The article addresses the aspects related to the study duration, and also the inclusion/exclusion criteria to be considered.
The document constitutes a draft guidance the authority has published in order to collect feedback from industry representatives and other parties involved regarding the regulatory approach suggested. Thus, the provisions described in the present draft guidance could be subject to changes due to new information becoming available to the authority.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 considered by medical device manufacturers and other parties involved to ensure compliance thereto. However, it is important to mention that provisions of the guidance are non-binding, 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 the underlying legislation and has been agreed with the authority in advance.
Study Duration and Follow-up
The scope of the guidance covers, inter alia, the aspects related to the duration of the study. Under the general rule, all the studies covered by the scope of the document should include a follow-up period corresponding to the risks associated with the device in question, and also the benefits it provides. It is further stated that if the medical device requires a surgical, endoscopic, or radiological procedure during use, and/or alters anatomy, or otherwise presents a high risk to study subjects, FDA recommends for a feasibility study to include at least a 12-month follow-up period to evaluate medical device safety and effectiveness, including an assessment of the durability of the effects on glycemic control.
The other recommendations provided by the authority regarding the matter include, inter alia, the following ones:
- Should the device subject to review be intended to interact with another product (mostly medicine), such interactions should be monitored during the follow-up period;
- It should be established that the information about any adverse events occurring should be properly collected;
- The appropriate specialist (diabetologist or endocrinologist) should be involved in the said assessments;
- The suggested protocol should explicitly state that follow-up should take place until all the adverse events would be fully stabilized;
- The protocol should also prescribe the procedure for “unscheduled” appointments that are necessary due to the incidents occurring.
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.
The document also describes in detail the inclusion and exclusion criteria to be considered when choosing the study subjects to be involved. Under the general rule, the premarket study population regarding disease state, health status, and potential comorbidities should be representative of the patient population for which the product is intended; however, for feasibility and early feasibility studies where medical device safety and treatment effect are not yet known, a narrow patient population as described below may be more appropriate depending on the anticipated risk that the medical device and/or medical device-related procedure(s) pose.
The authority emphasizes the importance of ensuring that in the course of clinical studies the targets associated with the patient treatment are duly met. The guidance further clarifies the specific criteria to be applied to determine whether a significant improvement has been achieved or not. It is also stated that all the inclusion and exclusion criteria used by a party responsible for a study (the sponsor) should be duly justified. At the same time, the authority also suggests certain inclusion/exclusion criteria be considered, namely:
- The subjects to be involved in a study should be the ones who will potentially benefit from the escalation of care. However, the risks associated with the treatment should be considered carefully as well. The document specifies the acceptable range for HbA1c to be taken into consideration when developing the inclusion/exclusion criteria to be followed.
- The subject selection should be also based on a rigorous evaluation of the benefit/risk balance. For instance, the patients who already have a significant positive effect from the existing treatment which is already being applied are less likely to benefit from participation in the study, at the same time, in such a way they will be exposed to additional risks that in other situations could be avoided. Moreover, such patients are not always representative when assessing the actual effectiveness of the new glycemic control methods. Hence, the data deriving from such studies would not be representative enough. Thus, the following criteria could be applied:
- In the case the option subject to review is associated with a relatively high risk, the patients involved should be the ones for whom all the existing options were not efficient enough. The document further specifies the particular criteria to be applied in this regard, and also mentions that any of the criteria applied should be duly justified and supported by the respective data.
- In case the use of a new medical device is neither associated with significant risk nor requires an extensive intervention, the inclusion threshold could be less strict. At the same time, the appropriate rationale should be provided as well.
- According to the existing clinical practice guidelines, it is important to attempt to achieve the glycemic targets by the virtue of medical nutrition therapy. The same approach should be followed concerning clinical studies described herein – it should be a duly documented attempt to achieve such a target in a way prescribed by the existing clinical practice guidelines before the treatment options subject to evaluation would be applied.
- Apart from having T2DM, the study subjects should be healthy to avoid potential complications resulting from other conditions or diseases the patient has. The document further outlines the scope of conditions that should be considered as blockers for inclusion in the study.
- It is also important to take into consideration the factors that could affect red blood cell turnover, as this could impact the interpretation of study results in terms of the actual effectiveness of the treatment option subject to review. Hence, the subjects with such factors should be excluded from participation in a study.
- The inclusion/exclusion criteria to be applied should cover all the aspects associated with the potential risks.
- Since dietary supplements could impact glycemic control in an unknown way, their use during the study should be limited and documented or, if possible, fully excluded to reduce the risks and ensure the accuracy and reliability of the study results.
In summary, the present FDA guidance describes in detail the approach to be applied when planning the duration of a clinical study and subsequent follow-up period. Additionally, the document provides recommendations regarding the inclusion/exclusion criteria to be used when selecting the patients to be involved in a study as subjects.
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