Informed Consent in Research

Under construction 2005-07-31. We appreciate your patience.

Information about informed consent is organized into sections:

• Introduction
• Dubious Research Recruitment Schemes (recruitment is the beginning of the process of informed consent)
• Required Elements in Informed Consent (in federally funded research)
• Informed Consent Checklist (coming soon)
• Red Flags in Informed Consent (a range of errors, mis-statements, or false statements regularly found in objectionable consent forms)
• Points to Consider
• Strengths and Limitations of This Information
• Additional Resources on Informed Consent

Introduction

Informed consent is the process in which you decide whether or not to enroll in research. The information disclosed during this process is summarized or perhaps expanded in the consent form. For a number of reasons, people have fallen into the habit of conflating the process with the paper, and continually refer to the consent form as the informed consent. This is unhelpful, so we try to distinguish the process from the paper form as clearly as possible. To people considering a study, the consent form is likely to appear very long indeed. Consent forms are about twelve pages on average, although consents can run to thirty pages or more in an unusually complicated study. To put this in perspective, a chapter in the last paperback book you read was probably shorter than thirty pages.

The process of informed consent begins when you first learn about a study, usually through advertising or recruitment. The process does not end when (or if) you decide to enroll and sign the consent document. New information may become available that could change your willingness to participate in the study after you're enrolled. For example, some clinical trials sponsored by NIH have a Data Safety & Monitoring Board (DSMB) which looks at unblinded raw study data several times during the trial. At the mid point in the trial, the DSMB might find that the experimental drug or device was so safe and effective that keeping a group of subjects on placebos could no longer be justified. As a result, subjects who were getting a placebo might be re-assigned to the active treatment arm, or a blinded controlled trial might continue with an open label design in which all subjects received the experimental drug or device. Perhaps an adverse drug reaction is discovered to occur more frequently than expected: this new information might prompt changes in drug dosage, removal of some subjects from the study, or even termination of the study. Materially important new information that alters the risks and benefits to the subjects, changes in the study design, and new information in general are examples of what might be presented to you in an updated, or emended consent form.

If you're presented with an updated consent form during a trial, it means the IRB, the sponsor, or the regulator (like FDA) believes the new information is important enough that subjects should re-evaluate whether or not continued participation is still in their best interest. By all means do so.

Signing the consent document should not stop you from asking more questions, or different questions, or even the same questions, about the study at any point during your enrollment. It is not as if information is only available to you before signing, and as if by magic, stops being available afterwards.

It's important to understand that the process of informed consent in research differs from informed consent for medical treatment. More than half of all studies with human subjects fall under federal regulations which specify the information to be disclosed to research subjects, how the information should be disclosed, and how disclosure should be documented. Consent for medical treatment, on the other hand, is governed by state law, and varies from state to state. People tend to confuse research with medical treatment, but research and medical treatment are not the same.

top

Requirements in Informed Consent

Widely shared social values expressed as ethical principles in human research require investigators to obtain voluntary informed consent from subjects or their representatives prior to enrolling them in research. Exceptions to this are few in number and narrowly circumscribed in scope. These ethical principles, however, are neither uniformly nor widely expressed in federal and state law. In certain research, federal administrative law requires that research subjects give voluntary legally effective informed consent and specifies mandatory elements. People sometimes inaccurately refer to these mandatory elements as rights, which they most assuredly are not. Federal administrative law, in the Code of Federal Regulations (hence the acronym CFR) does not create rights for research subjects; instead the law gives remedies to federal agencies to stop practices which fail to comply with federal regulations. Strictly speaking, research subjects do not have the right not to be enrolled in research without giving legally effective informed consent: rather, designated federal agencies have remedies to motivate investigators to obtain informed consent if they've enrolled subjects prior to obtaining consent (or violated other sections of the regulations). The main remedy available to the regulator is to write a very stern-sounding letter to investigators who violate the regulations. These letters, called warning letters (from FDA), or determination letters (from OHRP), are few in number considering how many trials are conducted in the US each year, are generally sent years after the fact, and have virtually no effect. Instead of pro-actively protecting research subjects during studies, our system scolds investigators after–the–fact when they harm research subjects, or scolds IRBs for failing to protect the rights and welfare of research subjects, or scolds sponsors for conducting poorly designed studies that endanger research subjects, or might scold a sponsor for failing to correct and report investigator non-compliance detected during the study.

Research with human subjects funded by the US federal government or conducted at an institution receiving federal funds must comply with 45 CFR 46, also called The Common Rule, as a condition of funding. Institutions agree to comply by filing a Federal Wide Assurance (FWA) with the Office for Human Research Protections (OHRP), a tiny agency within Health & Human Services (HHS). Studies testing products subject to regulation in research by the US Food & Drug Authority (FDA) must comply with requirements for informed consent as described in 21 CFR 50.120, Informed Consent of Human Subjects. When research falls under both categories, informed consent must meet both sets of regulations. Both sets of regulations are reproduced below; we comment, summarize or stress important points in blue text between brackets.

Requirements for informed consent in federally funded research under The Common Rule (OHRP):

45 CFR 46.116   General requirements for informed consent.

Except as provided elsewhere in this policy, no investigator may involve a human being as a subject in research covered by this policy unless the investigator has obtained the legally effective informed consent of the subject or the subject's legally authorized representative. An investigator shall seek such consent only under circumstances that provide the prospective subject or the representative sufficient opportunity to consider whether or not to participate and that minimize the possibility of coercion or undue influence. The information that is given to the subject or the representative shall be in language understandable to the subject or the representative. No informed consent, whether oral or written, may include any exculpatory language through which the subject or the representative 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.

[This section describes the conditions under which consent should be obtained such that it's legally effective informed consent.

• Timing: Consent must obtained before you are enrolled in research, not during or after
• Authority: If you are unable to consent on your behalf, consent must be obtained from your legally authorized representative
• Freely given: The investigator cannot rush, threaten, financially induce, or mislead you, nor exploit circumstances or relationships to obtain consent
• Understandable: The required information must be presented so can you understand it, whether you read it or somebody explains it to you
• No Waivers or Limitations: You cannot be asked to sign a consent form in which you agree not to sue (a waiver), or agree to limits on the circumstances in which you can sue (who, when, or for what reason), or agree not to sue one or more parties by releasing them from liability in advance]

(a) Basic elements of informed consent. Except as provided in paragraph (c) or (d) of this section, in seeking informed consent the following information shall be provided to each subject:

1. a statement that the study involves research, an explanation of the purposes of the research and the expected duration of the subject's participation, a description of the procedures to be followed, and identification of any procedures which are experimental;
2. a description of any reasonably foreseeable risks or discomforts to the subject;
3. a description of any benefits to the subject or to others which may reasonably be expected from the research;
4. a disclosure of appropriate alternative procedures or courses of treatment, if any, that might be advantageous to the subject;
5. a statement describing the extent, if any, to which confidentiality of records identifying the subject will be maintained;
6. for research involving more than minimal risk, an explanation as to whether any compensation and an explanation as to whether any medical treatments are available if injury occurs and, if so, what they consist of, or where further information may be obtained;
7. an explanation of whom to contact for answers to pertinent questions about the research and research subjects' rights, and whom to contact in the event of a research-related injury to the subject; and
8. a statement that participation is voluntary, refusal to participate will involve no penalty or loss of benefits to which the subject is otherwise entitled, and the subject may discontinue participation at any time without penalty or loss of benefits to which the subject is otherwise entitled.

[This section itemizes the information that must be disclosed so you can decide whether or not to enroll in the proposed study.

You must be given the following information:

• That you are offered enrollment in research, and (ideally) that this is not the same as providing you with medical care; the purpose of the study (what will it prove or disprove); how long you would be in the study; what will happen to you during the study, and which parts are experimental, if any
• Risk: (ideally) what the specific risks are, which risks are serious, how likely they are to happen (expressed in terms you understand), and that there are also risks that cannot be foreseen
• Benefits: whether or not there is a reasonable likelihood of direct medical benefit to you or others, in addition to the benefit to society from adding to general knowledge
• Alternatives to enrolling in the research: the standard medical treatment for your condition, when it exists, or not enrolling in the study
• Confidentiality: how the investigator intends to protect your privacy and the confidentiality of your protected health information
• Compensation and Medical Treatment: whether or not the sponsor has arranged for compensation or medical treatment if you're injured, and whom to contact for information, and (ideally) that this is unrelated to your right to sue
• Voluntary: a reminder that enrollment in research is voluntary, that if you decide to enroll, you can stop at any time, and that you won't loose anything if you decide not to enroll, or decide to stop]

(b) additional elements of informed consent. When appropriate, one or more of the following elements of information shall also be provided to each subject:

1. a statement that the particular treatment or procedure may involve risks to the subject (or to the embryo or fetus, if the subject is or may become pregnant) which are currently unforeseeable;
2. anticipated circumstances under which the subject's participation may be terminated by the investigator without regard to the subject's consent;
3. any additional costs to the subject that may result from participation in the research;
4. the consequences of a subject's decision to withdraw from the research and procedures for orderly termination of participation by the subject;
5. A statement that significant new findings developed during the course of the research which may relate to the subject's willingness to continue participation will be provided to the subject; and
6. the approximate number of subjects involved in the study.

[This section lists additional information which is appropriate in nearly all situations, but is not, however, mandatory:

• Pregnancy: an obvious reminder
• Involuntary withdrawal: in addition to deciding to stop, the circumstances in which you can be withdrawn from the research by the authority of somebody else (e.g., the sponsor, IRB, or FDA stops the trial, you get sicker, you can't get to study appointments, or don't take the test drug)
• Money: whether or not you're expected to pay for anything, and how much
• Leaving the study: a description of what the investigator would like you to do if you decide to leave. Some measures are for your safety, while others are designed to minimize the loss of your data; since nobody can forcibly detain you in a study, at best, it discloses hope.]

(c) An IRB may approve a consent procedure which does not include, or which alters, some or all of the elements of informed consent set forth above, or waive the requirement to obtain informed consent provided the IRB finds and documents that:

1. the research or demonstration project is to be conducted by or subject to the approval of state or local government officials and is designed to study, evaluate, or otherwise examine: (i) public benefit or service programs; (ii) procedures for obtaining benefits or services under those programs; (iii) possible changes in or alternatives to those programs or procedures; or (iv) possible changes in methods or levels of payment for benefits or services under those programs; and
2. the research could not practicably be carried out without the waiver or alteration.

(d) An IRB may approve a consent procedure which does not include, or which alters, some or all of the elements of informed consent set forth in this section, or waive the requirements to obtain informed consent provided the IRB finds and documents that:

1. the research involves no more than minimal risk to the subjects;
2. the waiver or alteration will not adversely affect the rights and welfare of the subjects;
3. the research could not practicably be carried out without the waiver or alteration; and
4. whenever appropriate, the subjects will be provided with additional pertinent information after participation.

(e) The informed consent requirements in this policy are not intended to preempt any applicable Federal, State, or local laws which require additional information to be disclosed in order for informed consent to be legally effective.

(f) Nothing in this policy is intended to limit the authority of a physician to provide emergency medical care, to the extent the physician is permitted to do so under applicable Federal, State, or local law.

45 CFR 46.117   Documentation of informed consent.

(a) Except as provided in paragraph (c) of this section, informed consent shall be documented by the use of a written consent form approved by the IRB and signed by the subject or the subject's legally authorized representative. A copy shall be given to the person signing the form.

(b) Except as provided in paragraph (c) of this section, the consent form may be either of the following:

1. A written consent document that embodies the elements of informed consent required by §46.116. This form may be read to the subject or the subject's legally authorized representative, but in any event, the investigator shall give either the subject or the representative adequate opportunity to read it before it is signed; or
2. A short form written consent document stating that the elements of informed consent required by §46.116 have been presented orally to the subject or the subject's legally authorized representative. When this method is used, there shall be a witness to the oral presentation. Also, the IRB shall approve a written summary of what is to be said to the subject or the representative. Only the short form itself is to be signed by the subject or the representative. However, the witness shall sign both the short form and a copy of the summary, and the person actually obtaining consent shall sign a copy of the summary. A copy of the summary shall be given to the subject or the representative, in addition to a copy of the short form.

(c) An IRB may waive the requirement for the investigator to obtain a signed consent form for some or all subjects if it finds either:

1. That the only record linking the subject and the research would be the consent document and the principal risk would be potential harm resulting from a breach of confidentiality. Each subject will be asked whether the subject wants documentation linking the subject with the research, and the subject's wishes will govern; or
2. That the research presents no more than minimal risk of harm to subjects and involves no procedures for which written consent is normally required outside of the research context.

In cases in which the documentation requirement is waived, the IRB may require the investigator to provide subjects with a written statement regarding the research.

Source: 45 CFR 46.116-117 The Common Rule Code of Federal Regulations, Title 45: Public Welfare, Department of Health and Human Services, National Institutes of Health, Office For Protection From Research Risks; Part 46: Protection of Human Subjects (13 December 2001).
Accessed 2005-06-09 at: http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm#46.116

top

Red Flags in Informed Consent

This study is being conducted by an Institutional Review Board.

Comment: This statement is false because an Institutional Review Board (IRB) does not conduct studies. Anyone who tells you this or advertises research in these terms is either deliberately attempting to mislead you or utterly clueless about the fundamentals of human research. Avoid studies associated with these claims.

For information on IRBs, see: 21 CFR 56 Institutional Review Boards: Code of Federal Regulations, Title 21 Food and Drugs, Food and Drug Administration, Department of Health and Human Services; Part 56: Institutional Review Boards.

This drug study is approved by FDA or this study is being conducted under an FDA–approved Investigational New Drug (IND) exemption.

Comment: These statements are false and misleading because FDA does not approve clinical trials conducted under an Investigational New Drug (IND) exemption or application. Rather, the sponsor may begin research if FDA does not object within 30 days of filing the IND application.

FDA is explicit on this issue:

Investigational drug and biologic studies are not officially approved by FDA. When a sponsor submits a study to FDA as part of the initial application for an investigational new drug (IND), FDA has thirty days to review the application and place the study on "hold" if there are any obvious reasons why the proposed study should not be conducted. Therefore, subjects are likely to impute a greater involvement by the Agency in a research study than actually exists if phrases such as, FDA has given permission … or FDA has approved … are used in consent documents. If FDA does not place the study on hold within the thirty day period, the study may begin (with IRB approval).
Source: FDA Guidance for Institutional Review Boards and Clinical Investigators, FDA Approval of Studies (1998)

Points to Consider

top

Strengths and Limitations of This Information

This information has important strengths and limitations. We offer this information about informed consent in research to help you understand what it is, how to evaluate it, and in particular, how to maximize the likelihood that you consider all the information presented to you. Put differently, we aren't telling you what to decide but rather how to go about deciding. We encourage readers to consult more than one source of quality information.

This information is not medical advice. CIRCARE officers and board members do not offer medical advice. CIRCARE firmly believes that medical decisions should be made by you and your primary care physician. Those CIRCARE officers or board members licensed to practice medicine are not offering you medical advice here.

Do not make medical decisions based upon what you read here.

This information is not legal advice. CIRCARE officers and board members do not offer legal advice. Only a licensed attorney can provide you with legal advice. Those CIRCARE officers or board members licensed to practice law are not offering you legal advice here.

CIRCARE strives for accuracy on this web site. Original third-party material is reproduced with citation. While we try very hard to ensure our information is accurate, we cannot guarantee it. If you're concerned about the accuracy of something, please let us know. Use the Contact link at the top of the page to bring it to our attention.

CIRCARE also offers opinion and advice based upon the insight and experience of its officers and board members as non-professional advocates for the protection of human subjects in research. We believe our opinions are reasoned and responsible in the context in which we offer them. To the extent possible, we explain the basis of our opinions. Our opinions are not facts, and other people may or may not agree with them. For this reason we discourage you from making decisions based only upon what you read here.

You should not decide whether or not to enroll in research based only on this or any other single source of information.

top

Last Updated by ew: 2005-08-18

If you find the information on this page helpful, please support CIRCARE with a tax-deductible contribution today. Help us advocate for meaningful protection of human subjects in research. Donating on-line with PayPal is quick and easy – find out more on our Support page.

---