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2011 01 16 NIS Training (Chcuk Generic)
 

2011 01 16 NIS Training (Chcuk Generic)

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Generic Non-Interventional Study (NIS) Training slides with a UK focus

Generic Non-Interventional Study (NIS) Training slides with a UK focus

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    2011 01 16 NIS Training (Chcuk Generic) 2011 01 16 NIS Training (Chcuk Generic) Presentation Transcript

    • NON-INTERVENTIONAL STUDIES? What are they? How do they differ from Clinical Trials? Stuart McCully, PhD 16th January 2011
    • 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. Introduction: A Snapshot of Key Events a. The Nazi Medical Experiments b. The Nuremberg Code and the Declaration of Helsinki c. The Tuskegee Syphilis (Observational) Study d. Ethical Principles in Biomedical Research 2. Clinical Research: Clinical Trials vs NIS a. Research or Audit/Service Evaluation? b. Research: Interventional or Non-Interventional? c. What is a Clinical Trial? d. The Regulatory Framework: Clinical Trials e. The Regulatory Framework: NIS f. What is a Non-Interventional Study? g. Country-Specific Regulation of NIS: UK h. How and Why are they Different? i. “GCP-lite” j. Ethical Principles in NIS k. The Principle of Observation
    • Feel Free to Ask Questions...
    • Introduction: A Snapshot of Key Events • Nazi Medical Experiments • Nuremberg Code • Declaration of Helsinki • The Tuskegee Syphilis Study • Ethical Principles
    • 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 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 (Observational) Study
    • The Tuskegee Syphilis (Observational) 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 (Observational) 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 (Observational) 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 (Observational) Study This case reaffirmed the principle that prior informed consent should be obtained from individuals before they are allowed to participate in human experimentation
    • Ethical Principles in Biomedical Research • Protect the rights, safety and well-being of human subjects • Independent ethical review • Informed consent • Balance the benefits, harms and risks of study participation • Safeguard confidentiality • Ensure scientific credibility
    • Clinical Research: Clinical Trial vs NIS
    • Research or Audit/Service Evaluation? • NRES reviews research proposals to protect the rights and safety of research participants and enables ethical research which is of potential benefit to science and society • Patients expect HCPs to undertake audit and service evaluation as part of quality assurance. These involve minimal additional risk, burden or intrusion for participants and are regulated outside of NRES. • Research may involve greater risk, burden or intrusion for participants than standard clinical practice. – Research requires review by a REC – Research Governance Framework for Health and Social Care Source: NRES Leaflet – Defining Research
    • Research or Audit/Service Evaluation? Research or Audit? Audit • Outside scope of NRES • Requires REC Review Research • Requires R&D Approval Interventional or Interventional • Requires MHRA Approval Non-Interventional? (i.e., Clinical Trial) Non-Interventional • Does Not Require MHRA (e.g., Observational study) Approval
    • Research: Interventional or Non-Interventional? Research or Audit? Audit • Outside scope of NRES • Requires REC Review Research • Requires R&D Approval Interventional or Interventional • Requires MHRA Approval Non-Interventional? (i.e., Clinical Trial) Non-Interventional • Does Not Require MHRA (e.g., Observational study) Approval
    • What is a Clinical Trial? “Clinical trial” means any investigation in human subjects, other than a non- interventional trial, intended: a) To discover or verify the clinical, pharmacological or other pharmacodynamic effects of one or more medicinal products, b) To identify any adverse reactions to one or more such products, or c) To study absorption, distribution, metabolism and excretion of one or more such products, With the object of ascertaining the safety or efficacy of these products (As per Regulation 2(1) of SI 2004/1031 (as amended))
    • The Regulatory Framework: Clinical Trials
    • 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)
    • Good Clinical Practice: 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
    • Overview of Clinical Trial Regs (UK) – 31st August 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, SI 2010/1882 Data Privacy 95/46/EC TMF Content & Archiving Data Protection Act 1998 Copyright © Dr Stuart McCully, 2009-2010 All Rights Reserved
    • Overview of Clinical Trial Regs (UK) – 7th September 2009 Clinical Research: How is it Regulated? Ethics of Human Research Bioethical Principles Declaration of Helsinki (1996) ICH GCP Guidelines Global GCP Guidelines ICH E6 EU Implementing Clinical Trials Directive GCP Directive Directives 2001/20/EC 2005/28/EC The Medicines for Human Use The Medicines for Human Use (Clinical Trials) Regulations (Clinical Trials) Amendments UK Law 2004 Regulations 2006 SI 2004/1031 SI 2006/1928 Copyright © Dr Stuart McCully, 2009 All Rights Reserved
    • Overview of Clinical Trial Regs (UK) – 7th September 2009 Clinical Research: How is it Regulated? Ethics of Human Research Bioethical Principles Declaration of Helsinki (1996) ICH GCP Guidelines Global GCP Guidelines ICH E6 Detailed Guidance Documents Eudralex Volume 10 Clinical Trials & GCP EU Implementing 2001/20/EC Directives “The Investigator and 2005/28/EC Sponsor shall consider all relevant guidance with respect to commencing and The Medicines for Human Use conducting a clinical trial” (Clinical Trials) Regulations UK Law 2004 (as amended) [Schedule 1, Part 2.8 of SI 2004/1031 (as amended by SI 2006/1928)] SI 2004/1031 Copyright © Dr Stuart McCully, 2009 All Rights Reserved
    • Country-Specific Regulation of NIS: UK Article 1.1 of the Clinical Trials Directive (2001/20/EC) which is implemented into UK law by SI 2004/1031 states that “this Directive does not apply to non- interventional trials”.
    • How and Why are they Different? “The purpose for excluding these [NIS] trials from the scope of the Directive 2001/20/EC is that these trials are typically of a lower risk than interventional clinical trials. Moreover, this restriction shall ensure that medical activities which are normal clinical practice and as such part of the general medical surveillance of a patient are excluded from the scope of the Directive 2001/20/EC.” (Source: Eudralex Volume 10 - Questions and Answers, Version 7.0, September 2010)
    • The Regulatory Framework: NIS
    • What is a Non-interventional Study? “non-interventional trial” means a study of one or more medicinal products which have a marketing authorisation, where the following conditions are met: a) The products are prescribed in the usual manner in accordance with the terms of that authorisation b) The assignment of any patient involved in the study to a particular therapeutic strategy is not decided in advance by a protocol but falls within current practice, c) The decision to prescribe a particular medicinal product is clearly separated from the decision to include the patient in the study (As per Regulation 2(1) of SI 2004/1031 (as amended))
    • What is a Non-interventional Study? “non-interventional trial” means a study of one or more medicinal products which have a marketing authorisation, where the following conditions are met: d) No diagnostic or monitoring procedures are applied to the patients included in the study, other than those which are ordinarily applied in the course of the particular therapeutic strategy in question, and e) Epidemiological methods are to be used for the analysis of the data arising from the study (As per Regulation 2(1) of SI 2004/1031 (as amended))
    • What is a Non-interventional Study? Source: ICH E2E – Pharmacovigilance Planning (2004)
    • The Regulatory Framework: NIS The regulatory requirements for non- interventional studies differ from clinical trials. As a minimum: • Highest standards of professional conduct and confidentiality must be maintained – Source: Eudralex Volume 9A, Part I, Section 7.7 With regards to conduct: • In observational studies, the investigator “observes and evaluates results of ongoing medical care without 'controlling' the therapy beyond normal medical practice.” – Source: ICH E2E, Section 3.2.1
    • Country-Specific Regulation of NIS: UK Applicable Legislation: Non-interventional studies (NIS) are controlled by a combination of legislation and codes of practice in the UK. • REC Approval Fundamental Ethical Principles: • Protocol • Protect rights, safety and well- • Informed Consent Declaration of being of patients NRES • Annual Progress Reports Helsinki/ ICH E6 • Independent Ethical Review • Substantial Amendments • Informed Consent • SAE Reporting • Protocol • End of Trial Notification • Scientific Credibility • Final Study Report SI 2004/1031 • Legal definition of “NIS” (as amended) • MHRA Approval Not Required • Ethical Considerations Eudralex Volume 9A • Data Confidentiality (IPSE GPP/ ICH • Professional Conduct E2E) • Safety Reporting in NIS • Protocol SI 1994/3144 • Final Report (as amended) • Safety Reporting Requirements ABPI COP • Essential Criteria for Industry- (Industry Code) Sponsored NIS Research Governance Framework for • REC Approval Required Health and Social • R&D Approval Required Care
    • Overview of NIS Regs (EU) – 8th Oct 2010 Regulation of Non-Interventional Studies: UK Ethics of Human Research Declaration of Helsinki (1996) ICH Guidelines ICH E2E ICH E6 EU Supporting Regulations & International Supporting Guidance European Directives Directives Non-Interventional Study or Clinical Trial? Medicinal Products Eudralex Volume 10 - Decision Tree Document Retention EC/726/2004 (as amended) 2001/83/EC (as amended) 2001/83/EC (as amended) IPSE Guidelines [Annex 1, Part I, Section 5.2.c] • Good Pharmacoepidemiology Practices • Data Privacy Data Privacy UK Law & Guidance • GRACE Principles (Endorsed by IPSE) 95/46/EC CIOMS International Ethical Guidelines Data Protection Act 1998 for Epidemiological Studies 2009 The Medicines for Human Use The Medicines for Human Use (Marketing Authorisations General Considerations for Post- (Clinical Trials) Regulations etc) Regulations 1994 (as Authorisation Studies and Post- 2004 (as amended) amended) Authorisation safety Studies SI 2004/1031 SI 1994/3144 Eudralex Volume 9a [Chapter I.7] • Safety Reporting • Protocol and Report Guidance MHRA Website • Competent Authority Notification • Ethical Considerations • Promotion of Medicinal Products NRES SOPs • Participation of Healthcare Professionals • Procedures for Complaints NHS Research Governance Framework(s) EFPIA Code of Practice October 2007 ABPI Code of Practice (2008) Copyright © Dr Stuart McCully, 2009 - 2010 All Rights Reserved
    • Industry Guidance: ABPI Code of Practice (2008)
    • Overview of NIS Regs (EU) – 29th June 2010 ABPI Code of Practice (2008): Non-Interventional Studies of Marketed Products According to Clause 13 of the ABPI Code of Practice (2008), non-interventional studies (NIS) that are prospective in nature and involve the collection of patient data must comply with all of the following criteria: 1. The study is conducted for a scientific purpose 2. There is a written protocol 3. There are written contracts between the Study Sponsor and Healthcare Professionals and/or Institutions 4. Any remuneration provided must be reasonable and reflect fair market value 5. The study protocol should be submitted for review in those countries where the Ethics Committees are prepared to review the document 6. Data protection legislation must be complied with 7. The Company’s Scientific Service must approve the protocol and must supervise the conduct of the study 8. The study results must be analysed and summaries be made available within a reasonable period of time to the Company’s Scientific Service and the Healthcare Professionals who participated in the study 9. If the study shows results that are important for the assessment of benefit-risk profile of the medicinal product, the summary report should be immediately forwarded to the relevant Competent Authority 10. Sales Representatives may only be involved in an administrative capacity and such involvement must be under the supervision of the Company’s Scientific Service Also: • Companies are encouraged to publicly disclose the summary details and results of non-interventional studies in a manner consistent with the parallel obligations for clinical trials • Companies are encouraged to apply the same requirements (to the extent applicable) to all other types of studies including epidemiological studies, registries and other studies that are retrospective in nature Copyright © Dr Stuart McCully, 2009 - 2010 All Rights Reserved
    • How and Why are they Different? Pre-Authorisation Higher Risk Clinical Trials Post-Approval Marketing Sponsor Driven Commitment (PAC) Authorisation Post-Authorisation Post-Authorisation Studies Non-Interventional Studies Post-Approval Sponsor Driven Commitment (PAC) Lower Risk Risk Management Post-Approval Safety Post-Approval Study Plan (RMP) Study (PASS) (PAS)
    • How and Why are they Different? Clinical Trial Non-Interventional Study • Ethical principles (DoH/GCP) • Ethical principles (DoH/GCP) – Ethical review – Ethical review • Novel/ “unknown” drug • Known/ Authorised drug • Higher risk to subject • Lower risk • Interventional • Non-interventional • Clinical practice driven by • Routine clinical practice – not protocol driven by protocol • Harmonised GCP Framework and • No harmonised legal framework regulations to ensure safety of (currently) due to lower risk to subject and scientific credibility subject however greater focus on • Strictly regulated due to higher data protection and scientific risk credibility – Routine monitoring, audits and • Less strictly regulated inspections – Routine audits
    • Good Clinical Practice: 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
    • “GCP-lite” • No IMP • SmPC rather than IB • Simplified Protocol • Simplified Informed Consent • Ethics Review • No Competent Authority Approval (e.g., MHRA or IMB) • Simplified TMF/ISF • Simplified CRF • Reduced Monitoring
    • Ethical Principles in Non-Interventional Studies For non-interventional post-authorisation safety studies, the Marketing Authorisation Holders and Investigators should follow relevant national legislation in those Member States where this exists, in addition to the guidance given here. The highest possible standards of professional conduct and confidentiality must always be maintained and legislation on data protection followed (see Directive 95/46/EC). The Patient’s right to confidentiality is paramount. The Patient’s personal identifiers should be replaced by a code in the study documents, and only authorised persons should have access to identifiable personal details if data verification procedures demand inspection of such details. Responsibility for the retrieval of information from personal medical records lies with the Healthcare Professional(s) responsible for the patient’s care. Such information from medical records should be provided to the Marketing Holder, who is thereafter responsible for the handling of such information. It is recommended that non-interventional post-authorisation safety studies are referred to an Ethics Committee. Studies conducted entirely using records not containing any personal identifiers e.g. anonymised records) may not require an ethical review of individual study protocols. National guidelines in this respect should be followed where they exist. According to European data protection legislation, explicit consent is required when the study plans to collect data containing personal identifiers, though some exceptions are envisaged. (Source: Eudralex Volume 9A, Part I, Section 7.7)
    • The Principle of Observation Observational Study: • Non-experimental study* • Epidemiological study that does not involve intervention* • Observe ‘real-life’ scenarios – E.g., a record of outcomes in routine clinical practice • Supplement existing data on authorised drugs or existing conditions * CIOMS International Ethical Guidelines for Epidemiological Studies, 2009 (ISBN 92-9036-081-X)