The new article highlights specific aspects related to the clinical studies and the way they should be undertaken to ensure the accuracy and reliability of the results, including the patient demographics, safety endpoints, and analysis.
The document constitutes a draft guidance the authority has published in order to collect feedback from industry representatives and other parties involved regarding the regulatory approach suggested. Thus, the provisions described in the present draft guidance could be subject to changes due to new information becoming available to the authority.
The Agency will accept comments within two months from the date the document has been initially published. Once finalized, the document will provide additional recommendations and clarifications on the matter.
Due to their legal nature, guidance documents do not introduce any requirements themselves. The approach described therein should be taken into consideration by the medical device manufacturers or other parties engaged in operations with medical devices in the context of achieving and sustaining compliance with the applicable regulatory requirements set forth by the current legislation. Additionally, the Agency states that an alternative approach could be applied, provided such an approach has been approved by the authority in advance.
Thus, the present FDA guidance provides suggested recommendations for the design of feasibility and early feasibility clinical studies for certain medical devices. These recommendations are mostly based on existing clinical practice guidelines.
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 feasibility and early feasibility clinical studies for certain medical devices intended to therapeutically improve glycemic control in patients with Type 2 Diabetes Mellitus (T2DM). The document is intended to provide additional clarifications regarding the applicable regulatory requirements, as well as recommendations to be taken into consideration by medical device manufacturers and study sponsors to ensure compliance thereto. At the same time, provisions of the guidance are non-binging in their nature and are not intended to introduce new rules or impose new obligations. Moreover, an alternative approach could be applied, provided such an approach is in line with existing legislation and has been agreed with the authority in advance.
To ensure the accuracy and reliability of the study results, the proper planning of a study should include the engagement of the appropriate participants (study subjects). The document states that it is important to outline the characteristics of the patient population that could potentially impact the study outcomes, including:
- Age, race, and ethnicity;
- Sex and gender;
- Body mass index (BMI); and
- State of T2DM disease (e.g., HbA1c levels).
In this respect, the authority also refers to the additional guidance document describing specific aspects related to the evaluation of different characteristics and the way they should be treated in the context of a clinical study.
Clinical Study Recommendations
According to the document, a clinical study should be carried out in order to assess and evaluate the safety and effectiveness of a medical device intended to be used for the purpose described herein. Such a study should be carried out under the Investigational Device Exemptions (IDE) framework. The Agency states that medical devices intended to therapeutically reduce glycemic levels for T2DM patients are associated with significant risks. Thus, the appropriate provisions on significant risk medical device studies should be applied. Should such an investigation take place in the US, it should also meet the requirements set forth under the current legislation in terms of institutional review boards and informed consent. However, clinical data deriving from clinical studies carried out abroad could be acceptable, provided it complies with the applicable regulatory requirements.
The present draft guidance highlights the most important aspects related to early feasibility studies, including the following:
1. Study objectives. As stated by the FDA, an early feasibility study is intended to evaluate the device design concept with respect to initial clinical safety and device functionality in a small number of subjects (generally fewer than ten initial subjects) when this information cannot be provided practically through additional nonclinical assessments or if appropriate nonclinical tests are unavailable. For instance, such an approach could be applied in the case of medical devices based on novel technologies. A party responsible for a clinical study (a sponsor) should take into consideration the provisions of this guidance when developing a study design. In general, a feasibility study is intended to collect initial safety and effectiveness data which would later be used as a basis for a clinical investigation. The Agency encourages sponsors to pay special attention to safety-related matters by gathering and analyzing information on adverse events associated with the medical device in question. From the effectiveness and performance standpoint, special attention should be paid to measuring glycated hemoglobin (HbA1c), while additional measures could be applied as well.
2. Study design. When determining the sample size, a sponsor shall take into consideration such factors as the current stage of medical device development, availability of data, and also the risks associated thereto. Under the general rule, the size of an early feasibility study should not exceed ten subjects. Consequently, the information to be collected by virtue of such a study would not be sufficient to completely assess the performance of the medical device subject to review. Nevertheless, performance-related aspects should also be taken into consideration. The Agency states that inaccurate or inefficient glycemic control will expose patients to additional risks. Thus, even if the data collected in the course of an early feasibility study is not sufficient for the assessment of all the aspects, it still provides a solid base for future clinical trials.
3. Study duration and follow-up. The studies described herein should include the appropriate follow-up period, which should be proportionate to the risks associated with the medical device subject to review. For instance, in the case of high-risk studies, such a period should exceed twelve months in order to assess the durability of effects. The protocol of the clinical study shall prescribe the way the information about adverse events should be collected and processed. Additionally, it should prescribe that the subjects be monitored until any and all adverse events are stabilized.
According to the guidance, a clinical study protocol should include a safety monitoring plan to ensure the timely detection of serious adverse events. The document further outlines the key points to be considered when developing such a monitoring plan. However, the authority additionally emphasizes that the below list is not exhaustive and could be extended depending on the specific situation and medical device in question. The aspects highlighted by the authority include, inter alia, the following ones:
- In case the device subject to review employs a novel technology for which there is still no sufficient safety data, it will be necessary to pre-define the stopping rules to be enforced to mitigate the risks associated with the potential adverse events. When developing such rules, the experience with similar devices should be considered, together with the clinical data available. As it is stated by the FDA, study-stopping rules should be based on the type and number of adverse events that would discontinue further enrolment of patients for safety until additional mitigation measures can be implemented. It is further explained that the rules should prescribe the criteria to be considered to ensure the safety of a specific patient. In particular, it should prescribe the approach to be applied when suspending treatment and removing the device or its parts. According to the guidance, patients who were subject to adverse events should be supervised till the resolution or stabilization.
- Since the primary goal of the treatment/intervention is to improve glycemic control and subjects should be protected from prolonged hyperglycemia, hence, for patient safety, a medication management plan for those not achieving glycemic control should be built into the clinical study protocol. The authority encourages study sponsors to conduct the periodic assessment at least once in three months to identify whether additional treatment is needed. Thus, if the study failed to achieve its efficiency target, additional treatment should be considered and applied. Moreover, the particular way such treatment should be applied is to be included in the aforementioned plan to be developed and implemented by the study sponsor. Based on the above, the authority emphasizes the importance of developing and implementing efficient mechanisms of glycemic control during the clinical study to ensure the safety of study participants.
- As it is stated by the FDA, the clinical study protocol should include a predetermined list of preferred rescue medications for study subjects to minimize study variables.
In general, the authority encourages study sponsors to provide additional details regarding the particular approaches to be applied to evaluate the risks arising during the study. These approaches should be based on clinical practice guidelines employing efficient methods with proven effectiveness.
Safety Endpoints and Data
According to the guidance, any adverse events occurring during the study should be collected as safety endpoints to be assessed and evaluated in the future. As explained by the FDA, such events should be:
- Prospectively collected without regard to medical device- or procedure-relatedness;
- Defined using pre-specified, standardized criteria;
- Graded for severity according to a standard adverse event grading system;
- Categorized according to whether they meet the established serious adverse event definitions;
- Assessed for resolution status; and
- Adjudicated by an independent clinical events committee.
As was mentioned before, any use of dietary supplements by the study participants should be duly documented, since this could potentially impact the accuracy and reliability of the study results. The information related to such use should be reflected properly in the documentation submitted to the FDA.
Effectiveness Analysis and Data
The authority encourages study sponsors to collect the data related to the actual effectiveness of medical devices subject to review in both early feasibility and feasibility clinical studies to be able to evaluate the way the product improves glycemic control. Furthermore, the authority mentions that the information about the particular assay use should be reflected in the clinical study protocol.
In summary, the present FDA guidance describes in detail the approach to be applied when developing and performing clinical studies for medical devices intended to improve glycemic control. The document outlines the most important aspects to be considered to ensure the accuracy and reliability of the results, as well as the safety of patients participating in a study.
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