By Adrienne R. Lenz –
Sponsors commonly receive a request for additional information (AI) during Food and Drug Administration (FDA) review of a 510(k) submission, de novo classification request, or premarket approval application. In some cases, a sponsor may conclude that one or more AI requests calls for information that is not relevant or necessary to fulfill the statutory criteria for clearance or approval. Such requests do not comply with the requirement in the Federal Food, Drug, and Cosmetic Act for FDA to require the “least burdensome” scientific evidence necessary to support clearance or approval.
In these situations, a useful first step is to turn to FDA’s guidance, Developing and Responding to Deficiencies in Accordance with the Least Burdensome Provisions – Guidance for Industry and Food and Drug Administration Staff. An updated version of this guidance was issued on September 29, 2017, in fulfillment of a Medical Device User Fee Amendments of 2017 (MDUFA IV) Commitment Letter. It aims to help FDA review staff and supervisors request additional information that represents the “minimum required” to make their regulatory decisions. See FD&C Act, Sections 513(i)(1)(D)(ii), 513(a)(3)(D)(iii), and 515(c)(5)(B).
The guidance was originally issued 17 years ago (on November 2, 2000). It applies to FDA’s requests for additional information, which they refer to as deficiencies, needed to complete reviews of premarket approval (PMA), humanitarian device exemption (HDE), premarket notification [510(k)] and De Novo premarket submissions. As in the original, the guidance sets forth principles for FDA in writing deficiency letters and provides a suggested format for industry responses to FDA deficiencies. A sponsor can use these principles when explaining to FDA why a particular AI request is not “least burdensome.”
New to the guidance are a set of six guiding principles for FDA review staff:
Information unrelated to the regulatory decision should not be part of the decision-making process.
Alternative approaches to resolving regulatory issues should be considered to optimize the necessary time, effort, and resources involved in developing a response.
Deficiencies should request the minimum (i.e., least burdensome) amount of information necessary to adequately address the identified issue in the most efficient manner at the right time. The balance between premarket and postmarket should be considered to determine when information should be provided to address the identified issue.
Major deficiencies are those based on least burdensome principles that, if not resolved, will preclude a favorable decision on the marketing application. Major deficiencies should only be included if their resolution is necessary in order to reach a final decision regarding the marketing authorization.
If the Agency is including minor deficiencies identified during the review in the deficiency letter, the Agency should identify these requests separately from major issues, and whenever possible, attempt to resolve minor questions/issues interactively. Minor deficiencies are FDA requests that can be resolved in a straightforward manner, but that need to be addressed to meet regulatory requirements or to prevent potential misbranding or adulteration. In general, the Agency should not issue a formal deficiency letter if only minor deficiencies remain, but instead should attempt to resolve them interactively.
FDA may also include additional considerations that are suggestions, recommendations, or requests that are not expected to preclude a favorable decision on the marketing application. Because additional considerations are not expected to preclude a favorable decision, they do not require an applicant response.
Also new is the requirement from the MDUFA IV Commitment Letter for all deficiency letters to undergo supervisory review prior to issuance. Additionally, the recommendation for FDA staff now includes the following: “where appropriate, reference to an applicable section of a final rule, final guidance, and/or an FDA recognized standard (unless the entire or most of the document is applicable). 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 the specific scientific issue and the information to support its position.”
Like the original guidance, the updated guidance provides a recommended format for responding to deficiencies. These recommendations include:
1. Restate the identified Agency issue; and
Provide one of the following:
the information or data requested;
an explanation why the issue is not relevant to the marketing authorization decision; or
alternative information and an explanation describing why the information adequately addresses the issue.
One of the biggest challenges in responding to an FDA deficiency letter is persuading FDA to actually accept to accept either alternative information or a sponsor’s explanation as to why additional information is not necessary. These are areas where sponsors and reviewers often struggle to reach agreement. Although some examples are provided, the new guidance provides no new insights on how best to approach this perennial problem. In our experience, the most persuasive case will be based on a deep understanding of the technology and careful attention to the concern FDA is raising. Simply reiterating the “least burdensome” mantra back to FDA reviewers is unlikely to yield positive results.
All in all, while the “least burdensome” requirement has never had a lot of teeth in it, we are hopeful that the new guiding principles, specific references and supervisory review will help keep FDA’s deficiency letters focused on the minimum information necessary to reach a regulatory decision.