FDA Guidance on the Least Burdensome Approach: Clinical Studies and Benefit-Risk Assessments

Table of Contents

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 least burdensome provisions. The document describes the least burdensome approach the authority applies to reduce the unneeded regulatory burden for medical device manufacturers and other parties involved in operations with medical devices to ensure and expand the availability of medical devices, especially the ones based on novel technologies, to healthcare professionals and patients. The document provides additional clarifications regarding the applicable regulatory requirements, as well as recommendations to be considered to ensure compliance thereto. At the same time, provisions of the guidance are non-binding in their legal nature and are not 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 existing legislation and has been agreed with the authority in advance. 

Clinical Studies 

The guidance describes, inter alia, the means for reducing the burden of traditional clinical studies. As it is stated by the authority, the most efficient means should be considered when determining the way to collect clinical data required to demonstrate compliance with the applicable regulatory requirements in terms of safety and effectiveness. Depending on the nature of the product in question, its intended use, and the risk associated thereto, various types of studies could be carried out to collect the data. The authority also mentions that in certain cases, alternative sources of data could be used, e.g., evidence from registries, claims data, and published literature. In this respect, the authority refers to the guidance document on Design Considerations for Pivotal Clinical Investigations for Medical Devices. 

Additional means to be used concerning the data necessary to assess compliance and substantiate the claims made by the medical device manufacturer include, inter alia, the following ones:

1. The use of historical control groups involves quantitatively comparing the results of the use of the device with prior experience derived from the adequately documented natural history of a disease or condition in comparable patients or populations who received no treatment or who followed an established effective regiment (therapeutic, diagnostic, prophylactic). The said approach allows for reducing the number of participants to be involved in clinical studies while ensuring the same level of accuracy and reliability of the results. This approach is widely used concerning generic types of medical devices when assessing their safety and effectiveness. 
2. Non-comparative clinical outcome studies, including those using OPCs, PGs, observational studies, registries, meta-analysis, and literature summaries. As further explained by the FDA, OPC refers to a target value derived from historical data within clinical studies or registries and is used in a pass/fail manner to assess safety and effectiveness endpoints, while PG is a numerical value used as a comparison for safety and/or effectiveness endpoints that may be accepted or developed by a professional society, standards development organization, or FDA. In such a way, it will be possible to reduce the sample size required to achieve the results. OPC could also be used when establishing a substantial equivalence to apply for marketing authorization, while PGs could be used when assessing substantial equivalence for a software device. 
3. Subject as own control is also the approach allowing to reduce the number of participants to be involved in a clinical study. 
4. Adaptive study designs, when used, may reduce resource requirements, decrease time to study completion, and/or increase the chance of study success. In this respect, the authority refers to the appropriate guidance document on Adaptive Designs for Medical Device Clinical Studies. Such an approach also allows for reducing the number of participants needed. 
5. Alternatives to prospective sample collection could be used in cases when certain circumstances make prospective patient samples for IVDs impractical, such as the low prevalence of a condition or the rarity of measuring certain concentration levels in a clinical setting. The alternative approaches include, inter alia, the use of banked and retrospective samples.

Benefit-Risk Assessments 

Another important aspect addressed in the present guidance relates to the use of benefit-risk assessments. According to the guidance, when applying the least burdensome principles, one should also consider the benefits and risks important in terms of the decision-making process. As further explained by the FDA, it considers, among other factors, the probable benefit to health from the use of the device weighed against any probable injury or illness from such use. Thus, the benefits and risks associated with the device in question are to be assessed in the context of existing uncertainty, as well as the disease the device is intended to address. For a positive decision to be taken, the benefits associated with the use of the device should outweigh the respective risks, i.e., it should be expected that the device will provide clinically significant results. According to the guidance, it could be a situation when even if the use of the device is associated with a significant risk, for a certain category the use of the such device could be reasonable since potential benefits outweigh the risks. For further details, the authority refers to the guidance document on Factors to Consider When Making Benefit-Risk Determinations in Medical Device Premarket Approval and De Novo Classification. 

In summary, the present FDA guidance describes the way the least burdensome approach should be applied concerning clinical trials and clinical data necessary to substantiate an application for marketing approval. The document also explains the use of a benefit-risk assessment in the context of the least burdensome principles. 

Sources:

https://www.fda.gov/regulatory-information/search-fda-guidance-documents/least-burdensome-provisions-concept-and-principles

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