European Communities (Clinical Trials on Medicinal Products for Human Use) Regulation s 2004 S.I No. 190 of 2004 What do Participants Need to Know Prof David Smith

Why Research?

Why Research in Healthcare? Research is essential to the successful promotion and protection of health and wellbeing and to a modern effective health and social care system. It also contributes to the efficiency and effectiveness of the content, planning, delivery and monitoring of health and social care. It plays an important role in the knowledge economy, contributing to Ireland’s international competitiveness, research and development investment from the pharmaceutical, biotechnology and medical devices industries and economic growth. Part of Government’s Strategic Plan

Governance of Clinical Trials The EU Clinical Trials Directive (2001/20/EC) was transposed into Irish law through the Clinical Trials on Medicinal Products for Human Use Regulations 2004, (S.I.190 of 2004). The Minister for Health in Ireland currently acts as the supervisory body in respect of recognised RECs. Ethics committee approval is an integral part of the regulation of clinical trials. Approval is also required from the competent authority in Ireland -- Health Products Regulatory Authority (HPRA) has a statutory role to ensure compliance with Clinical Trials legislation.

Governance of Clinical Trials REGULATIONS REGULATION (EU) No 536/2014 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 16 April 2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC

History of Ethical Review (RECs) The 1975 amended version of the Declaration of Helsinki referred to the basic principle that the protocol of a proposed research project should be submitted to an independent body for “consideration, comment, and guidance” Clinical Trial Directive instructed Member States to take the measures necessary for establishment and operation of Ethics Committees … (Article 6). Clinical Trials Regulation (EU) No 536/2014 “The ethical review shall be performed by an ethics committee in accordance with the law of the Member State concerned”. (Article 4)

Declaration of Helsinki The Declaration of Helsinki of the WMA. A set of ethical principles regarding human experimentation. It is not a legally binding instrument in international law, but has influenced national, regional legislation and regulation. Fundamental Principles include: –Respect for the individual –Right to self determination -- choice about participating –The right to make informed decisions regarding participation in research, both initially and during the course of the research –Safeguarding research subjects –Minimising risk –Adhering to an approved research plan/protocol.

International Codes/Guidelines Nuremburg Code1947 Helsinki Declaration 1964/200 8 /2013 Belmont Report1979 CIOMS (currently under revision) 1982, 2002 The European Convention on Human Rights and Biomedicine Additional Protocol concerning Biomedical Research Universal Declaration on Bioethics and Human Rights2005

Clinical Trials Defined

A Clinical Trial is defined as ‘any investigation in human subjects, other than a non-interventional clinical trial, intended: a.to discover or verify the clinical, pharmacological or other pharmacodynamic effects of one or more investigational medicinal products, or b.to identify any adverse reactions to one or more such investigational medicinal products, or c.to study absorption, distribution, metabolism and excretion of one or more such investigational medicinal products, or d.to discover, verify, identify or study any combination of the matters above with the object of generating data on the safety and/or efficacy of a medicinal product’.

EU (Clinical Trials on Medicinal Products for Human Use) Regulations, 2004: The following are dealt with in the European Communities (Clinical Trials on Medicinal Products for Human Use) Regulations, 2004: Procedures for obtaining a favourable ethics committee opinion (a single ethics committee opinion is required in the case of multi-centre trials) Procedures for obtaining authorisations for the conduct of clinical trials from the Health Products and Regulatory Authority (HPRA) Controls that are to apply to the manufacture, supply and importation of investigational medicinal products Obligations for the reporting of various adverse events encountered in subjects participating in clinical trials, including the recording, reporting and notifying of such events

EU (Clinical Trials on Medicinal Products for Human Use) Regulations, 2004(3): Obligations for compliance with standards of good clinical practice (GCP) and good manufacturing practice (GMP).

NEW REGULATIONS REGULATION (EU) No 536/2014 Single electronic submission through the EU portal, both for national and multinational studies. All communication between sponsor and reporting member state (MS) as well as between all stakeholders (sponsor, drug authority, ethics committee) via EU portal only. One national contact point per MS to facilitate the authorisation procedure.

REGULATIONS REGULATION (EU) No 536/2014 Part I: Trial protocol, scientific background, risk (harm) – benefit assessment, IB, details specified in Article 6 and Annex I Part II: Informed Consent material, qualification of investigators and suitability of study sites (centres) etc., details specified in Article 7 and Annex I Part I: Evaluated by all MS concerned, reporting MS coordinates the assessment and provides ‘single decision’ Part II: Evaluated by all MS concerned, each MS provides its decision

Protection of Subjects - General Rules - Following conditions have to be met: The anticipated benefits for the subject or public health justify the foreseeable risks and inconveniences, and the compliance with this condition is permanently monitored. The rights of the subject in physical and mental integrity, to privacy and to protection of the data are safeguarded.

Protection of Subjects - General Rules - The clinical trial has been designed to involve as little pain, discomfort, fear and any other foreseeable risk as possible, and both the risk threshold and the degree of stress are specifically defined in the protocol and constantly monitored. Medical care is provided by an appropriately qualified doctor. No undue influence, including that of a financial nature, shall be exerted on subjects. (Article 28)

What do participants need to know

Function of Informed Consent in Research The promotion of individual autonomy The protection of patients and subjects The avoidance of fraud and duress The encouragement of self-scrutiny by medical professionals The promotion of rational decisions The involvement of the public in controlling the direction of biomedical research

Components of a Valid Informed Consent for Research Informed consent is a process of communication between investigator and participant that begins with the initial contact and carries through to the end of the involvement of subjects in research. Voluntariness (free of controlling influences e.g. social/financial) Disclosure (reasonable person standard, forced information, breach of autonomy?) Understanding (two-way communication, info provided) Competence (sufficient rationality and intelligence value- laden?) Decision (documentary evidence)

What do participants need to know “Process not just signing a form” The information should be provided in writing The information provided shall enable the subject/legally designated representative to understand: Ensure consent if voluntary Why he/she is being approached Why the therapy is proposed in their case

What do participants need to know The evidence to support its use and the areas of uncertainty about it. The potential risks, benefits and harms (both immediate and long term) How it differs from standard treatment.

What do participants need to know The measures for safety monitoring and support that will be provided if things go wrong Possible treatment alternatives, including follow-up measures in case of discontinuation; The processes involved, such as randomization Arrangements for reporting adverse events The name of the doctor directly responsible for their care and the clinician’s experience with it the research and procedures

What do participants need to know The information should be provided in an interview with a member of the investigating team, who is appropriately qualified. It shall be verified that the subject has understood the information; Adequate time shall be given to the subject. (7 day rule??) Explain the duration of participation required How they can withdraw from the project That the withdrawal will not affect the quality of their health care.

What do participants need to know How incidental findings will be addressed. Discuss any remuneration/compensation including the applicable damage compensation regime; What information participants receive about the outcome Discuss mechanism to inform of study results The likely future use of the therapy, if successful. Discuss confidentiality arrangements/access to data How health data will be stored, used and published.

What do participants need to know If samples of human material are donated, whether they will be used for any other research or purpose. Whether and how DNA will be extracted, stored or disposed of

What do participants need to know The name of the researcher whom they can contact with enquiries If the researcher stands to benefit (for example, financially)

What do participants need to know Confirm ethical review has been obtained

Other Ethical Issues in Research Capacity and consent to Clinical Trials Renewal of Informed consent/Re-consent Research & Vulnerable populations Research and Children Research and Incapacitated Adults Research and Emergency/ICU Situations Genetic Research Incidental Findings: To tell or not to Tell? Withdrawal Consent and Controlling access to data

Beyond Informed Consent Significant limitations of informed consent process does it safeguard voluntariness? Is Informed Consent still fit for purpose in the era of biobank data? Types of Consent Broad Consent Layered Consent Presumed Consent/Opt Out Open Consent Contract Dynamic Consent

Beyond Informed Consent Consent Models Specific- Deemed unsuitable for biobanks as it allows the use of biological specimens and related data only in immediate research; precludes any future study that is not foreseen at the time of the original consent. Layered- Several options given to the research subject about future uses. Broad- permission for a broad range of research purposes (related to/in same area as original consent Finnish Biobanking Act) that were not specified at the time of recruitment (Caulfield 2009). When does broad consent become blanket consent? Dynamic-interactive relationship between custodians of biobanks and donors of material using web 2.0 technologies.

Beyond Informed Consent Broad Consent Consensus emerging: Broad consent with ethics approval, With the right to withdraw from the study, Acceptable if there is a continuous flow of information on project developments and the necessary governance framework is in place.

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