How to do clinical research at KEMU

Part I-Understanding the basics

Ahmad M Rashid MD,FCCP

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?

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.

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.

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

Clinical Trials-Building Blocks

• Clinical/Research Question

• Hypothesis

• Methods

• Observations

• Results-Statistics

• Conclusions

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?”

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

PICO

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”?

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.”

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.

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

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

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.

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.

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

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

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.

Dabigatran versus

Warfarin in the

Treatment

of Acute Venous

ThromboembolismSam 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.,

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?

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

• 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).

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.

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!