9. Subject Considerations

9.1 Clinical trial subject recruitment: Are digital advertisements (including social media streams such as TikTok) allowed and, if so, what regulations govern them? 

Yes, online advertisement is allowed. Facebook is the most effective recruitment service online.

https://www.anjusoftware.com/social-media-101-best-practices-for-clinical-trial-recruitment/

9.2 Vulnerable Subjects 

Terminally Ill Patients

Terminally ill patients or patients seeking new treatments are vulnerable as they are ready to give consent for any intervention that could help them. The EC should carefully review protocols and recruitment procedures for these studies and comply with the following requirements:

• Additional monitoring should be done to detect any adverse event as soon as possible.
• A benefit-risk assessment should be performed that considers the potential participant’s perception of benefits and risks.
• Post-trial access to the medication.

Indigenous People

Research on tribal populations should only be conducted if it is of a specific therapeutic, diagnostic, and preventative nature with appropriate benefits to the tribal population. A competent administrative authority’s approval, such as the tribal welfare commissioner or the district collector, should be obtained before an investigator enters the area. 

Whenever possible, it is desirable to seek the help of government functionaries/local bodies or registered, non-governmental organizations who work closely with the tribal groups and have their confidence. The tribal leader or other culturally appropriate authority may serve as the gatekeeper from whom permission to enter and interact should be obtained. 

A participant’s consent should be taken along with consulting with community elders and individuals who know the local language/dialect of the tribal population and in the presence of appropriate witnesses. Additional precautions should be taken to avoid including children, pregnant women, and elderly people belonging to particularly vulnerable tribal groups. Benefit sharing with the tribal group should also be ensured for any research done using tribal knowledge that may have the potential for commercialization.

The Elderly

Geriatric patients should be included in Phase II and Phase III clinical trials at the sponsor’s recommendation, in the following circumstances:

• The disease intended to be treated is typically a disease of aging.
• The population to be treated is known to include substantial numbers of geriatric patients.
• There is a specific reason to expect that conditions common in the elderly are likely to be encountered.
• The new drug is likely to alter the geriatric patient’s response (with regard to safety or efficacy) compared with that of the non-geriatric patient

Persons in Dependent Groups

While reviewing protocols involving participants who are engaged in subordinate or dependent relationships, the ethics committee (EC) must ensure the following:

• Participant enrolment is specifically relevant to the research questions and is not merely a matter of convenience.
• Extra efforts are required to ensure the autonomy of these individuals is respected, and that they can freely decide to participate or deny consent and/or later withdraw from the study without fear of any negative repercussions on their care.
• Mechanisms to avoid coercion due to being part of an institution or hierarchy should be described in the protocol.

Sexual Minorities and Sex Workers

Sexual minorities and sex workers require additional protections as they are more vulnerable to privacy, confidentiality, stigma, discrimination, and exploitation issues during a research study. Research proposals should ensure that the dignity of these participants is protected and that they have access to quality healthcare. Investigators should consult the community, if possible, prior to the proposal being finalized. It is also advised that a representative of the sexual minority group/lesbian/gay/bisexual and transgender (LGBT) community attends the ethics committee meeting as a special invitee/member.

Pregnant

The following conditions are required for research involving pregnant or nursing women to be conducted:

• Pregnant or nursing women should be included in clinical trials only when the drug is intended for use by pregnant or nursing women, fetuses, or nursing infants, and where the data generated from women who are not pregnant or nursing is unsuitable.
• For studies related to pregnancy termination, only pregnant women who undergo Medical Termination of Pregnancy as per the Medical Termination of Pregnancy Act, 1971 can be included.
• The research should carry no more than minimal risk to the fetus or nursing infant and the research objective is to obtain new knowledge about the fetus, pregnancy, and lactation.
• Clinical trials involving pregnant or nursing women would be justified to ensure that these women are not deprived arbitrarily of the opportunity to benefit from investigations, drugs, vaccines, or other agents that promise therapeutic or preventive benefits.
• Research related to prenatal diagnostic techniques in pregnant women should be limited to detecting fetal abnormalities or genetic disorders as per the Pre-Conception and Pre-Natal Diagnostic Techniques (Regulation and Prevention of Misuse) Act, 1994, amended in 2003, and not used to determine the sex of the fetus.
• Researchers must provide the ethics committee (EC) with proper justification for including pregnant and nursing women in trials designed to address the health needs of such women or their fetuses or nursing infants.
• If women of reproductive age are to be recruited, they should be informed of the potential risk to the fetus if they become pregnant, be asked to use an effective contraceptive method, and be told about the options available in case of failure of contraception.
• A woman who becomes pregnant must not automatically be removed from the study when there is no evidence showing potential harm to the fetus. The matter should be carefully reviewed, and she must be offered the option to withdraw or continue.
• If the female sexual partner of a male participant gets pregnant during his research participation, the EC should review the protocol and informed consent form (ICF) to determine if a plan exists to document this event, and both the pregnant partner and fetus must also be followed for the outcome and reported in the study results.
• Pregnant women have the right to participate in clinical research relevant to their healthcare needs (e.g., gestational diabetes, pregnancy-induced hypertension, and HIV).
• Benefit-risk assessment must be done at all stages for both the mother and the fetus.
• Research involving pregnant women and fetuses must only take place when the objective is to obtain new knowledge directly relevant to the fetus, the pregnancy, or lactation.
• Women should not be encouraged to discontinue nursing for the sake of participation in research except in those studies where breastfeeding is harmful to the infant.
• Appropriate studies on animals and non-pregnant individuals should have been completed first, if applicable.
• Researchers should not participate in decision-making regarding any termination of a pregnancy.
• No procedural changes that will cause greater than minimal risk to the woman or fetus will be introduced into the procedure for terminating the pregnancy solely in the interest of the trial.
• When research is planned on sensitive topics (e.g., domestic violence, genetic disorders, and/or rape) confidentiality should be strictly maintained and privacy protected.

Prisoners 

During the review process, the ethics committee (EC) must ensure compliance with the following:

• Enrolling participants is specifically pertinent to the research questions and is not merely a matter of convenience.
• Extra efforts are made to respect the autonomy of these individuals because they are in a hierarchical position and may not be able to disagree to participate for fear of authority.
• It is possible for the participant to deny consent and/or later withdraw from the study without any negative repercussions on her/his care.
• Mechanisms to avoid coercion due to being part of an institution or hierarchy should be described in the protocol.

Mentally Impaired

The presence of a mental disorder is not synonymous with the incapacity of understanding or the inability to provide informed consent. However, ethics committees (ECs) have special responsibilities when research is conducted on participants who are suffering from mental illness and/or cognitive impairment. ECs should exercise caution and require researchers to justify exceptions and their need to depart from the guidelines governing research. ECs should ensure that these exceptions are as minimal as possible and are clearly spelled out in the informed consent form. Every person, including a person with mental illness, must be deemed to have the capacity to make decisions regarding his/her mental healthcare or treatment provided he/she can engage in the following:

• Understand the information that is relevant to make a decision on treatment, admission, or personal assistance;
• Appreciate any reasonably foreseeable consequence of a decision or lack of decision on the treatment, admission, or personal assistance; or
• Communicate the decision by means of speech, expression, gesture, or any other means.

The information must be provided to a person with mental illness using simple and understandable language, sign language, visual aids, or any other means to enable him/her to understand the information. In the case in which a person makes a decision regarding his/her mental healthcare or treatment that is perceived by others as inappropriate or wrong, that by itself, must not be interpreted as the person not having the capacity to make such a decision, as long as the person has the capacity to meet the above-stated requirements.

The Mental Healthcare Act - MHA 2017 - further delineates that every person with mental illness who is not a minor must have the right to appoint a nominated representative. The nomination must be made in writing on plain paper with the person’s signature or thumb impression. The person appointed as nominated representative must not be a minor, be competent to discharge the duties or perform the functions assigned to him/her under the MHA 2017, and give his/her consent in writing to the mental health professional to discharge his/her duties and perform the functions assigned to him/her. A person who has appointed an individual as his/her nominated representative may revoke or alter the appointment at any time. The appointment of a nominated representative, or the inability of a person with mental illness to appoint a nominated representative, must not be construed as the lack of capacity of the person to make decisions about his/her mental healthcare or treatment. All persons with mental illness must have the capacity to make mental healthcare or treatment decisions but may require varying levels of support from their nominated representative to make decisions. When fulfilling his/her responsibilities, the nominated representative must have the right to give or withhold consent for research under the circumstances.

Pursuant to MHA 2017, professionals conducting research must obtain free and informed consent from all persons with mental illness for participation in any research that involves interviewing the person, or any research that involves psychological, physical, chemical, or medicinal interventions. In the case of research involving psychological, physical, chemical, or medicinal interventions to be conducted on a person who is unable to give free and informed consent, but does not resist participation in such research, permission to conduct such research must be obtained from the concerned State Authority. The State Authority may allow the research to proceed based on informed consent being obtained from the person’s nominated representative if the State Authority is satisfied that the following criteria are met:

1. The proposed research cannot be performed on persons who are capable of giving free and informed consent.
2. The proposed research is necessary to promote the mental health of the population represented by the person.
3. The purpose of the proposed research is to obtain knowledge relevant to the particular mental health needs of persons with mental illness.
4. Full disclosure of the interests of the persons and organizations conducting the proposed research is made and there is no conflict of interest involved.
5. The proposed research follows all the national and international guidelines and regulations concerning the conduct of such research, and ethical approval has been obtained from the institutional EC where such research is to be conducted.

A research-based study of the case notes of a person who is unable to give informed consent will be permitted so long as the anonymity of the person is secured. In addition, the person with mental illness or his/her nominated representative who gives informed consent for participation in any research under MHA 2017 may withdraw consent at any time during the research period.

https://clinregs.niaid.nih.gov/country/india#vulnerable_populations

9.3 Pediatrics (including whether consent from a single parent is sufficient vs. requiring both parents to sign)

Children are individuals who have not obtained the legal age of consent, which is 18.

As stated in the G-ICMR, the 2019-CTRules, and the G-Children, in the case of pediatric clinical trials, the participants are legally unable to provide written informed consent and are dependent on their legal representative(s) or guardian(s) to assume responsibility for their participation in a research study.

However, as specified in the 2019-CTRules, all pediatric participants should be informed to the extent compatible with the child’s understanding, and if capable, the pediatric participant should sign and personally date the informed consent form (ICF). In these studies, the following requirements should be complied with:

1. Written informed consent should be obtained from the legal representative(s) or guardian(s); however, all pediatric participants should be informed to the fullest extent possible about the study in a language and in terms that they are able to understand.
2. Where appropriate, pediatric participants should additionally provide their assent to enroll in the study, and mature minors and adolescents should personally sign and date a separately designed written assent form.
3. Although a participant’s wish to withdraw from a study must be respected, there may be circumstances in therapeutic studies for serious or life-threatening diseases in which, in the investigator’s and legal representative(s)’s or guardian(s)’s opinion, a pediatric patient’s welfare would be jeopardized by his/her failure to participate in the study. In this situation, continued legal representative(s) or guardian(s) consent should be sufficient to allow participation in the study.

The Clinical Trial Rules further specify requirements for pediatric studies involving new drugs. These studies must consider the following issues:

• The timing of new drug pediatric studies will depend on the medicinal product, the type of disease being treated, safety considerations, and the efficacy and safety of available treatments.
• If the new drug is for diseases predominantly or exclusively affecting pediatric patients, clinical trial data should be generated in the pediatric population except for initial safety and tolerability data, which will usually be obtained in adults, unless such initial safety studies in adults would yield little useful information or expose them to inappropriate risk.
• If the new drug is intended to treat serious or life-threatening diseases occurring in both adults and pediatric patients for which there are currently no or limited therapeutic options, the pediatric population should be included in the clinical trials early, following assessment of initial safety data and reasonable evidence of potential benefit. In circumstances where this is not possible, the lack of data should be justified in detail.
• If the new drug has a potential for use in pediatric patients, pediatric studies should be conducted.
• Pediatric studies should include clinical trials, relative bioequivalence comparisons between pediatric and adult formulations, and pharmacokinetic studies for dose selection across the age ranges of pediatric patients in whom the drug is likely to be used.
• If the new drug is a major therapeutic advance for the pediatric population, studies should begin early in the drug development, and this data should be submitted with the new drug application.

The reviewing ethics committee (EC) should also include members who are knowledgeable about pediatric, ethical, clinical, and psychosocial issues.

Assent Requirements

If the pediatric participant has the capacity for assent, his/her affirmative assent is required to participate in a study according to their developmental level and decision-making capacity. Per the CT Rules, mature minors and adolescents should personally sign and date a separately designed written assent form. Mature minors are those from age seven (7) up to age 18.

In addition to the children’s developmental level and capability of understanding, the assent process and form should also take into account their age, maturity, reading level, independence, autonomy as well as cultural and social factors. For children between ages seven (7) and 11, oral assent must be obtained in the presence of their legal representative(s) or guardian(s). For children between ages 12 and 18, written assent must be obtained.

A child’s dissent or refusal to participate must always be respected, and he/she must be informed in an understandable manner that he/she may withdraw his/her assent at any time during the study. The EC may also issue a waiver of assent in the following circumstances:

1. If the research has the potential to directly benefit the child and this benefit is only available through this study.
2. If the research involves children with intellectual and other developmental disabilities, they may not have the developmental level and intellectual capability to give assent.

Fetuses & Neonates

Study protocols involving neonates should take into consideration that this group is the most vulnerable within the pediatric population in terms of the risk of long-term effects of interventions, including developmental effects. ECs reviewing such proposed protocols should have an advisory member with expertise in neonatal research/care. ECs should scrutinize all proposed research for potential risks, weigh them against the possible benefits, and ensure a competent person(s) conducts a proper scientific review of the protocol. In addition, when possible, older children should be studied before conducting studies on younger children and infants.

The consent of one (1) parent is also required for neonate studies where research exposes them to no or minimal risk, or in studies that offer the prospect of direct benefit to the participant. However, for studies that do not offer the prospect of direct benefit or are high-risk, consent from both parents is required. Exceptions to this requirement include the following:

1. Only one (1) parent has legal responsibility for the care and custody of the child.
2. One (1) parent is deceased, unknown, incompetent, or not available. In such cases, it is the duty of the investigators to provide adequate justification.

If one (1) of the parents is a minor, then consent should not be taken from her/him. If both parents are minors, then enrollment of such a baby should be avoided as much as possible. Investigator(s) should provide adequate justification to the EC to enroll such neonates for research. A legally acceptable representative should provide informed consent in such situations.

https://clinregs.niaid.nih.gov/country/india#children/minors

9.4 Financial Disclosures

Researchers must disclose any financial activity which may be considered a real or perceived conflict of interest.  

9.5 ICF translations – Are Certificates Required?

Informed consent documents are required in English and the local language(s) including translation and back translation certificates, if applicable.

The ICF content should be briefly and clearly presented orally, in writing, and in a manner that is easy to understand, commensurate with the comprehension level of the participants, and without coercion or unduly influencing a potential participant to enroll in the trial. The ICF language should not only be scientifically accurate and simple but should also be sensitive to the participant’s social and cultural background. 

Investigator(s) must obtain an audio-video (AV) recording of the informed consent process for vulnerable participants in clinical trials of a new chemical entity or new molecular entity, including the procedure of providing information to the participant and his/her understanding of the consent. 

https://main.icmr.nic.in/sites/default/files/guidelines/ICMR_Ethical_Guidelines_2017.pdf

https://cdsco.gov.in/opencms/opencms/system/modules/CDSCO.WEB/elements/download_file_division.jsp?num_id=NDI2MQ==

https://clinregs.niaid.nih.gov/country/india#submission_content

9.6 Subject Compensation: Is there a need for a local sponsor to be listed on the insurance certificate, the insurance certificate to cover the duration of the study and specific minimum amounts of coverage to be specified, both for individual events occurring and in aggregate?

Yes, the local Sponsor should be listed on the insurance. The duration and amount of coverage are study-dependent.