CLINICAL TRIALS

Dr.Jayashree
ICRI
NEW DRUG DEVELOPMENT

 DRUG DISCOVERYAND SCREENING

 PRECLINICAL SAFETY AND TOXICITY

TESTING

 EVALUATION OF DRUGS IN HUMANS

 REGULATORY BODIES
 US-FDA

 UK-MHRA

 INDIA-DCGI
ICH-GCP GUIDELINES
 GCP-Provide the operative guidelines for
ethical and scientific standards for the
designs of trial protocol ,conduct,
recording, reporting procedures and
should be strictly adhered to while carrying
out a trial
RESEARCH IN HUMAN SUBJECTS

 THERAPEUTIC / NON THERAPEUTIC

 EXPERIMENTAL / OBSERVATIONAL
ETHICS IN HUMAN RESEARCH
 ETHICS OF RESEARCH
AUTONOMY
BENEFICENCE
NON-MALE FICENCE
JUSTICE

 ETHICS OF RANDOMISED AND PLACEBO

CONTROLLED TRIALS

 INJURY TO RESEARCH SUBJECT

 PAYMENT OF SUBJECTS IN CLINICAL TRIALS

 GENERAL PRINCIPLES

 PROTECTION OF CLINICAL TRIAL

SUBJECTS

 SCIENTIFIC APPROACH IN DESIGN AND

ANALYSIS
 PROTECTION OF CLINICAL
TRIAL SUBJECTS
 RESULTS OF NON CLINICAL INVESTIGATIONS OR
PREVIOUS HUMAN STUDIES

 EMERGING ANIMAL TOXICOLOGICAL AND

CLINICAL DATA SHOULD BE REVIEWED AND
EVALUATED

 INVESTIGATOR AND SPONSOR RESPONSIBILITY

TOGETHER WITH IRB/IEC
 SCIENTIFIC APPROACH IN
DESIGN AND ANALYSIS
 DESIGNED,CONDUCTED AND ANALYSED TO
ACHIEVE OBJECTIVES

 CLINICAL TRIALS BE CLASSIFIED BY THEIR

OBJECTIVES

 THE AVAILABILITY OF FOREIGN CLINICAL DATA

PHASES OF CLINICAL TRIALS
 PHASE-I HUMAN PHARMACOLOGY

 PHASE-II THERAPEUTIC EXPLORATION

 PHASE-III THERAPEUTIC CONFIRMATION

 PHASE-IV POST-MARKETING STUDIES

DEVELOPMENT METHODOLOGY
 CONSIDERATIONS FOR THE DEVELOPMENT
PLAN

 CONSIDERATIONS FOR INDIVIDUAL

CLINICAL TRIALS
 DEVELOPMENT PLAN
 NON CLINICAL STUDIES

 QUALITY OF INVESTIGATIONAL MEDICINAL

PRODUCTS

 PHASES OF CLINICAL TRIALS

 SPECIAL CONSIDERATIONS
 NON CLINICAL STUDIES
 DURATION AND TOTAL EXPOSURE PROPOSED IN
INDIVIDUAL PATIENTS

 CHARACTERISTICS OF THE DRUG

 DISEASE OR CONDITION TARGETED

 USE IN SPECIAL POPULATION

 ROUTE OF ADMINISTRATION
 NON CLINICAL STUDIES
 SAFETY STUDIES

 PHARMACOLOGICAL AND
PHARMACOKINETIC STUDIES

 DOSE RESPONSE OR CONC. RESPONSE

RELATIONSHIPS AND DURATION OF ACTION
 ROUTES OF ADMINISTRATION
 SYSTEMIC GENERAL PHARMACOLOGY
 PHARMACOLOGICAL BASIS OF PRINCIPAL
EFFECTS
 ADME
QUALITY OF INVESTIGATIONALMEDICINAL
PRODUCTS

 FORMULATION SHOULD BE
CHARACTERIZED(BA)

 FORMULATION SHOULD BE APPROPRIATE

 DIFFERENT FORMULATIONS- ESTABLISH BE

STUDIES
PHASES OF CLINICAL TRIALS

 DRUG DEVELOPMENT IS IDEALLY A

LOGICAL STEP WISE PROCEDURE-
INFORMATION FROM SMALLER EARLY
STUDIES IS USED TO SUPPORT AND PLAN
LATER, LARGER MORE DEFINITIVE
STUDIES.

 IDENTIFY CHARACTERISTICS OF THE

INVESTIGATIONAL MEDICINE IN THE EARLY
STAGES OF DEVELOPMENT AND TO PLAN A
APPROPRIATE DEVELOPMENT
 PHASES OF CLINICAL TRIALS

 INITIAL TRIALS
 SAFETY AND TOLERABILITY
 PK/PD – DOSAGE RANGE AND ADMINISTRATION
SCHEDULE
 INITIAL EXPLORATORY THERAPEUTIC
TRIALS
 LATER CONFIRMATORY STUDIES – LARGER
AND LONGER ON DIVERSE PATIENT
POPULATION
 POST MARKETING STUDIES
 PHASES OF CLINICAL TRIALS

 DOSE RESPONSE INFORMATION – AT ALL

STAGES

 NEW DATA SUGGEST NEED FOR

ADDITIONAL STUDIES

 SUPPORT NEW MARKETING APPROVAL FOR

THE SAME DRUG – NEW INDICATION
SPECIAL CONSIDERATIONS

 STUDIES OF DRUG METABOLITES

 DRUG-DRUG INTERACTION STUDIES

 SPECIAL POPULATION

 INVESTIGATIONS IN PREGNANT WOMEN

 INVESTIGATIONS IN NURSING WOMEN
 INVESTIGATIONS IN CHILDREN
 CONSIDERATIONS FOR
INDIVIDUAL CLINICAL TRIALS

 OBJECTIVES
 DESIGN
 SELECTION OF SUBJECTS
 SELECTION OF CONTROL GROUPS
 NUMBER OF SUBJECTS
 RESPONSE VARIABLES
 METHODS TO MINIMISE OR ASSESS BIAS
 CONDUCT
 ANALYSIS
 REPORTING
 OBJECTIVES

 CLEARLY STATED

 EXPLORATORY OR CONFIRMATORY
ASPECT OF SAFETY OR EFFICACY

 ASSESSMENT OF PK/PD PARAMETERS

 DESIGN

 APPROPRIATE STUDY DESIGN

 APPROPIATE COMPARATORS
 ADEQUATE NUMBER OF SUBJECTS
 PRIMARY AND SECONDARY
ENDPOINTS AND PLANS FOR
ANALYSIS
 ADR MONITORING
 PROCEDURE FOR FOLLOW UP
SELECTION OF SUBJECTS

 INCLUSION/EXCLUSION CRITERIA
 CLOSELY MONITORED
 NOT PARTICIPATE CONCURRENTLY
 NOT ENROLLED REPETITIVELY
 WOMEN OF CHILD BEARING
POTENTIAL
 MALE SUBJECTS – EXPOSURE TO
SEXUAL PARTNERS AND PROGENY
SELECTION OF CONTROL GROUPS

 ADEQUATE CONTROL GROUP

 PLACEBO
 NO TREATMENT
 ACTIVE CONTROL
 DIFFERENT DOSES
 HISTORICAL CONTROLS
 NUMBER OF SUBJECTS

 DISEASE INVESTIGATED

 OBJECTIVE OF THE STUDY

 STUDY END POINTS

 RESPONSE VARIABLES
 DEFINED PROSPECTIVELY (PROTOCOL)
 METHODS OF OBSERVATION
 QUANTIFICATION

 STUDY END POINTS – PK/PD , SAFETY,

EFFICACY

 PRIMARY END POINT REFLECT CLINICALLY

RELEVANT EFFECTS

 SECONDARY END POINTS ASSESS OTHER

DRUG EFFECTS
 MINIMISE OR ASSESS BIAS

 RANDOMISATION

 BLINDING

 COMPLIANCE
 CONDUCT
 ACCORDING TO ICH / GCP PRINCIPLES

 ADHERENCE TO STUDY PROTOCOL

 MODIFICATION OF PROTOCOL

 TIMELY ADVERSE EVENT REPORTING AND

DOCUMENTATION
 ANALYSIS
 STUDY PROTOCOL SHOULD HAVE
SPECIFIED ANALYSIS PLAN

 DESCRIPTION OF STATISTICAL METHODS

TO BE EMPLOYED – INCLUDED IN
PROTOCOL

 EARLY STOPPING

 SAFETY DATA COLLECTED , TABULATED

,ADVERSE EVENTS CLASSIFIED
ACCORDING TO THE SERIOUSNESS AND
THEIR CAUSAL RELATIONSHIPS
 REPORTING
 ADEQUATELY DOCUMENTED
CLINICAL TRIALS
PHASE 1

DR .JAYASHREE
IND Review Process
 IND SUBMISSION
 COVER SHEET(FDA FORM)
 TABLE OF CONTENTS
 INTRODUCTORY STATEMENT AND GENERAL
INVESTIGATIONAL PLAN
 INVESTIGATORS BROCHURE
 PROTOCOLS
 CHEMISTRY,MANUFACTORING AND CONTROL INFORMATION
 PHARMACOLOGY AND DRUG METABOLISM
 TOXICOLOGY:INTEGRATED SUMMARY,FULL DATA
TABULATION
 TOXICOLOGY: GLP CERTIFICATION
 PREVIOUS HUMAN EXPERIENCE WITH THE
INVESTIGATIONAL DRUGS
CLINICAL TRIAL PROCESS
 PROTOCOL
 ETHICS COMMITTEE
 SPONSOR
 INVESTIGATOR
 SITE OF INVESTIGATION
 SUBJECTS
 INFORMED CONSENT
CLINICAL TRIAL PROCESS
 PROTOCOL

o Planned, agreed and performed in a

uniform and reproducible manner

o Interactive process between the sponsor and

the investigator

o General information regarding study title ,

sponsor information, investigator, monitor,
research unit and laboratory involved.
 PROTOCOL
 INTRODUCTION

 OBJECTIVES AND PURPOSE

 STUDY DESIGN

 INVESTIGATIONAL PRODUCT

 SELECTION AND WITHDRAWL OF SUBJECTS

 STUDY PROCEDURES

 TREATMENT PROGRAMS
 PROTOCOL

 STATISTICAL CONSIDERATIONS

 ETHICS CONSIDERATIONS

 DATA HANDLING AND RECORD KEEPING

 FINANCE AND INSURANCE

 PUBLICATION POLICY AND CONFIDENTIALITY

 REFERENCES
 ETHICS COMMITTEE
 PROPERLY CONSTITUTED

 FOLLOW GUIDELINES WHICH COMPLIES WITH ICH-GCP

GUIDELINES

 CONSIDER

• INVESTIGATORS CV
• PAYMENTS TO SUBJECT
• CONSENT DOCUMENT
• ADVERTISING MATERIAL
• INVESTIGATOR’S BROCHURE
 SPONSOR
 MAINTAIN QUALITY ASSURANCE
 COMPLY WITH GCP

INVESTIGATOR

 QUALIFIED, EXPERIENCED,TRAINED,
COMPETENT AND COMPLY WITH GCP

 RESPONSIBLE FOR RESEARCH & PROTECTION

OF RIGHTS,HEALTH,WELFARE OF SUBJECTS
 SITE OF INVESTIGATION
 SPECIALISED UNITS

 STAFF
• CLINICAL PHARMACOLOGISTS
• NURSING STAFF
• FACILITIES FOR RESUSCITATION
• INPATIENT FACILITIES
• CLINICAL LABS

 PROXIMITY TO HOSPITAL
 TRIAL SUBJECTS

 HEALTHY VOLUNTEERS

 PATIENTS
 INFORMED CONSENT
 VOLUNTEER SHOULD UNDERSTAND PRECISE
NATURE OF THE STUDY AND WHAT IS EXPECTED

 INVESTIGATORS RESPONSIBILITY

 VOLUNTEER’S RESPONSIBILITY

 RIGHT TO WITHDRAW

 PATIENT’S POINT OF VIEW- THERAPEUTIC HOPE

AND BENEFIT
 HEALTHY VOLUNTEERS
ADVANTAGES
 NO DISEASE RELATED ADR

 NO DISEASE RELATED CHANGES IN PK/PD

 NO INTERFERENCE BY CO ADMINISTRATION

 GREATER PHYSIOLOGICAL RESERVE

 FASTER RECRUITMENT

 NO ETHICAL LIMITATIONS IN GIVING CONSENT

PATIENTS IN PHASE 1
PHASE-I PREREQUISITES
 PRE-CLINICAL STUDIES COMPLETED
 SINGLE DOSE TOXICITY STUDIES
 REPEATED DOSE
 SAFETY PHARMACOLOGY STUDIES
 LOCAL TOLERANCE STUDIES
 PHARMACOKINETIC STUDIES
 MUTAGENICITY STUDIES(INVITRO)
 CARCINOGENICITY STUDIES
 SELECTION OF DOSE
 FIRST HUMAN DOSE
 MAXIMUM RECOMMENDED STARTING DOSE

 DOSE ESCALATION STUDIES

 PHASE-I OBJECTIVES

 SAFETY & TOLERABILITY

o MAXIMUM TOLERATED DOSE

 PHARMACOKINETICS

 PHARMACODYNAMICS

 MEASUREMENT OF DRUG ACTIVITY

 SAFETY AND TOLERABILITY

 DETERMINE THE TOLERABILITY OF DOSE RANGE

 DETERMINE THE NATURE OF ADVERSE EFFECTS

 THESE STUDIES INCLUDE

SINGLE DOSE ADMINISTRATION

MULTIPLE DOSE ADMINISTRATION
PHARMACOKINETIC STUDIES
 PHARMACOKINETIC STUDIES
 CHARACTERISATION OF ADME

 IMP TO ASSESS THE

 CLEARANCE,HALF LIFE
 ACCUMULATION OF PARENT DRUG/MET
 POTENTIAL DD INTERACTION
 FOOD INTERACTION
 SUB POPULATION PK STUDIES
PHARMACODYNAMIC
STUDIES
 IN HEALTHY VOLUNTEER eg.
 PATIENTS eg.
EARLY MEASUREMENT OF
DRUG ACTIVITY
 PLAYERS IN PHASE-I
 PARTICIPANTS(20-50)
• HEALTHY VOLUNTEER SUBJECTS
• PATIENTS

 PLACE
• SPECIAL TESTING FACILITIES
• MONITORED CLOSELY

 PHYSICIAN
• TRAINED INVESTIGATOR
 EXPERIMENTAL DESIGNS

 OPEN ,BASELINE CONTROLLED

 RANDOMISATION

 BLINDING
 SAD
DESIGN
DOUBLE BLIND ,PLACEBO CONTROLLED
MAD
STUDY POPULATION
SAMPLE SIZE
ROUTE OF ADMINISTRATION

 INTENDED ROUTE FOR THE

COMMERCIALISED DRUG
DURATION OF STUDIES
 INTENDED DURATION OF DRUG
TREATMENT
 IN CHRONIC USE-DURATION OF
ADMINISTRATION BASED ON PK/PD
STUDIES
SELECTION OF SUBJECTS

 INCLUSION CRITERIA (PHASE I)

 HEALTHY VOLUTEERS(MEN 18-35 years)
 ELDERLY SUBJECTS
 WOMEN
 US FDA DEFINES NORMAL SUBJECTS AS

“WHO ARE FREE FROM ABNORMALITIES

WHICH COULD COMPLICATE THE
INTERPRETATION OF THE DATA FROM THE
EXPERIMENT OR WHICH MIGHT INCREASE
THE SENSITIVITY OF THE SUBJECT TO
TOXIC POTENTIAL OF THE DRUG”
SELECTION OF VOLUNTEERS

 EXCLUSION CRITERIA
• VARY WITH DIFFERENT DRUG TYPES
• INDIVIDUALS ON OTHER
MEDICATIONS
• ABUSING ALCOHOL OR OTHER
DRUGS OF DEPENDENCE
• CIGARETTE SMOKING
• ENZYME POLYMORPHISM
• PSYCHOLOGICAL FACTORS
 PHASE–I OBSERVATION

 EFFICACY
 ADVERSE EVENTS

(DRUG INTERACTION STUDIES)

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THANK YOU