5.1 What is ‘Informed Consent’?
The Council for International Organizations of Medical Sciences (CIOMS) Guidelines has defined informed consent as:
Approval to participate in a study or trial given by a competent individual who:
· Has received the necessary information (verbally and in writing).
· Has adequately understood the information.
· After considering the information, has arrived at a decision without having been subjected to compulsion, undue influence, incentive, or pressure.
· In the case of those who are not capable, has the legal authorization to approve on behalf of the incompetent.
Informed consent is based on the principle that competent individuals are entitled to choose freely whether to participate in research. It protects the individual's freedom of choice and respects the individual's autonomy. As an additional safeguard, it must always be complemented by the approval of an independent review of ac ethical research committee.
5.2 Obtaining informed consent:
Before requesting an individual's consent to participate in research, the investigator must provide the following information, in language or another form of communication that the individual can understand to the research subject:
1. The individual is invited to participate voluntarily in the research, explaining the reasons for considering him/her suitable for the research.
2. 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. An explanation of the features of the research design e.g., in controlled trials the method of 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. The subject 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. The 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 non-disclosure 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, to the 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.
20. Whether commercial products may be developed from biological specimens, and whether the participant will receive money or other benefits from the development of such products.
21. Whether the investigator is serving only as an investigator or as both investigator and subject’s physician.
22. The extent of the investigator's responsibility to provide medical services to the participant.
23. The 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. An ethical review committee has approved or cleared the research protocol.
5.3 Process:
Obtaining informed consent is a process that is begun when initial contact is made with a prospective subject and continues throughout the course of the study. By informing the prospective subjects, by repetition and explanation, by answering their questions as they arise, and by ensuring that each individual understands each procedure, investigators have to elicit the informed consent from their subjects. By doing so the investigator manifests respect for their dignity and autonomy.
Each individual must be given as much time as is needed to reach a decision, including time for consultation with family members or others. Adequate time and resources should be set aside for informed-consent procedures.
5.4 Language:
Informing the individual subject must not be simply a ritual recitation of the contents of a written document. Rather, the investigator must convey the information, whether orally or in writing, in language that suits the individual's level of understanding.
The investigator must bear in mind that the prospective subject’s ability to understand the information necessary to give informed consent depends on that individual's maturity, intelligence, education and belief system. It depends also on the investigator's ability and willingness to communicate with patience and sensitivity.
5.5 Comprehension:
The investigator must then ensure that the prospective subject has adequately understood the information. The investigator should give each one full opportunity to ask questions and should answer them honestly, promptly and completely. In some instances the investigator may administer an oral or a written test or otherwise determine whether the information has been adequately understood.
5.6 Documentation of consent:
Consent may be indicated in a number of ways. The subject may imply consent by voluntary actions, express consent orally, or sign a consent form. Generally, the subject should sign a consent form, or, in the case of incompetence, a legal guardian or other duly authorized representative should do so.
In some cases, particularly when the information is complicated, it is advisable to give subjects information sheets to retain; these may resemble consent forms in all respects except that subjects are not required to sign them. The ethical review committee should review their wording. When consent has been obtained orally, investigators are responsible for providing documentation or proof of consent.
5.7 Waiving of the consent requirement:
Investigators should never initiate research involving human subjects without obtaining each subject's informed consent, unless they have received explicit approval to do so from an ethical review committee. However, when the research design involves no more than a minimal risk and not greater than that expected with routine medical examination and the requirement of individual informed consent would make the conduct of the research impracticable (for example, where the research involves only data from subjects' records), the ethical review committee may waive some or all of the elements of informed consent. Such waiver may also be approved when the existence of a single consent form would be an unjustified threat to the subject’s confidentiality.
5.8 Renewing consent:
When material changes occur in the conditions or the procedures of a study, and periodically in long-term studies, the investigator should once again seek informed consent from the subjects. For example, new information may have become known, either from the study or from other sources, about the risks or benefits of products being tested or about alternatives to them. Subjects should be given such information promptly.
In many clinical trials, results are not disclosed to subjects and investigators until the study is concluded. This is ethically acceptable if an ethical review committee has approved their non-disclosure.
5.9 Cultural considerations:
In some cultures an investigator may enter a community to conduct research or approach prospective subjects for their individual consent only after obtaining permission from a community leader, a council of elders, or another designated authority. Such customs must be respected.
In no case, however, may the permission of a community leader or other authority substitute for individual informed consent. In some populations the use of a number of local languages may complicate the communication of information to potential subjects and the ability of an investigator to ensure that they truly understand it. Many people in all cultures are unfamiliar with, or do not readily understand, scientific concepts such as those of placebo or randomization.
Sponsors and investigators should develop culturally appropriate ways to communicate information that is necessary for adherence to the standard required in the informed consent process. In addition, they should describe and justify in the research protocol the procedure they plan to use in communicating information to subjects.
For collaborative research in developing countries the research project should include the provision of resources to ensure that informed consent can indeed be obtained legitimately within different linguistic and cultural settings.
5.10 Use of biological materials from subjects in clinical trials :
Consent forms for the research protocol should include a separate section for clinical-trial subjects requested to provide their consent for the use of their biological specimens for research. Separate consent may be appropriate in some cases (e.g., if investigators are requesting permission to conduct basic research which is not a necessary part of the clinical trial), but not in others (e.g., the clinical trial requires the use of subjects’ biological materials).
5.11 Use of medical records and biological specimens:
Medical records and biological specimens taken in the course of clinical care may be used for research without the consent of the patients/subjects. This can only be done if an ethical review committee has determined that:
the research poses minimal risk, that the rights or interests of the patients will not be violated.
patient privacy and confidentiality or anonymity are assured.
the research is designed to answer an important question and would be impracticable if the requirement for informed consent were to be imposed.
Patients have a right to know that their records or specimens may be used for research. Refusal or reluctance of individuals to agree to participate would not be evidence of impracticability sufficient to warrant waiving informed consent. Records and specimens of individuals who have specifically rejected such uses in the past may be used only in the case of public health emergencies.
5.12 Secondary use of research records or biological specimens :
Investigators may want to use records or biological specimens that another investigator has used or collected for use in the same or another institution or another country. This raises the issue of whether the records or specimens contain personal identifiers. If informed consent or permission was required to authorize the original collection or use of such records or specimens for research purposes, secondary uses are generally constrained by the conditions specified in the original consent.
Consequently, it is essential that the original consent process anticipate, to the extent that this is feasible, any foreseeable plans for future use of the records or specimens for research. Thus, in the original process of seeking informed consent a member of the research team should discuss with, and, when indicated, request the permission of, prospective subjects as to:
i. Whether there will or could be any secondary use and, if so, whether such
secondary use will be limited with regard to the type of study that may be
performed on such materials;
ii. The conditions under which investigators will be required to contact the research
subjects for additional authorization for secondary use;
iii. The investigators' plans, if any, to destroy or to strip off personal identifiers from
the records or specimens; and
iv. The rights of subjects to request destruction or removal of individual identification
of biological specimens or of records or parts of records that they might consider
particularly sensitive, such as photographs, videotapes or audiotapes.
5.13 Obligations of sponsors and investigators:
Sponsors and investigators have a duty to:
refrain from unjustified deception, undue influence, or intimidation;
seek consent only after ascertaining that the prospective subject has adequate understanding of the relevant facts and of the consequences of participation and has had sufficient opportunity to consider whether to participate;
as a general rule, obtain from each prospective subject a signed form as evidence of informed consent – investigators should justify any exceptions to this general rule and obtain the approval of the ethical review committee
renew the informed consent of each subject if there are significant changes in the conditions or procedures of the research or if new information becomes available that could affect the willingness of subjects to continue to participate.
renew the informed consent of each subject in long-term studies at pre-determined intervals, even if there are no changes in the design or objectives of the research.
5.14 Withholding information and deception:
Sometimes, to ensure the validity of research, investigators withhold certain information in the consent process. In biomedical research, this typically takes the form of withholding information about the purpose of specific procedures.
For example, subjects in clinical trials are often not told the purpose of tests performed to monitor their compliance with the protocol, since if they knew their compliance was being monitored they might modify their behaviour and hence invalidate results. In most such cases, the prospective subjects are asked to consent to remain uninformed of the purpose of some procedures until the research is completed and after the conclusion of the study they are given the omitted information.
In other cases, because a request for permission to withhold some information would jeopardize the validity of the research, subjects are not told that some information has been withheld until the research has been completed. Any such procedure must receive the explicit approval of the ethical review committee.
5.15 Intimidation and undue influence:
Intimidation in any form invalidates informed consent. Prospective subjects who are patients often depend for medical care upon the physician/investigator, who consequently has certain credibility in their eyes, and whose influence over them may be considerable, particularly if the study protocol has a therapeutic component. They may fear, for example, that refusal to participate would damage the therapeutic relationship or result in the withholding of health services. The physician/investigator must assure them that their decision on whether to participate will not affect the therapeutic relationship or other benefits to which they are entitled. In this situation the ethical review committee should consider whether a neutral third party should seek informed consent.
The prospective subject must not be exposed to undue influence. The borderline between justifiable persuasion and undue influence is imprecise, however. The researcher should give justifiable assurances about the benefits, risks or inconveniences of the research, for example, or induce a close relative or a community leader to influence a prospective subject's decision.
5.16 Equitable distribution of burdens and benefits in the selection of groups of subjects in research:
1- Groups or communities to be subjects of research should be selected so that the burdens and benefits of the research will be equitably distributed. The exclusion of groups or communities that might benefit from study participation must be justified.
2- Members of vulnerable groups also have the same entitlement to access to the benefits of investigational interventions that show promise of therapeutic benefit as non vulnerable groups particularly when no superior or equivalent approaches to therapy are available.
3- Overuse of certain groups, such as the poor or the administratively available, is unjustified.
5.17 Exception to the requirement for informed consent in studies of emergencies in which the researcher anticipates that many subjects will be unable to consent:
Research protocols are sometimes designed to address conditions occurring suddenly and rendering the patients/subjects incapable of giving informed consent. Examples are head trauma, cardiopulmonary arrest and stroke. The investigation cannot be done with patients who can give informed consent in time and there may not be time to locate a person having the authority to give permission.
In such circumstances it is often necessary to proceed with the research interventions very soon after the onset of the condition in order to evaluate an investigational treatment or develop the desired knowledge. Consent should be taken from the guardian if available or from an authorized body in the health facility. As this class of emergency exception can be anticipated, the researcher must secure the review and approval of an ethical review committee before initiating the study. If possible, an attempt should be made to identify a population that is likely to develop the condition to be studied. This can be done readily, for example, if the condition is one that recurs periodically in individuals; examples include grand mal seizures and alcohol binges. In such cases, prospective subjects should be contacted while fully capable of informed consent, and invited to consent to their involvement as research subjects during future periods of incapacitation. If they are patients of an independent physician who is also the physician-researcher, the physician should likewise seek their consent while they are fully capable of informed consent.
In all cases in which approved research has begun without prior consent of patients/subjects incapable of giving informed consent because of suddenly occurring conditions, they should be given all relevant information as soon as they are in a state to receive it, and their consent to continued participation should be obtained as soon as is reasonably possible.
5.18 Inducement to participate:
5.19 Incompetent persons
Subjects may be reimbursed for lost earnings, travel costs and other expenses incurred in taking part in a study; and may receive free medical services. Subjects, particularly those who receive no direct benefit from research, may be paid or otherwise compensated for inconvenience and time spent. The payments should not be so large, however, or the medical services so extensive as to induce prospective subjects to consent to participate in the research against their better judgment ("undue inducement"). An ethical review committee must have approved all payments, reimbursement and medical services provided to research subjects.
Incompetent persons may be vulnerable to exploitation for financial gain by guardians. A guardian asked to give permission on behalf of an incompetent person should be offered no recompense other than a refund of travel and related expenses.
5.20 Withdrawal from a study:
A subject who withdraws from research for reasons related to the study, e.g. Side-effects of a study drug, or who is withdrawn on health grounds, should be paid or recompensed as if full participation had taken place. A subject who withdraws for any other reason should be paid in proportion to the amount of participation. An investigator who must remove a subject from the study for willful non-compliance is entitled to withhold part or all of the payment.
5.21 Research involving vulnerable persons
Special justification is required for inviting vulnerable individuals to serve as research subjects and, if they are selected, the means of protecting their rights and welfare must be strictly applied. Individuals conventionally considered vulnerable are those with limited capacity or freedom to consent or to decline to consent. They include children, and persons who because of mental or behavioural disorders are incapable of giving informed consent.
Ethical justification of their involvement usually requires the investigators to satisfy the ethical review committees that:
a. The research could not be carried out equally well with less vulnerable subjects.
b. The research is intended to obtain knowledge that will lead to improved diagnosis, prevention or treatment of diseases or other health problems characteristic.
c. Research subjects and other members of the vulnerable class from which subjects are recruited will ordinarily be assured reasonable access to any diagnostic, preventive or therapeutic products that will become available as a consequence of the research;
d. the risks attached to interventions or procedures will not exceed those associated with routine medical or psychological examination of such persons unless an ethical review committee authorizes a slight increase over this level of risk.
e. when the prospective subjects are either incompetent or otherwise substantially unable to give informed consent, their agreement will be supplemented by the permission of their legal guardians or other appropriate representatives.
5.22 Research involving vulnerable groups include:
5.22.1 Research involving children:
Before undertaking research involving children, the investigator must ensure that:
The research might not equally well be carried out with adults;
The purpose of the research is to obtain knowledge relevant to the health needs of children;
A parent or legal representative of each child has given permission;
The agreement (assent) of each child has been obtained to the extent of the child’s capabilities;
A child’s refusal to participate or continue in the research will be respected.
5.22.2 Women as research subjects:
Investigators, sponsors or ethical review committees should not exclude women of reproductive age from biomedical research. The potential for becoming pregnant during a study should not be used as a reason for precluding or limiting participation. However, a thorough discussion of risks to the pregnant woman and to her foetus is a prerequisite for the woman’s ability to make a rational decision to enroll in a clinical study.
In this discussion, if participation in the research might be hazardous to a foetus or a woman if she becomes pregnant, the sponsors/ investigators should guarantee the prospective subject a pregnancy test and access to effective contraceptive methods before the research commences. Where such access is not possible, for legal or religious reasons, investigators should not recruit for such possibly hazardous research women who might become pregnant.
5.22.3 Pregnant women as research participants:
Pregnant women should be eligible for participation in biomedical research. Investigators and ethical review committees should ensure that prospective subjects who are pregnant are adequately informed about the risks and benefits to themselves, their pregnancies, the foetus and their subsequent offspring, and their fertility. Research in this population should be performed only if it is relevant to the particular health needs of a pregnant woman or her foetus, or to the health needs of pregnant women in general, and, when appropriate, if it is supported by reliable evidence from animal experiments, particularly as to risks of teratogenicity and mutagenicity.
5.23 References:
1. TDR/PRD/ETHICS/2000."Operational Guidelines for Ethics Committees That Review Biomedical Research"
2. Council for International Organizations of Medical Sciences (CIOMS) International Ethical Guidelines for Biomedical Research Involving Human Subjects. CIOMS, Geneva 2002. ISBN 92 9036 075 5