Levels of evidence and design of clinical trail

2. EVIDENCE BASED MEDICINE
• Definition:
“Evidence based medicine is the conscientious, explicit, and
judicious use of current best evidence in making decisions
about the care of individual patients.
The practice of evidence- based medicine means integrating
individual clinical expertise with the best available external
clinical evidence from systematic research”.

3. TYPES OF CLINICAL TRIAL

4. LEVELS OF EVIDENCE

5. LEVELS OF EVIDENCE
• The levels of evidence outlined by Sackett and his colleagues in
2000:
• 1A = Systematic Review of Randomized Controlled Trials (RCTs)
• 1B = RCTs with Narrow Confidence Interval
• 1C = All or None Case Series
• 2A = Systematic Review Cohort Studies
• 2B = Cohort Study/Low Quality RCT
• 2C = Outcomes Research
• 3A = Systematic Review of Case-Controlled Studies
• 3B = Case-controlled Study
• 4 = Case Series, Case Reports
• 5 = Expert Opinion

6. SYSTEMATIC REVIEW
• Systematic review is usually restricted to review of RCTs
• A group of reviewers search the available literature via bibliographic
databases and retrieve copies of all the articles written on a specific topic
• Critical evaluation of the methodologies and content
• The final product is a synthesis of the properly completed and
meaningful research into information that is relevant to practicing
medical practitioners/clinicians
• Meta-analysis:
- A subset of systematic reviews that use statistical methods to combine
analyze multiple investigations

7. SYSTEMIC REVIEW AND META-ANALYSIS

8. Systematic
review
Meta-analysis
Literature
review
20
SYSTEMIC REVIEW AND META-ANALYSIS

9. RANDOMIZED CONTROL TRIALS
• Study involves the randomization procedure
• Subjects in the study are randomly allocated to each group included
in the study
• Each subject has an equal chance of being assigned into an
intervention group, a control group, a placebo group
• Eliminates the over-representation of any one characteristic in one
group
• It eliminates any bias in the assignments of individuals
• Randomized controlled trials are known to be the ‘GoldStandard’
for establishing the effects of a treatment

10. RANDOMIZED CONTROLLED
STUDY

11. CASE CONTROL STUDIES
• This design involves choosing 2 patients or 2 groups of
patients who were exposed to 2 different interventions
• The investigator retrospectively looks back to which group
or patient achieved a better outcome

12. COHORT STUDIES
• This design is also called a prospective study, or a longitudinal
study
• It involves the selection of a large population of people who
have the same condition and/or receive a specific intervention
• They are followed over time and compared to a group not
affected by the condition
• This study employs observation as the research methodology
• The interventions are not manipulated

13. CASE SERIES & CASE REPORTS
• Case series:
-Reports on a series of patients with a pre- identified
problem
• Case reports:
-This involves a report on the intervention and outcome
for a single patient

14. BOTTOM OF THE EVIDENCE PYRAMID
• Guyatt et al. label one type “physiological studies.”
• Oxford Center for Evidence-Based Medicine identifies these studies as
bench research and animal research.
• The other type is identified as unsystematic clinical observations,
unpublished evidence, or unpublished clinical observations.
• Conclusions drawn from bench (that is, basic) science and animal
research cannot be generalized directly to human patients.

16. CLINICAL TRIALS
• Clinical trials are sets of tests in medical research and drug
development that generate safety and efficacy data
• Generate information about adverse drug reactions and
adverse effects of other treatments for health interventions
e.g.,
- drugs
- diagnostics
- device
- therapy protocols

17. WHY THEY ARE DONE?
1. As they provide better evidence of the effect or the outcome
that cannot be obtained with any other observational
method.
2. The variation is minimized and bias is controlled , hence
more valid and their results speak truth.
3. Providing maximum amount of assurance
4. Fastest and safest way to find treatments that work in
people and ways to improve health

18. WHEN THEY ARE DONE
• When the laboratory and animal studies yield the most promising
results of the intervention, those results are tested by clinical trials
• When the margin of the expected benefit or the outcome of an
intervention is doubtful or very narrow (10 to30% only).
• When the margin is large, obvious and beyond doubt, it will be
unnecessary to conduct clinical trials.

19. TYPES OF CLINICAL TRIAL
• Treatment trials
• Prevention trials
• Diagnostic trials
• Screening trials
• Quality of life trials

20. TREATMENT TRIALS
• New treatments
• New combination of drugs
• New approaches to Surgery
• New Radiation therapy

21. PREVENTION TRIALS
They try to find better ways to prevent disease in people and to prevent
disease recurrence using
Medicines
Vaccines
Vitamins
Minerals
Life style changes

22. DIAGNOSTIC TRIALS
To find better tests for diagnosis of a disease
To find better procedures for diagnosis of a disease

23. SCREENING TRIALS
To find out the best way to detect certain diseases
or conditions

24. LIFE STYLE TRIALS
• Also called Supportive care trials
• Often employed for the chronically ill patients
• They explore the ways to improve comfort and
• to improve the quality of life

25. PURPOSE OF TRIALS
• Assess the safety and effectiveness of a
• new medication or device on a specific kind of patient
• different dose of a medication than is commonly used
• already marketed medication or device for a new indication
• Compare the effectiveness in patients with a specific disease of
two or more already approved or common interventions for that
disease

27. RESEARCH QUESTION
• Start with a hypothesis
 must be in the form of a statement
 Null Hypothesis
 Alternative hypothesis
• Then turn it into a specific question
 the question must be “answerable”
 this forms the basis of the study “Objectives”

28. PHASES OF TRIALS
• Phase 0:
• Phase 1:
• Phase 2:
• Phase 3:
• Phase 4:
Pharmacodynamics and
Pharmacokinetics
Screening for safety
Establishing the efficacy of the drug,
usually against a placebo
Final confirmation of safety and
efficacy
Sentry studies during sales

29. PHASES OF TRIALS
- 20-80
- Evaluate-
- Safety
- Determine a safe dose
- Identify side side effect
- First-in-human trials
-Single sub-therapeutic doses of
the study drug are given
-10 to 15
-preliminary data on the agent's
pharmacodynamics and
pharmacokinetics
Phase 0 Phase 1

30. PHASES OF TRIALS
- 100-300
- see if it is effective and to
further evaluate its safety
- 1,000-3,000)
- Effectiveness
- Collect information that will
allow it to be used safely
- Compare it to commonly
used treatments
- Postmarketing studies
- including the treatment's
risks
- Benefits
- Optimal use
Phase 4
Phase 3
Phase 2

31. MINIMIZING VARIATION
• The larger the variation, the more difficult it is to identify
treatment effects.
• Thus minimizing variation is a fundamental element of clinical
trial design.
• Inclusion Criteria
• Exclusion Criteria

32. RANDOMIZATION
• People are allocated at random to the treatment groups in the trial,
usually by using a computer program.
• This is done so that each group has a similar mix of people of
different ages, sex and state of health.
• If the people are allocated to the treatment groups at random, like
will be compared with like.
• If one group does better than the other, it is likely to be because of
the treatment, as the two groups are very similar in every other
way.

33. SIMPLE RANDOMIZATION
 Think of tossing a coin each time a subject is eligible to be
randomized
HEADS: Treatment A
TAILS: Treatment B
 Approximately ½ will be assigned to treatments A and B
 Randomization usually done using a randomization schedule or
a computerized random number generator
May result in substantial imbalance in either
 an important baseline factor and/or
 the number of subjects assigned to each group
Solution: Use blocking and/or stratified randomization

34. BLOCKING
If we have two treatment groups (A and B) equal allocation, and a
block size of 4, random assignments would be chosen from the
blocks
1) AABB 4) BABA
2) ABAB 5) BAAB
3) ABBA 6) BABA
Blocking ensures balance after every 4th assignment

35. STRATIFICATION
• To ensure balance on an important baseline factor, create strata
and set up separate randomization schedules within each
stratum
• Example: if we want prevent an imbalance on age in a study,
first create the strata “< 75 years” and “ 75 years”
then randomize within each stratum separately
• Blocking should be also be used within each stratum

36. BLINDING
• Blinding is a fundamental tool in clinical trial design and a powerful
method for preventing and reducing bias
• Blinding refers to keeping study participants, investigators, or
assessors unaware of the assigned intervention so that this
knowledge will not affect their behavior, noting that a change in
behavior can be subtle, unnoticeable, and unintentional
• Single blind
• Double blind
• Triple blind
Single
blind
Double
blind
Triple blind
Outcome
assessor
X X X
Participant X X
Data
interpreter
X

37. SELECTION OF GROUP
Active Treatment Group
Group which is undergoing the research
Control group
provides data about what would have happened to participants if they
were not treated or had received a different intervention.
There are three primary types of control groups:
1) historical controls
2) placebo/sham controls
3) active controls

38. SELECTION OF GROUP
• Historical controls are obtained from studies that have already
been conducted and are often published in the medical literature
• placebo-controls he experimental intervention is compared with
intervention with a placebo
• active control is an active intervention that has often shown
effectiveness to treat the disease under study

39. PLACEBO CONTROL GROUP
• Participants are randomized to receive either the new intervention or a
placebo.
• Most placebo-controlled trials are also double blind
• Placebo-controlled trials also allow a distinction between adverse events
due to the intervention and those due to the underlying disease or other
potential interference

40. SELECTION OF A POPULATION
• In selecting a population to enroll into a trial, researchers must consider
the target use of the intervention since it will be desirable to generalize the
results of the trial to the target population.
• The selection of a population can depend on the trial phase since different
phases have different objectives.
• Early phase trials tend to select populations that are more homogenous
since it is easier to reduce response variation and thus isolate effects.
• Later phase trials tend to target more heterogeneous populations since it
is desirable to have the results of such trials to be generalizable to the
population in which the intervention will be utilized in practice.

41. SELECTION OF ENTRY CRITERIA
• consider the appropriateness of recruiting participants with various
conditions into the trial.
• Consider restricting entry criteria to reduce variation and potential
for bias.
• Entry criteria may need to be relaxed so that enrollment can be
completed within a reasonable time frame

42. SELECTION OF ENDPOINTS
• Selection of endpoints in a clinical trial is extremely important and
requires a marriage of clinical relevance with statistical reasoning
• Endpoints can generally be categorized by their scale of measurement.
• The three most common types of endpoints in clinical trials are
1. continuous endpoints (e.g., pain on a visual analogue scale)
2. categorical (including binary, e.g., response vs. no response) endpoints
3. event-time endpoints (e.g., time to death).
• Endpoints can be classified as being objective or subjective.
Objective endpoints- those that can be measured without prejudice
or favor..
Subjective endpoints - more susceptible to individual interpretation.

43. STATISTICAL CONSIDERATION
• At the planning stage some statistical considerations regarding the
manner in which the data will be tabulated and analyzed at the end
of the study should carefully be considered.
• It includes
1. Efficacy and safety assessment
2. Sample size estimation
3. Possible interim analysis and data monitoring
4. Clinical inference.

44. SAMPLE SIZE ESTIMATION
• For assessment of the effectiveness and safety of a study drug, a
typical approach is first to show that the study drug is statistically
significant compared to a placebo control.
• Statistically significant difference- high probability of correctly
detecting a clinically meaningful difference.
• The probability of correctly detecting a clinically meaningful
difference is known as the statistical power of the trial.
• In clinical trials, for a given significance level, we can increase the
statistical power by increasing the sample size.

45. INTERIM ANALYSIS AND DATA MONITORING
• A process of examining and/or analyzing data accumulating in a
clinical trial, either formally or informally, during the conduct of the
clinical trial.
• Provides an administrative tool for terminating a trial during which
either a superior efficacy or an excessive safety risk in the
treatment presented to patients is observed.
• If no interim analysis is intended, the reasons why an interim
analysis is not necessary for the study are to be clearly stated in the
study protocol.

46. STATISTICAL AND CLINICAL INFERENCE
• Statistical inference is only a part of induction process for the
conclusions obtained from clinical trials, and it should not preclude
the possibility of a meaningful clinical inference.
• Clinical inference is rarely based on the results of a single clinical
trial.
• In order to investigate the effectiveness and safety of a therapeutic
agent or a class of therapeutic agents, a series of clinical trials with
the same design and concurrent control is usually conducted over
patients with similar but different characteristics.

47. REFERENCES
• Umscheid CA, Margolis DJ, Grossman CE. Key concepts of clinical trials: a
narrative review. Postgraduate medicine. 2011 Sep 1;123(5):194-204.
• Evans SR. Fundamentals of clinical trial design. Journal of experimental
stroke & translational medicine. 2010 Jan 1;3(1):19.
• Chow SC, Liu JP. Design and analysis of clinical trials: concepts and
methodologies. John Wiley & Sons; 2008 Dec 4.
• Daly, Jeanne, et al. "A hierarchy of evidence for assessing qualitative health
research." Journal of clinical epidemiology60.1 (2007): 43-49.
• Evans CH, Ildstad ST. Small Clinical Trials. Issues and Challenges. 2001.

48. THANK YOU