GOOD CLINICAL PRACTICES

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GOOD CLINICAL PRACTICES

• Prof. S.D. Seth
• Chair in Clinical Pharmacology
• Indian Council of Medical Research
• New Delhi

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Good Clinical Practice

• A standard for the design, conduct, performance,
  monitoring, auditing, recording, analyses, and
  reporting of clinical trials that provides
  assurance that the data and reported results are
  credible and accurate, and that the rights,
  integrity, and confidentiality of trial subjects
  are protected.

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GOOD CLINICAL PRACTICE GUIDELINES

• These guidelines are established to ensure
  clinical research is consistently performed to
  high ethical and scientific standards
• ?
• Primary consideration are
• to protect the rights and safety of clinical
  subjects and
• ensure quality and integrity of data

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The Critical Path of Clinical Trial
Planning
Protocol . CRF
GCP. IND
Regulatory and Ethical Approval
Trial Documents . Materials
Select investigators
Initial Visits
Site Assessments
Patient Recruitment
Periodic Monitoring
Study Termination
Data Data Statistical
Final entry clean-up analysis
Report

• START

• END

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BASIC PRINCIPLE of Ethical Medical Research

• Every human subject has the right to understand
  the nature, and the risks benefits of the
  research, and to agree or not agree to
  participate
• It is the duty of physicians to observe and
  uphold this right of the patients/participants.

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Ethical Considerations

• The research involving human subjects should be
  conducted in accordance with the ethical
  principles contained in the current revision of
  Declaration of Helsinki, (2000).
• Four basic principles
• Justice,
• Respect for persons,
• Beneficence
• Non malafacience
• As defined by Ethical Guidelines for
  Biomedical Research on Human subjects issued by
  the Indian Council of Medical Research (2000)

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Roles and Responsibilities

• Sponsor
• Monitor
• Principal Investigator
• Co-investigator
• Study Coordinator

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Who is the Sponsor ?

• An individual, company, institution or
  organization which takes responsibility for the
  initiation, management, and / or financing of
  clinical trial.
• Refers to
• Management Staff
• Project Team (Clinician, Monitor, Others)
• Contractual Services (CRO, Lab)
• Delegated individuals
• Others

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Sponsor Responsibilities

• Statistics
• Organization
• Methodology
• Design
• Rationale
• Objectives
• The Protocol

• To design an ethical protocol that is capable of
  giving answers to the question asked by the
  study, at minimum risk to study patients.

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Sponsor Responsibilities

• Define, establish and allocate all trial- related
  duties and functions.
• To be available to answer questions.
• To provide study drug that is high-quality and
  provide information about the investigational
  product.
• To use the results of the study for the benefit
  of patients.
• Define data management analysis methods.
• Establish record keeping SOPs.
• To ensure adherence to protocol and GCP
• Quality assurance

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Sponsor Responsibilities, (Contd.)

• Notification/ Submission to Regulatory Authority
• Before planning the Clinical trial, the sponsor
  (or the sponsor and investigator if required by
  the applicable regulatory requirement) should
  submit any required application to the
  appropriate authority for review, acceptance and/
  or permission.

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Sponsor Responsibilities, (Contd.)

• To choose qualified investigators /staff and
  obtain agreement study conduct and GCP
• Who is an investigator ?
• What are their qualifications?
• How do sponsors choose them?

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Investigator

• Investigator A person responsible for the
  conduct of the clinical trial at a trial site.
• Co-investigator An individual designated and
  supervised by the investigator to perform trial
  related procedures, including trial-related
  decisions.

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Investigator Qualifications

• Appropriate education and training, with evidence
  thereof (e.g. CV / Certificates/ diploma)
• experience and respect in therapeutic field of
  study
• Publication record
• Reputation and integrity
• Adequacy and quality of staff
• Access to and adequate number of patients for the
  study

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Investigator Qualifications, Cont.

• Level of Cooperation
• Willingness to conduct the study
• Adequate time for the study
• Effect of concurrent studies
• Site Facilities, Location, Accessibility
• Site Equipment
• Time and Cost Factors
• GCP- Certification, or GCP experience

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Lesson from History

• The Harvard Fraud (U.S., 1980s)
• CV Training Fellow tutored by Dr. Eugene
  Braunwald, prominent U.S. cardiologist
• Fellow fabricated study data discovered because
  of too clean data intact dogs in the dumpster
• Outcome for fellow License withdrawn expelled
  from Harvard blackballed from research
• Outcome for Braunwald/ Harvard Written public
  apology retracted papers, greater embarrassment
  resulting from questioned credibility of past and
  future work

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Investigators Responsibilities

• Read, discuss and approve the study protocol
• Be familiar with all aspects of study and drug
• Know the status of the study at all times
• Take responsibility for the overall conduct of
  the study

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Investigators Responsibilities (cont)

• Obtain Ethics Committee approval
• Ensure GCP composition of Committee
• Preparation of Documents
• Submission and Follow-up
• Documentation of Process and Outcome
• Correspondence
• Approval

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Investigators Responsibilities (cont)

• Ensure Medical Care of Trial Subject
• Provided by a qualified physician
• All trial related medical decisions
• Adequate medical care during and after study, for
  AEs and intercurrent illnesses
• Informing patients primary physician of
  participation (subject to patient's consent)
• Exerting reasonable effort to ascertain
  patients reasons for withdrawing
• Monitor patient safety
• Report all serious adverse events (SAEs)

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Clinical Research Coordinator Responsibilities

• Subject recruitment and enrollment tracking
• Accurate specimen collection and processing
• Administration of Study medications
• Data Management
• Completion of CRF and other documents

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Monitor

• A person designated by the sponsor, with
  documented appropriate training, as responsible
  for overseeing the progress of a clinical trial,
  and of ensuring that it is conducted, recorded,
  and reported in accordance with the protocol,
  SOP, GCP and the applicable regulatory
  requirements.

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Monitors Responsibilities

• Visit the sites regularly. Answer questions from
  the staff. Hold regular staff meetings
• Give feedback to the sites staff restudy conduct
  

Whats going well What needs improvement?
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Monitors Responsibilities

• Ensure completion of the site regulatory book
• Safety evaluations and reporting of all adverse
  events
• Check trial drug accountability, drug and CRF
  storage lockers, and randomization blinded
  codes
• Assist the site in preparing for the eventuality
  of an audit or inspection by the local regulatory
  agency

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Monitors Responsibilities (Cont)

• Source Document Verification Compare clinic
  records to the CRF for accuracy and completeness.
  
• CRF ? Source ? Investigator ? Essential
• Documents Site File
  Documents

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Key Site Visits

• Before Recruitment
• Pre-study visit
• Study initiation Visit/ Placement visit
• During the Study
• Monitoring visits
• Co-monitoring visits
• Audits/ Inspections
• End of Study
• Study Close-Out/ Closure visit

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GCP During the Study

• Study Monitoring-
• - Develop/ review draft protocol
• Develop the CRF
• Order clinical supplies for investigator sites
• Present instructions on completing the CRF at
  investigator's meeting
• Conduct study initiation visit at the site.

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GCP During the Study (Contd.)

• Accessibility of Records Source Document
  Verification-
• Source documents should be available and
  complete, eg. EKGs or X-rays should have been
  read with written comments or report by the
  reader
• Investigator should be able to produce all source
  documents or reasonable explain why they are
  missing.

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GCP During the Study

• Monitor reviews all CRFs for
• adverse events and serious adverse events (SAEs)
  for proper time frame reporting, follow-up and
  correct information
• concomitant medications- stop/start dates
• study medication- change and dispensing
• signatures, dates
• corrections

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GCP at the End of the Study

• The Close- Out Visit-
• The Purpose
• The Process
• The review of Essential Documents
• CRF ? Source ? Investigator?Essential
  Documents Site File Documents

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Indian Traditional Medicines

• Traditional medicines are drugs which are
  formulated and used in the same clinical
  conditions as described in ancient literature
  they include Unani, Herbal, Ayurveda, Siddha and
  other formulations.

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Traditional Medicines

• Traditional medicines are used by some 60 of the
  worlds population.
• It is extensively incorporated into the public
  health system of India and many other countries.
• Traditional medication involves the use of herbal
  medicines, animal products and minerals.
• Herbal medicines are the most widely used of the
  traditional medications.

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COMPLEMENTARY MEDICINES

• Harmonization of research.
• Application of National and International
  Guidelines.
• Essential for global applications.

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Categories of Products from Traditional Medicines

• The product cited in literature of Ayurveda,
  Siddha or Unani system may directly undergo
  clinical trial for the indication for which it is
  being used traditionally.
• An extract of a plant/any product not originally
  described in the texts of Traditional System has
  to be treated as New Chemical Entity (NCE),
  therefore, should undergo all regulatory
  requirements as per Schedule Y before being
  evaluated clinically.

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Clinical Trial for Traditional Remedies

• Clinical basis for drugs already in use for years
• Clinical trials straightaway - No efficacy tests
  but validation for evidence based medicine
• Administration of drug for a specific disease in
  same specific modality as prescribed by
  traditional practitioners
• Single disease oriented intervention could be
  individualized - Flexible dosage
• For new herbal drugs biomarkers are used to
  conduct the pharmacokinetic study.

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Clinical Trial for Traditional Remedies

• Clinical basis for traditional or herbal drugs
  for new indication / new use require assessment
• For new herbal drugs biomarkers are used to
  conduct the efficacy study.
• All regulatory requirements have to be
  fulfilled for DCGIs approval as for the
  marketing of new drugs.

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Phase I (Human/ Clinical Pharmacology Trials)

• These trials are for the first exposure of drug
  in human subject.
• The dug is administered in a single dose.
• The subjects are normal healthy volunteers but
  few drugs like anticancer, AIDS are administered
  in-patients.
• Safety monitoring
• The evaluation of pharmacokinetic parameter that
  is dose, metabolism and excretion is done.
• Adverse drug reaction and tolerance is also
  observed.
• A trained person in clinical pharmacology is
  required to do the study.

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Phase II (Exploratory Trials)

• The second phase of trial is done in patients
  suffering from disease for which the drug is
  recommended.
• A limited number of specified patients are the
  human subjects
• They determine the therapeutic effects and dose
  range of the drug in patients. It further
  evaluates pharmacokinetic profile and safety of
  the drug.
• Trials are conducted under the guidance of a
  qualified Clinical Pharmacologist and Clinician

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Phase III (Confirmatory)

• These are therapeutic confirmation clinical
  trials
• conducted in large sample of patients
  population.
• Large numbers of patients are studied from
  various centers to confirm the clinical benefits.
• Safety and efficacy evaluation of the drug is
  continued in this phase.
• Qualified medical professional is required to
  conduct the Clinical Investigation.

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Phase IV (Post Marketing Surveillance)

• These are studies performed after the drug is
  marketed for general physicians use. It is
  prescribed for the specified/ recommended use in
  patients.
• The process of drug evaluation is continuous,
  that it monitoring of patterns of drug
  utilization and Adverse Drug Reaction.
• Phase IV studies are required to follow the same
  scientific and ethical standards as per marketing
  studies.

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THANK YOU