21 CFR 50.20 General requirements for informed consent

Except as provided in ß50.23, no investigator may involve a human being as a subject in research covered by these regulations 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 rights, or releases or appears to release the investigator, the sponsor, the institution, or its agents from liability for negligence.

The study team make sure that technical and scientific terms are adequately explained or that common terms (lay language terms) are substituted. The informed consent document should properly translate complex scientific concepts into simple concepts that the typical subject can read and comprehend.

Although not prohibited by the FDA regulations, use of the wording, "I understand..." in informed consent documents may be inappropriate as many prospective subjects will not "understand" the scientific and medical significance of all the statements. Consent documents are more understandable if they are written just as the clinical investigator would give an oral explanation to the subject, that is, the subject is addressed as "you" and the clinical investigator as "I/we." This second person writing style also helps to communicate that there is a choice to be made by the prospective subject. Use of first person may be interpreted as presumption of subject consent, i.e., the subject has no choice. Also, the tone of the first person "I understand" style seems to misplace emphasis on legal statements rather than on explanatory wording enhancing the subject's comprehension.

Subjects are not in a position to judge whether the information provided is complete. Subjects may certify that they understand the statements in the consent document and are satisfied with the explanation provided by the consent process (e.g., "I understand the statements in this informed consent document)." They should not be required to certify completeness of disclosure (e.g., "This study has been fully explained to me," or, "I fully understand the study.")

Consent documents should not contain unproven claims of effectiveness or certainty of benefit, either explicit or implicit, that may unduly influence potential subjects. Overly optimistic representations are misleading and violate FDA regulations concerning the promotion of investigational drugs [21 CFR 312.7] or investigational devices [21 CFR 812.7(d)] as well as the requirement to minimize the possibility of coercion or undue influence [21 CFR 50.20

Significant Differences in FDA and DHHS Regulations related to Research Consent

DHHS FDA Waiver of Parent/Guardian Permission in Minimal Risk Studies (45.404) For minimal risk studies involving children, the IRB may waive the requirement for consent if the research meets the criteria of 46.116(d) or is designed for conditions or a population for which parent/guardian permission is not a reasonable requirement to protect the subjects (examples include neglected and abused children). Waiver of parental permission is not allowed for FDA regulated research. Waiver of Parent/Guardian Permission in studies posing more than minimal risk to subjects and offering direct benefit to children participating. (45.405) For benefit studies with more than minimal risk involving children, the IRB may waive the requirement for consent if the research is designed for conditions or a population for which parent/guardian permission is not a reasonable requirement to protect the subjects (examples include neglected and abused children). Waiver of parental permission is not allowed for FDA regulated research. Waiver of Parent/Guardian Permission in Studies – a minor increase over minimal risk and no benefit to children participants (45.406) For studies not offering the prospect of direct benefit and that involve only a minor increase over minimal risk involving children, the IRB may waive the requirement for consent ONLY IF the research is designed for conditions or a population for which parent/guardian permission is not a reasonable requirement to protect the subjects (ex. include neglected and abused children). If parental permission is sought, both parents must provide consent (some exceptions.) Waiver of parental permission is not allowed for FDA regulated research. Dating consent forms DHHS regulations do not explicitly require consent forms to be dated. FDA explicitly requires that consent forms be dated as well as signed by the subject or the subject's legally authorized representative. 50.27(a) Waiver of Documentation of Informed Consent DHHS allows for waiver or alteration of the requirement for a signed informed consent document in certain minimal risk studies and when the principal risk is a breach of confidentiality. FDA does not permit waiver of documentation. Obtaining informed consent is “deemed feasible” except in two situations (clinical emergency and emergency research. 21 CFR 50.23, 50.24.  Waiver of Informed Consent/Consent not Required Waiver permitted under 46.116(d) if:
 

• The research involves minimal risk
• The waiver will not adversely affect the rights and welfare of subjects
• The research could not practicably be carried out w/out the waiver
• Where appropriate, subjects will be provided w/ additional information
   

Exceptions to informed consent requirements 21 CFR 50.23:

• Subject is confronted with life-threatening situation necessitating use of test article
• Informed consent not possible because of an inability to communicate with, or obtain legally effective IC from the subject
• No time to obtain consent from LAR
• No alternative method of approved therapy available that provides equal or greater likelihood of saving subject’s life
• IRB approves emergency research without requiring IC. 21 CFR 50.24
   

Costs of Research Informed consent document must include disclosure of any “additional costs to the subject that may result from participation in the research.” 46.116(b)(3)
 

• Disclosure of “additional costs” in the IC document
• Costs of IND product are not chargeable to the subject without FDA permission
• Costs of IDE product are chargeable to the subject, and are controlled by regulation.
   

Inspection of Study Records DHHS reserves the right to inspect records of studies it funds at a reasonable time and in a reasonable manner; it does not require that subjects provide informed consent for that inspection. FDA explicitly requires that subjects be informed that FDA may inspect the records of the study because FDA may occasionally examine a subject's medical records when they pertain to the study. 50.25(a)(5)
 

THE MOST COMMON REASON FOR DELAY OF APPROVAL OF A PROTOCOL IS AN IMPROPERLY PREPARED CONSENT FORM - EITHER CONTAINING INCOMPLETE INFORMATION OR UNINTELLIGBLE, COERCIVE OR CONFUSING LANGUAGE.

The consent form must include:

• A statement that the study involves research. The statement that the study involves research is particularly important for clinical research because the relationship between patient-physician is different than that between subject-investigator. 
• Purpose of the research. It should be clear to the subject that this is research. This section should include the rationale for the research that is being conducted and the specific purposes for the proposed research. Consent documents for studies of investigational articles (drugs, biologics or devices) should include a statement that a purpose of the study includes an evaluation of the safety of the test article. Statements that indicate test articles are safe or statements that the safety has been established in other studies are not appropriate when the purpose of the study includes the determination of safety. Studies that involve efficacy should also include the effectiveness of the test article, as a study purpose, but should not make claims of effectiveness. 
• Procedures. The subject must be informed exactly what his or her participation will involve, with particular attention to the way it will be experienced by the subject. This should include the length of time and frequency of each procedure ( e.g. , hospitalizations, visits to the investigator, types of medication, drug dosages, types and numbers of tests, amount of blood to be withdrawn, questionnaires, videotaping, diets, withholding of standard treatment, and follow up studies), as well as the overall length of time a subject is expected to participate. It should be made clear which of these procedures are being done in the interests of research and which are being done to provide diagnosis, prevention, or therapy. Of the various diagnostic maneuvers ( e.g. , laboratory tests) the consent form should specify which are extra in that they would not have been done during customary therapy or would not have been done as often. The approximate number of subjects to be involved in the study should also be included. 
• Risks or discomforts to the subject. These include not only physical injury, but also possible psychological, social or economic harm, discomfort or inconvenience. These may include side effects of drugs, hazards of procedures, or dangers of withholding a therapy of proven value. The subject should be told what will be done to minimize risks and counteract side effects and which, if any, side effects might be irreversible. In addition to the known risks of being in the study, there may be unforeseeable complications; the subject should be made aware of this fact. 
  Benefits of the research to the subject. If there is no expectation of direct benefit to the subject (treatment and non-treatment arms must be considered), state that clearly. Avoid use of the word "may". It should be made clear whether the subject will be offered continuing access to an investigational therapy after completion of the study; if so, whether it will be provided free or whether the subject will be expected to pay for it. 
• Treatment Alternatives. The consent form must identify the subject's alternatives to participation in the protocol and should offer a discussion of their relative advantages and disadvantages. It is usually not necessary to provide a full account of the risks and benefits of alternative treatments in the research consent form. In some cases it may be appropriate to state that one reasonable alternative for the prospective subject is to choose no therapy. 
• Costs of Participation. The financial consequences to the subject of participation in the project should be stated clearly. This includes disclosure of insurance co-payment obligations for services that will be billed to third-party payors as well as a subject's liability for costs not covered by a sponsor, insurer, or the provider. Third-party payers cannot be billed for procedures performed purely for research purposes. If the research treatment or procedure is not covered by Medicare, Medicaid, third-party insurers or the research sponsor, the subject may be responsible for payment. In such case, state which treatments or procedures are not likely to be covered by third-party payors and the approximate charge for each. 
• Confidentiality. Steps taken to assure confidentiality should be explained in the consent form. The subject should be informed about the disposition of information obtained during a study. Limits on confidentiality, such as inspection of medical records by the IRB or agents of the FDA, and the industrial sponsor in studies involving investigational drugs and devices, should also be explained. Subjects should be informed about information that will be included in the subject's medical record. If the study events are not directly related to diagnosis or therapy, the subject may decide whether or not such information shall be entered into a medical record, transmitted directly to a private physician or retained only in the Study record. 
• Voluntary Participation. The consent form must state that participation is voluntary and that refusal to participate will not result in any penalty or any loss of benefits that the person is otherwise entitled to receive. Subjects should be informed that they are free to decide whether or not to participate, and also free to withdraw from the study at any time unless the nature of the investigation, once commenced, precludes this. They should be assured that if they prefer not to participate or decide to withdraw, they will still receive standard treatment, if such a statement is appropriate. There should also be assurance that a decision not to participate will not adversely prejudice future interactions with the institution. This is particularly important when a dependent relationship exists between the investigator and the subject, such as physician-subject, employer-employee or faculty-student. If withdrawal or non-participation in the study would result in transfer of the subject to another service or institution, this must be made clear. 
  Right to Withdraw. A subject's right to withdraw from the study at any time without penalty, including without loss of credit or of financial reward for the work completed should be included. The right to withdraw includes the right to require that stored tissue specimens be destroyed or anonymized. When appropriate, it may be necessary that a consent form includes the consequences of a subject's decision to withdraw from the research and the procedures for the safe and orderly termination of participation by the subject. In some studies, abrupt withdrawal from a study may be dangerous to a subject. In such cases, this danger must be explained and it must be made clear that the subject should not withdraw without first discussing it with the investigator. 
• HIPAA : Covered entities may continue to use and disclose protected health information that was obtained prior to the time the individual revoked his or her authorization, as necessary to maintain the integrity of the research study. Additional information may be found in 45 CFR 164.508(b)(5)(i).However, the reliance exception would not permit a covered entity to continue disclosing additional protected health information to a researcher or to use for its own research purposes information not already gathered at the time an individual withdraws his or her authorization. 
• Termination of Participation. The consent form must include anticipated circumstances under which the subject's participation may be terminated by the Principal Investigator without regard to the subject's consent. 
• Compensation for Subject Injury. It is acceptable to include information on a sponsor's policy regarding compensation for injury in addition to the UVa policy as stated in the consent form template. The sponsor's policy regarding compensation for adverse events/ subject injury should reflect the compensation/subject injury terms appearing in the contract between the sponsor and UVA. 
• Significant New Findings. The form must include 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. (All such information must also be provided to and retained by the IRB in its records.) 
• Conflict of Interest. Principal Investigators must disclose to potential subjects any conflict that they have with the sponsor or in the research for which the subjects are being recruited, including capitation payments, bonuses or other incentives paid by the sponsor for enrollment (as opposed to reasonable payments for necessary study services) and any other personal conflict deemed necessary by the IRB. 
• Questions. The subjects and/or parents or guardians should be encouraged to ask questions. If the proposed procedures are complex or involve considerable risk, there should be adequate time provided for subjects to discuss their decision with their own physician or other respected persons before making a decision. Principal Investigators should be as certain as possible that subjects understand the purpose, the procedures involved, the risks and the benefits, if any, of participating in the study. 
• Continuing Contact. The consent form should include the name and telephone number of a person to contact for answers to questions and a person to contact in the event of a research-related injury or emergency. The name and telephone number of the Principal Investigator and the IRB office address and telephone number should be specified. 
• Signatures. Spaces should be provided for the signature of the person who consents to participate in the study or the legally authorized representative who consents on behalf of the individual who will be the subject of the study. There should also be a space also for the signature of the person who obtains the consent -- the Principal Investigator or the authorized representative. If the subject is a child or is legally incompetent, such subject should indicate her or his assent by signing the consent or assent form, depending on age of the minor, after the procedures have been explained (unless otherwise determined by the IRB). 
• Version Date/Page Numbering. Each page of the consent form should be numbered and should contain the current version date. Each time the consent form is revised , the version date should be changed accordingly.