The new article highlights the most important aspects related to the application of the least burdensome approach for deficiencies arising from the issues identified by the authority when reviewing the application for marketing approval.
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 developing and responding to deficiencies following the least burdensome provisions. The document describes in detail the way the Least Burdensome Approach should be applied for requests for additional information the authority may issue, should such additional information be reasonably necessary for the authority to complete the application review. The guidance provides additional clarifications regarding the existing regulatory requirements, as well as recommendations to be taken into consideration by medical device manufacturers and other parties involved 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. Moreover, the authority explicitly states that an alternative approach could be applied, provided such an approach is in line with the underlying legislation and has been agreed with the authority in advance.
According to the applicable legislation, the FDA determines the “safety and effectiveness of a device” by “weighing any probable benefit to health from the use of the device against any probable risk of injury or illness from such use” among other relevant factors. It is also stated that the least burdensome approach itself falls within the scope of the approach applied by the authority when reviewing the applications and making decisions based on the benefit-risk profile of the product in question. The authority also acknowledges that a certain level of uncertainty usually exists irrespectively of the completeness of the information provided. However, in certain cases, even a significant level of uncertainty will be acceptable – for instance, when the benefits from the use of the device significantly outweigh the risks associated thereto. For the assessment of the risk-benefit profile, the authority refers to a separate guidance document: Benefit-Risk Factors to Consider When Determining Substantial Equivalence in Premarket Notifications (510(k)) with Different Technological Characteristics.
The authority also mentions that the amendments to the applicable legislation adopted in 2022 provide further clarifications on the matter. These amendments are also taken into consideration for the deficiency letters and content thereof. In particular, it is stated that:
- Deficiency letters should include a statement of the basis for the deficiencies (e.g., a specific reference to applicable section(s) of a rule, final guidance, or recognized standard unless the entire or most of the document is applicable). In the instance when the deficiency cannot be traced in the manner above and relates to a scientific or regulatory issue pertinent to the determination, FDA will cite a specific scientific issue and the information to support its position.
- Deficiency letters will undergo supervisory review before issuance to ensure the deficiencies cited are relevant to a marketing authorization decision (e.g., 510(k) clearance, PMA approval, and De Novo classification).
The present document and recommendations provided therein are intended to guide the authority’s staff and supervisors when developing deficiencies to be included in deficiency letters related to the applications for marketing approval for the products to be marketed and used in the US. Under the general rule, an approach similar to the one described in the document could be applied under the various frameworks, however, the scope of the present guidance covers only the letters issued by the FDA when reviewing applications for marketing approval. Apart from this, the document is expected to be useful to medical device manufacturers and other parties involved in preparing responses to the said letters. The document also provides examples of various deficiencies and justification of such requests, together with an explanation of how the appropriate requests could be responded to by the industry.
The document further outlines the main principles the authority will follow when developing deficiency letters to be issued in the course of reviewing marketing applications. According to the guidance, these principles include, inter alia, the following ones:
- The decision should not be based on information that is not relevant in terms of marketing authorization.
- Should it be identified that there is an alternative approach allowing to resolve the issues more efficiently, such an approach should be taken into consideration.
- The information requested by the authority concerning an issue identified in the course of the application review should be limited to a minimum reasonably necessary to address the respective issue. In this respect, the document states that the balance between premarket and postmarket should be considered to determine when information should be provided to address the identified issue.
- When making decisions, the factors to be taken into consideration should include the scope of information necessary to evaluate the benefit-risk profile together with the uncertainty associated with such determination.
- According to the least burdensome approach, major deficiencies are the ones that prevent the authority from taking a positive decision regarding the marketing application unless resolved.
- Should minor deficiencies be included in a letter issued by the authority, such deficiencies should be separated from the major ones. Furthermore, as mentioned in the previous article, the authority intends to resolve minor deficiencies on spot.
- A deficiency letter may also include additional considerations that are suggestions, recommendations, or requests that are not expected to preclude a favorable marketing authorization decision. It is also stated that these points, when included, do not require a response to be provided.
In summary, the present guidance provides additional clarifications regarding the general approach for deficiencies and deficiency letters the authority may issue in the course of a marketing application review. The document also describes in detail the main principles the authority will follow when applying the least burdensome approach in the context of deficiency letters.
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