1. Clinical Trials

2. (testing of hypothesis)
Study designs
Study types
Descriptive
(formulation of hypothesis)
Individual based
Case studies
Case series
Cross-sectional
surveys
Population based
co-relational
Analytical
(testing of hypothesis)
Observational
Case-control
cohort
interventional
RCT’s (III)
Quazi experimental

3. Randomized Control Trials
In public health and clinical practice our objective is to modify natural history of disease i.e. to delay death or disability and to promote health
Challenge is to select best available preventive or therapeutic measure.
RCT is the ideal design to evaluate the effectiveness and efficiency of these measures

4. History of RCT Unintentional trial be Ambroise Pare (1537)
Treatment of battle wounds with
Hot oil
ointment made of rose oil, turpentine oil and egg yolk
Planned trial by James Lind (1747)
Treatment of scurvy on board “salisbury”
12 patients
2 had apple drink, 2 had elixir vitriol, 2 had vinegar, 2 had lemon, 2 had nutmeg and 2 had to drink sea water

5. Learning Objectives Students should learn at the end of this lecture
What is a clinical trial
What are the phases of clinical trials
How many types of clinical trials are available
Design of a clinical trial
Protocol
Informed consent
Sample size

6. What is clinical trial? It is an experimental epidemiological method.
Subjects are randomly allocated into groups (usually study and control group) to receive or not to receive an experimental, preventive or therapeutic procedure, maneuver, or intervention.

7. Why they are done?
As they provide better evidence of the effect or the outcome that cannot be obtained with any observational method.
The variation is minimized and bias is controlled, hence more valid and their results speak truth.

8. Why they are done?
3. Enjoying maximum confidence just like any other scientific laboratory experiment
4. Scientifically most rigorous, Fastest and safest method of testing hypothesis to find new treatments that work in patients and ways to improve quality of health

9. When They Are Done
When the margin of the expected benefit or the outcome of an intervention is doubtful.
After the laboratory and animal studies yield the most promising results of the intervention, these results are tested by clinical trials

10. Phases Of Clinical Trials
Phase -I trials
Phase -II trials
Phase -III trials
Phase -IV trials

11. Phase-l Trials
After laboratory and animal testing, first time human testing
In a small group of 2 – 10 usually terminally ill patients
Purpose is
To evaluate Maximum Tolerated Dose (MTD)
To determine a safe dosage range
Rectify side effects

12. Phase-ll Trials Tested in large group of 10-30 people
Purpose is to further evaluate
Effectiveness with optimal dose
Safety

13. Phase – lll Trials (RCT)
Still large group people are tested
Purpose is to confirm
Its effectiveness
Monitor side effects
Compare with commonly used treatments
To gather information regarding safe use

14. Phase-lV Trials Post marketing studies To know about
Drug risks after prolong use
Benefits
Optimal use

15. What are its types? Treatment trials Prevention trials
Diagnostic trials
Screening trials
Quality of life trials

16. 1) Treatment Trials They test New treatments New combination of drugs
New surgical techniques
New Radiation therapies

17. 2) Prevention Trials
They try to find better ways to prevent disease in people and to prevent disease recurrence using
Vaccines
Vitamins
Minerals
Life style changes
Preventive Medicines
Preventive med. Going to area which is endemic with malaria, and using antimalarials for prevention.

18. 3) Diagnostic Trials
To find better tests for diagnosis of a disease

19. 4) Screening Trials
To find out the best way to detect certain diseases or conditions

20. 5) Life Style Trials Also called Supportive care trials
Often employed for the chronically ill patients or old homes.
They explore the ways to improve comfort
To improve the quality of life

21. How is it done? Design of Clinical Trial
Selecting the reference population
Selecting the experimental population .
Selecting the study population
(Participants)
Random allocation into
Intervention group
Comparison group
Apply intervention
No intervention (placebo/standard treatment)
Uniform assessment of outcomes
Improved Not improved Improved Not improved

22. Randomized control study Design
Study Population
Randomization
Study Group (Experimental)
Control Group (Comparison)
Base line Data
Collection
Base line Data
Collection
Intervention
Compare
Data
Collection
Data
Collection 22

23. Quazi-Experimental study Design
Study Population
Study Group (Experimental)
Control Group (Comparison)
Base line Data
Collection
Base line Data
Collection
Intervention
Compare
Data
Collection
Data
Collection 23

24. Some further Designs Non-RCT; groups allocated without Randomization
Cross over designs; same person in intervention group and then shifted to control group and vice versa
Usually for analgesics
For non-fatal diseases

25. Some further Designs
Historical controls; single group intervention and it is compared with controls of the past (records/other studies)
Group allocation; groups are allocated instead of individuals (school, villages)
Hybrid designs; combination of 2 or more than 2 designs

26. PROTOCOL (STUDY PLAN) Study plan is designed
to safeguard the health of the participants
to answer the specific research question

27. PROTOCOL
Written agreement between researcher, participant and scientific community; should be developed before enrolment and once implemented should not change.
It has to be explained in detail, to all the participants, particularly regarding benefits and risks.
It should be submitted to the ethical committee for prior approval before commencing the study.

28. PROTOCOL It describes what types of people can participate,
the schedule of tests, procedures, medications, dosages
The duration of study

29. EXPLAINING THE BENEFITS
that the participants play active role in their own health care
They gain access to the new treatments before they are widely available
They obtain expert medical care
Help others by contributing to research

30. EXPLAINING THE RISKS TO PARTICIPANTS
Unpleasant, serious or even life threatening side effects
Failure of treatment
Time waste for the participants

31. Protocol Outline of the protocol A:- introduction of the study
B:- Objectives
Primary question and its response
Secondary question and its response
Adverse effects
C:- Design of the study
Study population (inclusion and exclusion criteria)
Sample size and enrolment of the subjects
Informed consent

32. Protocol 4:- Intervention 5:- Follow up 6:- Termination policy
Assessment of eligibility
Base line examination
Intervention allocation (Randomization)
4:- Intervention
Treatment schedule
Measure of compliance
5:- Follow up
6:- Termination policy

33. INFORMED CONSENT
Informed consent document will be obtained from the participants in the study population after explaining them
The purpose,
Duration of the study,
Required procedures,
Expectations,
Risks and benefits,
Adverse effects of the trial if any,
Participants’ rights

34. INFORMED CONSENT
It is a continuous process of learning of key facts by participants about a clinical trial.
It also explains the rights of the participant.
It is not a contract and the participant can withdraw from the trial at any time. Informed consent is only a communication document.

35. INFORMED CONSENT
Participants are human beings with a motive to help the researcher and society.
Researcher should never be over- enthusiastic in his intervention to get his results while dealing with participants.

36. RANDOM ALLOCATION
The participants in the study population are randomly allocated into two groups (Arms) using Random Number tables, or Computers to avoid selection and confounding biases.

37. Block Randomization
Disadvantage of Randomization is, it produces imbalance in the number of participants assigned to each group, if groups are small
Then we do block randomization; it produces more balanced groups

38. Block Randomization
The investigator wants that after every 4th randomized participant the number in each group is equal
Then block of four.
Four participants are ranked according to random number table;
eg; 1, 8, 4, 7 then these numbers are arranged as 1,4,7,8 and then one of the following 6 combination is used decided in advance
ABBA, ABAB, AABB, BBAA, BABA, BAAB
Suppose we are using the first combination then patients assigned the numbers 1 and 8 will go to group A and the others (4,7) to group B

39. 1000 Patients (600 males and 660 young)
Stratified Randomization To achieve between group comparability of certain characteristics. eg. Age and sex
1000 Patients (600 males and 660 young)
600 males
400 females
360 young
240 old
300 young
100 old
Intervention group
Control group

40. BENEFITS OF RANDOMIZATION?
Allocation or selection bias is minimized and produces groups comparable to known and unknown risk factors.
This elimination of allocation bias will greatly enhance the validity of the trial.
Allocation bias is minimized by selecting randomly.
Chance plays the role but not the choice of the investigator during randomization. Each individual will have equal chance of to enter the trial
Investigator will not have any have any choice to allocate into any group, either the intervention group or the comparison group by his choice according to his whims and fancies, if he allocates randomly into two arms.

41. After random allocation into groups
INTERVENTION
After random allocation into groups
The intervention (new drug or new procedure) is applied to the one group and placebo or standard or old procedure to the other group.

42. FOLLOW-UP
Better compliance will lead to better validity which in turn enables for better generalizability
Both the groups are similarly followed in all aspects like duration, type of follow-up

43. MAINTENANCE OF COMPLIANCE
Selecting high risk people as participants in study population (high risk are more motivated)
Frequent contacts with the participants through phone calls, home visits, clinic/hospital visits
Providing calendar packs to the participants and asking them to stick on to calendar packs without fail.
Giving incentives like free medical aid in future, giving some gifts.
*If the study population selected is at high risk for the disease for which the drug/intervention is tested, the participants will be strongly motivated and more cooperative compared to those at usual or normal risk.
Significant difference between the outcomes of the two groups depends not only on sample size and elimination of biases but also on the compliance.

44. NON-COMPLIANCE
Extent of non-compliance is directly proportional to the duration and complexity of the trial.
Compliance is difficult when the end –points are time taking like incidence of cancers or death
Non-compliance decreases the statistical power of the trial which speaks about the validity (truth of the results)

45. ASSESSMENT CRITERIA
Depends on whether the outcomes or end-points are single or multiple, subjective or objective
uniform & similar type of evaluation of end-points for both the groups is to be carried out.

46. ASSESSMENT CRITERIA
Subjectivity of the outcome e.g. reduction of pain, may lead to observer error and poor assessment.
Double blinding eliminates observer bias to a large extent.

47. HAWTHORNE EFFECT
Sometimes the participants in comparison group may exaggerate the effects/outcomes to please the investigator or when they like the study or for some other reasons.
This will affect the assessment unless controlled.

48. BLINDING
PURPOSE
Blinding or Masking is done to eliminate
Investigator bias
Evaluation bias
Investigator may influence the trial or manipulate evaluation of the results (investigator bias) or the participant may exaggerate the effects (Hawthorne effect),
Investigator may influence the trial or manipulate evaluation of the results (investigator bias) or the participant may exaggerate the effects (Hawthorne effect),

49. BLINDING (masking) The *participant, (study subject) the*investigator,
and sometimes even the *evaluator are all kept unaware (blinded) of the outcomes of the trial and secrecy is maintained to improve the validity.

50. Types of Blinding x ---- X -------- Single Double Triple Subject
Researcher
Data Analyst
= Blind with respect to subject’s allocation
= May be aware of subject’s allocation x
---- 50

51. UNBLINDING
In emergencies and life threatening situations for participants, unblinding can be done.

52. Kaplan Mayer method is usually used for analysis
ASSESSMENT
Kaplan Mayer method is usually used for analysis
In Veteran administration study for Hypertensive efficacy, impotence was observed 29% in intervention group & 28% in comparison group. If there is no comparison group, it may be erroneously considered that hypertensives will cause impotence
In Aspirin Myocardial Infarction Study (AMIS 1980) complaints of gastritis and peptic ulcer were reported 23.7% and 14.9% in intervention and comparison groups respectively, thereby lessening the blame on Aspirin.
Group A
Frequency of deaths
Group B
time

53. Sample size calculation for RCT
What should we know in order to estimate the sample size
The estimated difference in response rate of the two arms of RCT to be detected
An estimate of the response rate in one of the groups (either control or interventional)
Level of significance (alpha)
The value of power of the study desired (1 - beta)
One sided test or 2 sided test

54. Differences in cure rates between 2 groups
Sample size: Number of patients needed in each group to detect various differences in cure rate. (alpha=0.05, 1-beta= 0.8, 2-sided)
Lower cure rate
Differences in cure rates between 2 groups 5%
10%
15%
20%
25%
30%
40%
50%
420
130 69 44 36 31 20 14
680
195 96 59 41 35 23 17
910
250
120 71 48 39 25
1090
290
135 80 53 42 26 18
1250
330
150 88 57 28
1380
360
160 93 60 29
35%
1470
370
170 61
1530
390
175 97
45%
1560
391
176 -

55. Alpha, Beta, Power of Study
Reality
Your decision
Treatments not differ (H0: true)
Treatments differ (Ho: false)
Treatments do not differ (fail to reject H0)
Correct decision
Type 2 error (beta)
Treatments differ
(reject H0)
Type 1 error (alpha)
Correct decision (1 – beta)

56. Home Work
Prepare the proposal of a randomized control trial RCT on the topic of your own choice.