The new article highlights the aspects related to the determination of study duration, and also to the approach to be followed in order to mitigate the risks associated with missing data.

The Food and Drug Administration (FDA or the Agency), the US regulating authority in the sphere of healthcare products, has published a draft guidance document dedicated to clinical considerations for studies of devices intended to treat opioid use disorder (OUD). Once finalized, the guidance will provide an overview of the applicable regulatory requirements, as well as additional clarifications and recommendations to be taken into consideration by medical device manufacturers and other parties involved in order to ensure compliance thereto.

At the same time, provisions of the guidance are non-binding in their legal nature, nor are intended to introduce new rules or impose new obligations. 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 with the authority in advance.

The document outlines the key points related to the studies to be considered in order to ensure the accuracy and reliability of the results.

Study Length and Evaluation

First of all, the authority emphasizes the importance of determining the proper length of a clinical study involving the OUD devices. The authority expects the length of the study to be properly justified and clinically significant. For instance, for pivotal studies, the minimum duration of the treatment should be 6 months. As explained by the authority, appropriate study duration is necessary because OUD is a condition with a higher rate of relapse, and brief intervals of modification of drug use are unlikely to confer significant clinical benefit.

Thus, when determining the clinical study duration, a party responsible for a clinical study should take into consideration the durability of the effects, as well as any benefits and risks associated with the use of the device and their uncertainty. Moreover, it is also stated that because of the importance of a long study duration, the protocol should include a detailed description of the effective procedures for retaining study participants, risk-based ongoing data management, and procedures for obtaining primary outcome information that is missing while it is still available to be retrieved.

Participant Retention and Preventing Missing Data

As it was mentioned before, for OUD studies it is vitally important to develop and implement efficient procedures for patient retention due to the long enough study duration which is reasonably necessary to assess all the aspects related to the safety and effectiveness of an OUD device in question. Thus, study sponsors should take all the steps to ensure that the treatment plans and follow-up schedules are properly followed in order to maximize participant retention and mitigate the risks associated with missing data.

According to the guidance, new methods could be developed and used to achieve the above goal. In particular, the authority mentions that if participants do not adhere to the treatment and follow-up plan, the primary outcome may not be obtainable, which would weaken the credibility of the intention to treat analysis; because the methods of retention may affect the study outcomes, FDA recommends ensuring adequate blinding of the treatment assignment to minimize decision to drop out.

As explained by the FDA, the studies related to OUD devices are sensible to missing data issues resulting in the overall failure of the study. Hence, this issue should be taken into consideration when developing the study protocols, and the appropriate measures and controls should be duly implemented in order to mitigate the risks associated thereto. 

When assessing the importance of missing data, the party responsible for a clinical study should take into consideration the significance of the impact this will have on the study results and the potential uncertainty associated thereto. The authority further states that:

  • Methods to account for missing data should be pre-specified in full detail in the statistical analysis plan before the study starts;
  • Even if pre-specified, these methods are accompanied by a large amount of uncertainty when missing data exceeds more than a few percent;
  • The protocol should ensure that investigators have the resources and a powerful strategy to detect and correct missing data while allowing flexibility and adaptive procedures to reduce the loss of critical data. 

According to the guidance a set of various solutions could be reasonably necessary to ensure the potential missing data cases are duly addressed. Furthermore, data management should be proactive in terms of early detection of cases when missing data is critical to ensure the issue could be identified when it is still possible to retrieve the data missing. For this purpose, it could also be recommended to limit the amount of data collected in the course of a clinical investigation so it would be possible for investigators to focus on the most important data. 

The authority also mentions that sometimes missing data contains the details of adverse events. The appropriate information could be partially retrieved from the records held by healthcare providers. 

In summary, the present FDA draft guidance describes in detail the approach to be applied with respect to the risks associated with missing data, paying special attention to the impact it could have on the reliability and accuracy of the study results, and also to the measures and controls to be implemented by study sponsors in order to mitigate the risks associated thereto. The scope of the guidance also covers the aspects related to study length and the way it should be determined when planning a study involving an OUD device.

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