March 1, 2009 (Vol. 29, No. 5)
Jeffrey N. N. Gibbs
With Proper Use these Get-Togethers Can Be Valuable Assets for IVD Companies
In order to sell diagnostic devices in the U.S., in vitro diagnostic (IVD) manufacturers need to get marketing authorization from FDA. That raises an obvious question: How does a company know what data to submit and which regulatory pathway to use?
One way is to ask FDA for guidance. The Office of In Vitro Diagnostics has been receptive to meeting with companies and discussing clinical study plans and proposed regulatory pathway. These meetings are accomplished through the pre-IDE (investigational device exemption) process. (The term pre-IDE is something of a misnomer, because virtually all of these meetings occur without the company submitting an IDE.)
Should IVD companies request a pre-IDE meeting? If so, when? How can they get the most out of the meeting? This article will discuss these and other questions.
For many products, there is little point in seeking a pre-IDE meeting. Many IVDs—particularly ones that will go through the 510(k) process because these are virtually identical predicate devices—will traverse a well-defined process. FDA has issued guidance documents explaining what data are needed to obtain 510(k) clearance for many different diagnostics, such as drug-metabolizing enzyme-genotyping systems. These documents provide a road map for generating data and preparing the 510(k). Even where there is no guidance document, companies may be able to follow in the footsteps of predecessors. FDA posts on its website the internal review memorandum for many IVD 510(k)s; these documents can reveal what kinds of studies the 510(k) holder submitted. Although less detailed, the 510(k) summaries of safety and effectiveness are routinely posted on FDA’s website.
Companies, however, should not blindly follow these documents. Sometimes, pertinent details are omitted. If the documents are old, they may not be reliable; FDA frequently changes its data requirements. Just as road maps can become obsolete, so can FDA’s guidance documents and product-clearance precedents. Still, for well-established products, there is little reason to incur the delay and costs of holding a pre-IDE meeting.
Many IVDs, particularly new molecular diagnostic tests, are blazing their own paths, however. There are no maps to study, and the sponsor is facing terra incognito. Companies in this position should strongly consider requesting a pre-IDE meeting, even if a 510(k) is feasible.
Premarket Approval Application
Pre-IDE meetings are especially advisable for products that will be the subject of a premarket approval application (PMA). FDA makes a summary of the safety and effectiveness data for approved PMA publicly available. These summaries provide useful insights into what tests other companies conducted. Transcripts from panel meetings can be invaluable resources. Nevertheless, given the significant investment any PMA entails, it generally would be prudent to get FDA’s feedback on the study design. Assuming that what worked a few years ago for one company will still work today could be a costly mistake.
Holding Early-Stage Meetings
Once a company decides that a pre-IDE meeting is appropriate, it needs to determine when to hold the meeting. Some companies like to have meetings at an early stage, so they can introduce FDA to their technology and aspirations. In general, these meetings are not terribly productive. They do allow the company to meet some of the reviewers, and begin educating them on some of the novel features of the technology. FDA staffers are invariably polite and curious, and ask some good, probing questions.
Early meetings typically do not lend themselves to gaining targeted FDA feedback. They are more didactic, and less regulatory focused. Thus, while these meetings allow companies to put faces with names and familiarize FDA with their product and technology, the sponsor usually receives little information that will facilitate the clearance or approval process.
A company is better served if its pre-IDE meeting provides a forum for gaining feedback from FDA on well-defined questions. This requires there to be some crystallization of the company’s plans. Going into a meeting and asking FDA an open-ended question about what to do is a sure-fire way of courting trouble. For example, the company should never ask FDA what kind of clinical study to conduct; the company should seek FDA’s comments on the company’s own proposal. Therefore, a company should not ask to meet until it is prepared to provide to FDA an intended use (See GEN, November 15, 2008 “Adroit Crafting of Intended Use Critical”), a study population, a protocol, plans for preclinical testing, and a statistical plan.
Companies may also propose a regulatory pathway. There can be huge time and cost advantages in 510(k) review or de novo approval instead of a PMA (See GEN, August 2008, “Regulatory Pathways for Molecular Dx”). During the pre-IDE meeting, the FDA may indicate receptiveness toward a 510(k) or the de novo route. Other times, FDA will unequivocally state that a PMA is needed. This news may be unwelcome, but receiving it earlier helps planning and may provide an opportunity to revise the intended use and clinical protocol to restore the possibility of a 510(k). Other times, FDA will say that the classification decision must await the results of the study.
FDA will want the meeting materials long before the meeting. Sixty days or more is preferable, but FDA will often accept materials 30 days in advance. Thus, companies need to have a well-developed meeting and regulatory plan in advance of the meeting. The sponsor should also plan on submitting its meeting presentation in advance even though the document may be finalized only hours before the meeting.
As is the case for all FDA meetings, companies need to prepare. When rehearsing presentations, companies should not neglect practicing how to respond to FDA’s questions. Companies should expect to be challenged. It is therefore important not just to fine-tune the planned remarks, but to work on the responses to the foreseeable probing questions. Having an outsider or two ask questions during a practice session can help the company get ready for the difficult questions it is likely to face. It can also help the presenters gain experience in thinking on their feet and responding to questions they had not anticipated. Companies also need to consider who should attend the meeting. They will want to have sufficient personnel to address various issues, e.g., clinical, statistical, legal, and regulatory, without appearing in overwhelming numbers.
Companies need to have a realistic understanding of what can be accomplished at a pre-IDE meeting. They will not receive any binding assurances from FDA. The meeting may proceed smoothly, FDA may raise no objections, the meeting minutes may reflect a consensus on how the company should proceed, and then FDA may reverse its position once the application is submitted. To say that this happens is not to defend it.
The pre-IDE process does not provide absolute certainty. FDA may change its requirements for good reasons such as new scientific information or significant changes in clinical practice or, unfortunately, for less compelling reasons. Companies therefore need to be alert for developments that may bear upon FDA’s willingness to accept the proposed clinical and regulatory plan.
Companies can, however, be fairly confident that objections expressed at the pre-IDE meeting will not dissipate with the passage of time. If there are strong objections to the intended use, or the staffers say that a PMA will be needed, companies should pay close heed. Companies need to listen very carefully; the objections may take the form of pointed questions. To put this in diagnostic terms, the negative predictive value of pre-IDE meetings is very high, while the positive predictive value is not as robust.
These caveats notwithstanding, the sponsor should make sure that there is some agreement on the key points before the meeting adjourns. There may be issues that the sponsor and FDA acknowledge are left unresolved. It is important, though, for the sponsor to try to achieve an understanding with FDA on the pivotal issues. The sponsor may therefore want to assign some team member the responsibility of summing up the meeting outcome before the meeting ends. Subsequently, the sponsor should submit minutes to memorialize the meeting.
Used properly, pre-IDE meetings can be valuable tools, benefiting both FDA and the sponsor. It, therefore, behooves IVD companies to make the most of each pre-IDE meeting they have.
Jeffrey N. Gibbs ([email protected]) is director at Hyman, Phelps & McNamara. Web: www.hpm.com.