The new article highlights the key points related to clinical outcome studies that are not using concurrent (or historical) controls.

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 the design considerations for pivotal clinical investigations for medical devices. The document provides additional clarifications regarding the existing regulatory requirements, as well as recommendations to be considered by medical device manufacturers, study sponsors, and other parties involved to ensure compliance thereto. At the same time, provisions of the guidance are non-binding, nor 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 regulatory framework and has been agreed with the authority in advance.  

The scope of the guidance covers, inter alia, clinical outcome study designs that are not well-controlled studies since they do not use concurrent (or historical) controls and hence have no direct comparator. 


Single-Group Study with Objective Performance Criterion (OPC)

According to the guidance, an Objective Performance Criterion (OPC) refers to a numerical target value derived from historical data from clinical studies and/or registries and may be used in a dichotomous (pass/fail) manner by FDA for the review and comparison of safety or effectiveness endpoints. The authority further explains that as of now, there are only a few validated OPCs. In general, they are usually created when a technology used for medical devices is developed enough to ensure the availability of sufficient information. When developing an OPC, information from numerous sources should be taken into account. The authority also mentions that the use of generally accepted OPCs will be beneficial, as OPC usually cannot be developed by a single entity using its data, nor can it be developed by the authority itself. On a side note, the authority mentions that an OPC has limited validity in time and could become obsolete due to the further development of technology. The authority also encourages study sponsors intended to use OPCs in the context of pivotal clinical studies to get in touch in advance to discuss the related matters before commencing an investigation. 

Single-Group Study with Performance Goals (PG) 

As explained by the FDA, a performance goal (PG) provides a level of evidence that is inferior to an OPC and refers to a numerical value (point estimate) that is considered sufficient by the FDA for use as a comparison for safety and/or effectiveness endpoint. The authority also mentions that a PG could be based on the upper (or lower) confidence limit of effectiveness and/or safety endpoint. According to the guidance, the level of development of the technology required for a PG, in general, is lower than in the case of OPCs. Hence, the data which is not sufficient to be used as a basis for an OPC could be used when developing a PG. Thus, PGs could be used when the information available is not sufficient to use more advanced controls. At the same time, a PG developed by a scientific society will be considered more reliable, while it should not be developed for a particular submission by a party responsible for a study or the authority. As in the case of OPCs, PGs could have limited validity in time and become obsolete. Study sponsors intended to use PGs are also encouraged to discuss the applicable approach with the authority in advance. 

The authority also mentions that one should be careful when using PGs in the context of pivotal clinical studies. It is further explained that an important question to ask is whether there is convincing evidence that any device that achieves a performance goal for safety (or effectiveness) would successfully demonstrate such safety (or effectiveness) in a well-controlled investigation since the achievement of (or failure to achieve) a PG does not necessarily lead to immediate acceptance (or rejection) of the study results. Sometimes if the results are not clear and straightforward, they should be subject to an additional, more rigorous, assessment. In certain cases, the premarket applications based on the use of PGs could be subject to review by an advisory panel to obtain additional advice on the interoperation of the results of the respective study. 


Observational Studies or Registries 

According to the guidance, the mere examination of databases to compare the therapeutic effect is full of bias. Usually, randomization is used to address potential bias, but this is not the approach to be applied in observational studies. The authority mentions that sometimes the results of an observational study differ significantly from the results of a randomized clinical study related to the same medical device in question. The said difference could be explained by the dependence of the observational studies on the subjects’ prognoses. Due to the complexity of ensuring the representability of the study results, the authority recommends conducting observational studies at a post-market stage instead of conducting them as pre-market studies. 

In summary, the present guidance provides an overview of the regulatory requirements for non-comparative clinical outcome studies and outlines the key points associated with the main types of such studies. By virtue of the guidance, the authority explains the approach to be applied to minimize bias and ensure the accuracy and reliability of study results. 


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