Clinical trials Flashcards
Why do clinical trials
- To establish safety
- And efficacy of new drugs (do what they say there going to)
- To compare existing treatments to find out which is best
- To study different ways of using standard treatments so that they will be more effective, easier to use and or decrease side effects
- To learn how best to use a treatment in a different population such as children in whom the treatment was not previously tested (elderly or certain morbidities)
The research proces
1) Discovery research- basic research to understand disease
2) Pre-clinical development (0-3yrs)- synthesis, biological testing and pharmacological screening
3)Clinical development (clinical trial application) (3-9yrs)
-Phase 1: 50-100 subjects
-Phase 2: 200-400 patients
-Phase 3: 3000+ patients
NB year 9= Marketing applications
4)Regulatory review (9-11yrs)= MRHA decides that drug is safe to launch
NB year 11= MA and product launch
5) Post marketing developmeant- Phase 4 (Upto 15 yr)
Overview of drug development process
-Drug discovery \+Targets/receptors \+Small molecules \+Macromolecules -Drug development (W/clinical trial) \+ADME \+Toxicology \+Delivery systems -Product license applications -Marketed drug
Preclinical development in the pharmaceutical industry
-Drug metabolism and pharmacokinetics \+Determine absorption, distribution, metabolism and excretion (ADME) in various test species -Pharmaceutical development \+Formulations for biological testing \+Dosage forms for administration -Saftey assessment \+Saftey pharmacology \+In vitro and Vivo
Saftey testing
-Saftey assessed throughout the life of the product
+During pre-clinical investigations
+During pre-registration clinccal trials
+During post-marketing surveillance
-Not uncommon for drugs to be withdrawn after being in clinical use owing to unforeseen side-effects
+e.g. Terfenadine, rofecoxib, cerivastatin
Pre-clinical safety pharmacology
-Core test \+CNS- motor activity, behavioural changes, co-ordination, reflex, response, temperature \+CVS- BP, pulse, ECG \+Respiratory- rate, tidal volume -Follow up tests (Examples) \+Memory, CO, blood gases -Supplementary tests (Examples) \+Monitoring renal function, nervous system, GI system
Pre-clinical toxicology testing
-Exploratory toxicology
+Rough estimate of compound toxicity when given acutely
+Indictation of major organs/systems affected
-Regulatory toxicology
+Performed to GLP standards
+Required before drug may be administered to humans
pre-clinical toxicology testing
- 28 day repeated dose studies in 2 species, one of which is non-rodent (usually dogs)
- In vitro and in vivo genotoxicity tests
- Saftey pharmacology
- Reproductive toxicity assessment
- Chronic 3-12 month toxicological studies
- 18-24 month carcinogenicity and reproductive toxicity testing
- Drug-drug interaction testnig
Types of adverse drug effe cts
-Exaggerated pharmacological effect
+Dose related, generally predictable
-Side effects- Pharmacology effects due to action of drug on receptors other than that intended
-Toxic effects- dose related effects unrelated to intended action
-Iidiosyncratic reaction (rash development- not related to drug action)
+Rare, sometimes serious, reaction that occur in certain individuals
+Not dose related
Clinical drug development
-Approx 80% of the cost of brining a drug to market is incurred during clinical denvelopment
-Only 1 in 5 compounds is approved for clinical use
-Of the drugs that fail during clinical development
+30% fail od lack of efficacy
+25% fail for safety reasons
NB- only 9% of clinical trial drugs make it to market
Clinical trial protocols
-Objective- what do you want to achieve
-Hypothesis- how we decide if we’ve achieved the objective
-Method
+Inclusion criteria- Who will go in
+Exclusion criteria- who don’t you want
+Visits- what will you do
+Assessments- what will you measure
+Analysis- how will you test your hypothesis
-Administration
The clinical trial paradigm
-Administration of new, potentially therapuetic substances to man
-Controlled conditions to enable determination of
+Bioavailability, efficacy, saftey, tolerability and acceptability
-Legal requirement beore a new drug can be sold or any claims for its therapeutic benefit
-Studies are subject to internation, national and local regulation to meet requirements of 3 major pharmaceutical development regions
+USA, EU, JAPAN
Phase I clinical trials
-First Administration and safety evaluation in man
+Usually healthy (Male) volunteers
+Cytotoxic drugs tested in cancer patients
-Key aim is to collect pre-luminary information
+Saftey
+Tolerability
+Bio-availability
+Pharmacokinetics
Phase 1a Studies
-Single dose trials
+First dose in man- hugely critical time for drug development process
-Usually 4-8 cohorts of 6-8 subjects
+Subsequent cohorts reveive higher doses
+Dose escalation stopped if tolerability issues
+Provides Maximum tolerated dose data
-Each volunteer usually reveives one dose only
+Placebos are administered to some volunteers
Phase 1b clinical studies
-Repeated dose trials
+Tests saftey, tolerability and PK following repeated administration
+Frequency of dosing designed to maintain necessary PK profile for therapeutic effect
-2 or 3 step dose escalations
-Successive groups of 12-24 volunteers
+Take drug repeatedly for several days at each dose level
Phase II clinical trials
-Early exploratory and dose finding studies in patients
-Phase IIa studies
+Proof of concept and go/no-go decidion making
+First in class (first drug with a certain method of action) and follower drugs (e.g. a new ACEI)
-Phase IIb studies
+Confirmatory , dose-finding studies
+Clinical surprises at the are bad news
Phase III studies
-Large scale studies in patients
+Demonstrate efficacy compared to placebo and current medication
+Demonstrate advantages over existing treatments: Saftey; Efficacy; Acceptability; Compliance: Cost-effective
-Commonly designed to compare new drugs performance against competitor product
-Often multi-region studies
Phase IV clinical trials
-Post-marketing studies to monitor safety of drug in very large numbers of patients
+Not all adverse effects detected before drug is marketed
+Denying promosing new drugs is not patients best interests
-Around 1 in 5 new drugs may be ultimately recalled or cause serious side effects (Cant test every permutation in clinical trials e.g. 1 in 10,000 side effects may not be seen in 3000 patient trial)
+Hence requirement for phase IV studies
Further directed learning
-Compare and contrast the following types of clinical trials
- Single arm trial- No control only one arm that takes the medication
- Placebo controlled trials- Control and active
- Positive controlled trial- One arm takes established drug and one takes new drug
- Open trial- patients and healthcare professionals no which is placebo and which is drug
- Single blinded- either the patients OR the healthcare professionals no which are placebo or drug
- Double blinded trials- Neither the healthcare or the patients no which is placebo or drug (This takes out bias)
- Cross-over trials- when the patients go between placebo and drug
- Clinical trials in human: digital in clinical trials (patient diary, digital reminders)
