Informed consent in biomedical research-Its Importance and current global guidelines-A review of literature

Introduction

Informed consent is an essential step in the ethical conduct and regulation of research, and it has been a keystone in preparing guidelines for conducting research and the ethical oversight of research. It is the process in which a patient/participant consents to participate in a research project after being informed of its procedures, risks, and benefits.¹ There are many ethical issues that are entangled with the informed consent process. Essentially informed consent consists of three steps. First the research team provides full and transparent information about the nature of the project, Secondly, the participant must understand what is being asked and should be competent to decide. Thirdly, the person must decide freely whether to participate or not to participate.² (Fig-1)

This review aims to trace the evolution of guidelines for obtaining informed consent, knowledge of which is required in the ethical conduct of biomedical and health sciences research by researchers with varied background and experience. The following electronic databases were searched through October 15,2017: 1) PubMed/ MEDLINE; 2) Cochrane Database of Systematic Reviews; 3) Science Direct; and 4) ISI Web of Science. Two separate searches were performed. The first search used the following search parameters ([MeSH terms] Informed consent AND [MeSH Terms] (Codes of ethics OR Bioethical issues) AND [MeSH terms] (Challenges), and the second Used ([MeSH terms] Informed consent AND [MeSH terms] (Ethical committees).

Study Selection:

Articles were initially screened based on the titles and abstracts. The accepted articles were read for study design. All references cited in the accepted articles were reviewed to identify additional papers not identified in the database searches. Disagreement regarding inclusion or exclusion of the retrieved papers was resolved by discussion, producing the final set of articles used in this review.

The evolution of informed consent:

The basic principles of ethics in medical practice emanate from the Hippocratic code of conduct which specifies that the physician will use the treatment to help the sick according to his ability and judgment, but never with view to injury and wrong doing.

Claude Bernard extended it to the domain of research, saying that one should not injure one person regardless of the benefits that might come to others.³ The events that led to the implementation of the principles behind the informed consent process in scientific research were some of the most horrific in human history involving atrocities committed on prisoners by Nazi scientist which paved the way for creation of the Nuremberg Code. This Code states that all those who are participating in an experiment are required to give voluntary consent free of undue influence such as “coercion, fraud, duress, or deceit.”⁴ However, this Code did not establish a method that would ensure that its rules were enforced by the physicians/ scientists conducting research. Some of the   notable irregularity, such as Tuskegee syphilis study in USA⁵ and the landmark publication by Beecher on the irregularities that occurred in at least 22 medical research projects in United States changed all this.⁶

Ever since then, the scientific community has continued to revise such principles in order to ensure the ethical treatment of participants. The Declaration of Helsinki and the Belmont Report also indicate the ongoing need to refine the rules and regulations behind the informed consent process. The Belmont Report identified three basic principles which are to be followed by all researchers. -these include respect for person, beneficence, justice.  Among these, the ethical principle of respect for persons is the most important principle with regards to the informed consent process which establishes that all human participants are to “be treated as independent and autonomous individuals capable of selfdetermination.” This implies that all participants must be given informed consent to be involved in a research project, they must be provided with the adequate information about the project, they must understand the research protocol, and they must be able to withdraw from the project at any point.

In recent years widespread debates surrounding the trials of antiretroviral drugs in Africa have led to the reconsideration of several aspects of Inter nationally sponsored research.^7,8 The Declaration of Helsinki, issued by the World Medical Association in 1964, is the landmark document in the field of ethics in biomedical research and has guided the development of international, regional and national legislation and codes of conduct. The Declaration, amended several times, most recently in 2013, is a comprehensive international statement of the ethics of research involving human subjects. It regulates ethical guidelines for physicians engaged in both clinical and nonclinical biomedical research.

Helsinki Declaration(2000) on Informed Consent declared “In any research on human beings, each potential  subject must be adequately informed of the aims and objectives, methods, sources of funding, any possible conflict of interest , the researcher’s  institutional affiliations, the anticipated benefits and potential benefits and potential risks of 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.”⁹

2. Obstacles to Informed Consent

2.1. Language Barrier:

Web page related to the Federal regulation 45 CFR 46. 116 of the United States Department of Health and Human Services states that informed consent has to be given in a language that is understood by the participant or their representative, but misunderstandings can still occur because of inadequate language translations. The quality of the translation is almost as important as the informed consent itself. Research has shown that the use of untrained translators in clinical settings tend to make frequent errors that in some cases result in dangerous misinterpretations. Another problem with the use of untrained translators such as auxiliary staff in the hospital is that it can result in violation of the patient confidentiality which can strain the participant-researcher relationship.

Research has also shown that words or phrases translated from English to another language can result in drastic and erroneous change of meaning.¹⁰ Untrained translators will not realize how words that are spelled almost the same in other languages do not necessarily have the same meaning as they do in English.

2.2. Comprehension and capacity:

Although language is an issue in securing informed consent, obstacles to comprehension go beyond the linguistic barriers. 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 individual lacks capacity.

2.3. Literacy: 

Dine and Bhui¹¹ addressed the dilemmas of conducting research among individuals who are unable to read or write even in their own language. Illiteracy however must never be taken to mean that a potential participant is unable to understand the information that is given, but it does mean that the information may need to be presented differently. Moreover, in societies where verbal communication is often relied upon, written contracts may be mistrusted or not upheld and to asking for a signature may mean offence.

2.4. Religious and Cultural influence:

Researchers designing informed consent form must consider the negative effects that participants might experience due to religious beliefs when participating in research projects. Having a full understanding of the methods involved in the experiment will enable a person to adequately judge if they want to participate in the experiment. Researchers must consider how the methodology of the experiment can come into conflict with the rules of behaviour set by a participant’s religion. For example, the Jehovah Witness religion places strict rules of conduct on its followers when it comes to the type of medical attention they can receive.

2.5. Power relationship:

A researcher may be seen as an authority figure and the patient may be afraid that failure to comply will have serious consequences such refusal to treat. Such extreme differences in knowledge and authority must raise doubts about the validity of consent.¹²

3. Understood consent versus informed consent:

It is assumed that the individual who signs the consent form does so with full understanding of what is stated on the informed consent document. However, whether the participating subject has truly understood the information given is very difficult to evaluate since there is no established method to measure the level of understanding. Many individuals sign the consent form to participate without being fully aware of what they are signing.

A study conducted by Paul Appelbaum et al report that “research subjects systematically misrepresent the risk/benefits ratio of participating in research.” They implicated this to failure to understand the research methodology. This study showed that 69% of the participants failed to understand the meaning of randomization.¹³ Although not conclusive, available data suggest that research participants may frequently not understand disclosed information. For example, approximately 30% of participants in a cross-section of oncology clinical trials believed that their treatment had already been proven to be the best treatment for their cancer¹⁴ In a randomized trial of β-blocker drugs to prolong the lives of patients with history of myocardial infarction, 44% of research participants interviewed did not know that they were assigned to treatment or placebo by chance.¹⁵

Karim et al evaluated the consent process for HIV testing in an antenatal clinic in South Africa. They found that despite the fact that researchers followed the procedures for obtaining informed consent, 84% of participant believe that it was mandatory to participate.¹⁶ Many other studies suggest that similar shortfalls in understanding are widespread.^17-21

All too often the informed consent process is viewed by members of research teams as a challenge of getting participating subjects to sign on a form. Informed consent is, however, much more than a signed form. Rather, it is a process, often iterative, in which the participating subject is given sufficient information about a study in order that they can make a truly informed decision about participation. It demands substantial effort from the research team in producing appropriately formatted and readable and most importantly understandable informed consent documents using plain language.

Achieving truly understood consent involves the researcher spending significant one-on-one time with the subject, explaining in simple language what is proposed and then using so-called repeatback techniques to test the understanding of the participants. This is very important if the research involves randomization to different treatments or use of a placebo arm and, in particular if the research involves more than minimal risk.

4. Interventions to Improve Research Participant’s understanding in Informed Consent for Research:

Given the importance that informed consent is for both the protection of human rights and the ethical validity of research experiments, it is important and ethical to try to amend the problems caused by the misunderstanding of information.

The methods that have been suggested are:

1. Conducting a demographic analysis of the geographical location of the research projects.
2. Hiring professionals to translate all the information related to the experiment.
3. Taking extra time to fully explain the informed consent form. And
4. Administering small quizzes about the information covered in the consent form. Interventions using modern techniques like multimedia technology, detailed enhanced consent forms, and extended discussion with social scientists and educators have been proposed to improve research participants’ understanding of disclosed information and to give genuine consent. 

Flory and Emanuel in a systematic review concluded that multimedia and enhanced consent form interventions do not consistently improve research participants’ understanding. Personto-person interactions, more importantly the extended discussion interventions, may be more effective in improving understanding.²² Another method that can be implemented to the informed consent process is testing for understanding. A short quiz focusing on the important aspects of the research project such as its methodology, purpose, risks, and benefits after the informed consent form is explained would help researchers identify potential problem areas. Researchers can use the erroneous answers as a guide for conducting further explanation sessions.

5.    Global guidelines on informed consent:

     5.1. World Medical Association Helsinki guidelines, 2003:

Helsinki guidelines in their 2003 revision adopted following guidelines-The physician should obtain the potential participants freely given informed consent, preferably in writing. Even if the consent cannot be obtained in writing, consent must still be formally documented and witnessed. In cases in which the potential participant is legally incompetent, physically, or mentally incapable of giving consent or is legally incompetent minor, the investigator must obtain informed consent from the participant’s legally authorized representative in accordance with applicable law.

 5.2 . National Bioethics advisory Committee, 2000²³:

Research group should develop culturally appropriate ways of disclosing the information necessary for adherence to substantive ethical standards of informed consent, giving particular attention to disclosures relating to diagnosis and possible post trial benefits to the participant. Procedures must be developed and described in such a way to ensure that potential participants understand the information provided in the consent process.

While the permission of a community representative may be sought before researchers approach potential participants, in no case may such permission replace the requirement of obtaining a competent individual’s informed consent without coercion or inducement.

Researchers working in developing countries should indicate in their research protocol how they will minimize the likelihood that potential participants will mistakenly believe that the research purpose is solely to administer treatment rather than to contribute to scientific knowledge.

5.3. Nuffield Council on Bioethics, 2002²⁴:

Verbal consent is acceptable only if written consent is inappropriate. The consent of a senior member of the family member or community leader may be required in addition to individual’s consent. The council also recommends adopting the concept of “genuine consent” as opposed to “informed consent”

5.4. Council for International Organizations of Medical Sciences, (CIOMS) 2002 ²⁵:

In all biomedical research involving humans the investigator must obtain the voluntary informed consent of the potential participant or in the case of an individual who is not capable of giving informed consent ,the legally authorized representative in accordance with applicable law. The use of a waiver of informed consent is regarded as uncommon and exceptional and must in all cases be approved by an ethical review committee.

Written consent is preferably required when appropriate. Multiple forms of consent are acceptable. In the case of research posing minimal risks, participants may waive consent. The council lists 26 essentials of research that must be addressed during consent process. (Box-1)

5.5. European Union guidelines, 2001²⁶:

The consent of family or community leader may be required in addition to obtaining an individual’s consent. Verbal consent is appropriate only if the participant is illiterate. These guidelines provide a checklist of eight essential aspects of research that should be addressed during the consent process.

5.6. ICMR Guidelines regarding the Informed Consent process:

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. The guidelines that are framed are directed at application of these basic principles to research involving human 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 Form with Participant/ Patient Information Sheet should have the components as may be applicable as in Box-2.²⁷

In the context of developing countries like India, obtaining informed consent has been considered many times as difficult/ impractical/ not meeting the purpose on various grounds such as incompetence to comprehend the meaning or relevance of the consent and culturally being dependent on the decision of the head of the family or village/community head.. In the new “National Ethical Guidelines for Biomedical and Health Research involving Human Participants, 2017 speciaised areas like informed consent process, biological materials, biobanking and datasets and vulnerability have been expanded into separate sections. Essential and additional elements of Informed consent process is given in Box-3.²⁸

5.6. World Medical association, Helsinki guidelines (2013).²⁹:

Helsinki guidelines in their 2013 revision adopted following guidelines regarding informed consent as in Box-4.

5.7. Draft guidelines on Audio-visual Recording of Informed consent:

Process in Clinical trials issued by Central drugs standard control organization (CDSCO) and its pros and cons:

CDSCO (Central drugs standard control organization) vide F. No. GCT/20/SC/Clin./2013 DCG1 dated 19.11.2013 has issued direction that in all clinical trials, in addition to the requirement of obtaining written informed consent, audiovisual recording of the informed consent process of each trial subject, including the procedure of providing information to the subject and his/ her understanding on such consent is required to be done while adhering to the principles of confidentiality. Such audio-visual recording and related documentation would be preserved. This is applicable to the new subjects to be enrolled in all clinical trials including Global Clinical Trials. It is included as draft rule in the gazette of India notification dated 7th June 2013.³⁰ Details of the draft appear in Box-5.

5.7.1. Advantages and disadvantages of the audiovisual recording of the informed consent:

Have been discussed in depth by Kulkarni et al.³¹ There are many anticipated advantages of AV recording like reliability, transparency, and improvement in quality of conduct of informed consent process. However, at the same time the industry will need to address challenges in infrastructure, maintaining confidentiality, cost implication, and so on.

6. Assent and Dissent in Paediatric research:

Children are often proclaimed as being very important members of society because they represent our future. But it is often unclear how society uses its resources or creates policies to ensure that it invests in children’s health. History has shown that children may be exposed to serious unintended harms from medications if adequate research is not performed.^32-34 Most Child health care providers must often rely on evidence that has been generated on adult populations though children are not small adults³⁵ and both the safety and efficacy profiles of medications may be significantly different for children than adults due to differences in developmental physiology, disease pathophysiology, or developmental pharmacokinetics and pharmacodynamics.^32,36

Guidelines around the world require children to provide assent for their participation in most research studies. Yet, little further guidance is provided on how review committees should implement this requirement, including which children are capable of providing assent and when the requirement for  assent may be waived on the grounds that the research offers participating children the potential for important clinical benefit. This suggests children are capable of assent when they become able to understand the research in question. Investigators and review committees who attempt to implement the assent requirement must determine at what age children become capable of providing assent.

Unfortunately, research ethics guidelines provide little guidance in this regard. In USA, US federal regulations specify only that the determination of which children are capable of assent should be based on the children’s ‘ages, maturity, and psychological state’ (Department of Health and Human Services,11 45 CFR 46.608a). This guidance leaves many questions unanswered. Which aspects of children’s age, maturity, and psychological state should investigators take into account when determining whether they are capable of assent?

Some commentators defend the age seven threshold by appeal to the centuries old ‘‘Rule of Sevens’’, which ‘‘has stood at least ever since the time of Edward the Third’’(1327–1377) to determine an age threshold for assent.³⁷ Rule of Sevens states, roughly, that children under age seven do not have the capacity necessary to make their own decisions; children from seven to fourteen years of age are presumed not to have this capacity until proven otherwise in individual cases, and children over age 14 are presumed to have capacity to make their own decisions and lead their own lives, unless proven otherwise.

6.1. ICMR guidelines regarding informed consent in pediatric research:

Before undertaking trial in children, the investigator must ensure that guidelines are followed as in Box-6. In cases of research involving children, a parent or legal guardian of the child should give proxy consent. In case of research on children, 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 7-18 years of age²⁷.

As per the recent National ethical guidelines for biomedical research involving children, for children between 7 (84 months and above) and 11 years of age, oral assent must be obtained in the presence of parent/LAR (legally authorized representative).For children between 12 and 18 years of age, written assent must be obtained. If a child becomes 13 years old during the course of the study, then written assent must be obtained in addition to parent/LAR consent.³⁸ 

In most of the cases, children will not know whether research participation will be distressing until they experience it. Hence, requiring children to make a prospective decision whether to enrol does not offer an effective mechanism to protect them from harm, particularly when children may be reluctant to go back on agreements made with doctors. Children also may find it very distressing to be asked to make decisions about research they cannot understand. Thus, protecting children from harm does not seem to support, and may well conflict in certain cases, with the requirement to ask children to decide whether to enrol in non-beneficial research before they are able to understand the research in question.

In contrast, once children are enrolled in research, they will be in a very good position to assess whether it is causing them distress. And because these children who experience distress will communicate this verbally or through body movements, protection of children from harm supports adoption of a dissent requirement to supplement existing assent requirements: the dissent of all children should be respected in the context of research which is not beneficial.^39-41

7. Challenges of Informed consent In Cluster Randomized trials (CRT):

CRTs raises at least 4 concerns for handling participant informed consent.⁴² First, the hierarchical structure of such trials implies the consideration of 2 levels of consent. The first level is the ‘‘guardian,’’ as defined by Edwards et al.⁴³ who must agree to participation and randomization. The other level is participants embedded within clusters.

Second, some interventions (such as fluoridation of water supply or computer-based tools to help Physicians while prescribing) apply (or not) to the whole cluster, and individual participants have no opt-out option. Participant consent can therefore cover different things, and thus, Hutton⁴⁴ distinguished 3 types of consent: (i) consent that routinely held data on individuals be collected, (ii) consent regarding the collection of supplementary data and (iii) consent for active participation.

Third, randomizing large clusters such as hospitals, villages, or geographical areas implies logistic difficulties that cannot be overcome to obtain individual informed consent. Fourth, full information given to the cluster participant may compromise the internal validity of the trial because of selection bias (lack of allocation concealment induced by a randomization of clusters before recruitment of participants) and group contamination.

Blinding participants to the study hypothesis or delivering differential information   may then greatly help prevent or reduce bias. These situations led the CIOMS to consider the possibility of a transfer of consent from the individual to the cluster level. The person in charge of the cluster has authority to give permission for the cluster to participate in the study and to be assigned on a random basis to one arm or another of the study,’’ and thus, consent to the study is collective.

Conclusion

For all biomedical research involving humans the investigator must obtain the voluntary informed consent of the prospective participating subject or, in the case of a subject who is not capable of giving informed consent, the proxy consent of a legally authorized representative in accordance with applicable law. Waiver of informed consent is to be treated as uncommon and exceptional, and must in all cases be approved by an ethical review committee.

Valid informed consent is a decision to participate in research, taken by an individual who is competent to decide, who has received the necessary information; who has adequately understood the information; and who, after understanding the information that is given, has arrived at a decision without having been subjected to duress, undue influence or inducement, or intimidation. This safeguard of interest of the participating subject is particularly important as many individuals are limited in their capacity to give adequate informed consent; they include vulnerable population such as young children, adults with severe mental or behavioural disorders, and persons who are unfamiliar with medical concepts and technology.

Box-1: Text of guide lines of the International ethical guidelines for biomedical research involving human subjects.²⁵

1. That the individual is invited to participate in research, the reasons for considering the individual suitable for the research, and that participation is voluntary;
2. That the individual is free to refuse to participate and will be free to withdraw from the research at any time without penalty or loss of benefits to which he or she would otherwise be entitled;
3. The purpose of the research, the procedures to be carried out by the investigator and the subject, and an explanation of how the research differs from routine medical care;
4. For controlled trials,an explanation of features of the research design (e.g., randomization, double-blinding), and that the subject will not be told of the assigned treatment until the study has been completed and the blind has been broken;
5. The expected duration of the individual’s participation (including number and duration of visits to the research centre and the total time involved) and the possibility of early termination of the trial or of the individual’s participation in it;
6. Whether money or other forms of material goods will be provided in return for the individual’s participation and, if so, the kind and amount;
7. That, after the completion of the study, subjects will be informed of the findings of the research in general, and individual subjects will be informed of any finding that relates to their particular health status;
8. That subjects have the right of access to their data on demand, even if these data lack immediate clinical utility (unless the ethical review committee has approved temporary or permanent nondisclosure of data, in which case the subject should be informed of, and given, the reasons for such non-disclosure);
9. Any foreseeable risks, pain or discomfort, or inconvenience to the individual (or others) associated with participation in the research, including risks to the health or well-being of a subject’s spouse or partner;
10. The direct benefits, if any, expected to result to subjects from participating in the research
11. The expected benefits of the research to the community or to society at large, or contributions to scientific knowledge;
12. Whether, when and how any products or interventions proven by the research to be safe and effective will be made available to subjects after they have completed their participation in the research, and whether they will be expected to pay for them;
13. Any currently available alternative interventions or courses of treatment;
14. The provisions that will be made to ensure respect for the privacy of subjects and for the confidentiality of records in which subjects are identified;
15. The limits, legal or other, to the investigators’ ability to safeguard confidentiality, and the possible consequences of breaches of confidentiality;
16. Policy with regard to the use of results of genetic tests and familial genetic information, and the precautions in place to prevent disclosure of the results of a subject’s genetic tests to immediate family relatives or to others (e.g.,insurance companies or employers) without the consent of the subject;
17. The sponsors of the research, the institutional affiliation of the investigators ,and the nature and sources of funding for the research;
18. The possible research uses, direct or secondary, of the subject`s medical records and of biological specimens taken in the course of clinical care
19. Whether it is planned that biological specimens collected in the research will be destroyed at its conclusion, and, if not, details about their storage (where, how, for how long, and final disposition) and possible future use, and that subjects have the right to decide about such future use, to refuse storage, and to have the material destroyed (See Guideline 4 Commentary);
20. Whether commercial products may be developed from biological specimens ,and whether the participant will receive monetary or other benefits from the development of such products;
21. Whether the investigator is serving only as an investigator or as both investigator and the subject`s physician;
22. The extent of the investigator’s responsibility to provide medical services to the participant;
23. That treatment will be provided free of charge for specified types of research-related injury or for complications associated with the research, the nature and duration of such care, the name of the organization or individual that will provide the treatment, and whether there is any uncertainty regarding funding of such treatment.
24. In what way, and by what organization, the subject or the subject`s family or dependants will be compensated for disability or death resulting from such injury (or, when indicated, that there are no plans to provide such compensation);
25. Whether or not, in the country in which the prospective subject is invited to participate in research, the right to compensation is legally guaranteed;
26. That an ethical review committee has approved or cleared the research protocol

 Box-2: ICMR Guidelines regarding the Informed Consent process

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 it  results

Box-3 Essential and additional components of Informed consent.²⁸

An informed consent form must include the following:

1.      Statement mentioning that it is research.

2.      Purpose and methods of the research in simple language.

3.   Expected duration of the participation and frequency of contact with estimated number of participants to be enrolled, types of data collection and methods.

4.  Benefits to the participant, community or others that might reasonably be expected as an outcome of research.

5. Any foreseeable risks, discomfort or inconvenience to the participant resulting from participation in the study.

6.   Extent to which confidentiality of records could be maintained, such as the limits to which the researcher would be able to safeguard confidentiality and the anticipated consequences of breach of confidentiality.

7.    Payment/reimbursement for participation and incidental expenses depending on the type of study.

8.    Free treatment and/or compensation of participants for research-related injury and/or harm

9.   Freedom of the individual to participate and/or withdraw from research at any time without penalty or loss of benefits to which the participant would otherwise be entitled.

10. The identity of the research team and contact persons with addresses and phone numbers (for example, PI/Co PI for queries related to the research and Chairperson/Member Secretary/ or helpline for appeal against violations of ethical principles and human rights).

In addition, the following elements may also be required, depending on the type of study:

1. Any alternative procedures or courses of  treatment that might be as advantageous to the participant as the ones to which she/he is going to be subjected

2.  If there is a possibility that the research could lead to any stigmatizing condition, for example HIV and genetic disorders, provision for pretest-and post-test counselling

3.  Insurance coverage if any, for research-related or other adverse events

4. Foreseeable extent of information on possible current and future uses of the biological material and of the data to be generated from the research. Other specifics are as follows:

i. period of storage of the sample/data and probability of the material being used for secondary purposes.

ii. whether material is to be shared with others, this should be clearly mentioned.

iii. right to prevent use of her/ his biological sample, such as DNA, cell-line, etc., and related data at any time during or after the conduct of the research.

iv. risk of discovery of biologically sensitive information and provisions to safeguard confidentiality. v.post research plan/benefit sharing, if research on biological material and/or data leads to commercialization. vi. Publication plan, if any including, photographs and pedigree charts.

Box-4 World Medical Association Helsinki Guidelines 2013.²⁹

• Participation by individuals capable of giving unformed consent as subjects in medical research must be voluntary. Although it may be appropriate to consult family members or community leaders, no individual capable of giving informed consent may be enrolled in a research study unless he or she freely agrees.
• In medical research involving human subjects capable of giving informed consent, each potential subject must be adequately informed of the aims, methods. sources of fnding. any possible conflicts of interest, institutional affiliations of the researcher, the anticipated benefits and potential risks of the study and the discomfort it may entail, post-sandy provisions and any other relevant aspects of the study. The potential subject mint be informed of the right to refuse to participate in the study or to withdraw consent to participate at any time without reprisal. Special attention should be given to the specific information needs of individual potential subjects as well as to the methods used to deliver the information. After ensuring that the potential subject has tmderstood the information, the physician or another appropriately qualified individual must then seek the potential subject’s freely-given informed consent. preferably in writing. If the consent cannot be expressed in writing. the non-written consent must be formally documented and witnessed..All medical research subjects should be given the option of being informed about the general outcome and results of the study.
• When seeking informed consent for participation in a research study the physician must be particularly cautious if the potential subject is in a dependent relationship with the physician or may consent under duress. In such situations the informed consent must be sought by an appropriately qualified individual who is completely independent of this relationship.
• For a potential research subject Mx, is incapable of giving informed consent, the physician must seek informed consent from the legally authorised representative. These individuals must not be included in a research study that has no likelihood of benefit for them unless it is intended to promote the health of the group represented by the potential subject, the research cannot instead be performed with persons capable of providing informed consent. and the research entails only minimal risk and minimal burden.
• When a potential research subject who is deemed incapable of giving informed consent is able to give assent to decisions about participation in research. the physician must seek that assent in addition to the consent of the legally authorised representative. The potential subject’s dissent should be respected.
• Research involving subjects who are physically or mentally incapable of giving consent, for example. unconscious patients. may be done only if the physical or mental condition that prevents giving informed consent is a necessary characteristic of the research group. hi such circumstances the physician must seek informed consent from the legally authorised representative. If no such representative is available and if the testarch cannot be delayed. the stud). may proceed without informed consent provided that the specific masons for involving subjects with a condition that renders them unable to give informed consent have been stated in the research protocol and the study has been approved by a research ethics conunittee. Consent to remain in the research must be obtained as soon as possible from the subject or a legally authorised representative.
• The physician must fully inform the patient which aspects of their care are related to the research. The refusal of a patient to participate in a study or the patient’s decision to withdraw from the study must never adversely affect the patient-physician relationship. The physician must fully inform the patient which aspects of their care are related to the research. The refusal of a patient to participate in a study or the patient’s decision to withdraw from the study must never adversely affect the patient-physician relationship.
• For medical research using identifiable human material or data, such as research on material or data contained in biobanks or similar repositories, physicians must seek infomied consent for its collection. storage and/or reuse. There may be exceptional situations where consent would be impossible or impracticable to obtain for such research. In such situations the research may be done only after consideration and approval of a research ethics committee.

Box-5 : Draft guidelines on Audio-Visual recording of informed consent process in Clinical Trial

Principle of privacy and confidentiality:

During the audio-visual recording of informed consent process, the identity and records of the trial subjects are as far as possible kept confidential; and that no details about identity of said subjects, which would result in the disclosure of their identity, are disclosed without valid scientific and legal reasons which may be essential for the purposes of therapeutics or other interventions, without the specific consent in writing of the subject concerned, or someone authorised on their behalf, and after ensuring that the said subject does not suffer from any form of hardship, discrimination or stigmatisation as a consequence of having participated in the trial. The Investigator must safeguard the confidentiality of trial data, which might lead to the identification of the individual subjects. Data of individual subjects can be disclosed only in a court of law under the orders of the presiding judge or in some cases may be required to communicate to Drug regulatory/ Health authority. In order to maintain the confidentiality, the videographer should be engaged as part of the study team.

Consent of the subjects for audio-visual recording:

Prior to initiation of the study, the Investigator should define and allocate the activities of audio-video recording of informed consent process to the respective identified person as videographer. The Investigator shall maintain the details of the person to whom he has delegated the duties of audio video recording. Prior consent of the subject should be taken for audio-visual recording of informed consent process and the same should be documented by the Investigator. Such consent may be taken orally. Only those subjects who give the consent for the AV recording shall be included in the clinical trial.

Procedure of audio-visual recording:

At the beginning of the video recording process, the Investigator will identify the protocol, the subject/LAR/IW and the language understood by the subject/LAR/IW. If the Investigator does not know the language of the subject/LAR/IW a member of the study team who understands the language, would become the interpreter. In order to identify the subject/LAR/IW his/her photo ID may be documented. The video camera for the audio-visual recording should be of adequate capability to simultaneously capture the facial details of subject, LAR/Impartial Witness (if any), Investigator/authorised person present during the consent process. The audio-visual recording should be conducted in a room conducive to recording of disturbancefree audio and video of the consent process. During the videography process, care should also be taken not to include unrelated persons/patients at the hospital within the field of vision.

Quality of audio-visual recording:

The Video recording of informed consent may not serve the intended purpose if the quality of the recording fails to meet a minimum standard required for the purpose. The video recording should be done ty of the recording fails to meet a minimum standard required using video camera of appropriate resolution and in a room free from any disturbance to ensure that the image is recognizable and the audio is clearly audible.

Storage & archival of audio-visual recordings:

Audio visual recording of informed consent process and other related documents should be preserved safely after the completion / termination of the study for at least a period of 5 years if it is not possible to maintain the same permanently.

LAR-legally acceptable representative-Independent witness.

Box-6. Ethical guidelines regarding informed consent in pediatric research (ICMR guidelines, 2006)

• Children will not be involved in research that could be carried out equally well with adults:
• 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 t he drug has a therapeutic value in a primary disease of the children;
• A parent or legal guardian of each child has given proxy consent:
• 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.;
• Research should be conducted in settings in which the child and parent can obtain adequate medical and psychological support; 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;
• 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:
• 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:
• 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.