Methodology (II)

Tamer Hifnawy MD. Dr.PHAssoc ia te Pro fessor

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 eFa 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 Ta i b a h U n i v e r s i t y - K S AVi c e D e a n Fo 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 Aff a i r s

C e r t i fi e d Tr a i n e r Fo 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

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 ?

IT IS THE GOLD STANDARD

IN CLINICAL RESEARCH

RCTs

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 TrialsA 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

Treatments that

WORK

Those that

do

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

Participants

Ran

dom

ly

Ass

ign

ed

Follow - Up

Follow - Up

Ou

tcom

es

C

om

pare

d

Intervention Group (New Drug)

Control Group (Old Drug)

Intervention Group

Control Group

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.

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

T C C T C T C T

Stratified Randomization

Control

Age<40TestEnrolledControl

Age>40Test

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.

Trials are often described as:

Single-blind: subject

Double-blind: subject & investigators

(clinician, interviewers, laboratory

personnel).

Triple blind: subject, investigators &

Statistitian.

Blindness (continued)

Compliance:1. Questioning

2. Observing

3. Check drug Complications.

Completeness of follow-up.

Observe the following

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.

Outcome No outcome Outcome No outcome

Cross-Over Enrolled Population

Wash-out period

Drug APlacebo

Outcome No outcome Outcome No outcome

Drug APlacebo

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:. Iron3. 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.

3- Statistical analysis.

4- Power.

P < 0.05 ??

Good RCT should reportClear 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

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...

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

PRECLINICAL

The Pipeline Concept of Drug Development

APPROVAL $$$PIPELINE

The Pipeline Concept of Drug Development

Drug Discovery Period(Pre-Clinical) Drug Development Period Commercialization

Ideafor

NewDrug

Synthesis&

Purification

Specific Biological

Activity Found

Animal Testing

Candidate Compound Chosen and More Testing

Compound Evaluated to Project

Status

IND Plan Set

INDFiledWithFDA

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 TrialsPhases I, 2, & 3

Clinical Trials -- Phase 4

3.5 Years 8.5 Years 8 Years Left on Patent

(patent applied for)

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

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)

Ideafor

NewDrug

Synthesis& Purification

Specific Biological

Activity Found

Animal Testing

Candidate Compound Chosen and More Testing

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

Compound Evaluated

to Project Status

IND Plan Set

INDFiledWithFDA

Clinical Studies

Planned and Started

NDA Prepared and Submitted

to FDA

NDA Approval

Drug Launched

Clinical TrialsPhases I, 2, & 3

Clinical StudiesPhases 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 setting20-100 patientsTrials can last up to several monthsOpen 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 indicationDiseased patients; selected by relatively narrow criteriaTrials last from several months to 2 yearsExperienced physicians in the specialtyEarly Phase 2 trials may be called Phase 2a or pilot studies33% of drugs successfully complete Phase 2 and continue

on to Phase 3

Phase 3 Objectives

Therapeutic ConfirmatoryMain 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 relationshipProvide adequate basis for marketing approvalExtrapolate results to put in labeling25-30% 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

Conducted after submission for marketing but prior to approval

Phase 3b

Commercialization/Post Marketing

Commercialization

Post-Marketing

Studies Begun

New Clinical

Uses Pursued

Activities to Support

Market

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