INTRODUCTION TO CLINICAL

TRIALS

Oyindamola B. Yusuf
 What is a clinical trial?

A planned experiment on human beings

which is designed to evaluate the
effectiveness and/or safety of one or more
forms of treatment
 Experiment
• Controlled scientific investigation to
measure the effect of an intervention
(treatment) on a condition or to compare the
effects of two or more treatments and the
study units are allocated at random to the
study groups under investigation.
 Essential features of a true
experiment
• Intervention/manipulation/treatment
• Control: the use of a comparison group
• Randomization: experimental units are
allocated to treatment groups at random
 Example of an experiment
• experiment to measure the effect of vitamin
E supplementation on the incidence of
prolonged bleeding among users of a
contraceptive implant.
 Merits of experiments
• Powerful method for establishing causal
relationships
• Minimizes threats to internal validity of
conclusions.
 Internal validity
• Is concerned with the question: “ do the
experimental treatments in fact cause the
effects observed in the study, or can the
effects be ascribed to other factors?”.
 Weak points of experiments
• Not always feasible to carry out.

-Example assessing the effect of pelvic

inflammatory disease (PID) on later
infertility

• threats to external validity of conclusions.

 External validity
• This asks the question:

“Given these demonstrable effects caused by

the treatment under study, to what
populations or settings can they be
generalised?”.
 Quasi-experiments
• Similar to experiments but lack at least one
of the 3 essential features of a true
experiment
– the missing feature is usually randomization or
the control group or both.
Examples of quasi-experiments:
(a) The effects of vasectomy on blood pressure
levels measured before and after vasectomy.
(b) Changes in blood coagulation parameters in
users of hormonal contraceptives versus users
of intra uterine device (IUD).
 Merits of quasi-experiments:
• Convenient
• practical
 Weak points of quasi-experiments:
• Weak for establishing causal relationship
• Many threats to internal validity of
conclusions.
Factors affecting internal validity
• History
– Events other than the experimental treatments
occur during the time between pre-test and
post-test observations. Such events produce
effects that can be mistakenly attributed to
treatment under test.
Maturation
• Between any two observations, subjects
change in a variety of ways. Such changes
can produce differences that are
independent of the experimental treatments.
The problem of maturation is more acute in
long-running studies.
Testing
• Pretests at the beginning of experiments can
produce effects other than those due to the
experimental treatments.
Such effects can include sensitising subjects
to the true purposes of the experiment and
practice effects which produce higher
scores on post-test measures.
Instrumentation
• Unreliable tests or instruments can
introduce serious errors into experiments.
With human observers or judges, errors can
result from changes in their skills and levels
of concentration over the course of the
experiment.
Selection bias
• Bias may be introduced as a result of
differences in the selection of subjects for
the comparison groups or when intact
classes are employed as experimental or
control groups.
Withdrawals from the study
• The loss of subjects through dropout often
occurs in long-running experiments and
may result in confounding the effects of the
experimental variables: for whereas initially
the groups may have been randomly
selected, the residue that completed the
study is likely to be different from the
unbiased sample that began it.
Statistical regression (or regression
to the mean)
• Regression effects increase systematically with the
time interval between pretests and post-tests.
Regression means, simply that subjects scoring
highest on a pretest are likely to score relatively
lower on a post test; conversely, those scoring
lowest on a pretest are likely to score relatively
higher on a post-test.
Statistical regression (contd.)
Thus, in pretest/post-test situations, there is
regression to the mean.
Regression effects can lead the researcher
mistakenly to attribute post-test gains and
losses to treatment effects.
Factors affecting external validity
• Threats to external validity are likely to
limit the degree to which generalisations
can be made from the particular
experimental conditions to other
populations or settings.
The most important of the threats are:
Failure to describe independent
variables explicitly
– Unless independent variables are adequately
described by the researcher, future replications
of the experimental conditions are virtually
impossible.
Lack of representativeness of
available and target populations
– While those participating in the experiment
may be representative of an available
population, they may not be representative of
the population to which the experimenter seeks
to generalise his/her findings.
Hawthorne effect
– This is the tendency of people to react
differently from their normal self when they are
being observed or studied.
This is a psychological effect which has been
recognised also to arise out of mere
participation in drug trials, and placebos and
double blind designs are commonly employed
to counteract these biasing effects of
participation.
Inadequate operationalising of
dependent variable
– Dependent variable that the experimenter
operationalises must have validity in the non-
experimental setting to which the reseacher
wishes to generalise his/her findings.
For example a questionnaire for scoring pain
must have validity in measuring the amount of
pain felt by patients outside of the experimental
setting.
Sensitisation to experimental
conditions
– As with threats to internal validity, pretests may
cause changes in the subjects’ sensitivity to the
experimental variables and thus cloud the true
effects of the experimental treatment
End of diversion
• And back to the definition of a clinical trial.

– A planned experiment on human beings which

is designed to evaluate the effectiveness and/or
safety of one or more forms of treatment.
In a clinical trial “treatment” may be
anything such as:
• Drugs
• Surgical procedures
• Physiotherapy
• Diet
• Acupuncture
• Health education
• Administrative aspects of medical care, for example choice
of home or hospital care
• Medical devices
• etc
• A properly planned and executed clinical trial is a
powerful experimental technique for assessing the
effectiveness of a treatment.
• The definition of clinical trial does not require
that a comparison of treatments be made although
this is true of an important class of study designs
the so-called Phase III trials. A clinical trial
requires only the formal structure of an
experiment particularly control over treatment
assignment by the investigator.
 Apart from being true experiments
• Clinical trials also possess important general
characteristics of the scientific method
– instrumentalising perception or measurement
• enhances repeatability and quantification
– externalising plans and memory
• written record to facilitate reference and defence
– control of extraneous factors as part of study design
• using internal controls and methods to control bias
– submitting completed work to external recognition
• verification or disproof
 Some features of clinical trials
• A clinical trial is essentially prospective rather
than retrospective. Study participants must be
followed forward in time. They need not be
followed from an identical calendar date, but each
participant must be followed from a well-defined
time point which becomes time zero or baseline
for the study for that participant.
• A clinical trial must employ one or more
interventions or treatments. These may be
prophylactic, diagnostic or therapeutic agents,
devices, regimens, procedures, etc.
 Some features of clinical trials (ctd)
• A comparative trial must contain a control group
against which the intervention group is compared
– at baseline the control group must be sufficiently
similar in relevant respects to the intervention group so
that differences in outcome may reasonably be
attributed to the action of the intervention
– most often a new intervention is compared with the best
current standard therapy
– if no standard therapy exist the control group may
receive a placebo or nothing at all
 Examples of clinical trials
• Aspirin in the prevention of recurrent heart attacks
• Effect of the reduction of dietary sodium on blood pressure
• Calcium supplementation for the prevention of pre-
eclampsia among low calcium intake women
• Misoprostol and oxytocin for post-partum haemorrhage
• Phase I clinical trial of an advanced prototype hCG
immunocontraceptive
• Phase II trials of ‘fagara’ extract for anti-sickling
efficacy
Examples of clinical trials (ct’d.)
• Post-marketing surveillance of Norplant implant
• Open comparison of mefloquine,
mefloquine/sulfadoxine/pyrimethamin and chloroquine in
acute uncomplicated falciparum malaria in children
(Sowumi & Oduola)
• A comparative clinical evaluation of econazole nitrate,
miconazole and nystatin in the treatment of vaginal
candidiasis (Emele, Fadahunsi, Anyiwo and Ogunleye)
• Randomized controlled trial of low dose warfarin in the
primary prevention of ischaemic heart disease in men at
high risk
 Need for clinical trials
• A clinical trial is the clearest method of
determining whether a health or medical
intervention has the postulated effect
• Evaluation of safety and efficacy of therapies
should have basis that are non subjective and
scientifically valid, properly conducted clinical
trials which follow the principles of scientific
experimentation provide the only reliable basis for
evaluating the efficacy and safety of new
treatments
 Need for clinical trials ct’d
• Given the uncertain knowledge about course of
disease in humans and the usual large variations in
biologic measures it is almost impossible to say,
on the basis of uncontrolled clinical observation
whether a new treatment has made a difference to
outcome and if it has what the magnitude is. A
clinical trial offers the possibility of such
judgement because there is a control group which,
ideally, is comparable to the intervention group in
every way except for the intervention being
studied.
 Uses of clinical trials
• To develop and test interventions in nearly all areas of medicine and
public health
• Evaluation of new drugs, drug combinations and other treatment
modalities from Phase I through Phase IV studies
• For clarifying safety and efficacy concerns about new treatments prior
to marketing approval
• To develop surgical treatments and some medical devices
• To provide confirmatory evidence for findings from earlier studies that
may be unconvincing
• Two or more trials essential on the same research question may be
carried out in different countries, geographic zones, ethnic groups
• Confirmatory trials may be:
– inadvertent or
– planned
 HISTORICAL EVOLUTION OF CLINICAL
TRIALS
• Evolution dates from the 18th century
– * Lind in 1753
– Study on board of a ship the Salisbury
– Comparative trial of the most promising treatments for scurvy
– Evaluation of 6 treatments in 12 patients
• 2 patients per treatment
• T1 a quart of cider a day
• T2 25 gutts of elixir vitriol
• T3 2 spoonfuls of vinegar
• T4 a course of sea water
• T5 2 oranges and 1 lemon
• T6 1 nutmeg
 HISTORICAL EVOLUTION OF CLINICAL
TRIALS ct’d

• Several other studies in the 18th and 19th

centuries
– comparison groups comprised
• literature controls
• historical controls
• concurrent controls
 HISTORICAL EVOLUTION OF
CLINICAL TRIALS ct’d
• Several of these experiments had no appreciation
of the scientific method
– Ex: Rush in 1794 made extravagant and subjective
claims about the therapeutic effectiveness of treating
yellow fever by bleeding
– Louis in 1834 proposed the use of the numerical
method in assessing therapies which he enunciated as
the need for
• The exact observation of patient outcome
• Knowledge of the natural progress of untreated controls
• Precise definition of disease prior to treatment
• Careful observation of deviations from intended treatment
 HISTORICAL EVOLUTION OF
CLINICAL TRIALS ct’d
• Putting these principles into practice in 1835 he
was able to demonstrate the lack of effect
of bleeding in treating
– pneumonia
– erysipelas
– throat inflammation
• Louis was one of the founding figures who
established clinical trials and epidemiology on a
scientific footing
 HISTORICAL EVOLUTION OF
CLINICAL TRIALS ct’d
• In 1865 Sutton conducted a study in which only mint water was given
to 20 patients with rheumatic fever. This may have been the first
use of a placebo.He demonstrated:
– the immense natural variation in the disease process
– the tendency to a natural cure in some cases
• In 1891 Holmes ascribed the lack of progress in American clinical
research to counteract overmedication to the following reasons:
– incapacity for sound observation
– inability to weigh evidence
– the counting of only favourable cases
– the assumption that treatment was responsible for any favourable
outcome
– failure to learn from experience
– a public which insists on being poisoned
 HISTORICAL EVOLUTION OF
CLINICAL TRIALS ct’d
• In 1898 Fibiger in a trial of serum for diphtheria
showed an early application of alternate
assignment of patients to treatment and untreated
control
• In 1915 Greenwood and Yule in a review of
anticholera and antityphoid studies appear to be
the first to suggest some form of random
allocation of patients to treatment in order to
generate truly comparable treatment groups
 HISTORICAL EVOLUTION OF
CLINICAL TRIALS ct’d
• In 1927 in a study of vaccines for the common cold, Ferguson, Davey
and Topley may have been the first to introduce blinding. The study
was single blind in that the research workers but not the patients knew
who received saline or vaccine injections.
• In 1931 the first clinical trial that used a form of random allocation
was reported by Amberson, McMahon and Pinner. A flip of a coin
determined which of two groups of 12 patients each received
injections of sanocrysin (versus distilled water) for treating pulmonary
tuberculosis.
• The British Medical Research Council trial of streptomycin in patients
with tuberculosis reported in 1948 was the first clinical trial with a
properly randomized control group. It used random numbers in the
allocation to experimental and control groups.
 HISTORICAL EVOLUTION OF
CLINICAL TRIALS ct’d
• This trial represents many of the desired features of modern day
clinical trials such as:
– patient accrual from several centres at each of which random allocation to
treatment, streptomycin and bed rest or bed-rest alone
– the random allocation was contained in sealed envelopes
• evaluation of patient x-ray films was made independently by two
radiologists and a clinician independently of each other evaluators
were kept blind of the treatment received by the patient
• It is only in the last few decades (since about 1950) that the clinical
trial has emerged as the preferred method in the evaluation of medical
interventions.
• This development was due mainly to the work of Austin Bradford Hill
• In the early 1950’s he pioneered and wrote about techniques of
implementation, conduct and analysis of clinical trials.