The Food and Drug Administration (FDA or the Agency), the US regulating authority in the sphere of medical devices, has published a draft guidance document dedicated to clinical considerations for studies of devices intended to treat opioid use disorder (OUD). Once finalized, the document will provide an overview of the applicable regulatory requirements set forth under the existing framework, as well as additional recommendations and clarifications to be considered by medical device manufacturers and other parties involved in order to ensure compliance therewith.
At the same time, provisions of the guidance are non-binding in their legal nature, and are 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 legislation and has been agreed upon with the authority in advance. The authority also reserves the right to make changes to the guidance and recommendations provided therein, should it be reasonably necessary due to amendments to the underlying regulations or new information becoming available to the authority.
The scope of the guidance covers, inter alia, aspects related to clinical study design. In particular, CDRH acknowledges the challenges in study methodology in the field of OUD treatment and encourages sponsors to develop alternative methodologies to overcome these challenges while still producing valid scientific evidence that can be used to support a marketing submission.
As further stated in the guidance, the authority will consider alternative approaches applied by the sponsors when demonstrating compliance with the respective requirements for the safety and effectiveness of the products intended to be used in the context of OUD. The authority also encourages the use of the Q-Submission process, allowing the sponsors to obtain feedback from the authority before submitting the main application. – in such a way, the authority expects to establish a more efficient review process due to the better overall quality of submissions. In this respect, the authority refers to a separate guidance document.
The guidance further describes in detail the main considerations related to the clinical study design and highlights the key points associated thereto.
Patient Population and Assignment to Treatment and Control Groups
According to the guidance, the sponsors should clearly define the relevant population the device will be used for at the stage of designing a pivotal OUD device study. The authority believes that clearly defining the study population in practical terms will allow eventual prescribes to be confident that the evidence of effectiveness established in the OUD device studies is relevant to the patients for whom they prescribe or recommend the device.
The authority further explains that study subjects (participants), investigators, or evaluators should not be informed of the treatment assignment in order to ensure the study results are reliable and unbiased. The actual effectiveness of the device is usually demonstrated by comparing the results for two groups: the one for which the device has been used, and the control one. Such a comparison allows one to draw reasonable conclusions about the effectiveness of the device in question when used for its intended purpose.
The treatment provided to the control group should be similar to the one provided to the main group, and safe for the therapeutic elements or procedures that are being investigated. The authority encourages study sponsors to get in touch in advance to discuss the methods and approaches to be applied when providing the sham treatment to the control group (Q-Submission program could be used).
Recording Medication Use
According to the guidance, pivotal OUD device studies should record all baseline medications, including those used for treating OUD, prior to initiating treatment intervention with an investigational device. In particular, the parties responsible for clinical investigations are obliged to keep a record of all the medicines used, the applicable doses and duration, and any changes in their use, including start and stop dates or any changes to the dose. The specific methods used for this purpose include pill counting and toxicology screening to be performed on a regular basis.
Monitoring Prescribed and Non-Prescribed Drug Use
The authority also emphasizes the importance of ensuring efficient monitoring of prescribed and non-prescribed drug use, as it could significantly impact the results of the investigation, affecting their accuracy and reliability. The lack of the appropriate measures would make it unclear whether the device demonstrates that actual benefit when used for its intended purpose.
According to the guidance, false or inaccurate results can occur in self-reported outcome measures of opioid use. In order to avoid this, the authority recommends applying both participant self-reports and objective verification measures to ensure any drug use is properly recorded and will be taken into consideration when assessing the results of an investigation. Sometimes additional testing for non-prescribed drugs should be included in the study design. The authority mentions that typical objective measures to corroborate participant self-reports are random and scheduled urine tests using validated toxicology assays at times consistent with relevant drug pharmacokinetics.
Apart from this, study sponsors can consider blood screening and other alternative drug detection technologies. The authority additionally emphasizes that in the event of any discrepancies between self-reported abstinence and toxicology results confirmed by a quantitative reference method, the latter should prevail.
In summary, the present FDA guidance highlights the key points related to the patient population and the way it should be defined and considered. The document also describes in detail the approach to be applied with respect to establishing efficient mechanisms for monitoring any drug use during the investigation, as this could affect the accuracy and reliability of the results.
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