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Clinical Trial Regulations

Clinical Trial Regulations. P.Olliaro Nov04. Clinical Trials: a Phase of Product Development. R&D ATTRITION RATES. < discovery >. <pre-clinical>. < clinical >. MARKETING. DISCOVERY. REGULATORY REVIEW. PRE-DEVELOPMENT. IND filing. NDA filing. DEVELOPMENT.

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Clinical Trial Regulations

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  1. Clinical Trial Regulations P.Olliaro Nov04

  2. Clinical Trials: a Phase of Product Development

  3. R&D ATTRITION RATES < discovery > <pre-clinical> < clinical >

  4. MARKETING DISCOVERY REGULATORY REVIEW PRE-DEVELOPMENT IND filing NDA filing DEVELOPMENT PRE-CLINICAL CLINICAL PHARMACEUTICAL • Clinical trial packaging • post-IND tox • Bioanalytical sample analysis • Bulk active synthesis • Analytical development preformulation • Formulation development • Validation, QC analysis • Commercial packaging • Long-term stability • Phase I • Phase II • Phase III • Pharmacology • PK & metabolism • Toxicology TOTAL Discovery + Development 115-240 million (including cost of failure) $ 40-125 million $ 76-115 million $ 4.9-5.3 million $ 5.3-8.0 million $ 9.9-26.6 million Cost of TB New drug - Source: GATB webpage

  5. OPPORTUNITY NEW TOOL DEPLOYMENT IMPLEMENTATION INTELLIGENCE, SURVEILLANCE R&D NEED MONITORING & EVALUATION “OPERATIONAL RESEARCH”

  6. GCP, GCLP requirements Registration First In Humans Policy, Practice Post- registration studies to inform policy Discovery & Pre-clinical Research Regulatory Clinical studies (Phase I, II, III) Capacities & capabilities for sustained, durable clinical research in Developing Countries

  7. Planning Protocol • CRF 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 *END *START The Critical Path of a Clinical Trial

  8. Special features • Mission: provide affordable, adapted public health priority products • Corollary: provide data in support of registration, policy & practice; availability of quality product • Context: developing country capacities & capabilities

  9. GCPs (& GCLPs)ICH Guidelines

  10. Good Clinical Practice • Guidelines established to ensure clinical research is consistently performed to high ethical and scientific standards • Primary considerations are to: • protect the rights and safety of clinical subjects • ensure quality and integrity of data

  11. What is GCP ?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. Ref: ICH Harmonized Tripartite Guideline for Good Clinical Practice (1.24), 1997

  12. For what/whom? GCP Applies to All Research • All sponsors: private, government, university, industry • All study designs: RCTs, double-blind, open-label, comparator, etc • All study phases: Phase I to IV • All investigational products: new drugs, new indications, biomedical device, new methodology, new surgical techniques, etc • Ref: www.ifpma.org • www.fda.gov

  13. Why GCPs? Historical events

  14. Why GCPs? Historical events

  15. Continuing Development ofGCP Guidelines • USA( FDA GCP Regulations) • Protection of human subjects:Informed consent; Standards for IRB - 1981 • Guidelines for monitoring of Clinical Investigations – 1988 • EU: Good Clinical Practice for Trials on Medicinal Products in the European Community - 1991 • Japan: Good Clinical Practice, GCP Manual - 1991 • WHO: Guidelines for GCP for trials on Pharmaceutical Products - 1994

  16. GCP is a process, not a book Sponsor The standard Investigator

  17. ICH - International Conference on Harmonization

  18. ICH Guidelines: 4 major categories • Q: "Quality" Topics = chemical & pharmaceutical Quality Assurance.E.g: Q1 Stability Testing, Q3 Impurity Testing • S: "Safety" Topics = in vitro & in vivo pre-clinical studies. E.g : S1 Carcinogenicity Testing, S2 Genotoxicity Testing • E: "Efficacy" Topics = clinical studies in human subject. E.g : E4 Dose Response Studies, E6 Good Clinical Practices. (NB: Clinical Safety Data Management is also classified as an "Efficacy" topic - E2) • M: "Multidisciplinary" Topics = cross-cutting • M1: Medical Terminology (MedDRA) • M2: Electronic Standards for Transmission of Regulatory Information (ESTRI) • M3: Timing of Pre-clinical Studies in Relation to Clinical Trials • M4: The Common Technical Document (CTD) • M5: Data Elements and Standards for Drug Dictionaries

  19. ICH Harmonized Tripartite Guidelines for Good Clinical Practice (ICH-GCP) • Joint initiative by regulators and industry from three regions - US, EU & Japan. • A framework for pharmaceutical companies and investigators to conduct clinical trials • According to similar rules and regulations • Conforming to high ethical and scientific standards.

  20. ICH-GCP – Harmonized Tripartite Guidelines - Whom? • Founder members: • European Union: EC + EFPIA (European Federation of Pharmaceutical Industries’ Associations) • Japan: Ministry of Health & Welfare + JPMA ( Japan Pharmaceutical Manufacturers Association) • USA: FDA + PhRMA (Pharmaceutical Research and Manufacturers of America)

  21. ICH-GCP - When? Introduced in 1996 ICH 1 November 1991 Development of tripartite GCP agreement • Review of progress toward harmonization in areas of: • efficacy • safety • quality assurance ICH 2 October 1993 • Update status of: • tripartite agreement • progress toward harmonization ICH 3 November 1995 * 1996 Review and update of the implementation and impact of the ICH GCP Guideline ICH 4 July 1997

  22. ICH-GCP – Why? • Rapid increase in laws, regulations and guidelines for testing safety, quality and efficacy of new products • Different technical requirements by regulatory agencies, although fundamental guiding principals same • Industry becoming global • Duplication of time consuming & expensive testing.

  23. ICH-GCP - Goals Benefits • Reduce rising cost of health care • Reduce escalating R&D costs • Minimize delay in making new treatments available to patients Goals • Decrease country-to-country differences in guidelines • Decrease differences between regulatory authorities Goals are designed to: • Streamline drug development and regulatory process • Increase efficiency of clinical research and enforcement of GCP guidelines

  24. GCPs: roles of sponsor, investigators, monitor

  25. Sponsor • ICH sections E6 5.1-5.23 • Definition: an individual, company, institution, or organization which takes responsibility for the initiation, management, and/or financing of a clinical trial • Medical expertise; Trial design;Allocation of duties and functions

  26. Sponsor Responsibilities • Monitoring: SOPs • Trial Management, Data handling • Record Keeping • Investigator selection & support (adequacy of CI’s to comply with GCPs) • Provide insurance or indemnify CI; Trial subject compensation • Financing • Notification/Submission to Regulatory Authority • Confirmation of Review by IRB/IEC • Information on Investigational Product (IB) • Manufacturing, Packaging, Labelling & Coding • Supplying & Handling • Record access • QA and QC

  27. GCP– role of Sponsor Ability to conduct Pre-trial Data Archiving Regulatory Audit/ Inspection Monitor Protocol SPONSOR Patient Follow-up CRF Annual/Safety Rep. Informed Consent Documentation Drug Control Report SAEs

  28. Monitor • Selected by sponsor • Appropriately trained & familiar with GCPs, regulations, product, protocol, SOPs • Ensures that trial is conducted & documented properly • ‘Communication link’ between sponsor & CI • On site monitoring visits pre-, during, post-trial • Verify compliance to procedures • Notifications, applications, submission, reports are accurate, complete, timely/dated • Identifies & corrects problems. Communicates deviations to investigator

  29. Investigator • ICH sections E6 4.1 - 4.13 • A person responsible for the conduct of the clinical trial at a trial site. If a trial is conducted by a team of individuals, the investigator is the responsible leader of the team and may be called the principal investigator” ICH Guideline for GCP 1.34

  30. Investigator Qualifications • Appropriate education and training, with evidence there of (e.g. CV, certificate/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

  31. Investigator Responsibilities • (Contribute to) Understand & comply with protocol • Obtain ethical approval • Obtain inform consent • Ensure adequate medical care of trial subjects • Accountability & storage of investigational product • Ensure adequate resources (NB: capacities in DECs) • Appropriate supervision &/or delegation

  32. Investigator Responsibilities QUALITY CONTROL: PERMIT MONITORING, AUDITING AND INSPECTIONS • Sponsor: Section 5.1.1. ICH GCP • “The sponsor is responsible for implementing and maintaining quality assurance and quality control systems with written SOPs to ensure that trials are conducted and data generated, documented, and reported in compliance with the protocol, GCP and the applicable regulatory requirements.” • Investigator: Section 4.1.4 ICH GCP • “The investigator/institution should permit monitoring and auditing by the sponsor, and inspection by the appropriate regulatory authority(ies).”

  33. Investigator Responsibilities • Documentation • “If it is not written, it did not happen” • Document what happened and well as what did NOT happen • Assure direct access to records • Submit progress reports to IRB/EC • Promptly report all SAEs to sponsor and IRB/EC (if required) • Report all Adverse Events and lab abnormalities to sponsor

  34. Misconduct at Investigational Sitesn = 118, SW Woollen, FDA’s OGCP, 2001

  35. Ability to conduct Archiving Audit/ Inspection Monitor Patient Follow-up Annual/Safety Rep. Informed Consent Documentation Drug Control Report SAEs GCP – Role of Investigator Resources Medical Care Ethics Approval INVESTIGATOR Protocol Adherence

  36. Safety in clinical trials

  37. Safety: definitions • Adverse Event (or Adverse Experience) = Any untoward medical occurrence in a patient or clinical investigation subject administered pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment • Adverse Drug Reaction (ADR) = All noxious and unintended responses to a medicinal product related to any dose should be considered adverse drug reaction

  38. Safety: definitions • Unexpected Adverse Drug Reaction = An adverse reaction, the nature or severity of which is not consistent with the applicable product information (e.g., IB for an unapproved investigational medicinal product) • Serious adverse event (experience) or reaction = any untoward medical occurrence that at any dose: • results in death, • is life-threatening (an event in which the patient was at risk of death at the time of the event; not an event which hypothetically might have caused death if it were more severe) • requires inpatient hospitalization or prolongation of existing hospitalization • results in persistent or significant disability/incapacity, or • is a congenital anomaly/birth defect.

  39. Safety: definitions • Severe DIFFERENT from Serious • Severe = Refers to the intensity (severity) of a specific event (minor, moderate, severe) and can be of relatively minor medical significance (e.g. severe headache). • Serious = Refers to the previous definition. • Based on patient/event outcome or action criteria usually associated with events that pose a threat to a patient’s life or functioning. • Seriousness (not severity) serves as a guide for defining regulatory reporting obligations.

  40. Safety Information and reporting : Sponsor’s obligations • Responsible for the ongoing safety evaluation • Promptly notify all concerned investigators & regulatory authorities of findings that could affect adversely the subjects safety • Adverse drug reaction reporting • Expedite the reporting to all investigators of all adverse drug reactions that are both serious and unexpected + regulatory requirements • CI  Monitor, Sponsor  IRB/EC; Health/Regulatory authorities; DSMC • Alert form: 24h; SAE Report Form: 5 wd’s

  41. IEC / IRB:Independent Ethics Committees/ Institutional Review Boards

  42. IEC / IRB:Independent Ethics Committees/ Institutional Review Boards Any board, committee, or other group formally designated by an institution to • review, • approve the initiation of, and • conduct periodic review of, biomedical research involving human subjects.

  43. IEC / IRB • Independent body (a review board or a committee, institutional, regional, national or supranational) • Constituted of medical/scientific professionals and non-scientific professionals and non-scientific members, • Responsibility: • to protect the rights, safety and well-being of human subjects involved in a trial and • to provide public assurance of that protection by: • Reviewing and approving/providing favorable opinion on, trial protocol, suitability of the investigator(s), facilities, • And the methods and material to be used in obtaining and documenting informed consent of the trial subjects. Ref: Applied Clinical Trials Vol 6, No 12, Dec 1997

  44. IEC / IRB • The legal status, composition, function, operations, and regulatory requirements pertaining to IEC’s may differ among countries, but should allow the IEC to act in agreement with GCP as described in the ICH-GCP guideline. • Other names of such include: independent review board, institutional review board, independent ethics committee, institutional ethics committee, committee for the protection of human subjects. Ref: Applied Clinical Trials Vol 6, No 12, Dec 1997

  45. IEC/IRB Composition • Heterogeneous: at least 5 members; ar least one member with primary area of interest in a non-scientific area; at least one member independent of the trial site • Without conflicting interest • Nonmembers (special expertise) may be invited ad hoc • Functions and Operations • Meetings: frequency, scheduling, notification, quorum, hierarchy, minutes • Procedures: submission requirements, confidentiality, majority vote, appeal, amendments • Reports

  46. Criteria for Approval • Suitability of investigator • Qualifications • Experience • Time • Supporting staff • Available facilities • Suitability of protocol • Scientific efficiency • Justification of inconveniences and risks vs. Benefits • Equitable selection of subjects • Time provision • Monitoring the data • Confidentiality of subjects and data

  47. Remember ! • Inform subjects of any new relevant information as it becomes available • Consent should be in writing • Language used: non-technical and understandable by the subject • Provide sponsor with access to patient’s medical records • Provide patient with a copy of the signed and dated consent form

  48. Informed Consent in Clinical Trials

  49. Informed Consent • E6 Guideline for Good Clinical Practice: Section 4.8.1 - 4.8.15 • “A process by which a subject voluntarily confirms his or her willingness to participate in a particular trial, after having been informed of all aspects of the trial that are relevant to the subject’s decision to participate. Informed consent is documented by means of a written, signed and dated informed consent form.”

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