statisticalconsulting.co.uk By Mehdi Ehtesham

1. Clinical Trial Studies
By: Mehdi Ehtesham
MPH/ Epidemiologist,
Avicenna Research Consulting
London, UK

2. What is a Clinical Trial?
 Any planned experiment
 which involves patients
 is designed to reveal the most appropriate treatment of future patients
with a given medical condition.
 It uses results based on a limited sample of patients to make
inferences about how treatment should be conducted in the general
population of patients who will require treatment in the future.
 The majority of clinical trials are concerned with the evaluation of drug
therapy, but they can also be concerned with other forms of treatment,
e.g. surgical procedures, radiotherapy, etc., or quality of life, etc.

3. History of clinical trials
King Nebuchadnezzar II carries out
the first clinical trial
he ordered that a strict diet of meat and wine be followed. However,
four children convinced the king to allow them to exchange bread and
water for the required meal.
After ten days, those who have switched to bread and water appear
well nourished than those who have stuck to wine and meat.
605-562 BC

4. 1537
The first clinical trial of a novel therapy was
conducted unintentionally by the Renaissance
surgeon Ambroise Parè. He used a concoction
of turpentine, rose oil and egg yolk to prevent
the infection of battlefield wounds, noting that
the new treatment was much more effective
that the traditional formula.
History of clinical trials

5. Preventing
James Lind is considered as the father of clinical trials, as he
introduced control groups into his experiments.
Lind carried out trials while at sea on board the Salisbury in 1747. All
scurvy patients were supplemented with citrus fruits which was found
to be effective remedy
eventually lemon juice was made a compulsory part of the seafarer's
diet
This is why British sailors, and later the British in general, were called
'limeys' by the Americans.
History of clinical trials

6. From 1800 onwards, clinical trials began to proliferate and
more attention was paid to study design.
Modern clinical trials

7. 19th century
Trials utilizing the placebo emerge.
(Placebo is Latin, literally meaning, "I will please.")1
In medicine, a placebo "is any intentionally non-effective medical
treatment, especially an inactive or inert substance, prescribed to
replace medication that is desired by a patient but which cannot be
given or which would be inappropriate.
Placebos are often given to control groups used in experimental
research to compare the results with those of the experimental drug."
Modern clinical trials

8. 1938
After 107 people die after taking
sulfanilamide (which contained anti-
freeze ingredients), the US Food, Drug,
and Cosmetic Act enforces the need for
manufacturers to demonstrate safety.
1941
The FDA is required to analyze and attest
the potency and purity of insulin, the life-
saving drug for diabetes.
Modern clinical trials

9. 1944
Introduction of multicenter studies.
different sites but same protocol;
allows pooled results  increased statistical
'power'.
1945,
the ethical impact of clinical trials resulting in
strict regulation of medical experiments on
human subjects.
These regulations have been enshrined in
documents such as the Nuremburg Codex (1947)
and the Declaration of Helsinki
Modern clinical trials

10. 1947
The Nuremberg Codex establishes ten points
for the protection of subjects and patients in
clinical trials.
THE RIGHTS OF THE TRIAL PARTICIPANTS
voluntary declaration of consent to comprehensive
information on the nature, purpose, and potential risks
of the experiment; right to withdraw from the trial at
any time.
Performance of a trial must be based on anticipated
beneficial results, and the risk involved must be
proportionate to the social and humanitarian
significance of the problem being addressed.
Modern clinical trials

11. 1964
The World Medical Association develops
the Declaration of Helsinki.
placebo-controlled trials, extreme care
only in absence of existing proven therapy.
This serves as a statement of ethical codes to
provide direction for physicians and other
participants in medical research involving human
subjects.
The Declaration is subsequently amended in the years
1975, 1983, 1989, 1996, 2000, and 2001.
Modern clinical trials

12. However, a placebo-controlled trial may be
ethically acceptable, even if proven therapy
is available, under the following
circumstances:
Where for compelling and scientifically sound methodological reasons
its use is necessary to determine the efficacy or safety of a
prophylactic, diagnostic or therapeutic method; or
Where a prophylactic, diagnostic or therapeutic method is
being investigated for a minor condition and the patients who
receive placebo will not be subject to any additional risk of
serious or irreversible harm.
Ethical issues for clinical trials

13. 1970
commercial success alone does not
constitute substantial evidence of drug
safety and efficacy. In other words, this
must be provided by well-conducted,
well-controlled clinical trials.
Ethical issues for clinical trials

14. 1986
 Good Clinical Practice recommendations.
1987
 Revision of the investigation drug regulations
is carried out in the United States.
 The goal of this is to expand access to
experimental drugs for patients with serious
diseases with no alternative therapies - i.e.
availability without evidence of efficacy
from well-controlled, well-conducted clinical
trials.
Modern clinical trials

15. 1991
Regulations issued to accelerate the
examination of drugs for life-threatening
diseases.
establishment of the Women's Health Initiative
(WHI)
The three major components of WHI studies are:
1.randomized controlled clinical trial
2.observational study to identify predictors of
disease
3.study of community approaches to developing
healthful behaviors.
Modern clinical trials

16. 20th Century
Trials utilizing randomization develop.
Randomization is a process by which
subjects in a clinical trial are randomly
assigned to receive one of the treatments
offered.
Modern clinical trials

17. Clinical trials evolved
a standard procedure, focusing on
patient safety and requiring informed
consent from all participants. There will
always be a balance between medical
progress and patient safety, and the
regulation of clinical trials helps to ensure
that this balance is acceptable.

18.  We eliminate, to the best possible extent, influence of
extraneous factors (always not totally possible)
 Aim of the trial: Spell out clearly and lay down details
before starting trial.
 Randomization - allocate merely by chance.
 Sample size and balance.
 Eliminate effects of different variables (age, sex, S.E.
status, edn, living conditions, duration etc.)
Controlled Clinical Trials

19. Population
Sample
Treatment Dx No Dx
Control Dx No DxPlacebo
Randomization
Basic Trial Design

20. Target
population
Intervention
Control
Disease
Disease-free
Disease
Disease-free
TIME
Random
assignment
Disease-free, at-
risk cohort
Randomized Clinical Trial (RCT)

21. Target
population
Treatment
Control
Cured
Not cured
Cured
Not cured
TIME
Random
assignment
Patient population
Randomized Clinical Trial (RCT)

22. Target
population
Treatment
Control
Dead
Alive
Dead
Alive
TIME
Random
assignment
Patient population
Randomized Clinical Trial (RCT)

23. 1. Select participants
2. Measure baseline variables
3. Randomize
 Eliminates baseline confounding
 Types (simple, stratified, block)
4. Blinding the intervention
 As important as randomization
5. Follow subjects
6. Measure outcome
 Clinically important measures
 Adverse events
Steps in a randomized controlled
trial

24.  Randomization is the key
 Allocation is at random, not sampling
 Simple versus systematic Randomization
Samples

25.  Strict inclusion and exclusion criteria (impact on
generalisability)
 Ethical considerations
 Technical considerations
Considerations

26.  Eligibility criteria for participants
 settings and locations
 Precise details of the interventions
 Specific objectives and hypotheses
 Clearly defined primary and secondary outcome measures
 methods used to enhance the quality of measurements
 How sample size was determined
Methods

27.  Method of Randomization
 Method of Concealment
 Method of Implementation
 Level of blinding
 Participant flow
Also …

28. DesignObjective
Case series or report
Description of disease
Cross-Sectional study
Cross-Sectional studyEvaluate a new diagnostic test
Cohort studyDescribe prognosis
Cohort study
Determine cause-effect
Case-Control study
Randomized Clinical TrialCompare new interventions
Systematic reviewSummarize literature
Select study design to match
the research goals

29. Study population
Treatment No treatment
(usual care, placebo)
NoYes NoYes
follow-up
period
outcome of
interest
Random
assignment by
investigator
 Estimate of effect is rate (risk) of outcome in treatment vs. control
(e.g. risk[treatment]/risk[control])
Basic clinical trial design

30.  Compare groups before starting the trial.
 Limit questions.
 Construction of groups.
 Treatment schedules.
 Blind techniques
1. Single blind clinical trial.
2. Double blind clinical trial.
3. Triple blind clinical trial.
CONTROLLED CLINICAL TRIALS

31.  Details to be planned properly before the trial.
 Precisely when, who, how, what will be recorded.
 Frequency and intervals of recording.
 Training of staff.
 Standard record forms and uniformity.
 Analysis to be done before de-coding.
PLANNING A TRIAL

32.  Describe techniques used
 Conditions in which investigations were done
 Types of patients taken in the trial
 Definitions of criteria for selection of patients
 Criteria for trial and control group
 Treatment to be precisely stated
REPORTING THE RESULTS

33.  Assessment and measurements used must be clearly stated.
 Whether trial was blind or not?
 Pre-trial analysis of two groups.
 Deliberate exclusions and reasons for it to be given.
 Patient as his own control (cross-over trial).
 Matched controls.
REPORTING THE RESULTS

34. Advantages
 strong claims for causality
 control of most bias, confounding
 tight control on
exposure/treatment
 high internal validity
 possible to examine multiple
outcomes
Disadvantages
 time consuming
 expensive, resource intensive
 compliance, drop-out
 sometimes severe ethical
constraints
 may not mirror practice
 generalizability may be limited
(i.e. selection bias)
Relative merits: clinical trials

35.  Is the proposed treatment safe?
 Can a treatment be with-held?
 Which patients should be subjected to the trial?
 Is the consent necessary?
 Is it ethical to use a placebo?
 Is it proper for trial to be blind?
ETHICAL ISSUES

36.  Remove all bias and plan an ethically & carefully
well-designed randomized, preferably controlled trial.
 Publish results truthfully.
 Ideal controls may not always be available.
CONCLUSION

37.  Then take the “next best” or even more inferior
controls depending on the situation.
 Just because controls are not available trial/study
does not become null and void. Only results have
to be interpreted with adequate caution.
CONCLUSION

38. One final design, which in some respects is like an intervention study but
may draw on other study designs, is the natural experiment. This might be
used, opportunistically, when some substantial natural or man-made
event or policy change takes place.
A good example of such an event was the nuclear reactor explosion at
Chernobyl, which provided the opportunity (and duty) to study the
effects of radiation exposure.
Such studies may provide sometimes unique opportunities to study high-
risk exposures, such as radiation or toxic chemicals. We will not look furthe
at natural experiments as a specific study design in this book, but many
aspects of other designs and epidemiological methods in general would
be relevant in designing and carrying out such a study.
Natural experiments