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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
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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
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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
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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
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Pharmaceutical Medicine
Personnel- The Knowledge Gap
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Industry Academia
Regulationslocal /international
Companypolicy local /international
Regulationslocal
InstituteRegulations
Science PoliciesInternational
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Clinical Trial : Conduct and Plan
GoodFast
Cheap
Choose any two
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Guidelines for Clinical Trials
• 1996 : ICH Guidelines• 2000 : ICMR guidelines• 2001 : Indian GCP guidelines• 2003 : Revision of BE guidelines• 2003 : Revision of Schedule Y
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Applicability of Guidelines
All biomedicalresearch at allstages of drugdevelopment
Clinical trials forregulatory
submissionScope :
Guideline à LawGuidanceLegal Position :
GCP (India)ICH (in USA)
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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
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Ethical Principles of Indian GCP
• Essentiality• Voluntariness, Informed consent and
community agreement• Non-exploitation• Privacy and confidentiality•
Precaution & risk minimisation• Professional competence
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Ethical Principles of Indian GCP
• Accountability and transparency• Maximisation of the public interest and
Distributive justice• Institutional arrangements• Public domain•
Totality of responsibility• Compliance
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Indian and ICH-GCP :
Significant Differences• Investigator• Ethics Committee• Informed Consent• Compensation• Data Records
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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
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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
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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
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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
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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
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Data Records
• Sponsor to retain records for a period of 5years after completion of study or
submission of data
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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
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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
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Special Populations
• Children• Pregnant or nursing women• Socio-economically disadvantaged• Mentally challenged• Students, Subordinates, Employees• Army personnel• Prisoners
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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
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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
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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
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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
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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
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Checklists and Formats
• Content of Protocol• Structure and content of report• Undertaking by investigator• Checklist of contents for ICF• Format of EC approval, ICF
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Special Research Areas
• Vaccines• Contraceptives•
Herbal• Surgical procedures / Medical devices• Diagnostic agents – radioactive material• Genetics• Epidemiology• National priorities• Biotechnology
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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
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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
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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
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“ 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