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Consenting to participate in a clinical research study after being properly and correctly informed upholds the basic ethical principle of “autonomy” in human research. The informed consent is a process by which the physician sensitizes the patient about the nature, procedures, risks benefits, treatment schedules, etc of the study in a language that is non-technical and understandable by the study participant. Informed consent document (ICD) has got two parts: the ‘Subject Information Sheet’ and the ‘Informed Consent Form’ (ICF); and they have to be approved by the Institutional Ethics Committee (IEC) before administration. Consent should be obtained without any coercion. In case of a situation where a participant is not able to give informed consent (e.g. unconscious, minor or those suffering from severe mental illness or disability) or is illiterate, it has be obtained from a legally acceptable representative (LAR). If the participant or LAR is unable to read/write, then an impartial witness should be present during the entire informed consent process and must append his/her signatures to the consent form. For children < 7 years, verbal consent is essential and for mature minors (age group 7 to 18 years) informed assent should be obtained.
What was known?
Doctors are aware of taking consent of patient during intervention or procedures wherein the focus is on the description of the risks/complications that are involved with the procedure, and obtaining the signature of the patient and relative who give their consent.
The informed consent process upholds the basic ethical principle of “autonomy” in human research. In any clinical trial, a freely given, informed written consent has to be obtained from each research participant to comply with the requirements of Good Clinical Practices (GCP), the Indian Council of Medical Research (ICMR) guidelines, and Schedule Y.
The informed consent is a process by which the physician sensitizes the patient about the nature of the study in a language that is nontechnical and understandable by the study participant. Informed consent document (ICD) has got two parts: the “subject information sheet” and the “informed consent form” (ICF), and they have to be approved by the Institutional Ethics Committee (IEC) before administration. The format of ICF should be in accordance with the Appendix V of Schedule Y (Annexure III). The content of the document should be brief, lucid, nontechnical, and simple enough to be understood by the participant. Consent should be obtained without any coercion.
Informed consent process is of paramount importance to safeguard the autonomy of a person with regard to his willingness to participate in a trial. It is especially relevant in the present day scenario when the mistrust among the study participants is growing, and according a recent report in 26% of Indian patients, mistrust is the barrier for study participation. The proper consent process can rebuild this trust and can bridge the rapport between the physician and study participants. The issue has come into attention with the Supreme Court order on October 21, 2013, with respect to five clinical trials, where informed consent, which is the most important aspect of GCP, was not properly obtained.
In case of a situation where a participant is not able to give informed consent (e.g., unconscious, minor, or those suffering from severe mental illness or disability), it has be obtained from a legally acceptable representative (LAR). A LAR is an individual or a legal body authorized under applicable law to consent, on behalf of a prospective participant, to the individuals’ participation in the clinical trial. If the participant or LAR is unable to read/write, then an impartial witness should be present during the entire informed consent process and must append his/her signatures to the consent form. An impartial witness is a person who is independent of the trial and cannot be unduly influenced by the people involved with the trial and who attends the informed consent process if the participant or the participant's LAR cannot read and who reads the ICF and any other written information supplied to the participant. Usually, the patient party of the subsequent patient is taken as impartial witness. Staff nurse or technician is usually not regarded as impartial witness as they can be unduly influenced by the investigator. In case of a matured minor (as defined by the ICMR guidelines as an individual <18 years but ≥7 years), informed assent needs to be taken apart from parental/LAR consent as explained later.
Practical tip: The next educated patient or his/her relative in the OPD can act as the best LAR.
Flowcharts describing the process of obtaining ICF a literate participant, illiterate participant, and when both participant and LAR are illiterate are shown in Figures Figures11--3,3, respectively.
In spite of having a nicely drafted ICD, it was observed that the elements of informed consent were not followed in letter and spirit. In view of the recent scenario, CDSCO has emphasized that the Rule 122DAC (which highlights that clinical trials be conducted following GCP guidelines) be strictly followed. Accordingly, the office of DCGI has made it mandatory that the audiovisual (AV) recording of process (in effect from November 2013) of providing information to the participant and his/her understanding on such consent has to be done with proper maintenance of confidentiality. However, in the fifth amendment of the Drug and Cosmetic Rules, it was stated that the investigator should obtain AV recording of the informed consent process for vulnerable participants in clinical trials of new chemical entity or new molecular entity. In cases where clinical trials are conducted on anti-human immunodeficiency virus (HIV) and antileprosy drugs, the investigator should only obtain an audio recording of the informed consent process.
To identify the participant/LAR/impartial witness, his/her photo ID needs to be documented. The video camera for the AV recording needs to be of adequate enough to capture the facial details of study participant, LAR/impartial witness (if any), and investigator/authorized person present during the consent process. The place where the AV recording is performed should be conducive to recording of disturbance-free audio and video of the consent process. It is important that, during the process of AV recording, unrelated persons/patients at the hospital are not included in this study. AV 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 permanently.
Schedule Y states the checklist that is required to be incorporated into the ICF. They are as follows:
The ICF should include a statement that describes the anticipated payment to the participant for his participation as a research subject in the clinical trial. This payment is to reimburse the inconvenience and time spent, expenditure for travel, food, and loss of wages. Such payment should not be so excessive as to induce a patient to participate. The ICF also includes a statement that states that compensation and medical treatment will be available if any adverse event occurs. The Ethics Committee approves all the payments, reimbursements that will be provided to the participant. When a legal representative or guardian gives consent on behalf of an incompetent participant, no remuneration should be offered except to refund out-of-pocket expenses.
The ICF addresses the basic rights of a research participant during an informed consent process. The participation in the research is entirely voluntary, and the participant may refuse to participate in the trial or withdraw his assent at any time during the ongoing study. Such refusal will not involve in any penalty, and such patient will receive his due standard care from the physician. The research participant has the right to be informed about the purpose, anticipated duration of the research study, study procedures, any potential benefits or risks, any compensation for participation or injury/treatment, and any significant new information regarding the research study. Participants have the right to privacy and confidentiality, and a statement must be provided in the ICF that recognizes this right. The investigator may assign serial numbers or initials to protect the identity, records, or data of the participants. The research participant has his right to inquire about any information about the trial and report any adverse event that might occur during the course of the trial. The contact information of the investigator and Ethics Committee are provided in the ICF to aid the participants seek out the investigator for any query or appeal in case of violation of his rights. The GCP and Declaration of Helsinki state that the participant's right to safety and protection of his health takes precedence over the objectives of biomedical research.
Special circumstances may arise in case of emergencies, dealing with unconscious patients, children, elderly age groups, and others. Schedule Y and ICMR guidelines mention the provision for protecting the rights for such research participants.
The life of the participant becomes of paramount importance in such situation, and treating such a research participant without his/her consent is permissible if the participant is unconscious, mentally ill, or gravely sick, and no one who is authorized to provide consent is unavailable. The LAR or guardian, if available, can give consent in such cases on behalf of the patient. Consent from the patient is taken once he regains consciousness or recovers his mental capacity to understand the research study. The ICF should address such circumstance if it is so anticipated. Such provision must be explicitly stated in the protocol.
The GCP defines “vulnerable” population as those research participants who have diminished autonomy such as those with incurable diseases, in nursing homes, in detention, unemployed or impoverished, prisoners, students, service personnel, in emergency rooms, homeless persons, nomads, refugees, and any ethnic or racial minority groups. Such individuals should not be included unless the research is essential to promote the health of the population represented, and this research cannot instead be performed on other participants. The mode of consent for these participants must be carefully considered and approved by the Ethics Committee.
Schedule Y states that geriatric population can be included in Phase II and III trials when the disease intended to be treated is typically a disease of aging, or the new drug is likely to differ in the safety and efficacy response of geriatric patients compared to nongeriatric population.
According to the ICMR guidelines, minor refers to an individual <18 years. The Schedule Y states that children will not be involved in research that could be carried out equally in adults, and the research purpose is to obtain knowledge relevant to health-care needs of children. Pediatric participants are dependent on their legal representatives or guardians to provide consent on their behalf. However, all pediatric patients should be informed to the fullest extent possible about the study in nontechnical, simple understandable language. If the child refuses to participate, his refusal should be respected even if the parent or guardian consents. This brings us to the concept of “informed assent” in which mature minors (age group 7–18 years) consent is verbally taken after they have read and understood a specially designed assent form. Such assent form should be more simplistic than the standard ICF so that the child can understand the contents. The parent/LAR will sign and the investigator will sign indicating that informed assent has been taken. Thus, for mature minors, two sets of consent forms are required, one the ICF for the guardian and the other is the informed assent form.
Pregnant or nursing women should only be included if the drug in trial is intended to be used by pregnant or nursing mothers or fetuses, and data on the nonpregnant women are unsuitable. Such research should carry less than minimal risk to the developing fetus and such participants should not be debarred unnecessarily from benefit from investigations, drugs, vaccines, or other agents that promise therapeutic or preventive benefits during pregnancy or lactation.
Since such patients are not capable of consenting on their own, the proxy consent is obtained from the legal guardian or representative.
The informed consent process is thus much beyond just a sheet of paper on which the participant signs but is also the beginning of a good researcher and participant bonding. A well-taken consent makes the participant confident about the new arena of clinical research that he is faced with, makes him continue through all the follow-ups of the study, and adheres to study intervention regimen.
There are no conflicts of interest.
What is new?
In clinical research, the crux of ethics lies on the Informed consent process which ensures the most important principle, autonomy. The informed consent document is a robust document which has got a section on patient information sheet detailing the research procedure, its benefits, risks, responsibilities of participants, compensation, confidentiality, alternative options and most importantly voluntary participation. The process of obtaining consent in literate, illiterate, children are also important and has to be ensured that the participant in not forced/coaxed to agree. Understanding that there may be breech in obtaining the informed consent, audio-visual recording of the process is also warranted in trials involving new molecular entities in vulnerable population.
The authors thankfully acknowledge Prof. Debabrata Bandyopadhyay (Professor and Head, Department of Dermatology, Medical College, Kolkata) and Professor Avijit Hazra (Professor, Department of Pharmacology, IPGME and R, Kolkata) for reviewing the manuscript and providing valuable inputs.