Discusses the newly revised MDUFMA (Medical Device User Fee and Modernization Act) and FDA standards for the timely review of 510ks, PMAs, PMA Supplements, BLAs, and BLA Supplements.
In the medical device industry, guidance documents set forth by the FDA are often the skeletal backbone for medical device design and development. When a new guidance emerges, the med device industry pays attention.
A recent guidance is no exception.
Interactive Review for Medical Device Submissions
The guidance, entitled Interactive Review for Medical Device Submissions: 510ks, Original PMAs, PMA Supplements, Original BLAs, and BLA Supplements, has been published as an effective clarification piece for the Food and Drug Administration Amendments Act of 2007 (i.e. the reauthorization of the Medical Device User Fee and Modernization Act/ MDUFMA). The reauthorization may be a welcome one for many medical device companies who may not have been satisfied with the original MDUFMA amendment, signed as amended law in 2002.
Out with the Old
The outdated MDUFMA is in effect similar to the new MDUFMA. Both amendments were designed with the purpose of increasing review resources (i.e. allowing the FDA to legally garner fees from medical device companies directly) and (in return) making the review process of applications more efficient and in some cases significantly abbreviated. However, some major distinctions remain between MDUFMA #1 and #2. Although many medical device companies were originally willing to pay increased fees in return for shorter review times, they were surprised to find that under the first MDUFMA amendment fees were higher than expected1 and that returns in the form of more efficient review times weren’t always measurable.
In with the New
The reauthorized MDUFMA is designed to more effectively meet standards of efficient review and “fine tune the user fee program”2. The Interactive Review guidance is focused exclusively on aspects of efficient review and describes the FDA and medical device industry roles for interactive review during 510k, PMA, BLA and supplement application review processes.
Fees for the fiscal year of 2008 and throughout the lifespan of the reauthorized MDUFMA will also be adapted. 3-4 Fee changes however (within the reauthorized MDUFMA) will not be a major topic within this article.
Interactive Review Sub-Part Goals
To accomplish the goal of a more efficient application process via interactive review, the FDA has recorded a series of sub-part goals and provided guidance support for achieving those goals. These goals include the following:
- Make informal communication between the FDA and medical device companies easier;
- Intend to provide clear communication regarding concerns expressed to the medical device applicant;
- Lessen formal request questions made to medical device applicants.
Strategies for Interactive Review
Strategies for achieving the interactive review’s purposes and goals include methods for handling “types of interaction” and “timing of interaction”. These methods are considered by the FDA to be the “least burdensome approach” for accomplishing efficient interactive review application processes.
Interaction: Appropriate Types
The guidance for interaction types acts as a base for the entire interactive review process. For instance, the FDA spells out those “types of interaction” that will most effectively improve FDA/medical device applicant communication during the application processes. Within the guidance, the FDA states the following: “Appropriate communication tools include email, facsimile, telephone calls, meetings (i.e., telephone conferences, videoconferencing, face-to-face meetings), and letters.”5 Of these types, facsimiles and emails are preferred primarily to all other types of communication but the FDA also recognizes that additional forms of communication are valuable and can be utilized during appropriate instances. Some of the guidance information for the utilization of communication tools (or types) is summarized below:
As stated earlier, email communication is preferred by the FDA in addition to facsimiles. One reason for this ‘email predilection” is that emails can be quickly saved and neatly ordered as electronic records of interactions that occur between the FDA and medical device applicants.
Facsimiles (or faxes) are also preferred as a mode of communication by the FDA.
- Phone Calls
Phone calls are not always the most efficient method for communication between the FDA and the medical device applicants, primarily because they are not easily recorded and/or archived and the FDA has the responsibility of maintaining appropriate records of the interactive review process. The Interactive Review guidance further clarifies the issue of phone contact by stating that “telephone calls should be used primarily for requests for clarification that the FDA reviewer can easily document” and that “Any telephone call that leads to a request for data should be followed by an email from the applicant to FDA that summarizes the commitment(s) made.” The guidance also specifies that the “FDA should respond via email to confirm the accuracy of the commitment(s) and then add the emails to the submission’s official administrative record.”
Meetings--of course--can require large amounts of planning and preparation time. However, the FDA is aware that meetings are at times necessary especially “when there are significant issues regarding the review that cannot be resolved by email, facsimile, or telephone calls.”6 When a meeting is determined to be necessary by the FDA and the applicant, the FDA will schedule a time for the meeting. In addition, the Interactive Review guidance states that the “FDA should attempt to schedule the meeting in a timely manner” and that the applicant in turn has a responsibility to “provide suggested meeting times,” and “questions to be discussed at the meeting in advance.”
- Letters or “Snail-Mail”
Letters are not generally useful tools during the interactive review process. However, when reason arises for an official hold on an application, the FDA will send notice to the applicant via an official hold letter.
Timing for Interactive Review
Another strategy for more efficient interactive review lies in providing additional counsel (via the Interactive Review guidance) regarding interaction timing for both the FDA and for medical device applicants. Interactive timing is, according to the FDA, “a cornerstone of interactive review,” and the guidance also states that “interaction should occur as needed to facilitate a timely and efficient review process.”
The important thing to remember when it comes to managing the timing of interaction throughout the interactive review is that the FDA wields the power and primary responsibilities of delineating interactive timing. For example, the Interactive Review guidance states that “With the exception of the Day 100 Meeting for PMAs, there are no fixed intervals within a review cycle or deadlines by which FDA is expected to interact with the applicant. Instead, the interactive process is driven by FDA's need, on a case-by-case basis, for additional information or clarification to complete its review and to help ensure compliance with MDUFA,12 Office, or Center timelines.” The guidance also states that “The established timeframe should be based on the impending review deadline, the estimated time that the applicant should need to respond, and the estimated time that FDA should need to review the response.” In addition, the FDA wields ‘the timing sword’ when it comes to determining time limits for the receipt of applicants’ responses to informal requests. On that note, the guidance states: “There are no pre-established timelines for applicants to respond to FDA’s informal requests for additional information during the review cycle. Instead, FDA should determine the appropriate timeframe on a case-by-case basis.”
It is also the FDA’s responsibility to comprehensively review sections of related information within an application before initiating any type of interaction with the medical device applicant. Medical Device Applicants: Primary Roles During an Interactive Review
Medical device applicants play a very essential role during the interactive review of their respective applications. For example, the FDA’s Interactive Review guidance provides the criterion for the successful submission of medical device 510k, PMA, BLA, and supplement applications. These criteria include the following:
- Complete Information for Contacts
Contact information, when submitted to the FDA, should be complete and listed on the cover letter of the submission itself. Contact information should include a name, phone number, fax number and an email address.
- Complete Application
Submissions to the FDA should always be complete, and pre-submission queries should be handled with the FDA before an application is submitted. Applications will generally be complete when regulations and guidance documents are understood and carefully observed.
- Appropriate Testing Standards
In regards to the application of appropriate testing standards and material usage, the guidance requires “the necessary declarations or data to support the use of the standard(s);”
- Status Updates
Applicants, in order to support the greatest possible speed for the review of their applications, should not request status updates from the FDA. (See below for situations in which a lead FDA reviewer can or should be contacted).
- Respond to Informal Deficiency Notices
The FDA may (throughout the process of an application review) communicate a variety of informal deficiencies to medical device applicants. These deficiencies must be responded to and as mentioned above, the timeframe for response will be determined by the FDA reviewer or by one of the reviewer’s team members.
- Respond to Formal Deficiency Notices
During the review process the FDA may cite deficiencies within a hold letter. This hold letter is a formal deficiency notice and must be responded to during the timeframe specified by the FDA reviewer.
Contacting the FDA
Although a medical device applicant should forbear from contacting the FDA for status updates, there are situations in which the applicant can or should contact the lead FDA reviewer assigned to his or her application. These situations are included below:
- A Need for Clarification
If a medical device applicant needs additional information regarding deficiencies presented by the lead reviewer, he or she may contact the FDA.
- A Need for Clarification with a Consulting Reviewer
At times, a consulting reviewer will be assigned the task of reviewing an application (or parts of an application) in lieu of and usually under the direction of the lead reviewer. When questions regarding deficiencies arise and the deficiencies have been “cited by the consulting reviewer” the applicant should “contact the consulting reviewer” and NOT the lead reviewer.
- Questions of Procedure
If an applicant has questions related to the procedures of a submission, he or she may contact his or her respective reviewer.
Disagreements between the applicant and the reviewer may arise in regards to cited deficiencies. These disagreements may be resolved by contacting the FDA.
- Correction of Errors
If an applicant realizes (post-submission) that there are errors within the submission material, he or she should contact the FDA to clarify or remedy the information. The same may be said for information that the applicant thinks might appear unclear to the reviewer.
- Timeframe Adjustments
At times, a medical device applicant may find it difficult (or impossible) to meet the timeframe specified for response to a deficiency. In this situation, the applicant may contact his or her assigned reviewer for a possible extension of the timeframe.
- New Material
If an applicant needs to submit new data or other types of material to the submission, he or she may contact the FDA. Certain addendums however may require an additional application.
At times (see meetings section above), an applicant may deem it necessary to schedule a meeting with his or her respective reviewer.
The Interactive Review guidance also contains information regarding the FDA’s role in regards to 510ks and to PMA/BLAs. The guidance further discusses minor and major issues associated with PMAs and BLAs and concludes with two sections entitled FDA Review Team Considerations and Placement of Submission on Hold. To access the guidance text online please visit: http://www.fda.gov/cdrh/ode/guidance/1655.pdf.
References and Resources1 http://www.medicaldevices.org/public/issues/
documents/NumbersBehindMDUFMA.pdf“Within just two years, MDUFMA user fees have skyrocketed at an unreasonable andunsustainable pace – 55% for PMAs and PMA Supplements and 60% for 510ks. Thisdramatically exceeds the annual 12-14% increase envisioned by members of industry. ForFY05, the compensating adjustment would have increased fees an additional 15%, but FDA elected to defer the compensating adjustor to FY06 and FY07.”2 http://www.fda.gov/cdrh/mdufma/presentations/mdufmaii-043007.pdf3 http://www.fda.gov/cdrh/mdufma/092807-reauthorized.html4 http://www.medicaldevicestoday.com/2007/04/mdufma_renewal_.html5 As a note of interest to the medical device industry, the guidance also states that the “…FDA is ultimately responsible for ensuring a complete administrative record for each submission.”
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