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    1 INTRODUCTION.doc 1 INTRODUCTION.doc Document Transcript

    • Tata Memorial Centre Ethics Committee Policy and Procedures Manual Compiled by Dr R Batura March 2002
    • TABLE OF CONTENTS Page Section 1 Introduction .................................................................................................... 1 1.1 Background Information................................................................................ 1 1.2 History .......................................................................................................... 2 Section 2 Constitution of the Hospital Ethics Committee ................................................ 6 2.1 Mandate of the Hospital Ethics Committee ................................................... 6 2.2 Composition of the Hospital Ethics Committee ............................................. 6 2.3 Membership.................................................................................................. 7 2.4 Terms of appointment................................................................................... 7 2.5 Conditions of appointment ............................................................................ 8 2.6 Officers ....................................................................................................... …9 Section 3 Review ......................................................................................................... 10 3.1 Application requirements ............................................................................ 10 3.2 Elements of Review .................................................................................... 11 3.3 Meeting requirements ................................................................................ 13 3.4 Expedited review.......................................................................................... 13 3.5 Decision making ......................................................................................... 13 3.6 Communicating a decision.......................................................................... 14 3.7 Follow up..................................................................................................…..14 3.8 Documentation and archiving...................................................................…..15 Section 4 Continuing Review of Activities Involving the Use of Human Subjects ........................................................................ 15 4.1 The Continuing Review Procedure ............................................................. 15 4.2 Amendments to Protocols........................................................................... 16 4.3 Adverse Event Reporting............................................................................ 16 Section 5 Appendices .................................................................................................. 11 2
    • APPENDICES Appendix A - Policies Appendix A-1 Policy on Recruitment of TMC Students and Staff........................23 Appendix A-2 Policy on the Recruitment of Research Subjects.........................24 Appendix A-3 Policy on Research Costs to Subjects………………....................25 Appendix A-4 Guidelines on Compensation for Research Subjects...................26 Appendix A-5 Policy on the Use of Third Party/Surrogate Consent 27 Appendix A-6 Policy on Blood Withdrawal For Research Purposes...................28 Appendix A-7 Policy for Review of Human Research Involving Investigational Drugs...................................................................30 Appendix A-8 IND Application Exemption Checklist…………………...................31 Appendix A-9 Procedures for Filing a Notice of Claimed Investigational Exemption for a New Drug…………………………33 Appendix A-10 Guidelines and Policy on Informed Consent...............................34 Appendix A-11 Policy for Documentation of Informed Consent…………………...37 Appendix A-12 Policy on Reporting Serious Adverse Events Examples of Categories of Research that may be Reviewed by the HEC through an ExpeditedReview…………………………………41 Appendix A-13 Health Record Research...........................................................44 Appendix A-14 Guidelines for Research Protocols That Require Collection and/or Storage of Genetic Materials.......................46 Appendix A-15 Guidelines for Submission and EC Review of Gene Therapy/Gene Transfer Protocols................................48 Appendix A-16 EC Policy for Data and Safety Monitoring in Clinical Research......................................................................52 Appendix A-17 Policy for Submission of Audit Reports…………………………..54 3
    • Appendix B - Forms Appendix B-1 Adverse Event Reporting Form...................................................59 Appendix B-2 Sample Informed Consent Forms................................................60 Recommended Terms for Use in Consent Forms………………..68 Appendix B-3 Protocol Review Standards.........................................................75 1 INTRODUCTION 1.1 BACKGROUND INFORMATION Contemporary models of ethical behavior derive from diverse philosophical roots. Perhaps the oldest concept in ethics is “virtue”- a human characteristic or habit thought to benefit the persons possessing it and those around them. The traits that human societies have valued through the ages have been consistent. Dissimilar cultures throughout the course of history have agreed in recognising qualities like compassion, courage, generosity, honesty and self-control as virtues. The concept of justice and fairness-the equitable treatment of all parties and the avoidance of favouritism, emerged first as personal virtues and then evolved into a social principal of reciprocity or the so called “Golden Rule” expressed in many legal, literary, philosophical and religious texts – Do to others only what you would want others to do to you. Eighteenth century humanist philosophers Jean-Jacques Rousseau and Immanuel Kant argued the existence of “human rights”. According to them, all individuals have a basic right to make choices for themselves and by those choices to define themselves as unique, independent and special beings, not pawns of the privileged or splinters of a collective whole. The basic human right derives its strength from numerous subsidiary rights, which gave impetus to various democratic movements including those that affected the scientific sector: • The right to the truth – the right to accurate information affecting the choices one makes. • The right to privacy – the right to conduct one’s life as one pleases, provided it does not violate the rights of others. • The right to the care and control of one’s body – the right to avoid personal injury, unless one freely and knowingly chooses to risk such an injury. • The right to what has been agreed upon – the right to what others have promised through free and knowing agreement, oath or contract. In the nineteenth century, utilitarian philosophers like Jeremy Bentham and John Stuart Mill proposed a model for analysing the ethics of particular deeds based on a calculation of each deed’s probable consequences. 1. One should identify the realistic courses of action available 2. One should consider whom each course of action would most benefit and what possible harm could derive from each 4
    • 3. One should select the course of action that most likely provides the greatest benefit to the greatest numbers while posing the least harm to any. In the twentieth century, existentialist thinkers like Martin Heidegger and Jean-Paul Sartre suggested that the individual’s absolute freedom of choice and action was the only ethical consideration. The methodology of contemporary clinical research involves three components specifically designed to address ethical concerns. First, the investigators with their medical and scientific knowledge and experience are held morally and legally responsible for weighing the risks and benefits of the research to be pursued and otherwise protecting the human subjects in their care. Second, the Independent Ethics Committee ensures the protection of the rights and the well being of participating human subjects. Third, the process of informed consent helps to safeguard the integrity and liberty of individuals participating in scientific study. 1.2 HISTORY 1.2.1 The History Of The Human Subjects Protection System The modern story of human subjects protections begins with the Nuremberg Code, developed for the Nuremberg Military Tribunal as standards by which to judge the human experimentation conducted by the Nazis. The Code captures many of what are now taken to be the basic principles governing the ethical conduct of research involving human subjects. The first provision of the Code states "the voluntary consent of the human subject is absolutely essential." Freely given consent to participation in research is thus the cornerstone of ethical experimentation involving human subjects. The Code goes on to provide the details implied by such a requirement: capacity to consent, freedom from coercion, and comprehension of the risks and benefits involved. Other provisions require the minimization of risk and harm, a favorable risk/benefit ratio, qualified investigators using appropriate research designs, and freedom for the subject to withdraw at any time. Similar recommendations were made by the World Medical Association in its Declaration of Helsinki: Recommendations Guiding Medical Doctors in Biomedical Research Involving Human Subjects, first adopted by the 18th World Medical Assembly in Helsinki, Finland, in 1964, and subsequently revised by the 29th World Medical Assembly, Tokyo, Japan, 1975, and by the 41st World Medical Assembly, Hong Kong, 1989. The Declaration of Helsinki further distinguishes therapeutic from nontherapeutic research. 1.2.2 The Belmont Report On September 30, 1978, the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research submitted its report entitled "The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research." The Report, named after the Belmont Conference Center at the Smithsonian Institution where the discussions which resulted in its formulation were begun, sets forth the basic ethical principles underlying the acceptable conduct of research involving human subjects. Those principles, respect for persons, beneficence, and justice, are now accepted as the three quintessential requirements for the ethical conduct of research involving human subjects. Respect for persons involves recognition of the personal dignity and autonomy of individuals, and special protection of those persons with diminished autonomy. Beneficence entails an obligation to protect persons from harm by maximizing anticipated benefits and minimizing possible risks of harm. 5
    • Justice requires that the benefits and burdens of research be distributed fairly. The Report also describes how these principles apply to the conduct of research. Specifically, the principle of respect for persons underlies the need to obtain informed consent; the principle of beneficence underlies the need to engage in a risk/benefit analysis and to minimize risks; and the principle of justice requires that subjects be fairly selected. As was mandated by the congressional charge to the Commission, the Report also provides a distinction between "practice" and "research." The text of the Belmont Report is thus divided into two sections: (1) boundaries between practice and research; and (2) basic ethical principles. 1.2.3 Boundaries Between Practice and Research While recognizing that the distinction between research and therapy is often blurred, practice is described as "interventions that are designed solely to enhance the well-being of an individual patient or client and that have a reasonable expectation of success. The purpose of medical or behavioral practice is to provide diagnosis, preventive treatment, or therapy to particular individuals." The Commission distinguishes research as "an activity designed to test an hypothesis, permit conclusions to be drawn, and thereby to develop or contribute to generalizable knowledge” (expressed, for example, in theories, principles, and statements of relationships). Research is usually described in a formal protocol that sets forth an objective and a set of procedures designed to reach that objective." The Report recognizes that "experimental" procedures do not necessarily constitute research, and that research and practice may occur simultaneously. It suggests that the safety and effectiveness of such "experimental" procedures should be investigated early, and that institutional oversight mechanisms, such as medical practice committees, can ensure that this need is met by requiring that "major innovations be incorporated into a formal research project." 1.2.4 Applying the Ethical Principles Respect for Persons. Required by the moral principle of respect for persons, informed consent contains three elements: information, comprehension, and voluntariness. First, subjects must be given sufficient information on which to decide whether or not to participate, including the research procedure(s), their purposes, risks and anticipated benefits, alternative procedures (where therapy is involved), and a statement offering the subject the opportunity to ask questions and to withdraw at any time from the research. Responding to the question of what constitutes adequate information, the Report suggests that a "reasonable volunteer" standard be used: "the extent and nature of information should be such that persons, knowing that the procedure is neither necessary for their care nor perhaps fully understood, can decide whether they wish to participate in the furthering of knowledge. Even when some direct benefit to them is anticipated, the subjects should understand clearly the range of risk and the voluntary nature of participation." Incomplete disclosure is justified only if it is clear that: (1) the goals of the research cannot be accomplished if full disclosure is made; (2) the undisclosed risks are minimal; and (3) when appropriate, subjects will be debriefed and provided the research results. Second, subjects must be able to comprehend the information that is given to them. The presentation of information must be adapted to the subject's capacity to understand it; testing to ensure that subjects have understood may be warranted. Where persons with limited ability to comprehend are involved, they should be given the opportunity to choose whether or not to participate to the extent they are able to do so, and their objections should not be overridden, unless the research entails providing them a therapy unavailable outside of the context of research. Each such class of persons should be considered on its own terms (e.g., minors, persons with impaired mental capacities, the terminally ill, and the comatose). Respect for 6
    • persons requires that the permission of third persons also be given in order to further protect them from harm. Finally, consent to participate must be voluntarily given. The conditions under which an agreement to participate is made must be free from coercion and undue influence. ECs should be especially sensitive to these factors when particularly vulnerable subjects are involved. Beneficence. Closely related to the principle of beneficence, risk/benefit assessments "are concerned with the probabilities and magnitudes of possible harms and anticipated benefits." The Report breaks consideration of these issues down into defining the nature and scope of the risks and benefits, and systematically assessing the risks and benefits. All possible harms, not just physical or psychological pain or injury, should be considered. The principle of beneficence requires both protecting individual subjects against risk of harm and consideration of not only the benefits for the individual, but also the societal benefits that might be gained from the research. In determining whether the balance of risks and benefits results in a favorable ratio, the decision should be based on thorough assessment of information with respect to all aspects of the research and systematic consideration of alternatives. The Report recommends close communication between the EC and the investigator and EC insistence upon precise answers to direct questions. The EC should: (1) determine the "validity of the presuppositions of the research;" (2) distinguish the "nature, probability and magnitude of risk with as much clarity as possible;" and (3) "determine whether the investigator's estimates of the probability of harm or benefits are reasonable, as judged by known facts or other available studies." Five basic principles or rules apply when making the risk/benefit assessment: (1) "brutal or inhumane treatment of human subjects is never morally justified;" (2) risks should be minimized, including the avoidance of using human subjects if at all possible; (3) ECs must be scrupulous in insisting upon sufficient justification for research involving "significant risk of serious impairment" (e.g., direct benefit to the subject or "manifest voluntariness of the participation" (4) the appropriateness of involving vulnerable populations must be demonstrated; and (5) the proposed informed consent process must thoroughly and completely disclose relevant risks and benefits. Justice. The principle of justice mandates that the selection of research subjects must be the result of fair selection procedures and must also result in fair selection outcomes. The "justness" of subject selection relates both to the subject as an individual and to the subject as a member of social, racial, sexual, or ethnic groups. With respect to their status as individuals, subjects should not be selected either because the researcher favors them or because they are held in disdain (e.g., involving "undesirable" persons in risky research). Further, "social justice" indicates an "order of preference in the selection of classes of subjects (e.g., adults before children) and that some classes of potential subjects (e.g., the institutionalized mentally infirm or prisoners) may be involved as research subjects, if at all, only on certain conditions." Investigators, institutions, or ECs may consider principles of distributive justice relevant to determining the appropriateness of proposed methods of selecting research subjects that may result in unjust distributions of the burdens and benefits of research. Such considerations may be appropriate to avoid the injustice that "arises from social, racial, sexual, and cultural biases institutionalized in society." 7
    • Subjects should not be selected simply because they are readily available in settings where research is conducted, or because they are "easy to manipulate as a result of their illness or socioeconomic condition." Care should be taken to avoid overburdening institutionalized persons who "are already burdened in many ways by their infirmities and environments." Nontherapeutic research that involves risk should use other, less burdened populations, unless the research "directly relate[s] to the specific conditions of the class involved." In February 1980, the Indian Council of Medical Research released a ‘Policy Statement on Ethical Considerations involved in Research on Human Subjects’ for the benefit of all those involved in clinical research in India. In 1982, the World Health Organisation (WHO) and the CIOMS issued the ‘Proposed International Guidelines for Biomedical Research involving Human Subjects.’ Subsequently the CIOMS brought out the ‘International Guidelines for Ethical Review in Epidemiological studies’ in 1991 and ‘International Ethical Guidelines for Biomedical Research involving Human subjects’ in 1993. Over the years, various bodies in national jurisdictions have also laid down general and specific principles in specific areas of scientific research entailing the use of human beings as subjects in medical research. These ‘national’ Codes (drawn from the international codes and the universal principles underlying them) outline ‘guidelines’ to be followed in their respective jurisdictions. Indian Council Of Medical Research has laid down Ethical Guidelines for Biomedical Research on Human Subjects in 2000. 2. CONSTITUTION OF THE HOSPITAL ETHICS COMMITTEE (HEC) The Hospital Ethics Committee is constituted by the authority vested in the Director Tata Memorial Centre by the Governing Council of the Tata Memorial Centre. The Hospital Ethics Committee of Tata Memorial Centre was established in 1996 to function in accordance with ICH and GCP guidelines and those laid down in the Ethical Guidelines for Biomedical Research on Human Subjects by Indian Council of Medical Research New Delhi. 2.1 PURPOSE The HEC was established to formalize and specify the Institution's commitment to promotion of high ethical standards in patient care, professional education and clinical research, community interests. The mission of the HEC is to provide a multidisciplinary forum for the analysis and discussion of ethical standards effecting Tata Memorial Centre in all its activities. This mission is fulfilled through the Committee’s advisory, educational, policy development, and service functions. The HEC, through its delegated sub-committees and task forces, is charged with assisting the Institution in conducting its patient care and operations within a consistent ethical framework and in the integration of ethical values into practice, policy, relationships, and organizational activities. 2.1.2 Mandate 8
    • The purpose of the IEC is to cultivate a pluralistic and democratic exchange of ethical values and concerns and to critically analyze that discussion for opportunities to enhance the ethical integrity of the Institution. 2.1.3 HEC has responsibility within the institution for the following objectives: o To ensure the competent review and evaluation of all ethical aspects of the research project received, to ensure compliance with the appropriate laws and safe guard welfare of subjects. o Patient care services o Clinical ethics consultation o Education of professional, administrative, and support staff about ethical issues o Continuing education and training programs that assure that HEC members are qualified to perform their specific duties within the HEC. 2.2. COMPOSITION The HEC is composed of a Chairperson, a Secretary, and 15-20 active members who represent an appropriate balance of professional, ethical, legal, cultural, educational, and community interests. The members will be selected to have an equitable representation of all specialties in the institution. It includes scientists, clinicians, members of the community, a lawyer /expert in ethics, a social worker.  There will be adequate representation of age, gender, community, etc. in the Committee to safeguard the interests and welfare of all sections of the community / society. Members should be aware of local, social and cultural norms, as this is the most important social control mechanism.  The committee will comprise a diverse working group without any gender bias. 2.2.1 The following qualities are sought in HEC members:  interest and motivation,  commitment and availability,  experience or education,  respect for divergent opinions,  interest in committee work,  integrity, and  diplomacy. The Hospital Ethics Committee can have as its members, individuals from other institutions or communities if required. If required, subject experts could be invited to offer their views, for example for drug trials a clinical pharmacologist, may be included. 9
    • 2.2.2 The Chairperson of the Committee will necessarily be a person of stature with a scientific slant and adequate familiarity with the principles of ethics and related issues. He/she will preferably be from outside the Institution to maintain the independence of the Committee. The Member Secretary will belong to TMC to conduct the business of the Committee. 2.2.3 The composition may be as follows:- 1. Chairperson 2. 1-2 basic medical scientists. 3. 1-2 clinicians from each specialty 4. One legal expert or retired judge 5. One social scientist / representative of non-governmental voluntary agency 6. One philosopher / ethicist / theologian 7. One lay person from the community 8. Member Secretary 2.3 MEMBERSHIP •All members are nominated by the Director TMC in consultation with the Chairperson and Member, Secretary. •Conflictof interest will be avoided when making appointments, but where unavoidable there will be transparency with regard to such interests. •A rotation system for membership will be followed that allows for continuity, the development and maintenance of expertise within the EC, and the regular input of fresh ideas and approaches. •Alternate members may be appointed in case of prolonged absence of a standing member with the concurrence of the Committee Members. 2.4 TERMS OF APPOINTMENT 2.4.1 Duration The members of the Tata Memorial Hospital Ethics Committee will be appointed for duration of 2 years. 2.4.2 Renewal The membership may be renewed after the stated term of 2 years. 2.4.3 Replacement procedure The members may be replaced at the discretion of the appointing authority for the same. 2.4.4 Removal procedure A member may be relieved of his/her membership in case of a of conduct unbecoming for a member of the Ethics Committee or inability to participate in the meetings on any grounds 10
    • 2.4.5 Voting status All nominated members have the right to vote. 2.5 CONDITIONS OF APPOINTMENT 2.5.1 Name, age, gender, profession, and affiliation will be publicized whenever the committee is reconstituted or there is a change in the membership. 2.5.2 Conflict of interest to be disclosed if any exists. 2.5.3 Members must apprise themselves of the relevant documents, codes, GCP, ICH guidelines and the ICMR code. 2.5.4 An investigator can be a member of the EC; however, the investigator-as-member cannot participate in the review and approval process for any project in which he or she has a present or potential conflict of interest. 2.6 OFFICERS The Ethics Committee will have the following Office bearers who have the expertise and professional qualification to review what comes in. 2.6.1 Chairperson The HEC chairperson should be a highly respected individual preferably from outside the institution, fully capable of managing the HEC and the matters brought before it with fairness and impartiality. The task of making the HEC a respected part of the institutional community will fall primarily on the shoulders of this individual. The HEC must be perceived to be fair and impartial, immune from pressure either by the institution's administration, the investigators whose protocols are brought before it, or other professional and nonprofessional sources. 2.6.2 Secretary The Secretary will be a senior member of the staff, committed to the task of coordinating and managing the activities of the committee. He/she will be responsible for scheduling the meetings, describing the agenda and ensuring that the function of the committee is conducted as per the norms and policies described in this manual. 2.7 QUORUM REQUIREMENTS More than half the minimum number of members is required to be present to compose a quorum. At least one Representative of each major clinical specialty, Social worker, Secretary/Chairperson must be present to constitute a quorum; no quorum should consist entirely of members of one profession or one gender; a quorum should include at least one member whose primary area of expertise is in a non-scientific area, and at least one member who is independent of the institution/research site. 2.8 INDEPENDENT CONSULTANTS 11
    • The HEC may call upon, or establish a standing list of, independent consultants who may provide special expertise to the HEC on proposed research protocols. These consultants may be specialists in ethical or legal aspects, specific diseases or methodologies, or they may be representatives of communities, patients, or special interest groups. 2.9 EDUCATION FOR HEC MEMBERS HEC members have a need for initial and continued education regarding the ethics and science of biomedical research. All EC members must be conversant with GCP guidelines, ICH and ICMR guidelines for research involving human subjects. HEC members will receive introductory training material in the work of an HEC as well as ongoing opportunities for enhancing their capacity for ethical review. 12
    • 3. REVIEW Application A qualified researcher responsible for the ethical and scientific conduct of the research should submit an application for review of the ethics of proposed biomedical research. 3.1 DOCUMENTATION All documentation required for a thorough and complete review of the ethics of proposed research should be submitted by the applicant.  signed and dated application form;  the protocol of the proposed research clearly identified and dated, together with supporting documents and annexure;  a summary in non-technical language, synopsis, or diagrammatic representation (‘flowchart’) of the protocol;  a description of the ethical considerations involved in the research;  case report forms and other questionnaires intended for research participants;  when the research involves a study product such as a pharmaceutical or device under investigation, an adequate summary of all safety, pharmacological, pharmaceutical ,and toxicological data available on the study product, together with a summary of clinical experience with the study product to date e.g., recent investigator’s brochure, published data, a summary of the product’s characteristics;  investigators’ curriculum vitae updated, signed, and dated;  material to be used including advertisements for the recruitment of potential research participants;  a description of the process used to obtain and document consent; written and other forms of information for potential research participants clearly identified and dated in the languages understood by the potential research participants;  informed consent form clearly identified and dated in and in English, Hindi and Marathi ;  budget allocation as per the TMH format  a statement describing any compensation for study participation including expenses and access to medical care to be given to research participants;  a description of the arrangements for indemnity, if applicable;  a description of the arrangements for insurance coverage for research participants, if applicable;  a statement of agreement to comply with ethical principles set out in relevant guidelines;  all significant previous decisions (e.g., those leading to a negative decision or modified protocol by other HECs or regulatory authorities for the proposed study whether in the same location or elsewhere and an indication of modifications to the protocol made on that account. The reasons for previous negative decisions should be provided. All properly submitted applications will be reviewed within four weeks and according to the established review procedure. 3.2 ELEMENTS OF THE REVIEW The primary task of the HEC lies in the review of research proposals and their supporting documents, with special attention given to the informed consent process, documentation, and 13
    • the suitability and feasibility of the protocol. HEC will take into account prior scientific review by the Scientific Review Committee, and the requirements of applicable laws and regulations. The following will be considered, as applicable: 3.2.1 Scientific Design and Conduct of the Study  the appropriateness of the study design in relation to the objectives of the study, the statistical methodology (including sample size calculation), and the potential for reaching sound conclusions with the smallest number of research participants;  the justification of predictable risks and inconveniences weighed against the anticipated benefits for the research participants and the concerned communities;  the justification for the use of control arms;  criteria for prematurely withdrawing research participants;  criteria for suspending or terminating the research as a whole;  the adequacy of provisions made for monitoring and auditing the conduct of the research, including the constitution of a data safety monitoring board (DSMB);  the adequacy of the site, including the supporting staff, available facilities, and emergency procedures;  the manner in which the results of the research will be reported and published; 3.2.2 Care and Protection of Research Participants  the suitability of the investigators’ qualifications and experience for the proposed study;  any plans to withdraw or withhold standard therapies for the purpose of the research, and the justification for such action;  the medical care to be provided to research participants during and after the course of the research;  the adequacy of medical supervision and psycho-social support for the research participants;  steps to be taken if research participants voluntarily withdraw during the course of the research;  the criteria for extended access to, the emergency use of, and/or the compassionate use of study products;  the arrangements, if appropriate, for informing the research participant’s general practitioner or family doctor, including procedures for seeking the participant’s consent to do so;  a description of any plans to make the study product available to the research participants following the research;  a description of any financial costs to research participants; the rewards and compensations for research participants (including money, services, and/or gifts);  the provisions for compensation/treatment in the case of the injury/disability/death of a research participant attributable to participation in the research;  the insurance and indemnity arrangements; 3.2.3 Protection of Research Participant Confidentiality  a description of the persons who will have access to personal data of the research participants, including medical records and biological samples;  the measures taken to ensure the confidentiality and security of personal information concerning research participants. 3.2.4 Informed Consent Process  a full description of the process for obtaining informed consent, including the identification of those responsible for obtaining consent; 14
    •  the adequacy, completeness, and understandability of written and oral information to be given to the research participants, and, when appropriate, their legally acceptable representative(s);  clear justification for the intention to include in the research individuals who cannot consent, and a full account of the arrangements for obtaining consent or authorization for the participation of such individuals;  assurances that research participants will receive information that becomes available during the course of the research relevant to their participation including their rights, safety, and well-being;  the provisions made for receiving and responding to queries and complaints from research participants or their representatives during the course of a research project. 3.2.5 Community Considerations  the impact and relevance of the research on the local community and on the concerned communities from which the research participants are drawn;  the steps taken to consult with the concerned communities during the course of designing the research;  the influence of the community on the consent of individuals;  proposed community consultation during the course of the research;  the extent to which the research contributes to capacity building, such as the enhancement of local healthcare, research, and the ability to respond to public health needs;  a description of the availability and affordability of any successful study product to the concerned communities following the research;  the manner in which the results of the research will be made available to the research participants and the concerned communities. 3.2.6 Recruitment of Research Participants  the characteristics of the population from which the research participants will be drawn (including gender, age, literacy, culture, economic status, and ethnicity);  the means by which initial contact and recruitment is to be conducted;  the means by which full information is to be conveyed to potential research participants or their representatives;  inclusion criteria for research participants;  exclusion criteria for research participants. 15
    • 3.3 MEETING REQUIREMENTS HEC will meet at 8.30 am on the last Friday of every month unless otherwise specified. The meeting requirements are: 3.3.1 HEC members will be given all the relevant documents at least one week in advance of the meeting for review; 3.3.2 Meetings will be minuted and the minutes approved in the subsequent meeting; 3.3.3 The applicant, sponsor, and/or investigator may be invited to present the proposal or elaborate on specific issues; 3.4.4 Independent consultants may be invited to the meeting or to provide written comments, subject to applicable confidentiality agreements. 3.4 EXPEDITED REVIEW An expedited review procedure consists of a review of research involving human subjects by the HEC chairperson or by one or more experienced reviewers designated by the chairperson from among members of the HEC. Research activities that  present no more than minimal risk to human subjects, and  involve only procedures listed in one or more of the categories, may be reviewed by the HEC through the expedited review procedure. (See Appendix 13 for details) A brief summary and review decision of the protocol will be placed before the HEC members in the next meeting. The expedited review procedure may not be used where identification of the subjects and/or their responses would reasonably place them at risk of criminal or civil liability or be damaging to the subjects' financial standing, employability, insurability, reputation, or be stigmatizing, unless reasonable and appropriate protections will be implemented so that risks related to invasion of privacy and breach of confidentiality are no greater than minimal. The expedited review procedure may not be used for classified research involving human subjects. The standard requirements for informed consent (or its waiver, alteration, or exception) apply regardless of the type of review, expedited or convened, utilized by the HEC. 3.5 DECISION-MAKING In making decisions on applications for the ethical review of biomedical research, the HEC will take the following into consideration: 3.5.1 A member will withdraw from the meeting for the decision procedure concerning an application where there arises a conflict of interest; the conflict of interest should be indicated to the chairperson prior to the review of the application and recorded in the minutes; 3.5.2 Decision may only be taken when sufficient time has been allowed for review and discussion of an application in the absence of non-members (e.g., the investigator, representatives of the sponsor, independent consultants) from the meeting, with the exception of EC staff. 3.5.3 Decisions will only be made at meetings where a quorum is present. 16
    • 3.5.4 The documents required for a full review of the application should be complete and the relevant elements considered before a decision is made. 3.5.5 Only members who participate in the review will participate in the decision. 3.5.6 Decisions will be arrived at through consensus, where possible; when a consensus is not possible, the HEC will vote. 3.5.7 Any advice that is non-binding will be appended to the decision. 3.5.8 In cases of conditional decisions, clear suggestions for revision and the procedure for having the application re-reviewed will be specified. 3.5.9 A negative decision on an application will be supported by clearly stated reasons. 3.6 COMMUNICATING A DECISION A decision will be communicated in writing to the applicant, preferably within two weeks’ time of the meeting at which the decision was made. 3.6.1 The communication of the decision will include, but is not limited to, the following:  the exact title of the research proposal reviewed;  the clear identification of the protocol of the proposed research or amendment, date and version number (if applicable).  the names and specific identification number version numbers/dates of the documents reviewed, including the potential research participant information sheet/material and informed consent form;  the name and title of the applicant;  the name of the site(s);  the date and place of the decision;  a clear statement of the decision reached;  any advice by the HEC;  in case of a conditional decision, any requirements by the HEC, including suggestions for revision and the procedure for having the application re-reviewed;  in the case of a positive decision, a statement of the responsibilities of the applicant; for example, confirmation of the acceptance of any requirements imposed by the HEC; submission of progress report(s); the need to notify the HEC in cases of protocol amendments (other than amendments involving only logistical or administrative aspects of the study); the need to notify the HEC in the case of amendments to the recruitment material, the potential research participant information, or the informed consent form; the need to report serious and unexpected adverse events related to the conduct of the study; the need to report unforeseen circumstances, the termination of the study, or significant decisions by other HEC; the information the HEC expects to receive in order to perform ongoing review; the final summary or final report;  the schedule/plan of ongoing review by the DSMSC;  in the case of a negative decision, clearly stated reason(s) for the negative decision;  signature (dated) of the chairperson (or other authorized person) of the HEC. 3.7 FOLLOW-UP HEC will follow-up progress of all studies for which a positive decision has been reached, from the time the decision was taken until the termination of the research. 3.7.1 Follow-up procedure: The follow-up review intervals will be determined by the nature and the events of research projects, though each protocol will undergo a follow-up review at least once a year. 17
    • The Data and Safety Monitoring Subcommittee will undertake the follow up process and forward the recommendations to the HEC. The process is described in the SOP for the Data and Safety Monitoring Subcommittee. 3.7.2 A decision of a follow-up review will be issued and communicated to the applicant, indicating a modification, suspension, or termination of the HEC’s original decision or confirmation that the decision is still valid. 3.7.3 In the case of the premature suspension/termination of a study, the applicant must notify the HEC of the reasons for suspension/termination. 3.7.4 A summary of results obtained in a study prematurely suspended/terminated should be communicated to the HEC. 3.7.5 HEC should receive notification from the applicant at the time of the completion of a study 3.7.6 HEC should receive a copy of the final summary or final report of a study. 3.8 DOCUMENTATION AND ARCHIVING All documentation and communication of HEC will be dated, filed, and archived. Documents be archived for a minimum period of 3 years following the completion of a study. 3.8.1 Documents that will be filed and archived include, but are not limited to,  the constitution, written standard operating procedures of the HEC, and regular (annual) reports;  the curriculum vitae of all HEC members;  a record of all income and expenses of the HEC, including allowances and reimbursements made to the secretariat and HEC members;  the published guidelines for submission established by the HEC;  the agenda of the HEC meetings;  the minutes of the HEC meetings;  one copy of all materials submitted by an applicant;  the correspondence by HEC members with applicants or concerned parties regarding application, decision, and follow-up;  a copy of the decision and any advice or requirements sent to an applicant;  all written documentation received during the follow-up;  the notification of the completion, premature suspension, or premature termination of a study;  the final summary or final report of the study. 18
    • 4. THE CONTINUING REVIEW OF ACTIVITIES INVOLVING THE USE OF HUMAN SUBJECTS 4.1 THE CONTINUING REVIEW PROCEDURE Any research activity involving the use of human subjects that has received initial review and approval by HEC is subject to continuing review and approval. Time intervals for such reviews shall be made at the discretion of the Data and Safety Monitoring Subcommittee but shall occur no less than annually. 4.2 AMENDMENTS TO PROTOCOLS Amendments to protocols or consent forms must be requested in writing, and reviewed and approved by the HEC prior to making any changes in study procedures. Requests must describe what modifications are desired, why the changes are required, and if the changes pose any additional risks to the subjects. Minor changes (those that do not increase the risk or decrease the potential benefit to subjects) may be administratively approved. Changes considered to be more than minor must be reviewed at a convened meeting of the HEC. All amendments are reported to, discussed and approved by the HEC at a convened meeting. 4.3 SERIOUS ADVERSE EVENT REPORTING When a subject who is participating in a research study experiences an unexpected or serious adverse event, the PI must promptly report the incident to the Data and Safety Monitoring Subcommittee of the HEC. A summary of the adverse event must be submitted to the Data and Safety Monitoring Subcommittee of the HEC. For adverse events or reactions that occur at TMC the following apply (hospitalization for any reason must be reported): • If the adverse event or reaction was anticipated in the protocol and the subject was informed about the possibility of the event in the consent form, there is no need to inform the Data and Safety Monitoring Subcommittee of the HEC unless the adverse event was unexpectedly serious, life threatening, or fatal. • If the adverse event or reaction was unanticipated, unexpectedly serious, life- threatening or fatal, the adverse event must be reported to the Data and Safety Monitoring Subcommittee of the HEC office within 24 hours. If the adverse event occurs after hours or on a week-end, notification should be sent to the Secretary Data and Safety Monitoring Subcommittee of the HEC at the extension 7109. • If the research study is being supported by an industry sponsor, the PI is also responsible for notifying the sponsor. The sponsor must then notify the regulatory authorities within 24 hours. • If the PI holds the Investigational New Drug (IND) or Investigational New Device Exemption (IDE) in his/her name, he/she is required to notify the regulatory authorities of the adverse event or reaction within 24 hours, in addition to notifying the Data and Safety Monitoring Subcommittee of the HEC. • Notifying the Data and Safety Monitoring Subcommittee of the HEC does not relieve the PI from his/her responsibility to notify the sponsor, regulatory authorities. A Within 10 working days, the PI must submit a written report of the adverse event or reaction to the Data and Safety Monitoring Subcommittee of the HEC in the specified format. 19
    • For industry sponsored research trials of drugs or devices, sponsors are required to inform investigators of adverse events or reactions that occur at other sites. When PIs are informed of the adverse events in sponsor safety memos and other correspondence, the PI must review the adverse event report and then notify the Data and Safety Monitoring Subcommittee of the HEC. This should be done as promptly as possible after receipt of the report from the sponsor. 20
    • APPENDIX A - POLICIES 21
    • Appendix A-1 POLICY ON RECRUITMENT OF TMC STUDENTS AND STAFF FOR RESEARCH DEFINITIONS “Student” means any individual who is enrolled at TMC and those individuals who are in training as, Residents, Fellows, or Postdoctoral trainees, including individuals enrolled at a training facility other than TMC training or work program. “Staff” means all other TMC employees, including faculty. POLICY GUIDELINES TMC students and staff have the same rights as any other potential subject to participate in a research project, irrespective of the degree of risk, provided all of the following conditions exist: • The research must not bestow upon participating TMC subjects any competitive academic or occupational advantage over other TMC students or staff who do not volunteer, and the researchers must not impose any academic or occupational penalty on those TMC students or staff who do not volunteer. • TMC students and staff must not be systematically treated differently from non- TMC subjects as part of the project. • Due to the potential for perceived or real coercion to participate, TMC students and staff who desire to participate in the research (especially those under the direct supervision of the principal investigator or listed research collaborators) must be reviewed by Director TMC. 22
    • Appendix A-2 POLICY ON THE RECRUITMENT OF RESEARCH SUBJECTS SPECIFIC RECRUITMENT GUIDELINES (1) In addition to its review for scientific merit and protection of subjects from unnecessary research risks, the HEC will evaluate all protocols for subject recruitment especially with respect to women with childbearing potential, minority groups and children. Exclusion of minorities, women or children will be recommended or approved when inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. (2) TMC PATIENTS - Patients may be identified as potential research subjects through direct contact of the PI with his or her patients, collaboration with physicians of other medical specialties, contact with individual attending physicians, posted written notices, radio announcements, or other HEC approved methods. a. Inpatients - May be recruited by the investigator or other member of the research team only after consultation with the patient's attending physician. b. Outpatients - (i)For minimal risk research which does not bear directly upon a specific continuing therapeutic relationship between the individual and a TMC physician, outpatients may be recruited* without prior notification of their personal physicians. However, when possible, each subject’s personal physician should be notified of the study and informed that the patient has been entered into a minimal risk study. (ii)For more than minimal risk research or any research bearing directly upon a specific diagnosis or treatment, the subject’s personal physician should be notified before enrolling* the subject. * If the potential research subject is a minor, then contact must be via a parent or legal guardian. 23
    • Appendix A-3 POLICY ON RESEARCH COSTS TO SUBJECTS If a research participant may have to bear any costs, which would be unnecessary if the subject had declined to participate in the research, all potential subjects must be fully informed of the nature and estimated extent of these costs when obtaining consent. Examples of additional research costs include: 1) Prolongation of treatment or hospitalization. 2) Extra diagnostic tests necessary for the research. 3) Extra clinical or laboratory assessments to evaluate research treatment outcome. 4) A research treatment (whether randomly assigned or not) which may be more costly that a standard treatment. 5) Other substantial costs associated with extra visits to TMC. 24
    • Appendix A-4 GUIDELINES ON COMPENSATION FOR RESEARCH SUBJECTS COMPENSATION FOR PARTICIPATION (ICMR Code 2000) Subjects may be paid for the inconvenience and time spent, and should be reimbursed for expenses incurred, in connection with their participation in research. They may also receive free medical services. However, payments should not be so large or the medical services so extensive as to induce prospective subjects to consent to participate in research against their better judgement (inducement). All payments, reimbursement and medical services to be provided to research subjects should be approved by the HEC. Care should be taken: 1) when a guardian is asked to give consent on behalf of an incompetent person, no remuneration should be offered except a refund of out of pocket expenses; 2) when a subject is withdrawn from research for medical reasons related to the study the subject should get the benefit for full participation; 3) when a subject withdraws for any other reasons he/she should be compensated in proportion to the amount of participation. Prospective participants in research should also be informed of the sponsorship of research, so that they can be aware of the potential for conflicts of interest and commercial aspects of the research. During the initial review of a research protocol, the HEC is required to review both the amount of compensation proposed and the method and timing of disbursement to assure that neither are coercive or present undue influence. The following are some additional guidelines: 1) Any compensation should not be contingent upon the subject completing the study, but should accrue as the study progresses. 2) Unless it creates undue inconvenience or a coercive practice, compensation to subjects who withdraw from the study should be made at the time they would have completed the study, had they not withdrawn. 3) Compensation given as a “bonus” or incentive for completing the study is acceptable, providing that the amount is not coercive. The HEC is responsible for determining if the incentive amount is not so large as to be coercive or represent undue influence. 4) The amount of compensation should be clearly set forth in the informed consent document. Reference: ICMR Code 2000 25
    • Appendix A-5 POLICY ON THE USE OF THIRD PARTY/SURROGATE CONSENT IN RESEARCH AT TMC APPLICABILITY When a TMC investigator proposes to conduct a research project utilizing adult subjects who by virtue of age, physical impairment, mental impairment, language barrier or any other reason may not be able to personally execute legally effective informed consent, the HEC shall review the project on the basis of "risk" and "benefit" and shall determine that each project be assigned to one of the categories below. This policy does not mean to imply that the requirement for written documentation of consent is waived. Rather, it applies to those studies in which third party/surrogate consent is obtained from a legally authorized representative. Investigators must complete and submit an HEC Form for review and approval of inclusion of subjects who are decisionally impaired. Category I - Risks to subjects are minimal, direct benefits may or will accrue to subjects. Category II - Risks to subjects are minimal, direct benefits will not, or are unlikely, to accrue to subjects but potential societal benefits are inherent in research. Category III - Risks to subject are greater than minimal, direct benefits may or will accrue to subjects. Category IV - Risks to subjects are greater than minimal, direct benefits will not, or are unlikely, to accrue to subjects but potential societal benefits are inherent in the research. EC RECOMMENDATIONS TO THE ADMINISTRATION When categorization has been accomplished, the HEC will recommend to the TMC Administration to consider implementation or non-implementation of the project based upon the level of benefit to be gained by the individual or society from this project as compared to the level of risk involved. It is the intent of the HEC to cause to recommend Category I projects to be initiated. It is the intent of the HEC not to recommend initiation of any Category IV projects. 26
    • Appendix A-6 POLICY ON BLOOD WITHDRAWAL FOR RESEARCH PURPOSES APPLICABILITY For many studies where the only research intervention is the collection of blood for analysis, the HEC categorizes the following procedures for obtaining blood from children and adults as minimal risk: A. General Requirements 1) There are no special health reasons (e.g., anemia) to contraindicate blood withdrawal. 2) In patients from whom blood is already being drawn for clinical purposes, there are no other health reasons to preclude additional blood collection. 3) In subjects from whom blood is not already being drawn for clinical purposes, the withdrawal method is by cutaneous sticks (e.g., heel or finger) or by standard venipuncture in a reasonably accessible peripheral vein, and the frequency of punctures does not exceed two per week. 4) The volume of blood drawn from lactating or known pregnant subjects does not exceed 20 ml per week. 5) All blood withdrawals and collections are carried out by experienced professional or technical personnel. B. Additional Requirements for Adults (Subjects over 18 years of age) 1) If less than 50 ml is being collected, there are no additional restrictions with regard to hemoglobin or hematocrit. 2) If a volume greater than 50 but less than 200 ml is being collected for “no-benefit” studies, hemoglobin levels should be >11.0 g/dl for males and >9.5 g/dl for females with MCVs >85 fl (These restrictions would not apply if iron deficiency anemia or other forms of anemia were critical for inclusion in the study.). 3) The cumulative volume withdrawn or collected may not exceed 450 ml per twelve-week period (this maximum includes blood being drawn for clinical purposes) from patients 18 years of age or older in good health and not pregnant. C. Additional Requirements for Children (Subjects under 18 years of age 1) No more than three (3) skin punctures are to be made in any single attempt to draw blood, and the frequency of punctures does not exceed twice per week. 2) The volume of blood withdrawn, including blood for clinical purposes, does not exceed the lesser of 50 ml or 3 ml/kg in an eight week period and collection may not occur more frequently than 2 times per week. 27
    • 3) The cumulative volume of clinical and research blood withdrawn per eight-week period does not exceed six per cent (6.0%) of the child's total blood volume. 4) In patients from whom blood is already being drawn for clinical purposes and when the research is directly related to the child's condition, there is no maximum number of extra volume specimens which can be collected as long as the preceding requirements are met. 5) In subjects from whom blood is not already being drawn for clinical purposes, the maximum number of allowable separate specimens (again, within the limits of the preceding restrictions) depends upon the child's age and whether the research is directly related to the child's condition. D. Cord Blood Cord blood from newborns can be used without restrictions when blood is extracted from the placental side of the cord after it has been clamped and severed. E. Consent Oral consent is generally sufficient to collect additional volume (within the limits specified above for minimal risk) from patients in whom blood is being drawn for clinical purposes. 28
    • Appendix A-7 POLICY FOR REVIEW OF HUMAN RESEARCH INVOLVING INVESTIGATIONAL DRUGS Research on investigational drugs or DCGI/RA-approved drugs being used in non-approved ways, or for non-approved populations (e.g., children) must be reviewed by the HEC. If the investigational drug is DCGI/RA-approved and is to be used in a non-approved fashion or with a non-approved population, the HEC may require that the investigator obtain approval from the DGCI/RA. The investigator must supply the approval before the research can be commenced. Following approval by the HEC, the HEC office will send a copy of the approval letter to the Dispensary Department. The investigator should supply the Dispensary with a copy of the research protocol as well as the investigational use material generated by the drug company prior to starting the study. The Department of Medical Oncology/PI will be responsible for the storage, and dispensing of the drugs used in oncology protocols. The drugs should be physically located in the TMH Dispensary. It will be the responsibility of the PIs in the Adult and Pediatric Oncology groups to insure that patients receiving these drugs have signed the appropriate consent forms and that the patient record contains an investigational drug information sheet containing a brief description of the drug action, possible side effects, dosage and phone number of the investigator. 29
    • Appendix A-8 IND APPLICATION EXEMPTION CHECKLIST This checklist is intended to be used by the investigator as a preliminary test of whether an IND application needs to be submitted to the DCGI for studies involving DCGI/RA-approved drugs. If any question is answered "yes", an IND application must be submitted to the DCGI. If the answers to all questions are "no", then the study may meet the criteria for an exemption from an IND. 1. Name of drug Dosage Route 2. Does the study involve a different route of administration of the marketed drug than already approved? YES NO 3. Does the study involve the administration of different drug dosage levels that significantly increase risk or decrease the acceptability of risk to study subjects? YES NO 4. Does the study involve the administration of the drug to a different patient population for whom there may be increased risk or decreased acceptability of risk? YES NO 5. Does the study entail any other factor that significantly increases the risk or decreases the acceptability of risk to study subjects? YES NO 6. Are the results of the study intended to be reported to the DCGI/RA in support of any significant change in labeling or advertising for the drug (only for corporate sponsored studies)? YES NO Signature of Investigator Date 30
    • APPENDIX A-9 PROCEDURES FOR FILING A NOTICE OF CLAIMED INVESTIGATIONAL EXEMPTION FOR A NEW DRUG A. INTRODUCTION 1. Before a new drug may be tested on human subjects, the sponsor (usually a pharmaceutical firm or possibly a physician) must give the DCGI/RA the information specified as a "Notice of Claimed Investigational Exemption for a New Drug" (IND) B. REQUIREMENTS FOR THE IND 1. Complete composition of the drug, its source, and manufacturing data to insure its safety. 2. Results of all pre-clinical investigations including animal studies. These data must demonstrate that there will be no unreasonable hazard in using the drug with humans. Further animal studies may be conducted concurrently with the clinical studies. 3. A detailed outline (protocol) of the planned investigation. 4. Information regarding the training and experience of the investigators. 5. Copies of all informational material supplied to each investigator. 6. An agreement from the sponsor to notify the DCGI/RA and all investigators if any adverse effects arise during either the animal or human tests. 7. The investigators agreement to obtain the consent of the person on whom the drug is to be tested prior to the testing. 8. Agreement to submit annual progress reports and commitments regarding disposal of the drug when studies are discontinued. C. PHASES OF INVESTIGATIONAL DRUG TESTING 1. Phase I Studies are designed to determine the toxicity, metabolism absorption and elimination, pharmacological actions, preferred route of administration and safe dosage range. These studies generally involve a small number of subjects and are conducted under the careful direction of people trained in Medical Oncology. 31
    • 2. Phase II Studies are clinical trials on a limited number of patients for a specific disease treatment or prevention. Additional pharmacological studies on animals may be performed concurrently in order to indicate safety. 3. Phase III Studies are in order if the information obtained for Phase I and II studies demonstrate reasonable assurance of safety and effectiveness, or suggests that the drug may have a potential value that outweighs its possible hazards. Phase III studies are intended to assess the drug's safety, specific disease in a large group of subjects. D. INVESTIGATOR QUALIFICATIONS The following information is generally required about the clinical investigator: 1. Education, training and experience. 2. Information about the hospital or medical institution where the study will be conducted. E. OBLIGATIONS OF INVESTIGATORS 1. The investigator must keep careful records of his study and retain them for at least two years after IND approval. 2. The records must be made available to the sponsor and the DCGI/RA when required. 3. Regular progress reports must be sent to the sponsor. 4. Reports of adverse reactions must be sent to the sponsor immediately. 5. The investigator must observe the regulations regarding consent of human subjects involved in research. 32
    • APPENDIX A-10 GUIDELINES AND POLICY ON INFORMED CONSENT A GENERAL REQUIREMENTS Except as described below, investigators may not enroll human subjects in research unless they have obtained the legally effective, written, informed consent of the subject or the subject’s legally authorized representative, prior to enrollment of the subject in the research. Investigators are responsible for insuring that subjects, or their representatives, are given sufficient opportunity to consider whether or not to participate and must seek to avoid coercion or undue influence. Information given to potential subjects or their representatives must be in language that is understandable to the subject or representative. No process of obtaining consent may include language through which the subject waives any of their legal rights or releases or appears to release the investigator, sponsor, or institution or its agents from liability for negligence. B ELEMENTS OF INFORMED CONSENT A current sample informed consent document with required phraseology may be found in Appendix B-2. The sample consent form contains all the required elements of consent. The HEC requires that all consent forms be written in the first person, e.g., “I understand that…”. The following are the basic required elements: 1) A statement that the study involves research, an explanation of the purpose of the proposed research, the duration of the subject’s participation, a description of the procedures, and which procedures are experimental; 2) The number of subjects that will be involved with the study, totally and at TMC; 3) A description of reasonably foreseeable risks or discomforts that the subjects may encounter, and, if appropriate, a statement that some risks are currently unforeseeable; 4) A description of possible benefits, if any, to the subject and others which may be reasonably expected. It should be stated that since it is an experimental treatment or procedure, no benefits can be guaranteed; 5) A discussion of possible alternative procedures or treatments, if any, which are available to the subject. One alternative might be to choose not to participate in the research and this will not affect the usual standard of care; 6) A discussion of how confidentiality of records associated with the subject will be maintained; 7) A description of any compensation or reimbursement for time, inconvenience, travel, parking, and other similar costs to the subject; 8) A description of any provisions for treatment of or compensation for research related 33
    • injury; 9) A statement of whom to contact for answers about the research and in the event there is a research related injury. (This is generally the PI or another staff member closely associated with the study.) A separate contact must be named for questions concerning the subject’s rights; 10) A statement that the subjects’ participation is voluntary, that refusal to participate will not involve penalty or loss of benefits to which the subject is entitled, and that the subject may discontinue participation at any time without penalty or loss of benefits; 11) If appropriate, any circumstances under which the subjects participation may be terminated, with or without the subjects consent; and 12) A description of additional costs for which the subject will be responsible, that are likely to result from participation in the research study. C WAIVER OF INFORMED CONSENT The HEC may waive the requirements for obtaining informed consent or approve a consent procedure which does not include, or which alters, some or all of the elements of informed consent listed above, provided that: 1) The research involves no more than minimal risk to the subjects 2) The waiver or alteration will not adversely effect the rights and welfare of the subjects 3) The research could not practicably be carried out without the waiver or alteration; and 4) Whenever appropriate, the subjects will be provided with additional pertinent information after participation. D DOCUMENTATION OF INFORMED CONSENT Informed consent must be documented by the use of a written consent form reviewed and approved by the HEC and signed by the subject or subject’s legally authorized representative. A copy must be given to the subject or person signing the form. For TMC patients, a copy of the signed consent form should also be placed in the subject’s medical record. It is assumed that the consent form is only part of the total consent process in which the investigator, perhaps using the written consent form as an outline, describes all facets of the study and answers the subject’s questions. The investigator is responsible for insuring that research subjects understand the research procedures and risks. Failure of the subjects to ask questions should not be construed as understanding on the part of the subject. 34
    • E RECORD RETENTION REQUIREMENTS FOR SUBJECT CONSENT FORMS 1) The principal investigator or project director shall maintain, in a designated location, all executed subject consents. These consent forms are to be available for inspection by authorized officials of the HEC, DSMSC, regulatory agencies and sponsors. For DGCI/RA regulated test article studies, all signed subject consent forms shall be retained by the principal investigator for the appropriate period(s) specified below. Drugs: Two (2) years following the date a marketing application is approved or the study is discontinued. Devices: Two (2) years after a study is terminated or completed and the records are needed to support DCGI/ RA approval. 35
    • APPENDIX A-11 POLICY FOR DOCUMENTATION OF INFORMED CONSENT I. INFORMED CONSENT PROCESS 1. Informed Consent of Subject : For all biomedical research involving human subjects, the investigator must obtain the informed consent of the prospective subject or in the case of an individual who is not capable of giving informed consent, the consent of a legal guardian. Informed consent is based on the principle that competent individuals are entitled to choose freely whether to participate in research or not. Informed consent protects the individual’s freedom of choice and respect for individual’s autonomy. When research design involves not more than minimal risk (for example, where the research involves only collecting data from subject’s records) the HEC may waive off some of the elements of informed consent. Waiver of informed consent could also be considered during conditions of emergency. However, this would be permissible only if HEC has already approved the study or use of drug. However, the patient or the legal guardian should be informed after she/he regains consciousness or is able to understand the study. 2. Obligations of investigators regarding informed consent : The investigator has the duty to - i. Communicate to prospective subjects all the information necessary for informed consent. There should not be any restriction on subject’s right to ask any questions related to the study as any restriction on this undermines the validity of informed consent. ii. Exclude the possibility of unjustified deception, undue influence and intimidation. Deception of the subject is not permissible. However, sometimes information can be withheld till the completion of study, if such information would jeopardize the validity of research. iii. Seek consent only after the prospective subject is adequately informed. Investigator should not give any unjustifiable assurances to prospective subject, which may influence the subject’s decision to participate in the study. iv. As a general rule obtain from each prospective subject a signed form as an evidence of informed consent (written informed consent) preferably witnessed by a person not related to the trial, and in case of incompetence to do so, a legal guardian or other duly authorised representative. v. Renew the informed consent of each subject, if there are material changes in the conditions or procedures of the research or new information becomes available during the ongoing trial. vi. Not use intimidation in any form which invalidates informed consent. The investigator must assure prospective subjects that their decision to participate or not will not affect the patient - clinician relationship or any other benefits to which they are entitled. 3. Essential information for prospective research subjects: Before requesting an individual’s consent to participate in research, the investigator must provide the individual with the following information in the language he or she is able to understand which should not only be scientifically accurate but should also be sensitive to their social and cultural context : i. the aims and methods of the research; ii. the expected duration of the subject participation; iii. the benefits that might reasonably be expected as an outcome of research to the subject or to others; iv. any alternative procedures or courses of treatment that might be as advantageous to the subject as the procedure or treatment to which she / he is being subjected; 36
    • v. any foreseeable risk or discomfort to the subject resulting from participation in the study; vi. right to prevent use of his / her biological sample (DNA, cell-line, etc.) at any time during the conduct of the research; vii. the extent to which confidentiality of records could be maintained ie., the limits to which the investigator would be able to safeguard confidentiality and the anticipated consequences of breach of confidentiality; viii. responsibility of investigators; ix. free treatment for research related injury by the investigator / institution; x. compensation of subjects for disability or death resulting from such injury; xi. freedom of individual / family to participate and to withdraw from research any time without penalty or loss of benefits which the subject would otherwise be entitled to; xii. the identity of the research teams and contact persons with address and phone numbers; xiii. foreseeable extent of information on possible current and future uses of the biological material and of the data to be generated from the research and if the material is likely to be used for secondary purposes or would be shared with others, clear mention of the same; xiv. risk of discovery of biologically sensitive information; xv. publication, if any, including photographs and pedigree charts. The quality of the consent of certain social groups requires careful consideration as their agreement to volunteer may be unduly influenced by the Investigator. This is accomplished as part of the total consent process by using a consent form that has been reviewed and approved by the HEC. Confusion sometimes arises as to who can obtain consent and who can be designated to sign the consent form. The following are the acceptable methods for documentation of informed consent of human research subjects at TMC: 1. The HEC must be made aware of the person (s) who will be conducting the consent interviews. These faculty/staff members should be the only personnel allowed to obtain consent unless indicated otherwise. The HEC requires that the person obtaining consent is medically trained. 2. Each subject (or their legally authorized representative) must be provided adequate time to read and review the consent form, in addition to being advised of the procedures, risks, potential benefit, alternatives to participation, etc. This is frequently accomplished using the consent form as an outline for the interview process. 3. After completing the consent interview and assuring that the subject (or their representative) has no further questions and agrees to participate in the research activity, the interviewer should instruct the subject to sign and date the consent form in the appropriate spaces. 4. A witness must sign and date in the appropriate spaces. The witness cannot be the person conducting the consent interview, but is not further restricted. 5. The person conducting the consent interview must then sign and date the consent form in the appropriate spaces (PI or designee). It is assumed that in most cases, all persons signing the consent form will do so at the conclusion of the consent interview. 37
    • 6. Each subject (or their representative) must be given a copy of the signed consent form. The original consent form should be filed in such a manner as to insure immediate retrieval when required by auditing entities, HEC, or sponsor monitors. 7. The regulations are clear that written documentation informed consent is required. Therefore, obtaining consent from an authorized third party via the telephone is not acceptable. 8. The regulations also include provisions for approval of a waiver or alteration of part or all of the consent process. The HEC will consider written requests for waiver or alteration of the process when accompanied by sufficient justification. 9. Obtaining informed consent from subjects must be accomplished prior to performing the research activity and using only an HEC approved consent form. Written requests for amendments to an existing consent form must be approved by the HEC prior to implementation. 10. Upon receipt of an HEC approved consent form, all old versions should be discarded to prevent inadvertent use of an outdated consent form. Copies of the most recently approved consent form may be made and should be used until superceded by an amended consent form. The consent form must be reviewed at least annually as part of the continuing review process. 38
    • APPENDIX A-11 POLICY ON REPORTING SERIOUS ADVERSE EVENTS AT TATA MEMORIAL CENTRE APPLICABILITY When a person who is participating in research protocol experiences a serious adverse reaction, the principal investigator is required to report the incident to the HEC. If the adverse events were anticipated as a part of the protocol and the research subject was informed in the consent form, the HEC does not need to be notified unless the adverse event was unexpectedly serious, life threatening or fatal. If the adverse events were unanticipated, required that the subject be hospitalized or death has occurred, the adverse event(s) must be reported to the HEC within 24 hours. If the research project is being supported with funds from outside the institution, the investigator is responsible also for notifying the sponsor. The sponsor may also be required to notify the DCGI/RA or other government agencies within 24 hours of the occurrence of the adverse event(s). If the faculty member holds an Investigational New Drug (IND) or Investigational Device Exemption (IDE) in his/her name, he/she is required to notify the DGCI/RA within 24 hours of any unanticipated adverse reactions in addition to notifying the HEC. Notifying the HEC does not relieve the investigator from his/her responsibility to notify the sponsor, DGCI/RA. PROCEDURES Within 24 hours of learning about an adverse event, the principal investigator is responsible for notifying the HEC Office. The investigator is to submit a written report to the HEC within 10 working days. 39
    • Appendix A-12 EXAMPLES OF CATEGORIES OF RESEARCH THAT MAY BE REVIEWED BY THE HEC THROUGH AN EXPEDITED REVIEW PROCEDURE An expedited review procedure consists of a review of research involving human subjects by the HEC chairperson or by one or more experienced reviewers designated by the chairperson from among members of the HEC. Applicability A Research activities that 1present no more than minimal risk to human subjects, and 2involve only procedures listed in one or more of the following categories, may be reviewed by the HEC through the expedited review procedure. The activities listed should not be deemed to be of minimal risk simply because they are included on this list. Inclusion on this list merely means that the activity is eligible for review through the expedited review procedure when the specific circumstances of the proposed research involve no more than minimal risk to human subjects. B The categories in this list apply regardless of the age of subjects, except as noted. C The expedited review procedure may not be used where identification of the subjects and/or their responses would reasonably place them at risk of criminal or civil liability or be damaging to the subjects' financial standing, employability, insurability, reputation, or be stigmatizing, unless reasonable and appropriate protections will be implemented so that risks related to invasion of privacy and breach of confidentiality are no greater than minimal. D The standard requirements for informed consent (or its waiver, alteration, or exception) apply regardless of the type of review, expedited or convened, utilized by the HEC. E Categories one (1) through seven (7) pertain to both initial and continuing HEC review. 1Clinical studies of drugs and medical devices only when condition a or b is met. a Research on drugs for which an investigational new drug application is not required. (Note: Research on marketed drugs that significantly increases the risks or decreases the acceptability of the risks associated with the use of the product is not eligible for expedited review.) b Research on medical devices for which iian investigational device exemption application is not required; or iiithe medical device is cleared or approved for marketing and the medical device is being used in accordance with its cleared/approved labeling. 2Collection of blood samples by finger stick, heel stick, ear stick, or venipuncture as follows: afrom healthy, non-pregnant adults who weigh at least 110 pounds. For these subjects, the amounts drawn may not exceed 550 ml in an 8 week period and collection may not occur more frequently than 2 times per week; or 40
    • b from other adults and children, considering the age, weight, and health of the subjects, the collection procedure, the amount of blood to be collected, and the frequency with which it will be collected. For these subjects, the amount drawn may not exceed the lesser of 50 ml or 3 ml per kg in an 8 week period and collection may not occur more frequently than 2 times per week. 3 Prospective collection of biological specimens for research purposes by noninvasive means. Examples: a hair and nail clippings in a non-disfiguring manner; b deciduous teeth at time of exfoliation or if routine patient care indicates a need for extraction; c permanent teeth if routine patient care indicates a need for extraction; d excreta and external secretions (including sweat); e uncannulated saliva collected either in an unstipulated fashion or stimulated by chewing gumbase or wax or by applying a dilute citric solution to the tongue; f placenta removed at delivery; g amniotic fluid obtained at the time of rupture of the membrane prior to or during labor; h supra- and subgingival dental plaque and calculus, provided the collection procedure is not more invasive than routine prophylactic scaling of the teeth and the process is accomplished in accordance with accepted prophylactic techniques; i mucosal and skin cells collected by buccal scraping or swab, skin swab, or mouth washings; j sputum collected after saline mist nebulization. 4 Collection of data through noninvasive procedures (not involving general anesthesia or sedation) routinely employed in clinical practice, excluding procedures involving x-rays or microwaves. Where medical devices are employed, they must be cleared/approved for marketing. (Studies intended to evaluate the safety and effectiveness of the medical device are not generally eligible for expedited review, including studies of cleared medical devices for new indications.) Examples: a physical sensors that are applied either to the surface of the body or at a distance and do not involve input of significant amounts of energy into the subject or an invasion of the subject's privacy; b weighing or testing sensory acuity; c magnetic resonance imaging; d electrocardiography, electroencephalography, thermography, detection of naturally occurring radioactivity, electroretinography, ultrasound, diagnostic infrared imaging, doppler blood flow, and echocardiography; e moderate exercise, muscular strength testing, body composition assessment, and flexibility testing where appropriate given the age, weight, and health of the individual. 5 Research involving materials (data, documents, records, or specimens) that have been collected or will be collected solely for non-research purposes (such as medical treatment or diagnosis). 6 Collection of data from voice, video, digital, or image recordings made for research purposes. 7 Research on individual or group characteristics or behavior (including, but not limited to, research on perception, cognition, motivation, identity, language, communication, cultural beliefs or practices, and social behavior) or research 41
    • employing survey, interview, oral history, focus group, program evaluation, human factors evaluation, or quality assurance methodologies. 8 Continuing review of research previously approved by the convened HEC as follows: A where (i) the research is permanently closed to the enrollment of new subjects; (ii) all subjects have completed all research-related interventions; and (iii) the research remains active only for long-term follow-up of subjects; or B where no subjects have been enrolled and no additional risks have been identified; or C where the remaining research activities are limited to data analysis. 9 Continuing review of research, not conducted under an investigational new drug application or investigational device exemption where categories two (2) through eight (8) do not apply but the HEC has determined and documented at a convened meeting that the research involves no greater than minimal risk and no additional risks have been identified. 42
    • Appendix A-13 HEALTH RECORD RESEARCH The following is the HEC policy concerning research involving the study of medical records or other forms of health information. Research projects may involve the study of Patient case files with the stipulations described below. Such studies raise issues of confidentiality that must be carefully addressed by the investigator and the official custodian of the records. If it is anticipated that an individual's records or specimens will likely be used for research purposes, the potential subject should be informed of the potential use of such materials upon entry into the institution or program in which the materials will be developed or collected and be given an opportunity to either provide or refuse consent to such research. Patient case files may always be used or disclosed for research purposes if it has been de-identified and linkage back to a specific patient would not be possible. To use or disclose identifiable Patient case files without authorization of the research participant, the investigator must accomplish one of the following: 1) complete and submit an HEC Form to request waiver of the requirements for obtaining informed consent; 2) provide written documentation that the use of disclosure of patient case files is solely used to design a research protocol or to assess feasibility of conducting a study, or; 3) document that the use or disclosure is solely for research on the patient case files of decedents. Investigators must maintain in their files a letter from the HEC identifying the date on which the waiver or alteration of the requirements to obtain informed consent was approved by the HEC, and a statement that the HEC has determined that the waiver or alteration satisfies the following criteria: 1) The use or disclosure of patient case files involves no more than minimal risk to the research participants; 2) The alteration or waiver will not adversely affect the privacy rights and welfare of the subjects; 3) The research cannot practicably be conducted without the alteration or waiver; 4) The research could not practicably be conducted without access to or the use of the patient case files; 5) The privacy risks to individuals whose Patient case files is to be used or disclosed are reasonable in relation to the anticipated benefits, if any, to the individuals, and the importance of the knowledge that may reasonable be expected to result from the research; 6) There is an adequate plan to protect the identifiers from improper use and disclosure; 7) There is an adequate plan to destroy the identifiers at the earliest possible opportunity consistent with the conduct of the research, unless there is a health or research justification for retaining the identifiers, and; 43
    • 8) There are adequate written assurances that the Patient case files will not be reused or disclosed to any other person or entity, except as required by law, for authorized oversight of the research project, or for other research for which the use or disclosure of Patient case files would be permitted by this policy. The HEC letter should also contain a brief description of the Patient case files for which use or access has been determined by the HEC to be necessary, a statement that the waiver or alteration was approved by Expedited Review or at a convened meeting, and the letter should be signed by the HEC Chair or the Chair’s designee. Research use or disclosure of identifiable Patient case files with authorization of the research participant is permitted providing that use or disclosure is for only the Patient case files that was originally authorized. In order to use or disclose additional information, the investigator would either have to obtain consent or request a waiver of the requirements to obtain consent. 44
    • Appendix A-14 GUIDELINES FOR RESEARCH PROTOCOLS WHICH REQUIRE COLLECTION AND STORAGE OF GENETICS MATERIALS For the purpose of these guidelines, "Genetic Materials" are defined as human tissue samples (blood, serum, tumor, etc.) on which genetic related research, such as biochemical studies of inherited human traits or identification of DNA mutations, may be performed. A. Previously acquired samples 1. Previously acquired genetic material may be used if identifiers are stripped irrevocably from samples. 2. If identifiers are present, experiments not described in present protocols must be submitted for HEC review. B. Prospectively acquired samples 1. Anonymous samples (further identification made impossible) a) Ownership of genetic material will generally remain with the institution. This must be stated in the consent form. b) The general scope of the investigations must be explained in the consent form, but new avenues of investigation in the future are permissible if this possibility is explained in the consent form. c) Whether the genetic material will be shared by other investigators should be explicit in the consent form. d) The consent form should make clear that no specific information relative to the individual donor will be forthcoming; however, information that accrues from the study that is valuable to society may be shared with the individual. 2. Identified samples a) If genetic material is linked to the donor by specific identifiers, ownership of the material will generally remain with the institution. If a commercial use is anticipated for the genetic material, the individual must be notified. The general policy of ownership should be stated in the consent form using the following wording: "I understand that additional or "leftover" (blood, serum, tumor, etc.) tissue may be used for future research which may result in financial gain for TMC and the researchers. I also understand that my donated tissue will be one of many that are used in the research and it will be virtually impossible to attribute findings to any one sample. I understand, however, that I am not otherwise waiving any of my legal rights by participating in this study." b) If identifiers are present, new experiments must be reviewed by the EC and new consent obtained from the research participant regardless of the details of ownership. 45
    • c) The investigator may include a provision in the consent form for new experiments not requiring new consent if identifiers are irrevocably removed from the samples. If the investigator anticipates future experiments without identifiers, this possibility should be present in the original consent form. The methods for removal of identifiers must be approved by the EC. Removal of identifiers must not be employed as a method of avoiding ownership issues. d) A satisfactory method for sharing or withholding information gained by the research must be in the research protocol and clearly indicated in the consent form. e) Details for sharing or not sharing the genetic material with other investigators must be present in the protocol and clearly indicated in the consent form. f) The length of time the genetic material will be maintained must be indicated in the consent form. C. Donation of genetic material as a requirement for participation in a research protocol. 1. Donation of genetic material may be required for participation in a protocol only if the presence of the genetic material is necessary to satisfy the central question of the research. 2. The investigator will be required to make a clear case in the research protocol for the necessity of the genetic material, if donation of genetic material is mandatory. 3. This policy applies to genetic material with or without identifiers. 46
    • Appendix A-15 GUIDELINES FOR SUBMISSION AND EC REVIEW OF GENE THERAPY/GENE TRANSFER PROTOCOLS As of October 10, 2000 the ICMR formulated Ethical Guidelines for Biomedical Research on Human Subjects. ICMRs goal is to insure that no research participant is enrolled in a human gene therapy/gene transfer research protocol before the local HEC have the benefit of the broad perspective and experience in protocol review and risk assessment. In November 2001, the Department of Biotechnology also finalised the Ethical Policies on the Human Genome, Genetic Research and Services. Guidelines are available at the Office of Biotechnology Activities Internet site http://dbtindia.nic.in/ethical.html The following items are required to be addressed in the protocol to provide the necessary information for EC review: A Background and justification • Why is this disease a good candidate for gene transfer or gene therapy? • What previous work has been done, including studies of animals and cultured cell models? Does the work demonstrate effective gene delivery? How does the proposed study relate to previous work? • Is the disease course sufficiently predictable to allow for meaningful assessment of the results of the treatment proposed? • What level of gene expression is presumed to be required to achieve the desired effect? • Given responses to the above questions, is there a sufficient justification for the investigator to proceed at this point to a clinical trial? B Research design • What are the objectives of the proposed study (e.g., establishing feasibility or relative safety of the gene transfer, determining therapeutic effectiveness, establishing a safe dose range, demonstrating proof of principle, etc.)? • Is the goal of the study to ameliorate or cure disease or to enhance healthy individuals? • What is the target tissue for gene transfer (e.g., bone marrow cells, skeletal muscle cells, respiratory epithelial cells, central nervous system tissue, etc.)? • What method(s) (e.g., direct injection, inhalation, ex vivo genetic modification with injection of modified cells) and reagent(s) (e.g., vectors based on retroviruses, adenoviruses, adeno- associated viruses, herpes viruses) will be employed for gene delivery? What is the 47
    • rationale for their use? Are other methods or reagents known that are more appropriate with regard to efficacy, safety, and stability? • How will the investigator determine the proportion of cells that acquires and expresses the added DNA? • How will the investigator determine if the product is biologically active? • Is the planned statistical treatment appropriate: i.e., is it likely to provide valid answers to the study question? • Is it reasonable to expect that the research design proposed will meet the investigator’s objectives? C Procedures • What research-specific procedures and research-specific investigations are required by the study over and above those that would be required for patients receiving standard clinical care (e.g., physical examinations, venous or arterial blood tests, collection of target cells, imaging procedures, irradiation, chemotherapy, direct injection of vector, re-injection of genetically modified cells, organ or tissue transplantation, surgery, tissue/tumor donation, questionnaires, interviews)? • Is long term follow-up appropriate or essential for this protocol? If long term follow-up is proposed, is there justification for the number of visits and the length of time required? Is such follow-up feasible in the case of this protocol (e.g., have provisions been made for subjects who move? Is adequate funding available for such follow-up?)? • What are the procedures for obtaining or maintaining information in a data/DNA bank (e.g., use of identifiers, limitation on access, need for consent, sharing with other investigators, duration of storage, future subject contact)? • Are all of the research-specific procedures necessary? In combination with data collected in the course of clinical care, is it reasonable to expect that the information produced by this study will be sufficient to answer the research question? D Confidentiality • Are the practical steps for maintaining confidentiality of data/records/database information clearly specified and adequate (e.g., encryption, use of unique identifiers, sequestering of records, security measures)? E Subject selection • How has the study population been defined? • Has an adequate rationale been provided for each eligibility criterion (e.g., safety considerations, definition of disease, avoidance of additional concurrent therapies, administrative considerations)? Do they strike a defensible balance between scientific 48
    • validity and generalizability (i.e., is the study population sufficiently, but not unduly, restricted so as to yield interpretable results)? • How will subjects be recruited? If a cohort of eligible patients exists, how will selection be made amongst them? If several trials exist for which the same patients are eligible, how will this be presented to prospective subjects? • Does the definition of the research population reflect appropriate scientific, clinical, and ethical norms? In recruiting and negotiating with potential subjects, have the norms of nondiscrimination been respected? F Risks, discomforts, and benefits • What risks and discomforts are associated with the research-specific procedures and investigations (e.g., surgery, chemotherapy, radiation, bone marrow transplantation)? Have they been minimized? • If a virus-mediated gene transfer is proposed, what is the potential for the presence of a replication-competent or pathological virus or other form of contaminants? How sensitive are the tests to detect such viruses or contaminants? What level of viral presence or other form of contamination would be tolerable in this protocol? • Has the possibility of vertical transmission (i.e., gene insertion into germ cells or a fetus) or horizontal transmission (e.g., to family members or health care staff) been considered? What measures have been taken to minimize the risks of transmission? Are other measures possible? If transmission were to occur, what would be the consequences? • What are the risks for the vector to activate an oncogene or inactivate a tumor suppressor gene leading to vector-related malignancy? • Are the risks and discomforts of the study justified given the potential benefit to subjects and the scientific importance of the research? F Information to subjects • Have prospective participants been adequately informed of the following: 1. What is being studied and why, giving details about study procedures, known or potential risks, discomforts and benefits, and alternatives to participation; 2. Their rights: (a) to information on an ongoing basis, confidentiality with regard to their participation and handling of their data, and the right to consult with others before making a decision whether to participate; and (b) to withdraw from the study without penalty or loss of benefits, as well as of any health consequences of withdrawal for themselves or their immediate contacts, or limitations on withdrawal, if any; 3. Any special issues related to this gene therapy trial, such as uncertainty associated with short and long term risks and benefits or the possibility of media attention; and 4. Any commercial or financial interests in the research. 49
    • • Have prospective participants been provided this information in simple language, using translation where necessary, with answers to their questions, referral to other sources of information, and adequate time to make up their minds whether to participate? • If there is no individual benefit from participation in the research, has this been appropriately disclosed? • Will the general study results be made available to subjects? • Do all of the elements of the consent process combine to allow subjects a full opportunity to make an informed choice? 1. Reference: Ethical Guidelines for Biomedical Research on Human Subjects ICMR 2000 50
    • APPENDIX A-16 HEC POLICY FOR DATA AND SAFETY MONITORING IN CLINICAL RESEARCH Concerns for assuring the safety and welfare of subjects participating in clinical research studies have prompted the issuance of guidance and policies on oversight of clinical trials. More specifically, investigators are now required to establish plans for ongoing, real time data and safety monitoring. Specific responsibility for and methods of data and safety monitoring depend on the sponsor of the study and the phase of the study. The methods and amount of monitoring required are somewhat dictated by the degree of risk involved to the individual subjects and the complexity of the clinical research. Some clinical research activities may require the establishment of a Data and Safety Monitoring Board/Committee to review interim analyses of data and cumulative toxicity data to determine if the research activities should continue as originally designed, be changed, or be terminated. The following policy describes the parties responsible for data and safety monitoring and the acceptable methods of conducting the monitoring. Industry Sponsored For these types of studies, it is the responsibility of the sponsor (person or persons initiating the clinical trial) to notify the DCGI/RA of any serious and/or unexpected adverse event. Most sponsors establish their own Data and Safety Monitoring Committee (DSMC) to review interim analysis, toxicity data and adverse events, and recommend a course of action to the sponsor if it appears that there are unreasonable risks to subject safety. Investigators are required to promptly report adverse events to the HEC and the sponsor. If review of adverse event reports from TMC or other sites raises concerns that subject safety and welfare are at increased risk, the HEC may suspend the study locally even if the sponsor decides to continue with the study. Supported Studies 1. Phase I and II studies may be monitored by the investigator/project manager, or a designee, or by both. There is no requirement for establishment of a DSMC but there is a requirement for written policies and procedures that describe the monitoring and reporting processes. HEC must approve these policies and procedures. 2. Phase III clinical studies must be monitored by a DSMC. If the studies are to be conducted at multiple sites, the DSMC must be established by the “study leadership” that may or may not be at TMC. The HEC must be informed of the composition and location of the DSMC in either case. In addition, a plan for DSMC submission of a periodic summary of adverse events to the HEC must be in place. This does not relieve the investigator of his/her responsibility of promptly reporting adverse events that occur at TMC. 51
    • Investigator Initiated Clinical Studies Investigator initiated studies are defined as clinical research activities with a drug or device that are not supported by or solicited by an industry sponsor, although the study may receive support from an industry sponsor. The Data and Safety Monitoring Sub Committee of the HEC will monitor the studies at TMC sites. If they involve multiple sites with a TMC investigator acting as the “study leadership”, an independent DSMC must be established. Detailed information of the Data and Safety Monitoring Subcommittee is available in the SOPs of the DSMSC. 52
    • APPENDIX A-17 POLICY FOR SUBMISSION OF AUDIT REPORTS The HEC is responsible for local oversight of all human subject research and for assuring, to the greatest extent possible, the safety and welfare of the research subjects. To carry out its responsibilities, the HEC reviews all new proposals, provides continuing review of research activities, reviews adverse event reports, and, if necessary, undertakes on-site audits of investigator research records. Conducting research utilizing human subjects, by regulation and from a practical standpoint, is based on a system of trust in the integrity of the investigator. Specifically, the HEC trusts that the investigator will conduct responsible research and keep the safety and welfare of the subjects in mind at all times. It also assumes that when inadvertent protocol deviations occur, the investigator will notify the HEC of the deviation and the corrective actions taken to prevent future occurrences. Oversight of clinical trials may occur by several methods, one of which is the audit process conducted by a Contract Research Organization (CRO), sponsor monitor etc. The audit process, often viewed in a negative sense, can also be viewed as a valuable oversight function. The audits may identify potential issues of concern regarding subject safety and welfare that can be corrected, thereby preventing injury to a research subject. It is the policy of the HEC that a copy all reports of audits performed by CROs, sponsor monitors, or any other external or internal entity is submitted to the HEC/DSMSC promptly upon receipt of the report from the auditing entity. This policy exists to ensure oversight by the HEC and appropriate TMC officials so that research subjects may be better protected. 53
    • APPENDIX B – FORMS 54
    • APPENDIX B1 REPORT FORM FOR ADVERSE EVENTS IN HUMAN SUBJECTS AT TATA MEMORIAL CENTRE Within 24 hours of learning about an adverse event, the principal investigator is responsible for notifying the HEC. Within 10 working days the principal investigator is to submit a written report to the HEC in the following format: 1) The title of the project is: The principal investigator is: Summary of subject with the adverse event: Case No. Sex: M F Age: 2) Please provide a succinct description of the adverse events (who, what, where and when) and attach any other pertinent documentation. (Please indicate if this is a follow- up report and if so, include follow-up information only.) 3) Describe the specific adverse event and check all that apply. Anticipated Event Unanticipated Event Death Hospitalization Significant Disability Other 4) Describe the medical treatment (if any) that was provided to the research subject and the subject’s response. 5) How far into the protocol had the subject progressed before the adverse event occurred? 6) What is the long-term prognosis of the patient and will the patient continue to receive treatment? 7) Was the research subject continued on the research protocol? yes no 8) In your opinion, was the adverse event a result of participation in the research protocol? probably possibly unlikely unknown or not enough information to judge 9) Please provide your estimation of the severity of the event by circling the appropriate number associated with the descriptions below: 0. No Disability: No significant resultant discomfort; no cosmetic or functional impairment, and no increased length of stay or significant use of additional resources as a result of the AE. 1. Minor Temporary: Minimal to moderate clinical effect requiring no or minimal clinical intervention, or no increased length of stay or re-hospitalization for the same or related problem. 2. Minor Permanent: Minimal to moderate clinical effect with permanent residual effect but without significant functional or cosmetic impairment. 3. Major Temporary: Moderate to severe clinical effect with no significant cosmetic or functional residual effect. This usually results in increased length of stay or re- hospitalization and requires moderate to major clinical intervention. 55
    • 4. Major Permanent: Moderate to severe clinical effect with significant functional or cosmetic residual effect. 5. Potential Major or Major Continuing: When doubt exists as to the outcome, but the probability is that major impairment or repeated re-hospitalization will be necessary. 6. Death. 10) a) Was the protocol followed in recruitment of the subject? yes no b) Did the patient meet the exclusion/inclusion criteria of the protocol? yes no c) Was informed consent obtained as outlined in the protocol? yes no If no to any part of question 8, please explain: 11) In your opinion, does this report require that the consent form for subjects be revised? _____ no_____ yes If yes, submit two revised consent forms. One with the proposed changes emphasized in some fashion (highlighter, bolded, etc.) and another clean copy. Signature of PI Date Upon receipt of this report, the HEC/DSMSC will decide whether additional information is needed or whether further investigation of the incident is required. Do Not Write Below This Line. For HEC Use Only. I agree disagree with the assessment of the principal investigator. DSMSC Reviewer Date Explanation: 56
    • 1 APPENDIX B-2 SUBJECT CONSENT FORM SAMPLE CONSENT FORM INFORMED CONSENT Title of Protocol You are invited to participate in a study of (state what is being studied). We hope to learn (state what the study is designed to discover or establish). You were selected as a possible participant in this study because (state why the subject was selected). Your participation in this study is entirely voluntary. Your decision whether or not to participate will not prejudice you or your medical care. If you decide to participate, you are free to withdraw your consent and to discontinue participation at any time without prejudice to you or effect on your medical care. If you decide to participate, we (or Dr. _______ and his or her associates) will (describe procedures to be followed, including their purposes, how long they will take and their frequency). (Describe the discomforts and inconveniences reasonably to be expected and the amount of blood to be drawn, if any.) (Describe any reasonably foreseeable risks.) (State the approximate number of subjects to be enrolled, and the total time subjects will be involved.) (Describe any benefits that may be reasonably expected.) (After describing the potential benefits, state:) WE CANNOT AND DO NOT GUARANTEE OR PROMISE THAT YOU WILL RECEIVE ANY BENEFITS FROM THIS STUDY. You will be told if any new information is learned which may affect your condition or influence your willingness to continue participation in this study. While participating in this study, you should not take part in any other research project without approval from all of the investigators. This is to protect you from possible injury arising from such things as extra blood drawing, extra x-rays, interaction of research drugs, or similar hazards. Describe appropriate alternative procedures, if any, that might be advantageous to the subject. Any standard treatment that is being withheld must be disclosed. If there is no alternative treatment state: "the alternative is not to participate". Any data that may be published in scientific journals will not reveal the identity of the subjects. Patient information may be provided to Governmental and regulatory agencies as required. (If applicable, state the persons or agencies to whom the information will be furnished and the nature of the information to be furnished). (Please include the amount of payment, if any, and the schedule of payment.) If payment is made in money or gifts the following statement must be included (verbatim): If the patient will not be paid please use the following statement- No payment will be provided for participation in this project. 57
    • (Please include information regarding the cost of participating in the study.) The sponsor will pay for _________. You or your insurance company will be responsible for ________________. (Disclose what institution(s) or companies are involved in the study through funding, cooperative research, or by providing study drugs or equipment. The following generic disclosure is acceptable __________________________________ (Name of institution /company) is providing financial support and/or material for this study. (If consultative or financial relationships exist, include the following statement): One or more of the investigators has a (state whether paid or unpaid) consultative and/or financial relationship with the sponsoring organization(s) involved in this research. At the discretion of the protocol director subjects may be taken out of this study due to unanticipated circumstances. Some possible reasons for withdrawing a subject from the study. (Note to investigator: you may use these reasons and/or add some of your own). - failure to follow instructions - the investigator decides that continuation could be harmful to you - you need treatment not allowed in the study - the study is canceled - other administrative reasons (If this study falls within the jurisdiction of the DCGI, use the following sentences:) 1) The purpose of this research is to obtain data or information on the safety and effectiveness of (name of drug, device, etc.); the results will be provided to the sponsor, Drug Controller General of India, the Food and Drug Administration and other agencies as required. 2) If you think you have experienced a research related injury call name of doctor at phone number. If you have any questions, we expect you to ask us. If you have any additional questions later, (doctor's name) at (doctor's telephone number) will be happy to answer them. If the study includes MRI (Magnetic Resonance Imaging) include the following: 1 MRI (Minimal revisions may be made to fit your study) This MRI machine uses a strong magnet and radio waves to make images of the body interior. The scanning procedure is very much like an x-ray CT scan. You will be asked to lie on a long narrow couch for a certain amount of time (state how long) while the machine gathers data. During this time you will not be exposed to x-rays, but rather a magnetic field and radio waves. You will not feel either. You will, however, hear repetitive tapping noises that arise from the radio antenna around your body. We will provide earplugs or ear phones that you will be required to wear. The space within the large magnet in which you lie is somewhat confined, although we have taken many steps to relieve the "claustrophobic" feeling. There are no known significant risks with this procedure at this time because the radio waves and magnetic fields, at the strengths used, are thought to be without harm. The exception is if you 58
    • have a cardiac pacemaker, or a certain type of metallic clip in your body (i.e., an aneurysm clip in your brain). There is a possibility that you will experience a localized twitching sensation due to the magnetic field changes during the scan. This is not unexpected and should not be painful. However, you can discontinue the exam at anytime. The magnetism and radio waves do not cause harmful effects at the levels used in the MRI machine. National and Stanford guidelines have been developed for these machines, and these recommendations will be followed. However, because the MR scanner uses a very strong magnet that will attract metal, all metallic objects must be removed from your person before you approach the scanner. In addition, watches and credit cards should also be removed as these could be damaged. (These items will be watched for you). RISKS: If you have any history of head or eye injury involving metal fragments, if you have ever worked in a metal shop, if you have some type of implanted electrical device (such as a cardiac pacemaker) , if you have severe heart disease (including susceptibility to arrhythmias), if you are wearing metal braces on your teeth, or ( for women) if you could be pregnant, you should not have an MR scan. (optional – only if MRI is done in hospital) If you wish, we can prescribe a mild sedative to help you to relax during the scan session. Because you may still feel sleepy after taking this medication, you should not plan on driving yourself after the MRI. NOTE: IF ALL OF THE SEQUENCING TO BE USED HAS NOT BEEN APPROVED BY THE FOOD AND DRUG ADMINISTRATION, THIS MUST BE STATED IN THE CONSENT FORM. (The following language is recommended when women of childbearing potential (non- pregnant) will be enrolled in an investigational drug study.) WOMEN OF CHILDBEARING POTENTIAL If you are a woman who is able to become pregnant, it is expected that you will use an effective method of birth control to prevent exposing a fetus to a potentially dangerous agent with unknown risk. If you are pregnant or currently breast feeding, you may not participate in this drug study. You understand that if you are pregnant, if you become pregnant, or if you are breast-feeding during this study, you or your child may be exposed to an unknown risk [or state specific risk]. To confirm to the extent medically possible that you are not pregnant, you agree [to have a pregnancy test done before beginning this research study] [to begin the study after the onset of your next menstrual period] (choose one). You must agree to avoid sexual intercourse or use a birth control method judged to be effective by the investigator and which will not interfere with the proposed investigation. You must accept the risk that pregnancy could still result despite the responsible use of reliable method of birth control. You agree to notify the investigator as soon as possible of any failure of proper use of your birth control method, or if you become pregnant, either of which may result in your being withdrawn from the study. 59
    • CONSENT FOR TISSUE SAMPLING OR BANKING FOR RESEARCH Research using tissues is an important way to try to understand human disease and/or the role genes play in disease. You have been given this consent form because the investigators want to include your tissues in a research project, or because they want to save such samples for research. There are several things you should know before allowing your tissues to be studied: 1. You are invited to participate in a study of-----------------------------------------------------------------------. We hope to learn (state what the study is designed to discover or establish). You were selected as a possible participant in this study because (state why the subject was selected). 2. Your tissues will be stored [under your name or other unique identifier] (choose one). Your name or other public identifiers will not be included with any data shared with other investigators. OR Once the sample is taken, it will forever be separated or unlinked from your name. This will protect your identity and preserve anonymity. However, once you donate the sample, you will not be able to withdraw your tissues from the research project because the samples will not be traceable. 3. There are no risks involved in research on the samples provided by you. 4. You will be told the results of the tests, but not of any other research tests in the future. OR You will not be told the results, even if there might be some potential benefit to you. 5. You have the right to refuse to allow your tissues to be studied now or saved for future study. You may withdraw from this study at any time. The investigators might retain the identified samples, e.g., as part of your routine clinical care, but not/and for additional research. 6. The investigator will not provide genetic information about you to your familly members, but you may wish to. OR You [ consent / withhold consent ] for the investigator to provide genetic information about you to your family members. 7. Investigators in this study may try to recontact you in the future. If you are, understand the following possibilities: Information may be too sketchy to give you particular details or consequences. You may be determined to carry a gene for a particular disease that can be treated. You may be determined to carry a gene for a particular disease for which there is no current treatment. 8. Any tissues you have donated which are used in research may result in new products, tests or discoveries. In some instances, these may have potential commercial value and may be developed and owned by the Investigators, of TMC or others. However, donors of tissues 60
    • do not retain any property rights to the materials. Therefore, you would not share in any financial benefits from these products, tests or discoveries. Signature of Participant Date ________________________________ Person Obtaining Consent I attest that the requirements for informed consent for the medical research project described in this form have been satisfied. I have discussed the research project with the participant and explained to him or her in nontechnical terms all of the information contained in this informed consent form, including any risks and adverse reactions that may reasonably be expected to occur. I further certify that I encouraged the participant to ask questions and that all questions asked were answered. ________________________________ ___________________ Signature of Person Obtaining Consent Date ________________________________ ____________________ Signature of Parent or Guardian Date (If consent is to be obtained from a parent(s), legal guardian CONSENT FOR GENE THERAPY STUDIES (If the protocol involves gene therapy the following two items must be included): 1.) The approximate number of people who have previously received the genetic material under the study; 2.) "To obtain vital information about the safety and efficacy of gene transfer, at the time of death, no matter what the cause, permission for an autopsy will be requested of your family. Please advise your family of this request and of its scientific and medical importance". *All forms of medical diagnosis and treatment -- whether routine or experimental -- involve some risk of injury. In spite of all precautions, you might develop medical complications from participating in this study. If such complications arise, the researchers will assist you in obtaining appropriate medical treatment but this study does not provide financial assistance for additional medical or other costs. (Additionally TMC is not responsible for research and medical care by other institutions or personnel participating in this study.) You do not waive any liability rights for personal injury by signing this form. In addition, if you are not satisfied with the manner in which this study is being conducted or if you have any questions concerning your rights as a study participant, please contact the Ethics Committee Tata Memorial Hospital. *Please add the following Bill of Rights to your consent. As a human subject you have the following rights. These rights include but are not limited to the subject's right to: ۰ be informed of the nature and purpose of the experiment; ۰ be given an explanation of the procedures to be followed in the medical experiment, and any drug or device to be utilized; ۰ be given a description of any attendant discomforts and risks reasonably to be expected; 61
    • ۰ be given an explanation of any benefits to the subject reasonably to be expected, if applicable; ۰ be given a disclosure of any appropriate alternatives, drugs or devices that might be advantageous to the subject, their relative risks and benefits; ۰ be informed of the avenues of medical treatment, if any available to the subject after the experiment if complications should rise; ۰ be given an opportunity to ask questions concerning the experiment or the procedures involved; ۰ be instructed that consent to participate in the medical experiment may be withdrawn at any time and the subject may discontinue participation without prejudice; ۰ be given a copy of the signed and dated consent form; ۰ and be given the opportunity to decide to consent or not to consent to a medical experiment without the intervention of any element of force, fraud, deceit, duress, coercion or undue influence on the subject's decision. NOTE: The following paragraph and signature lines should appear on a page with another part of the consent, it should not start a page. YOUR SIGNATURE INDICATES THAT YOU HAVE READ AND UNDERSTAND THE ABOVE INFORMATION, THAT YOU HAVE DISCUSSED THIS STUDY WITH THE PERSON OBTAINING CONSENT, THAT YOU HAVE DECIDED TO PARTICIPATE BASED ON THE INFORMATION PROVIDED, AND THAT A COPY OF THIS FORM HAS BEEN GIVEN TO YOU. ________________________________ ________________ Signature of Participant Date Person Obtaining Consent I attest that the requirements for informed consent for the medical research project described in this form have been satisfied – that the participant has been provided with the Experimental Subject’s Bill of Rights, if appropriate, that I have discussed the research project with the participant and explained to him or her in nontechnical terms all of the information contained in this informed consent form, including any risks and adverse reactions that may reasonably be expected to occur. I further certify that I encouraged the participant to ask questions and that all questions asked were answered. ________________________________ ___________________ Signature of Person Obtaining Consent Date (If consent is to be obtained from a parent(s), legal guardian or conservator, signature line(s) for Parent or Guardian must be included on the consent form.) ________________________________ ____________________ Signature of Parent or Guardian Date *Approval Date: ____________________ Expiration Date: __________________ 62
    • RECOMMENDED TERMS FOR USE IN CONSENT FORMS To facilitate understanding of consent forms by the subject, it is recommended that the language used is at a reading level of an 12 year old. The following lay terms, definitions and suggestions are recommended to help investigators in this process. Term Lay Definition abdominal the body cavity containing the stomach, intestines, liver, and other organs acute new; recent; sudden adjuvant helpful; assisting; aiding adverse effect bad side effect agitation upset allergic reaction itching and swelling; rash; trouble breathing ambulate (-ation –ory) walk; able to walk; ability to walk ameliorate make smaller or less, reduce analgesia pain relief anaphylactic reaction a severe and sometimes dangerous reaction which may cause problems breathing, fainting, itching and skin rash anemia low red blood cell count anesthetic (local) a drug used to decrease the feeling of pain by numbing an area of the body, without putting you to sleep. anesthetic (general) a drug used to decrease the feeling of pain or eliminate the feeling of pain by putting you to sleep. anorexia lack of appetite arrhythmia abnormal heartbeat aspiration removal by using a sucking machine; fluid entering the lungs asymptomatic without symptoms; having no symptoms barrier method diaphragm and condom (with spermicide), cervical cap, or sponge 63
    • benign not malignant; usually without serious consequences bolus an amount given all at once bradycardia slow heartbeat carcinogenic capable of causing cancer carcinoma a type of cancer cardiac heart catheter a tube in a vein for withdrawing or putting fluids into my blood central nervous system the brain and spinal cord cerebral the brain; of the brain cessation stopping CHD coronary heart disease; heart disease chemotherapy treatment of a disease, usually cancer, with chemical agents chronic continuing for a long time clinical status state of health, how you are doing and feeling clinical trial an experiment in patients completed done congenital occurring prior to birth, due to parent’s genetic input conjunctivitis irritation and redness of the thin covering of the eye consequences result or effects controlled trial study in which the experimental treatment is compared to a standard treatment conventional therapy standard treatment coronary pertaining to the blood vessels that supply the heart CT (CAT) scan computerized series of x-rays cutaneous relating to the skin culture take a sample of blood, fluid, or tissue to see if bacteria or viruses can be found in it 64
    • dehydration loss of fluids dermatologic pertaining to the skin diastolic the lower number in a blood pressure reading dilation expansion or stretching discomfort pain; uncomfortable feeling disseminated widely-spread, all through the body distal toward the end; away from the center of the body diuretic water pill; drug that causes an increase in urination double-blind neither the subject nor physician can know what is being given dysfunction improper function dysplasia abnormal cells echocardiogram sound wave test of the heart edema fluid in the tissues; puffiness; swelling efficacy producing a positive result electrocardiogram heart test; tracing of heartbeat or heart rhythm emesis vomiting endoscopic examination of the inside of the body with a lighted tube epidural outside the spinal cord eradicate get rid of erythrocyte red blood cell FDA Food and Drug Administration; the branch of the government that approves new drugs fibrillation irregular heartbeat fibrous like scar tissue gastrointestinal stomach and intestines 65
    • granulocyte white blood cell hematocrit number of red blood cells hematoma bruise; black and blue mark holter monitor portable machine for recording heartbeats hormonal therapy treatment with hormones hypertension high blood pressure hypotension low blood pressure hypoxia low oxygen level in the blood immunosuppressive a drug or therapy that reduces the body’s ability to fight infection; helps prevent rejection of a transplanted organ incidence number of times it happens infarct death of tissue due to loss of blood flow infectious occurrences infections inflammation swelling which is usually painful, red and warm infusion putting a substance into the body, usually into the blood intravenous putting it into the vein intubate the placement of a tube into the airway ischemia decrease in oxygen in a tissue, usually because of decreased blood flow lactating producing milk laparotomy a procedure where an incision is made in the abdominal wall to enable a physician to look at the organs lethargy sleepiness; lack of energy lumen cavity of an organ; inside a blood vessel lymphocyte a type of white blood cell important for defense against infections malaise feeling bad; a feeling of bodily discomfort malignancy cancer which usually spreads and may be fatal if not successfully treated 66
    • marrow suppression decreased growth of the bone marrow metastasis spread of cancer cells from one part of the body to another monoclonal antibody very specific, purified antibody morbidity sickness/illness mortality death motility the ability to move MRI pictures of the body created using magnetic rather than x-ray energy murine obtained from mice myalgia muscle aches myocardial infarction heart attack nasogastric tube a tube from the nose to the stomach necrosis death of tissue neoplasia a tumor that may be cancerous or non-cancerous neural brain or nerves neutropenia decrease in white blood cells non-invasive not breaking, cutting or entering the skin obviate to prevent occlusion closing; obstruction occult blood test testing a stool sample for trace amounts of blood oncology the study of tumors or cancer ophthalmic pertaining to the eye orthopedic pertaining to bones osteoporosis bone disorder resulting from loss of bone leading to increased risk of fracture ovaries female sex glands that release the egg cells pancytopenia low number of blood cells percutaneous through the skin 67
    • 68
    • Appendix B-3 PROTOCOL REVIEW STANDARDS CHECK QUESTIONS FOR HEC DISCUSSION 1) The proposed research design is scientifically sound & will not unnecessarily expose subjects to risk. a) Is the hypothesis clear? Is it clearly stated? b) Is the study design appropriate to prove the hypothesis? c) Will the research contribute to generalizable knowledge and is it worth exposing subjects to risk? 2) Risks to subjects are reasonable in relation to anticipated benefits, if any, to subjects, and the importance of knowledge that may reasonably be expected to result. a) What does the EC consider the level of risk to be? b) What does the PI consider the level of risk/discomfort/ inconvenience to be? c) Is there prospect of direct benefit to subjects? 3) Subject selection is equitable. a) Who is to be enrolled? Men? Women? Ethnic minorities? Children (rationale for inclusion/exclusion addressed)? Seriously-ill persons? Healthy volunteers? b) Are these subjects appropriate for the protocol? 4) Additional safeguards required for subjects likely to be vulnerable to coercion or undue influence. a) Are appropriate protections in place for vulnerable subjects, e.g., pregnant women, fetuses, socially- or economically-disadvantaged, decisionally-impaired? 5) Informed consent is obtained from research subjects or their legally authorized representative(s). a) Does the informed consent document include the eight required elements? b) Is the consent document understandable to subjects? ‘ c) Who will obtain informed consent (PI, nurse, other?) & in what setting? d) If appropriate, is there a children’s assent? e) Is the EC requested to waive or alter any informed consent requirement? 6) Subject safety is maximized. a) Does the research design minimize risks to subjects? b) Would use of a data & safety monitoring board or other research oversight process enhance subject safety? 7) Subject privacy & confidentiality are maximized. a) Will personally-identifiable research data be protected to the extent possible from access or use? b) Are any special privacy & confidentiality issues properly addressed, e.g., use of genetic information? 8) Additional considerations 1. Ionizing radiation. If ionizing radiation is used in this protocol is it medically indicated or for research use only? 69
    • 2. Collaborative research. Is this domestic/international collaborative research? If so, are SPAs or other assurances required for the sites involved? Risk/Benefit Assessment RISK Definition : Minimal risk means that the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests Check appropriate risk category: 1. The research involves no more than minimal risk to subjects. 2. The research involves more than minimal risk to subjects. -The risk(s) represents a minor increase over minimal risk, or -The risk(s) represents more than a minor increase over minimal risk BENEFIT Definition: A research benefit is considered to be something of health-related, psychosocial, or other value to an individual research subject, or something that will contribute to the acquisition of generalizable knowledge. Money or other compensation for participation in research is not considered to be a benefit, but rather compensation for research-related inconveniences. Check appropriate benefit category: 1. The research involves no prospect of direct benefit to individual subjects, but is likely to yield generalizable knowledge about the subject’s disorder or condition. 2. The research involves the prospect of direct benefit to individual subjects. 70