Medical Device Link.

Originally Published IVD Technology March 2003

Regulations & Standards

Part 3: FDA panel meetings—and beyond

Thomas M. Tsakeris

Thomas M. Tsakeris is a former director of FDA's Division of Clinical Laboratory Devices. He is now president of Devices and Diagnostics Consulting Group (Rockville, MD) and a member of the IVD Technology editorial advisory board.

IVD manufacturers whose products are subject to FDA’s premarket approval (PMA) process have good reason to exercise great care in the preparation of such applications. Although the PMA requirement applies to only a handful of IVDs annually, development of an approvable application is both complex and labor-intensive. Moreover, delay or denial of approval can readily become a business-endangering decision, especially for small start-up companies. 

The first two installments of this article (IVD Technology, November/December 2002 and January/February 2003) discussed the criteria that FDA employs to determine whether an IVD product is subject to the PMA requirement, and how manufacturers can best go about managing the development of their PMA applications. This installment looks at the part of the PMA process that many sponsors consider the riskiest and most uncertain phase of all—the FDA panel hearing.1 This part examines the role of FDA advisory panels in the PMA process, and offers recommendations about how IVD manufacturers can best prepare for a panel meeting. 

The uncertainty of FDA panel meetings stems from the fact that once the meeting commences, the dynamics and interactions among panel members and sponsor representatives can often lead the discussions in unpredictable directions. Although FDA staff may attempt to keep such discussions under control, the degree to which an individual panel maintains its focus often depends on the stewardship of the panel chairman, which can vary greatly from panel to panel.

Adding to the anxiety of PMA sponsors is the fact that panel meetings occupy an important role in FDA’s process. In the great majority of instances, FDA will concur with panel recommendations with regard to the approval, conditional approval, or nonapproval of the PMA application under discussion.

Preparing for the FDA Panel Meeting

With so much on the line, it is obviously imperative that the sponsors of IVD PMAs prepare very carefully for the defense of their PMA applications before the advisory panel. Diligence at this stage of the process can help sponsors to anticipate questions that may be asked by panel members and ensure a successful outcome to the panel hearing. Sponsors should pay special attention to the following areas.
FDA Feedback. The first step in preparing for an advisory panel hearing is to review carefully any feedback that the sponsor has previously received from FDA about the progress of the review. 

During the course of the panel review, FDA reviewers frequently communicate with PMA sponsors, either informally (by phone, fax, or e-mail) or formally (through official action letters, such as filing letters, deficiency letters, and so on). FDA usually apprises sponsors of comments and issues that have been raised during this phase of the panel review. 

Manufacturers should take special note of any comments or questions that relate to the clinical utility of the test, or concerns about when and under what circumstances the test should be performed. Adequately responding to questions such as these can be crucial, since FDA depends on its panels for advice concerning clinical issues above all others, and often defers to them on questions about the clinical utility of tests. 

The Panel Presentation Team. The IVD sponsor should ensure that its panel presentation team is appropriately selected and well prepared. Often, a panel presentation team is headed up by a lead spokesperson (frequently the company’s regulatory affairs professional), who is responsible for introductions, for providing an overview of the PMA application, and for designating appropriate company spokespersons to respond to panel questions.

Other sponsor representatives typically include a person who can provide a concise description of the test; a person who can discuss the preclinical study data; a person who can discuss the details of the clinical study; a person who can discuss the test results and data analysis (often the firm’s biostatistician); and a person who can discuss the conclusions of the study and provide a clinical perspective on the test results.  Whenever possible, PMA sponsors should seek to restrict their panel presentations to a maximum of one hour.

It is imperative that each member of the panel presentation team be well prepared for the company’s own presentation as well as for the questioning by panel members that will follow. The key to such successful preparation is to rehearse and rehearse, and then rehearse some more. To help members of the presentation team rehearse for the panel meeting, many successful PMA sponsors recruit independent outside experts in the relevant medical and scientific disciplines. Such moderated rehearsals sometimes take the form of a mock panel meeting, which can be a very effective way of preparing team members for unexpected lines of questioning and discussion. 

Read the Panel. The interests and pursuits of individual panel members can have a profound influence on the line of questioning that a panel pursues and the direction of its discussions as a whole. For this reason, sponsors would be well advised to ask FDA’s executive secretary for the names of the members who will compose the panel. It will not always be possible to discover the exact composition of a panel until a few days before the meeting, because scheduling conflicts or conflict-of-interest considerations may result in last-minute changes. 

Nevertheless, sponsors should attempt to discover the scientific and medical backgrounds and pursuits of as many panel members as possible. Such information can prove valuable in predicting the types of questions and issues that may be raised at the meeting. 

FDA Staff Presentation. In addition to the PMA sponsor’s presentation, FDA staff will also schedule time to make their own panel presentation. Such FDA staff presentations usually focus on the sponsor’s indications for use, the supporting validation studies submitted in the PMA application, and the results of the sponsor’s data analysis.

FDA staff will also present at least one slide that focuses on topics, issues, or questions that the agency would like the panel to address as part of its deliberations. FDA is usually willing to share copies of its slide presentation with the PMA sponsor prior to the panel meeting. However, agency staff are often working on their presentation up to the day before the meeting, so PMA sponsors may not have the benefit of much advance notice about the content of the FDA presentation.

Sponsors should also be aware that FDA reserves time at panel meetings to entertain comments from interested public attendees with respect to the PMA under review. At many panel meetings, however, there are few or no public comments.

The Panel Recommendation. Following all the presentations and panel deliberations, FDA will ultimately ask the panel to make a recommendation for disposition of the PMA application. The panel may recommend one of three options: approval with no conditions, approval with conditions, or nonapproval. 

If the panel votes for nonapproval, the agency typically requests that it also advise the sponsor about what additional information would be needed to make the PMA approvable. Such a recommendation can easily set a company’s product-approval efforts back by months, especially if the panel advises that additional clinical studies must be performed. Avoiding such a possibility should be one of the major goals of a company’s PMA planning. 

Fortunately, most panels recommend that the sponsors’ PMA applications be approved with conditions. Conditions recommended by advisory panels typically involve revisions of product labeling, additional minor studies involving analytical test issues, or, in some cases, performance of postapproval studies.

Bringing Closure to the PMA Process 

Given a favorable panel hearing, many PMA sponsors expect that FDA will grant final approval within a few weeks. However, it often takes more time than that to resolve the various technical issues that emerged during FDA’s scientific review of the PMA application, including any such questions that arose during the panel meeting. 

Even more PMA applications could be approved soon after panel meetings if it were not for FDA’s frequent discovery of other deficiencies requiring resolution. Such PMA deficiencies often arise from the agency’s bioresearch-monitoring inspections or PMA inspections of the sponsor’s manufacturing facilities. However great their euphoria over a successful panel meeting, PMA sponsors must remember that deficiencies in their manufacturing operations can bring a halt to the PMA process just as quickly as a panel recommendation of nonapproval. Since sponsors will be required to correct all such deficiencies before final approval will be granted, they would be well advised to ensure that the ramp-up of manufacturing facilities is carried out in time to meet FDA’s schedule of inspections. 

One factor that works in favor of sponsors is FDA’s desire to continually improve its administrative record for bringing closure to PMA applications soon after panel meetings. Pressure to show advances in this area is likely to become even more intense in light of the recent enactment of device user fees.2 

Several years ago, FDA’s former Division of Clinical Laboratory Devices instituted a pilot program to streamline the PMA process for IVDs meeting certain criteria.3 Although it is not known whether the pilot will ever become part of the mainstream PMA review process, certain elements of the pilot could reasonably be applied to expedite final processing of the PMA application.

Immediately following the panel meeting, for example, sponsors should consider requesting a meeting with FDA to resolve outstanding issues such as product labeling and bioresearch-monitoring deficiencies. If such a meeting is successful in resolving the remaining issues, the sponsor could then request that FDA move to issue a final PMA approval action rather than the intermediate step of issuing an approvable action. 

Conclusion

Prospective IVD sponsors have every reason to be apprehensive about the prospect of having their products undergo the PMA review process. For the small IVD start-up in particular, preparing a successful PMA can be a strain on company resources. 

With good planning, commitment, and management, however, any IVD company should be able to join the multitude of other companies that have successfully passed the test. 

References

1. Guidance on Amended Procedures for Advisory Panel Meetings, in CDRH Home Page [on-line] (Rockville, MD: FDA, Center for Devices and Radiological Health, Office of Device Evaluation, 2000 [cited 12 December 2002]); available from Internet: http://www.fda.gov/cdrh/ modact/amendpan.pdf. 

2. Medical Device User Fee and Modernization Act of 2002, Pub. L. 107-250. 

3. “In Vitro Diagnostic Model for a Pilot for Streamlined PMA Review,” in CDRH Home Page [on-line] (Rockville, MD: FDA, Center for Devices and Radiological Health, Office of Device Evaluation, 1998 [cited 12 December 2002]); available from Internet: http://www.fda. gov/cdrh/pmat/streampmat.html. 

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