Full article reprinted from "The Gray Sheet" - December 15, 2008
Find out how FDA finalized guidelines Dec. 11 explaining what PMA supplement submissions are required for certain product modifications, largely mirroring 2007 draft guidance that device makers considered "incomplete."
Full article reprinted from "The Gray Sheet" - December 15, 2008
The closely-watched document, "Modifications to Devices Subject to Pre-market Approval (PMA) - The PMA Supplement Decision-Making Process," is intended to ease industry's confusion about when to submit a new regulatory application after modifying the design, labeling or manufacturing process for a PMA-approved device.
The 1final guidance describes the types of changes likely to necessitate each type of PMA supplement, or a new original PMA, and provides examples to illustrate FDA's thinking.
New indications for use, labeling changes, changes in sterilization procedures or in the performance or design specifications of a device may require a PMA supplement application "if such changes affect the safety or effectiveness of the device," FDA writes.
The guidance says companies should conduct a risk analysis and validation of the changes to help assess if a regulatory submission is needed.
FDA intended to emphasize "the importance of the internal assessment performed by the company for each change prior to the company sending in a submission," said Nicole Wolanski, director of FDA's PMA program.
"This assessment is not merely an exercise, but a meaningful way for the company to ensure that they have determined not only the appropriate type of submission but also whether or not a submission is needed," Wolanski explained in an e-mail.
The guidance does not, however, provide a straightforward decision-making flow chart to help identify which supplements should be submitted for specific types of changes, as industry has requested, because the "complexity and variability" of PMA products make such a chart "unfeasible."
"Instead of trying to develop a flow chart ... that took up half of a wall and was incomprehensible ... we decided to go back to using examples," FDA Office of Device Evaluation Director Donna-Bea Tillman said at a Dec. 10 LifeScience Alley industry meeting in Minneapolis.
Device trade group AdvaMed is still reviewing the new draft and preparing its comments.
In 2005, FDA abandoned and removed from its Web site a 1998 draft guidance that offered decision pathways for five types of modifications, including changes due to recalls, or due to labeling, technology, packaging or materials changes (2"The Gray Sheet" June 15, 1998, p. 5).
The agency had decided that the 1998 draft was out of date. Since that time, industry has not had much to go on, and has anxiously anticipated the 2007 draft.
The final 2008 guidance addresses when an original PMA is required versus a panel-track supplement or 180-day, real-time or special "changes being effected" supplement. The guidance also addresses 30-day notices, but not 30-day supplements.
For instance, a change that results in a drastically different device would require a new original PMA to re-establish safety and effectiveness, while design, indication or contraindication changes that require substantial clinical data gathering but do not create a "new" device would require a panel-track PMA supplement.
When Is A Supplement Needed In The First Place?
After the draft was issued, companies asked for more discussion targeting when a supplement is necessary at all, concerned that ambiguity in the guidance could lead to unnecessary regulatory filings (3"The Gray Sheet" July 2, 2007, p. 6).
AdvaMed has put emphasis on liberal allowances for including more changes in already-required annual reports, rather than in separate supplement applications.
Ultimately, FDA made few substantial edits to the draft, but it did add a new section on what types of changes can be included in annual reports.
"For changes that do not require the submission of a traditional PMA or a PMA supplement, you should provide this information as part of your annual report," FDA states.
For example, changes such as extending the expiration date of a device based on data obtained under an approved protocol, or increasing the number of products sampled for release testing, can all be submitted in the annual report solely.
Simple changes to documentation, such as rewording, clarifications, translations and typographical corrections, do not need to be reported.
Reformatting or any changes that alter the appearance of the labeling, however, should be in the annual report, Wolanski noted.
AdvaMed is strongly contesting a separate draft guidance document issued by the device center in January 2007 on what needs to be included in PMA device annual reports, charging FDA with over-reaching its authority in what it is asking for from companies (4"The Gray Sheet" Jan. 29, 2007, p. 5).
Agency Aims To Clarify Definitions
FDA tried, at industry's behest, to better define key terms such as "substantial clinical data" and "limited confirmatory clinical data" in the finalized PMA supplement guidance.
Substantial clinical data consists of a new clinical data set intended to provide valid scientific evidence of the safety and effectiveness of a modified device, not just human factors data, FDA says.
Limited confirmatory clinical data, which is permitted even in 180-day supplements, typically involves a limited number of patients, shorter study duration or a subset of endpoints compared to the original PMA study.
Further, the final guidance slightly amends the section on "changes being effected" supplements to mirror a final rule on the topic issued in August (5"The Gray Sheet" Aug. 25, 2008, p. 5).
These special supplements can only be used when a company acquires new safety-related information that was not previously submitted to FDA, resulting in labeling changes that add or strengthen contraindications, warnings or other safety-related information.
CDRH says that it will issue separate guidance for manufacturers on "manufacturing site change" supplements, a type of 180-day supplement required for a move to a different facility or establishment.
The guidance will describe the criteria for a site change supplement and when an FDA inspection would likely occur in these situations.
510(k) Modification Process Under Fire
FDA's policies on when modifications to a Class II, pre-market notification device will necessitate a new 510(k) submission are addressed in separate 6guidance, published in 1997.
But FDA frequently cites companies, through warning letters, for failing to submit 510(k)s for significantly modified Class II devices.
Safety concerns related to a modified mitral valve product from Edwards Lifesciences recently prompted Sen. Chuck Grassley, R-Iowa, to question how FDA's 510(k) product modification assessment process works (7"The Gray Sheet" Dec. 8, 2008, p. 5).
According to 510(k) staff director Heather Rosecrans, the 1997 510(k) modification guidance is still in use.
She noted that the document is not on the list of guidance documents that FDA plans to update in fiscal 2009.
"We are not aware of anything that has changed regarding its principles," added FDA's Tillman.
- Jessica Bylander
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