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GCP Refresher Training (Chcuk) V2

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Stuart McCully

The document provides an overview of Good Clinical Practice (GCP) training, including: 1. A refresher on the key events that led to the development of GCP guidelines like the Nuremberg Code and Declaration of Helsinki in response to unethical medical experiments and drug issues. 2. An overview of the regulatory framework for clinical trials in Europe and the UK, including EU directives and UK laws that implement GCP principles. 3. A discussion of what guidelines and regulations are applicable for the conduct of clinical trials today, including ICH E6 and EU Clinical Trials and GCP directives.

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Clinical Trials
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GCP REFRESHER TRAINING A Recap of the Essentials and a Look at What’s New Stuart McCully, PhD 29th June 2010
DISCLAIMER Although this material contains information of a legal nature, it has been developed for informational purposes only and does not constitute legal advice or opinions as to the current operative laws, regulations, or guidelines of any jurisdiction. In addition, because new standards are issued on a continuing basis, this training material is not an exhaustive source of all current applicable laws, regulations, and guidelines relating to clinical research. While reasonable efforts have been made to assure the accuracy and completeness of the information provided, researchers and other individuals should check with local authorities and/or research ethics committees before starting clinical research activities
Topics Covered 1. Definitions a. What is GCP? 2. GCP: A Snapshot of Key Events a. The Nazi Medical Experiments b. The Tuskegee Syphilis Story c. Thalidomide d. From Human Abuse to Regulated Use 4. The Regulatory Framework: Clinical Trials a. Regulation of Clinical Trials in the UK b. How Does it All Fit Together? c. What do we Follow? ICH E6? 3. What’s Changed Recently? a. Updates to the UK Law b. Updates to the European Guidelines c. Useful Resources 4. GCP Considerations a. Informed Consent b. Monitoring c. The Protocol Compliance d. IMP e. CRFs f. Trial Documents
Feel Free to Ask Questions...
GCP Refresher Training (Chcuk) V2
What is GCP? According to 2001/20/EC... According to ICH E6... Good clinical practice is a set of GCP is...a standard for the design, internationally recognised ethical conduct, performance, monitoring, and scientific quality requirements auditing, recording, analyses, and which must be observed for reporting of clinical trials that designing, conducting, recording and provides assurance that the data and reporting clinical trials that involve reported results are credible and the participation of human subjects. accurate, and that the rights, Compliance with this good practice integrity, and confidentiality of trial provides assurance that the rights, subjects are protected (as per safety and well-being of trial subjects Section 1.27 of ICH E6) are protected, and that the results of the clinical trials are credible (as per Article 1.2 of 2001/20/EC)
Monitoring: The Human Touch • Protecting the rights and well-being of human subjects • Many things change on the surface, but the essentials stay the same
The Nazi Medical Experiments • Experiments on twins • Freezing experiments • Malaria experiments • Mustard gas experiments • Sulfonamide experiments • Sea water experiments • Sterilization experiments • Experiments with poison • Incendiary bomb experiments • High altitude experiments
The Nazi Medical Experiments: Twins
The Nuremberg Code (1947) & The Declaration of Helsinki (1964) • Voluntary consent is absolutely essential • Studies should be based on good science • The benefit should outweigh the risks • Participants should be at liberty to withdraw • The experiment should be conducted by scientifically qualified persons • Research protocols should be reviewed by an independent committee
The Nuremberg Code (1947) The voluntary consent of the human subject is absolutely essential. This means that the person involved should have legal capacity to give consent; should be so situated as to be able to exercise free power of choice, without the intervention of any element of force, fraud, deceit, duress, over-reaching, or other ulterior form of constraint or coercion; and should have sufficient knowledge and comprehension of the elements of the subject matter involved, as to enable him to make an understanding and enlightened decision. This latter element requires that, before the acceptance of an affirmative decision by the experimental subject, there should be made known to him the nature, duration, and purpose of the experiment; the method and means by which it is to be conducted; all inconveniences and hazards reasonably to be expected; and the effects upon his health or person, which may possibly come from his participation in the experiment. The duty and responsibility for ascertaining the quality of the consent rests upon each individual who initiates, directs or engages in the experiment. It is a personal duty and responsibility which may not be delegated to another with impunity. Source: The Nuremberg Code
The Declaration of Helsinki (1964) • Research with humans should be based on laboratory and animal experimentation • Research protocols should be reviewed by an independent committee • Informed Consent is necessary • Research should be conducted by medically/ scientifically qualified individuals • Risks should not exceed benefits The Interests of the Patient should prevail over those of science and society
The Tuskegee Syphilis Study • In 1932 the US Government misled 623 African- Americans into participating into a study of untreated syphilis • The government induced these men to participate in a study in which the government represented that the participants were being treated for whatever their ailments were – They were never told what their ailment was – They never gave their consent to be involved in a study – Nor did they realise they were part of a study until the story broke in July 1972 – Treatment was knowingly withheld for 40 years Fred D Gray – Attorney, 8th April 1997
The Tuskegee Syphilis Study “Men who were poor and African American, without resources and with few alternatives believed they had found hope when they were offered free medical care by the United States Public Health Service. They were betrayed. For 40 years, hundreds of men were betrayed, along with their wives and children, along with a community in Macon County, Alabama, the City of Tuskegee, the fine university there, and the larger African American community. The United States government did something that was wrong – deeply, profoundly, morally wrong. It was an outrage to our commitment to integrity and equality for all of our citizens.” President Bill Clinton, 16th May 1997
The Tuskegee Syphilis Study “Medical professionals willingly and intentionally let human beings suffer from a treatable, and then later a curable illness. These researchers knew that mercury and arsenic compounds could treat the disease, but the Tuskegee men did not receive the medicine. Later the researchers knew that penicillin could cure the disease, but again, the Tuskegee men did not get the medicine. They didn’t get treated until the 40 year study was discovered and stopped amid public outcry in 1972. It was a disgraceful episode for American Scientists.” Vice President Al Gore, 16th May 1997
The Tuskegee Syphilis Study This case reaffirmed the principle that prior informed consent should be obtained from individuals before they are allowed to participate in human experimentation
Thalidomide: 1957 - 1961 Thalidomide claimed 8000 victims in “They are all victims not merely of a forty-six countries where it was drug accident but of the dangerous prescribed by doctors and sold myth invented in Germany and across the counter under a variety of exported to a credulous world; that trade names on licence from the thalidomide was better than all other original German inventors, Chemie tranquilisers because it was non- Grunenthal. toxic and had no side effects, and was completely safe for pregnant women. None of these statements, announced by the drug companies and accepted by the doctors, was true.” The Sunday Times Insight Team, Suffer the Children: The Story of Thalidomide, 1979
GCP Refresher Training (Chcuk) V2
Thalidomide: UK Government Apology (Jan 2010) On the 14th January 2010 Health Minister Mike O'Brien expressed the government's "sincere regret and deep sympathy" for victims of the drug thalidomide. It comes four decades after expectant mothers suffering from morning sickness took the drug between 1958 and 1961. Thousands of their offspring suffered from physical disabilities as a result. Of them, 466 members of the UK’s Thalidomide Trust remain. The government has announced a £20 million three-year pilot scheme which will meet survivors' needs "in a more personalised way". Mr O'Brien told MPs: "The government wishes to express its sincere regret and deep sympathy for the injury and suffering endured by all those affected when expectant mothers took the drug thalidomide between 1958 and 1961. "We acknowledge both the physical hardship and the emotional difficulties that have faced both the children affected and their families as a result of this drug, and the challenges that many continue to endure, often on a daily basis." The new funding for 'thalidomiders' will prioritise looking after their health needs for the long-term. After the drug's negative side-effects were first realised the government launched a major review of the machinery for marketing, testing and regulating drugs, which resulted in the Medicines Act 1968. (Source: Thalidomide UK Website)
Regulation of Pharmaceuticals in the EU • The first European Community pharmaceutical directive was issued in 1965 • Much of the impetus behind Directive 65/65/EEC stemmed from determination to prevent a recurrence of the thalidomide disaster in the early 1960s • This experience, which shook public health authorities and the general public, made it clear that to safeguard public health, no medicinal product must ever again be marketed without prior authorisation.
From Human Abuse to Regulated Use Tuskegee Syphilis Nuremberg Declaration Study Code of Helsinki 1996 1932-1972 1947 1964 ICH E6 1938 - 1945 1957 -1961 Directive Clinical WWII Thalidomide 65/65/EC Trials 1965 Directives 2001 & 2005 Cause Effect (Abuse) (Regulations)
The Regulatory Framework: Clinical Trials
What are the ‘Applicable Regulations’?
Regulation of Clinical Trials in Europe & UK Nuremberg Code 1947 Declaration of Helsinki 1964, 1975, 1983, 1989, 1996, 2000, 2008 Guidelines ICH E6 1996 2001/20/EC 4th April 2001 EU Directives 2003/94/EC 8th October 2003 2005/28/EC 8th April 2005 S.I. 2004/1031 1st May 2004 S.I. 2006/1928 29th August 2006 UK Law S.I. 2006/2984 12th Dec 2006 S.I. 2008/941 1st May 2008 SI 2009/1164 8th May 2009 Policies, Standards & SOPs QMS Protocol
Regulation of Clinical Trials in Europe & UK Nuremberg Code 1947 Declaration of Helsinki 1964, 1975, 1983, 1989, 1996, 2000, 2008 Guidelines ICH E6 1996 2001/20/EC 4th April 2001 EU Directives EUDRALEX VOLUME 10 2003 2003/94/EC 8th October 2005/28/EC 8th April 2005 S.I. 2004/1031 1st May 2004 S.I. 2006/1928 29th August 2006 UK Law S.I. 2006/2984GCP WEBSITE 2006 MHRA 12th Dec S.I. 2008/941 1st May 2008 SI 2009/1164 8th May 2009 Policies, Standards & SOPs QMS Study Protocol Protocol
GCP Refresher Training (Chcuk) V2
So how does it all fit together?
Overview of Clinical Trial Regs (UK) – 29th June 2010 Regulation of Clinical Trials: UK Ethics of Human Research Declaration of Helsinki (1996) GCP Guidelines ICH Efficacy (E) Series ICH E6 EU Implementing Directives Clinical Trials & GCP 2001/20/EC 2005/28/EC EU Supporting Regulations & EU Detailed Guidance Directives Interventional or Non-Interventional? UK Law Document Retention Decision Tree 2001/83/EC (as amended) The Medicines Act 1968 [Annex 1, Part I, Section 5.2.c] Competent Authority Submissions GMP ENTR/CT 1 The Medicines for Human Use 2003/94/EC (Clinical Trials) Regulations [Annex 13] 2004 2001/83/EC (as amended) IEC Submissions SI 2004/1031 ENTR/CT 2 Paediatric Studies Amendments Ethical Considerations… Safety Reporting SI 2004/3224, SI 2005/2754, 1901/2006/EC ENTR/CT 3 SI 2005/2759, SI 2006/1928, 1902/2006/EC SI 2006/2984, SI 2008/941, IMP vs Non-IMP SI 2009/1164 Data Privacy 95/46/EC TMF Content & Archiving Data Protection Act 1998 Copyright © Dr Stuart McCully, 2009-2010 All Rights Reserved
The Clinical Trials Directive (2001/20/EC) Approximation of the laws, regulations and administrative procedures relating to the implementation of GCP in the conduct of trials – Relevant to interventional trials – Sets out principles of GCP and clinical trial definitions – Informed Consent – Ethical review/ favoural opinion and Competent Authority approval – Substantial amendments – Urgent safety measures and safety reporting – GMP: Manufacture, import, labelling & release of IMP – End of trial notification – Publication of detailed guidance documents
The GCP Directive (2005/28/EC) Lays down principles and detailed guidance for GCP & IMP manufacture & importation as regards IMP for human use – Clarifies the principles of GCP – EC document retention – EC & CA communication – Clarifies the responsibilities of the sponsor – IB to be validated and updated annually – SPC can be used in place of IB for marketed products – Further details on the manufacture or importation of IMP – TMF & Archiving – Inspectors and Inspection procedures
Overview of Clinical Trial Regs (UK) – 29th June 2010 Regulation of Clinical Trials: UK (Detailed) Primary Legislation The Medicines Act 1968 MARKETED PRODUCT Secondary Legislation CLINICAL TRIAL REGULATIONS REGULATIONS The Medicines for Human Use The Clinical Trials Directive The Medicines (Marketing (Clinical Trials) Regulations 2004 2001/20/EC Authorisations and Miscellaneous SI 2004/1031 Amendments) Regulations 2004 SI 2004/3224 The Medicines for Human Use The GCP Directive (Clinical Trials) Amendment 2005/28/EC Regulations 2006 The Medicines (Advisory Bodies) SI 2006/1928 (No.2) Regulations 2005 SI 2005/2754 The Medicines for Human Use (Clinical Trials) Amendment (No.2) Regulations 2006 The Medicines (Marketing SI 2006/2984 Authorisations etc) Amendment Regulations 2005 The Medicines for Human Use SI 2005/2759 (Clinical Trials) and Blood Safety and Quality (Amendment) Regulations 2008 SI 2008/941 The Medicines for Human Use (Miscellaneous Amendments) Regulations 2009 SI 2009/1164 Copyright © Dr Stuart McCully, 2009-2010 All Rights Reserved
Overview of Clinical Trial Regs (UK) – 29th June 2010 Summary of the UK Clinical Trial Regulations SI 2004/1031 • Implements the Clinical Trials Directive (2001/20/EC) into UK law In force from 1st May 2004 • Requires Urgent Safety Measures to be notified to the Ethics Committees The Medicines for Human Use and MHRA immediately and no later than 3 days after the measures were (Clinical Trials) Regulations 2004 taken (Regulation 30) SI 2004/3224 • Amends the definition for “the European Medicines Agency” in In force from 1st January 2005 Regulation 2 of SI 2004/1031 The Medicines (Marketing Authorisations and Miscellaneous Amendments) Regulations 2004 SI 2005/2754 • Completely replaces Schedule 5 of SI 2004/1031 (Procedural Provisions In force from 30th October 2005 Relating to the Refusal or Amendment of, or Imposition of Conditions The Medicines (Advisory Bodies) Relating to, Clinical Trial Authorisations and the Suspension or Termination (No.2) Regulations 2005 of Clinical Trials) • Amends paragraphs 4 and 5 of Schedule 8 (procedural provisions relating to proposals to grant, refuse to grant, vary, suspend or revoke manufacturing authorisations) of SI 2004/1031 • Amends the definition for an “appropriate committee” in Regulation 2 of SI 2004/1031 • Amends Regulation 19(10) of SI 2004/1031 • Amends Regulation 26 of SI 2004/1031 • Amends Regulation 31 of SI 2004/1031 Copyright © Dr Stuart McCully, 2009-2010 Crown Copyright material is reproduced with the permission of the Controller of HMSO All Rights Reserved
Overview of Clinical Trial Regs (UK) – 29th June 2010 Summary of the UK Clinical Trial Regulations SI 2005/2759 • Amends the definition for an “marketing authorisation” in Regulation 2 of In force from 20th November 2005 SI 2004/1031 The Medicines (Marketing Authorisations etc) Amendment Regulations 2005 SI 2006/1928 • Implements the GCP Directive (2005/28/EC) into UK law In force from 29th August 2006 • Introduces Regulation 29A to SI 2004/1031 and requires the sponsor to The Medicines for Human Use notify the MHRA within 7 days of any occurrence of a serious breach of (Clinical Trials) Amendment GCP or the protocol Regulations 2006 – Implements Section 5.20 of ICH E6 SI 2006/2984 • Amends Schedule 1, Part 1 of SI 2004/1031 to allow incapacitated adults In force from 12th December 2006 into a clinical trial without the prior consent of their legal representative The Medicines for Human Use assuming certain conditions are met (Clinical Trials) Amendment – Implements Section 4.8.15 of ICH E6 (No.2) Regulations 2006 Copyright © Dr Stuart McCully, 2009-2010 Crown Copyright material is reproduced with the permission of the Controller of HMSO All Rights Reserved
Overview of Clinical Trial Regs (UK) – 29th June 2010 Summary of the UK Clinical Trial Regulations SI 2008/941 • Amends Schedule 1, Part 1 of SI 2004/1031 to allow minors into a clinical In Force from 1st May 2008 trial without the prior consent of their legal representative assuming The Medicines for Human Use certain conditions are met (Clinical Trials) and Blood Safety – Implements Section 4.8.15 of ICH E6 and Quality (Amendment) • Amends Regulation 15 of SI 2004/1031 to allow the Gene Therapy Regulations 2008 Advisory Committee (GTAC) to notify UKECA that its advice is not required for routine gene therapy trials and allows such applications to be transferred to another EC for an opinion • Amends Regulation 15 and Schedules 2 & 3 of SI 2004/1031 to modify the procedures for operation of ECs to widen the available expertise, reduce administrative burden and rationalise the documents an applicant must submit for an opinion • Amends the definition for of “the Directive”, “Directive 2001/83/EC” and “the Gene Therapy Advisory Committee” in Regulation 2 of SI 2004/1031 SI 2009/1164 • Amends Regulation 30 of SI 2004/1031 to allow Urgent Safety Measures In force from 8th May 2009 to be notified to the Ethics Committees and MHRA ‘as soon as possible’ The Medicines for Human Use rather than the usual restrictive 3 days during any period when a disease is (Miscellaneous Amendments) pandemic and is a serious risk, or potentially a serious risk, to human Regulations 2009 health Copyright © Dr Stuart McCully, 2009-2010 Crown Copyright material is reproduced with the permission of the Controller of HMSO All Rights Reserved
What do we follow? ICH E6?
Overview of Clinical Trial Regs (UK) – 7th September 2009 So what do we follow? “The Investigator and The Medicines for Human Use Sponsor shall consider all (Clinical Trials) Regulations UK Law 2004 relevant guidance with SI 2004/1031 respect to commencing and conducting a clinical trial” [Schedule 1, Part 2.8 of SI 2004/1031 (as amended by SI 2006/1928)] EU Implementing Clinical Trials & GCP 2001/20/EC Directives 2005/28/EC Detailed Guidance Documents Eudralex Volume 10 ICH GCP Guidelines Global GCP Guidelines ICH E6 Ethics of Human Research Bioethical Principles Declaration of Helsinki (1996) Copyright © Dr Stuart McCully, 2009 All Rights Reserved
What’s Changed Recently?
Updates to the UK Clinical Trial Regulations: 2006 - 2010 Date Details Source 29th Aug 2006 • Implement GCP Directive SI 2006/1928 • Introduce ‘Serious Breaches’ The Medicines for Human Use (Clinical Trials) Amendment Regulations 2006 12th Dec 2006 • Allows incapacitated adults into a clinical SI 2006/2984 trial without the prior consent of their legal The Medicines for Human Use representative assuming certain conditions (Clinical Trials) Amendment (No.2) are met Regulations 2006 1st May 2008 • Allows minors into a clinical trial without SI 2008/941 the prior consent of their legal The Medicines for Human Use representative assuming certain conditions (Clinical Trials) and Blood Safety are met and Quality (Amendment) Regulations 2008 8th May 2009 • Allows Urgent Safety Measures to be SI 2009/1164 notified to the Ethics Committees and MHRA The Medicines for Human Use ‘as soon as possible’ rather than the usual (Miscellaneous Amendments) restrictive 3 days during any period when a Regulations 2009 disease is pandemic and is a serious risk, or potentially a serious risk, to human health
Updates to the European Clinical Trial Guidelines: 2009 - 2010 Date Guideline Details 3rd Dec 2009 QUESTIONS &ANSWERS • New Document SPECIFIC TO ADVERSE • Supplement to ENTR/CT 3 REACTION REPORTING IN CLINICAL TRIALS 31st Jan 2010 Annex 13 • Revision to reinforce the principle of independence between (Deadline for coming in to production and quality control functions in cases where the number operation is 31st July 2010) Annex 13 to the Guidelines on of personnel involved is small. good manufacturing practice • Changes to sections 36 and 37 to supplement, for IMPs, the — Manufacture of guidance for reference and retention samples given in Annex 19. investigational medicinal • Clarified the meaning of “reconstitution” as referred to in article products 9.2 of Directive 2005/28/EC. • The content of the Batch Certificate referred to in Art. 13(3) of Directive 2001/20/EC has been added. March 2010 ENTR/CT 1 • Updated to provide more comprehensive guidance on: o Substantial vs Non-substantial Amendments Detailed guidance on the o Urgent t safety Measures request to the competent o Non-Compliance with the Protocol authorities for authorisation of a clinical trial on a medicinal product for human use, the notification of substantial amendments and the declaration of the end of the trial (CT-1)
Updates to the European Clinical Trial Guidelines: 2009 - 2010 Date Guideline Details 1st Jun 2010 Eudralex Volume 10: • New Q&A added: Questions and Answers • Question 2.5: Can a sponsor established in a third country (Version 6) open a subsidiary or branch in a Member State in order to comply with the requirement of Directive 2001/20/EC that the sponsor or a legal representative of the sponsor must be established in the EU?
GCP Refresher Training (Chcuk) V2
Useful Resources • GCP Regulatory Maps • GCP Considerations - Informed Consent in Clinical Trials • GCP Considerations - Contraception in Clinical Trials • GCP Considerations - The Investigator's Brochure • GCP Considerations - Useful Links
GCP Considerations: • Informed Consent • Monitoring • Protocol Compliance • IMP • CRFs • ISF • Filing & Archiving
ICH E6 1. Glossary 2. The Principles of GCP 3. Ethics Committees 4. Investigator 5. Sponsor 6. Clinical Trial Protocol & Amendments 7. Investigator’s Brochure 8. Essential Documents for the Conduct of a Clinical Trial
ICH E6 ‘Exclusives’ 1. Glossary 2. The Principles of GCP 3. Ethics Committees 4. Investigator  Informed Consent 5. Sponsor  Monitoring 6. Clinical Trial Protocol & Amendments 7. Investigator’s Brochure 8. Essential Documents for the Conduct of a Clinical Trial  TMF
GCP Considerations: • Informed Consent
The Regulatory Framework: Informed Consent
Informed Consent Regulations & Guidance: EU & UK Regulation/ Reference Applicability Detail Guideline ICH E6 Section 4.8 ‘Global’ Set out the principles and details of informed consent Provides guidance on the principles and details of informed ICH E11 Section 2.6.3 ‘Global’ consent/ assent for trials in minors/ paeds 2001/20/EC Article 2(j) EU Defines Informed Consent 2001/20/EC Articles 3 - 5 EU Set out the principles of informed consent Ethical Provides detailed guidance on the consent/ assent EU Considerations considerations for trials in minors
Informed Consent Regulations & Guidance: EU & UK Regulation/ Reference Applicability Detail Guideline SI 2004/1031 Schedule 1, Set out the conditions and principles in relation to informed UK (as amended)* Parts 3 – 5 consent SI 2006/2984 Amends Schedule 1, Part 1 of SI 2004/1031 to allow incapacitated adults into a clinical trial without the prior UK consent of their legal representative assuming certain conditions are met – Implements Section 4.8.15 of ICH E6 SI 2008/941 Amends Schedule 1, Part 1 of SI 2004/1031 to allow minors into a clinical trial without the prior consent of their legal UK representative assuming certain conditions are met – Implements Section 4.8.15 of ICH E6 NRES Guidance on UK Provides guidance and templates for PILs and ICFs PILs & ICFs * As amended by SI 2004/3224, SI 2005/2754, SI 2005/2759, SI 2006/1928, SI 2006/2984, SI 2008/941, and SI 2009/1164
Let’s Shed Some Light on Informed Consent...
Informed Consent Content: The Basic Building Blocks
Informed Consent Content: The Basic Building Blocks ICH E6 Basic Considerations 4.8.6 Wording 4.8.10 (a) (f) Research Notion 4.8.10 (b) (h) Goals of the Trial 4.8.10 (c) Design of the Trial 4.8.10 (h) Expected Therapeutic Benefits 4.8.10 (i) Alternative Treatments 4.8.10 (m) Voluntary Nature of the Participation 4.8.10 (m) Withdraw from the Trial without Prejudice 4.8.10 (q) Contact Point 4.8.10 (p) Informed of New Data that May Influence Decision to Participate 4.8.10 (r) Stopping the Trial 4.8.10 (e) Subject’s Responsibilities 4.8.10 (s) Length of Study
Informed Consent Content: The Basic Building Blocks ICH E6 Basic Considerations 4.8.10 (t) Recruitment 4.8.10 (d) Invasive Procedures 4.8.10 (g) Foreseeable Risks 4.8.10 (j) Compensation and/or treatment available in the event of a trial-related injury 4.8.10 (j) Third Party Liability 4.8.10 (l) Payment and Costs 4.8.10 (k) Remuneration 4.8.10 (o) Data Confidentiality 4.8.10 (n) Access to Records
Informed Consent Content: The Basic Building Blocks ICH E6 Additional Considerations 4.8.15 Emergency Situations 4.8.12-15 Enrolment of ‘legally incompetent’ subjects – Minors – Incapacitated Adults
Informed Consent : Additional Considerations • Paediatric Trials • Vulnerable Groups • Data Protection • Genetic Trials • Biological Samples • Future use/re-use of Information • Language of Consent • Medical Device Investigations • Non-Interventional Studies
Useful Resources Informed Consent: Pages 43 - 55 • Definitions • General Considerations • NRES Guidance on PILs & ICFs • The Participants Perspective • Minors • Incapacitated Adults • MHRA GCP Inspection Findings
Useful Resources Contents: • Definitions • Recent History – Nazi War Experiments – The Tuskegee syphilis study – The Thalidomide Tragedy – From Human Abuse to Regulated Use – Informed Consent - Regulatory Framework – Informed Consent - Regulatory Framework in Europe and the UK – Informed Consent – General Considerations • Informed Consent: UK – Regulatory Overview – Regulatory Bodies – Country-Specific Informed Consent Considerations – Informed Consent – Detailed Considerations – Informed Consent Guidance and Templates – Applicable Legislation – MHRA GCP Inspection Findings – Useful Links
Informed Consent... ...Adequately informed and consent freely given
Informed Consent • Before informed consent may be obtained, the Investigator should provide the subject with ample time and opportunity to inquire about details of the trial • The Investigator should fully inform the subject of all pertinent aspects of the trial including the written information and the approval/favourable opinion by the EC and MHRA – Must ensure that only the current approved version of the informed consent information/documentation is used ICH E6, Section 4.8
Informed Consent • The subject should receive a copy of the signed and dated informed consent form and any other written information provided to subjects – This includes any subsequent amendments to the form and/or information ICH E6, Section 4.8
GCP Considerations: • Monitoring
Monitoring ‘This study will be monitored according to the currently approved protocol, GCP, and with the applicable regulatory requirements’ What Type of Study are What are the Applicable you Monitoring? Regulations?
What Type of Study are you Monitoring? Clinical Trials Food Supplement Studies Non-Interventional Studies
GCP Considerations: • Protocol Compliance • Serious Breach • Urgent Safety Measures
Food for Thought: Protocol Compliance, Serious Breaches and Emergency measures • The Investigator should conduct the trial in compliance with the approved protocol – The Investigator should sign the protocol to confirm agreement • The Investigator should not implement any deviations from, or changes to, the protocol without agreement by the Sponsor and prior approval from the REC/MHRA – Unless to eliminate an immediate hazard to trial subjects (Urgent Safety Measure) – The Sponsor must notify the MHRA within 3 days of the USM being taken or, – ‘as soon as possible’ rather than the usual restrictive 3 days during any period when a disease is pandemic and is a serious risk, or potentially a serious risk, to human health • As per Regulation 30 of SI 2004/1031 (as amended by SI 2009/1164) ICH E6, Section 4.5
Protocol Compliance, Serious Breaches and Emergency measures • The Investigator should document and explain any [retrospective] deviation from the approved protocol – IMPORTANT: Protocol waivers are not allowed • MHRA: GCP Frequently asked questions • EMEA: GCP Questions and Answers – Refer to Regulation 29 of SI 2004/1031 ICH E6, Section 4.5
Food for Thought: Protocol Compliance, Serious Breaches and Emergency measures Persistent or systematic non-compliance with GCP or the protocol that has a significant impact on the integrity of trial subjects in the UK or on the scientific value of the trial • For example, widespread and uncontrolled use of protocol waivers affecting eligibility criteria, which leads to harm to trial subjects in the UK or which has a significant impact on the scientific value of the trial. Another example would be of an investigator repeatedly failing to reduce or stop the dose of an IMP in response to a trigger (e.g. abnormal laboratory results) defined in the protocol. MHRA Guidance for the notification of serious breaches of GCP or the trial protocol
Protocol Waivers Q1. Can a sponsor prospectively approve deviations (so-called “protocol waivers”) from the inclusion/exclusion criteria of the approved protocol without additional approval of the Ethics Committee and competent regulatory authority? A1. Adherence to the protocol is a fundamental part of the conduct of a clinical study. Any significant change to the protocol should be submitted as an amendment to the competent regulatory authority and Ethics Committee. Significant changes to the protocol include any change in inclusion and exclusion criteria, addition or deletion of tests, dosing, duration of treatment etc (see the definition of a substantial amendment in the 'Detailed guidance for the request for authorisation of a clinical trial on a medicinal product for human use to the competent authorities, notification of substantial amendments and declaration of the end of the trial' published by the European Commission in Chapter I, Volume 10 of The Rules Governing Medicinal Products in the European Community). Deviations from the inclusion / exclusion criteria of the protocol might erode the scientific and ethical value of the protocol and its authorisation and might have an impact on the processes put in place for the care and safety of the study subjects. Sponsors and investigators should not use systems of prospectively approving protocol deviations, in order to effectively widen the scope of a protocol. Protocol design should be appropriate to the populations required and if the protocol design is defective, the protocol should be amended. The GCP does permit deviations from the protocol when necessary to eliminate immediate hazards to the subjects but this should not normally arise in the context of inclusion/exclusion criteria, since the subject is not yet fully included in the trial at that point in the process GCP inspectors have observed a number of sponsors implementing systems where the investigator can contact the sponsor, usually the Medical Monitor, and request a prospective approval to deviate from the inclusion and/or exclusion criteria. The use of such systematic waiver systems in clinical trials is not considered to be appropriate and studies using such a system might be regarded as non-compliant with GCP. EMA: GCP Questions and Answers
GCP Considerations: • IMP • CRFs
Investigational Medicinal Product (IMP) • Responsibility for IMP accountability at the trial site rests with the Investigator – IMP accountability logs must be maintained • Usually provided by the Sponsor and checked by the CRA at the monitoring visit – IMP must be stored and used as specific in the protocol • The Investigator may assign some/all of the IMP duties to a Pharmacist or other appropriate individual – In the UK IMP responsibility should really lie with the Pharmacist who should be abiding by the Royal Pharmaceutical Society Practice Guidance on Pharmacy Services for Clinical Trials (2005) ICH E6, Section 4.6
Randomisation & Unblinding • The Investigator should follow the trial’s randomisation procedure, if any, and should ensure the code is broken only in accordance with the protocol – Details, processes and relevant documents will be documented in the protocol and/or provided by the Sponsor • If the trial is blinded, the Investigator should promptly document and explain to the Sponsor any premature unblinding of the IMP – As per the protocol and/or Sponsor’s instructions ICH E6, Section 4.7
Case Report Forms (CRFs) • The Investigator should ensure the accuracy, completeness, legibility, and timeliness of the data reported in the CRFs and all required reports • Data reported on the CRF that are derived from source documents, should be consistent with the source documents or the discrepancies should be explained • Any change or correction to a CRF should be dated, initialled, and explained (if necessary) and should not obscure the original entry (i.e., an audit trail is maintained) – Sponsors should provide guidance on making such corrections ICH E6, Section 4.8
Correcting CRFs – A Simple Guide • Complete the case report form (CRF) fully and legibly. Data entered Age (yrs) 2 5  should be accurate • Avoid missing out any data Age (yrs)  • Date and initial all changes that you make Age (yrs) 2 5 4  • Make sure that any changes you make are clear • Do not obliterate the previous entry Age (yrs) 2 5  • Do not use Tipex
GCP Considerations: • ISF • Filing • Archiving
The Investigator Site File (ISF) • Essential documents are those documents which individually and collectively permit evaluation of the conduct of a trial and the quality of the data produced • Serve to demonstrate the compliance of the investigator, sponsor and monitor with GCP and the applicable regulations – Hence the focus on these documents during monitoring, audits and inspections • The minimum list is captured in Section 8 of ICH E6 • TMFs should be established at the beginning of a trial at the investigator and sponsor sites • A final close-out visit can only be done when the monitor has reviewed the investigator and sponsor files and confirmed that all necessary documents are in the appropriate files ICH E6, Section 8
The Investigator Site File (ISF) • The Investigator should maintain trial documents as specified in Section 8 of ICH E6 and as per the applicable regulatory requirements – The filing requirements for essential documents at the trial site(s) are generally listed by the trial Sponsor in an Investigator Site File (ISF) index or equivalent – Information should be documented and filed as it becomes available (ICH E6, Section 8.3) • The Investigator/Institution should take measures to prevent accidental or premature destruction of these documents • Upon request of the CRA, auditor, REC or MHRA, the Investigator should make available for direct access all requested trial-related records ICH E6, Section 4.9
Archiving Requirements • Documents to be retained for – 5 years if not part of a marketing authorisation package • Article 17 of 2005/28/EC – 15 years if part of a marketing authorisation package • Section 5.2.c of Annex I of 2001/83/EC (as amended)
Archiving Requirements Marketing authorisation holders must arrange for essential clinical trial documents (including case report forms) other than subject's medical files, to be kept by the owners of the data: • for at least 15 years after completion or discontinuation of the trial, • or for at least two years after the granting of the last marketing authorisation in the European Community and when there are no pending or contemplated marketing applications in the European Community, • or for at least two years after formal discontinuation of clinical development of the investigational product. Subject's medical files should be retained in accordance with applicable legislation and in accordance with the maximum period of time permitted by the hospital, institution or private practice. The sponsor or other owner of the data shall retain all other documentation pertaining to the trial as long as the product is authorised. Section 5.2.c of Annex I of 2001/83/EC (as amended)
In general this means... ...that all trial documents need to be retained by the Investigator until otherwise notified by the Sponsor
The Changing Face of Clinical Research... “In times of change, learners inherit the Earth, while the learned find themselves beautifully equipped to deal with a world that no longer exists.” Eric Hoffer (American social writer and philosopher)
GCP Refresher Training (Chcuk) V2
Contact Information Email: stuart.mccully@chcuk.co.uk Phone: +44 (0) 1997 42 33 11 Mobile: +44 (0) 7909 111 510 Website: www.chcuk.co.uk

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GCP Refresher Training (Chcuk) V2

  • 1. GCP REFRESHER TRAINING A Recap of the Essentials and a Look at What’s New Stuart McCully, PhD 29th June 2010
  • 2. DISCLAIMER Although this material contains information of a legal nature, it has been developed for informational purposes only and does not constitute legal advice or opinions as to the current operative laws, regulations, or guidelines of any jurisdiction. In addition, because new standards are issued on a continuing basis, this training material is not an exhaustive source of all current applicable laws, regulations, and guidelines relating to clinical research. While reasonable efforts have been made to assure the accuracy and completeness of the information provided, researchers and other individuals should check with local authorities and/or research ethics committees before starting clinical research activities
  • 3. Topics Covered 1. Definitions a. What is GCP? 2. GCP: A Snapshot of Key Events a. The Nazi Medical Experiments b. The Tuskegee Syphilis Story c. Thalidomide d. From Human Abuse to Regulated Use 4. The Regulatory Framework: Clinical Trials a. Regulation of Clinical Trials in the UK b. How Does it All Fit Together? c. What do we Follow? ICH E6? 3. What’s Changed Recently? a. Updates to the UK Law b. Updates to the European Guidelines c. Useful Resources 4. GCP Considerations a. Informed Consent b. Monitoring c. The Protocol Compliance d. IMP e. CRFs f. Trial Documents
  • 4. Feel Free to Ask Questions...
  • 6. What is GCP? According to 2001/20/EC... According to ICH E6... Good clinical practice is a set of GCP is...a standard for the design, internationally recognised ethical conduct, performance, monitoring, and scientific quality requirements auditing, recording, analyses, and which must be observed for reporting of clinical trials that designing, conducting, recording and provides assurance that the data and reporting clinical trials that involve reported results are credible and the participation of human subjects. accurate, and that the rights, Compliance with this good practice integrity, and confidentiality of trial provides assurance that the rights, subjects are protected (as per safety and well-being of trial subjects Section 1.27 of ICH E6) are protected, and that the results of the clinical trials are credible (as per Article 1.2 of 2001/20/EC)
  • 7. Monitoring: The Human Touch • Protecting the rights and well-being of human subjects • Many things change on the surface, but the essentials stay the same
  • 8. The Nazi Medical Experiments • Experiments on twins • Freezing experiments • Malaria experiments • Mustard gas experiments • Sulfonamide experiments • Sea water experiments • Sterilization experiments • Experiments with poison • Incendiary bomb experiments • High altitude experiments
  • 9. The Nazi Medical Experiments: Twins
  • 10. The Nuremberg Code (1947) & The Declaration of Helsinki (1964) • Voluntary consent is absolutely essential • Studies should be based on good science • The benefit should outweigh the risks • Participants should be at liberty to withdraw • The experiment should be conducted by scientifically qualified persons • Research protocols should be reviewed by an independent committee
  • 11. The Nuremberg Code (1947) The voluntary consent of the human subject is absolutely essential. This means that the person involved should have legal capacity to give consent; should be so situated as to be able to exercise free power of choice, without the intervention of any element of force, fraud, deceit, duress, over-reaching, or other ulterior form of constraint or coercion; and should have sufficient knowledge and comprehension of the elements of the subject matter involved, as to enable him to make an understanding and enlightened decision. This latter element requires that, before the acceptance of an affirmative decision by the experimental subject, there should be made known to him the nature, duration, and purpose of the experiment; the method and means by which it is to be conducted; all inconveniences and hazards reasonably to be expected; and the effects upon his health or person, which may possibly come from his participation in the experiment. The duty and responsibility for ascertaining the quality of the consent rests upon each individual who initiates, directs or engages in the experiment. It is a personal duty and responsibility which may not be delegated to another with impunity. Source: The Nuremberg Code
  • 12. The Declaration of Helsinki (1964) • Research with humans should be based on laboratory and animal experimentation • Research protocols should be reviewed by an independent committee • Informed Consent is necessary • Research should be conducted by medically/ scientifically qualified individuals • Risks should not exceed benefits The Interests of the Patient should prevail over those of science and society
  • 13. The Tuskegee Syphilis Study • In 1932 the US Government misled 623 African- Americans into participating into a study of untreated syphilis • The government induced these men to participate in a study in which the government represented that the participants were being treated for whatever their ailments were – They were never told what their ailment was – They never gave their consent to be involved in a study – Nor did they realise they were part of a study until the story broke in July 1972 – Treatment was knowingly withheld for 40 years Fred D Gray – Attorney, 8th April 1997
  • 14. The Tuskegee Syphilis Study “Men who were poor and African American, without resources and with few alternatives believed they had found hope when they were offered free medical care by the United States Public Health Service. They were betrayed. For 40 years, hundreds of men were betrayed, along with their wives and children, along with a community in Macon County, Alabama, the City of Tuskegee, the fine university there, and the larger African American community. The United States government did something that was wrong – deeply, profoundly, morally wrong. It was an outrage to our commitment to integrity and equality for all of our citizens.” President Bill Clinton, 16th May 1997
  • 15. The Tuskegee Syphilis Study “Medical professionals willingly and intentionally let human beings suffer from a treatable, and then later a curable illness. These researchers knew that mercury and arsenic compounds could treat the disease, but the Tuskegee men did not receive the medicine. Later the researchers knew that penicillin could cure the disease, but again, the Tuskegee men did not get the medicine. They didn’t get treated until the 40 year study was discovered and stopped amid public outcry in 1972. It was a disgraceful episode for American Scientists.” Vice President Al Gore, 16th May 1997
  • 16. The Tuskegee Syphilis Study This case reaffirmed the principle that prior informed consent should be obtained from individuals before they are allowed to participate in human experimentation
  • 17. Thalidomide: 1957 - 1961 Thalidomide claimed 8000 victims in “They are all victims not merely of a forty-six countries where it was drug accident but of the dangerous prescribed by doctors and sold myth invented in Germany and across the counter under a variety of exported to a credulous world; that trade names on licence from the thalidomide was better than all other original German inventors, Chemie tranquilisers because it was non- Grunenthal. toxic and had no side effects, and was completely safe for pregnant women. None of these statements, announced by the drug companies and accepted by the doctors, was true.” The Sunday Times Insight Team, Suffer the Children: The Story of Thalidomide, 1979
  • 19. Thalidomide: UK Government Apology (Jan 2010) On the 14th January 2010 Health Minister Mike O'Brien expressed the government's "sincere regret and deep sympathy" for victims of the drug thalidomide. It comes four decades after expectant mothers suffering from morning sickness took the drug between 1958 and 1961. Thousands of their offspring suffered from physical disabilities as a result. Of them, 466 members of the UK’s Thalidomide Trust remain. The government has announced a £20 million three-year pilot scheme which will meet survivors' needs "in a more personalised way". Mr O'Brien told MPs: "The government wishes to express its sincere regret and deep sympathy for the injury and suffering endured by all those affected when expectant mothers took the drug thalidomide between 1958 and 1961. "We acknowledge both the physical hardship and the emotional difficulties that have faced both the children affected and their families as a result of this drug, and the challenges that many continue to endure, often on a daily basis." The new funding for 'thalidomiders' will prioritise looking after their health needs for the long-term. After the drug's negative side-effects were first realised the government launched a major review of the machinery for marketing, testing and regulating drugs, which resulted in the Medicines Act 1968. (Source: Thalidomide UK Website)
  • 20. Regulation of Pharmaceuticals in the EU • The first European Community pharmaceutical directive was issued in 1965 • Much of the impetus behind Directive 65/65/EEC stemmed from determination to prevent a recurrence of the thalidomide disaster in the early 1960s • This experience, which shook public health authorities and the general public, made it clear that to safeguard public health, no medicinal product must ever again be marketed without prior authorisation.
  • 21. From Human Abuse to Regulated Use Tuskegee Syphilis Nuremberg Declaration Study Code of Helsinki 1996 1932-1972 1947 1964 ICH E6 1938 - 1945 1957 -1961 Directive Clinical WWII Thalidomide 65/65/EC Trials 1965 Directives 2001 & 2005 Cause Effect (Abuse) (Regulations)
  • 22. The Regulatory Framework: Clinical Trials
  • 23. What are the ‘Applicable Regulations’?
  • 24. Regulation of Clinical Trials in Europe & UK Nuremberg Code 1947 Declaration of Helsinki 1964, 1975, 1983, 1989, 1996, 2000, 2008 Guidelines ICH E6 1996 2001/20/EC 4th April 2001 EU Directives 2003/94/EC 8th October 2003 2005/28/EC 8th April 2005 S.I. 2004/1031 1st May 2004 S.I. 2006/1928 29th August 2006 UK Law S.I. 2006/2984 12th Dec 2006 S.I. 2008/941 1st May 2008 SI 2009/1164 8th May 2009 Policies, Standards & SOPs QMS Protocol
  • 25. Regulation of Clinical Trials in Europe & UK Nuremberg Code 1947 Declaration of Helsinki 1964, 1975, 1983, 1989, 1996, 2000, 2008 Guidelines ICH E6 1996 2001/20/EC 4th April 2001 EU Directives EUDRALEX VOLUME 10 2003 2003/94/EC 8th October 2005/28/EC 8th April 2005 S.I. 2004/1031 1st May 2004 S.I. 2006/1928 29th August 2006 UK Law S.I. 2006/2984GCP WEBSITE 2006 MHRA 12th Dec S.I. 2008/941 1st May 2008 SI 2009/1164 8th May 2009 Policies, Standards & SOPs QMS Study Protocol Protocol
  • 27. So how does it all fit together?
  • 28. Overview of Clinical Trial Regs (UK) – 29th June 2010 Regulation of Clinical Trials: UK Ethics of Human Research Declaration of Helsinki (1996) GCP Guidelines ICH Efficacy (E) Series ICH E6 EU Implementing Directives Clinical Trials & GCP 2001/20/EC 2005/28/EC EU Supporting Regulations & EU Detailed Guidance Directives Interventional or Non-Interventional? UK Law Document Retention Decision Tree 2001/83/EC (as amended) The Medicines Act 1968 [Annex 1, Part I, Section 5.2.c] Competent Authority Submissions GMP ENTR/CT 1 The Medicines for Human Use 2003/94/EC (Clinical Trials) Regulations [Annex 13] 2004 2001/83/EC (as amended) IEC Submissions SI 2004/1031 ENTR/CT 2 Paediatric Studies Amendments Ethical Considerations… Safety Reporting SI 2004/3224, SI 2005/2754, 1901/2006/EC ENTR/CT 3 SI 2005/2759, SI 2006/1928, 1902/2006/EC SI 2006/2984, SI 2008/941, IMP vs Non-IMP SI 2009/1164 Data Privacy 95/46/EC TMF Content & Archiving Data Protection Act 1998 Copyright © Dr Stuart McCully, 2009-2010 All Rights Reserved
  • 29. The Clinical Trials Directive (2001/20/EC) Approximation of the laws, regulations and administrative procedures relating to the implementation of GCP in the conduct of trials – Relevant to interventional trials – Sets out principles of GCP and clinical trial definitions – Informed Consent – Ethical review/ favoural opinion and Competent Authority approval – Substantial amendments – Urgent safety measures and safety reporting – GMP: Manufacture, import, labelling & release of IMP – End of trial notification – Publication of detailed guidance documents
  • 30. The GCP Directive (2005/28/EC) Lays down principles and detailed guidance for GCP & IMP manufacture & importation as regards IMP for human use – Clarifies the principles of GCP – EC document retention – EC & CA communication – Clarifies the responsibilities of the sponsor – IB to be validated and updated annually – SPC can be used in place of IB for marketed products – Further details on the manufacture or importation of IMP – TMF & Archiving – Inspectors and Inspection procedures
  • 31. Overview of Clinical Trial Regs (UK) – 29th June 2010 Regulation of Clinical Trials: UK (Detailed) Primary Legislation The Medicines Act 1968 MARKETED PRODUCT Secondary Legislation CLINICAL TRIAL REGULATIONS REGULATIONS The Medicines for Human Use The Clinical Trials Directive The Medicines (Marketing (Clinical Trials) Regulations 2004 2001/20/EC Authorisations and Miscellaneous SI 2004/1031 Amendments) Regulations 2004 SI 2004/3224 The Medicines for Human Use The GCP Directive (Clinical Trials) Amendment 2005/28/EC Regulations 2006 The Medicines (Advisory Bodies) SI 2006/1928 (No.2) Regulations 2005 SI 2005/2754 The Medicines for Human Use (Clinical Trials) Amendment (No.2) Regulations 2006 The Medicines (Marketing SI 2006/2984 Authorisations etc) Amendment Regulations 2005 The Medicines for Human Use SI 2005/2759 (Clinical Trials) and Blood Safety and Quality (Amendment) Regulations 2008 SI 2008/941 The Medicines for Human Use (Miscellaneous Amendments) Regulations 2009 SI 2009/1164 Copyright © Dr Stuart McCully, 2009-2010 All Rights Reserved
  • 32. Overview of Clinical Trial Regs (UK) – 29th June 2010 Summary of the UK Clinical Trial Regulations SI 2004/1031 • Implements the Clinical Trials Directive (2001/20/EC) into UK law In force from 1st May 2004 • Requires Urgent Safety Measures to be notified to the Ethics Committees The Medicines for Human Use and MHRA immediately and no later than 3 days after the measures were (Clinical Trials) Regulations 2004 taken (Regulation 30) SI 2004/3224 • Amends the definition for “the European Medicines Agency” in In force from 1st January 2005 Regulation 2 of SI 2004/1031 The Medicines (Marketing Authorisations and Miscellaneous Amendments) Regulations 2004 SI 2005/2754 • Completely replaces Schedule 5 of SI 2004/1031 (Procedural Provisions In force from 30th October 2005 Relating to the Refusal or Amendment of, or Imposition of Conditions The Medicines (Advisory Bodies) Relating to, Clinical Trial Authorisations and the Suspension or Termination (No.2) Regulations 2005 of Clinical Trials) • Amends paragraphs 4 and 5 of Schedule 8 (procedural provisions relating to proposals to grant, refuse to grant, vary, suspend or revoke manufacturing authorisations) of SI 2004/1031 • Amends the definition for an “appropriate committee” in Regulation 2 of SI 2004/1031 • Amends Regulation 19(10) of SI 2004/1031 • Amends Regulation 26 of SI 2004/1031 • Amends Regulation 31 of SI 2004/1031 Copyright © Dr Stuart McCully, 2009-2010 Crown Copyright material is reproduced with the permission of the Controller of HMSO All Rights Reserved
  • 33. Overview of Clinical Trial Regs (UK) – 29th June 2010 Summary of the UK Clinical Trial Regulations SI 2005/2759 • Amends the definition for an “marketing authorisation” in Regulation 2 of In force from 20th November 2005 SI 2004/1031 The Medicines (Marketing Authorisations etc) Amendment Regulations 2005 SI 2006/1928 • Implements the GCP Directive (2005/28/EC) into UK law In force from 29th August 2006 • Introduces Regulation 29A to SI 2004/1031 and requires the sponsor to The Medicines for Human Use notify the MHRA within 7 days of any occurrence of a serious breach of (Clinical Trials) Amendment GCP or the protocol Regulations 2006 – Implements Section 5.20 of ICH E6 SI 2006/2984 • Amends Schedule 1, Part 1 of SI 2004/1031 to allow incapacitated adults In force from 12th December 2006 into a clinical trial without the prior consent of their legal representative The Medicines for Human Use assuming certain conditions are met (Clinical Trials) Amendment – Implements Section 4.8.15 of ICH E6 (No.2) Regulations 2006 Copyright © Dr Stuart McCully, 2009-2010 Crown Copyright material is reproduced with the permission of the Controller of HMSO All Rights Reserved
  • 34. Overview of Clinical Trial Regs (UK) – 29th June 2010 Summary of the UK Clinical Trial Regulations SI 2008/941 • Amends Schedule 1, Part 1 of SI 2004/1031 to allow minors into a clinical In Force from 1st May 2008 trial without the prior consent of their legal representative assuming The Medicines for Human Use certain conditions are met (Clinical Trials) and Blood Safety – Implements Section 4.8.15 of ICH E6 and Quality (Amendment) • Amends Regulation 15 of SI 2004/1031 to allow the Gene Therapy Regulations 2008 Advisory Committee (GTAC) to notify UKECA that its advice is not required for routine gene therapy trials and allows such applications to be transferred to another EC for an opinion • Amends Regulation 15 and Schedules 2 & 3 of SI 2004/1031 to modify the procedures for operation of ECs to widen the available expertise, reduce administrative burden and rationalise the documents an applicant must submit for an opinion • Amends the definition for of “the Directive”, “Directive 2001/83/EC” and “the Gene Therapy Advisory Committee” in Regulation 2 of SI 2004/1031 SI 2009/1164 • Amends Regulation 30 of SI 2004/1031 to allow Urgent Safety Measures In force from 8th May 2009 to be notified to the Ethics Committees and MHRA ‘as soon as possible’ The Medicines for Human Use rather than the usual restrictive 3 days during any period when a disease is (Miscellaneous Amendments) pandemic and is a serious risk, or potentially a serious risk, to human Regulations 2009 health Copyright © Dr Stuart McCully, 2009-2010 Crown Copyright material is reproduced with the permission of the Controller of HMSO All Rights Reserved
  • 35. What do we follow? ICH E6?
  • 36. Overview of Clinical Trial Regs (UK) – 7th September 2009 So what do we follow? “The Investigator and The Medicines for Human Use Sponsor shall consider all (Clinical Trials) Regulations UK Law 2004 relevant guidance with SI 2004/1031 respect to commencing and conducting a clinical trial” [Schedule 1, Part 2.8 of SI 2004/1031 (as amended by SI 2006/1928)] EU Implementing Clinical Trials & GCP 2001/20/EC Directives 2005/28/EC Detailed Guidance Documents Eudralex Volume 10 ICH GCP Guidelines Global GCP Guidelines ICH E6 Ethics of Human Research Bioethical Principles Declaration of Helsinki (1996) Copyright © Dr Stuart McCully, 2009 All Rights Reserved
  • 38. Updates to the UK Clinical Trial Regulations: 2006 - 2010 Date Details Source 29th Aug 2006 • Implement GCP Directive SI 2006/1928 • Introduce ‘Serious Breaches’ The Medicines for Human Use (Clinical Trials) Amendment Regulations 2006 12th Dec 2006 • Allows incapacitated adults into a clinical SI 2006/2984 trial without the prior consent of their legal The Medicines for Human Use representative assuming certain conditions (Clinical Trials) Amendment (No.2) are met Regulations 2006 1st May 2008 • Allows minors into a clinical trial without SI 2008/941 the prior consent of their legal The Medicines for Human Use representative assuming certain conditions (Clinical Trials) and Blood Safety are met and Quality (Amendment) Regulations 2008 8th May 2009 • Allows Urgent Safety Measures to be SI 2009/1164 notified to the Ethics Committees and MHRA The Medicines for Human Use ‘as soon as possible’ rather than the usual (Miscellaneous Amendments) restrictive 3 days during any period when a Regulations 2009 disease is pandemic and is a serious risk, or potentially a serious risk, to human health
  • 39. Updates to the European Clinical Trial Guidelines: 2009 - 2010 Date Guideline Details 3rd Dec 2009 QUESTIONS &ANSWERS • New Document SPECIFIC TO ADVERSE • Supplement to ENTR/CT 3 REACTION REPORTING IN CLINICAL TRIALS 31st Jan 2010 Annex 13 • Revision to reinforce the principle of independence between (Deadline for coming in to production and quality control functions in cases where the number operation is 31st July 2010) Annex 13 to the Guidelines on of personnel involved is small. good manufacturing practice • Changes to sections 36 and 37 to supplement, for IMPs, the — Manufacture of guidance for reference and retention samples given in Annex 19. investigational medicinal • Clarified the meaning of “reconstitution” as referred to in article products 9.2 of Directive 2005/28/EC. • The content of the Batch Certificate referred to in Art. 13(3) of Directive 2001/20/EC has been added. March 2010 ENTR/CT 1 • Updated to provide more comprehensive guidance on: o Substantial vs Non-substantial Amendments Detailed guidance on the o Urgent t safety Measures request to the competent o Non-Compliance with the Protocol authorities for authorisation of a clinical trial on a medicinal product for human use, the notification of substantial amendments and the declaration of the end of the trial (CT-1)
  • 40. Updates to the European Clinical Trial Guidelines: 2009 - 2010 Date Guideline Details 1st Jun 2010 Eudralex Volume 10: • New Q&A added: Questions and Answers • Question 2.5: Can a sponsor established in a third country (Version 6) open a subsidiary or branch in a Member State in order to comply with the requirement of Directive 2001/20/EC that the sponsor or a legal representative of the sponsor must be established in the EU?
  • 42. Useful Resources • GCP Regulatory Maps • GCP Considerations - Informed Consent in Clinical Trials • GCP Considerations - Contraception in Clinical Trials • GCP Considerations - The Investigator's Brochure • GCP Considerations - Useful Links
  • 43. GCP Considerations: • Informed Consent • Monitoring • Protocol Compliance • IMP • CRFs • ISF • Filing & Archiving
  • 44. ICH E6 1. Glossary 2. The Principles of GCP 3. Ethics Committees 4. Investigator 5. Sponsor 6. Clinical Trial Protocol & Amendments 7. Investigator’s Brochure 8. Essential Documents for the Conduct of a Clinical Trial
  • 45. ICH E6 ‘Exclusives’ 1. Glossary 2. The Principles of GCP 3. Ethics Committees 4. Investigator  Informed Consent 5. Sponsor  Monitoring 6. Clinical Trial Protocol & Amendments 7. Investigator’s Brochure 8. Essential Documents for the Conduct of a Clinical Trial  TMF
  • 46. GCP Considerations: • Informed Consent
  • 47. The Regulatory Framework: Informed Consent
  • 48. Informed Consent Regulations & Guidance: EU & UK Regulation/ Reference Applicability Detail Guideline ICH E6 Section 4.8 ‘Global’ Set out the principles and details of informed consent Provides guidance on the principles and details of informed ICH E11 Section 2.6.3 ‘Global’ consent/ assent for trials in minors/ paeds 2001/20/EC Article 2(j) EU Defines Informed Consent 2001/20/EC Articles 3 - 5 EU Set out the principles of informed consent Ethical Provides detailed guidance on the consent/ assent EU Considerations considerations for trials in minors
  • 49. Informed Consent Regulations & Guidance: EU & UK Regulation/ Reference Applicability Detail Guideline SI 2004/1031 Schedule 1, Set out the conditions and principles in relation to informed UK (as amended)* Parts 3 – 5 consent SI 2006/2984 Amends Schedule 1, Part 1 of SI 2004/1031 to allow incapacitated adults into a clinical trial without the prior UK consent of their legal representative assuming certain conditions are met – Implements Section 4.8.15 of ICH E6 SI 2008/941 Amends Schedule 1, Part 1 of SI 2004/1031 to allow minors into a clinical trial without the prior consent of their legal UK representative assuming certain conditions are met – Implements Section 4.8.15 of ICH E6 NRES Guidance on UK Provides guidance and templates for PILs and ICFs PILs & ICFs * As amended by SI 2004/3224, SI 2005/2754, SI 2005/2759, SI 2006/1928, SI 2006/2984, SI 2008/941, and SI 2009/1164
  • 50. Let’s Shed Some Light on Informed Consent...
  • 51. Informed Consent Content: The Basic Building Blocks
  • 52. Informed Consent Content: The Basic Building Blocks ICH E6 Basic Considerations 4.8.6 Wording 4.8.10 (a) (f) Research Notion 4.8.10 (b) (h) Goals of the Trial 4.8.10 (c) Design of the Trial 4.8.10 (h) Expected Therapeutic Benefits 4.8.10 (i) Alternative Treatments 4.8.10 (m) Voluntary Nature of the Participation 4.8.10 (m) Withdraw from the Trial without Prejudice 4.8.10 (q) Contact Point 4.8.10 (p) Informed of New Data that May Influence Decision to Participate 4.8.10 (r) Stopping the Trial 4.8.10 (e) Subject’s Responsibilities 4.8.10 (s) Length of Study
  • 53. Informed Consent Content: The Basic Building Blocks ICH E6 Basic Considerations 4.8.10 (t) Recruitment 4.8.10 (d) Invasive Procedures 4.8.10 (g) Foreseeable Risks 4.8.10 (j) Compensation and/or treatment available in the event of a trial-related injury 4.8.10 (j) Third Party Liability 4.8.10 (l) Payment and Costs 4.8.10 (k) Remuneration 4.8.10 (o) Data Confidentiality 4.8.10 (n) Access to Records
  • 54. Informed Consent Content: The Basic Building Blocks ICH E6 Additional Considerations 4.8.15 Emergency Situations 4.8.12-15 Enrolment of ‘legally incompetent’ subjects – Minors – Incapacitated Adults
  • 55. Informed Consent : Additional Considerations • Paediatric Trials • Vulnerable Groups • Data Protection • Genetic Trials • Biological Samples • Future use/re-use of Information • Language of Consent • Medical Device Investigations • Non-Interventional Studies
  • 56. Useful Resources Informed Consent: Pages 43 - 55 • Definitions • General Considerations • NRES Guidance on PILs & ICFs • The Participants Perspective • Minors • Incapacitated Adults • MHRA GCP Inspection Findings
  • 57. Useful Resources Contents: • Definitions • Recent History – Nazi War Experiments – The Tuskegee syphilis study – The Thalidomide Tragedy – From Human Abuse to Regulated Use – Informed Consent - Regulatory Framework – Informed Consent - Regulatory Framework in Europe and the UK – Informed Consent – General Considerations • Informed Consent: UK – Regulatory Overview – Regulatory Bodies – Country-Specific Informed Consent Considerations – Informed Consent – Detailed Considerations – Informed Consent Guidance and Templates – Applicable Legislation – MHRA GCP Inspection Findings – Useful Links
  • 58. Informed Consent... ...Adequately informed and consent freely given
  • 59. Informed Consent • Before informed consent may be obtained, the Investigator should provide the subject with ample time and opportunity to inquire about details of the trial • The Investigator should fully inform the subject of all pertinent aspects of the trial including the written information and the approval/favourable opinion by the EC and MHRA – Must ensure that only the current approved version of the informed consent information/documentation is used ICH E6, Section 4.8
  • 60. Informed Consent • The subject should receive a copy of the signed and dated informed consent form and any other written information provided to subjects – This includes any subsequent amendments to the form and/or information ICH E6, Section 4.8
  • 61. GCP Considerations: • Monitoring
  • 62. Monitoring ‘This study will be monitored according to the currently approved protocol, GCP, and with the applicable regulatory requirements’ What Type of Study are What are the Applicable you Monitoring? Regulations?
  • 63. What Type of Study are you Monitoring? Clinical Trials Food Supplement Studies Non-Interventional Studies
  • 64. GCP Considerations: • Protocol Compliance • Serious Breach • Urgent Safety Measures
  • 65. Food for Thought: Protocol Compliance, Serious Breaches and Emergency measures • The Investigator should conduct the trial in compliance with the approved protocol – The Investigator should sign the protocol to confirm agreement • The Investigator should not implement any deviations from, or changes to, the protocol without agreement by the Sponsor and prior approval from the REC/MHRA – Unless to eliminate an immediate hazard to trial subjects (Urgent Safety Measure) – The Sponsor must notify the MHRA within 3 days of the USM being taken or, – ‘as soon as possible’ rather than the usual restrictive 3 days during any period when a disease is pandemic and is a serious risk, or potentially a serious risk, to human health • As per Regulation 30 of SI 2004/1031 (as amended by SI 2009/1164) ICH E6, Section 4.5
  • 66. Protocol Compliance, Serious Breaches and Emergency measures • The Investigator should document and explain any [retrospective] deviation from the approved protocol – IMPORTANT: Protocol waivers are not allowed • MHRA: GCP Frequently asked questions • EMEA: GCP Questions and Answers – Refer to Regulation 29 of SI 2004/1031 ICH E6, Section 4.5
  • 67. Food for Thought: Protocol Compliance, Serious Breaches and Emergency measures Persistent or systematic non-compliance with GCP or the protocol that has a significant impact on the integrity of trial subjects in the UK or on the scientific value of the trial • For example, widespread and uncontrolled use of protocol waivers affecting eligibility criteria, which leads to harm to trial subjects in the UK or which has a significant impact on the scientific value of the trial. Another example would be of an investigator repeatedly failing to reduce or stop the dose of an IMP in response to a trigger (e.g. abnormal laboratory results) defined in the protocol. MHRA Guidance for the notification of serious breaches of GCP or the trial protocol
  • 68. Protocol Waivers Q1. Can a sponsor prospectively approve deviations (so-called “protocol waivers”) from the inclusion/exclusion criteria of the approved protocol without additional approval of the Ethics Committee and competent regulatory authority? A1. Adherence to the protocol is a fundamental part of the conduct of a clinical study. Any significant change to the protocol should be submitted as an amendment to the competent regulatory authority and Ethics Committee. Significant changes to the protocol include any change in inclusion and exclusion criteria, addition or deletion of tests, dosing, duration of treatment etc (see the definition of a substantial amendment in the 'Detailed guidance for the request for authorisation of a clinical trial on a medicinal product for human use to the competent authorities, notification of substantial amendments and declaration of the end of the trial' published by the European Commission in Chapter I, Volume 10 of The Rules Governing Medicinal Products in the European Community). Deviations from the inclusion / exclusion criteria of the protocol might erode the scientific and ethical value of the protocol and its authorisation and might have an impact on the processes put in place for the care and safety of the study subjects. Sponsors and investigators should not use systems of prospectively approving protocol deviations, in order to effectively widen the scope of a protocol. Protocol design should be appropriate to the populations required and if the protocol design is defective, the protocol should be amended. The GCP does permit deviations from the protocol when necessary to eliminate immediate hazards to the subjects but this should not normally arise in the context of inclusion/exclusion criteria, since the subject is not yet fully included in the trial at that point in the process GCP inspectors have observed a number of sponsors implementing systems where the investigator can contact the sponsor, usually the Medical Monitor, and request a prospective approval to deviate from the inclusion and/or exclusion criteria. The use of such systematic waiver systems in clinical trials is not considered to be appropriate and studies using such a system might be regarded as non-compliant with GCP. EMA: GCP Questions and Answers
  • 69. GCP Considerations: • IMP • CRFs
  • 70. Investigational Medicinal Product (IMP) • Responsibility for IMP accountability at the trial site rests with the Investigator – IMP accountability logs must be maintained • Usually provided by the Sponsor and checked by the CRA at the monitoring visit – IMP must be stored and used as specific in the protocol • The Investigator may assign some/all of the IMP duties to a Pharmacist or other appropriate individual – In the UK IMP responsibility should really lie with the Pharmacist who should be abiding by the Royal Pharmaceutical Society Practice Guidance on Pharmacy Services for Clinical Trials (2005) ICH E6, Section 4.6
  • 71. Randomisation & Unblinding • The Investigator should follow the trial’s randomisation procedure, if any, and should ensure the code is broken only in accordance with the protocol – Details, processes and relevant documents will be documented in the protocol and/or provided by the Sponsor • If the trial is blinded, the Investigator should promptly document and explain to the Sponsor any premature unblinding of the IMP – As per the protocol and/or Sponsor’s instructions ICH E6, Section 4.7
  • 72. Case Report Forms (CRFs) • The Investigator should ensure the accuracy, completeness, legibility, and timeliness of the data reported in the CRFs and all required reports • Data reported on the CRF that are derived from source documents, should be consistent with the source documents or the discrepancies should be explained • Any change or correction to a CRF should be dated, initialled, and explained (if necessary) and should not obscure the original entry (i.e., an audit trail is maintained) – Sponsors should provide guidance on making such corrections ICH E6, Section 4.8
  • 73. Correcting CRFs – A Simple Guide • Complete the case report form (CRF) fully and legibly. Data entered Age (yrs) 2 5  should be accurate • Avoid missing out any data Age (yrs)  • Date and initial all changes that you make Age (yrs) 2 5 4  • Make sure that any changes you make are clear • Do not obliterate the previous entry Age (yrs) 2 5  • Do not use Tipex
  • 74. GCP Considerations: • ISF • Filing • Archiving
  • 75. The Investigator Site File (ISF) • Essential documents are those documents which individually and collectively permit evaluation of the conduct of a trial and the quality of the data produced • Serve to demonstrate the compliance of the investigator, sponsor and monitor with GCP and the applicable regulations – Hence the focus on these documents during monitoring, audits and inspections • The minimum list is captured in Section 8 of ICH E6 • TMFs should be established at the beginning of a trial at the investigator and sponsor sites • A final close-out visit can only be done when the monitor has reviewed the investigator and sponsor files and confirmed that all necessary documents are in the appropriate files ICH E6, Section 8
  • 76. The Investigator Site File (ISF) • The Investigator should maintain trial documents as specified in Section 8 of ICH E6 and as per the applicable regulatory requirements – The filing requirements for essential documents at the trial site(s) are generally listed by the trial Sponsor in an Investigator Site File (ISF) index or equivalent – Information should be documented and filed as it becomes available (ICH E6, Section 8.3) • The Investigator/Institution should take measures to prevent accidental or premature destruction of these documents • Upon request of the CRA, auditor, REC or MHRA, the Investigator should make available for direct access all requested trial-related records ICH E6, Section 4.9
  • 77. Archiving Requirements • Documents to be retained for – 5 years if not part of a marketing authorisation package • Article 17 of 2005/28/EC – 15 years if part of a marketing authorisation package • Section 5.2.c of Annex I of 2001/83/EC (as amended)
  • 78. Archiving Requirements Marketing authorisation holders must arrange for essential clinical trial documents (including case report forms) other than subject's medical files, to be kept by the owners of the data: • for at least 15 years after completion or discontinuation of the trial, • or for at least two years after the granting of the last marketing authorisation in the European Community and when there are no pending or contemplated marketing applications in the European Community, • or for at least two years after formal discontinuation of clinical development of the investigational product. Subject's medical files should be retained in accordance with applicable legislation and in accordance with the maximum period of time permitted by the hospital, institution or private practice. The sponsor or other owner of the data shall retain all other documentation pertaining to the trial as long as the product is authorised. Section 5.2.c of Annex I of 2001/83/EC (as amended)
  • 79. In general this means... ...that all trial documents need to be retained by the Investigator until otherwise notified by the Sponsor
  • 80. The Changing Face of Clinical Research... “In times of change, learners inherit the Earth, while the learned find themselves beautifully equipped to deal with a world that no longer exists.” Eric Hoffer (American social writer and philosopher)
  • 82. Contact Information Email: stuart.mccully@chcuk.co.uk Phone: +44 (0) 1997 42 33 11 Mobile: +44 (0) 7909 111 510 Website: www.chcuk.co.uk