The new article highlights the most important aspects related to the investigation plan and the elements it should contain.
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 Investigational Device Exemptions (IDEs) in the context of early feasibility medical device clinical studies, including certain First in Human (FIH) studies. The document is intended to provide additional clarifications regarding the existing regulatory framework, as well as recommendations to be considered to achieve and sustain compliance thereto. However, the authority also mentions that the document is non-binding in its legal nature, nor intended to introduce new rules or requirements the parties involved should follow. Moreover, an alternative approach could be applied, provided such an approach is in line with the applicable legislation and has been agreed with the authority in advance.
Investigation Plan: Key Points
The scope of the guidance covers, inter alia, the aspects related to the investigation plan for early feasibility studies related to IDE applications. In particular, the authority describes the approach to be applied in the context of early feasibility studies. For instance, the authority states that the IDE application should contain an indication that it relates to an early feasibility study, while the latter should consider the specifics of the product in question. The FDA also encourages medical device manufacturers to follow the Pre-Submission pathway to obtain feedback at the early development stages. The authority explicitly states that small clinical trials to determine device feasibility are specifically excluded from the definition of “applicable device clinical trials” requiring registration on [the respective portal].
Risk Analysis and Mitigation
According to the guidance, the Investigation Plan should contain a detailed assessment of all the risks associated with the product, as well as the information regarding the measures implemented to mitigate these risks, together with the justification explaining why the risks are acceptable. Apart from this, the applicant should outline the benefits associated with the use of the device in question, and also the details about the risks associated with the potential failure of the device and the disease itself. As further explained by the FDA, for an early feasibility study, the methods to minimize risks may include the use of standard approaches, with additional mitigation strategies to protect individual study subjects and future study participants during the ongoing early feasibility study. The document further provides examples of such mitigation strategies including, inter alia, the following ones:
- Conducting studies in facilities that are capable to overcome potential incidents that may take place;
- Engaging healthcare professionals having necessary knowledge and training;
- Collecting the information related to human factors, and later considering it when making changes to the device in question;
- Specifying appropriate study inclusion and exclusion criteria;
- Using a reasonable number of samples;
- Continuous monitoring of the safety and effectiveness of a medical device;
- Reporting severe adverse events promptly as prescribed by the applicable regulatory requirements;
- Submitting reports confirming that the product operates as intended;
- Involving study subjects that are falling within the scope of the target audience, but do not have specific characteristics that could impact adversely the effectiveness of the device in question;
- Following a pre-defined plan of patient outcome assessment.
As it is stated in the document, an interested party should submit the Investigation Plan containing the objectives referring to the purpose of a study. In particular, the study protocol should include study endpoints, endpoint assessment methods, and adverse event definitions as appropriate for an early feasibility study. Apart from this, the study protocol should also outline the methodology to be followed, including the details about the study participants (subjects) to be engaged. As was mentioned before, a party responsible for a study should not involve participants having certain health-related issues that could potentially negatively impact adversely the effectiveness of the device. The authority also explains that the level of detail required for the study protocol of an early feasibility study could be lower than the respective protocol for a pivotal study – this will provide the study sponsor with additional flexibility. At the same time, it is important to ensure that any adverse events are duly captured, together with the general information on the safety and performance of the medical device in question.
Human Subject Protection Measures
The authority also describes in detail the specific measures to be applied to ensure the safety of patients participating in a study. In this regard, a party responsible for a study should comply with any requirements set by the respective regulations on clinical studies. When applying these measures, the study sponsor should consider specific characteristics of study participants, as well as the risks associated with the device itself. Protection requirements include the following ones:
- Informed consent. According to the applicable regulatory requirements, a party responsible for a study should duly communicate to study participants all important information regarding the study and the device to be used, clearly stating that the proposed investigation is an early feasibility study (e.g., a small study of an innovative device or innovative clinical use of a device for which there may be less nonclinical data that would be required for a larger study). All the specific aspects of the device should be explained in a way ensuring the study participants would understand them and interpret them correctly. The authority additionally emphasizes the importance of communicating information about the elevated risks associated with the studies covered by the scope of the guidance. In particular, subjects must be made aware during the informed consent process that there may be unforeseeable risks associated with participation in the study due to limitations in available data and experience with the device. Apart from this, the details about potential benefits should be communicated as well. The way the information is provided should not create an impression that the benefits associated with participation in the study and use of the device are higher than they are. The authority also refers to the respective appendix of the guidance where additional clarifications regarding the context of the informed consent form are provided.
- Institutional Review Boards, as explained by the FDA, must determine if the risks to the subjects are minimized to the extent possible, and consider whether the risks to the subjects are reasonable about anticipated benefits and the importance of the knowledge that may be obtained.
In summary, the document provides an overview of the regulatory requirements to be applied concerning investigation plans related to early feasibility studies. The guidance describes in detail the content of such a plan and highlights the most important aspects to be considered in this respect.
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