Principles of ICH GCP & Ethical Consideration in Vulnerable subjects Assist. Prof. Chanchai Traivaree MD. Msc.(Clini Epi) Chief , Division of Hematology / Oncology Phramongkutklao Hospital &College of Medicines

International Ethical Standards Nuremberg Code 1947 Declaration of Helsinki (WMA) 1964 Belmont Report (USA) 1979 CIOMS (WHO) 1982 ICH (EU, Japan, USA) 1996

วัตถุประสงค์ของแนวปฏิบัติ ICH GCP เพื่อให้มีมาตรฐานเพียงหนึ่งเดียว สําหรับการศึกษาวิจัยทางคลินิกของประเทศใน สหภาพยุโรป ญี่ปุ่น และ สหรัฐอเมริ กา ซึ่ งจะเอื้อให้หน่วยงานควบคุมระเบียบกฎหมายยอมรับข้อมูลทางคลินิกของกันและกัน

International Conference on Harmonization (ICH) E6 The Principles of ICH GCP Glossary Institutional Review Board (IRB/IEC) Investigator Sponsor Clinical Trial Protocol And Protocol Amendment(s) Investigator’s Brochure Essential Documents for Conducting a Clinical Trial

13 Principles of ICH-GCP 1 Clinical trials should be conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, and that are consistent with GCP and the applicable regulatory requirement(s).

13 Principles of ICH-GCP 2 A trial should be initiated and continued only if the anticipated benefits justify the risks.

13 Principles of ICH-GCP 3 The rights, safety, and well-being of the trial subjects are the most important considerations and should prevail over interests of science and society.

13 Principles of ICH-GCP 4 The available nonclinical and clinical information on an investigational product should be adequate to support the proposed clinical trial.

13 Principles of ICH-GCP 5 Clinical trials should be scientifically sound, and described in a clear, detailed protocol.

13 Principles of ICH-GCP 6 A trial should be conducted in compliance with the protocol that has received prior institutional review board (IRB)/independent ethics committee (IEC) approval/favorable opinion.

13 Principles of ICH-GCP 7 The medical care given to, and medical decisions made on behalf of, subjects should always be the responsibility of a qualified physician or, when appropriate, of a qualified dentist.

13 Principles of ICH-GCP 8 Each individual involved in conducting a trial should be qualified by education, training, and experience to perform his or her respective task(s).

13 Principles of ICH-GCP 9 Freely given informed consent should be obtained from every subject prior to clinical trial participation.

13 Principles of ICH-GCP 10 All clinical trial information should be recorded, handled, and stored in a way that allows its accurate reporting, interpretation, and verification.

13 Principles of ICH-GCP 11 The confidentiality of records that could identify subjects should be protected, respecting the privacy and confidentiality rules in accordance with the applicable regulatory requirement(s).

13 Principles of ICH-GCP 12 Investigational products should be manufactured, handled, and stored in accordance with applicable good manufacturing practice (GMP). They should be used in accordance with the approved protocol.

13 Principles of ICH-GCP 13 Systems with procedures that assure the quality of every aspect of the trial should be implemented.

Ethical Consideration In Vulnerable subjects Assist. Prof. Chanchai Traivaree MD. Msc.(Clini Epi) Chief , Division of Hematology / Oncology Phramongkutklao Hospital &College of Medicines

CONTENTS Definition of vulnerable groups Ethical issues related How to protection

Subjects with diminished Vulnerable Subjects Subjects with diminished ( limited) autonomy Harm more than normal ( need protection)

Autonomy & vulnerability Informed consent Limited capacity or freedom to consent or to decline to participate in research Vulnerability

Mental Capacity Voluntariness AUTONOMY Mental Capacity To understand and process information Ex: children, mentally disabled Voluntariness Freedom from the control or influence of others Ex: emergency situation, social structure, incurable disease, educationally disadvantaged

Vulnerability : Board considerations General guidelines 1. The research in intended to obtain knowledge that will lead to improved health problems characteristics of, or unique to the vulnerable class. 2. The research could not be carried out equally well with less vulnerable subjects. 3. If the research involves greater than minimal risk, it should present a prospect of direct benefit to the person.

Categories of Risk and Benefit in Vulnerable subjects Direct Benefit No Direct Benefit Minimal Risk More than Minimal Risk

Vulnerability Considerations Are subjects vulnerable? Are additional safeguards put in place? Additional safeguard Appropriate recruitment (อิสระในการตัดสินใจ) Adequate informed consent process: witness available, capacity evaluated, LAR present, re-consenting considered (เข้าใจง่าย,อิสระในการตัดสินใจ) Acceptable stopping rules (เข้าใจง่าย) Optimal treatment available (เข้าใจง่าย)

Vulnerable Populations Vulnerable populations include: Children Individuals whose capacity to give consent is questionable Fetuses and pregnant women Terminally ill subjects Students Minorities

Vulnerable Populations: Children A child is a person less than 18 years of age unless emancipated or married. Children cannot legally give consent. Any study involving children requires IRB review and approval. Parental consent must be obtained in all cases; a parent is the child’s legal parent or guardian.

Vulnerable Populations: Children, Assent of Child The child’s signed assent is required. An assent form is a simplified, single page version of the consent form signed by the parent or guardian; the assent explains to the child what will happen should they agree to participate in the research. Federal guidelines recommend children 7-12 be given a separate assent form; children 13-17 may be given the same consent form given to their parent or guardian.

Assent การเจาะเลือดตรวจหาพาหะ โรค ธาลัสซีเมีย การศึกษานี้มีวัตถุประสงค์เพื่อดูว่า เด็กไทยในจังหวัดของหนู เป็นโรคเลือดกี่คน หนูจะถูกเจาะเลือดเพื่อตรวจ 1 ช้อนชา หนูจะเจ็บบริเวณที่เจาะเลือดเล็กน้อย การเข้าร่วมในการวิจัย ขึ้นอยู่กับการตัดสินใจของหนู และหนูจะเปลี่ยนใจไม่เข้าร่วมเมื่อไรก็ได้

Waiver of child assent The capability of some or all of the children is so limited that they cannot reasonably be consulted ( e.g. emergency) The intervention or procedure involved the research holds out a prospect of direct benefit that is important to the health or well-being of the children and is available only in the context of the research ( e.g. oncology patients)

Waiver of parental permission Emancipated or mature minors Married Pregnant Living independently Studies involve investigation of adolescents’ beliefs and behavior regarding sexuality or use of recreational drugs Research that involves only minimal risk, does not negatively affect the welfare of the subjects, and cannot be practically performed without the waiver ( e.g. survey) 4. Research addresses domestic violence or child abuse

Vulnerable Populations: Questionable Capacity to Consent Vulnerable populations may include persons with: Psychiatric disorders Neurological conditions Substance abuse

Vulnerable Populations: Questionable Capacity to Consent Research involving persons whose capacity to consent is questionable requires careful consideration to ensure such persons are provided additional safeguards for their safety and welfare. In some cases, individuals who are not able to give informed consent may receive permission to participate from a legally authorized representative and then give their own assent.

Vulnerable Populations: Questionable Capacity to Consent Special precautions: Additional use of witnesses for consent Renewing consent at specific stages of the research Limiting time period for approval

Vulnerable Populations: Pregnant Women Pregnant women may only be involved in bio-medical research if the study regards the health needs of the mother and the fetus will be placed at risk only to the minimal extent to meet the health needs of the mother or risk to the fetus is minimal. The father’s signature is required unless: The purpose of the study is to meet the mother’s health needs, or The father is not reasonably available, or The pregnancy was the result of sexual assault

Vulnerable Populations: Terminally ill subjects Protections Consent form states clearly the potential risks and benefits and characterizes the potential benefits appropriately Impartial third party perform IC and/or use patient advocate, consent monitor Potential subjects should not be approached: participation immediately after diagnosis or after they’ve learned a standard treatment has failed

Vulnerable Populations: Students Various procedures may be used to reduce the possibility of unintentional coercion: Posting IRB approved advertisements throughout the campus to recruit from a broad base of students Recruitment procedures should not involve direct solicitation by superiors Informed consent state clearly that participation is voluntary, without authority figures present, protections in place to prevent retaliation Providing alternative and equal methods for meeting course requirements other than participating as a research subject.

Vulnerable Populations: Minorities Protections Keep data strictly confidential Consider whether study design could incorporate participants from all segments of society Consult with community and include representatives of this group in study design and oversight to reduce potential for stereotyping and stigmatization Translated ICF, and translator present for IC process (not family member), & include provisions for continued communication Group- undervalued by society in which they live. Devalues their interests welfare or contributions- they are stereotyped and may be discriminated against. Also- for non-english speakers- may be vulnerable because their comprehension is compromised. Many times investigators don’t want to include these subjects because of the time/difficulty/money involved in translating the forms and having a translator involved. Important NOT to exclude this population- especially in treatment studies- just because it’s too hard.

Conclusion Ethical research is guided by the principles of justice, respect for persons, and beneficence. Vulnerable subjects should be included but also deserve special protections. Carefully about the populations and take steps to ensure their rights and welfare are protected.

Principles of ICH GCP & Ethical Consideration in Vulnerable subjects Assist. Prof. Chanchai Traivaree MD. Msc.(Clini Epi) Chief , Division of Hematology / Oncology Phramongkutklao Hospital &College of Medicines