1. How to do clinical research at
KEMU
Part I-Understanding the basics
Ahmad M Rashid MD,FCCP

2. Research Basics
• What are clinical trials/studies?
• Why do we need research?
• How are the clinical trials conceived?
• What are the steps needed to get a trial started?
• What are the types of clinical trials we can do?
• How to collect and report data?
• How to form conclusions?
• How to write a trial up?

3. Clinical Trials
• In 18th century Scurvy was
a common ailment for
seamen
• British trading ships and
Navy were suffering
• It was known that citrus
fruit might help cure
scurvy
• James Lind-a Scottish
physician conducted one
of the first known clinical
trials.

5. Clinical Trials-the beginning
• 12 scorbutic sailors into six groups of two.
• They all received the same diet but, in addition,
– Group 1: was given a quart of cider daily
– Group 2: twenty-five drops of elixir of vitriol (sulfuric acid),
– Group 3: six spoonful of vinegar
– Group 4: half a pint of seawater
– Group 5: received two oranges and one lemon
– Group 6: a spicy paste plus a drink of barley water
• The treatment of group five stopped after six days when
they ran out of fruit, but by that time one sailor was fit for
duty while the other had almost recovered. Apart from
that, only group one also showed some effect of its
treatment.

6. Clinical Trials-Building Blocks
• A clinical study involves research using human
volunteers (also called participants) that is
intended to add to medical knowledge
• There are two main types of clinical studies:
clinical trials and observational studies

7. Clinical Trials-Building Blocks
• Clinical/Research Question
• Hypothesis
• Methods
• Observations
• Results-Statistics
• Conclusions

8. The Researchable Question
• A researchable question is an uncertainty
about a problem that can be challenged,
examined and analyzed to provide useful
information.
• “Can Scurvy be treated by addition of citrus
fruit to the diet of sailors?”

9. PICO
• P: Population of interest :Patient or the
problem to be addressed
• I: Intervention: Exposure to be considered–
treatments/ tests
• C: Control :Control or comparison intervention
treatment/placebo/standard of care
• O: Outcome :Outcome of interest

10. PICO

11. How to formulate a researchable
question?
• Background research
• Literature review
• Dissect the questions into parts
• Other relevant questions
• “Does addition of citrus fruit to the diet of
sailors offer better protection from Scurvy,
compared with other dietary supplements”?

12. Clinical Hypothesis
• Clinical hypotheses are theories that could
explain presenting behavior or facts. Their
purpose is to guide current assessment and
intervention.
• “Citrus fruit will stop “putrefcation” of sailors’
bodies hence preventing Scurvy.”

13. Clinical Hypothesis
• A hypothesis should concern information that still
needs to be established.
• A hypothesis should be a statement worded precisely
and objectively in the present tense
• A hypothesis can relate to a range of factors: nature of
impairment, severity of impairment, impact of
impairment etc.
• A hypothesis should be based on clear evidence
(reported or theoretical) which provides a rationale for
formulating it.
• A hypothesis should be specific enough to lead towards
clear assessment and intervention objectives.

14. FINER-before you jump in!
• F: Feasibility :sufficient resources
in terms of time, staff, and
funding.
• I: Interesting :researcher or
collaborator Investigator’s
motivation to make it interesting
• N: Novel: thorough literature
search New findings or extension
of previous findings .Guidance
from mentors and experts
• E: Ethical :following ethical
guidelines Regulatory approval
from Institutional Review Board
• R: Relevant :Influence on clinical
practice Furthering research and
health policy
Table: Vascularspecialitiesonline.com

15. Methods
• Clinical Study Types:
• Experimental Studies:
– allocation or assignment of individuals is under control of investigator
and thus can be randomized.
– investigator controls the assignment of the exposure or of the
treatment
– symmetry of potential unknown confounders is maintained through
randomization
• Observational Studies:
– allocation or assignment of factors is not under control of investigator
– the combinations are self-selected or are "experiments of nature“
– For those questions where it would be unethical to assign factors,
investigators are limited to observational studies

16. Experimental Studies
• Randomized Controlled Clinical Trial (RCT):
– Individuals similar at the beginning
– Randomly allocated to two or more treatment groups
– outcomes the groups are compared after sufficient follow-up
time.
• Randomized Cross-Over Clinical Trial:
– Individuals with a chronic condition are randomly allocated to
one of two treatment groups
– After a sufficient treatment period and often a washout period,
are switched to the other treatment for the same period.
• Randomized Controlled Laboratory Study:
– A prospective, analytical, experimental study using primary data
generated in the laboratory environment.

17. Observational Studies
• Cohort (Incidence, Longitudinal Study) Study:
– A prospective, analytical, observational study, based on data, usually primary
– follow-up period of a group in which some have had, have or will have the exposure of interest,
– to determine the association between that exposure and an outcome.
• Case-Control Study:
– A retrospective, analytical, observational study often based on secondary data
– the proportion of cases with a potential risk factor are compared to the proportion of controls (individuals
without the disease) with the same risk factor
• Ecologic (Aggregate) Study:
– An observational analytical study based on aggregated secondary data.
– Aggregate data on risk factors and disease prevalence from different population groups is compared to
identify associations.
• Cross-Sectional (Prevalence Study) Study:
– A descriptive study of the relationship between diseases and other factors at one point in time (usually) in a
defined population.
• Case Series:
– A descriptive, observational study of a series of cases, typically describing the manifestations, clinical
course, and prognosis of a condition.
– Case series are best used as a source of hypotheses for investigation by stronger study designs
• Case Report:
– Anecdotal evidence. A description of a single case, typically describing the manifestations, clinical course,
and prognosis of that case.

18. Steps in a Clinical Trial
• IRB approval
• Randomization
• Recruiting Participants
• Baseline Characteristics
• Participant Adherence
• Data Collection and Quality Control
• Assessing and Reporting Adverse Effects
• Monitoring variables
• Closeout

19. IRB
• An institutional review board (IRB), also known as
an independent ethics committee or ethical
review board, is a committee that has been
formally designated to approve, monitor, and
review biomedical and behavioral research
involving humans
• The number one priority of IRBs is to protect
human subjects from physical or psychological
harm
• Exemptions

20. IRB
• The IRB must have at least five members
• The members must have enough experience, expertise, and diversity
• If the IRB works with studies that include vulnerable populations, the IRB
should have members who are familiar with these groups.
• The IRB should include both men and women, as long as they aren't
chosen specifically for their gender
• The members of the IRB must not be all of the same profession
• The IRB must include at least one scientist and at least one non-scientist.
The IRB must include at least one person who is not affiliated with the
institution or in the immediate family of a person affiliated with the
institution.
• IRB members may not vote on their own projects
• The IRB may include consultants in their discussions to meet requirements
for expertise or diversity, but only actual IRB members may vote.

21. Dabigatran versus
Warfarin in the
Treatment
of Acute Venous
Thromboembolism
Sam Schulman, M.D., Clive Kearon, M.D.,
Ajay K. Kakkar, M.D.,
Patrick Mismetti, M.D., Sebastian
Schellong, M.D., Henry Eriksson, M.D.,
David Baanstra, M.Sc., Janet Schnee,
M.D., and Samuel Z. Goldhaber, M.D.,

22. Background
The direct oral thrombin inhibitor dabigatran has a predictable
anticoagulant effect and may be an alternative therapy to warfarin for
patients who have acute venous thromboembolism.
The Question/Hypothesis
Can Dabigatran which has a
predictable anticoagulant effect be
safely used as an alternative to
warfarin for patients with acute
venous thromboembolism?

23. Design
Methods
In a randomized, double-blind, noninferiority trial involving patients
with acute venous thromboembolism who were initially given
parenteral anticoagulation therapy for a median of 9 days
(interquartile range, 8 to 11), we compared oral dabigatran,
administered at a dose of 150 mg twice daily, with warfarin that was
dose-adjusted to achieve an international normalized ratio of 2.0 to
3.0. The primary outcome was the 6-month incidence of recurrent
symptomatic, objectively confirmed venous thromboembolism and
related deaths. Safety end points included bleeding events,
acute coronary syndromes, other adverse events, and results of
liver-function tests.
Experimental study-
prospective
Study duration 6 months
Outcome-incidence of recurrent
clots
Adverse events studied

24. • Results
• A total of 30 of the 1274 patients randomly assigned to receive
dabigatran (2.4%),as compared with 27 of the 1265 patients randomly
assigned to warfarin (2.1%),had recurrent venous thromboembolism; the
difference in risk was 0.4 percentage points (95% confidence interval [CI],
−0.8 to 1.5; P<0.001 for the prespecified noninferiority margin).
• The hazard ratio with dabigatran was 1.10 (95% CI, 0.65 to 1.84). Major
bleeding episodes occurred in 20 patients assigned to dabigatran (1.6%)
and in 24 patients assigned to warfarin (1.9%) (hazard ratio with
dabigatran,0.82; 95% CI, 0.45 to 1.48), and episodes of any bleeding
were observed in 205 patients assigned to dabigatran (16.1%) and 277
patients assigned to warfarin (21.9%;hazard ratio with dabigatran, 0.71;
95% CI, 0.59 to 0.85).
• The numbers of deaths, acute coronary syndromes, and abnormal liver-
function tests were similar in the two groups. Adverse events leading to
discontinuation of the study drug occurred in 9.0% of patients assigned to
dabigatran and in 6.8% of patients assigned to warfarin (P = 0.05).

25. Conclusion
Conclusions
For the treatment of acute venous
thromboembolism, a fixed dose of
dabigatran is as effective as warfarin, has
a safety profile that is similar to that of
warfarin, and does not require laboratory
monitoring.

26. Happy Endings?
• Lind published his paper
on scurvy in 1753
• Despite of skeptics-the
British Navy mandated
the use of lemon juice
aboard all ships in 1760’s
• This lead to more
effective naval power for
the empire-contributed to
the next two centuries of
conquest and
colonization!