Methodology (II)

Tamer Hifnawy MD. Dr.PH

Associate Professor
Public Health & Community Medicine
Faculty Of Medicine – BSU- Egypt
College Of Dentistry Taibah University - KSA
Vice Dean For Quality, Development & International Affairs
Certified Trainer For International Research Ethics
What is a Clinical Trial?
A prospective study comparing the effect
and value of intervention (s) against a
control in human being.
Friedman, 1998
 Intervention studies

Objective
To measure the effect of a
particular intervention (a drug,
other treatment, a vaccine or a
health promotion program)
 WHAT IS THE
RANDOMIZED
CONTROLLED TRIAL ?
 RCTs
IT IS THE
GOLD STANDARD
IN CLINICAL RESEARCH
 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
 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
 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.
 Goals of Clinical Trials

Finding Drugs or Those that

Treatments that do

WORK NOT WORK

 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.
 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.
 PLACEBO

 A pill, liquid, or powder that contains

no drug and has no treatment value.
 A placebo looks just like the real drug.
 Control arm

WHY? Spontaneous cure Side effects

HOW? Criteria Historical Ethical
 Examples of control arm

 Standard care.
 Placebo.
 Careful follow-up.
 Early or late application of
same intervention.
 Higher or lower dose level.
 Randomized Clinical Trials
Intervention Group Intervention
(New Drug) Group

Outcomes Compared
Follow - Up
Randomly Assigned

Control Group Control

(Old Drug) Group

Follow - Up

Participants
 Randomization

Means that subjects recruited from

the study population are allocated
to either intervention or control
arm by chance.

Random procedure = haphazard

procedure
 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.
 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?!).
 Randomization techniques

 Fixed allocation randomization:

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

1. Sealed envelopes.

2. Random number tables.

3. Computer generation.
 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.

C T C T T T C C C C T T

T C C T T C T C
 Stratified Randomization

Control
Age<40
Test
Enrolled
Control
Age>40
Test
 Baseline measurements

Useful to check that comparability has

been successfully achieved.
 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.
 Blindness

Means ensuring that a person remains

unaware of which arm a subject has
been allocated to.
 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.
 Blindness (continued)
Trials are often described as:

 Single-blind: subject

 Double-blind: subject & investigators

(clinician, interviewers, laboratory personnel).

 Triple blind: subject, investigators &

Statistitian.
 Observe the following

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

 Completeness of follow-up.
 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

 Complex designs

2- Cross-over trial

Each subject receives both the active and

control treatments during two periods
separated by a wash-out period.
 Cross-Over Enrolled Population

Placebo Drug A
Outcome No outcome Outcome No outcome

Wash-out period

Placebo Drug A
Outcome No outcome Outcome No outcome
 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

 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.
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.
 Interpretation of trial

1- Reporting the data.

2- Statistical methods. P < 0.05 ??

3- Statistical analysis.
4- Power.
 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.
 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

Statistics
Did you know that...

 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
PhRMA Pharmaceutical Industry Profile 2006
The Drug Development Process
 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
 The Pipeline Concept of
Drug Development

PRECLINICAL APPROVAL $$$

PIPELINE
The Pipeline Concept of Drug Development

Drug Discovery Period

Drug Development Period Commercialization
(Pre-Clinical)
Clinical
IND NDA
Studies Post-
Idea Specific Candidate Plan Approval
Planned Marketing
for Biological Compound Set
and Studies New Activities
New Activity Chosen and
Started Begun Clinical to Support
Drug Found More Testing
Uses Market
Compound IND NDA Drug
Synthesis Animal Pursued
Evaluated Filed Prepared Launched
& Testing to Project With and
Purification New Dosage Forms
Status FDA Submitted
and Formulas
to FDA
Developed

Clinical Trials Clinical Trials --

Phases I, 2, & 3 Phase 4
(patent applied for)
3.5 Years 8.5 Years 8 Years Left on Patent
 The Pipeline Concept of Drug
Development

While in the pipeline, the drug could be

halted for several reasons.

Lack of Funds Lack of Efficacy

Pre-Clinical Marketed

Lack of Safety Unethical Conduct

 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)
 Pre-Clinical

Drug Discovery Period

(Pre-Clinical)

Idea Specific Candidate

for Biological Compound
New Activity Chosen and
Drug Found More Testing

Synthesis Animal Testing

& Purification
 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
 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.
 Drug Development

Drug Development Period

Clinical
IND NDA
Studies
Plan Approval
Planned and
Set
Started

Compound IND NDA Prepared Drug

Evaluated Filed and Launched
to Project Status With Submitted to
FDA FDA

Clinical Trials
Phases I, 2, & 3
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)
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
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
 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
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
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
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
Phase 3b
Conducted after submission for
marketing but prior to approval
Commercialization/Post Marketing

Commercialization

Post-
New Activities
Marketing
Clinical to Support
Studies
Uses Market
Begun
Pursued

New Dosage Forms

and Formulas
Developed
 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.
 Phase 4

 Increases patient experience

 Safety in practice environment
 Information to support marketing claims / change
labeling
 Pharmacoeconomics, quality of life, Pediatric
patent extension trials
 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