1. Methodology (II)
Tamer Hifnawy MD. Dr.PH
Associate Professor
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.
Friedman, 1998
6. What Is The RCT ?
It is one of the simplest, most powerful,
revolutionary tools of research in which ;
Participants
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
Treatments that
WORK
Those that
do
NOT WORK
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
conditions.
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.
12. PLACEBO
A pill, liquid, or powder that contains
no drug and has no treatment value.
A placebo looks just like the real drug.
14. Examples of control arm
Standard care.
Placebo.
Careful follow-up.
Early or late application of
same intervention.
Higher or lower dose level.
16. Randomization
Means that subjects recruited from
the study population are allocated
to either intervention or control
arm by chance.
Random procedure = haphazard
procedure
17. Why Randomization
Ensures comparability of the two arms
regarding known and unknown factors.
Avoid selection bias.
Provides basis for standard statistical
analysis.
Differences in baseline characteristics of
the study arms indicate break in
randomization.
18. Why Randomization is difficult
Any randomization technique must insure:
1. Every new subject has an equal
chance to be allocated to either
arms (alternation?!)
2. Nearly equal number of subjects
in each arm (coin toss?!).
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
TCCT CTCT
24. Design of the trial
Methodology section should include
the following:
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.
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:
Single-blind: subject
Double-blind: subject & investigators
(clinician, interviewers, laboratory personnel).
Triple blind: subject, investigators &
Statistitian.
Blindness (continued)
29. Complex designs
1- Multiple treatment groups
More than 2 different treatments (or doses) may
be compared with a control group.
Sample population
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
Wash-out period
Drug APlacebo
Outcome No outcome Outcome No outcome
Drug APlacebo
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
Sample population
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.
4- Power.
P < 0.05 ??
36. Good RCT should report
Clear definition of patients.
Comparison group.
Randomization and blindness.
Outcome criteria and variables.
Compliance and completeness.
Complications of treatment.
Statistical manipulation.
37. 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
38.
39. Statistics
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
$800 million
The average number of studies conducted on a
new drug prior to market approval are 64
Did you know that...
42. Goals and Objectives
Basic understanding of drug development process as a
whole, i.e.
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
44. The Pipeline Concept of Drug Development
Drug Discovery Period
(Pre-Clinical)
Drug Development Period Commercialization
Idea
for
New
Drug
Synthesis
&
Purification
Specific
Biological
Activity
Found
Animal
Testing
Candidate
Compound
Chosen and
More Testing
Compound
Evaluated
to Project
Status
IND
Plan
Set
IND
Filed
With
FDA
Clinical
Studies
Planned
and
Started
NDA
Prepared
and
Submitted
to FDA
NDA
Approval
Drug
Launched
Post-
Marketing
Studies
Begun
New
Clinical
Uses
Pursued
Activities
to Support
Market
New Dosage Forms
and Formulas
Developed
Clinical Trials
Phases I, 2, & 3
Clinical Trials --
Phase 4
3.5 Years 8.5 Years 8 Years Left on Patent
(patent applied for)
45. The Pipeline Concept of Drug
Development
While in the pipeline, the drug could be
halted for several reasons.
Pre-Clinical Marketed
Lack of Safety
Lack of Funds Lack of Efficacy
Unethical Conduct
46. Pre-Clinical Research
Why?
Per FDA requirement, a sponsor must
first submit data showing that the drug is
reasonably safe for use in initial, small-
scale clinical studies
Therefore:
Preclinical research must be initiated
prior to submission of Investigational
New Drug application (IND)
48. Animal Testing
Provide sufficient information to support
selection of initial human dose and safe
duration of exposure
Evaluate drug’s toxic and pharmacologic
effects
Toxicology: predicts potential hazards in man
Pharmacology: investigates action of drug
Pharmacokinetics
Pharmacodynamics
49. 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
drug: ADME.
50. Drug Development
Drug Development Period
Compound
Evaluated
to Project Status
IND
Plan
Set
IND
Filed
With
FDA
Clinical
Studies
Planned and
Started
NDA Prepared
and
Submitted to
FDA
NDA
Approval
Drug
Launched
Clinical Trials
Phases I, 2, & 3
51. Clinical Studies
Phases 1, 2, 3
Ultimate premarket testing ground for
unapproved drugs
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)
52. 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
expected
Assess clearance of drug and to anticipate possible
accumulation of parent drug or metabolites and potential
drug-drug interactions
53. Phase 1 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 1 and continue
on to Phase 2
54. Phase 2 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 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
55. 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
56. Phase 3 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
57. Phase 3 Demographics
Several hundred to several thousand
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 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
objectives.
61. Phase 4
Increases patient experience
Safety in practice environment
Information to support marketing claims / change
labeling
Pharmacoeconomics, quality of life, Pediatric
patent extension trials
62. Post Marketing Surveillance
Continued evaluation of adverse events after
marketing
FDA reporting required
May result in labeling changes or restrictions or
in extreme cases withdrawal from market