Clinical Trials -gen Cons

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 PROCEDUREINFORMATION 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 o

& TOLERABILITY

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) • •



PLACE • •



HEALTHY VOLUNTEER SUBJECTS PATIENTS

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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