This document provides an overview of the methodology used in clinical trials. It defines key terms like randomized controlled trials, control groups, randomization, and blinding. It describes the various phases of clinical trials including phases 1-3 and post-marketing studies. Phase 1 trials test safety in healthy volunteers while phases 2 and 3 test efficacy in larger patient populations. The goals of each phase are explained as well as important demographic information. The document also outlines the drug development process from preclinical research through regulatory approval and commercialization.

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

3. Intervention studies
Objective
To measure the effect of a
particular intervention (a drug,
other treatment, a vaccine or a
health promotion program)

4. WHAT IS THE
RANDOMIZED
CONTROLLED TRIAL ?

5. IT IS THE
GOLD STANDARD
IN CLINICAL RESEARCH
RCTs

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.

13. Control arm
WHY? Spontaneous cure Side effects
HOW? Criteria Historical Ethical

14. Examples of control arm
 Standard care.
 Placebo.
 Careful follow-up.
 Early or late application of
same intervention.
 Higher or lower dose level.

15. Randomized Clinical Trials
Participants
RandomlyAssigned
Follow - Up
Follow - Up
OutcomesCompared
Intervention Group
(New Drug)
Control Group
(Old Drug)
Intervention
Group
Control
Group

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?!).

19. Randomization techniques
 Fixed allocation randomization:
1. Simple randomization.
2. Blocked randomization.
3. Stratified randomization.
 Outcome adaptive designs:
Play the winner.
 Others.

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
TCCT CTCT

22. Stratified Randomization
Control
Age<40
Test
Enrolled
Control
Age>40
Test

23. Baseline measurements
Useful to check that comparability has
been successfully achieved.

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.

25. Blindness
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:
 Single-blind: subject
 Double-blind: subject & investigators
(clinician, interviewers, laboratory personnel).
 Triple blind: subject, investigators &
Statistitian.
Blindness (continued)

28.  Compliance:
1. Questioning
2. Observing
3. Check drug
 Complications.
 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.
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

33. Outcome variables
Continuous variables: hypertension
Dichotomous variables: dead/alive.
Time-to-event variables: time to remission.
Ordered variables: mild, moderate, severe.
Repeated measures: visual acuity.
Composite measures: score, cost-benefit.

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

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...

40. PhRMA Pharmaceutical Industry Profile 2006

41. The Drug Development Process

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

43. PRECLINICAL
The Pipeline Concept of
Drug Development
APPROVAL $$$
PIPELINE

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)

47. Pre-Clinical
Drug Discovery Period
(Pre-Clinical)
Idea
for
New
Drug
Synthesis
& Purification
Specific
Biological
Activity
Found
Animal Testing
Candidate
Compound
Chosen and
More Testing

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

58. Conducted after submission for
marketing but prior to approval
Phase 3b

59. Commercialization/Post Marketing
Commercialization
Post-
Marketing
Studies
Begun
New
Clinical
Uses
Pursued
Activities
to Support
Market
New Dosage Forms
and Formulas
Developed

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