1. Methodology (II)
Tamer Hifnawy MD. Dr.PH
P u b l i c H e a l t h & C o m m u n i t y M e d i c i n e
F a c u l t y O f M e d i c i n e – B S U - E g y p t
C o l l e g e O f D e n t i s t r y T a i b a h U n i v e r s i t y - K S A
V i c e D e a n F o r Q u a l i t y , D e v e l o p m e n t & I n t e r n a t i o n a l A f f a i r s
C e r t i f i e d T r a i n e r F o r I n t e r n a t i o n a l R e s e a r c h E t h i c s
2. What is a Clinical Trial?
A prospective study comparing the effect
and value of intervention (s) against a
control in human being.
3. Intervention studies
To measure the effect of a
particular intervention (a drug,
other treatment, a vaccine or a
health promotion program)
4. WHAT IS THE
CONTROLLED TRIAL ?
5. IT IS THE
IN CLINICAL RESEARCH
6. What Is The RCT ?
It is one of the simplest, most powerful,
revolutionary tools of research in which ;
are allocated at Random
into 2 or > groups (one of them is Control)
to receive one or more Interventions, then
Followed up in time, and
Outcomes are compared
7. Clinical Trials
A research study to test new treatments in
people for specific illnesses or conditions
(Malaria, HIV, Cancer, etc).
Clinical Trials are the fastest and safest way to
find out which treatments work
8. Definition of Clinical Trials
Pre-Planed usually Controlled
studies of the Safety, Efficacy, or
Optimum Dosage schedule of one or
more Diagnostic, Therapeutic, or
Prophylactic drugs in humans
selected according to pre-determined
criteria of Eligibility and observed for
pre-defined evidence of Favorable
and Unfavorable effects.
9. Goals of Clinical Trials
Finding Drugs or
10. 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
Quality of Life (or Supportive Care): improve
comfort and QOL in chronic disease states.
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.
A pill, liquid, or powder that contains
no drug and has no treatment value.
A placebo looks just like the real drug.
13. Control arm
WHY? Spontaneous cure Side effects
HOW? Criteria Historical Ethical
14. Examples of control arm
Early or late application of
Higher or lower dose level.
15. Randomized Clinical Trials
Follow - Up
Follow - Up
Means that subjects recruited from
the study population are allocated
to either intervention or control
arm by chance.
Random procedure = haphazard
17. Why Randomization
Ensures comparability of the two arms
regarding known and unknown factors.
Avoid selection bias.
Provides basis for standard statistical
Differences in baseline characteristics of
the study arms indicate break in
18. Why Randomization is difficult
Any randomization technique must insure:
1. Every new subject has an equal
chance to be allocated to either
2. Nearly equal number of subjects
in each arm (coin toss?!).
20. Simple Randomization
1. Sealed envelopes.
2. Random number tables.
3. Computer generation.
21. Blocked Randomization
Blocks containing specific number of
participants are generated ( 5 blocks each
containing 4 participants for a study with
total of 20 participants).
Within each block, participants are
randomly allocated to either arms.
TCTC CCTT TTCC
22. Stratified Randomization
23. Baseline measurements
Useful to check that comparability has
been successfully achieved.
24. Design of the trial
Methodology section should include
1-Patient inclusion criteria.
2-Time of patients inclusion in the study.
3-Presence of a comparison group.
4-Matching criteria of the two groups.
5-Method used for randomization.
Means ensuring that a person remains
unaware of which arm a subject has
been allocated to.
26. Why Blindness(continued):
To reduce selection bias.
to avoid bias in outcome measures.
Blinding is not possible in all studies
so, one needs to consider how
important it is, and to what extent it
can be achieved.
27. Trials are often described as:
Double-blind: subject & investigators
(clinician, interviewers, laboratory personnel).
Triple blind: subject, investigators &
3. Check drug
Completeness of follow-up.
Observe the following
29. Complex designs
1- Multiple treatment groups
More than 2 different treatments (or doses) may
be compared with a control group.
Control Drug A Drug B Drug C
30. Complex designs
2- Cross-over trial
Each subject receives both the active and
control treatments during two periods
separated by a wash-out period.
31. Outcome No outcome Outcome No outcome
Cross-Over Enrolled Population
Outcome No outcome Outcome No outcome
32. Complex designs for clinical trials
3- Factorial design
used to evaluate the separate and combined
effects of two different factors:
1. Group 1: Placebo.
2. Group 2:. Iron
3. Group 3: Folate.
4. Group 4: Iron + Folate
Control Surgery Radiotherapy Surgery+Radio
34. Losses to follow-up
•One of the most important sources of
bias, since those lost may be different
from those seen.
•Compare drop-outs to non-drop-outs.
•Perform sensitivity analysis.
35. Interpretation of trial
1- Reporting the data.
2- Statistical methods.
3- Statistical analysis.
P < 0.05 ??
36. Good RCT should report
Clear definition of patients.
Randomization and blindness.
Outcome criteria and variables.
Compliance and completeness.
Complications of treatment.
37. Risks and Benefits of Clinical Trials
Unpleasant or serious side effects
You may receive a placebo
No guarantee that the experimental drug will be an effective
treatment for you.
May experience health benefits from a new treatment
Free lab tests and expert treatment
Contributing to the development of a new medication
Only 1 in 10,000 of the compounds synthesized
for potential drug use ever reach market
Of all drugs tested in human beings, only 1 in 10
becomes a new medicine
Only 33% of all drugs that are marketed make
profits that exceed the costs of development
The average cost of bringing a drug to market is
The average number of studies conducted on a
new drug prior to market approval are 64
Did you know that...
39. PhRMA Pharmaceutical Industry Profile 2006
40. The Drug Development Process
41. Goals and Objectives
Basic understanding of drug development process as a
How a drug goes from test tube to market
Connections between preclinical testing, chemistry and
clinical research as they relate to drug development
Understanding of what goes into an Investigational New
Drug Application (IND) and New Drug Application
(NDA), including FDA involvement
Know how GLP, GMP, and GCP regulations and
guidelines fit into the drug development picture
The Pipeline Concept of
43. The Pipeline Concept of Drug Development
Drug Discovery Period
Drug Development Period Commercialization
New Dosage Forms
Phases I, 2, & 3
Clinical Trials --
3.5 Years 8.5 Years 8 Years Left on Patent
(patent applied for)
44. The Pipeline Concept of Drug
While in the pipeline, the drug could be
halted for several reasons.
Lack of Safety
Lack of Funds Lack of Efficacy
45. Pre-Clinical Research
Per FDA requirement, a sponsor must
first submit data showing that the drug is
reasonably safe for use in initial, small-
scale clinical studies
Preclinical research must be initiated
prior to submission of Investigational
New Drug application (IND)
Drug Discovery Period
47. Animal Testing
Provide sufficient information to support
selection of initial human dose and safe
duration of exposure
Evaluate drug’s toxic and pharmacologic
Toxicology: predicts potential hazards in man
Pharmacology: investigates action of drug
48. Animal Testing (cont.)
Pharmacodynamics The effect the drug has on the
body. Looks at bodily responses
to pharmacological, biochemical,
physiological, and therapeutic
effects: ED50, LD50
Pharmacokinetics The effect the body has on the
49. Drug Development
Drug Development Period
to Project Status
Phases I, 2, & 3
50. Clinical Studies
Phases 1, 2, 3
Ultimate premarket testing ground for
Investigation drug administered to humans and
evaluated for its safety and effectiveness
Results from trials decide approval or
disapproval of drug
Involves three phases of clinical studies
(21 CFR 312.21)
51. Phase 1 Objectives
Main purpose: assessing safety of drug
Human Pharmacology (PK and PD –e.g. ADME)
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
Assess clearance of drug and to anticipate possible
accumulation of parent drug or metabolites and potential
52. Phase 1 Demographics
Usually healthy volunteers or certain types of patients (e.g.
new chemotherapeutic agent for cancer patients with end
Often conducted in a medical setting
Trials can last up to several months
Open label –everyone knows what they are getting.
70% of drugs successfully complete Phase 1 and continue
on to Phase 2
53. Phase 2 Objectives
Main purpose: assessing efficacy for particular indication
(Efficacy-A product's ability to produce beneficial effects on
the course or duration of a disease)
Safety (side-effect profile-AE / SAE)
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 3
54. Phase 2 Demographics
200-300 (up to 1000) patients with targeted indication
Diseased patients; selected by relatively narrow criteria
Trials last from several months to 2 years
Experienced physicians in the specialty
Early Phase 2 trials may be called Phase 2a or pilot studies
33% of drugs successfully complete Phase 2 and continue
on to Phase 3
55. Phase 3 Objectives
Main purpose: safety, effectiveness - confirm therapeutic
benefit for use in intended indication and recipient
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
56. Phase 3 Demographics
Several hundred to several thousand
Patients with the disease; more diverse
Inclusion/Exclusion criteria less
Trials last from 1-4 years
Less experienced investigators -
Approaches general use (the “real world
Overall: on average, 20%
of drugs ultimately gain FDA
approval to market
57. Conducted after submission for
marketing but prior to approval
58. Commercialization/Post Marketing
New Dosage Forms
59. Phase 4- Post Marketing Trial
Post Marketing trials are studies (other than routine
surveillance) performed after drug approval and related to
the approved indication(s).
These trials go beyond the prior demonstration of the
drug’s safety, efficacy and dose definition.
These trials may not be considered necessary at the time
of new drug approval but may be required by the
Licensing Authority for optimizing the drug’s use.
They may be of any type but should have valid scientific
60. Phase 4
Increases patient experience
Safety in practice environment
Information to support marketing claims / change
Pharmacoeconomics, quality of life, Pediatric
patent extension trials
61. Post Marketing Surveillance
Continued evaluation of adverse events after
FDA reporting required
May result in labeling changes or restrictions or
in extreme cases withdrawal from market