Paola Antonini, Meditrial Scientific Director.
It is estimated that more than 90% of clinical trials fail due to limited patient recruitment, investigator inefficiencies, insufficient understanding of local ethical and regulatory aspects, site and region selected for conducting the study. Conducting an Initial Feasibility Study also called Early feasibility studies-Efs-can reduce these failures, which are caused by assumptions and misinterpretations.
Efs represent the first fundamental step in the development of an innovative medical device; they are therefore performed early in the development process to assess its functionality and preliminary clinical safety, particularly when pre-clinical testing has been unable to provide comprehensive information. They are effective tools for understanding and predicting investigator and study site performance, patient recruitment potentials, and estimating overall study timing and costs.
FDA Regulatory Framework
The Early Feasibility Study is an idea that originated in the United States: The Fda’s Center for Devices and Radiological Health (Cdrh) established the Efs program with the main goal of facilitating patient access to safe and effective new technologies. In support of this strategic priority, of the agency published in October 2013 the guideline “Investigational Device Exemptions (IDEs) for Early Feasibility Medical Device Clinical Studies, Inclusive Certain First in Human Studies (FIH)” .
This provides an overview of the regulatory requirements applicable to Efs in the context of submissions for Investigational Device Exemptions (IDEs). As stated in the guideline, it is important to point out that the Fda is authorized to grant an exemption from certain requirements to studies with devices for investigational use that fall under Efs studies. This is so that experts qualified by training and scientific experience can preliminarily investigate the safety and efficacy of the devices. This process is referred to as Investigational Device Exemption (Ide).
The main considerations for a successful EFS study
In order for an Efs not to be inadequate and the results unsuccessful, it should be designed so that it can provide as much information as possible and sufficient to continue the study pathway until device approval. As with any clinical trial, the best way to minimize delays is to define expectations, clearly delineate risk, and identify shared goals among all stakeholders.
To this end, certain aspects are crucial and must be closely considered in order to successfully complete an Efs.
Here are what they are:
- Initiate preliminary comparisons with Fda to present the project, providing the rationale for why it is deemed necessary to conduct an Efs. Then establish an active discussion on the device evaluation strategy, testing plan, and clinical investigation survey to be adopted.
- Since Efs can be conducted before all preclinical testing has been completed, it is crucial to define an accurate device development strategy by identifying all possible risks and actions to mitigate them.
- The success of the Efs study is closely related to the Principal Investigator (PI). The latter must be willing to apply throughout the study the rigorous and articulate criteria for patient selection that are usually required by Efs. The PI must have sufficient time to spend with patients, explaining the study and the associated risks. In addition, he or she must be able to actively collaborate with the sponsor to refine the techniques of device use and be willing to make suggestions to improve device design if appropriate, refine the specifications of the evaluation tests, and define with the sponsor the inclusion/exclusion criteria for subsequent clinical trials.
- Patients are active partners in the study and must fully understand the nature of these types of studies and the relative uncertainty regarding risks and potential benefits. They must be willing to constantly communicate with the investigators and provide thorough accounts of their experience with the device.
- Given the unique nature of Efs studies, it is important that the referring Institutional Review Board (Irb) has experience with Efs and the risks associated with it. The informed consent document and documentation submitted to the Irb should highlight how the potential benefits are less certain and the risks less understood and predictable than in traditional clinical trials. Potential risks and subject protection measures should be clearly stated in the informed consent.
Differences between EFS and pivotal study
The guideline published by the Fda states that Efs are not intended to generate definitive data to support an application for submission to the authority unless followed by the Pivotal study. Rather, Efs are to be understood as complementary to the latter. So it is critical to fully understand what the main differences are between an Efs and a Pivotal Study and why sometimes Efs are a necessary step in order to succeed in bringing a new technology to market.
A clinical trial can be initiated as an Efs only when pre-clinical testing has not provided complete information to advance the device development process, whereas in the case of Pivotal Studies, the device design and results of pre-clinical studies have already been well defined and captured. Thus, unlike a Pivotal Study, Efs approval can be based on reduced pre-clinical data (Ide), and yet more robust risk analyses and risk mitigation strategies will be needed to compensate for this reduction in pre-clinical data.
An Efs is designed for a small number of patients, usually ten or fewer, but is based on a comprehensive and extensive collection of information on the functionality and safety of the device as designed. In contrast, Pivotal studies are designed to confirm the safety and efficacy of a device with an already defined design and for a specific indication for use by including a large number of patients.
An Efs bases its process on open-ended questions to allow the collection of as much information as possible, useful for defining and completing device development, while in Pivotal studies data are collected already from well-defined device characteristics.
Other differences between Efs and Pivotal studies concern the study’s monitoring plans: an Efs requires more intensive monitoring given the complex nature of the study, so the risk-based monitoring plans used for Pivotal studies, may not be the best monitoring strategy for an Efs.
The benefit of flexibility
In addition, a feature of Efs not found in Pivotal studies is flexibility. Protocol and device changes are more common in Efs than in Pivotal studies, and protocol changes can sometimes be one of the expected outcomes. As envisioned in the Efs program, more flexible procedures are applied to address this need, allowing for device and protocol changes more quickly and in line with the early stage of development.
Another key difference: the Efs program involves constant interaction with the Fda before and during the conduct of the study and provides researchers with a mode of multiple interaction with sponsors, agency review teams, and other clinicians. Sponsors initiating an Efs are encouraged to contact the Fda prior to the start of a study to request additional information and redefine the study plan if necessary. In particular, an informal “Pre-Pre-Submission” is provided for in the guideline. Through this procedure, a sponsor can obtain preliminary and informal feedback from the authority on specific aspects of the clinical trial and the draft protocol.
The possibility of establishing an ongoing and dynamic dialogue within an established procedural framework allows for the promotion of a real exchange, a better understanding of the characteristics of the device and the proposed development plan, fosters knowledge, mutual trust between manufacturers, researchers and the regulatory authority. Ultimately, it improves the efficiency of the study.
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