The document discusses experimental study designs and randomized clinical trials. It provides information on the different phases of clinical trials including objectives, demographics, and goals. Phase I trials test safety and dosing in small groups. Phase II explores biological effects and estimates response rates. Phase III confirms efficacy in larger and more diverse populations to provide evidence for marketing approval. Randomization, blinding, and placebos are used to reduce bias. Experimental studies directly manipulate variables under controlled conditions to measure outcomes compared to control groups.

1. Experimental Designs
STUDY DESIGNS

2. STUDY DESIGNS
EPIDEMIOLOICAL
STUDIES
EXPERIMENTAL
STUDIES
OBSERVATIONAL
STUDIES
Case report
Case series
Cross sectional
Case control
Cohort study
DESCRIPTIVE ANALYTICAL

3. Experimental studies
• In experimental research, the study subjects are
observed under predetermined conditions using carefully
designed approaches to data & specimens
• The gold standard of clinical research

4. The experimental study designs differ from
the analytical study designs
1. The conditions in which the study is carried are under direct
control of the investigator
2. The experimental studies involve some action or
intervention or manipulation in the experiment group while
making no change in the control group
3. In analytical studies, no action but only observation of the
natural course of events or outcomes

5. The aims of experimental studies
1. To provide scientific evidence of etiological or risk
factors to permit modification or control of disease
2. To provide a method of measuring the
effectiveness or efficiency of the health services
for prevention, control & treatment of disease and
to improve the health of the community

6. GOALS OF CLINICAL TRIALS
Finding Drugs or
Treatments that
WORK
Those that
do
NOT WORK

7. USES OF CLINICAL TRIALS
• Treatment: test experimental treatments, combinations of
drugs, new approaches
• Prevention: look for better way to prevent disease or its
recurrence
• Diagnostic: develop better tests
• Screening: to detect diseases or health conditions
• Quality of Life (or Supportive Care): improve comfort and
QOL in chronic disease states

8. The disadvantages of the experimental studies
•They are costly
• Ethical problems
• Feasibility

9. CLINICAL TRIAL DESIGN
• In early smaller studies, where the drug is
being tested for safety and dose, each
person who participates gets the new drug
being tested
• In the following larger trials, doctors
compare the new drug with another
treatment to see which works better on
participants

10. • The later larger trials, may work like
this:
One group of
participants gets the
new drug
The other group gets a drug that
is used to treat the problem
OR
gets a “look alike” pill that
contains no drug
(called a placebo)

11. COMMON CLINICAL TRIAL TERMS
CONTROLLED STUDY: A study in which a test article is
compared with a treatment / placebo
 A test drug is given to one group of people. This group is
often called the “treatment group”
 Another drug, or no drug, is given to a second group of
people with the same illness. This is often called the “control
group”
 Then the results of the two groups are compared

12. PLACEBO
• A pill, liquid, or powder that contains no drug
and has no treatment value.
• A placebo looks just like the real drug.

13. RANDOMIZED STUDY
• Involves randomly allocating the Research Participants
across the treatment groups

14. BLINDED STUDY
• A study in which the research subject or the investigator (or
both) are unaware of what trial product the subject is taking
 Single-Blinded: Subjects do not know what treatment they
are getting but their research doctor and team do.
 Double-Blinded: Neither the subject nor the research doctor
knows which treatment the subject is getting

15. RANDOMIZED CLINICAL TRIALS
Participants
Randomly
Assigned
Follow - Up
Follow - Up
Outcomes
Compared
Intervention Group
(New Drug)
Control Group
(Old Drug)
Intervention
Group
Control
Group

16. RCT DESIGNS

17. RCT DESIGNS
[1] According to exposure to intervention:
 Parallel design Each group is subjected one
intervention ( the most common design)
Group A
Group B
TREATMENT A
TREATMENT B / Placebo

18. RCT DESIGNS
[1] According to exposure to intervention:
 Cross – Over design Each participant is given
both interventions in successive periods. Each
participant acts as his or her own control.
Treatment Placebo
TREATMENT A TREATMENT B

19. RCT DESIGNS
[1] According to exposure to intervention
 Factorial design: When interventions are
compared separately, in combination and
against a control in different groups.
TREATMENT A
TREATMENT B
TREATMENT A +B
PLACEBO
Group A
Group B
Group C
Group D

20. Double-Blinded Single-Blinded
Blinding
“Hiding who gets what”
• The treated patient and/or
treating doctor should not
know what drug is used
• Fair evaluation of outcomes

21. RCT DESIGNS
[2] According to “Blindness” to the interventions
 Open RCT everybody involved in the trial knows which
intervention is given to each participant
 Single blind RCT either the participants or the investigators do
not know the identity of interventions
 Double blind RCT Both the participants or the investigators do
not know the identity of the interventions
 Triple blinded RCT: Participant, investigators or person who
evaluates do not know the identity of the intervention

22. Non-randomized trials
Those departing from strict randomization for
practical purposes but in such a manner that non-
randomization does not seriously affect the
theoretical basis of conclusions

23. The quasi-experimental study designs
In this design the control over the external
factors is not possible and this might alter the
outcome variables

24. Phases of Clinical Trial
• Phase I : maximum tolerated dose
• Phase II : effectiveness, safety
• Phase III : efficacy, safety
• Phase IV : effectiveness, compliance and
safety

25. RISKS AND BENEFITS OF CLINICAL TRIALS
• Risks:
• Unpleasant or serious side effects
• You may receive a placebo
• No guarantee that the experimental drug will be an effective
treatment for you
• Benefits:
• May experience health benefits from a new treatment
• Free lab tests and expert treatment
• Contributing to the development of a new medication

26. The features of the experimental study designs
• Random allocation of individuals to experimental & control groups
• Systematic manipulation of the experimental group
• Control over the other important factors affecting experimental &
control groups
• Measurement of some outcome variables with which to compare two
groups

27. The basic steps in conduct of randomized
controlled trials
1. Drawing a protocol
2. Selecting reference & experimental population
3. Randomization
4. Manipulation or intervention
5. Follow up
6. Assessment of the outcome

28. DESIGN OF A RANDOMIZED CLINICAL
CONTROL TRIAL

29. The protocol
One of the essential features of the randomized trials
The protocol specifies:
1. The objectives
2. The selection criteria
3. The sample size
4. The procedures of allocation of the subjects into
experimental and control groups
5. Outcomes & endpoints
6. The treatment applied: how, where and to what types of patients
7. The details of the scientific techniques and investigations

30. Once a protocol has been evolved, it
should be strictly adhered to
throughout the study
(Protocol Violation)

31. Selection of the reference & the
experimental populations
The reference population:
• It is the population to which the findings of the trial, if
found to be successful, are expected to be applicable

32. The experimental population:
• The experimental (study) population is derived from the
reference population
• It is the actual population that participates in the experimental
study
• It should be randomly selected from the reference population
• If the study population differs from the reference population, it
may not be possible to generalize the findings to the reference
population

33. Participants or the volunteers of the experiment must fulfill
the following criteria:
• They must give informed consent
•They should be representative of the reference population
• They should be eligible or qualified for the trial

34. Randomization
• Randomization is the statistical procedure by
which the participants are allocated into groups
usually called study & control groups to receive
or not to receive an experimental or therapeutic
procedure or intervention.

35. • Randomization aims to make the groups comparable
• Randomization ensures that the investigator has no
control over the allocation of the participants to either the
study or control group, thus eliminating the selection
bias
• Every individual has an equal chance of being allocated
into either group
• Randomization is best done by using statistical random
table

36. The essential difference between a randomized trial and analytical
study is that:
• In the latter there is no randomization because differentiation
into cases & controls exposed and non-exposed groups has
already taken place
• Thus the only option left to ensure comparability in analytical
studies is by matching

37. MANIPULATION
• Manipulation or intervention is usually done by application or
withdrawal of the suspected factor e.g. drugs, vaccine or
dietary factor
• This manipulation creates an independent variable (drug,
vaccine or new procedure) whose effect is then determined
by the measurement of the final outcome which constitutes
the dependent variable e.g. incidence of disease, recovery

38. FOLLOW UP
• This includes examination of the study & control
groups subjects at defined intervals of time in
standard manner under the same conditions in the
same time frame till the final assessment
Main difficulties encountered in the follow up process
include:
• Attrition, death, migration, displacement and loss of
interest

39. Assessment
The final assessment of the trial is carried in terms of:
• Positive results: these include the benefits of the
experimental study such as reduced incidence of the
disease or severity of the disease, cost of health
services or other appropriate outcome

40. • Negative results: these include the severity
& frequency of side-effects and complications
• The incidence of positive/negative results is
compared in both groups and the differences
are tested statistically

41. BIAS
Bias is the systematic difference between observed results
and the actual results
Sources of bias:
1. participant’s bias:
The participants report subjectively that they feel better or
improved if they knew that they were receiving new
treatment

42. 2. Observer’s bias:
The influence of the investigator measuring the
outcome of the trial if he knew beforehand the
particular procedure to which the patient has been
subjected
3. Evaluation bias:
There may be bias in evaluation as the investigator
may involuntarily give favorable report of the
outcome of the study

43. How to reduce the sources of bias?
1. Randomization
2. Blinding

44. Blinding is carried in three ways:
1. Single blind trial: the trial is so planned that the
participant is not aware whether he belongs to the
study or control group.
2. Double blind trial: the trial is so planned that
neither the doctor nor the participant is aware of
the group allocation and treatment received.

45. 3. Triple-blind trial:
• The trial is so planned that the participant, the
investigator& the person analyzing the data are
all blind.
• This is the ideal but double-blinding is the
most commonly used.

46. PHASES OF CLINICAL TRIALS
• A properly planned and implemented clinical trial is a
powerful technique for assessing the effectiveness of an
intervention
• A clinical trial is a prospective study comparing the effect
of intervention(s) against a control in human beings
• A clinical trial is prospective rather than retrospective

47. • Study participants must be followed foreword in
time.
• Follow up of the study subjects overtime without
active intervention may measure the natural
history of disease but this is not a clinical trial

48. Clinical trials Phases
Phase (I):
• The first step or phase is to understand how well the
intervention can be tolerated in a small number of healthy
individuals or sometimes patients
• It does not meet the standard definition of a clinical trial
• Most phase I designs are relatively simple

49. • Evaluating drugs, needs first step is to estimate how a dose can
be administered before unacceptable toxicity is experienced by
patients
• This dose is usually called maximally tolerated dose (MTD)

50. PHASE I OBJECTIVES
• Main purpose: assessing safety of drug
• Human Pharmacology
• Typically non-therapeutic objectives
• Determine tolerability of dose range expected to be
needed for later trials (Maximum tolerated Dose -MTD)
• Determine nature of adverse reactions that can be
expected
• Assess clearance of drug and to anticipate possible
accumulation of parent drug or metabolites and
potential drug-drug interactions

51. PHASE I DEMOGRAPHICS
• Usually healthy volunteers or certain types of patients (e.g.
new chemotherapeutic agent for cancer patients with end
stage disease)
• Often conducted in a medical setting
• 20-100 patients
• Trials can last up to several months
• Open label –everyone knows what they are getting.
• 70% of drugs successfully complete Phase I and continue
on to Phase II

52. Phase (II) trials
• Once the MTD is established: the next step is to
evaluate whether the drug has any biological
effect and to estimate the rate of adverse effects.

53. • If the design of phase I has not been adequate, the
investigator may evaluate the dose
• phase II design depends on the quality of adequacy of
phase I
• The design usually encounters a limited number of
patients and then the response rate is estimated

54. • If the response rate is less than the 20%: the drug is
omitted.
• If the response is greater than 20%: more patients
are recruited according to the precision desired:
usually 10-20

55. PHASE II OBJECTIVES
 Therapeutic Exploratory
 Main purpose: assessing efficacy for particular
indication (Efficacy-A product's ability to produce
beneficial effects on the course or duration of a
disease)
 Initial evaluation:
 Safety (side-effect)
 Well-controlled, closely monitored studies
 Active or placebo controlled -- double blind
 Includes dose-response and/or dosing schedule
studies
 Determine dose and regimen for Phase III

56. PHASE II DEMOGRAPHICS
• 200-300 (up to 1000) patients with targeted indication
(Relevant disease)
• Diseased patients; selected by relatively narrow
criteria
• Trials last from several months to 2 years
• Experienced physicians in the specialty
• Early Phase II trials may be called Phase 2a or pilot
studies
• 33% of drugs successfully complete Phase II and
continue on to Phase III

57. Phase III
• Phase III trials have a short period of evaluation
• Purpose: Confirm efficacy, monitor adverse reactions from long term
use
• In Phase III studies, a drug is tested under conditions more closely
resembling those under which the drug would be used if approved
for marketing
• The goal is to gather additional information about efficacy and
tolerability that is needed to evaluate the overall benefit-risk
relationship of the drug and to provide an adequate basis for
physician labeling
• Focus on effectiveness but knowledge on safety is also necessary

58. PHASE III OBJECTIVES
• Therapeutic Confirmatory
• Main purpose: safety, effectiveness - confirm therapeutic
benefit for use in intended indication and recipient population
• Effectiveness-The desired measure of a drug's influence on a
disease condition as proved by substantial evidence from
adequate and well-controlled investigations such as clinical
trials
• Evaluate overall benefit-risk relationship
• Provide adequate basis for marketing approval
• Extrapolate results to put in labeling
• 25-30% of drugs complete Phase 3 trials

59. PHASE 3 DEMOGRAPHICS
• Several hundred to several thousand
patients (250 – 1000 patients)
• Patients with the disease; more diverse
population
• Inclusion/Exclusion criteria less
restrictive
• Trials last from 1-4 years
• Less experienced investigators -
Approaches general use (the “real
world population)
• Overall: on average, 20%
of drugs ultimately gain FDA
approval to market

60. PHASE IV OR POST MARKETING
SURVEILLANCE
• No fixed duration / patient population
• Starts immediately after marketing
• Report all acute adverse reactions (ADRs)
• Helps to detect
• Rare ADRs
• Drug interactions
• Also new uses for drugs [Sometimes called Phase V]
• Do not involve control groups to evaluate properly the
proper role of an intervention

61. 2. PREVENTIVE TRIALS
• In general the term preventive trials implies trials of
primary preventive measures.
• The trials are designed to prevent or eliminate disease
on an experimental basis.
• The most frequently occurring type of preventive trials
are the trials of vaccines and chemoprophylaxis.

62. DESIGN OF A RANDOMIZED PREVENTIVE
CONTROL TRIAL