October 1, 2012 (Vol. 32, No. 17)

Though Not Revolutionary, New Act Could Offer Significant Benefits to In Vitro Diagnostic Firms

On July 9, President Obama signed into law the Food and Drug Administration Safety and Innovation Act (FDASIA). FDASIA significantly affects both pharmaceutical and device manufacturers. It has a direct impact on all in vitro diagnostic (IVD) manufacturers, and for IVD companies developing companion diagnostics, an indirect effect as well through FDASIA’s numerous provisions relating to drugs.

FDASIA is long and complex with over 130 different sections. Some of the legislative language is confusing, and debates about how to apply it are inevitable. This article will focus on the provisions most important to IVD companies.

Historically, IVD companies have submitted relatively few investigational device exemptions (IDEs). With the rise in companion diagnostics, though, the number has increased. FDASIA limits the grounds for denying an IDE.

Specifically, FDA could not deny an IDE based on its determination that: 1) the study may not support a substantial equivalence, de novo, or approval decision; 2) the investigation may not meet a requirement for approval or clearance of a device; or 3) the sponsor may need to conduct an additional or different investigation to support clearance or approval of the device. In other words, an IDE cannot be denied simply because FDA doesn’t believe the ensuing study will be adequate.

The long-term utility of this change for IVD companies is debatable. Though it could lead to the approval of more IDEs, gaining IDE approval may not be helpful if it generates data that will not ultimately support clearance or approval. Still, it should facilitate the initiation of research, which could be beneficial in various ways.

IVD firms in the past tended to submit few investigational device exemptions (IDEs). With the growth of companion diagnostics, the number has increased. FDASIA limits the grounds for denying an IDE. [Rob Byron/Fotolia]


FDASIA requires the Center for Devices and Radiological Health (CDRH) to make available to an applicant a “substantive summary of the scientific and regulatory rationale for any significant decision” regarding 510(k) submissions or premarket approval (PMA) or IDE applications. The summary must include “documentation of significant controversies or differences of opinion and the resolution of such controversies or differences of opinion.”

FDA must provide the substantive summary to the party “seeking to submit, or who has submitted” a 510(k) notification or PMA or IDE application. (This language does not permit a party to request a substantive summary of a decision relating to a third party.)

While the section doesn’t define what constitutes a “significant decision,” it presumably would be decisions to deny 510(k)s, PMAs, or IDEs, or adverse statements by FDA regarding a company’s prospects for success or the pathway it must follow.

After receiving the documentation, the applicant may appeal an adverse “significant decision.” The appeal must be submitted within 30 days. CDRH then has 30 days to schedule the appeal in-person meeting or telephone call. CDRH then has 30 days to issue its decision after the appeal is heard. If a company submits a written appeal in lieu of a meeting or telephone call—an option which should rarely if ever be used—CDRH must issue its decision within 45 days.

The appeals process has not been one of CDRH’s strong suits. A major problem has been timing: the meetings take too long to schedule, and CDRH is slow in issuing decisions. This provision will speed up the appeals process. The access to documentation should give companies new insight into FDA decisions, thereby helping frame the appeal. The long delays in having appeals heard and decided have deterred appeals.

FDASIA makes the appeals process a more attractive option. Unfortunately, the legislation neither addresses CDRH’s strong inclination to deny appeals nor improves the fairness of the appeals process, which is procedurally stacked against the manufacturer.

Modifications Requiring Premarket Notification

FDA has cleared thousands of IVD 510(k)s. One challenge for 510(k) holders has been deciding when a product change requires a new 510(k). This has long been a vexing issue.

By January 9, 2014, FDA must submit a report to Congress on the criteria for when a device modification requires a new 510(k) submission. The regulation controlling when a new 510(k) must be submitted contains pivotal but ambiguous phrases: “could significantly affect the safety or effectiveness of the device,” “a significant change or modification in design, material, chemical composition, energy source, or manufacturing process,” and “major change or modification in the intended use of the device.” FDA’s report must provide FDA’s interpretation of these phrases.

FDASIA requires FDA to consider the input of “interested stakeholders” when developing the report. FDA may not issue any draft guidance or proposed regulation until Congress receives the report, and may not issue any final guidance or regulation until at least one year later. Given the importance of this issue, it is one that IVD 510(k) holders will want to monitor carefully.

FDA had issued a proposed draft guidance on July 27, 2011. This draft provoked widespread opposition. FDASIA states that FDA may not use the draft “as part of, or the basis of, any premarket review or any compliance or enforcement decisions or actions,” and that the old 1997 guidance on device modifications remains in effect. IVD companies should be alert to FDA staff trying to apply the rejected draft guidance.

De Novo Application Process

The 510(k) process is generally the preferred route for IVD companies. However, to obtain 510(k) clearance requires demonstrating “substantial equivalence” to a “predicate device.” For newer IVDs, there may not be a clear predicate device. The de novo process provides a solution, essentially allowing low and moderate risk devices to go through the 510(k) process despite the lack of a predicate.

FDASIA tries to improve the de novo process. Previously, a sponsor had to submit a 510(k) notification to FDA and receive a “not substantially equivalent” letter before submitting a de novo petition, even if the sponsor and FDA knew no appropriate predicate device existed. Moreover, there was no way to definitively find out in advance whether FDA would agree the product was eligible for de novo review.

FDASIA allows a sponsor to ask FDA if an IVD can go through the de novo process without first submitting a 510(k). FDA can agree that the de novo route is appropriate. Alternatively, FDA could identify a predicate device that the company could use. This action would mean there is no need for the de novo process because a traditional 510(k) can be used instead.

On the other hand, CDRH can decide that there is no predicate and the product is not eligible for de novo review if it finds that the device is not “low-moderate” risk or that general controls would be inadequate to control risks and special controls cannot be developed. Unless overturned, this decision means a PMA will be necessary.

This provision could have a significant positive effect. It creates a vehicle for IVD companies to learn early on whether the de novo pathway is open, a 510(k) can be submitted, or a PMA will be required. Many novel IVD products lack clear-cut predicate devices.

Unfortunately, because Congress gave FDA 120 days to respond to the request, the process may not provide speedy answers for sponsors. Even so, gaining that information early in the process could be helpful. Moreover, Congress’ actions may encourage FDA to use the de novo process more.

FDASIA contains other provisions that may be relevant, such as expanding the Humanitarian Device Exemption Program for products for rare diseases, modifying FDA’s device recall program, and reinforcing the importance of the “least burdensome” standard.

In addition, FDA has committed to new user fee goals, which should result in faster decision making. One direct effect is FDA’s issuance of a Refuse to Accept draft policy for 510(k)s. Companies submitting 510(k)s should carefully examine this checklist before sending their notification to FDA.

FDASIA does not revolutionize FDA regulation of IVDs. However, some of the provisions may offer significant benefits to IVD companies. Companies therefore should evaluate what impact the law may have on their regulatory situation and how to use the law to their advantage.

Jeffrey N. Gibbs ([email protected]) is a director at Hyman, Phelps & McNamara.

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