研究におけるインフォームド・コンセント／Informed Consent in Research_HSR [TEXT]

English Modules

Drafted date: 2016.3.31
Last update: 2018.5.2
Informed Consent in Research
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APRIN, Association for the Promotion of Research Integrity
Contents
Introduction
Requirements for Informed Consent
General Requirements
Additional Requirements
The Process and the Four Key Elements of Informed Consent
1. Providing Information: What Does This Entail?
2. Improving Understanding: How Is This Done?
3. Subjects Who Merit Special Consideration
4. Considerations of the Cultural Norms of Japan
Obtaining Informed Consent by Proxy from a Subject’s Representative
Cases Where Informed Consent May Be Simplified or Waived
Opt-out
Simplification and Wavier Conditions Indicated by Japanese Ethics Guidelines
Things to Do Before Carrying Out an Interview or a Survey in a Study
Conclusion
References
Informed Consent in Research
Introduction
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Many experts from a variety of fields now emphasize the importance of understanding informed consent as a process consisting of a series of actions. It begins with the recruitment and screening of a subject, and is followed by communicating with the subject, understanding his or her desires and getting the consent document signed. It continues throughout the subject’s involvement in the research and beyond the study’s termination. As informed consent is a course of action, the following points must be kept in mind:
  • Information provided at the time of recruitment becomes a crucial basis for the candidate’s decision to take part in the research. In this way, it can be said that informed consent starts at the recruitment stage. As soon as approval is received from the institutional review board, the investigators start giving information through their efforts to recruit candidates, e.g., by means of attractive descriptions in advertisements and other recruitment materials, and may directly contact candidates by reviewing medical records. Investigators must take care to provide accurate information at all stages of the recruitment process.
  • Information relating to the research must be given to the candidates in a way that is understandable to them, and their questions must be answered. Then the candidates must be given adequate time to consider their participation.
  • The decision to take part in the research must be made voluntarily by each candidate. Candidates may agree to participate in the research, and may also withdraw at any time. The process of informed consent does not end at the time of initial consent: It requires the investigators to keep verifying the subject’s continued willingness to participate in the study.
  • Even after the study ends, when information that is important to the subjects has been obtained, it may be necessary to provide this information to them. The means to communicate this information should be discussed and agreed upon in advance.
Consideration of the following three points is extremely important:
  • Making sure that potential study subjects have clearly understood the benefits and risks associated with their participation in a study
  • Ensuring that the potential study subjects are provided with all the information they need to reach a proper decision to participate in the research or not
  • Making sure that the subject’s agreement to take part is entirely voluntary
The purpose of this module is to provide a basic understanding of informed consent and the process of obtaining informed consent.

Learning Objectives:
  • To understand the requirements for complying with administrative guidelines relating to informed consent
  • To understand the process of informed consent
  • To understand which subjects are vulnerable subjects
  • To understand the conditions for waiving informed consent
Informed Consent in Research
Requirements for Informed Consent
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General Requirements
Japanese administrative guidelines for research provide a framework for informed consent, but there is more than one set of guidelines and each lists different items to be explained in the informed consent process. Thus when developing a research protocol, it is necessary to check the applicable set of guidelines and design an informed consent process, information sheet and consent form in a way that conform with these requirements.

However, there are basic requirements set forth common to all guidelines. To obtain informed consent appropriately, the subjects or representatives who give proxy consent on the subjects’ behalf must understand the following relating to the research:

1. It is not medical care as usual but a research study that the subject is being asked to take part in.
  • The following four points, in particular, must be thoroughly explained:
    1. (i) The significance and purpose of the research;
    2. (ii)The reason(s) why the subject has been selected;
    3. (iii)The expected duration of the research (the duration of the subject’s participation); and
    4. (iv)The method of the research.
2. Any foreseeable risks to the subject
  • The following three issues must be covered in the explanation about risks:
    (i)
    The explanation’s content must be accurate. However, simply providing accurate information is not enough: The information must be understood by the subject. It is important to give the explanation in a manner and use language that is clear and comprehensible to the particular listener, making sure that he or she accepts all of the benefits and risks of the research.
    (ii)
    When clarifying risks, clearly distinguish those that directly relate to the subject’s involvement in the research from other categories of risks, e.g., (a) give an explanation clearly distinguishing the difference between the risks involved in the study such as an adverse reaction due to a test or control drug and the progression of the primary disease, or (b) if the study is to be conducted using blood sampled as part of usual medical treatment, explain that there is to be no new physical risks due to the research, but that there is still the general physical risk involved from blood sampling.
    (iii)
    If there is concern that the subject and/or members of his or her family might experience some social disadvantage as a result of participating, such as becoming a target of social discrimination, the risks should be explained in a way that is understandable to all of them. This consideration is especially required in human genome/gene analysis research.
3. Any benefits to the subject or others to be reasonably expected from the research
  • Informing the subject whether there is an expected benefit to him or her or to others (such as other members of the same society and patients) if the person were to become the subject of the study
4. Other options
  • If another method for treatment is generally practiced and available, the subject must be informed that he or she may receive said treatment instead of participating in the study.
5. The method of securely managing personal information
  • The explanation must ensure the following six points:
    (i)
    Explaining whether anonymization, the procedure that makes it impossible to identify subjects from the data used in the research, will take place;
    (ii)
    If anonymization is to be conducted, describing whether it would be (a) by a method that allows the investigators to identify an individual who is the source of particular data by using a certain means or (b) by a method that makes it impossible to identify an individual by any means;
    (iii)
    Making clear that personal information may be reviewed by the members of the institutional review board or officers of the regulatory authority (in particular, in the case of clinical trials) or by those who monitor or audit the study;
    (iv)
    Explaining that the research outcome may be published, and what the measures are for protecting privacy in case of publication;
    (v)
    Revealing if there are any possibilities that the research results will be provided to another institution, and if so under what conditions; and
    (vi)
    If any aspects of the research data, such as genomic information, may not be disclosed to the subject, identifying the relevant items and explaining the reason for nondisclosure.
6. Information about compensation for any damage to health as a result of the research:
  • Describing whether any compensation is available in case of any damages to the subject’s health, such as insurance payouts, the method and provider of compensation, the limit and period of compensation, the degree and scope of damage to be covered by compensation, the method of treatment in place of insurance or in addition to compensation by insurance, whether or not information will be continually provided in the future and the name of the medical institution where one would receive treatment.
7. Whom to contact
  • Explaining whom the subject should contact for answers to pertinent questions about their rights and the research itself or for a response to a complaint or whom to notify (name and contact number) in the event of damage to the subject’s health incurred as a result of the research.
8. Voluntary participation in the research
  • Making clear that the decision to participate in the study and to continue to participate in it are voluntary decisions on the part of the candidate or subject. The following points should be emphasized in particular:
    (i)
    The decision not to participate or to withdraw in the middle of a research study (withdrawal of consent) will involve no penalty or loss of benefits to which the subject is otherwise entitled;
    (ii)
    Except for the information of research subject can’t be identified, informed consent given by the subject can be withdrawn at any time (or if a due date for withdrawal is given, anytime up until the due date). Also, withdrawal will involve no penalty or loss of benefits to which the subject is otherwise entitled. However, you need to explain that there are cases where it is difficult to delete the data even though the informed consent can be withdrawn.
9. The source of the research funding and any financial benefit to the investigator
  • Explain which institutions or organizations are funding the research in which the subject will participate, and whether or not the investigator has a personal or organizational interest in the research outcomes.
10. The method of storing and using information relating to an individual or samples
  • Explain plans for the storage and disposal of the information and any samples relating to individuals after the expiration of the research period. If there is a possibility of using it in future research, even if a plan of the research is uncertain at this time, let’s explain as much as possible.
11. Access to information relating to the research
12. Information relating to collaborative investigators
  • If the research is collaborative research, provide the names of collaborators and items of any personal information to be shared with the collaborative investigators.
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Additional Requirements
Taking account of the spirit and basic policies of informed consent, investigators should give particular attention to the following:
  1. Whenever another treatment option or alternative is available, it must be presented to the subject, and any new information that becomes known to the investigator must be given as well.
  2. Inform the subject that his or her participation may lead to unforeseen risks.
  3. There may be circumstances under which the subject’s participation is terminated by the investigator without the subject’s consent.
  4. If any significant new findings that may relate to the subject’s willingness to continue participation become known to the investigator while the research is ongoing, these findings should be provided to the subject.
  5. Inform the subject of anticipated psychological and physical risks associated with his or her decision to withdraw from the research in the middle of the study and ways for the safe termination of participation.
  6. Provide information on any expected financial burden to the subject that may result from participation, any travel expenses or remuneration that will be paid to the subject.
Informed Consent in Research
The Process and the Four Key Elements of Informed Consent
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When obtaining informed consent, the following three steps are involved:
(i)
Providing information to the subject
(ii)
Answering questions he or she may have to improve his or her comprehension
(iii)
Obtaining consent from the subject to participate in the study on a voluntary basis
To ensure these steps are taken, it is important to understand the next four points.
Informed Consent in Research
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1. Providing Information: What Does This Entail?
In the process of obtaining informed consent, provide information to the subjects (candidates) while giving attention to the following:
  • The process of informed consent begins at the recruitment stage. Advertising should not be coercive nor make false promises or claims. The institutional review board will also determine whether an advertisement is appropriate. In addition, for recruitment, the following two points must be taken into account:
    1)
    Make sure that internal rules of the institution where the research takes place permits remuneration for the subjects. If it is to be provided, the recruitment materials must avoid using the remuneration in such a way that it becomes the best incentive for participation in the study.
    2)
    If recruitment is directed to people in a particular region or to a certain population, the effort must not be coercive or unduly influence potential subjects to decide to participate in the research.
  • Investigators must accurately and carefully determine the subject’s ability to understand the information being given to them.
  • The necessary information must be provided in a manner and language that is clear and understandable, and should be communicated in an organized fashion that goes beyond merely avoiding technical jargon: Create an atmosphere that makes the subject feel comfortable asking the questions he or she needs to.
  • The information communicated should not use exculpatory language either in the written consent or in discussions about the research. No informed consent, whether oral or written, may include any exculpatory language through which the subject is made to waive or appear to waive any of the subject’s legal rights or releases or appears to release the investigator, the sponsor, the institution or its agents from liability for negligence.
Informed Consent in Research
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2. Improving Understanding: How Is This Done?
To improve the subject (or representative)’s understanding, the following considerations must be made:
  • In the process of informed consent, use a language that is understandable to the subject or his or her representative.
  • Give the subject enough time to think and make decision about his or her participation in the research before giving consent.
  • If the subject or representative is not fully capable of communicating in Japanese, use a translated informed consent document in a language that is understandable to him or her during the process of informed consent. The contents of the translated documents must accurately reflect the Japanese text as determined by the institutional review board. Even if a translator is present, providing a written translation of the consent document is still required.
Informed Consent in Research
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3. Subjects Who Merit Special Consideration
The concept of a “vulnerable subject” is important to research ethics and to regulatory compliance. The “Ethical Guidelines for Medical and Health Research Involving Human Subjects” clearly sets forth that if the subject is at a disadvantage due to a financial or medical reason, too young or too old, or the like, the investigators must give adequate consideration to ensure that the subject voluntarily makes his or her decision to participate. If candidates could be vulnerable to coercion or undue influence in making their decision or when they are likely to be excluded from the research, special safeguards must be set in place to protect the rights and welfare of these people. It is difficult to give a definition of vulnerable subjects, but those likely to be vulnerable to undue influence include children, prisoners, pregnant women, the handicapped or mentally disabled or the economically or educationally disadvantaged. Details are provided in the module on Research Subjects Who Merit Special Considerations.
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4．Considerations of the Cultural Norms of Japan
The subject’s right to self-determination cannot be ensured without the subject’s “ability to understand” and “voluntary participation in the research (voluntary will).” In the process of informed consent, including before and after the commencement of the research, the subject’s situation must fully be taken into account. In Japan, many people are likely to believe along the lines of the following: “Asking questions of medical personnel, especially doctors might be rude,” “Declining the doctor’s request for a favor is rude, because he is helping me,” or “If I say no, it may adversely affect my future treatment.” This tendency has begun to change, but still persists in Japan. Therefore, the question of who conducts the informed consent process and how it is explained are very important. In medical treatment, informed consent is established with the word “I will leave it to the doctor because I do not know well.” But the same thing will not work in medical research field. Those who engage in the informed consent process, in particular, those who will be or are likely to be in contact with the subjects in a setting different from that of research, for example, medical personnel such as physicians and nurses, should be very cautious about ensuring voluntariness of the patient’s participation in the research.
Informed Consent in Research
Obtaining Informed Consent by Proxy from a Subject’s Representative
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In some cases, research may be carried out with a subject who is unable to give valid informed consent. Examples of such a subject include:
  • One who is objectively determined to be unable to give valid informed consent due to a reason such as disease or death and has not previously expressed a clear willingness to participate in the research; and
  • One who is under 20 years old and has never been married.
When conducting research involving such a subject, the study may be carried out if proxy informed consent is obtained; and all of the following conditions are met with the subject’s representative:
1)　Risks to the subject are minimal;
2)　The research is socially significant and the subject’s participation in the research is essential;
3)　The representative is capable of speaking for the subject.
*In the case of a subject (or candidate) who is a minor too, it is still necessary to explain in a language easily understandable to the subject so that he or she can make sense of the research. In addition, it is important to note that, in many cases where the subject is 16 years old or older, informed consent must also be obtained from the subject himself or herself, in addition to proxy consent from the representative. On the other hand, if invasion is not involved in the research and information is disclosed, informed consent from the representative is unnecessary as long as he has opportunities for rejection.
4)　With regard to all of the previous points, approval of the institutional review board and authorization by the head of the research institution have been obtained.

In addition, a representative who is qualified to give proxy consent is generally defined as a person who is capable of speaking on the will and interests of the subject on his or her behalf, thus, the person is not necessarily a member of the subject’s family. Although it is generally assumed that a family member is suitable as a representative, in some cases, interests of the subject and the family member regarding participation in the research may conflict. In such a case, the family member is not appropriate as the subject’s representative.

Even if informed consent has been obtained from the subject’s representative, you must endeavor to obtain informed assent, if you determine that the subject is capable of expressing their wishes regarding the research.

Informed assent is the process in which a subject who is objectively determined to lack the capacity to give informed consent receives an explanation of the research in easily comprehensible words appropriate to their ability to understand, and expresses their understanding and approval for the conduct/continuation of the research. If the subject indicates their refusal during the informed consent procedure, you must endeavor to respect their wishes. However, this does not apply if there are hopes that the research will result in direct health benefits to the subject and the subject’s representative gives their consent. In other countries, informed assent is often used in the case of children, but bear in mind that it is not restricted to children in these guidelines.

The diagram below summarizes the processes of informed consent and informed assent in the case of a subject who is a minor, as described in the Ethical Guidelines for Medical and Health Research Involving Human Subjects. (The opt-out process will be described later)

(From Guidance on the Ethical Guidelines for Medical and Health Research Involving Human Subjects (December 22 2014 Public Notice by MEXT/MHLW as amended in May 29 2017))

Informed consent or informed assent when research subjects are minor

The age of research subject the research subject has not completed junior high school and is under 16 years the research subject has completed junior high school or is 16 years or older the research subject is over 20 years old or has been married before
Procedures for legally acceptable representatives Informed consent Informed consent (The research to be implemented involve any invasiveness)
Opportunities to withdraw such consent for parental authority* (The research to be implemented does not involve any invasiveness)
Procedures for research subject Informed assent (when the research subject is considered to be able to express his/her will) Informed consent*
* When the research subject is considered to have enough judgment concerning the research to be implemented on him/herself.
Informed Consent in Research
Cases Where Informed Consent May Be Simplified or Waived
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When conducting medical and health studies involving human subjects, the investigators must, as a general rule, provide an explanation in writing, make sure that the candidate has understood the explanation and obtain informed consent in accordance with the provisions of the “Ethical Guidelines for Medical and Health Research Involving Human Subjects” (by the MELW and the MEXT).

However, in the case of observational or interventional studies that are not invasive, or the like, the informed consent process may be simplified or waived.

The researcher must understand the relationship between the nature and content of the research and the forms and methods of informed consent, and make appropriate judgments. The considerations are 1) whether or not it is invasive; 2) whether or not it involves intervention; 3) and whether new human material or information will be gathered. If existing material will be used, the considerations are 4) whether it will be used at your facility; 5) whether it will be donated to another institution; and 6) whether you will receive the material to be used from another institution. The appropriate consent procedures — including whether written IC is required or whether oral IC is acceptable, and what form of anonymization will be used — will depend on these considerations.

Examples of written IC is required:
1)
Research using unapproved drugs / medical equipment
2)
Research using approved drugs
3)
Research involving behavior regulation throughout
4)
Research with blood sampling
Examples of written IC or oral IC with record is required:
1)
Research using food
2)
Research on lifestyle, such as verification of the presence or absence of gargling effect
3)
Research carried out by exercise load at the level occurring in daily life
4)
Analytical research on saliva and urine (no invasion at collection)
5)
Research using residual specimens (existing specimens)
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Opt-out
Opt-out is a method involving prior notification/announcement of information to ensure that subjects have an opportunity to voice their refusal. Methods of notification/announcement include sending a document to the subject, distributing pamphlets, placing an announcement on a website, and posting a written notice in a place where the subject can view it.

When obtaining consent via an opt-out, the notification/announcement must contain the following details:
1)
An overview of the research;
2)
The name of the research institution and the name of the principal investigator;
3)
The fact that the research protocol and materials concerning the research method can be obtained or viewed, and how to go about obtaining/viewing them;
4)
Procedures relating to the disclosure of personal information;
5)
Response to the requirement to provide a notification/announcement regarding the purpose of use;
6)
Method of responding to inquiries from subjects and other relevant individuals.
In the case of research that involves obtaining personal information from the subject directly in writing, by such means as a questionnaire, you must indicate the purpose of its use, even if you intend to obtain informed consent by means of the opt-out method. You must ensure that people who do not choose to opt out (in other words, those who intend to participate in the research) understand the content of the research.
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Simplification and Waiver Conditions Indicated by Japanese Ethics Guidelines
Even for research involving human subjects, informed consent procedures may be simplified or waiver. The “Ethical Guidelines for Medical and Health Research Involving Human Subjects” requires that any simplification or waiver of a procedure be approved by the institutional review board, confirming that the following conditions are met:

(i) Do not involve invasion (except minimal invasion) in the research.
(ii) Using said method will not result in any detriment to the subject;
(iii) Without said method, said epidemiological studies will not be conducted, or the value of said epidemiological studies will be significantly undermined;
(iv) Said epidemiological studies are recognized to be of enormous social importance.

In addition, researchers are required to take appropriate measures for the following when simplifying informed consent.
1)
To disclose information on purpose, content, and method concerning collection and use of samples / information for groups including research subjects.
2)
After conducting the research, explain promptly, including the group to which the research subject belongs.
3)
If samples and information are continuously collected and used over a long period of time, the actual situation should be publicized and disseminated to society.
Informed Consent in Research
Things to Do Before Carrying Out an Interview or a Survey in a Study
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In Japan, interviews and/or questionnaires may be administered as a part of clinical studies. Both are also subject to the informed consent requirements, and, in some cases, approval of the institutional review board is necessary. The research institution should inform the researchers whether or not a clinical study using either methods requires approval of their institutional review board. Before beginning a study that uses interviews and/or questionnaires, complete the necessary procedures while keeping in mind the various points learned in this module. Also, be sure to consult with the institutional review board beforehand.
Reference case 1:
A survey conducted by means of a questionnaire is deemed to cause little mental harm or distress to the subject and is therefore judged to involve “minor invasiveness” if adequate consideration has been demonstrated, by such means as disclosing in advance the fact that the questionnaire includes content that could cause the subject mental distress and that the subject can respond anonymously or refuse to respond. (Guidance on the Guidelines, p. 7)

Reference case 2:
On the other hand, “questions related to the subject’s mental trauma” refers to distressing experiences that the subject does not want to recall (for example, disaster, accident, abuse, previous critical illnesses, etc.) Be alert to the fact that not only questions such as these, but also causing mental distress to the subject through actions that disrupt the subject’s mental stability, such as intentionally causing nervousness or anxiety for research purposes, is included in the concept of “invasiveness,” even if the survey is conducted by means of a questionnaire. (Guidance on the Guidelines, p. 6)
Informed Consent in Research
Conclusion
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The purpose of informed consent is to provide accurate information in an easily understandable manner and improve the subject (or candidate)’s understanding through dialogue, that it is assured that the subject voluntarily decides whether to participate in the research. Thus when a new method of treatment is discovered, or when there is any change in the subject’s circumstances, it is necessary to go through the procedure again to obtain informed consent again. It is also important to understand that a situation that requires reacquiring informed consent may occur even after starting the research.
Informed Consent in Research
References
This module is adapted for the APRIN research community from “Informed Consent” (Author: Diane Paul) kindly offered by the CITI Program of BRANY (Biomedical Research Alliance of New York). Adaption was carried out by the APRIN supporting experts in accordance with the various pertinent laws and guidelines, whose names are listed elsewhere.
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