On July 15, 2014, the FDA released a draft guidance document (“Guidance”), proposing recommendations to Institutional Review Boards (IRBs), clinical investigators and research sponsors relating to the informed consent process for FDA-regulated clinical studies.^[1] Once finalized, the Guidance will supersede FDA’s previous informed consent guidance issued in 1998. The Guidance discusses basic elements of informed consent and offers suggestions as to approaches that IRBs, clinical investigators and sponsors may follow to ensure that the informed consent process is adequately carried out. Throughout the Guidance, the FDA emphasizes that ensuring informed consent is a continuing responsibility rather than an act of simply obtaining a study subject’s signature on a consent form, and that such responsibility poses unique and important challenges in certain circumstances, including when significant new findings in a study reveal additional risks of participation, and in cases of subjects with diminished or fluctuating consent capacity (among other circumstances).

FDA Informed Consent Regulations

The Guidance discusses individual provisions of informed consent regulations pertaining to FDA-regulated clinical research (at 21 C.F.R. Part 50) and provides illustrations of both acceptable and unacceptable methods and forms for satisfying these informed consent requirements.

For example, as noted in the Guidance, the informed consent process must: allow a subject sufficient opportunity to consider whether to participate in a study; minimize the potential for coercion and undue influence; provide information to the subject in a language understandable to the subject; not include exculpatory language whereby a subject is made to waive any of his or her legal rights; and not include statements that claim investigational test articles are safe or effective for the purpose for which they are being investigated. Illustrating these requirements, the Guidance notes that statements such as “FDA has given permission for the clinical investigation to proceed” should be avoided because they may contribute to the impression that the investigation has FDA’s endorsement. To illustrate the exculpatory language prohibition, the Guidance notes the following as an example of language that cannot appear in consent forms: “In the event that you suffer a research-related injury, your medical expenses will be your responsibility or that of your third party payer.”

The Guidance also contains interesting recommendations about the required basic elements to be included in informed consent forms. For example, the Guidance notes that it may be difficult to fully describe a complex, lengthy clinical study^[2] without overwhelming a subject with information. In this circumstance, the FDA suggests limiting the information in the consent form to a general description of study procedures, and leaving the more detailed information (such as procedures applicable to each individual study visit) to be included in an addendum. The Guidance also notes that alternatives to participation in the research study^[3] may be difficult to describe (e.g., for a study involving an investigational product for an aggressive cancer, the alternative to study participation may be a complex combination of standard treatments). The FDA suggests that in such circumstances it may be appropriate to refer the subject to a health care professional in order to ensure that the subject receives an adequate description of alternatives to participating in the study. With respect to description of risks and benefits^[4], the FDA notes that if applicable, the consent document should include a description of the reasonably foreseeable risks not only to the subject but also to “others” (for example, radiation therapy, where close proximity to subjects post procedure may pose some risk to others).

The Guidance also discusses additional elements of informed consent that are included, as appropriate, pursuant to 21 C.F.R. 50.25 (b) – i.e., (i) that the study involves unforeseeable risks to the subject; (ii) anticipated circumstances under which the subject’s participation in the study may be involuntarily terminated by the investigator; (iii) additional costs to the subject resulting from participation in the study; (iv) consequences to the subject of withdrawing from participation; (v) that significant new findings in the study potentially affecting the subject’s willingness to continue participating will be communicated to the subject; and (vi) the approximate number of subjects involved in the study. The Guidance notes that to satisfy element (ii) above, a broad statement indicating that a subject’s participation may be terminated at any time will not suffice; rather, a description of specific situations that would trigger termination of the subject’s participation is required. For example, the Guidance indicates that an informed consent document may state that a subject’s participation may be terminated if the subject consistently fails to attend protocol-required visits or follow device or dosing instructions. Regarding element (v), the type of study being conducted should determine whether to include in the consent document a statement that significant new findings will be relayed to the subject. For instance, it would be appropriate to include this statement where the study involves novel therapies or significant risk.

Responsibilities of the IRB, Clinical Investigator and Sponsor in Ensuring Informed Consent

Although the IRB, investigator and sponsor each has distinct responsibilities in ensuring that adequate informed consent is obtained and maintained, the Guidance makes clear that coordination among them is critical in performing certain functions. Below is a list of circumstances under which a coordinated effort facilitates an effective informed consent process:

• Subject Recruitment: Under FDA regulations, in recruiting subjects, investigators are required to obtain legally effective informed consent - and IRBs are required to review all recruitment materials and information provided to subjects. As such, investigators and IRBs have an interest in working cooperatively to develop a plan that utilizes appropriate recruitment material and is sensitive to issues such as avoiding coercion and undue influence, particularly in advertising study participation and in describing payment that subjects may receive as a result of participation.

• Re-consents: When new information about a study is discovered which may affect subjects’ continued willingness to participate and consequently require re-consenting those subjects, the IRB must approve of the revised consent form. Coordination between the investigator and sponsor to closely monitor study data and promptly report significant new findings to the IRB provides the IRB opportunity to timely reassess the welfare and safety of subjects, approve of a revised consent form when appropriate, and facilitate ongoing efficient conduct of the study.

• Informed Consent Form Standard Language: An investigator’s institution may have requirements that specified standard language appear in any informed consent form (e.g., language relating to confidentiality of subjects’ records). If either a sponsor or investigator prepares an informed consent form, they should coordinate with the IRB to ensure that such institutional requirements are satisfied prior to the IRB’s initial review of the form.

• Consent Forms Submitted for FDA Review: In some circumstances, sponsors are required to submit informed consent materials to the FDA. Generally, when informed consent materials are submitted, FDA reviews them to assure that they appropriately communicate reasonably foreseeable safety issues and other required elements. If the FDA finds a consent form to be misleading, inaccurate or incomplete, it directs comments to the sponsor, and may require the sponsor to submit a revised form prior to the study commencement. However, FDA’s review of the consent form does not substitute for the responsibility or authority of the IRB to review and approve the consent form and process. Upon receipt of FDA comments, the sponsor should promptly share them, as well as informed consent revisions, with the investigator so that the investigator may assure that the revised form is submitted to the IRB for approval.

• Study Suspension: When a study is suspended for safety or other reasons, the IRB, investigator and sponsor should consider what, if any, information should be shared with subjects to ensure that their rights and welfare are protected and enable them to consider whether to continue participating in the study. This consideration may be affected by factors such as whether the test article in the study holds out the prospect of conferring a direct benefit to the subject, or whether transition to medical management outside the research context may be in the best interest of the subject. The Guidance notes that in addition to the IRB, investigator and sponsor collaborating in this effort, involving subjects’ treating physicians may be advisable under certain circumstances, as well.

Documentation of Informed Consent

With limited exceptions, informed consent must be documented in a signed and dated written consent form. The Guidance notes that a subject’s electronic signature on a consent form is permissible provided it is in compliance with 21 CFR Part 11. The Guidance additionally describes the importance of the requirement that a subject date the consent form upon giving consent so that it is documented that the consent occurred prior to the subject’s participation in the study.

Use of a long form or short form consent document may be an important consideration depending on the subject demographic for a study, as the Guidance illustrates. By way of background, a long form embodies all elements of informed consent required under FDA regulations, while a short form simply states that elements of informed consent were presented orally to the subject. The oral presentation must be witnessed (preferably by an impartial third party), and a written summary of that oral presentation must be provided to the subject, although the subject is required to sign the short form only and not the summary document.

Use of a short form may be appropriate with subjects who are blind or unable to read due to illiteracy. A translated short form may also be useful when obtaining consent from subjects who do not speak or understand English. As the Guidance recognizes, however, the investigator and IRB often cannot reasonably anticipate enrollment of a subject for whom translation of a consent document is needed. This becomes a problem when the timeframe for subject enrollment is too short for the investigator to obtain the IRB’s approval of the translated consent documents. The Guidance suggests the following approach in such a situation:

• The IRB arranges ahead of time for use of a generic short form in multiple languages and prospectively approves the use of such short forms for enrollment of subjects who do not understand English, as needed for any research protocol.

• The investigator, in consultation with the IRB Chair (or designee), determines that there is sufficient justification to use this short form without waiting for the IRB’s approval of a translated long form document (e.g., there is a limited therapeutic window).

• The investigator obtaining informed consent, with assistance of an interpreter if needed, provides orally to the subject the required elements of informed consent, and any additional pertinent information in the IRB-approved English version of the long form, in the presence of a witness who is fluent in the language of the oral presentation.

• The subject signs and dates the IRB-approved translated short form document and is provided the short form and a copy of the IRB-approved English version of the long form.

• The witness signs both the short and long forms.

• The person obtaining consent signs the long form.

• After the subject has been enrolled in the study, the investigator promptly seeks preparation of a translated version of the IRB-approved English version of the long form, obtains the IRB’s approval of that translated document, and provides it to the subject.

What's Next?

Comments on the Guidance are due by September 15, 2014. The Guidance indicates that the FDA is particularly interested in receiving comments regarding methods of obtaining informed consent that are alternative to the traditional face-to-face interview and signed paper consent form. With advanced technologies--video conferencing, web portals, and mobile applications, to name a few--that are capable of contributing to or detracting from the informed consent process, it will be interesting to note forthcoming comments on this subject and the FDA’s response to them. Stay tuned for an additional alert once the Guidance is finalized.

The Guidance is available for review on the FDA’s website, or through the following link.

_{^[1] In the draft guidance, the FDA recognizes that the Office of Human Research Protections (OHRP) has explored, and continues to explore, changes to the Common Rule -- regulations relating to the safety, ethics and oversight of research -- and that FDA plans to coordinate with OHRP and other agencies to the extent future changes to the Common Rule may intersect with the FDA’s informed consent guidance.}

_{^[2] Description of the study is required by 21 C.F.R. 50.25(a)(1).}

_{^[3] Description of alternative procedures or treatments is required by 21 C.F.R. 50.25 (a)(4).}

_{^[4] Description of reasonably foreseeable risks or discomforts is required by 21 C.F.R. 50.25 (a)(2).}