The new article highlights aspects related to the role and responsibilities of the US regulatory authority with respect to informed consent to be obtained before commencing clinical investigations involving human subjects.
Table of Contents
The Food and Drug Administration (FDA or the Agency), the US regulating authority in the sphere of healthcare products, has published a guidance document dedicated to the concept of informed consent. The document provides an overview of the applicable regulatory requirements as well as additional recommendations and clarifications to be taken into consideration by medical device manufacturers, parties responsible for clinical investigations (study sponsors), and other parties involved in clinical investigations involving human subjects. It is also important to mention that the document and recommendations provided therein are non-binding in their legal nature, nor are they intended to introduce new rules or impose new obligations. Moreover, the authority explicitly states that an alternative approach could be applied, provided such an approach is in line with the existing regulatory framework and has been agreed upon with the authority in advance.
The document describes, inter alia, the aspects related to the responsibilities of the parties involved in the process and highlights the key considerations associated therewith.
FDA Role: Overview
First of all, the document mentions that the authority plays an important role when it comes to clinical investigations and the regulatory requirements to be followed in order to ensure the accuracy and reliability of their results, as well as the safety of study participants. According to the guidance, the sphere of responsibility of the authority covers various matters related to the submission processes and assessment criteria for informed consent materials in drug and device studies. These regulatory processes and criteria are established to ensure the protection of the subjects participating in clinical investigations.
Alternative Methods of Obtaining Informed Consent
The FDA acknowledges the technological advancements that offer alternative solutions for obtaining informed consent, as opposed to the traditional face-to-face methods using paper consent forms. Parties interested in exploring these alternatives and benefiting from the flexibility they could provide should consult with their IRB for approval. It is also suggested that they contact the FDA for additional advice.
Even when using paper forms, there may be exceptional circumstances, such as the subject or their LAR being unable to physically visit the investigational site, where alternative methods may be deemed suitable. In such instances, written documentation of informed consent is still mandated and cannot be replaced by oral communication alone, even via telephone. Methods other than a face-to-face discussion can be considered acceptable if they ensure the proper exchange and documentation of information.
For instance, the consent form could be sent via fax or email to the subject or their LAR, followed by a discussion conducted over the telephone or video conference. After such a discussion, the subject or their LAR can manually or electronically sign and date the consent form and return it through a secure electronic method. This signed document should then be maintained by a responsible entity as part of the subject’s case history, in strict accordance with the requirements set forth in regulations 21 CFR 312.62(b) and 812.140(a)(3).
Differentiating the Requirements
The FDA clearly distinguishes the regulations concerning the submission of informed consent materials, emphasizing that drug (including biologic products) investigations have requirements distinct from those applicable to device investigations. This distinction even further emphasizes the unique considerations and potential risks associated with different types of clinical investigations.
However, it is also important to mention that the FDA does not require informed consent materials for all clinical investigations as a standard practice but rather applies a differentiated approach in order to avoid imposing unnecessary regulatory burdens while ensuring the proper level of public health protection. Specific conditions and regulations, such as 21 CFR 312.2(b) and 21 CFR 812.2(b) and (c) outline the circumstances under which submissions become necessary, adding more complexity to the submission process the party responsible for a clinical investigation should follow in order to comply with the respective regulatory requirements.
Assessment Approach
The document further describes the approach the authority applies when reviewing the information and documentation submitted by the interested party. As explained by the authority, upon receipt of these materials, the FDA conducts a rigorous assessment in line with the relevant procedures. The said process is based on the criterion of adequate communication about the foreseeable risks or discomforts that participants might encounter in the context of the planned investigation. The appropriate requirements to be considered in this respect are outlined in the regulation 21 CFR 50.25.
However, the authority acknowledges that sometimes errors can take place. There are cases where the FDA finds discrepancies in the consent forms, categorizing them as misleading, incomplete, or inaccurate. Such discrepancies can jeopardize the entire clinical investigation, and the FDA may issue a request for explicit revisions to rectify these issues. This proactive intervention reiterates the FDA’s commitment to ensuring that the rights and safety of study participants are protected to the extent possible.
At the same time, the guidance also emphasizes that despite the important role the FDA plays in the review process, the assessment it conducts does not supersede or replace the authority or responsibility of the Institutional Review Board (IRB). The IRB remains responsible for reviewing the consent form and the entire consent process. The dual oversight mechanism provided by both the FDA and the IRB ensures that clinical investigations comply with the highest standards of ethics and safety.
FDA Areas of Review Explained
The guidance also describes in detail the specific aspects to be assessed by the authority when conducting a review related to a planned clinical investigation, depending on the product in question and its regulatory status.
Investigational New Drugs (IND) and Biologics
- Despite the stringent regulations, it is worth noting that the IND regulations do not require sponsors to always submit the consent form with the IND application. However, the FDA reserves the right to request this form from a sponsor, should it be reasonably necessary from a safety perspective.
- When reviewing the information and documentation, the authority will focus on treatment INDs, treatment protocols, and specific INDs such as the ones covered by the Exception From Informed Consent Requirements for Emergency Research. In particular, the FDA will assess compliance with the requirements set forth under 21 CFR 50.25.
- The authority also evaluates, inter alia, unique toxicities, any unusual known toxicities, the vulnerability of the study participants, specifics of study design, and postmarketing safety clinical trials. Each factor plays a critical role in determining the risk profile of the study and the adequacy of the informed consent materials.
Investigational Medical Devices
- According to the guidance, medical devices introduce a unique set of challenges and considerations. For those clinical studies that require an IDE application submission, the sponsor will be requested to provide all materials related to informed consent.
- Following its detailed review, the FDA might identify deficiencies in the consent form. Should that be the case, a party responsible for a clinical investigation would have to take all the steps necessary to ensure these deficiencies are duly repealed. The clinical investigation remains on hold until the sponsor adequately addresses and rectifies it.
In summary, the present FDA guidance describes the approach the authority will apply when reviewing submissions related to clinical investigations. According to the guidance, the oversight responsibilities are shared between the FDA and IRB in order to ensure all the important aspects are duly covered.
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