Disclaimer. Objectives 5/30/2016

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1 Good Clinical Practice Informed Consent Training Presented by Jacqueline Everett Clinical Trial Governance Manager, Research Integrity Disclaimer The material in this presentation has been prepared by Jacqueline Everett on behalf of The University of Sydney. This presentation provides general information about Good Clinical Practice (GCP). This information is given in summary form and does not purport to be complete. Information in this presentation, including technical clinical trial information, should not be considered as specific advice or a recommendation to researchers in relation to undertaking a clinical trial and does not take into account your particular clinical trial requirements. Before acting on any information you should consider the appropriateness of the information having regard to these matters, any relevant legislation, HREC requirements and in particular, you should seek independent accredited clinical trial training, through ARCS Australia 2 Objectives Define Good Clinical Practice (GCP) What are the PI responsibilities with GCP? What is the GCP Informed Consent process? How do you undertake informed consent in Clinical Trials? Common audit findings Tips 3 1

2 What is a Clinical Trial? Clinical Trial is a form of research designed to find out the effects of an intervention, including a treatment or diagnostic procedure. A clinical trial can involve testing a drug, a surgical procedure, other therapeutic procedures and devices, a preventive procedure, or a diagnostic device or procedure. Intervention A process or action that is the focus of a clinical study. This can include giving participants drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches such as surveys, education, and interviews. University of Sydney 4 What is Good Clinical Practice (GCP)? GCP is defined as a standard for the design, conduct, performance, monitoring, auditing, recording, analysis and reporting of clinical trials or studies 5 13 Principles of ICH GCP Ethics: 1. Ethical conduct of clinical trials 2. Benefits justify risks 3. Rights, safety and well being of participants prevail Protocol and science: 4. Nonclinical and clinical information supports the trial 5. Compliance with a scientifically sound, detailed protocol 6 2

3 13 Principles of ICH GCP Responsibilities: 6. HREC approval prior to initiation 7. Medical care/decisions by a qualified, licensed physician 8. Each individual is qualified (education, training, experience) to perform the tasks assigned Informed consent: 9. Freely given from every participant prior to participation 7 13 Principles of ICH GCP Data quality and integrity: All trial information is recorded, handled, and stored 10. Accurate reporting, interpretation and verification 11. Protects privacy and confidentiality of records Investigational products: 12. Conform to GMP and must be appropriately secured, stored and used per the protocol Quality control / Quality assurance 13. Systems with procedures to ensure quality of every aspect of the trial 8 Investigator (per 21 CFR (a)) who, what, why? qualified by training and experience as the appropriate expert to investigate the study in humans Responsible for the conduct of the clinical trial at the site Responsible for leading the research team 9 3

4 5/30/2016 Investigator Responsibilities Section ICH GCP Protocol adherence: No changes are allowed to the clinical trial without HREC approval expect to remove immediate hazard Properly qualified to assume responsibility for conduct of the study Personally conduct and supervise the study, including delegated responsibilities Ensure initial / continuing HREC review and approval Obtain informed consent prior to undertaking any trial related activities Report all adverse events Maintain protection of participant and data confidentiality 10 Investigator Responsibilities cont. Handle investigational products appropriately Read / Understand Investigator Brochure content, including risks and side effects Prepare and maintain adequate and accurate source information (e.g. xrays, medical records) Permit monitoring Promptly report changes in research, unanticipated risks Inform all individuals assisting with study of obligations in meeting these commitments 11 What is Informed Consent? Informed consent is an ongoing process that must occur before any clinical trialrelated procedures are conducted. The process consists of a document and a series of conversations between the clinical trial participant and the principal investigator (PI) and delegated health care professionals, as appropriate. This ongoing process of communication and mutual understanding between a participant and investigator is demonstrated by the participant s voluntary agreement to enter a clinical trial. The participant s initial and ongoing agreement is evidenced by signing of the informed consent document. The clinical trial informed consent document provides a summary of the trial, including its purpose, the treatment procedures and schedule, potential risks and benefits, and alternative treatments. It also explains the participants rights as a clinical trial participant. The informed consent process begins with the development of recruitment materials including advertisements. 12 4

5 5/30/2016 Informed Consent Guidelines Investigators must follow the International Council on Harmonisation (ICH) good clinical practice (GCP) guidelines. Section 1.28 describes the informed consent process, while the requirements and process for obtaining informed consent from a clinical trial participant are explained in section 4.8. The guiding principles of the Informed Consent process are taken from the Declaration of Helsinki, Nuremberg Code, and the Belmont Report. Nuremberg Code Voluntary consent Participant is free to stop at any time Belmont Report People are autonomous agents & should be treated with respect Informed consent must be freely and voluntarily given Those of diminished capacity require additional protection Besides following ICH GCP guidelines, investigators need to adhere to national and local regulatory requirements, sponsor requirements, and privacy and personal data security regulations applicable in the country in which the study is being conducted. 13 Informed Consent Guidelines In Australia, investigators are required to comply with the National Statement on Ethical Conduct in Human Research (2007, updated 2015). Chapter 2.2 outlines the general requirements for consent while Chapter 2.3 outlines the qualifying or waiving conditions for consent. Title 21 Code of Federal Regulations Section 50 requires the use of an HREC approved document, voluntary participation after sufficient time has lapsed for consideration, minimisation of coercion and undue influence, the information presented in an understandable manner with no exculpatory language. The FDA released a guidance document entitled Informed Consent Information Sheet in July The informed consent document must be fully approved by an Human Research Ethics Committee (HREC) prior to its use with trial participants Informed Consent ICH GCP essential elements The participant must be informed of the following: Statement that the study involves research Statement that participation is voluntary Information about purpose, duration, and procedures Number of participants involved in the study Description of risks, benefits, and alternatives Information about compensation/care for injury Statement regarding confidentiality of records Description of possible unforeseen risks Circumstances for termination without participant consent Consequences of withdrawing from the study Additional costs that may result from participation Statement that new research findings will be shared Contact information for questions/concerns 15 5

6 ls.com/investigators/informed_consent.htm 5/30/2016 Informed Consent What s Wrong? 16 Informed Consent Process Informed consent begins with the initial approach of an investigator to a potential participant (e.g., through a flyer, brochure or any advertisement regarding the clinical trial). The Principal Investigator (PI) determines if the participant has capacity to provide informed consent. The PI refers to the informed consent form when discussing the trial s risks, benefits and other aspects with the potential participant and, if required, the participant s legal representative, before any trial procedures are undertaken. A copy of the information sheet and consent form should be given to the participant for further review prior to them making a decision. The PI should give the potential participant ample time and opportunity to ask questions about the trial and discuss it with relatives and family members. If the potential participant decides to get involved in the trial, he or she provides voluntary consent by signing and dating the written informed consent document of which he or she also receives a copy. The participant has the right to withdraw consent at any time without penalty, repercussions or reason. While the PI may delegate the task of administering and obtaining informed consent to a qualified individual, he or she is ultimately responsible for ensuring the process is conducted properly. Informed consent continues until the completion of the clinical trial, or until the individual completes clinical trial participation, withdraws consent, or is withdrawn from the clinical trial. 17 Modifications to Informed Consent Informed consent documents must be revised every time new safety information becomes available or there is a change in trial procedures, participant compensation or personnel noted on the information sheet / consent form. Revisions to the informed consent document must be approved by an HREC prior to its use, and the informed consent process with the new information and documentation needs to be repeated with every clinical trial participant. The participant is then required to sign the revised consent form

7 Informed Consent Process Waiver The HREC can approve a consent procedure which does not include, or which alters, some or all of the elements of informed consent, or may waive the requirement to obtain informed consent from some or all of the research participants provided that each of the following criteria are met: The research involves no more than low risk to the participants; The waiver or alteration will not adversely affect the rights and welfare of the participants; It is impracticable to obtain consent The research could not reasonably be carried out without the waiver or alteration; and There is sufficient protection of their privacy There is an adequate plan to protect the confidentiality of data Whenever appropriate, the participants will be provided with additional pertinent information after participation. The waiver is not prohibited by State, federal, or international law. 19 Informed Consent Process Opt Out The HREC can approve opt out consent provided that each of the following criteria are met: involvement in the research carries no more than low risk to participants the public interest in the proposed activity substantially outweighs the public interest in the protection of privacy the research activity is likely to be compromised if the participation rate is not near complete, and the requirement for explicit consent would compromise the necessary level of participation reasonable attempts are made to provide all prospective participants with appropriate plain language information explaining the nature of the information to be collected, the purpose of collecting it, and the procedure to decline participation or withdraw from the research a reasonable time period is allowed between the provision of information to prospective participants and the use of their data so that an opportunity for them to decline to participate is provided before the research begins a mechanism is provided for prospective participants to obtain further information and decline to participate the data collected will be managed and maintained in accordance with relevant security standards there is a governance process in place that delineates specific responsibility for the project and for the appropriate management of the data the opt out approach is not prohibited by State, federal, or international law. 20 Informed Consent Process Considerations Careful consideration should be given to ensuring the freedom of consent obtained from members of a group with a hierarchical structure such as medical, pharmacy and nursing students, hospital and laboratory personnel, employees of the pharmaceutical industry, and members of the armed forces. In such cases the willingness to volunteer may be unduly influenced by the expectation, whether justified or not, of benefits associated with participation or of a retaliatory response from senior members of the hierarchy in case of refusal to participate. Other vulnerable groups whose consent also needs special consideration include patients with incurable diseases, people in nursing homes, prisoners or detainees, the unemployed or people on a very low income, patients in emergency departments, some ethnic and racial minority groups, the homeless, nomads and refugees. If such categories are part of the population to be enrolled in a clinical trial, the ethics committee should consider carefully the appropriateness of the informed consent process. In a non therapeutic study, i.e. when there is no direct clinical benefit to the participant, consent must always be given by the participant and documented by his or her signature. Reference: The principles of informed consent in the current revisions of the Declaration of Helsinki and the International Ethical Guidelines for Biomedical Research Involving Human Subjects as noted in the WHO Guidelines for GCP for trials on pharmaceutical products ( 21 7

8 Informed Consent Process Assent Informed consent is valid only with adults age 18 Assent is obtained from children and adults who are unable to make their own decisions regarding research participation when possible. Legal permission must be provided for the participant to enroll. The participant must verbally / in writing assent to their participation. Failure of the participant to object should not be construed as assent. Assent is the affirmative agreement to participate in research. The participant should be competent and have capacity to assent. Consent can be provided by: Surrogate One appointed to act in place of another Legally Authorized Representative (LAR) Guardian (court appointed) Durable Power of Attorney (DPA) For children who assented, they will need to be consented when they become 18 years of age 22 Informed Consent Process Assent Some states have legislation that addresses the issue of a minor's consent to medical treatment. According to the Minors (Property and Contracts) Act 1970 (NSW), a child aged 14 years or over may consent to his or her medical or dental treatment, and the consent of the minor will be effective in terms of defending an action for assault or battery relating to the treatment. The NSW Act also allows parents of children under the age of 16 to validly consent to their child's medical or dental treatment. The Consent to Medical Treatment and Palliative Care Act 1995 (SA) prescribes that an individual of 16 years of age or over can consent to medical and dental treatment 'as validly and effectively as an adult'. Provided that a medical practitioner, supported by another medical practitioner, believes that certain treatment is in the best interests of the child and the child is 'capable of understanding the nature, consequences and risks' involved, that child can validly consent to their own treatment. The SA legislation also provides that medical treatment can be administered to a child if the child's parent or guardian consents to it. The common law applies in those Australian jurisdictions that have not specifically legislated in relation to the issue of minors' consent to medical treatment. The common law position relating to a minor's competency to consent to treatment was established by the English House of Lords decision in Gillick v West Norfolk and Wisbech Area Health Authority [1986] AC 112, which was approved by the High Court of Australia in Secretary, Department of Health and Community Services v JWB and SMB (Marion's case) (1992) 175 CLR 218. In Gillick, it was held that the authority of a parent decreases as their child becomes increasingly competent. Gillick prescribes that the parental right to determine their child's treatment terminates once a child under the age of 16 is capable of fully understanding the medical treatment proposed. of consent to medical treatment.aspx 23 Informed Consent Process Non english speaking participants The investigator must prepare: A participant information sheet and consent form translated to a language understandable to the participant. Translation should be done by a certified translator and back translated into English. When using an interpreter, a written summary of the consent conversation is required. This summary may be written in English. The HREC must approve both the participant information sheet / consent form and the summary. In the case of where disability prevents participants from being able to physically sign his/her name, or in the case of illiterate participant, a person who speaks and understands English, but does not read and write, can be enrolled in a study by "making their mark" on the informed consent document. The HREC will consider these persons are likely to be vulnerable to coercion and undue influence and should determine that appropriate additional safeguards are in place when enrollment of such persons is anticipated. A person who can understand and comprehend spoken English, but is physically unable to talk or write, can be enrolled in a study using an informed consent document. The medical record document should include the method used for communication with the participant and the specific means by which the participant communicated agreement to participate in the study. An impartial witness must be present for the entire consent process and should sign and date the consent document. 24 8

9 Informed Consent Process Other participants For deaf subjects who are fluent in American Sign Language (ASL), the HREC may approve a consent process using ASL and the HREC approved written consent form. When this process is approved, the individual authorized to consent prospective participants must use an interpreter fluent in ASL to conduct the consent process and the documentation of the consent process must conform to the requirements set by the HREC. For blind subjects who read Braille, the HREC may approve a consent document prepared in Braille. In order to assure itself that a Braille consent document is accurate, the HREC may require a transcription into print text. If possible, the subject will sign the Braille consent; otherwise verbal consent will be obtained, witnessed and documented If there is any concern about an individual s cognitive ability to provide informed consent or assent, an appropriate assessment should be performed by a qualified individual. Additional approval will be required by the Guardianship Tribunal for persons 16years of age or older who are unable to provide informed consent to treatment. 25 Informed Consent Process Withdrawal The ethical principals guiding research with participants require that that no person participates in research unless their individual participation is voluntary, based upon a full disclosure of the procedures, and their continued right to withdraw at any time. An important caveat to the right to withdraw however is that data collected from a participant up to the point of withdrawal remains part of the study database. A consent document cannot give a participant the option of having data removed from the study dataset. FDA law and regulations require the collection and maintenance of complete clinical study data. This includes information on participants who withdraw from a clinical investigation, whether the participant decides to discontinue participation in the clinical trial (21 CFR 50.25(a)(8)) or is discontinued by the investigator because the participant no longer qualifies for the research. According to the ICH Good Clinical Practice guideline (E6 6.53), study protocols should include the following information: Participant withdrawal criteria (i.e., terminating investigational product treatment/trial treatment) and procedures specifying: a. When and how to withdraw participants from the trial/investigational product treatment b. The type and timing of the data to be collected for withdrawn participants c. Whether and how participants are to be replaced d. The follow up for participants withdrawn from investigational product treatment/trial treatment Protocols should also describe any special requirements related to participant withdrawal, e.g., post study safety monitoring. Unless it is important for the participant s health, do not require the participant to submit to any testing or data collection as a condition of withdrawal. Under some circumstances, e.g., pregnancy, a participant might stop receiving the study drug but stay in the study for follow up visits for safety monitoring and data collection purposes. Local regulations and ICH guidelines require consent forms to include a statement about the participant s right to withdraw from a clinical trial. References: 45 CFR (5) (8), 21 CFR 50.25(c), Withdrawal of Subjects from Research: Data Retention and Other Related Issues: OHRP Guidance (2010), Guidance for Sponsors, Clinical Investigators, and IRBs, Data Retention When Subjects Withdraw from FDA Regulated Clinical Trials (2008). 26 Informed Consent Process Termination The participant s participation in a clinical trial may be terminated without his or her consent in cases like the following: Continued participation in the clinical trial could be harmful to the participant s health, e.g., because of a side effect from the clinical trial medication. The participant becomes pregnant or becomes ill with a condition that prohibits participation. After enrollment, it is discovered that the participant does not meet the eligibility criteria, e.g., based on false information provided by the participant. The participant needs a medicine or other medical treatment that is not allowed in the clinical trial. The participant does not take, or is unable to take, the clinical trial medication as instructed, does not keep appointments, or otherwise does not adhere to protocol requirements. The participant was enrolled by error, e.g., due to misinterpretation of the eligibility criteria or during a poorly managed competitive enrollment period. The clinical trial is terminated prematurely by the investigator, research institution, sponsor, HREC, or TGA Before terminating a participant s participation, make every reasonable attempt to address the issue(s), which might or might not be under his or her control. Some flexibility might be required to retain the participant. For example, the participant s work schedule might have changed, necessitating visits at odd hours. Once a termination decision is made, first attempt to inform the participant in person or by telephone and then by that his or her participation in the study is being concluded, and explain the reason. If necessary, conduct a final visit like that for voluntary withdrawals. If a participant dies, where required, obtain a death certificate, coroner s report, or other documentation of the death. 27 9

10 Informed Consent Process Questions The following represents a sample list of questions that the participant could ask during the informed consent process: About the clinical trial What is the main purpose of the study? Why is this study important to me? What are the chances that this drug /device / health intervention will work? What kinds of risks are involved? What are the possible benefits? How much of my time will this take? How will the trial affect my daily life? Does the study involve a placebo or a treatment already on the market? What are my chances of getting the experimental product / drug / device / health intervention? Will results of the study be provided to me? About my care What kinds of tests will be done? Will they hurt? If so, for how long? How will the tests in the study compare to tests I would have outside the trial? Will I be able to continue to see my own doctor during the study? Will I be able to continue to take my regular medications during the trial? If I have side effects, can they be treated during the trial? About personal matters Who will review information collected about me during the trial? What happens if I decide to quit / withdraw from the study? Can the investigator take me out of the study even if I want to continue? About compensation and costs Do I have to pay for any part of the study? If so, will insurance cover these costs? How will I be protected? What are my options if I am injured during the study? Will transportation be provided if I need it? 28 Informed Consent Audit Findings Common audit findings: Title of the protocol not consistent Participant information sheet / consent form (PISCF) does not match the protocol (procedures listed in incorrect order) Incorrect version signed of PISCF at study visit PISCF not updated with modifications to protocol Participants not re consented with the correct version / date Poor version and date control with PISCF Missing signature / date of relevant people (PI) Incomplete PISCF. Not all essential elements included: Financial disclosure, sample size, tissue / genetic banking, secondary use of data, telephone / photo / video images not referenced, no record of verbal consent being taken 29 Informed Consent Tips Informed consent should be given at a comfortable pace, with time allowed for the participant to think it over and ask questions. The PI should make every effort to be sure that the participant understands the information they have provided. The PI can do this by having the participant fill out a questionnaire, asking the participant questions, or having the participant tell the PI about the clinical trial in their own words. Some clinical trials offer a video, audio recording, or an interactive computer module to help the participant better understand the information in the consent form. If the protocol specific testing is done the same day as informed consent documents are signed, the chronological order must be clearly documented in the medical record. ICH GCP Impartial witness a person who is independent of the trial, who cannot be unfairly influenced by people involved in the trial, who attends the informed consent process

11 Summary Defined Good Clinical Practice (GCP) Outlined the goals of GCP What is Informed Consent? Process of undertaking Informed Consent in Clinical Trials Common audit findings Tips 31 Links FURTHER INFORMATION: Jacqueline Everett Clinical Trial Governance Manager Phone: FDA TGA ICH GCP ISO National Statement publications/e72 USYD CTG University of Sydney 32 University of Sydney 33 11