Are active comparables reviewable? Yes, active comparables are reviewable, and this process is essential for ensuring the protection of human subjects in research. compare.edu.vn offers detailed comparisons and analyses to help you understand the review process, ensuring transparency and adherence to regulations. Understanding IRB reviews, regulatory compliance, and ethical considerations is crucial for successful research.
1. Understanding Institutional Review Boards (IRBs)
1.1. What Is an Institutional Review Board (IRB)?
An Institutional Review Board (IRB) is a formally designated group constituted to review and monitor biomedical research involving human subjects. According to FDA regulations, an IRB is authorized to approve, require modifications to secure approval, or disapprove research. This group review is vital in safeguarding the rights and welfare of human research participants.
The primary goal of IRB review is to guarantee, both in advance and through periodic reviews, that appropriate measures are in place to protect the rights and welfare of individuals participating in research. To achieve this, IRBs employ a group process to evaluate research protocols and related materials, such as informed consent documents and investigator brochures, ensuring the protection of human subjects’ rights and well-being.
1.2. Do IRBs Need to Be Formally Called by That Name?
No, the term “IRB” is a generic term used by the FDA (and HHS) to refer to any group whose function is to review research to assure the protection of the rights and welfare of human subjects. Each institution can choose its preferred name. Regardless of the name, the IRB is subject to the Agency’s IRB regulations when studies of FDA-regulated products are reviewed and approved.
1.3. Does an IRB Need to Register with FDA Before Approving Studies?
Yes, as mandated by the amendment to 21 CFR Part 56, Institutional Review Boards, published in the Federal Register on January 15, 2009, (74 FR 2358), IRB registration is required [21 CFR 56.106]. Each IRB in the United States (U.S.) that reviews FDA-regulated studies must register. This registration information is entered into an Internet-based system maintained by the Department of Health and Human Services (HHS). For further details, see the Guidance for Institutional Review Boards (IRBs) Frequently Asked Questions – IRB Registration.
1.4. What Is an “Assurance” or a “Multiple Project Assurance?”
An “assurance” is a document negotiated between an institution and the Department of Health and Human Services (HHS) following HHS regulations. For research involving human subjects conducted by or supported by HHS, these regulations require a written assurance from the performance-site institution that it will comply with HHS protection of human subjects regulations [45 CFR part 46]. The assurance mechanism is detailed in 45 CFR 46.103. Once HHS approves an institution’s assurance, a number is assigned to it. The assurance may cover a single grant or contract (a “single project assurance”), multiple grants (“multiple project assurances,” formerly called “general assurances”), or specific study types like oncology or AIDS research (“cooperative project assurances”). The Office for Human Research Protection (OHRP) is responsible for enforcing HHS regulations. The contact details for OHRP are: 1101 Wootton Parkway, The Tower Building, Suite 200, Rockville, MD 20852; Toll-Free Telephone within the U.S.: (866) 447-4777, Telephone: (240) 453-6900, FAX: (240) 453-6909.
1.5. Is an “Assurance” Required by FDA?
No, currently, FDA regulations do not mandate an assurance. FDA regulations [21 CFR parts 50 and 56] apply to research involving FDA-regulated products, regardless of federal funding or support. When research studies involving FDA-regulated products are funded or supported by HHS, the research institution must adhere to both HHS and FDA regulations. A table of significant differences between 45 CFR Part 46, Subpart A and 21 CFR Parts 50 and 56 is available on the FDA website.
1.6. Must an Institution Establish Its Own IRB?
No. While institutions engaged in research involving human subjects commonly have their own IRBs, FDA regulations allow an institution without an IRB to arrange for an “outside” IRB to oversee studies. These arrangements should be documented in writing. Individuals in non-institutional settings often use established IRBs (independent or institutional) rather than forming their own. Also, review the information sheets entitled “Non-local IRB Review” and “Cooperative Research.”
1.7. May a Hospital IRB Review a Study Conducted Outside the Hospital?
Yes, IRBs can review research from affiliated or unaffiliated investigators, but FDA does not mandate this. If the IRB routinely conducts such reviews, its policies should authorize this, and the process should be described in written procedures. A hospital IRB may review outside studies if the minutes show the members are aware of the study’s location and possess appropriate knowledge about the study site(s).
1.8. May IRB Members Be Paid for Their Services?
FDA regulations do not prevent compensating members for their services, provided the payment is not contingent upon a favorable decision. Expenses, such as travel costs, may also be reimbursed.
1.9. What Is the FDA Role in IRB Liability in Malpractice Suits?
FDA regulations do not address IRB or institutional liability in malpractice suits. The FDA does not have the authority to limit IRB or member liability, but compliance with FDA regulations may help minimize potential liability.
1.10. Is the Purpose of the IRB Review of Informed Consent to Protect the Institution or the Subject?
The fundamental purpose of IRB review of informed consent is to ensure the protection of the rights and welfare of subjects. A signed informed consent document is evidence that the document has been provided and explained to the subject and that the subject has agreed to participate. IRB review also ensures institutional compliance with applicable regulations.
1.11. Does an IRB or Institution Have to Compensate Subjects if Injury Occurs as a Result of Participation in a Research Study?
Institutional policy, not FDA regulation, determines whether compensation and medical treatments will be offered. The FDA informed consent regulation on compensation [21 CFR 50.25(a)(6)] requires that, for research involving more than minimal risk, the subject must be informed whether any compensation and medical treatments are available if injury occurs, and if so, what they are, or where further information may be obtained. Statements that compensation is not offered must avoid waiving any of the subject’s rights or releasing the investigator, sponsor, or institution from liability for negligence [21 CFR 50.20].
2. IRB Membership
2.1. May a Clinical Investigator Be an IRB Member?
Yes, but IRB regulations [21 CFR 56.107(e)] prohibit any member from participating in the initial or continuing review of any study in which they have a conflicting interest, except to provide information requested by the IRB. Potential conflicts of interest should be considered when selecting IRB members. Frequent conflicts can diminish contributions to the review process and hinder the procedure, especially if the person is the IRB chairperson.
2.2. May One Member Satisfy More Than One Membership Category?
Yes. For example, a member could be unaffiliated with the institution and have a primary concern in a non-scientific area, satisfying two membership requirements. However, IRBs should strive for a diverse membership with varied representative capacities and disciplines.1
2.3. When IRB Members Cannot Attend a Convened Meeting, May They Send Someone from Their Department to Vote for Them?
No. Formally appointed alternates listed in the membership roster may substitute, but ad hoc substitutes are not permissible. However, a member unable to attend may participate via video-conference or conference call if they have received the documents to be reviewed. These members may vote and be counted in the quorum. Ad hoc substitutes may attend as consultants to gather information but cannot be counted toward the quorum or participate in deliberation or voting. Opinions transmitted by mail, telephone, or email may be considered but not counted as votes or the quorum for convened meetings.
2.4. May the IRB Use Alternate Members?
The use of formally appointed alternate IRB members is acceptable to the FDA, provided that the IRB’s written procedures describe the appointment and function of alternate members. The IRB roster should identify the primary member(s) for whom each alternate member may substitute. To ensure maintaining an appropriate quorum, the alternate’s qualifications should be comparable to the primary member to be replaced. The IRB minutes should document when an alternate member replaces a primary member. When alternates substitute for a primary member, the alternate member should have received and reviewed the same material that the primary member received or would have received.
2.5. Does a Non-Affiliated Member Need to Attend Every IRB Meeting?
No. While 21 CFR 56.108(c) does not explicitly require the presence of a non-affiliated member to constitute a quorum, FDA considers their presence an important element of the IRB’s diversity. Frequent absence of all non-affiliated members is not acceptable to FDA. Many IRBs appoint more than one non-affiliated member. FDA encourages IRBs to appoint members in accordance with 21 CFR 56.107(a) who will be able to participate fully in the IRB process.
2.6. Which IRB Members Should Be Considered Scientists and Non-Scientists?
21 CFR 56.107(c) requires at least one IRB member to have primary concerns in a scientific area and one in a non-scientific area. Most IRBs include physicians and Ph.D.-level scientists, satisfying the scientist requirement. When a study involves science beyond the members’ expertise, the IRB may use a consultant as provided by 21 CFR 56.107(f).
FDA believes the requirement for diversity of disciplines was intended to include members with little or no scientific or medical training. Therefore, nurses, pharmacists, and other biomedical health professionals should not be regarded as having “primary concerns in the non-scientific area.” Lawyers, clergy, and ethicists have been cited as examples of persons whose primary concerns would be in non-scientific areas.
Some members have training in both scientific and non-scientific disciplines, such as a J.D., R.N. While such members are valuable, other members who are unambiguously non-scientific should be appointed to satisfy the non-scientist requirement.
3. IRB Procedures
3.1. What Does “Subsequent Use” Mean?
The FDA regulations [21 CFR 56.104(c)] exempt an emergency use of a test article from prospective IRB review, however, “… any subsequent use of the test article at the institution is subject to IRB review.” FDA regulations allow one emergency use of a test article without prospective IRB review, provided the emergency use is reported to the IRB within five working days. An emergency use is a single use (or single course of treatment) with one subject. “Subsequent use” would be a second use with that subject or the use with another subject.
If the test article may be used again, the IRB should request a protocol and consent document(s) be developed. FDA believes it is inappropriate to deny emergency treatment when the only obstacle is lack of time for IRB review and approval.
3.2. Are Clinical Investigators Required to Report Study Completion to the IRB?
IRBs must function under written procedures, including ensuring “prompt reporting to the IRB of changes in a research activity” [21 CFR 56.108(a)(3)]. Study completion is a change in activity and should be reported to the IRB. This allows the IRB to close its files and provides information for evaluating and approving related studies.
3.3. What Is Expedited Review?
Expedited review is a procedure where certain research may be reviewed and approved without convening an IRB meeting. FDA regulations [21 CFR 56.110] permit an IRB to review certain research through an expedited procedure if it involves no more than minimal risk. A list of categories was last published in the Federal Register on January 27, 1981 [46 FR 8980].
The IRB may also use expedited review for minor changes in previously approved research. Review may be carried out by the IRB chairperson or designated experienced members. The reviewer(s) may exercise all the IRB’s authorities except disapproval, which requires review by the full committee. The IRB must keep all members advised of studies approved by expedited review.
3.4. Must the Full Review Package Be Sent to All IRB Members?
The IRB system was designed for open discussion and debate at convened meetings. While it is preferable for every IRB member to have personal copies of all study materials, each member must be provided with sufficient information to be able to actively and constructively participate. Some institutions use a “primary reviewer” system, where studies are assigned to one or more IRB members for a full review. The study is then presented by the primary reviewer(s) at the meeting, followed by discussion and a vote.
The “primary reviewer” procedure is acceptable if each member receives at least a copy of consent documents and a summary of the protocol in sufficient detail to determine the appropriateness of the study-specific statements in the consent documents. The complete documentation should be available to all members before and during the meeting, with materials received sufficiently in advance for adequate review.
Some IRBs are exploring electronic submissions and computer access for IRB members. Whatever system is used, it must ensure adequate review and protection of subjects’ rights and welfare.
3.5. Are Sponsors Allowed Access to IRB Written Procedures, Minutes, and Membership Rosters?
FDA regulations do not require public or sponsor access to IRB records but do not prohibit the sponsor from requesting them. The IRB and institution may establish a policy on providing minutes or pertinent portions to sponsors. IRBs must be aware of state and local laws regarding access to IRB records.
3.6. Must an Investigator’s Brochure Be Included in the Documentation When an IRB Reviews an Investigational Drug Study?
For studies conducted under an investigational new drug application, an investigator’s brochure is usually required by FDA [21 CFR 312.23(a)(5) and 312.55]. Even though 21 CFR part 56 does not mention the investigator’s brochure by name, much of the information contained in such brochures is clearly required to be reviewed by the IRB. The regulations outline the criteria for IRB approval of research. 21 CFR 56.111(a)(1) requires the IRB to assure that risks to the subjects are minimized. 21 CFR 56.111(a)(2) requires the IRB to assure that the risks to subjects are reasonable in relation to the anticipated benefits. The risks cannot be adequately evaluated without review of the results of previous animal and human studies, which are summarized in the investigator’s brochure.
There is no specific regulatory requirement that the Investigator’s Brochure be submitted to the IRB. There are regulatory requirements for submission of information which normally is included in the Investigator’s Brochure. It is common that the Investigator’s Brochure is submitted to the IRB, and the IRB may establish written procedures which require its submission. Investigator’s Brochures may be part of the investigational plan that the IRB reviews when reviewing medical device studies.
3.7. To What Extent Is the IRB Expected to Actively Audit and Monitor the Performance of the Investigator with Respect to Human Subject Protection Issues?
FDA does not expect IRBs to routinely observe consent interviews, study conduct, or review study records. However, 21 CFR 56.109(f) gives the IRB the authority to observe the consent process and the research. If the IRB is concerned about study conduct or the consent process, it may consider whether an active audit is warranted.
3.8. How Can a Sponsor Know Whether an IRB Has Been Inspected by FDA, and the Results of the Inspection?
The Division of Scientific Investigations, Center for Drug Evaluation and Research, maintains an inventory of inspected IRBs, including inspection dates and classifications. The Division recently began including results of inspections assigned by the Center for Biologics Evaluation and Research and the Center for Devices and Radiological Health. This information is available through Freedom of Information Act (FOIA) procedures. Once an investigational file has been closed, the correspondence between FDA and the IRB and the narrative inspectional report are also available under FOI.
3.9. If an IRB Disapproves a Study, Should the Second IRB Be Told of the Disapproval?
Yes. When an IRB disapproves a study, it must provide a written statement of the reasons for its decision to the investigator and the institution [21 CFR 56.109(e)]. If the study is submitted to a second IRB, a copy of this written statement should be included with the study documentation so that it can make an informed decision about the study. 21 CFR 56.109(a) requires an IRB to “… review … all research activities [emphasis added] ….” The FDA regulations do not prohibit submission of a study to another IRB following disapproval. However, all pertinent information about the study should be provided to the second IRB.
3.10. May an Independent IRB Review a Study to Be Conducted in an Institution with an IRB?
Generally, no. Most institutional IRBs have jurisdiction over all studies conducted within that institution. An independent IRB may become the IRB of record for such studies only upon written agreement with the administration of the institution or the in-house IRB.
3.11. Could an IRB Lose Its Quorum When Members with a Conflict of Interest Leave the Room for Deliberation and Voting on a Study?
Yes. “The quorum is the count of the number of members present. If the number present falls below a majority, the quorum fails. The regulations only require that a member who is conflicted not participate in the deliberations and voting on a study on which he or she is conflicted. The IRB may decide whether an individual should remain in the room.”
3.12. Does FDA Expect the IRB Chair to Sign the Approval Letters?
FDA does not specify the procedure that IRBs must use regarding signature of the IRB approval letter. The written operating procedures for the IRB should outline the procedure that is followed.
3.13. Does FDA Prohibit Direct Communication Between Sponsors and IRBs?
It is important that a formal line of communication be established between the clinical investigator and the IRB. Clinical investigators should report adverse events directly to the responsible IRB, and should send progress reports directly to that IRB. However, FDA does not prohibit direct communication between the sponsor and the IRB, and recognizes that doing so could result in more efficient resolution of some problems.
FDA does require direct communication between the sponsors and the IRBs for certain studies of medical devices and when the 21 CFR 50.24 informed consent waiver has been invoked. Sponsors and IRBs are required to communicate directly for medical device studies under 21 CFR 812.2, 812.66 and 812.150(b). For informed consent waiver studies, direct communication between sponsors and IRBs is required under 21 CFR 50.24(e), 56.109(e), 56.109(g), 312.54(b), 312.130(d), 812.38(b)(4) and 812.47(b).
4. IRB Records
4.1. Are Annual IRB Reviews Required When All Studies Are Reviewed by the IRB Each Quarter?
The IRB records for each study’s initial and continuing review should note the frequency (not to exceed one year) for the next continuing review in either months or other conditions, such as after a particular number of subjects are enrolled.
An IRB may decide to review all studies on a quarterly basis. If every quarterly report contains sufficient information for an adequate continuing review and is reviewed by the IRB under procedures that meet FDA requirements for continuing review, FDA would not require an additional “annual” review.
4.2. Is the “Research Proposal” the Same as the Formal Study Protocol?
21 CFR 56.115(a)(1) requires the IRB to maintain copies of “research proposals reviewed.” Yes. The IRB should receive and review all research activities [21 CFR 56.109(a)]. The documents reviewed should include the complete documents received from the clinical investigator, such as the protocol, the investigator’s brochure, a sample consent document, and any advertising. Some IRBs also require the investigator to submit an institutionally developed protocol summary form. A copy of all documentation reviewed is to be maintained for at least three years after the completion of the research at that institution [21 CFR 56.115(b)]. However, when the IRB makes changes, such as in the wording of the informed consent document, only the finally approved copy needs to be retained in the IRB records.
4.3. What IRB Records Are Required for Studies That Are Approved but Never Started?
When an IRB approves a study, continuing review should be performed at least annually. All records listed in 21 CFR 56.115(a)(1) – (4) are required to be maintained. The clock starts on the date of approval, whether or not subjects have been enrolled. Written progress reports should be received from the clinical investigator for all studies that are in approved status prior to the date of expiration of IRB approval. If subjects were never enrolled, the clinical investigator’s progress report would be brief. Such studies may receive continuing IRB review using expedited procedures. If the study is finally canceled without subject enrollment, records should be maintained for at least three years after cancellation [21 CFR 56.115(b)].
5. Informed Consent Process
5.1. Is Getting the Subject to Sign a Consent Document All That Is Required by the Regulations?
No. The consent document is a written summary of the information that should be provided to the subject. Many clinical investigators use the consent document as a guide for the verbal explanation of the study. The subject’s signature provides documentation of agreement to participate in a study but is only one part of the consent process. The entire informed consent process involves giving a subject adequate information concerning the study, providing adequate opportunity for the subject to consider all options, responding to the subject’s questions, ensuring that the subject has comprehended this information, obtaining the subject’s voluntary agreement to participate and continuing to provide information as the subject or situation requires. To be effective, the process should provide ample opportunity for the investigator and the subject to exchange information and ask questions.
5.2. May Informed Consent Be Obtained by Telephone from a Legally Authorized Representative?
A verbal approval does not satisfy the 21 CFR 56.109(c) requirement for a signed consent document, as outlined in 21 CFR 50.27(a). However, it is acceptable to send the informed consent document to the legally authorized representative (LAR) by facsimile and conduct the consent interview by telephone when the LAR can read the consent as it is discussed. If the LAR agrees, he/she can sign the consent and return the signed document to the clinical investigator by facsimile.
5.3. Does the Consent Document Have to Be a Photocopy of the Form with the Subject’s Signature Affixed?
21 CFR 50.27(a) requires that a copy of the consent document be given to the person signing the form. No. The regulation does not require the copy of the form given to the subject to be a copy of the document with the subject’s signature, although this is encouraged. It must, however, be a copy of the IRB approved document that was given to the subject to obtain consent [21 CFR 50.27(a) or 21 CFR 50.27(b)(2)]. One purpose of providing the person signing the form with a copy of the consent document is to allow the subject to review the information with others, both before and after making a decision to participate in the study, as well as providing a continuing reference for items such as scheduling of procedures and emergency contacts.
5.4. If an IRB Uses a Standard “Fill-In-The-Blank” Consent Format, Does the IRB Need to Review the Filled Out Form for Each Study?
Yes. A fill-in-the-blank format provides only some standard wording and a framework for organizing the relevant study information. The IRB should review a completed sample form, individualized for each study, to ensure that the consent document, in its entirety, contains all the information required by 21 CFR 50.25 in language the subject can understand. The completed sample form should be typed to enhance its readability by the subjects. The form finally approved by the IRB should be an exact copy of the form that will be presented to the research subjects. The IRB should also review the “process” for conducting the consent interviews, i.e., the circumstances under which consent will be obtained, who will obtain consent, and so forth.
5.5. Does the Informed Consent Document Waive the Subject’s Legal Right to Privacy?
The informed consent regulations [21 CFR 50.25 (a)(5)] require the consent document to include a statement that notes the possibility that FDA may inspect the records. No. FDA does not require any subject to “waive” a legal right. Rather, FDA requires that subjects be informed that complete privacy does not apply in the context of research involving FDA-regulated products. Under the authority of the Federal Food, Drug, and Cosmetic Act, FDA may inspect and copy clinical records to verify information submitted by a sponsor. FDA generally will not copy a subject’s name during the inspection unless a more detailed study of the case is required or there is reason to believe that the records do not represent the actual cases studied or results obtained.
The consent document should not state or imply that FDA needs clearance or permission from the clinical investigator, the subject, or the IRB for such access. When clinical investigators conduct studies for submission to FDA, they agree to allow FDA access to the study records, as outlined in 21 CFR 312.68 and 812.145. Informed consent documents should make it clear that, by participating in research, the subject’s records automatically become part of the research database. Subjects do not have the option to keep their records from being audited/reviewed by FDA.
When an individually identifiable medical record (usually kept by the clinical investigator, not by the IRB) is copied and reviewed by the Agency, proper confidentiality procedures are followed within FDA. Consistent with laws relating to public disclosure of information and the law enforcement responsibilities of the Agency, however, absolute confidentiality cannot be guaranteed.
5.6. Who Should Be Present When the Informed Consent Interview Is Conducted?
FDA does not require a third person to witness the consent interview unless the subject or representative is not given the opportunity to read the consent document before it is signed, see 21 CFR 50.27(b). The person who conducts the consent interview should be knowledgeable about the study and able to answer questions. FDA does not specify who this individual should be. Some sponsors and some IRBs require the clinical investigator to personally conduct the consent interview. However, if someone other than the clinical investigator conducts the interview and obtains consent, this responsibility should be formally delegated by the clinical investigator, and the person so delegated should have received appropriate training to perform this activity.
5.7. How Do You Obtain Informed Consent from Someone Who Speaks and Understands English but Cannot Read?
Illiterate persons who understand English may have the consent read to them and “make their mark,” if appropriate under applicable state law. The 21 CFR 50.27(b)(2) requirements for the signature of a witness to the consent process and the signature of the person conducting the consent interview must be followed if a “short form” is used. Clinical investigators should be cautious when enrolling subjects who may not truly understand what they have agreed to do. The IRB should consider illiterate persons as likely to be vulnerable to coercion and undue influence and should determine that appropriate additional safeguards are in place when enrollment of such persons is anticipated, see 21 CFR 56.111(b).
5.8. Must a Witness Observe the Entire Consent Interview or Only the Signature of the Subject?
FDA does not require the signature of a witness when the subject reads and is capable of understanding the consent document, as outlined in 21 CFR 50.27(b)(1). The intended purpose is to have the witness present during the entire consent interview and to attest to the accuracy of the presentation and the apparent understanding of the subject. If the intent of the regulation were only to attest to the validity of the subject’s signature, witnessing would also be required when the subject reads the consent.
5.9. Should the Sponsor Prepare a Model Informed Consent Document?
Although not required by the IND regulations, the sponsor provides a service to the clinical investigator and the IRB when it prepares suggested study-specific wording for the scientific and technical content of the consent document. However, the IRB has the responsibility and authority to determine the adequacy and appropriateness of all of the wording in the consent, see 21 CFR 56.109(a), 111(a)(4), and 111(a)(5). If an IRB insists on wording the sponsor cannot accept, the sponsor may decide not to conduct the study at that site. For medical device studies that are conducted under an IDE, copies of all forms and informational materials to be provided to subjects to obtain informed consent must be submitted to FDA as part of the IDE, see 21 CFR 812.25(g).
5.10. Is the Sponsor Required to Review the Consent Form Approved by the IRB to Make Sure All FDA Requirements Are Met?
For investigational devices, the informed consent is a required part of the IDE submission. It is, therefore, approved by FDA as part of the IDE application. When an IRB makes substantive changes in the document, FDA reapproval is required, and the sponsor is necessarily involved in this process.
FDA regulations for other products do not specifically require the sponsor to review IRB-approved consent documents. However, most sponsors do conduct such reviews to assure the wording is acceptable to the sponsor.
5.11. Are There Alternatives to Obtaining Informed Consent from a Subject?
The regulations generally require that the investigator obtain informed consent from subjects. Investigators also may obtain informed consent from a legally authorized representative of the subject. FDA recognizes that a durable power of attorney might suffice as identifying a legally authorized representative under some state and local laws. For example, a subject might have designated an individual to provide consent with regard to health care decisions through a durable power of attorney and have specified that the individual also has the power to make decisions on entry into research. FDA defers to state and local laws regarding who is a legally authorized representative. Therefore, the IRB should assure that the consent procedures comply with state and local laws, including assurance that the law applies to obtaining informed consent for subjects participating in research as well as for patients who require health care decisions.”
Alternatives 1 and 2 are provided for in the regulations and are appropriate. Alternative 3 allows a designated individual to provide consent for a patient with regard to health care decisions and is appropriate when it specifically includes entry into research. FDA defers to state and local laws regarding substituted consent. Therefore, the IRB must assure itself that the substituted consent procedures comply with state and local law, including assurance the law applies to obtaining informed consent for subjects participating in research as well as for patients who require health care decisions.
5.12. When Should Study Subjects Be Informed of Changes in the Study?
Protocol amendments must receive IRB review and approval before they are implemented, unless an immediate change is necessary to eliminate an apparent hazard to the subjects (21 CFR 56.108(a)(4)). Those subjects who are presently enrolled and actively participating in the study should be informed of the change if it might relate to the subjects’ willingness to continue their participation in the study (21 CFR 50.25(b)(5)). FDA does not require reconsenting of subjects that have completed their active participation in the study or of subjects who are still actively participating when the change will not affect their participation, for example, when the change will be implemented only for subsequently enrolled subjects.
6. Informed Consent Document Content
6.1. May an IRB Require That the Sponsor of the Study and/or the Clinical Investigator Be Identified on the Study’s Consent Document?
Yes. The FDA requirements for informed consent are the minimum basic elements of informed consent that must be presented to a research subject [21 CFR 50.25]. An IRB may require inclusion of any additional information which it considers important to a subject’s decision to participate in a research study [21 CFR 56.109(b)].
6.2. Does FDA Require the Informed Consent Document to Contain a Space for Assent by Children?
No, however, many investigators and IRBs consider it standard practice to obtain the agreement of older children who can understand the circumstances before enrolling them in research. While the FDA regulations do not specifically address the enrollment of children (other than to include them as a class of vulnerable subjects), the basic requirement of 21 CFR 50.20 applies, i.e., the legally effective informed consent of the subject or the subject’s legally authorized representative must be obtained before enrollment. Parents, legal guardians, and/or others may have the ability to give permission to enroll children in research, depending on applicable state and local law of the jurisdiction in which the research is conducted. (Note: permission to enroll in research is not the same as permission to provide medical treatment.) IRBs generally require investigators to obtain the permission of one or both of the parents or guardian (as appropriate) and the assent of children who possess the intellectual and emotional ability to comprehend the concepts involved. Some IRBs require two documents, a fully detailed explanation for parents and older children to read and sign, and a shorter, simpler one for younger children. [For research supported by DHHS, the additional protections at 45 CFR 46 Subpart D are also required. The Subpart D regulations provide appropriate guidance for all other pediatric studies.]
On April 24, 2001, FDA issued an interim final rule, Additional Protections for Children, as subpart D to 21 CFR Part 50. Assent by children is addressed in subpart D. This interim final rule and its preamble are available at Additional Protections for Children.
6.3. Does FDA Require the Signature of Children on Informed Consent Documents?
As indicated above, researchers may seek the assent of children of various ages. Older children may be well acquainted with signing documents through prior experience with testing, licensing, and/or other procedures normally encountered in their lives. Signing a form to give their assent for research would not be perceived as unusual and would be reasonable. Younger children, however, may never have had the experience of signing a document. For these children, requiring a signature may not be appropriate, and some other technique to verify assent could be used. For example, a third party may verify, by signature, that the assent of the child was obtained.
As noted in the previous answer, on April 24, 2001, FDA issued an interim final rule, Additional Protections for Children, as subpart D to 21 CFR Part 50. Informed consent of children who participate in clinical trials is addressed in subpart D. This interim final rule and its preamble are available at Additional Protections for Children.
6.4. Who Should Be Listed on the Consent as the Contact to Answer Questions?
21 CFR 50.25(a)(7) requires contacts for questions about the research, the research subject’s rights, and in case of a research-related injury. It does not specify whom to contact. The same person may be listed for all three. However, FDA and most IRBs believe it is better to name a knowledgeable person other than the clinical investigator as the contact for study subject rights. Having the clinical investigator as the only contact may inhibit subjects from reporting concerns and/or possible abuses.
6.5. May the “Compensation” for Participation in a Trial Offered by a Sponsor Include a Coupon Good for a Discount on the Purchase Price of the Product Once It Has Been Approved for Marketing?
No. This presumes, and inappropriately conveys to the subjects, a certainty of favorable outcome of the study and prompt approval for marketing. Also, if the product is approved, the coupon may financially coerce the subject to insist on that product, even though it may not be the most appropriate medically.
6.6. Must Informed Consent Documents Be Translated into the Written Language Native to Study Subjects Who Do Not Understand English?
The signed
