Informed Consent: Essential Ingredients, Procedure, Importance and Special precautions for vulnerable

groups

 What is informed consent?

Informed consent is a legal procedure to ensure that a patient or client knows all of the risks and costs involved in a
treatment. The elements of informed consents include informing the client of the nature of the treatment, possible
alternative treatments, and the potential risks and benefits of the treatment.

In order for informed consent to be considered valid, the client must be competent and the consent should be given
voluntarily.

 STATEMENT OF GENERAL PRINCIPLES IN BIOMEDICAL

RESEARCH INVOLVING HUMAN PARTICIPANTS

This statement of Ethical Guidelines for Biomedical Research on Human Participants shall be known as
the ICMR Code and shall consist of the following:-

(a) Statement of General Principles on Research using Human Participants in Biomedical Research

(b) Statement of Specific Principles on Research using Human Participants in specific areas of Biomedical
Research

These Statements of General and Specific Principles may be varied, amended, substituted and added
from time to time.

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-maleficence (do
no harm) and justice. The guidelines laid down are directed at application of these basic principles to
research involving human participants. The Principal Investigator is the person responsible for not only
undertaking research but also for observance of the rights, health and welfare of the participants
recruited for the study. S/he should have qualification and competence in biomedical research
methodology for proper conduct of the study and should be aware of and comply with the scientific,
legal and ethical requirements of the study protocol.

I. INFORMED CONSENT PROCESS

1. Informed Consent of Participants : For all biomedical research involving human participants,
the investigator must obtain the informed consent of the prospective participant or in the case of an
individual who is not capable of giving informed consent, the consent of a legal guardian. Informed
consent protects the individual’s freedom of choice and respect for individual’s autonomy and is
given voluntarily to participate in research or not. Adequate information about the research is given
in a simple and easily understandable unambiguous language in a document known as the Informed
Consent Form with Participant/ Patient Information Sheet. The latter should have following
components as may be applicable :
1. Nature and purpose of study stating it as research
2. Duration of participation with number of participants
3. Procedures to be followed
4. Investigations, if any, to be performed
5. Foreseeable risks and discomforts adequately described and whether project
involves more than minimal risk
6. Benefits to participant, community or medical profession as may be applicable
7. Policy on compensation
8. Availability of medical treatment for such injuries or risk management
9. Alternative treatments if available
10. Steps taken for ensuring confidentiality
11. No loss of benefits on withdrawal
12. Benefit sharing in the event of commercialization
13. Contact details of PI or local PI/Co-PI in multicentric studies for asking more
information related to the research or in case of injury
14. Contact details of Chairman of the IEC for appeal against violation of rights
15. Voluntary participation
16. If test for genetics and HIV is to be done, counseling for consent for testing
must be given as per national guidelines
17. Storage period of biological sample and related data with choice offered to
participant regarding future use of sample, refusal for storage and receipt of its
results

A copy of the participant/patient information sheet should be given to the participant for her/ his
record. The informed consent should be brief in content highlighting that it is given of free will or
voluntarily after understanding the implications of risks and benefits and s/he could withdraw
without loss of routine care benefits. Assurance is given that confidentiality would be maintained and
all the investigations/ interventions would be carried out only after consent is obtained. When the
written consent as signature or thumb impression is not possible due to sensitive nature of the project
or the participant is unable to write, then verbal consent can be taken after ensuring its documentation
by an unrelated witness. In some cases ombudsman, a third party, can ensure total accountability for
the process of obtaining the consent. Audio-visual methods could be adopted with prior consent and
adequate precaution to ensure confidentiality, but approval of EC is required for such procedures. For
drug trials, if the volunteer can give only thumb impression then another thumb impression by the
relative or legal custodian cannot be accepted and an unrelated witness to the project should then
sign.
Fresh or re-consent is taken in following conditions :
1. Availabilty of new information which would necessitate deviation of protocol.
2. When a research participant regains consciousness from unconscious state or is mentally
competent to understand the study. If such an event is expected then procedures to address it should
be spelt out in the informed consent form.
3. When long term follow-up or study extension is planned later.
4. When there is change in treatment modality, procedures, site visits.
5. Before publication if there is possibility of disclosure of identity through data presentation or
photographs (which should be camouflaged adequately).
Waiver of consent
Voluntary informed consent is always a requirement for every research proposal. However, this can
be waived if it is justified that the research involves not more than minimal risk or when the
participant and the researcher do not come into contact or when it is necessitated in emergency
situations elaborated in the previous Chapter. If such studies have protections in place for both
privacy and confidentiality, and do not violate the rights of the participants then IECs may waive off
the requirement for informed consent in following instances:
i. When it is impractical to conduct research since confidentiality of personally identifiable
information has to be maintained throughout research as may be required by the sensitivity of the
research objective, eg., study on disease burden of HIV/AIDS.
ii. Research on publicly available information, documents, records, works, performances,
reviews, quality assurance studies, archival materials or third party interviews, service programs for
benefit of public having a bearing on public health programs, and consumer acceptance studies.
iii. Research on anonymised biological samples from deceased individuals, left over samples after
clinical investigation, cell lines or cell free derivatives like viral isolates, DNA or RNA from
recognised institutions or qualified investigators, samples or data from repositories or registries etc.
iv. In emergency situations when no surrogate consent can be taken.

2. Obligations of investigators regarding informed consent : The investigator

has the duty to -
i. communicate to prospective participants all the information necessary for informed consent. Any
restriction on participant’s right to ask any questions related to the study will undermine the validity
of informed consent;
ii. exclude the possibility of unjustified deception, undue influence and intimidation. Although
deception is not permissible, if sometimes such information would jeopardize the validity of research
it can be withheld till the completion of the project, for instance, study on abortion practices;
iii. seek consent only after the prospective participant is adequately informed. The investigator
should not give any unjustifiable assurances to prospective participant, which may influence the
her/his decision to participate;
iv. obtain from each prospective participant a signed form as an evidence of informed consent
(written informed consent) preferably witnessed by a person not related to the trial, and in case the
participant is not competent to do so, a legal guardian or other duly authorised representative;
v. take verbal consent when the participant refuses to sign or give thumb impression or cannot do so.
This can then be documented through audio or video means;
vi. take surrogate consent from the authorized relative or legal custodian or the institutional head in
the case of abandoned institutionalized individuals or wards under judicial custody;
vii. renew or take fresh informed consent of each participant under circumstances described earlier in
this chapter;
viii. if participant loses consciousness or competence to consent during the research period as in
Alzeimer or psychiatric conditions, surrogate consent may be taken from the authorized person or
legal custodian.
ix. The investigator must assure prospective participants that their decision to participate or not will
not affect the patient - clinician relationship or any other benefits to which they are entitled.

3. Essential information for prospective research participants : Before requesting an individual’s

consent to participate in research, the investigator must provide the individual with the following
information in the language she or he is able to understand which should not only be scientifically
accurate but should also be sensitive/ adaptive to their social and cultural context :
i. the aims and methods of the research;
ii. the expected duration of the participation;
iii. the benefits that might reasonably be expected as an outcome of research to the participant or
community or to others;
iv. any alternative procedures or courses of treatment that might be as advantageous to the participant
as the procedure or treatment to which s/he is being subjected;
v. any foreseeable risk or discomfort to the participant resulting from participation in the study;
vi. right to prevent use of her/ his biological sample (DNA, cell-line, etc.) at any time during the
conduct of the research;
vii. the extent to which confidentiality of records could be maintained ie., the limits to which the
investigator would be able to safeguard confidentiality and the anticipated consequences of breach of
confidentiality;
viii. responsibility of investigators;
ix. free treatment for research related injury by the investigator and/ institution and sponsor(s);
x. compensation of participants for disability or death resulting from such injury;
xi. insurance coverage if any, for research related or other AEs;
xii. freedom of individual / family to participate and to withdraw from research any time without
penalty or loss of benefits which the participant would otherwise be entitled to;
xiii. the identity of the research teams and contact persons with address and phone numbers;
xiv. foreseeable extent of information on possible current and future uses of the biological material
and of the data to be generated from the research and if the material is likely to be used for secondary
purposes or would be shared with others, clear mention of the same;
xv. risk of discovery of biologically sensitive information and provision to safeguard confidentiality;
xvi. publication, if any, including photographs and pedigree charts.

The quality of the consent of certain social and marginalized groups requires careful consideration as
their agreement to volunteer may be unduly influenced by the Investigator.

 Guidelines for Obtaining Informed Consent for Clinical Research

Informed consent is a process, not just a form signed by prospective study subjects. Documents such as the Code of Federal Regulations
describe the elements of informed consent, but lack substantive direction on the process of obtaining consent. 1-2 The purpose of this article is
to provide guidelines for obtaining informed consent. This guide can be useful to anyone involved in clinical research, particularly newcomers
to the industry.

The process of obtaining informed consent from subjects is a critical point of entry for research participants. Although the basic principles of
obtaining informed consent transcend therapeutic areas and vulnerable patient populations, significant differences must be considered when
research designs include individuals at increased risk. Special attention must be given to meeting the needs of vulnerable populations such
as children, the critically ill, or the mentally impaired. The atmosphere for the family of a trauma patient during the first few critical hours of
admission is far removed from the unhurried pace of the outpatient clinic. The focus of this article, however, is the process of obtaining
consent from a population of patients who are not under duress at the time of consent.

Typically, the introduction of a potential subject to a clinical trial occurs in one of the following ways:

 The subject may have been identified as part of a recruitment campaign.

 The subject may simply be part of a patient population being studied.
 The clinical trial may be offered as a treatment option after a patient has been given the facts concerning a diagnosis and
prognosis.
Although there are several ways that patients learn about clinical trial "little is known about the factors that influence decisions to participate
in scientific research."3 Kuczewski and Marshall recommend adopting the approach that consent is an interactive and dynamic process and
many factors can influence the study participant's willingness to sign the document. These factors include socioeconomic background,
cultural traditions, literacy and language ability, and interactions with physicians and other healthcare professionals.

Bosk found "what, how, and when information is presented does make a difference to a subject's understanding of research and to
subsequent enrollment."4 The investigator should carefully weigh the consequences of trying to obtain consent after the patient has just been
diagnosed with a life-threatening illness. A subject's ability to make decisions may also be affected by his/her emotional state. 5 Emotional
stress can be a cause of failure to consent. It is recommended that the subject be given a week to accept her diagnosis before discussing
enrollment in the study.

Trechan found that risk levels influence a subject's willingness to participate in clinical research. 6Furthermore, negative media attention, such
as Ellen Roche's death at Johns Hopkins, may adversely affect decisions to participate. 7 Getz suggests that subjects who successfully
complete other clinical trials are more likely to consent again. 8

Problems with the consent process The

informed consent process presents some major challenges for study participants and research staff.
Several papers have addressed problems with the current process. Among them, Brady identifies the following issues: 9

 Subject's hesitation to ask detailed questions

 Variable presentation of the content
 Difficulty verifying the subject's comprehension.

Additionally, a survey of 1600 respondents performed by CenterWatch in 2002 found that 14% of subjects did not read the consent before
signing, and a high percentage of volunteers admitted to not fully understanding the risks and not knowing what questions to ask. The
concept of "therapeutic misconception" in research is another problem that has received much attention in both legal and bioethics literature.
Generally, it is important that potential subjects are aware that research is not the only therapeutic alternative for them. 10-12 Lack of subject
understanding and comprehension is possibly compounded by the increasing regulations that govern the performance of study personnel
and the cost pressures, meaning that there is ever-decreasing time available for study personnel to spend reviewing the consent with the
subject.

Setting The informed consent process begins when a potential subject is first approached to participate in a clinical trial. Whether informed
consent is obtained over the phone (remember-there may be a specific protocol for doing this at your institution), or in a doctor's office or
hospital, the setting should be the same. It should be an unhurried, private atmosphere where the subject has time to review the document
and ask questions. The subject should be approached in a respectful manner and the person obtaining consent should introduce themselves
by name and role, stating the purpose of their communication. As already indicated, the timing of this process is very important.

The person obtaining consent must have appropriate credentials and be qualified to do so. She/he should have experience in the field of
study-otherwise, how will she answer questions posed by the subject? Additionally, this person should be familiar with good clinical practice
guidelines for informed consent and with his/her own institutional review board's requirements for the process.

The researcher should determine the ability of the potential subject to understand the information and give consent before proceeding
further. If the subject does not read or speak English adequately, an assessment should be performed to determine the subject's needs. The
researcher should then make the decision to call in an interpreter. Kuczewski and Marshall suggest that misunderstandings are more likely to
occur when investigators (or coordinators) and participants speak different languages, especially when "there are no equivalent expressions
for particular biomedical concepts or when the notion of informed consent is unfamiliar." They offer strategies to help minimize language
barriers:

Use an effective process of translation and back-translation when an informed consent document must be translated from one language
to another. This process must include adequate pretesting of the consent document to determine that it is comprehensible to individuals who
will be recruited for a research project.

Enlist the help of individuals who can act as "cultural experts" on ways in which to communicate difficult scientific concepts for study
populations who may be unfamiliar with the biomedical problem being investigated.

Keep the consent document as short as possible, using simple language and a format that is clear and understandable for potential
research participants.

The issue of using family members when there is a language barrier is a gray area. Most subjects feel more comfortable if one or more family
members are available to help them with decision-making, though this is not always the case. Additionally, excluding family or friends from
the discussion may eliminate bias for or against participation; however, this must be balanced with the subject's wishes. Tailor the discussion
to the subject's needs.

The informed consent process is based on complete disclosure of the facts. During this process, the study coordinator or principal
investigator should endeavor to establish a rapport and trusting relationship with the potential subject.
The coordinator or investigator should thoroughly review each section of the informed consent with the study subject. The consent form is, in
essence, a teaching tool-a nontechnical, understandable document, written at an eighth-grade reading level. It is imperative that subjects
understand the nature of the research study, the risks and the benefits, alternatives to research, and their rights as study subjects. Study
subjects need to read (or have read to them) and comprehend the informed consent document. Ensure that they understand the nature of
the study, that is, why the research is being done and why they are being asked to participate. The coordinator of the study should use
whatever resources are available to promote subject understanding of the study such as, graphics, video, or even the device to be used, if
possible. Care must be taken to avoid medical jargon that subjects could not possibly understand. Avoid presenting an overly positive (or
negative) picture of the clinical trial for which consent is being obtained.

There is a growing body of data showing that research subjects have an unrealistic view of what their participation entails. Emphasis must be
placed on the risks as well as the benefits. As has already been mentioned, subjects should understand the distinction between what is
research and what is routine medical therapy. 13 The idea is not to coerce but to provide the subject with the facts.

Finally, subjects should be allowed-and encouraged-to ask questions about the study. They should be able to take the document home with
them if time permits.

Consent should be obtained when the investigator is available to answer questions or address concerns. The principal investigator is
ultimately responsible for all aspects of conducting the research.

About HIPAA It is incumbent upon the study team to understand how Health Insurance Portability and Accountability Act (HIPAA) regulations
affect research and the informed consent process. However, with regard to HIPAA regulations, institutional practices and policies may vary
significantly. HIPAA mandates "Standards for Privacy of Individually Identifiable Health Information." HIPAA applies to health information
created or maintained by healthcare providers who engage in certain electronic transactions. Due to this and HIPAA's strong emphasis on
confidentiality, HIPAA impacts many facets of the work we do in clinical research-specifically with the informed consent process. HIPAA
requires subjects to sign an authorization. This authorization is like a consent form for HIPAA and may be a stand-alone document or may be
integrated into the study consent form.

HIPAA requires that the following information be included in the authorization or consent form: 14

 the information that is provided or disclosed

 who may use or disclose the information
 who may receive the information
 each purpose of the use or disclosure of the information
 expiration date or event of the consent and authorization
 individual's signature and date
 the subject's right to revoke authorization
 the subject's right to refuse to sign authorization
 the fact that subsequent disclosures by the recipient may not be protected under HIPAA.

In summary  Greg Koski, former director of the Office for Human Research Protections, recently said, "We must move beyond the culture of
compliance, to move to a culture of conscience and responsibility." These are challenging times in clinical research. The coordinator has an
ever-increasing load of regulations to deal with in an environment of severe time constraints. While there are many regulations governing the
content of consent forms, there is very little to guide the process. With the emphasis on the patient as subject, it is easy to overlook the
patient as human.

For specific tips from the Office for Protection from Research Risks go to http://ohrp.osophs.dhhs.gov/humansubjects/guidance/ictips.htm|
~ohrp.osophs.dhhs.gov/humansubjects/guidance/ictips.htm .

1. Code of Federal Regulations, Title 21, Part 50, (U.S. Government Printing Office, Washington, DC).

2. Code of Federal Regulations, Title 45, Part 46, (U.S. Government Printing Office, Washington, DC).

3. M.G. Kuczewski, P. Marshall, "The Decision Dynamics of Clinical Research: The Context and Process of Informed Consent," Medical
Care, 40 (9 Suppl) 45-54 (2002).

4. C.L. Bosk, "Obtaining Voluntary Consent for Research in Desperately Ill Patients," Medical Care, 40 (9 Suppl) 64-8 (2002).

5. E. Wager, P.J. Tooley, M.B. Emanuel, S.F. Wood, "How To Do It. Get Patients' Consent to Enter Clinical Trials," British Medical Journal,
311 (7007) 734-737 (1995).

6. T.A. Treschan, T. Scheck, A. Kober, E. Fleischmann, B. Birkenberg, B. Petschnigg, O. Akca, F.X. Lackner, E. Jandl-Jager, D.I. Sessler,
"The Influence of Protocol Pain and Risk on Patients' Willingness to Consent for Clinical Studies: A Randomized Trial," Anesthesia &
Analgesia, 96 (2) 498-506 (2003).

7. M. Karigan, "Ethics in Clinical Research: The Nursing Perspective," American Journal of Nursing, 101 (9) 26-31 (2001).
8. K.A. Getz, "Informed Consent Process: A Survey of Subjects Assesses Strengths and Weaknesses," Applied Clinical Trials, November
2002, 30-36.

9. J.S. Brady, "Multimedia Delivery Can Enhance the Consent Process," Applied Clinical Trials, January 2003, 36-42.

10. S. Horng, C. Grady. "Misunderstanding in Clinical Research: Distinguishing Therapeutic Misconception, Therapeutic Misestimation, and
Therapeutic Optimism," IRB: A Review of Human Subjects Research, 25 (1) 11-6 (2003).

11. E. Fried, "The Therapeutic Misconception, Beneficence, and Respect," Accountability in Research, 8 (4) 331-48 (2001).

12. P.S. Appelbaum, "Clarifying the Ethics of Clinical Research: A Path Toward Avoiding the Therapeutic Misconception," American Journal
of Bioethics, 2 (2) 22-3 (2002).

13. J.P. Kahn, A.C. Mastroianni, "Moving From Compliance To Conscience: Why We Can and Should Improve on the Ethics of Clinical
Research," Archives of Internal Medicine, 161 (7) 925-8 (2001).

14. Available at http://irb.mc.duke.edu|~irb.mc.duke.edu Retrieved April 2003.