Informed Consent in clinical research Dr. Hari Obulesu Global Clinical Research Services Definition. Informed consent- Myth and Reality Historical Evaluation of informed consent. Importance of informed consent – Historical events. Informed consent – Ethical aspects. Obstacles to informed consent ICH GCP- Informed consent ICMR – Informed consent Model ICF How Informed consent may be improved Definition and discussion Voluntary written assent of a subject‘s willingness to participate in a particular study and in its documentation. Informed consent is a process by which a potential clinical trial participant voluntarily confirms their willingness to participate after being informed of aspects of the trial that are relevant to their decision to participate. Informed consent is documented by means of a written, signed, and dated informed consent form. The independent ethics committee or institutional review board reviews and approves the informed consent information prior to the start of the clinical trial. You may already have experience with signing consent forms for other kinds of medical procedures, such as surgery, or for cancer treatments such as radiation or chemotherapy. However, informed consent for a clinical trial involves much more than just reading and signing a piece of paper. Rather, it involves two essential parts: a document and a process. The informed consent document provides a summary of the clinical trial (including its purpose, the treatment procedures and schedule, potential risks and benefits, alternatives to participation, etc.) and explains your rights as a participant and it should be communicated in a non-technical style and in a language understandable to a lay person. It is designed to begin the informed consent process, which consists of conversations between you and the research team. If you then decide to enter the trial, you give your official consent by signing the document. You can keep a copy and use it as an information resource throughout the course of the trial. The informed consent process provides you with ongoing explanations that will help you make educated decisions about whether to begin or continue participating in a trial. Researchers and health professionals know that a written document alone may not ensure that you fully understand what participation means. Therefore, before subject takes a decision, the research team will discuss with the subject about the trial‘s purpose, procedures, risks and potential benefits, and his /her rights as a participant. If he/she decides to participate, the team will continue to update the subject on any new information that may affect his/her situation. Before, during, and even after the trial, subject will have the opportunity to ask questions and raise concerns. Thus, informed consent is an ongoing, interactive process, rather than a one-time information session Informed consent - Myth and Reality Myth: Informed consent is designed primarily to protect the legal interests of the research team. Reality: The purpose of the process is to protect you and other participants by providing access to information that can help you make an informed choice. It also is designed to make you aware of your rights as a participant. Myth: The most important part of this process is signing the informed consent document. Reality: Actually, the heart of this process is your ongoing interaction and discussions with the research team and other medical personnel–before, during, and after the trial. The document is designed to get this conversation started. Myth: My doctor knows best; he or she can tell me whether or not I should consent to participate. Reality: Your doctor is likely to be a valuable source of advice and information, but only you can make this decision. No one–not even medical experts–can predict whether a treatment, screening, prevention, or supportive care method under evaluation in a trial will prove successful. The informed consent process is designed to help you weigh all of the information and make the right choice for you or your child. Myth: Once I sign the consent form, I have to enroll and stay enrolled in the trial. Reality: That's not true. Even after you sign the form, you are free to change your mind and decide not to participate. You also have the right to leave a clinical trial at any time for any reason, without forfeiting access to other treatment. Myth: Medical personnel are busy, so I can't really expect them to keep me informed as the trial progresses or listen to my questions. Reality: The research team has a duty to keep you informed, make sure that you understand the information they provide, and answer your questions. If you ever feel that you are not getting what you need, do not hesitate to speak up. You will be given the name and phone number of a key contact person who can answer your questions throughout the course of the trial. Keep in mind that people like you are making this research possible through their willingness to participate The Historical evaluation of informed consent. The twentieth century was a time of many scientific advances, especially in the field of medicine. Doctors were able to use advancing technology to understand more about the human body and the many diseases that attack it. During the twentieth century, a great many medicines and vaccines were developed that were able to almost entirely eradicate diseases such as small pox and polio. These advances required years of research and testing. However, some of these wonder drugs have a dark past. Many of the early advances in medicine were made at the expense of many marginal groups such as asylum inmates and prisoners. These test subjects were involved in these clinical trials without being informed, or even asked. Over the past half-century, the international and U.S. medical communities have taken numerous steps to protect people who take part in Clinical research. The following timeline provides an overview of some of the key events that have contributed to the development of the current system. The Nuremberg Code (1947) Developed in response to the Nuremberg Trials of Nazi doctors who performed unethical experimentation during World War II, the Code was the first major international document to provide guidelines on research ethics. It made voluntary consent a requirement in clinical research studies, emphasizing that consent can be voluntary only if: a) Participants are able to consent; b) They are free from coercion (i.e., outside pressure); and c) They comprehend the risks and benefits involved. The Code also states that researchers should minimize risk and harm, make sure that risks do not significantly outweigh potential benefits, use appropriate study designs, and guarantee participants' freedom to withdraw at any time. The Nuremberg Code was adopted by the United Nations General Assembly in 1948. Declaration of Helsinki (1964) At the 18th World Medical Assembly in Helsinki, Finland, the World Medical Association adopted 12 principles to guide physicians on ethical considerations related to biomedical research. It emphasizes the distinction between medical care that directly benefits the patient and research that may or may not provide direct benefit. These guidelines were revised at subsequent meetings in 1975 (Tokyo, Japan), 1983 (Venice, Italy), and 1989 (Hong Kong). The National Research Act (1974) The U.S. Congress signed this act into law, creating the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. The Commission was charged with: a) Identifying the basic ethical principles that should govern medical research involving people, and then b) Recommending steps to improve the Regulations for the Protection of Human Subjects. The Belmont Report (1979) After four years of work, the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research issued "The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research." The report sets forth three principles underlying the ethical conduct of research: a) Respect for persons: recognizing the autonomy and dignity of individuals, and the need to protect those with diminished autonomy (i.e., impaired decision-making skills), such as children, the aged, and the disabled; b) Beneficence: an obligation to protect persons from harm by maximizing benefits and minimizing risks; c) Justice: fair distribution of the benefits and burdens of research. The Belmont Report explains how these apply to research practices; for example, it identifies informed consent as a process that is essential to the principle of respect. In response to the report, both the U.S. Department of Health and Human Services and the U.S. Food and Drug Administration revised their regulations on research studies that involve people. Federal Policy for the Protection of Human Subjects (1991) This policy was adopted to ensure a uniform system of protections in all federal agencies and departments that conduct research. Importance of informed consent- Historical events During World War II, doctors in Nazi Germany were conducting horrifying research on prisoners in concentration camps. This research was done on involuntary participants who usually died as a result of the experiments. After the war, many of these doctors were tried at the Nuremberg trials for their crimes. The International community was shocked by the revelations of their research. As a result of the trial, the Nuremberg Code was created in 1948. This international document was one of the earliest to address ethics in medical research. It stated that voluntary consent was mandatory for any clinical research. Voluntary consent meant that the participants were able to consent, were not being coerced to do the study and understood the risks and benefits involved. The Code was adopted by the United Nations in 1948. However, there were many unethical clinical research trials being done during World War II in America and Britain. President Franklin Roosevelt created an Office of Scientific Research and Development to combat diseases such as dysentery, influenza and malaria, diseases that commonly affect soldiers. One of the research teams created a potential vaccine for dysentery. To test it the researchers used orphans and mentally retarded individuals in institutions. The orphans developed dangerously high fevers, thus proving that the vaccine did not work. Another research team purposefully gave psychotic patients at then Illinois State Hospital with malaria, in order to test a cure. Penicillin, the wonder drug of the century, was tested on prisoners to find the most effective dosage. At the time, many attitudes were that it was necessary for some sacrifices to be made to benefit the whole of society. After the war and creation of the Nuremberg code, many American medical researches still felt the same and continued with unethical medical research. Much medical advancement came from World War II, the US government sought to continue this trend by creating the National Institutes of Health, which provided funds for experimentation. These funds were given with no stipulations about the rights of the experiments and the participants. In the period of time 1945-1966 the NIH funded 2,000 research projects, and none of them used informed consent. During this same period of time a drug called thalidomide was being developed. This drug was supposed to prevent miscarriages. The head of the Food and Drug Administration did not want to approve the drug for use because she was unsatisfied with test results. However, 200,000 American women were given the drug without knowing that it had not been approved. These women were essentially taking part in a drug trial without knowing it. They were not warned of the risks. The result was that many babies of women taking this drug were born with extreme birth defects. This caused a huge scandal. Congress passed an amendment to the Food, Drug and Cosmetic Act that required doctors to tell patients if they were taking a trial drug. The mindset that these sorts of unethical trials were permissible because they helped the whole society was slowly changing. One major event that caused this was an article written by Henry Beecher that appeared in the June 16, 1966 issue of the New England Journal of Medicine. This article exposed many clinical research trials that had been funded by the government that very highly unethical. He gave 22 examples of unethical research. One of the examples was that mentally retarded children at a state school were infected with hepatitis virus. The researcher who carried out this experiment eventual became head of the pediatrics department at New York University. He felt that he was justified because a cure for hepatitis would help many more people. In each of Beecher‘s examples, clinical trials were done on marginal members of society such as the poor, developmentally disabled and senile. These marginalized members of society were unable to decide to participate in these trials. The NIH had already been working to make clinical research more ethical. In July 1966 a set of standards was issued that called for an independent Institutional Review Board to review all research done by an institution. These Review Boards examined risks and benefits of research and how the researcher intended to obtain informed consent. Shortly after the FDA also created rules for obtaining informed consent in its investigations of new medicines. One of the major events that brought the issue of obtaining informed consent to the public was the revelation of the Tuskegee Syphilis Study. The study was conducted by the United States Public Health Service. The Tuskegee study began in 1932 and continued till 1972, when it was revealed to the public. The purpose of the study was to examine the long term affects of syphilis. The subjects of the study were 400 African American males, who were primarily poor sharecroppers. These men all had syphilis, but were unaware of it. They were also unaware of the true nature of the experiment. The most horrifying aspect of the experiment was in the 1950‘s penicillin was proved to be effective at curing syphilis. The researchers did not treat the men‘s syphilis and even prevented other doctors who saw the participants from treating the syphilis. As many as one hundred men may have died from complications from their untreated syphilis. The study was revealed in 1972 by a researcher who had worked on the project. His newspaper article shocked the country and caused the project to be shut down. In 1997 President Clinton formally apologized for the study. The many revelations of unethical medical research in the 1960‘s and 1970‘s led Congress to pass the National Research act which created the National Commission for the Protection of Human Subjects in Biomedical and Behavioral research. The commission‘s final report and recommendations is known as the Belmont report. The intent was to create a cohesive set of guidelines for conducting ethical research. The commission felt that medical advancement should not require a loss of human rights. The commission reaffirmed the role of the Institutional Review Boards that had been created in the 1960‘s. The Belmont Report also expanded the definition of informed consent, making sure that participants were kept informed throughout the experiment and more fully understand risks and benefits. It also stated that individuals with a lower capacity for making decisions, such as children, the elderly and the developmentally disabled needed to be protected. The US departments of Health and Human Services and the FDA revised their research rules based on this report. However participants in research trials may still be at risk. On September 17, 1999 an 18 year old research participant died. He was involved in a study being done at the University of Pennsylvania. In investigations of his death, it was discovered that the participant and his father had not been told enough about the risks of the procedure. Because he did not understand all of the possible risks, the participant put himself in a dangerous situation and died as a result. As a result of this incident, the Department of Health and Human Services worked to make sure that people were properly informed. One of the measures they enacted was legislation that would allow the FDA to fine research projects up to one million dollars for informed consent violations. The horrors of World War II and unethical clinical trials done by the U.S. health service made the public and medical community aware the need for the field of bioethics. Bioethics is a field that strives to create fair and ethical medical procedures, covering a wide range of procedures from organ transplantation to clinical trials. Clinical trials were made more ethical by the creation of Institutional Review Boards, and the notion of informed consent. Before an individual can participate in a clinical trial, they must properly be informed of the risks and give their consent. Examining the history of informed consent demonstrates the importance it has had in protecting the rights and health of individuals participating in clinical trials. Informed consent is one of the most important facets of bioethics. Informed consent is designed to protect individuals participating in clinical research trials. An individual interested in participating in a medical research trial will receive a document that contains information about the benefits and risk of the trial, the research procedures and the reasons for the research. The participant should be able to review the document with doctors and ask questions about things they do not understand. Official consent to participate in the trial is given when this document is signed, with the researcher and the participant retaining a copy. However, the process of informed consent should not end there. The researchers are obligated to keep the participant updated and answer any questions the participant has. Informed consent does not obligate the participant to finish the trial. A participant has the right to leave the trial at any time during the study. Doctors are obligated to make sure that a patient understands the risks and benefits of any medical procedure Informed Consent - Ethical Aspect The ethics governing research are evolving rapidly, and we need to be sure that the principles of good practice are applied in all social groups. When research involves people from ethnic minorities, a major but neglected issue is the validity of consent. Informed consent, a legal concept developed over the years in Western Europe and North America, demands much more than a signed document. It is a process of communication in which the underlying ethical concepts, especially that of respect for autonomy, are not shared by all cultures. Here is what the Helsinki Declaration, in its 2000 version, says about informed consent: All the research involving human participants should be conducted in accordance with the four basic ethical principles, namely autonomy (respect for person / participant) beneficence, non-malfeasance (do no harm) and justice 'In any research on human beings, each potential subject must be adequately informed of the aims, methods, sources of funding, any possible conflict of interest, institutional affiliations of the researcher, the anticipated benefits and potential risks of the research and the potential discomforts it may entail. The subject should be informed of the right to abstain from participation in the study or to withdraw at any time without reprisal'. Essentially informed consent consists of three steps. First, the research team provides full and transparent information about the nature of the project and the rights of the participant. Second, the participant must understand what is being asked and be competent to decide. Third, the person must decide freely whether or not to contribute. Because each element of this process may conflict with cultural values. Obstacles to informed consent 1. Comprehension and capacity Although language is an issue in securing informed consent, obstacles to comprehension go beyond the obvious linguistic barriers. The use of an interpreter may help, but different concepts of illness and issues of translation and cultural bias on the interpreter's part can compromise the extent to which information is understood. In some cultural groups there may be little or no understanding of biomedicine, and researchers lacking knowledge of traditional belief systems may be wrong to conclude that the individual lacks capacity. 2. Literacy Members of certain ethnic minority groups are unable to read or write even in their own language. Moreover, in societies where verbal communication is heavily relied upon, written contracts may be mistrusted or not upheld. To ask for a signature may thus cause offence. Illiteracy does not signify an inability to comprehend complex information; but it does mean the information must be presented in a special way. Consent in research can be seen not as a 'one-off' event but as a continuing process of negotiation between researcher and informant. This implies a long-term relationship of trust. 3. Autonomy The notion of autonomy varies considerably between cultural groups. In contrast to the emphasis on personal choice seen in the USA and Europe, communal and hierarchical patterns of decision-making may take precedence. Family members will often take medical decisions on behalf of a relative; in India, patients place much trust in their family. The sense of wellbeing depends less on a feeling of personal control. Thus, the Western idea of respect for the individual may conflict with traditions that define persons by their relations to others. In the doctor—patient relationship elements such as loyalty, integrity, solidarity and compassion may be considered more important than autonomy. 4. Disclosure When a life-threatening condition such as cancer is diagnosed, the custom in many parts of the world is to tell the relatives rather than the patient. This is generally true of South Asian cultures. Among such groups, the disclosure of negative information is considered potentially harmful and health professionals will sometimes collude with the family to prevent the patient discovering the diagnosis. 5. Familiarity with research methodology Groups living in isolation from mainstream culture may have little grasp of scientific method; and without such understanding a consent form will make little sense. Although this may be partly a cultural issue, lack of education is an important determinant. Indeed, Hussain-Gambles et al. judged that South Asians (Indian, Pakistani, Bangladeshi) differed little from the general population in their attitudes to participation in clinical trials: '... poor understanding of science and increasing commercialization of clinical trials means that the general population is just as likely as ethnic minority people to be mistrustful of medical research. Empirical evidence also illustrates more similarities than differences in attitude towards clinical trial participation between South Asian lay and the general population. There was little evidence of antipathy to the concept of clinical trials amongst South Asian lay people and awareness of trials appears to be a high correlate of social class, education and youth.... The presence of diverse attitudes amongst South Asian respondents also suggests that the relevance of ethnicity and culture needs to be kept in perspective'. Aspects of the process that researchers may find especially difficult to explain are randomization, risks, side-effects, and voluntary participation. 6. Power relationships A difficulty with informed consent in any context, and especially when the researcher is 'high socioeconomic' and the potential subject is from an ethnic minority group, is the unequal power relationship and the patient's feeling of obligation to the doctor. The researcher may be seen as an authority figure and the patient may worry that failure to comply will have serious consequences such as possible deportation. Such asymmetry in knowledge and authority, when extreme, must raise doubts about the validity of consent. CASESTUDY Mr. Abdul (a pseudonym) is a farmer from Bangladesh, age 55, who immigrated to the UK not long ago. Three months before arriving he was diagnosed as having Dukes grade C bowel cancer and he is a candidate for inclusion in a drug trial. The patient does not speak English, has little formal education and is illiterate. He now lives with his wife and two sons. In Bangladesh he was not told of his diagnosis or prognosis. Although he has now received a full explanation of the benefits and risks of the investigational drug (translated through his son) he does not appear to understand the details. During the consultation his son, who is fluent in English, says 'Can I sign the consent form for him'? He points out, 'at home it is the family who make decisions about health'. Can Mr. Abdul give informed consent, when the process is so alien to the way he and his family normally make healthcare decisions? One obvious response is to say no, and exclude him from the trial; another is to make strong efforts to increase his comprehension of the research project, to the point where he can propose a decisionmaking process that suits him. Exclusion of ethnic minority patients from clinical trials is highly undesirable because the findings will then be based on unrepresentative populations. Also it undermines efforts to reduce inequalities. Mr. Abdul is not aware of his diagnosis and this in itself will make his consent uninformed. He lacks any sense of autonomy since, just as in Bangladesh, he expects his family to make decisions for him. An attempt to explain the issues would cover scientific research and how it works, but there would be difficulty in addressing a tradition of healthcare in which spiritual and religious values and a host of different healing methods are deployed alongside conventional medicine. His desire may be to defer to his relatives, but the doctors may not permit this to be the basis of consent; or he may defer to the doctors for fear of adverse repercussions, in which case the consent will have been obtained under a form of coercion, real or imagined. WHAT CAN BE DONE? In extreme cases such as that of Mr. Abdul the difficulties may be too great, but in principle the ethical standards should be the same for everyone. The answer is to adapt the process, and on this matter there is useful experience from South Asia. One strategy is to concentrate on the information side. For literate individuals, information sheets can be written in the vernacular, and researchers can use a questionnaire or interview to make sure the information has been understood before consent is formally sought. For the illiterate, videos or illustrations can enhance comprehension and retention and consent can be either witnessed or recorded by video or audio. A later interview is desirable, in accordance with the trend to replace one-off informed consent with a process model in which the patient is accepted as a member of the team, possessing knowledge of contextual facts that are unavailable to the healthcare providers. This may be a useful model for members of minority groups whose concepts of healing and sickness differ from the dominant biomedical model. The cultural sensitivity of informed consent procedures could be improved by inviting community members to liaise with researchers. The problem of undue influence over participants might be addressed by appointing an independent person such as a clinic nurse or patients' representative to monitor the process and ensure that consent is freely given. This is a commonly used procedure in non-Western cultures. Where the issues are complex and cultural issues loom large, the answer might be a panel including family and lay members who volunteer to safeguard the interests of the patient. The legal position of such a panel, however, might be questioned; the law does not allow one person to give informed consent on behalf of another. Moreover, in cases such as that of Mr. Abdul, no progress could be made until the family had been persuaded to allow disclosure of the diagnosis and prognosis. Conclusion Despite the difficulties of gaining informed consent from ethnic minority patients, the answer must not be to exclude such patients from clinical research. Some of the obstacles apply equally patients with poor education. Cultural issues demand strategies that take account of traditional views of healthcare and the role of the family in decision-making. ICH GCP -Informed Consent In ICH GCP, informed consent was discussed in detailed under section 4, investigator responsibilities while conducting informed consent 4.8 4.8.1 In obtaining and documenting informed consent, the investigator should Comply with the applicable regulatory requirement(s), and should adhere to GCP and to the ethical principles that have their origin in the Declaration of Helsinki. Prior to the beginning of the trial, the investigator should have the IRB/IEC's written approval/favorable opinion of the written informed consent form and any other written information to be provided to subjects. 4.8.2 The written informed consent form and any other written information to be provided to subjects should be revised whenever important new information becomes available that may be relevant to the subject‘s consent. Any revised written informed consent form, and written information should receive the IRB/IEC's approval/favorable opinion in advance of use. The subject or the subject‘s legally acceptable representative should be informed in a timely manner if new information becomes available that may be relevant to the subject‘s willingness to continue participation in the trial. The communication of this information should be documented. 4.8.3 Neither the investigator, nor the trial staff, should coerce or unduly influence a subject to participate or to continue to participate in a trial. 4.8.4 None of the oral and written information concerning the trial, including the written informed consent form, should contain any language that causes the subject or the subject's legally acceptable representative to waive or to appear to waive any legal rights, or that releases or appears to release the investigator, the institution, the sponsor, or their agents from liability for negligence. 4.8.5 The investigator, or a person designated by the investigator, should fully inform the subject or, if the subject is unable to provide informed consent, the subject's legally acceptable representative, of all pertinent aspects of the trial including the written information given approval/favorable opinion by the IRB/IEC. 4.8.6 The language used in the oral and written information about the trial, including the written informed consent form, should be as non technical as practical and should be understandable to the subject or the subject's legally acceptable representative and the impartial witness, where applicable. 4.8.7 Before informed consent may be obtained, the investigator, or a person designated by the investigator, should provide the subject or the subject's legally acceptable representative ample time and opportunity to inquire about details of the trial and to decide whether or not to participate in the trial. All questions about the trial should be answered to the satisfaction of the subject or the subject's legally acceptable representative. 4.8.8 Prior to a subject‘s participation in the trial, the written informed consent form should be signed and personally dated by the subject or by the subject's legally acceptable representative, and by the person who conducted the informed consent discussion. 4.8.9 If a subject is unable to read or if a legally acceptable representative is unable to read, an impartial witness should be present during the entire informed consent discussion. After the written informed consent form and any other written information to be provided to subjects is read and explained to the subject or the subject‘s legally acceptable representative, and after the subject or the subject‘s legally acceptable representative has orally consented to the subject‘s participation in the trial, and, if capable of doing so, has signed and personally dated the informed consent form, the witness should sign and personally date the consent form. By signing the consent form, the witness attests that the information in the consent form and any other written information was accurately explained to, and apparently understood by, the subject or the subject's legally acceptable representative, and that informed consent was freely given by the subject or the subject‘s legally acceptable representative. 4.8.10 Both the informed consent discussion and the written informed consent form and any other written information to be provided to subjects should include explanations of the following: (a) That the trial involves research. (b) The purpose of the trial. (c) The trial treatment(s) and the probability for random assignment to each treatment. (d) The trial procedures to be followed, including all invasive procedures. (e) The subject's responsibilities. (f) Those aspects of the trial that are experimental. (g) The reasonably foreseeable risks or inconveniences to the subject and, when applicable, to an embryo, fetus, or nursing infant. (h) The reasonably expected benefits. When there is no intended clinical benefit to the subject, the subject should be made aware of this. (i) The alternative procedure(s) or course(s) of treatment that may be available to the subject, and their important potential benefits and risks. (j) The compensation and/or treatment available to the subject in the event of trial-related injury. (k) The anticipated prorated payment, if any, to the subject for participating in the trial. (l) The anticipated expenses, if any, to the subject for participating in the trial. (m) That the subject's participation in the trial is voluntary and that the subject may refuse to participate or withdraw from the trial, at any time, without penalty or loss of benefits to which the subject is otherwise entitled. . (n) That the monitor(s), the auditor(s), the IRB/IEC, and the regulatory authority (i.e.) will be granted direct access to the subject's original medical records for verification of clinical trial procedures and/or data, without violating the confidentiality of the subject, to the extent permitted by the applicable laws and regulations and that, by signing a written informed consent form, the subject or the subject's legally acceptable representative is authorizing such access. (o) That records identifying the subject will be kept confidential and, to the extent permitted by the applicable laws and/or regulations, will not be made publicly available. If the results of the trial are published, the subject‘s identity will remain confidential. (p) That the subject or the subject's legally acceptable representative will be informed in a timely manner if information becomes available that may be relevant to the subject's willingness to continue participation in the trial. (q) The person(s) to contact for further information regarding the trial and the rights of trial subjects, and whom to contact in the event of trial-related injury. (r) The foreseeable circumstances and/or reasons under which the subject's participation in the trial may be terminated. (s) The expected duration of the subject's participation in the trial. (t) The approximate number of subjects involved in the trial. 4.8.11 Prior to participation in the trial, the subject or the subject's legally acceptable representative should receive a copy of the signed and dated written informed consent form and any other written information provided to the subjects. During a subject‘s participation in the trial, the subject or the subject‘s legally acceptable representative should receive a copy of the signed and dated consent form updates and a copy of any amendments to the written information provided to subjects. 4.8.12 When a clinical trial (therapeutic or Non therapeutic) includes subjects who can only be enrolled in the trial with the consent of the subject‘s legally acceptable representative (e.g., minors, or patients with severe dementia), the subject should be informed about the trial to the extent compatible with the subject‘s understanding and, if capable, the subject should assent, sign and personally date the written informed consent. 4.8.13 Except as described in 4.8.14, a Non therapeutic trial (i.e., a trial in which there is no anticipated direct clinical benefit to the subject) should be conducted in subjects who personally give consent and who sign and date the written informed consent form. 4.8.14 Non therapeutic trials may be conducted in subjects with consent of a legally acceptable representative provided the following conditions are fulfilled: (a) The objectives of the trial cannot be met by means of a trial in subjects who can give informed consent personally. (b) The foreseeable risks to the subjects are low. (c) The negative impact on the subject‘s well-being is minimized and low. (d) The trial is not prohibited by law. (e) The approval/favorable opinion of the IRB/IEC is expressly sought on the inclusion of such subjects, and the written approval/favorable opinion covers this aspect. Such trials, unless an exception is justified, should be conducted in patients having a disease or condition for which the investigational product is intended. Subjects in these trials should be particularly closely monitored and should be withdrawn if they appear to be unduly distressed. 4.8.15 In emergency situations, when prior consent of the subject is not possible, the consent of the subject's legally acceptable representative, if present, should be requested. When prior consent of the subject is not possible, and the subject‘s legally acceptable representative is not available, enrollment of the subject should require measures described in the protocol and/or elsewhere, with documented approval/favorable opinion by the IRB/IEC, to protect the rights, safety, and wellbeing of the subject and to ensure compliance with applicable regulatory requirements. The subject or the subject's legally acceptable representative should be informed about the trial as soon as possible and consent to continue and other consent as appropriate (see section 4.8.10) should be requested. ICMR – Informed consent I. Informed consent process 1. Informed Consent of Participants: For all biomedical research involving human participants, the investigator must obtain the informed consent of the prospective participant or in the case of an individual who is not capable of giving informed consent, the consent of a legal guardian. Informed consent protects the individual‘s freedom of choice and respect for individual‘s autonomy and is given voluntarily to participate in research or not. Adequate information about the research is given in a simple and easily understandable unambiguous language in a document known as the Informed Consent Form with Participant/ Patient Information Sheet. The latter should have following components as may be applicable: 1. Nature and purpose of study stating it as research 2. Duration of participation with number of participants 3. Procedures to be followed 4. Investigations, if any, to be performed 5. Foreseeable risks and discomforts adequately described and whether project involves more than minimal risk 6. Benefits to participant, community or medical profession as may be applicable 7. Policy on compensation 8. Availability of medical treatment for such injuries or risk management 9. Alternative treatments if available 10. Steps taken for ensuring confidentiality 11. No loss of benefits on withdrawal 12. Benefit sharing in the event of commercialization 13. Contact details of PI or local PI/Co-PI in multi centric studies for asking more information related to the research or in case of injury 14. Contact details of Chairman of the IEC for appeal against violation of rights 15. Voluntary participation 16. If test for genetics and HIV is to be done, counseling for consent for testing must be given as per national guidelines 17. Storage period of biological sample and related data with choice offered to participant regarding future use of sample, refusal for storage and receipt of its results A copy of the participant/patient information sheet should be given to the participant for her/ his record. The informed consent should be brief in content highlighting that it is given of free will or voluntarily after understanding the implications of risks and benefits and s/he could withdraw without loss of routine care benefits. Assurance is given that confidentiality would be maintained and all the investigations/ interventions would be carried out only after consent is obtained. When the written consent as signature or thumb impression is not possible due to sensitive nature of the project or the participant is unable to write, then verbal consent can be taken after ensuring its documentation by an unrelated witness. In some cases ombudsman, a third party, can ensure total accountability for the process of obtaining the consent. Audio-visual methods could be adopted with prior consent and adequate precaution to ensure confidentiality, but approval of EC is required for such procedures. For drug trials, if the volunteer can give only thumb impression then another thumb impression by the relative or legal custodian cannot be accepted and an unrelated witness to the project should then sign. Fresh or re-consent is taken in following conditions: 1. Availability of new information which would necessitate deviation of protocol. 2. When a research participant regains consciousness from unconscious state or is mentally competent to understand the study. If such an event is expected then procedures to address it should be spelt out in the informed consent form. 3. When long term follow-up or study extension is planned later. 4. When there is change in treatment modality, procedures, site visits. 5. Before publication if there is possibility of disclosure of identity through data presentation or photographs (which should be camouflaged adequately)? Waiver of consent Voluntary informed consent is always a requirement for every research proposal. However, this can be waived if it is justified that the research involves not more than minimal risk or when the participant and the researcher do not come into contact or when it is necessitated in emergency situations. If such studies have protections in place for both privacy and confidentiality, and do not violate the rights of the participants then IECs may waive off the requirement for informed consent in following instances: i. When it is impractical to conduct research since confidentiality of personally identifiable information has to be maintained throughout research as may be required by the sensitivity of the research objective, eg., study on disease burden of HIV/AIDS. ii. Research on publicly available information, documents, records, works, performances, reviews, quality assurance studies, archival materials or third party interviews, service programs for benefit of public having a bearing on public health programs, and consumer acceptance studies. iii. Research on anonymised biological samples from deceased individuals, left over samples after clinical investigation, cell lines or cell free derivatives like viral isolates, DNA or RNA from recognized institutions or qualified investigators, samples or data from repositories or registries etc. iv. In emergency situations when no surrogate consent can be taken. 2. Obligations of investigators regarding informed consent: The investigator has the duty to i. communicate to prospective participants all the information necessary for informed consent. Any restriction on participant‘s right to ask any questions related to the study will undermine the validity of informed consent; ii. exclude the possibility of unjustified deception, undue influence and intimidation. Although deception is not permissible, if sometimes such information would jeopardize the validity of research it can be withheld till the completion of the project, for instance, study on abortion practices; iii. Seek consent only after the prospective participant is adequately informed. The investigator should not give any unjustifiable assurances to prospective participant, which may influence the her/his decision to participate; iv. obtain from each prospective participant 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 the participant is not competent to do so, a legal guardian or other duly authorized representative; v. take verbal consent when the participant refuses to sign or give thumb impression or cannot do so. This can then be documented through audio or video means; vi. Take surrogate consent from the authorized relative or legal custodian or the institutional head in the case of abandoned institutionalized individuals or wards under judicial custody; vii. renew or take fresh informed consent of each participant under circumstances described earlier in this chapter; viii. if participant loses consciousness or competence to consent during the research period as in Alzheimer or psychiatric conditions, surrogate consent may be taken from the authorized person or legal custodian. ix. The investigator must assure prospective participants 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 participants : Before requesting an individual‘s consent to participate in research, the investigator must provide the individual with the following information in the language she or he is able to understand which should not only be scientifically accurate but should also be sensitive/ adaptive to their social and cultural context : i. The aims and methods of the research; ii. The expected duration of the participation; iii. The benefits that might reasonably be expected as an outcome of research to the participant or community or to others; iv. Any alternative procedures or courses of treatment that might be as advantageous to the participant as the procedure or treatment to which s/he is being subjected; v. any foreseeable risk or discomfort to the participant resulting from participation in the study; vi. Right to prevent use of her/ his 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 and/ institution and sponsor(s); x. Compensation of participants for disability or death resulting from such injury; xi. Insurance coverage if any, for research related or other AEs; xii. Freedom of individual / family to participate and to withdraw from research any time without penalty or loss of benefits which the participant would otherwise be entitled to; xiii. The identity of the research teams and contact persons with address and phone numbers; xiv. 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; xv. Risk of discovery of biologically sensitive information and provision to safeguard confidentiality; xvi. Publication, if any, including photographs and pedigree charts. The quality of the consent of certain social and marginalized groups requires careful consideration as their agreement to volunteer may be unduly influenced by the Investigator. II. COMPENSATION FOR PARTICIPATION Participants 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. When this is reasonable then it cannot be termed as benefit. During the period of research if the participant requires treatment for complaints other than the one being studied necessary free ancillary care or appropriate referrals may be provided. However, payments should not be so large or the medical services so extensive as to make prospective participants consent readily to enroll in research against their better judgment, which would then be treated as undue inducement. All payments, reimbursement and medical services to be provided to research participants should be approved by the IEC. Care should be taken: i. 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; ii. When a participant is withdrawn from research for medical reasons related to the study the participant should get the benefit for full participation; iii. When a participant withdraws for any other reasons s/he should be paid an amount proportionate to the amount of participation. III. CONFLICT OF INTEREST A set of conditions in which professional judgment concerning a primary interest like patient‘s welfare or the validity of research tends to be or appears to be unduly influenced by a secondary interest like non-financial (personal, academic or political) or financial gain is termed as Conflict of Interest (COI). Academic institutions conducting research in alliance with industries/ commercial companies require a strong review to probe possible conflicts of interest between scientific responsibilities of researchers and business interests. Eg (ownership or part-ownership of a company developing a new product). In cases where the review board/ committee determines that a conflict of interest may damage the scientific integrity of a project or cause harm to research participants, the board/ committee should advise accordingly. Significant financial interest means anything of monetary value that would reasonably appear to be a significant consequence of such research including salary or other payments for services like consulting fees or honorarium per participant; equity interests in stocks, stock options or other ownership interests; and intellectual property rights from patents, copyrights and royalties from such rights. The investigators should declare such conflicts of interest in the application submitted to IEC for review. Institutions and IECs need self-regulatory processes to monitor, prevent and resolve such conflicts of interest. The IEC can determine the conditions for management of such conflicts in its SOP manual. 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. Those who have also to be informed of the secondary interest in financial terms should include the institution, IEC, audience when presenting papers and should be mentioned when publishing in popular media or scientific journals. Undue inducement through compensation for individual participants, families and populations should be prohibited. This prohibition however, does not include agreements with individuals, families, groups, communities or populations that foresee technology transfer, local training, joint ventures, provision of health care reimbursement, costs of travel and loss of wages and the possible use of a percentage of any royalties for humanitarian purposes. Undue compensation would include assistance to related person(s) for transport of body for cremation or burial, provision for insurance for unrelated conditions, free transportation to and fro for examination not included in the routine, free trip to town if the participants are from rural areas, free hot meals, freedom for prisoners, free medication which is generally not available, academic credits and disproportionate compensation to researcher / team/ institution. However, in remote and inaccessible areas some of the features mentioned above may be a necessity and culture specific. Therefore, the IEC should examine this on a case-by-case basis, as some of these elements may be justifiable for collecting vital data for national use or necessary to find if some interventions may significantly have direct impact on health policies. IV. SELECTION OF SPECIAL GROUPS AS RESEARCH PARTICIPANTS i. Pregnant or nursing women: Pregnant or nursing women should in no circumstances be the participant of any research unless the research carries no more than minimal risk to the fetus or nursing infant and the object of the research is to obtain new knowledge about the foetus, pregnancy and lactation. As a general rule, pregnant or nursing women should not be participants of any clinical trial except such trials as are designed to protect or advance the health of pregnant or nursing women or foetuses or nursing infants, and for which women who are not pregnant or nursing would not be suitable participants. a. The justification of participation of these women in clinical trials would be that they should not be deprived arbitrarily of the opportunity to benefit from investigations, drugs, vaccines or other agents that promise therapeutic or preventive benefits. Examples of such trials are, to test the efficacy and safety of a drug for reducing perinatal transmission of HIV infection from mother to child, trials for detecting foetal abnormalities and for conditions associated with or aggravated by pregnancy etc. Women should not be encouraged to discontinue nursing for the sake of participation in research and in case she decides to do so, harm of cessation of breast-feeding to the nursing child should be properly assessed except in those studies where breast feeding is harmful to the infant. Compensation in terms of supplying supplementary food such as milk formula should be considered in such instances. b. Research related to termination of pregnancy : Pregnant women who desire to undergo Medical Termination of Pregnancy (MTP) could be made participants for such research as per The Medical Termination of Pregnancy Act, GOI, 1971. c. Research related to pre-natal diagnostic techniques : In pregnant women such research should be limited to detect the foetal abnormalities or genetic disorders as per the Prenatal Diagnostic Techniques (Regulation and Prevention of Misuse) Act, GOI, 1994 and not for sex determination of the foetus . ii. Children: Before undertaking trial in children the investigator must ensure that a. children will not be involved in research that could be carried out equally well with adults; b. the purpose of the research is to obtain knowledge relevant to health needs of children. For clinical evaluation of a new drug the study in children should always be carried out after the phase III clinical trials in adults. It can be studied earlier only if the drug has a therapeutic value in a primary disease of the children; c. a parent or legal guardian of each child has given proxy consent; d. the assent of the child should be obtained to the extent of the child‘s capabilities such as in the case of mature minors from the age of seven years up to the age of 18 years.; e. research should be conducted in settings in which the child and parent can obtain adequate medical and psychological support; f. interventions intended to provide direct diagnostic, therapeutic or preventive benefit for the individual child participant must be justified in relation to anticipated risks involved in the study and anticipated benefits to society; g. the child‘s refusal to participate in research must always be respected unless there is no medically acceptable alternative to the therapy provided/ tested, provided the consent has been obtained from parents / guardian; h. interventions that are intended to provide therapeutic benefit are likely to be at least as advantageous to the individual child participant as any available alternative interventions; i. the risk presented by interventions not intended to benefit the individual child participant is low when compared to the importance of the knowledge that is to be gained. iii. Vulnerable groups: Effort may be made to ensure that individuals or communities invited for research be selected in such a way that the burdens and benefits of the research are equally distributed. a. research on genetics should not lead to racial inequalities; b. persons who are economically or socially disadvantaged should not be used to benefit those who are better off than them; c .rights and welfare of mentally challenged and mentally differently able persons who are incapable of giving informed consent or those with behavioral disorders must be protected. Appropriate proxy consent from the legal guardian should be taken after the person is well informed about the study, need for participation, risks and benefits involved and the privacy and confidentiality procedures. The entire consent process should be properly documented; d. adequate justification is required for the involvement of participants such as prisoners, students, subordinates, employees, service personnel etc. who have reduced autonomy as research participants, since the consent provided may be under duress or various other compelling reasons. V. ESSENTIAL INFORMATION ON CONFIDENTIALITY FOR PROSPECTIVE RESEARCH PARTICIPANTS Safeguarding confidentiality - The investigator must safeguard the confidentiality of research data, which might lead to the identification of the individual participants. Data of individual participants can be disclosed under the following circumstances: a. only in a court of law under the orders of the presiding judge or b. there is threat to a person‘s life or c. in cases of severe adverse reaction may be required to communicate to drug registration authority or d. if there is risk to public health it takes precedence over personal right to privacy and may have to be communicated to health authority. Therefore, the limitations in maintaining the confidentiality of data should be anticipated and assessed and communicated to appropriate individuals or authorities as the case may be. VI. COMPENSATION FOR ACCIDENTAL INJURY Research participants who suffer physical injury as a result of their participation are entitled to financial or other assistance to compensate them equitably for any temporary or permanent impairment or disability. In case of death, their dependents are entitled to material compensation. Obligation of the sponsor to pay :- The sponsor whether a pharmaceutical company, a government, or an institution, should agree, before the research begins, in the a priori agreement to provide compensation for any physical or psychological injury for which participants are entitled or agree to provide insurance coverage for an unforeseen injury whenever possible. An Arbitration committee or appellate authority could be set up by the institution to decide on the issue of compensation on a case-by-case basis for larger trials where such a step is feasible. Alternately an institution can also establish such a committee to oversee such claims, which would be common for projects being undertaken by it. Compensation for ancillary care for unrelated illness as free treatment or appropriate referrals may also be included in the a priori agreement with the sponsors whenever possible. VII. POST - TRIAL ACCESS The Helsinki Declaration of the World Medical Assembly (WMA), 2000 states that at the end of the trial every participant should be assured of access to the best proven prophylactic, diagnostic and therapeutic methods identified by the study. This led to a lot of debate globally on account of lack of even basic drugs in most of the developing countries. The Declaration of the WMA in 2004 reaffirmed ―its position that it is necessary during the study planning process to identify post-trial access by study participants to prophylactic, diagnostic and therapeutic procedures identified as beneficial in the study or access to other appropriate care. Post-trial access arrangements or other care must be described in the study protocol so the ethical review committee may consider such arrangements during its review.‖ Therefore, whenever possible I\EC should consider such an arrangement in the a priori agreement. Sometimes more than the benefit to the participant, the community may be given benefit in indirect way through improving their living conditions, establishing counseling centers, clinics or schools, and giving education on maintaining good health practices. For smaller scale or student projects post trial benefit to the participants may not be feasible but keeping in mind the post trial responsibility conscious efforts should be made by the guides and the institution to initiate steps to continue to support and give better care to the participants. VIII. INTERNATIONAL COLLABORATION / ASSISTANCE IN BIO-MEDICAL / HEALTH RESEARCH Research in biomedical and health areas has gained greater momentum only by the second half of the 20th Century, especially since the 1960s, the scope of international co-operation and collaboration assumed such proportions as to have exploitative connotations with commercial and human dimensions. On the one hand, collaboration in medical research suggests an interest in a humane and civil society, while on the other it could give the impression of experimentation on the population of one country by another. Different levels of development in terms of infrastructure, expertise, social and cultural perceptions, laws relating to intellectual property rights etc., necessitate an ethical framework to guide such collaboration. The same concerns are applicable even when there is no formal collaboration between countries, but the research is undertaken with assistance from international organizations as Sponsors (Governmental like National Institutes of Health, USA, nonGovernmental like Bill & Melinda Gates Foundation, Ford Foundation or others like WHO, UNICEF, UNAIDS etc.). Special Concerns 1. Given the magnitude and severity of the health problems in different countries, capacity building to address ethical issues that arise out of collaborative research must be promoted on a priority basis. Strategies should be implemented so that various countries and communities can practice meaningful self-determination in health development and can ensure the scientific and ethical conduct of research. 2. The collaborating investigators, institutions and countries can function as equal partners with sponsors even when in a vulnerable position by building appropriate safeguards. Community representatives should be involved early enough while designing the protocol and in a sustained manner during the development, implementation, monitoring and dissemination of results of research. 3. Careful consideration should be given to protect the dignity, safety and welfare of the participants when the social contexts of the proposed research can create foreseeable conditions for exploitation of the participants or increase their vulnerability to harm. The steps to be taken to overcome these should be described and approval taken from concerned IEC/Ind EC. 4. Every adult participant in the research should voluntarily give informed consent and child her/his assent as may be applicable. 5. As different kinds of research (epidemiological studies, clinical trials, product development, behavioral and social science oriented research etc.) have their own particular scientific requirements and specific ethical challenges, the choice of study populations for each type of study should be justified in advance in scientific and ethical terms regardless of the place from where the study population is selected. Generally, early clinical phases of research, particularly of drugs, vaccines and devices, should be conducted in communities that are less vulnerable to harm or exploitation. However, for valid scientific and public health reasons, if sufficient scientific and ethical safeguards are ensured it may be conducted in any phase after obtaining relevant regulatory clearances. 6. The nature, magnitude, and probability of all foreseeable harms resulting from participation in a collaborative research programme should be specified in the research protocol and explained to the participants as fully as can be reasonably done. Moreover, the modalities by which to address these, including provision for the best possible nationally available care to participants who experience adverse reactions to a vaccine or drug under study, compensation for injury related to the research, and referral for psychosocial and legal support if necessary, need to be described. 7. The research protocol should outline the benefits that persons / communities / countries participating in such research should experience as a result of their participation. Care should be taken so that these are not presented in a way that unduly influences freedom of choice in participation. The burden and the benefit should be equally borne by the collaborating countries. 8. Guidelines, rules, regulations and cultural sensitivities of all countries participating in collaborative research projects should be respected, especially by researchers in the host country and the sponsor country. These could be with reference to intellectual property rights, exchange of biological materials (human, animal, plant or microbial), data transfer, security issues, and issues of socially or politically sensitive nature. In this context, it is essential for researchers to follow the GOI notification on ―Exchange of Human Biological Material for Biomedical Research‖ issued on 19.11.97 and obtains appropriate regulatory clearances as prevalent in the country for international collaboration and EC approval from all trial sites before the initiation of research. IX. RESEARCHER’S RELATIONS WITH THE MEDIA AND PUBLICATION PRACTICES Researchers have a responsibility to make sure that the public is accurately informed about results without raising false hopes or expectations. It should also not unnecessarily scare the people. Researchers should take care to avoid talking with journalists or reporters about preliminary findings as seemingly promising research that subsequently cannot be validated or could lead to misconcepts if reported prematurely. Or, the results of research may be reported in such a way that it would seem that the human application is round the corner, only to be told later by the researchers that considerable time has to pass before these findings can be translated into tools for human use. In such circumstances, retractions most often do not appear in the media. Therefore, it is important to avoid premature reports and publicity stunts. The best safeguard against inaccurate reporting is for the researcher to talk to media on condition that the reporter submit a full written, rather than oral version, of what will be reported, so that it enables the researcher to make necessary corrections, if needed, prior to publication. Investigator‘s publication plans should not threaten the privacy or confidentiality of participants, for example publication of pedigrees in the report on research in genetics can result in identification of study participants. It is recommended that a clear consent for publication be obtained besides the consent for participation in research or treatment and such a consent should preferably be obtained on two different occasions and not as a blanket one at the commencement of the study. Maintenance of confidentiality while publishing data should be taken care of. In case there is need for publication / presentation of photographs/ slides / videos of participant (s), prior consent to do so should be obtained. Identification features should be appropriately camouflaged. The same safeguard should be observed for video coverage. With regard to authorship, the International Committee of Medical Journal Editors (ICJME) has laid down criteria based on credit and accountability. Only those who make substantial contribution to the article and take responsibility for the published matter can be co-authors. Plagiarism or falsification of data and authorship are important ethical issues in publications. The term ‗misconduct in research‘ means fabrication, falsification, plagiarism, selective omission of data and claiming that some data are missing, ignoring outliers without declaring it, not reporting data on side effects/ adverse reactions in a clinical trial, publication of post-hoc analysis. without declaring it, gift authorship, not citing others‘ work, not disclosing conflict of interest, redundant publication, and failure to adequately review existing research. The Commission on Research Integrity in US created by US Congress addresses the scientific, ethical, social and legal issues involving scientific misconduct in research. Consolidated standards of reporting trials (CONSORT) guidelines have been prescribed for publishing results of clinical research especially RCTs (Randomized Controlled Trials) and are available at http://www.consortstatement. org. General Ethical Issues What Will I Find in the Informed Consent Form? While informed consent documents do vary from place to place, they should communicate all of the information described below in language that you can understand, with some help from the research team (if needed). Even if your trial is not federally funded and therefore not governed by these regulations, you should know that any scientifically valid trial will provide an informed consent document that supplies such information The information covered should include: TITLE PURPOSE [Why is this clinical trial being done?] In this section, researchers explain why they are conducting the trial. Their reasons will depend on the type of cancer and the trial type (i.e., whether they are investigating new prevention, screening, supportive care, or treatment methods). Researchers conduct treatment trials either because they have not found an effective treatment for a certain type of cancer, or they are not sure which treatment method works best. In these trials, Phase I tests the safety and effectiveness of a new treatment, or aims to find out what dosage of a new drug can be given safely. Phase II treatment trials evaluate the effects (good and bad) that a treatment may have on people with a certain type of cancer. Phase III treatment trials compare the effectiveness of a new treatment or treatment combination with that of standard treatment. Researchers use prevention, screening, and supportive care trials to evaluate new strategies for preventing cancer, detecting it more accurately and effectively, and alleviating treatment side effects. DESCRIPTION OF PROCEDURES [What is involved in the trial?] This section describes the procedures that you will undergo, how frequently you will have them, and where they will take place (at home, in the hospital or clinical center, or in an outpatient setting). For treatment trials, this section should include: procedures that are part of regular cancer care and may be done even if you do not join the trial; standard procedures being done because you are in the trial; and procedures that are being tested or evaluated by the trial. If this is a "randomized" trial, then you will be assigned at random (by computer) into one of two or more study groups. People in the different groups will receive different treatments or treatment combinations, so that researchers can evaluate which is most effective. If this is the case, the document should make clear what procedures each group will undergo. It should also indicate what your chances are of being placed in any one group. DURATION [How long will I be in the trial?] This section indicates how long the trial will last and whether it involves follow-up, and if so, for how long. It also includes information about any circumstances under which the researcher might remove you from the trial (for example, if your condition worsens or new information indicates you shouldn't continue). The document should make clear that you have the right to stop participating at any time, and it should describe any possible medical consequences of sudden withdrawal. RISKS [What are the risks of the trial?] This section includes the foreseeable physical and nonphysical risks of participating in the trial. A nonphysical risk might be time away from work, while physical risks might include side effects such as nausea, vomiting, pain, or susceptibility to infection, among others. The document should indicate the likelihood of these risks occurring, how serious they may be, and whether they are more likely to be short-term (last only during the trial or shortly afterward) or long-term (last weeks, months, or even years after the trial is over). The document should make clear which risks are related to the investigational aspects of the trial. It also should include specific information about reproductive risks (Could participating make you infertile? Should you not get pregnant or father a child while on the trial? Can you nurse a child during the trial?). BENEFITS [Are there benefits to taking part?] The document describes any benefits to you or to others which may reasonably be expected. A trial may or may not involve direct medical benefits to you, but it might lead to new knowledge that can help others in the future. ALTERNATIVES TO PARTICIPATION [What are my options if I don't participate?] For treatment trials, this section describes what care options you have besides participating in the trial, such as other commonly-used therapies or no treatment at all. CONFIDENTIALITY This statement tells you the extent to which your information will be kept confidential. It should inform you about any groups or organizations that may have access to your records for quality assurance and data analysis (such as the National Cancer Institute, the Food and Drug Administration, or other trial sponsor). COSTS/ ADDITIONAL EXPENSES [What are the costs?] This section indicates whether participating in the trial will result in added costs to you or your insurance company (see Clinical Trials and Insurance Coverage - A Resource Guide for more information on this topic). It also covers other cost issues, such as who will pay for emergency medical treatment in case of injury or illness, whether you will have to pay for drugs that become commercially available during the trial (if this is a drug trial), and whether or not you will receive payment for participating. PARTICIPANT'S RIGHTS [What are my rights as a participant?] The document should specify that: your participation is voluntary; you can choose not to take part or leave at any time without penalty or loss of benefits; and any new information that might affect your participation will be shared with you. CONTACT INFORMATION [Whom do I call if I have questions or problems?] You should have a contact name and phone number (usually of a member of the research team) for getting answers to questions about the study or a research-related injury. You also should be given a phone number for the Institutional Review Board or a patient representative, in case you have questions about your rights as a research participant. SUPPLEMENTAL INFORMATION [Where can I get more information?] This section lists additional resources that may prove useful as you make your decision, such as NCI's Cancer Information Service, informational booklets, community organizations, and Web resources. THE SIGNATURE Your signature represents your legal consent to participate in the trial. If any of these sections appears to be incomplete or missing from the informed consent document, don't hesitate to ask for the information. Other Useful Tips Keep a copy of the informed consent document as a helpful resource for the duration of the trial. Ask for a copy if one isn't offered to you. You may also request a copy of the protocol (full study plan). According to Federal regulations, no informed consent document may include any language that asks or appears to ask you to waive your legal rights, or that releases or appears to release the investigator, the sponsor, or the institution from liability for negligence. If you cannot understand the forms you are signing, don't be afraid to let someone know that you are having trouble. If you have difficulties reading the document at first, try not to get upset. Many people feel anxious about reading and signing documents and communicating with physicians. Just take your time and ask for help when you need it. Expectable Questions from the Subjects Regarding the Study 1. 2. 3. 4. 5. 6. 7. 8. What is the purpose of the study? Why do researchers think the approach may be effective? Who will sponsor the study? Who has reviewed and approved the study? How are study results and safety of participants being checked? How long will the study last? What will my responsibilities be if I participate? Whom can I speak with about questions I have during and after the trial? to find out the study results? 9. What steps will be taken to protect my privacy and the confidentiality of my medical records? 10. Shall I pay any thing to participate in the study? Risks and Benefits 1. 2. 3. 4. 5. 6. What are my possible short -term benefits? What are my possible long -term benefits? What are my short - term risks, such as side effects? What are my possible long -term risks? What are the other options to treat my disease? How do the possible risks and benefits of this trial compare with those options? Participation and Care 1. What kinds of therapies, procedures and /or tests will I have during the trial? 2. How do the tests in the study compare with those I would have outside of the trial? 3. Will I be able to take my regular medications while in the clinical trial? 4. Where will I have my medical care? 5. Will I have to be hospitalized? If so, how often and for how long? 6. Who will be in charge of my care? 7. What type of follow-up care is part of the study? 8. If any thing bad happens who will take care of me? Personal Issues 1. How could being in the study affect my daily life? 2. Can I talk to other people in the study? Informed Consent form to participate in a clinical trial Study Title: Study Number: Subject‘s Initials: _______________ Date of Birth / Age: _________________ (i) Please initial box (Subject) I confirm that I have read and understood the information sheet dated [ ] ___ for the above study and have had the opportunity to ask questions. (ii) (iii) (iv) (v) I understand that my participation in the study is voluntary and that I am free to withdraw at any time, without giving any reason, without my medical care or legal rights being affected. I understand that the Sponsor of the clinical trial, others working on the Sponsor‘s behalf, the Ethics Committee and the regulatory authorities will not need my permission to look at my health records both in respect of the current study and any further research that may be conducted in relation to it, even if I withdraw from the trial. I agree to this access. However, I understand that my identity will not be revealed in any information released to third parties or published. I agree not to restrict the use of any data or results that arise from this study provided such a use is only for scientific purpose(s) I agree to take part in the above study. [ ] [ ] [ [ ] ] Signature (or Thumb impression) of the Subject/Legally Acceptable Representative:_____________ Date: _____/_____/______ Signatory‘s Name: ______________________________________________________ Signature of the Investigator: _______________________ Date: _____/_____/______ Study Investigator‘s Name: __________________________________________________ Signature of the Witness ______________________ Name of the Witness: ____________________ Date:_____/_____/_______ INFORMED CONSENT CHECKLISTS There are eight REQUIRED ELEMENTS of informed consent. These elements MUST be present in the informed Consent Form or the summary for the short form: 1. The informed Consent Form must CLEARLY state that the study involves RESEARCH. State the study purpose in terms that the subject can understand. Identify all experimental drugs, delivery techniques, or treatments. Give a description of the experimental aspects of the study. State the expected duration of participation in the study. Describe briefly the procedures to be performed (e.g., lab evaluations, X-rays, office visits) State the route of administration of the experimental agent. 2. Define RISKS attributable to the experimental agent and/or procedures. 3. Discuss any expected BENEFITS from participation in the trial. 4. Discuss ALTERNATIVE TREATMENTS. 5. State the policy for protection of CONFIDENTIALITY of records, noting that a qualified representative of the sponsor and the FDA may inspect subject study records. Discuss whether COMPENSATION for study-related injuries is provided and if EMERGENCY TREATMENT will or will not be provided by the institution. 6. 7. List the names and numbers of CONTACT PERSONS for research-related questions and for patient rights-related questions and questions regarding study-related injuries. 8. Clearly state that participation is VOLUNTARY and the decision to not participate or to withdraw from the study will not affect the patient's treatment plan. Additionally, when appropriate the following items also must be included: 9. State that unexpected risks may be involved. 10. Discuss the circumstances under which the patient's participation may be terminated by the investigator or sponsor without the patient's consent. 11. Note that additional costs may be incurred by the subject due to study participation. 12. Inform the subject of the consequences of his/her decision to withdraw from the study. 13. Provide the subject with any significant new findings that relate to the subject's treatment and continued participation in the trial. 14. State the estimated number of subjects to be involved in the trial. Other items to consider: 15. State that a copy of the informed Consent Form shall be given to the subject. 16. The form should use terminology that the subject can understand. In presenting the informed Consent Form, the subject must understand what he is agreeing to. Additional suggestions: Have the subject initial each page of the document. Keep the original in the study file or the subject's permanent record with a copy in the other file. Identify each version of the consent form by date or appropriate revision number. Note that if the informed consent is revised while the study is ongoing, subjects currently enrolled may need to sign the revised informed consent. HOW INFORMED CONSENT MAY BE IMPROVED In order to facilitate the disclosure process we commonly employ information sheets. However, as a result of increasing complexity of some clinical studies and possibly medico-legal reasons, there is a tendency for these information sheets to evolve into lengthy, turgid documents which paradoxically may detract from patient understanding. Over 20 years ago Gray et al (1978) showed that, as assessed by standard accepted criteria, only 7% of consent forms could be deemed ‗readable‘. Ten years later, LoVerde et al (1989) showed that consent forms were becoming increasingly unreadable and lengthy, with probably no improvement in patient understanding. In 1994, Grossman et al (1994) found that only 1-6% of any consent form could be read by 12-year olds, while accurate reading of an average consent form required a minimum 2 years college education. Readability and comprehension, however, may be substantially improved by having the information sheets checked, or written, by a professional linguist. A study by Simes et al (1986) compared total disclosure by written consent form with interactive verbal disclosure at the discretion of the investigator. While the former was associated with better patient understanding, full written disclosure also resulted in an initial increase in trial-related anxiety and less willingness to participate in the study. However, 3 or 4 weeks after the full written disclosure process, there was no significant detrimental impact on physician-patient relationship. It is important to point out that patient in this study received information either by full written disclosure or verbal discretionary disclosure, not both, while in most situations a combination of the two is employed. In fact, a third method, namely that of information in electronic form, is now becoming commonplace. More and more patients and their relatives are accessing the Internet in order to obtain information regarding their diagnosis, prognosis and treatment options. While initially some doctors may have felt threatened by patients bearing reams of down-loaded information from the Internet, we now realize that the Internet could provide another, more popular, means of communicating with patients. The Internet is a maze with many monsters; however, since there is no control over content, many of the claims by individuals, companies, and institutions are either unsubstantiated or wholly misleading. Looking for information regarding "cancer", a search of the Internet using the popular search engine ‗Alta Vista‘ yielded 3,058,730 web sites. Using the same search engine to look-up "breast cancer" identified 362,001 pages. Patients, therefore, should be directed to good quality web sites, which provide accurate, up-to-date and relevant information. Such sites include, in the US: (a) the American Society of Clinical Oncology(http://www.asco.org/) (b) the National Cancer Institute (http://cancernet.nci.nih.gov/) (c) Cancernet (http://www.cancernet.co.uk/) (d) the Cancer Research Campaign (http://www.crc.org.uk/) (e) cancer BACUP (http://www.cancerbacup.org.uk/) The use of taped interviews with the patient or even pre-prepared videos for the patient to review in their own time, may become more widespread in future.20 Suggested 3-stage disclosure process: Initial discussion - Doctor has preliminary discussions with patient to explain diagnosis, prognosis and treatment options, both standard and investigational. Information sheet - The patient is given an information sheet which contains comprehensive details of study treatment including rationale for study, possible benefits as well as adverse effects sub-divided into likely, less likely and remote possibilities. Additional information about relevant Internet sites may also be given if appropriate. Adequate time is then allowed for the patient to read and assimilate the information. Discussion - The trial is again explained to the patient and the patient encouraged to ask questions.
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