‘A clinical trial is a planned experiment on human beings which is designed to evaluate the effectiveness of one, or more, forms of treatment.’ (Altman, 1991)
‘A clinical trial is an experiment testing medical treatment on human subjects.’ (Piantadosi, 1997)
’An experiment is a series of observations made under conditions controlled, or arranged, by the investigator’. (Piantadosi, 1997)
Treatment: a drug or other form of medical treatment (e.g. surgery, radiotherapy, diet, counseling); method of organising and or delivering health care (e.g. pro-active call-centre based treatment support (PACCTS), education leaflet or monitoring App).
Classification of clinical trials is done by purpose, generally, or by phase in drug developmemt.
In general settings trials are often defined by their purpose:
treatments e.g. drug therapy: formoterol/salbutamol for asthma
primary and secondary prevention (e.g. aspirin for stroke, statins for heart disease, vitamins, vaccines)
studies involving drugs, behaviours, procedures (note: not necessarily at the individual level, e.g. community-based, general practice-based)
e.g. evaluation of screening programs for breast cancer/PSI levels for prostrate cancer.
concerns Pharmacokinetics/Pharmacodynamics (e.g. the absorption, distribution, metabolism and excretion of a drug or vaccine) and drug safety: toxicity/tolerability (MTD). Typically small trials involving healthy volunteers.
concerns initial clinical investigation into dosing schedules and early indications of efficacy.
Randomised Controlled Trial (RCT) aimed at full scale evaluation (efficacy) of a new, experimental, treatment compared to standard therapy or placebo, acting as a control. This is the pivotal phase with larger samples.
effectiveness and post-marketing surveillance uncommon side effects, long term effects and efects in sub-populations.
A research protocol is a formal document specifying the research plan for a clinical trial. It is the single most important quality control tool and:
necessary when applying for a grant to carry out a trial
required for local ethics committee review
provides sufficient detail to serve developmental, ethical and peer review purposes
guidelines: “Good Clinical Practice” (GCP), ICH E6
publication is encouraged, examples:
http://controlled-trials.com/mrct
http://thelancet.com
Features of the Research Protocol
background and clear statement of study objectives
information on patient selection (in/ex-clusion)
details of treatment schedules
methods of evaluation patients response to treatment
the general trial design
the recruitment and methods of randomisation of patients
how patient consent was acquired
the required study size
details of the planned monitoring of trial progress
explicit details of the forms and data handling
the intended handling of protocol deviations
plans for the statistical analysis
details of administrative responsibilities.
(Pocock, 1983.P28-31)
Many bodies have written and adopted guidelines for Good Clinical Practice, particularly for assessing safety and efficacy of medicinal products:
Committee for Proprietary Medicinal Products (CPMP)
International Conference on Harmonisation of technical requirements for registration of pharmaceuticals for human use (ICH). Adopted on 1st May 1996 by European Union, the United States and Japan
ICH E6: Guideline for Good Clinical Practice
ICH E9: Statistical Principles for Clinical Trials
ICH E10: Choice of control group in Clinical Trials
http://www.ema.europa.eu
Food and Drug Administration (FDA): US Dept. of Health and Human Services Agency
http://www.fda.gov
guidelines also available from International Federation of Pharmaceutical Manufacturers Associations
http://www.ifpma.org
‘difference between what happened to the patient as a result of treatment and what would have happened if treatment had been denied’, (Senn, 1997).
‘the true biological effect of a treatment’ (Piantadosi, 1997, p 521 ) and relates to the question: Does the treatment work under (idealised) study conditions?
‘the effect of a treatment when widely used in general practice’ (Piantadosi, 1997, p 521) and relates to the the question: Does the treatment work in practice? (i.e. in the real world).
the economics of treatment (time and cost related).
Efficacy trials (phase II/III)::
purpose: show efficacy of a treatment. Phase II trials gauge efficacy and phase III trials aim to confirm efficacy
focus on internal validity, homogeneous cohort, greater degree of compliance.
Effectiveness trials (phase IV)::
sometimes called “public health trials”
purpose: show effectiveness of a treatment
focus on external validity, heterogeneous cohort, larger than efficacy trials.
Further reading: Piantadosi (1997), Section 8.4.2.