Clinical trials Flashcards
CTIMPS
clinical trials investigational medicinal product
what makes a study a CTIPM
a study that looks at safety or efficacy of a medicine, foodstuff, placebo in humans - as defined by the Medicines for Human Use (clinical trials) regulations 2004
Examining the safety and efficacy of an IMP includes
Intending to discover or confirm the clinical, pharmacological and/or other pharmacodynamic effects of one or more medicinal products,
identify any adverse reactions or
study the absorption, distribution, metabolism and excretion
adverse reaction
health complication resulting from taking a drug
what is an investigational medicinal product (IMP)?
new drug
established drug which you want to assemble in a different way from its licence/marketing authorisation
used for an indication not included in its authorisation.
How do we determine whether a study is a CTIMP?
Algorithm on MHRA
website (table which has questions/sections that it needs to be to be an IMP)
what won’t the Algorithm on MHRA website tell you
what clinical phase of study is
all clinical trials should be approved by
Sponsor (eg NHS Trust or Pharmaceutical company)
NHS Research Ethics Committee
If within the NHS, Health Research Authority
In UK, CTIMPs additional approved, overseen and monitored by:
Medicines and healthcare products Regulatory Agency (MHRA)
Who are clinical trials for?
Who needs to be convinced?
Approval agencies (UK: European Medicines Agency /MHRA) - Data used as evidence for licensing / authorising the drug
Prescribing doctors / NHS / National Institute of Clinical Excellence
- Especially opinion leaders
Patients
- Some countries allow direct-to-patient marketing of prescription drugs
- Patient groups may also be active and vocal
Insurance agencies
Pharmaceutical marketing teams will use information gathered in clinical trials
When planning a clinical trial you need to consider…
What condition do you want to licence / label it for?
Who are the patients?
Are there different groups or special populations (eg elderly or renal patients)?
What real benefit to patients do you want to show?
Lower event rates?
Do you need Patient Reported Outcome Measures (PROMs?)
But be flexible
Stuff happens
Sildenafil (Viagra) was originally developed for angina, but volunteers reported an interesting side effect!
Drug can be licenced for lots of indications – but you need to
be able to show it is effective in all of them
what was sidenafil originally developed for but what is it used for now
angina originally but now used erectile disfunction
What information must the clinical trials support?
Dosing regime
Including any special populations (e.g. elderly)
Clinical pharmacology/mechanism of action
Drug interactions
Contraindications
Warnings
Safety & side effects
what happens in the PRE-clinical trials
drug discovery and pharmaceutical development
Optimise scale-up for quality and cost
Develop analytical methods:
Assay methods
Develop formulation
Multiple forms (e.g. i.v., solid & liquid oral?)
Specialised forms? (e.g. slow release)
Stability (preferably at room temperature)
what 2 things would happen in the preclinical trial with understanding animals…..
- Animal Pharmacokinetics
Understand absorption, distribution, metabolism and excretion
Active metabolites will need to be understood in detail - Animal safety assessment
Safety pharmacology
In vitro and in vivo toxicology
phase 1 clinical trial
First in human use
determine the lowest dose at which the treatment is effective and the highest dose at which it can be taken without causing harm.
phase 2 clinical trial
Tend to be first in patient use
Exploratory efficacy (Phase IIa)
Dose ranging and efficacy (Phase IIb)
phase 3 clinical trials
Multi-centre trials
Pivotal efficacy and safety
phase 4 clinical trial
post marketing surveillance
how many volunteers would you have in phase 1 studies
50-100
what is “first man” SAD - what is it for?
first man single ascending dose
- for safety and pharmacokinetics
how would you do single ascending dose
Dose is escalated in successive cohorts
ascending repeat dose - safety and pharmacokinetis
what would you look at in phase 1
- clinical pharmacology,
- bioavailability and comparisons of alternate formulations
- Absorption, distribution, metabolism, excretion
- Including radiolabel studies
- Safety pharmacology (e.g. cardiac and hepatic function)
- Subgroup pharmacokinetics (e.g. elderly, ethnic)
- Drug-drug interaction
why is the aim of the SAD
Aim to find the maximum tolerated dose
Or the maximum dose that can be given
Or a maximum pre-specified limit (should be clearly above expected therapeutic dose)
who is used to work out SAD
Usually men aged 18-45
Double-blind placebo-controlled
what is assessed through SAD
Assess safety, tolerability & pharmacokinetics
PK: Cmax, Tmax, AUC, t1/2, VD, Cl
Assess more detailed pharmacokinetics (e.g. fasted vs. fed) at one dose (e.g. 25% of maximum tolerated dose)
multiple ascending dose
phase 1
- Healthy volunteers
- Escalate dose over days
- Typical duration 7-10 days for drugs to be given chronically
- Monitor safety, tolerability and PK as with Single Ascending Dose study
phase 1 - pharmacodynamic studies
drugs under investigation may have a pharmacological effect in healthy volunteers that relates to target clinical effect in patients (e.g. heart rate, gastric acid secretion)
- may give confidence that drug will work - use with caution
may sometimes put mild disease in patients - phase 1 - patient volunteers - blurring boundaries w phase 2
phase 1 -other
drug- drug interactions - (steady state of drug then single dose of interacting drug - monitor pharmokinetics)
focus on drugs used for the same condition
formula comparisons
radiojlabel studies - detailed ADME
specific safety pharmacology - ECG - monitor QT prolongation (risk of ventricular arrhythmia
example of where phase 1 has gone wrong
BIA 10-2474 caused one death and five severe brain injuries.
what is phase 2a and how many patients would you use
exploratory efficacy - 20-50 patients
Phase 2a
first studies in patients (selected to maximise chance of seeing clinical effect)
proof of concept - marker of effect
give confidence to continue
design - double blind place or add on to current treatment (when unethical to withhold treatment)
what may be necessary in IIa
flexibility as it is exploratory
what is phase 2b? and number of patients?
dosing range
50-200 patients
Phase IIb is bridge between
- Phase IIa and Phase III
- Phase IIb is last chance to be flexible
what is the primary aim of phase 2b
to determine the dose to be used in Phase III multi-centre studies and to determine the expected efficacy measure
Phase IIb will be the basis for statistically powering Phase IIIb
Phase IIb is critical: a mistake here could mean that the Phase III trial is inconclusive
what is the design for phase 2b
Randomised double blind* placebo controlled often preferred
*Neither patient nor trial docs know which has been given, until all results decoded at end of trial
Comparator arm may also be performed at this stage
when is the last chance to have any flexibility in the clinical trial
phase 2b
phase 3
Phase III – confirmatory efficacy and safety
what happens in phase 3
- multi trial centres (one trial in each major market/country)
- design criteria are locked down before trial (end point clinically meaningful)
- Selection of patients must match planned prescribing label
what are the designs of phase 3 trial
Randomised double-blind placebo-controlled
Comparator trial
Essential for European approval unless no comparator exists
Need to decide whether to test for superiority or equivalence (with advantage elsewhere, e.g. better safety or preferable dosing regime)
what is compared in phase 3
Non-inferiority vs. Superiority vs. Equivalence
Non-inferiority:
The new drug is at least as good as the old drug.
Superiority
The new drug is better than the old drug.
Equivalence
The new drug is equivalent to the old drug.
statistical significance (alpha)
the probability of false positive (type 1 error) and is reported after a trial
eg. p<0.05 means there is a less than 5% chance of the declared effect being mistaken
statistical power (beta)
the probability of detecting a positive response (at a given level) if one exists.
1-beta is the probability of a false negative is a positive effect exists
when is statistical power normally calculated
before a trial to help set sample size - frequently not reported
what is phase 3b
label and licence extensions
eg Studies in children, additional dosage forms, related clinical conditions
Doctors are free to use drugs off-label without these studies, but no marketing can take place.
what is phase 4
post marketing pharmacovigilance
Drug companies conduct post-marketing / licencing pharmacovigilance to monitor long term safety of a drug after its launch.
Findings are published in Periodic Safety Update Reports
where would you be unlikely to pick up rare but serious side effects
phase 3 trials
a fatal reactions may occur in fewer than 1 in 10,000 patients
eg thalidomide - picked up post marketing
What happens after authorisation and post-marketing pharmacovigilance?
Unexpected adverse events and reactions of all licenced drugs are reported to MHRA by healthcare professionals or patients using the ‘yellow card’ system.
Practicalities of setting-up and running a CTIMP
Is the study a CTIMP?
Are you testing the drug or using it as a tool?
Time needed to get approval from all relevant organisations.
Fees
Feasibility of identifying and recruiting participants.
Sufficient sample size and relevant outcome measures.
What is your source / original reference data
Are the participants fully informed about the study including risks.
Does all equipment fulfil IQ OQ PQ
IQ: Installation quality installed correctly?
OQ: Operational quality working correctly?
PQ: Performance quality performing as expected?
