The new article highlights the key points to be considered when conducting a study in order to sustain its quality, as well as to ensure the accuracy and reliability of its result. 
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 design considerations for pivotal clinical investigations for medical devices. The document provides additional clarifications regarding the applicable regulatory requirements, as well as recommendations to be considered by medical device manufacturers, study sponsors, and other parties involved in operations with medical devices. At the same time, it is important to mention that FDA guidance documents are non-binding in their legal nature, 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 legislation and has been agreed with the authority in advance. 

The scope of the guidance covers, inter alia, the aspects related to sustaining the quality of clinical studies, including the ones to be considered when conducting a study. 


Regulatory Background 

First of all, the authority mentions that all the progress reports submitted by the parties responsible for clinical trials are subject to a rigorous review. Should it be identified that a clinical study is being conducted in a way that is not compliant with the applicable practices and standards, the authority has a right to disqualify investigators from further participation. In this respect, the authority refers to separate guidance documents where these aspects are described in detail. The authority expects that compliance with the recommendations provided in the guidance would contribute to the overall improvement of the accuracy and reliability of study results to make sure the data collected could be used to substantiate the claims made with respect to the medical device in question by its manufacturer with respect to the safety and effectiveness. 

Recommendations: Key Points 

In particular, the authority provides the following recommendations to be considered by study sponsors and other parties involved: 

  • The randomization code and procedure should be carefully preserved (the authority mentions that in case the adaptive randomization is applied, special attention should be paid the algorithms used).
  • The study blind should be strictly maintained and the integrity of the blind should be evaluated (the authority recommends to maintain a record of unblinding events that occurred). 
  • The study protocol should be strictly followed and all types of protocol deviations, including those deemed minor, should be minimized. Furthermore, it is also stated that it the approach to be used when determining whether the deviations are minor or major should also be described in the said protocol. Under the general rule, a party responsible for a clinical study should report deviations from the protocol. This becomes especially important since once a certain level of major deviations has been reached, the reliability of study results will be questionable. 
  • Study subjects should be consistently and completely followed according to the study protocol. In particular, study sponsors should take all the measures necessary to mitigate the impact of missing data. For this purpose, the protocol could provide the procedures for a follow-up in case of missed visits. As further explained by the FDA, the best way to address issues of missing data due to loss-to-follow-up is to plan to minimize its occurrence during the planning and management of the clinical study. At the same time, the protocol should anyway describe the approach to be applied with respect to missing data. 
  • Vigilant data monitoring should be conducted to ensure reliable, accurate data and minimize missing data. For this purpose, a party responsible for a clinical study should select carefully the persons who will conduct monitoring during the trial based on their training and relevant experience. The authority also mentions that in order to ensure the reliability of monitoring, the person handling it should not be involved in the study itself. Moreover, a clinical quality assurance program should be implemented to ensure that the study is conducted as designed and intended. 
  • Consistent adherence and/or commitment to optimal clinical care should be maintained. 
  • The study data should be carefully protected to prevent biases due to early looks unless explicitly pre-planned in the Statistical Analysis plan. According to the guidance, the same approach should be applied with respect to open-label studies. 
  • Measures should be in place to avoid premature discontinuation of the study unless a planned interim analysis or stopping rules is pre-defined in the study protocol or the discontinuation decision is based on safety concerns. The authority additionally emphasizes that even in case the study itself has been discontinued, the obligations related to safety-related monitoring would remain valid. 
  • Sponsors must select investigators qualified by training and experience to investigate the device. It is also stated that the appropriate training is required for all the personnel participating in the study. 


According to the guidance, the aspects highlighted hereabove should be duly addressed in the study protocol, while all the persons involved should receive proper training on their implementation. 

In summary, the present FDA guidance describes in detail the main considerations related to the way clinical trials should be conducted in order to ensure the accuracy and reliability of the results. The document also addresses the aspects related to the study protocol and potential deviations from it.




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