GOOD CLINICAL PRACTICES WORKING GROUP

GOOD CLINICAL PRACTICES WORKING GROUP Update and Proposal IV Pan American Conference on Drug Regulatory Harmonization República Dominicana 2-4 March, 2005

Good Clinical Practices WG Members • ARGENTINA: Patricia Saidón, ANMAT, Coordinator (*) • BRASIL: Granville García de Oliveira, ANVISA Sergio Nishioka , ANVISA (*) • CHILE: Beatriz Marincovich, ISP Eduardo Johnson, ISP (*)

Good Clinical Practices WG Members • COSTA RICA: • Guillermo Rodriguez • Graciela Salazar • Hernán Collado • Jorge López • Gilda Granados Gavelman , Consejo Nacional de Investigación, Ministerio de Salud (*) • CARICOM: • Henri Fraser, Prof. University of West Indies, Barbados

Good Clinical Practices WG Members • CUBA: • María Amparo Pascual, Centro Coordinador de Ensayos Clínicos (CENCEC) (*) • MEXICO: • Alberto Frati • Juan Jesús Sanchez • USA: • David Lepay • Stan Woollen, Food and Drug Administration (*)

Good Clinical Practices WG Members • VENEZUELA: • María Aguilar, Centro Nacional de Farmacología, Instituto Nacional de Higiene “Rafael Rangel” (*) • ALIFAR: • José Cortez, • Luis Yushimito • Manuel Ruiz Caballero (*)

Good Clinical Practices WG Members • FIFARMA: • León Arango, • Silvia Zieher, • Noemí Rosa • Celso Arabehety(*) • SECRETARIAT: • Rosario D´Alessio, PAHO • Alejandro Midzuaray, PAHO/WHO, Perú • Juana Mejía de Rodriguez: PAHO/WHO PWR Guatemala

BACKGROUND • Until recently, clinical trials were concentrated in developed countries • The number of patients enrolled in international multi-centre clinical trials has increased in some countries of our region. • In 1993 2.1% of clinical trials were done in Latin America; in 1997, 5.1% and in 2000, 7.5%. (IMS Health)

BACKGROUND • L.A. has been included in early phases of new drug development • As a result, there are more sites, investigators, committees, CROs, and research-related staff in pharmaceutical companies

BACKGROUND • 1995: Guidelines for GCP for Trials on Pharmaceutical Products (WHO) • ICDRA recommendations (Madrid 2004) • Member countries should implement the document • Member countries should guarantee the informed consent process • Biological Samples in Genetics Studies should follow GCP guidelines • Gene Therapy is a new area of medicine requiring rigorous implementation of GCPs and ethics • WHO was asked to explore options for providing experts to strengthen the R.A. of countries with limited resources

BACKGROUND • International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) • E6: Good Clinical Practices • E2a, E2b, E2c, E2ca, E2d, E2e: Clinical safety data Management • E3: Structure and content of Clinical Study Report • E5: Ethnic Factors in the acceptability of foreign clinical data • E7: Geriatrics: General Considerations for Clinical Research • E9: Statistical Principles for Clinical Research • E10: Choice of Control Groups • E11: Clinical Investigation of Medicinal Products for Pediatrics Population

BACKGROUND IN LATIN AMERICA • Meeting of Experts on GCP (1999, Bs As) • II Pan American Conference on Drug Regulatory Harmonization, established the GCP WG (1999) • Assessment of GCP situation in the area (2000) • Mission and Objectives of the GCP WG were defined

BACKGROUND IN AMERICA • III Pan American Conference on Drug Regulatory Harmonization (2002): Approved Ethics Committee and Informed Consent documents • III Pan American Conference on Drug Regulatory Harmonization (2002) recommended harmonizing procedures for evaluating protocols of clinical trials and developing guidelines for inspections and directives on pediatric investigation

BACKGROUND GCP DOCUMENT OF THE AMERICAS • Guideline for Regulatory Authorities on the authorization • Guideline for Regulatory Authorities on the Inspection • Guideline to Investigators, Ethics Committees, Universities and Industry

GOOD CLINICAL PRACTICESDocument of the Americas

Introduction Principles IEC/IRB Informed Consent Investigator Responsibilities Sponsor Responsibilities GCP Compliance Monitoring Program by R:A Protocol Glossary ANNEXES Operational Guidelines for IEC A Self-Evaluation Questionnaire for IEC´s (Check List) Operational Guidelines for Informed Consent A Inspections Guide to Clinical Investigator Essential Documents Good Clinical Practices Document of the Americas

Chapter 1: Introduction • Clinical trial is a systematic study with drugs and/or medicinal specialties in human volunteers that strictly follows the scientific method. Its purpose is to explore and verify the effects and/or the adverse reactions to an investigational product and/or the pharmacokinetics of the active ingredients, in order to determine their efficacy and safety • Clinical Trials involving human beings contribute significantly to the improvement of human health

Chapter 1: Introduction • Clinical trials are needed to demonstrate the efficacy and safety of the drugs • Since the relevance of developing these trials for national and international standards for clinical pharmacological research are necessary. • It becomes necessary to establish harmonized criteria for GCP in the Americas

Chapter 2: PRINCIPLES Clinical trials are conducted aiming and obtaining evidence regarding efficacy and safety of products that, in addition to non-clinical evidence and quality data should support their registration by a regulatory authority. Ethical principles based primarily on the Declaration of Helsinki should be the basis for the approval and conduction of clinical trials. Three basic ethical principles of equal moral force, namely respect for persons, beneficence and justice, permeate all the GCP principles enumerated below

Chapter 2: PRINCIPLES • Clinical trials should be conducted only if the anticipated benefits for the individual trial subject and society clearly outweigh the risk involved • Although the benefit of the results of the clinical trial to science and society are important and should be taken into account, the most important considerations are those related to the rights, safety and well-being of the trial subjects

Chapter 2: PRINCIPLES • A trial should be conducted in compliance with the protocol that has received prior institutional review board (IRB)/independent ethics committee (IEC) approval/favorable opinion • Approval of clinical trials of investigational products should be supported by adequate non-clinical and, when applicable, clinical information

Chapter 2: PRINCIPLES • Clinical trials should be scientifically sound, and described in a clear, detailed protocol • Freely given informed consent should be obtained from every subject prior to clinical trial participation

Chapter 2: PRINCIPLES • Qualified physicians (or, if appropriate, qualified dentist) should be responsible for the medical care of trial subjects, and for any medical decision made on their behalf • These professionals should be adequately qualified by education, training and experience to perform their tasks regarding the trial and trial subjects • Recording, handling and storage of all clinical trial information should be appropriate to allow accurate trial reporting, interpretation and verification

Chapter 2: PRINCIPLES • The confidentiality of records that could identify subjects should be protected respecting the privacy and confidentiality rules in accordance with the applicable regulatory requirements • Investigational products should be manufactured, handled, and stored in accordance with applicable good manufacturing practices (GMP), and should be used in accordance with the approved protocol • Systems with procedures that assure the quality of every aspect of the trial should be implemented

Chapter 3: Investigational Ethics Committee/Institutional Review Board • The III Pan American Conference approved the document • Investigational Ethics Committee/Institutional Review Board (IEC/IRB) • Structure and Responsibilities of the Ethics Committee • Composition of the IEC/IRB • Functions and operations • Procedures • Records

Chapter 4: INFORMED CONSENT • The Document was approved by the III Pan American Conference • Informed Consent: • Definition • Parts of Informed Consent • Guidelines for obtaining Informed Consent • Elements of Informed Consent

Chapter 5: Investigator Resposibilities • Investigator´s Qualifications and Agreements • Adequate Resources • Medical Care of Trial Subjects • Informed Consent- Communication with IRB/IEC • Compliance with Protocol • Investigational Product

Chapter 5: Investigator Resposibilities • Randomization Procedures/ Records and Reports • Progress Reports/Final Report • Safety Reporting • Premature Termination or Suspention of a Trial • Financial Aspects

Chapter 6: Sponsor Responsibilities • Quality Assurance and Quality Control • Contract Research Organization • Medical Expertise • Trial Design • Trial Management, Data Handlling, Recordkeeping and Independent Data Monitoring Committee

Chapter 6: Sponsor Responsibilities • Investigator Selection • Allocation of Duties and Functions • Compensation to Subjects and Investigators • Financing • Notification/Submission to regulatory Authority(ies)

Chapter 6: Sponsor Responsibilities • Confirmation of Review by IEC/IRB • Information on Investigational Product(s) • Manufacturing, Packaging, Labeling and Coding Investigational Product(s) • Supplying and Handling Investigational Product(s) • Record Access

Chapter 6: Sponsor Responsibilities • Safety Information • ADR reports • Monitoring • Audit • Noncompliance • Premature Discontinuation and Suspension of a Trial • Clinical Trial Reports • Multicentre Trials

GCP Compliance Monitoring Programs by R.A. • Objective:The aim of the program is to monitor compliance with GCP through inspections to all parties involved in the clinical trial • Purpose of the National GCP Compliance Program: A GCP Compliance Monitoring Program is indented to ascertain whether clinical trials have been conducted in accordance with acceptable GCP standards as necessary to ensure the quality and integrity of study data and the protection of the rights and welfare of research subjects. RA should publish the details of their (National) GCP Compliance Program

GCP Compliance Monitoring Programs by R.A. Organization/Administration: • A (National) GCP Compliance Monitoring Program should be the responsibility of a properly constituted, legally identifiable body adequately staffed and working within a defined administrative framework. It is recommended that such program be under the responsibility of the existing DRA

GCP Compliance Monitoring Programs by R.A. Personnel and Training: • A (National) GCP Compliance Monitoring Authorities should: • Ensure that an adequate number of Inspectors are available • Ensure that Inspectors are adequately qualified and trained • Inspectors should have qualifications and practical expertise in the range of scientific and regulatory disciplines relevant to GCP

GCP Compliance Monitoring Programs by R.A. Personnel and Training: • A (National) GCP Compliance Monitoring Authorities should ensure that inspectorate personnel, including experts under contract, have no financial or other interest in the trial sites or products and studies inspected or the firms sponsoring such studies • Inspectors may be on the permanent staff of the GCP Monitoring authority or on the permanent staff of a body separate from GCP Monitoring Authority or employed on contract by the GCP Monitoring Authority to perform inspections ( in the last case the GCP Monitoring Authority has the ultimate responsibility for determining GCP compliance status , the acceptability of the data and for taking actions.

Clinical Protocol The Clinical Trial will follow an written Protocol, signed by the sponsor and the investigator Every amendment should be also signed by both parties

Clinical Protocol • General Information • Background • Objectives • Design • Selection Criteria • Treatment

Clinical Protocol • Efficacy Evaluation • Safety Evaluation • Statistics • Direct Access to Data • Quality Control and Quality Assurance

Annexes

Operational Guidelines for Ethics Committees that Review Biomedical Research (TDR-WHO 2000) • These Guidelines are intended to facilitate and support ethical review • They are based on a closed examination of the requirements for ethical review as established in international guidelines, as well as on an evaluation of existing practices of ethical review in countries around the world

Surveying and Evaluating Ethical Review Practices: a complementary guideline (TDR- WHO 2002) • This guideline is intended to be complementary to the Operational Guidelines • Its purpose is to facilitate and support procedures for assisting the development of quality and transparency in ethical review • It´s developed as a tool to contribute to the education of IEC through review and evaluation of their practices • It´s intended to contribute to justified public trust in the ethical review and to assist public authorities and national associations involved with developing ethical review systems in promoting Good Ethical Practices

A Self-Evaluation Questionnaire for IEC´s (CHECK LIST) This questionnaire may be useful to define procedures of new IEC/IRBs, and for reviewing organization and operation procedures of established IEC/IRBs. Most items listed are applicable also to ethics committees that are not affiliated with a particular institution (Independent). The written procedures can be audited to verify appropriate compliance

Model for Basic Structure of the Informed Consent Document • The III Pan American Conference on Drug Regulatory Harmonization approved the Document • General Information • Specific Information • Rights of the Subjects • Signature Model

Operational Guidelines for Informed Consent • The III Pan American Conference on Drug Regulatory Harmonization approved the document • This Guideline will be an instrument to: • To write an Informed Consent. • To obtain the Informed Consent • Contents of the document: • Language • Information to the subjects • Signature Form • Guidelines for obtaining Informed Consent

Check List of Requirements for the Informed Consent Form • This Check List may be useful for Investigators, IECs/IRBs , sponsors and R.As to check the elements of the Informed Consent • The Document was approved by the III Pan American Conference on Drug Regulatory Harmonization

A Guide to Clinical Investigator Inspections This Document provides a guide to inspectors and R.A for planning, conducting and reporting clinical investigator inspections The objectives of these inspections are to assure the quality and integrity of clinical trial data relied upon by R.A. and to assure that the rights and welfare of research subject are protected

A Guide to Clinical Investigator Inspections Planning the Inspection • Selection of the studies • Identification of Inspectors • Preparing the Inspection • Scheduling the Inspection

A Guide to Clinical Investigator Inspections Conducting the Inspection • Opening Interview • Study Records review • Records inventory • Protocol • Subjects’ Records • Human subjects protection documentation • Drug Accountability • Planning the Inspection • Scheduling the Inspection

A Guide to Clinical Investigator Inspections Documenting and Reporting the Inspection • Documentation during the Inspection • Reporting after the Inspection

Essential Documents for Clinical Trials • Essential Documents are those documents that individually and collectively permit evaluation of the conduct of a trial and the quality of the data produced • The minimum list of Essential Documents are grouped in three sections • Before the clinical trial commences • During the clinical conduct of the trial • After completion of the trial • The list of Essential Document are listed in investigator/institution documents and sponsor documents

GOOD CLINICAL PRACTICES WORKING GROUP