drbhatt gcp oppi mar04

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Guidelines for ConductingClinical Trials in India

Dr Arun Bhatt MD (Med) FICP (Ind)

Member, Faculty of PharmaceuticalMedicine

PresidentClinInvent Research Pvt Ltd



Challenges for Pharmaceutical

Medicine Personnel• Sophisticated products• Alternative medicine•

New public health threats• International commerce• Consumer awareness• Information technology• Regulatory activism• Global ethics• Media pressure



Kerala Controversy: Inquiry

Commission’s Findings• Trial at RCC started without approval from Drugs

Controller• No clearance from Health Ministry for

collaboration with a foreign Institute• Banned drug smuggled by the Johns Hopkins

scientist• Patients signed informed consent in language

other than their native language• Neither ICH-GCP nor the ICMR guidelines for

biomedical research on human subjects followed• Clinical trials suspended at RCC for 6 months



Critical Path of a Clinical TrialPlanning

Protocol • CRF

Regulatory andEthical Approval

Trial Documents • MaterialsSelectInvestigators

Initial Visits

Patient Recruitment

Periodic Monitoring

Data Data Statistical FinalEntry Clean-up Analysis Report

Site Assessments

StudyTermination

*START *END



Pharmaceutical Medicine

Personnel- The Knowledge Gap



Industry Academia

Regulationslocal /international

Companypolicy local /international

Regulationslocal

InstituteRegulations

Science PoliciesInternational



Clinical Trial : Conduct and Plan

GoodFast

Cheap

Choose any two



Guidelines for Clinical Trials

• 1996 : ICH Guidelines• 2000 : ICMR guidelines• 2001 : Indian GCP guidelines• 2003 : Revision of BE guidelines• 2003 : Revision of Schedule Y



Applicability of Guidelines

All biomedicalresearch at allstages of drugdevelopment

Clinical trials forregulatory

submissionScope :

Guideline à LawGuidanceLegal Position :

GCP (India)ICH (in USA)



Structure

ICH E6• Glossary•

Principles• IRB/IEC• Investigator• Sponsor• Protocol• Investigators’ Brochure• Essential Documents

Indian GCP• Definitions•

Pre-requisites• Responsibilities• Records & Data• Quality Assurance• Statistics• Special Concerns• Appendices



Ethical Principles of Indian GCP

• Essentiality• Voluntariness, Informed consent and

community agreement• Non-exploitation• Privacy and confidentiality•

Precaution & risk minimisation• Professional competence



Ethical Principles of Indian GCP

• Accountability and transparency• Maximisation of the public interest and

Distributive justice• Institutional arrangements• Public domain•

Totality of responsibility• Compliance



Indian and ICH-GCP :

Significant Differences• Investigator• Ethics Committee• Informed Consent• Compensation• Data Records



Investigator

• Qualifications as prescribed by MCI• Sign on a copy of the protocol and SOPs• Sign and forward the data (CRFs, results

and interpretations, analyses and reports)of the study from his / her centre to thesponsor and the ethics committee



Ethics Committee

• Details of composition• Quorum - minimum of 5 members• Decision making process• Can order discontinuation of trial if the

goals are achieved or unequivocal results

obtained• Records to be retained for at least 5 yearsafter completion / termination of study



Informed Consent• Ensure freedom of consent for vulnerable

groups and members of group with ahierarchical structure

• Right to prevent use of biological samples• Free treatment of research-related injury• Possible current and future use of

biological material•

Risk of discovery of biologically sensitiveinformation• Publication plan



Compensation

• All payments, reimbursements and medicalservices for subjects to be approved by IEC

• Liability of involved parties (investigator, sponsor/ manufacturers, institutions) etc to be clearlyagreed and stated before initiation of study

• Sponsor (company, government, institution) toagree to provide compensation for any seriousphysical or mental injury or to provide insurancecoverage



Compensation

• Research subjects who suffer physical injury in atrial entitled to financial / other assistance tocompensate them equitably for any temporary orpermanent impairment or disability subject toconfirmation from IEC

• In case of death, their dependents entitled tomaterial compensation

• When a subject is withdrawn from research formedical reasons related to the study, he shouldget benefit of full participation



Data Records

• Sponsor to retain records for a period of 5years after completion of study or

submission of data



Revised Schedule Y : Clinical Trials

• Definition of Phases I – IV• Concurrent Phase II-III• Central lab and trial samples• Flexibility in data requirements for new

drugs for life threatening / seriousconditions or disease of relevance to India

• Classification of Fixed Dose Combinationsfor clinical studies



Phase IV Studies

• Same scientific and ethical standards as appliedin pre-marketing studies

• Outside the purview of the ethical however, theadverse reactions induced by drugs, if any,should be brought to the notice of the EC

• In post-marketing stage, clinical trials designed toexplore new indications, new methods ofadministration or new combinations, etc.considered as trials for new pharmaceuticalproducts



Special Populations

• Children• Pregnant or nursing women• Socio-economically disadvantaged• Mentally challenged• Students, Subordinates, Employees• Army personnel• Prisoners



Clinical Trials in Children

• EC for paediatric trials to includemembers knowledgeable about paediatric,

ethical, clinical and psychosocial issues• Mature minors and adolescents to sign an

assent form



Ethics Committee

• EC approval of protocol / informedconsent form (ICF) and notification to

DCGI prior to initiation• EC approval for sites without EC• EC approval of protocol amendments and

notification to DCGI• Composition of EC



Schedule Y:

Commitments by Investigator• Study not to begin until EC / DCGI

approval•

Adherence to protocol• Personal supervision• Ensure requirements of IC and EC review• Report of ADE to sponsor• Understanding of investigator’s brochure• Maintenance of records and availability for

audits / sponsor inspection / EC and DCGI



Commitments by Investigator

• Ensure that all associates, colleagues andemployees suitably qualified andexperienced and aware of their obligations

• Cooperation in audits• Report to EC promptly about changes and

unanticipated problems•

Confidentiality of data and patients• Compliance with all other obligations of

clinical investigators



Responsibility of Sponsor

• Quality assurance to ensure complianceto GCP guidelines of CDSCO

•

Submission of status report at prescribedperiodicity; reasons for prematuretermination to be communicated

• Serious adverse event to becommunicated promptly (within 14calendar days) to DCGI and otherinvestigators



Checklists and Formats

• Content of Protocol• Structure and content of report• Undertaking by investigator• Checklist of contents for ICF• Format of EC approval, ICF



Special Research Areas

• Vaccines• Contraceptives•

Herbal• Surgical procedures / Medical devices• Diagnostic agents – radioactive material• Genetics• Epidemiology• National priorities• Biotechnology



Herbal Research

Approach as per DCGI guidelines for• Herbal remedies for use in Allopathic

system• Extract by method different from

Ayurvedic text• Indication different from Ayurvedic text• Isolated chemical compound• Plant not described in Ayurvedic text



Herbal Research• Toxicity studies (4-6 weeks toxicity) study in 2

species of animals) needed for phase 2 trials, ifreports suggesting toxicity or trial use for morethan 3 months, or before Phase 3 trial

• Preparation of plants and herbal remedies as perthe literature and GMP norms withstandardization and identification of markers

• Ethical guidelines (patient information, informedconsent, protection of vulnerable populations etc)for biomedical research should be followed.

• Ayurvedic, Siddha or Unani physician as a co-investigator



Bioequivalence Guidelines• Organization premises and facilities• Protocol and study design for conventional• Release dosage forms and extended release

dosage forms•

Methodology for conduct of study• Analytical methodology and validation• In-vitro dissolution• Statistical evaluation•

Documentation• In-vitro in-vivo correlation• Adverse drug reaction• Good laboratory practice



“ By three methods we may learn wisdom:first, by reflection, which is noblest;second, by imitation, which is easiest;andthird by experience, which is thebitterest. “

Confucius