guide for preparing and conducting clinical research study


What Are Informed Consent and Assent?

"Informed consent" is the voluntary agreement of an individual, or his or her authorized representative, who has the legal capacity to give consent, and who exercises free power of choice, without undue inducement or any other form of constraint or coercion to participate in research. The individual must have sufficient knowledge and understanding of the nature of the proposed research, the anticipated risks and potential benefits, and the requirements of the research to be able to make an informed decision. (Levine, R.J. "Ethics and Regulations of Clinical Research." New Haven: Yale University Press, 1988.)

"Assent" is a term used to express willingness to participate in research by persons who are by definition too young to give informed consent but who are old enough to understand the proposed research in general, its expected risks and possible benefits, and the activities expected of them as subjects. Assent by itself is not sufficient, however. If assent is given, informed consent must still be obtained from the subject's parents or guardian. State laws define who constitutes a "child," and such definitions dictate whether or not a person can legally consent to participate in a protocol. The State of Maryland considers a person 18 years and older to be an adult and therefore one who can provide consent without parental permission. The CC follows Maryland law in such cases. The 1998 "NIH Policy and Guidelines on the Inclusion of Children as Participants in Research Involving Human Subjects" defines "pediatric subject" as an individual under the age of 21. Thus, an individual 18 years old would be considered an adult for consent purposes, but would also be considered a pediatric subject for study purposes according to CC policy.

At the CC, each research participant, or his or her legally authorized representative, must grant informed consent before undergoing any medical activity. In general, research participants give informed consent after discussing the protocol with the PI, or others as appropriate. To indicate this consent, the participant signs the written protocol consent or assent documents that have been previously reviewed and approved by the IRB. Unless the consent process is waived by the IRB, PI's must ensure that valid informed consents or assents are obtained from all research participants (or their legally authorized representatives).

At the CC, the informed consent process begins when the patient receives and signs form NIH-1225-1, "General Admission Consent," at the Admissions Desk (figure 5). This form explains to research participants the research nature of the CC, the likelihood that they may undergo standard or routine medical tests to determine their eligibility for research participation, their return to their private physicians for continuing care when their participation is completed, and the degree of confidentiality that they are provided while at the CC.

Figure 5: NIH-1225-1 -- General Admission Consent

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Prospective subjects are then given the protocol consent documents, form NIH-2514-1, "Consent to Participate in a Clinical Research Study," and form NIH-2514-2, "Minor Patient's Assent to Participate in a Clinical Research Study." The protocol consent documents explain the nature of the study, the risks and benefits of participating, and all the information necessary to allow a thoughtful and well-informed decision about participating in the protocol.

In addition, there are a number of procedures for which separate consent or assent must be given, usually just before proceeding, even though they have been detailed in the earlier-signed agreement to take part in the protocol. These procedures include general anesthesia, endoscopy, marrow aspiration, lumbar puncture, and HIV testing. Form NIH-2626, "Request for Administration of Anesthesia and for Performance of Operations and Other Procedures," is the most widely used general-purpose consent form. A special consent is not required for photographs, videotapes, or interviews intended to be used for research or treatment only, although they should be discussed in the protocol consent. However, if such materials are intended for publication or broadcast, patients must sign form NIH-549, "Authorization for Public Information Audiovisual Materials Involving Patients," which is available from OCCC.

Explaining to patients what clinical research means and how it will affect them is extremely important. Clinical research at the CC is undertaken with the clear intent of making the research participant a full partner in the process. Not only are the investigators responsible for informing potential participants about the nature of the protocol and the risks and benefits of participating, and giving them all the information necessary for making a thoughtful decision, they are also responsible for determining that prospective and currently enrolled participants understand the information provided and are giving consent free from coercion. Although the focus of this discussion is on the written protocol consent, conversations between the PI and the research participant are vital to the latter's understanding and agreement to participate. Conversations between the PI, or others as appropriate, and the participant may continue over several days. The PI or his or her designee signs and witnesses the participant's written agreement.

In the proper ethical and legal framework of informed consent, the protocol consent document is an educational supplement to the personal discussions between investigator and participant. These discussions with and evaluation of research participants should continue after the protocol consent document is signed and until the protocol is completed or the participant is no longer a part of the protocol.

Protocol Consent Document and Required Elements

It is true that many of our patients, sick for some time, are quite sophisticated and have heard a lot of medical talk, have had multiple procedures, and know the difference between a catheter and a biopsy. However, the protocol consent document should be written by the PI at a reading level understandable to all research subjects. Health care professionals often do not seem to comprehend the degree to which even simple medical terms sound incomprehensible to a person who is unfamiliar with them. A general rule of thumb is that consent documents should be written so that people who have not graduated from high school can understand them. Short sentences, examples and analogies, and the consistent use of the second person singular ("You, the patient, will receive…") and first person plural ("We, the staff, will be available…") are all helpful to the research participant. Phrases implying that the participant understands, such as "you understand" or "you know," should not be used in the consent document. Generic drug names, made clearer with the addition of trade names if needed, are preferred. To foster clarity and simplicity, a sample of suggested lay language for complex terms, procedure descriptions, and explanations of concepts is included in appendix C-1, "Lay Language and Terms." The sample is far from exhaustive, but is a model of interpretations of medical phrases; the verbatim descriptions are, of course, not mandatory.

Keeping all this in mind, the PI must incorporate into every protocol consent document the following eight elements as defined in 45 CFR 46.116 and shown in table 1. The PI and the IRB should consider incorporating the six additional concepts shown in table 2.

Table 1: Eight Elements Mandatory in Every Protocol Consent Document

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

When appropriate, one or more of the following elements should also be provided to each subject:

Table 2: Additional Concepts for the Protocol Consent Document

  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 becomes pregnant) that 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 research that may relate to the subject's willingness to continue participation will be disclosed to the subject.
  6. The approximate number of subjects involved in the study.

The first four of the eight required elements are general in nature and have been incorporated in standard language printed on the consent form NIH-2514-1. Element 1 is on the first page (figure 6) and elements 2, 3, and 4 are on the signature page (figure 7). The MEC approved these carefully prewritten statements as standard elements of the NIH-2514-1 form. The other required elements are protocol specific and should be written into the consent document by the PI.

Figure 6: NIH-2514-1 -- Consent to Participate in a Clinical Research Study

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Figure 7: Signature Page

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Element 5 describes the purpose of the research. It often covers the current state of information, the knowledge sought, and the anticipated benefits of that knowledge to society in general, if not to the research participant. This element also addresses why the particular research participant was chosen for study. For patients, the relationship of the protocol to their disease is described here. For healthy clinical research volunteers, the type of normative data sought by the protocol may be explained. Lastly, element 5 mandates a description of each test, examination, and procedure in the protocol, from preliminary screening to final evaluation of the research participant, as well as the anticipated amount of time required for the tests or activities and for the entire protocol. Any treatment or procedure that is experimental must be clearly identified as such.

Although specific consent documents are required for certain procedures, such as biopsy or lumbar puncture, the procedures – especially their risks – should be outlined briefly in the NIH-2514 form. In some instances, a procedure will be performed on the basis of facts unknown at the time the patient is being informed; as a rule of thumb, if one third or more of the participants will undergo a procedure, a brief outline of that procedure should be provided. Appendix C-2, "Lay Description of Common Research Procedures," contains illustrative language for some of these procedures.

Although risks and discomforts, element 6, can be described where they fit best, they are most easily described in a separate section of the consent document. The PI should address any foreseeable risk of harm to the participant's health for each procedure. In addition, the discomforts and inconveniences of physical tests, administered drugs, hospital procedures, or merely the expenditure of the research participant's time and effort should also be addressed here. Although a procedure may be standard in medical practice, it still must be spelled out in the consent document because, while the procedure is part of the protocol, it may not be necessary for the health care of the individual. The discomforts of venipuncture and arthrocentesis, for example, do not need to be described in the protocol body because they are known to a majority of the IRB; but they must be described to a potential subject. The participant should not be surprised, especially about physical effects such as pain, bruising, and scars. Participants who know the possible physical or psychological effects of the protocol are better able to alert the investigator if something unexpected occurs.

Three elements should be included in the explanation of each risk: probability, magnitude, and duration. Any risk of death must be stated openly with a quantitative probability, if possible. Even remote risks should be identified and written in the draft sent to the IRB. The IRB is a good forum for deciding what is and is not included in the protocol consent document.

Element 7 describes the benefits that the research participant or others may reasonably expect from the research. Benefits also can be set forth by using the concepts of probability, magnitude, and duration. If the protocol is therapeutic in intent, the benefits section may incorporate element 8, a discussion of appropriate alternative treatments or procedures that might benefit the participant and how those alternatives compare to the proposed investigational treatment.

The PI is strongly encouraged to group the foregoing information into sections, introduced by headings, that clearly and simply identify and describe each of the required elements. Such a format enhances comprehension and readability. The participant should have sufficient time, information, and opportunity to consider, free of coercion or undue influence, whether or not to participate in the protocol. Just above the signature line on the last page of the consent document is a clear statement of consent to take part. The participant's informed consent is documented by his or her signature on the line.

Assent Document and Required Elements

"Assent" means a child's affirmative agreement to participate in research; that is, to say "OK." Assent may be gained by talking with the child and supporting that talk with a written assent document (form NIH-2514-2) appropriate to the child's age and comprehension level. In determining if children are capable of giving meaningful assent, the IRB will take into account the ages, maturity, and psychological state of the children, either individually or as a group, as it deems appropriate.

Children's ages and maturational levels are only gross indices of mental level and reasoning capacity. For example, young children can best understand very concrete explanations; after 12 or 13 years of age, most can adequately deal with abstract ideas. Pictures are often used to clarify concepts to children – and adults. A child's level of comprehension and reasoning will be altered by anxiety and physical or emotional disturbances.

Every protocol assent document should include an explanation of the purpose of the protocol; what is required of the participants; what they will experience while participating in the protocol (e.g., not going home, separation from parents, presence of other patients); an explanation of risks, discomforts, or inconveniences; and a description of benefits to the child or to others.

The IRB, in consultation with the PI, will decide if the protocol requires the usual protocol consent form earlier described or an assent document for the child in addition to a protocol consent form for the parents or guardian. The decision will be based primarily on the expected level of comprehension of the proposed research participants.

The parents or guardian of a child participant are fully informed and given a protocol consent document to read and sign before their child participates in the protocol. If the child cannot read and oral assent is obtained from the child, this must be documented on the consent document. The prewritten statement found on the signature page of the consent document reads, "The information in the above consent was described to my child and my child agrees to participate in the study" (see figure 7). The parent's or guardian's signature indicating consent is in addition to the one confirming the above statement of oral assent.

Any research involving children requires their assent in one form or another, except when the IRB determines that (a) the capability of the child to be involved in the assent process is limited because of age, state of consciousness, or other factors, or (b) the protocol holds out a prospect of direct benefit for the child available only in the context of the research. In the latter case, the regulations recognize that parents and physicians control treatment choices and may properly override a child's refusal to participate in a protocol.

Editing the Protocol Consent and Assent Documents

The protocol consent and assent documents are two of the most important parts of the protocol. The documents represent the CC and NIH to the "outside world," that is, the patient who receives a copy of the consent document and those persons with whom the patient decides to share it. Thus, the PI has ample reason to write the consent at a reading level understandable to research participants. The consent document should be free of undue jargon, unacceptable abbreviations, poor grammar, and spelling errors.

The OCCC offers a consent-editing service to help investigators meet these goals. The PI is encouraged to submit a draft of the protocol consent/assent documents to OCCC. Drafts must be double-spaced to allow room for written comments from the consent editor.

The PI should allow sufficient time for the consent editor's review before submitting the protocol to the IRB. Drafting the consent document early in the process is a good idea. When OCCC returns the edited consent document to the PI, the PI has the discretion to incorporate or reject any or all of the recommendations of the consent editor. Although not required, editing improves the protocol consent and assent documents and reduces IRB stipulations.

Electronic Protocol Consent and Assent Documents

Forms NIH-2514-1 and NIH-2514-2 are available electronically from each Institute's Protocol Coordinator and the PCSC. Macintosh and IBM-formatted protocol consent templates are available on request from the PCSC. These templates offer investigators the ease and flexibility of modifying a protocol consent or assent document by using a personal computer instead of a typewriter. The templates are also helpful because the protocol consent and assent documents should be submitted in both electronic and hard copy format to the various review bodies and individuals, from the IRB to the CC Director.

Once the CC Director approves the protocol review action, the protocol consent documents are valid for 12 months. They must be valid when signed by the research participant. Approved protocol consent and assent documents for all active protocols are placed on the CC website at A search feature enables users to search by sponsoring Institute, PI name, protocol number, protocol title, and keywords. Protocol consent and assent documents may be viewed and printed via the NIH intranet, but the documents cannot be revised on-line. Revisions to protocol consent and assent documents must be approved by the appropriate Institute controls at the time of an amendment or continuing review action. The PCSC is responsible for updating the master electronic files with any approved protocol consent or assent revisions. Current consent and assent documents can be tracked by the IRB approval date, which is located on the first page of each consent and assent document. The PCSC updates the IRB approval information at the time of every amendment or continuing review.

The PCSC is responsible for providing Institute Protocol Coordinators with an electronic watermarked copy of the appropriate protocol consent and assent documents. The electronic watermarked consent documents enable the investigators to revise the documents before submitting them to the IRB for amendment or continuing review.

Informed Consent for HIV Testing

The CC encourages HIV testing in all scientifically appropriate studies – for example, protocols that involve administering immunosuppressive, cytotoxic, or immunomodulating substances; and protocols for evaluating the use of therapeutic interventions on the natural history of an illness. Knowledge of the patient's HIV serology in these settings is relevant to the protocol or the type of care delivered. Although clear scientific justification exists for excluding HIV-infected subjects from some protocols, a rationale for such exclusion must be explained in the protocol.

CC policy requires specific informed consent before HIV testing for any reason. If HIV testing is part of a protocol, the protocol consent document must include form NIH-2514-3, "Inclusion of HIV Testing in Consent to Participate in a Clinical Research Study" (figure 8). The form now cites the availability of a CC HIV counselor. The NIH-2514-3 form should be incorporated into the protocol consent document as a separate page, directly preceding the signature page.

Figure 8: NIH-2514-3 -- Inclusion of HIV Testing in Consent to Participate in a Clinical Research Study

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Durable Power of Attorney

Illnesses such as Alzheimer's disease, Huntington's chorea, cerebrovascular disease, severe psychotic conditions, alcoholic dementia, and other medical conditions causing significant cognitive impairment are a considerable health problem in the United States. For many years, investigators at the CC have conducted research involving cognitively impaired subjects in order to investigate the causes and treatment of these diseases. Three levels of research risks, described in the Federal regulations, are permitted in NIH intramural research that uses impaired participants:

  • Level 1 – Research having minimal risk, that is, where the risks of harm anticipated are not greater, considering probability and magnitude, than those ordinarily encountered in daily life. Examples include medical tests or procedures carried out in the routine physical examination, diagnosis, and treatment of patients.
  • Level 2 – Research having greater than minimal risk but presenting the prospect of direct benefit to individual participants. Examples include a drug trial with minimal side effects or tests involving minimal radiation but providing useful diagnostic information (computerized axial tomography scan).
  • Level 3 – Research having greater than minimal risk with no prospect of direct benefit to research participants, but likely to yield general knowledge about the participant's disorder or condition. Examples include added lumbar punctures or ionizing radiation done for research.

Dementia and severe psychotic disorders may compromise or destroy an individual's ability to give informed consent to participate in research. How should institutions and investigators conducting research on cognitively impaired participants balance the societal commitment to advance important scientific knowledge with the obligation to protect the rights and welfare of human research subjects?

"The Belmont Report" established three fundamental ethical principles that are relevant to all research involving human subjects: respect for persons, beneficence, and justice. The first principle, respect for persons, incorporates at least two ethical convictions: First, individuals should be treated as autonomous agents. Second, persons with diminished autonomy are entitled to protection. The PI and the IRB are required to protect the impaired subject by including appropriate additional safeguards.

Guidance on such safeguards appears in CC policy M87-4, "Consent Process in Research Involving Impaired Human Subjects." It represents an attempt to protect the rights and welfare of the impaired participant while encouraging much-needed research in diseases that carry cognitive deficits. The policy, currently under review, is based on two key principles:

  • Protection should be proportionate to the risk involved, with the least protection required when research involves no more than minimal risk; and
  • Although the assent of cognitively impaired participants is necessary, it is not sufficient. More must be done to verify that such participants would do what they are being asked to do if they were able to make decisions for themselves.

An additional safeguard for the subject is the Durable Power of Attorney (DPA). The form NIH-200, "Durable Power of Attorney," (figure 9) is a legal document by which prospective research participants who are capable of doing so can appoint someone else to make decisions for them regarding their involvement in research and clinical care at the CC should they become unable to do so. The document ensures that as long as the participant is able to make decisions, he or she does so; only if the participant becomes mentally incapacitated does the surrogate make the decisions. The major consideration when appointing a representative is that he or she (usually a family member or a close, trusted friend) knows the research participant well enough to make decisions about research participation that the participant would make if able to do so. A DPA is used in general hospitals for decision-making in health care. Its use in the CC is designed to protect the rights and welfare of human research participants who are temporarily or permanently cognitively impaired. The DPA forms with instructions are available at all nursing stations and in the Department of Clinical Bioethics.

Figure 9: NIH-200 -- Durable Power of Attorney

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The CC policy M87-4 describes eight different research situations in which the IRB's should require additional protections to the informed consent process on the basis of the following:

  • The participant's current ability to comprehend the protocol;
  • The level of research risk of the protocol; and
  • Whether or not the research offers prospective benefit to the participant.

The policy suggests appropriate solutions for each of the eight research situations. These considerations determine whether the DPA or another approach, such as court-appointed guardianship, should be used to select a representative for the research participant. When submitting research protocols that involve impaired or potentially impaired subjects, investigators are expected to describe which of the eight research situations apply to their protocols, and request approval for using the DPA or other appropriate measures as suggested by the policy. The Department of Clinical Bioethics can and will assist on these issues, but the IRB's ultimately decide how to handle them.

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