagenerally more subjects in the tested tion treatment group than the control group used best on a population > 1000 subjects are divided into alternative groups as they are enrolled NO BLINDNESS, comparability of the groups may be questionable what is alternative randomisation 5/9 subjects are divided into subgroups (STRATA) separate randomisation lists are prepared most common type of randomisation used what is stratified randomisation what are random permutated blocks for example: if age influences the outcome of treatment - randomisation has to accommodate for this - subjects are divided into subgroups - each STRATA is randomised separately - each treatment group contains equal numbers of subjects from each category subjects are in randomised blocks useful when continued enrolment onto the trial disadvantages: - during the recruitment process there may be undesirable differences in the numbers assigned to each treatment - if the entry characteristics of the patients change with time this could result in differences between treatment groups in the distribution of patient characteristics e.g. initial patients may be healthier than later patients not disclosing the identity of the treatment to some or all of the participating members of the trial what is blinding? types of trials that use blinding: - open - single blinded - double blinded 6/9 everyone (subjects, investigators, sponsors etc) knows who is receiving what treatment (no blinding at all) what is an open study? can only be used when knowing the treatment doesn't jeopardise the potential of bias only one side (investigator or subject) knows whos is receiving treatment - potential for bias what is a single blinded study? neither the subject nor the investigator know the identity of the treatments given what is a double blinded study? - this is the maximum control of bias - needs a contingency plan in case something goes wrong - trial design should describe how the blind nature of the trial is to be maintained if test and comparative treatments have different physical characteristics or dosing regimes practical issues with blinding this can be overcome by double dummy blinding (introducing placebos to account for the differences) a) parallel - each subject receives the test OR the control intervention and they are studied together what is comparative trial design b) crossover - each subject receives the test and the control intervention at different times during the trial +ives: - direct comparison between patient groups - no possibility of drug interaction 7/9 advantages and disadvantages of parallel comparative trial design - no issue with the stability of the disorder as the trials are shorter -ives: - subject groups have to be matched +ives: - subjects act as own control - good for investigating drug interaction - number of subjects is smaller advantages and disadvantages of crossover comparative trial design -ives: - trial time is longer - may cause a double blinded study to become unblinded due to side effects - possibility of period effect, results due to duration of treatment not the treatment itself - affected by the nature of the disorder what is the ICH International Council on Harmonisation - covers Europe, Japan and US - purpose = achieve greater harmonisation in interpretation and application of guidelines and requirements for product registration ICH guideline topics (4) Q = quality guidelines S = safety guidelines E = efficacy guidelines M = multidisciplinary guidelines What is the MRC Medical Research Council - publicly funded - supports research across biomed area - owns research units + works with other institutes and universities What is the EMA European Medicines Agency - established by EU, headquarters in London - promotes improvement in public and 8/9 animal health - offers advice on quality, safety and efficacy of medicinal products what is the MHRA Medicines and Healthcare products Regulatory Agency - government agency - responsible for ensuring medicine and medical devices work and are acceptably safe - an executive agency of the department of health 9/9