November 15, 2008 (Vol. 28, No. 20)

Regulatory Fate of a New IVD May Well Depend on a Few Dozen Words

In vitro diagnostic (IVD) devices are comprehensively regulated by the FDA. The FDA, however, does not regulate just the physical materials and software comprising an IVD.

When developing a new assay, IVD companies tend to focus on key physical aspects: the composition of the assay, what it detects and how well, and how the results might be used clinically. Developing and refining the assay necessarily require— and receive—the bulk of the attention. Whatever kind of test, it cannot be successful unless the tangible components, such as reagents, instruments, and software, result in a diagnostic product with the requisite clinical performance.

Thus, it is completely understandable that the research and development phases concentrate on the composition of the assay and improving its performance. This focus, however, can overshadow another fundamental attribute of the product—its intended use.

From a regulatory perspective, a key component of the IVD is an intangible attribute—the product’s intended use. It is no exaggeration to say that the regulatory fate of a new IVD may hinge on the few dozen words comprising the proposed intended use.

The intended use also plays a pivotal role in determining the commercial success of the product by establishing the claims that can be made when marketing the product. Thus, IVD companies need to understand what the term “intended use” means and its regulatory significance.


By FDA regulation, 21 C.F.R. § 801.4, the intended use of a device refers “to the objective intent of the persons legally responsible for the labeling of device.” Thus, the intended use is controlled by the company’s own words.

The definition does go on to say that the intended use can be established by known off-label use of the device. That portion of the regulation, which has created considerable confusion, can essentially be ignored.

The intended use is determined by the applicant, not by subsequent third party use. If FDA believes that a device that is the subject of a 510(k) premarket notification is likely to be used off-label and that a particular use may present health risks, FDA can mandate a warning against that use. FDA cannot, however, reject a 510(k) because of anticipated off-label use.

The intended use will delineate and circumscribe the company’s ability to promote its IVD. All “labeling” must be consistent with the intended use.

Labeling is broadly defined by law, and covers virtually all promotional materials created or distributed by the company or its agents. Oral communications, such as statements by sales representatives, must also be consistent with the intended use statement. Claims that go beyond the labeled intended use are deemed off-label and can result in FDA enforcement action.

Thus, submitting an application for a narrow, unmarketable intended use simply to obtain FDA clearance can result in a commercial dead end. The product may lawfully be sold, but the ability to promote it would be fatally constrained.

Intended use should not be drafted solely with the input of regulatory personnel. Sales and marketing personnel should provide guidance, as well. Companies must consider the potential impact of the intended use on the commercial success of the product.

The FDA regulatory process will culminate in an approval or clearance for a clearly defined intended use. The final labeling will explicitly state the product’s intended use.

For 510(k) notices, the intended use (or, more precisely, “Statement of Indications for Use”) is actually recited in a special, publicly available form submitted by the company to the FDA. While the meaning of the intended-use statement can be ambiguous, there is no uncertainty as to the words themselves. These words constrain product promotion. As an FDA guideline says, the intended use “must be consistent with your labeling, advertising, and instructions for use.”

They also play a pivotal role in the ability to secure adequate insurance coverage. Therefore, they need to be consistent with the company’s long-term commercial objectives.

Regulatory Pathway

The level of FDA regulation of an IVD is heavily influenced by the regulatory risk. At one extreme, a very low risk Class I IVD may be exempt from the need for any FDA clearance and from compliance with most elements of the Good Manufacturing Practice (GMP) regulation. IVDs that present higher risks may need to meet GMP requirements and receive a 510(k) clearance.

At the other end of the spectrum are high risk Class III IVDs that must comply with the GMP regulation and go through the far more demanding premarket approval application (PMA) process before entering the market. The regulatory costs and timelines vary widely between these groups.

The IVD’s intrinsic properties, for example the biomarkers that are detected, will influence the level of regulatory control that applies. However, the intended use may ultimately determine whether a product needs a 510(k) or PMA before entering the market, or is eligible for de novo classification.

Seemingly small changes in wording may have a huge impact. Tests to measure prostate specific antigen (PSA) to screen for prostate cancer have required a PMA; the same test needs a 510(k) if intended to monitor PSA levels in patients diagnosed with prostate cancer. Similarly, an IVD that screens for ovarian cancer will need a PMA. An IVD intended to help stratify the risk of ovarian cancer in women who have pelvic masses and are scheduled to have surgery may be reviewed via the 510(k) or de novo process.

Thus, for these two examples, it is not sufficient to say that they are “PSA tests” or “ovarian cancer tests.” Those terms are not intended uses and therefore do not define the regulatory pathway. The intended use describes not only what is measured but also what is to be done with that information—screen, diagnose, monitor, or give a prognosis and in what population.

In analyzing how long it will take to get to market and regulatory costs, the company must evaluate the specific intended use that will be submitted to FDA. When developing a regulatory strategy for a new IVD, it is crucial that the company precisely define its intended use, because those words may control the route to market.

Intended Use and Clinical Studies

The failure to have a well-defined intended-use statement can undermine the company’s clinical strategy as well. The majority of new types of assays will need clinical data to meet FDA’s requirements. These data will be evaluated against the proposed intended use. The data may show good performance vis-à-vis the protocol, but that will not satisfy the FDA unless the data are generated in a study that essentially mirrors the proposed intended use.

For example, showing that a PSA test is accurate in patients already diagnosed with prostate cancer does not necessarily mean that the device will perform satisfactorily in a screening population. Creating the necessary parallelism between intended use and protocol can be particularly challenging when working with banked tissue.

Therefore, before embarking on its clinical study, the IVD company must have established its proposed intended use. The protocol should be designed to secure data that is directly supportive of the proposed intended use. Otherwise, the company may be stuck with having to fit its intended use statement into the data that have already been generated. This Procrustean bed process of stretching and cutting can be painful, unwieldy, and unsuccessful.

This is not to say that the proposed intended-use statement will emerge intact from the regulatory process. That is relatively uncommon. The FDA process often results in some revisions. However, a fundamental disconnect between the study design and projected intended use can preclude clearance or approval, or yield a very different intended use than what was desired.

For these reasons, it is critical for IVD companies to carefully draft their intended use early in the regulatory process. This statement will have a major impact on study design, regulatory pathway, marketing position, and reimbursement. Something this important should receive careful, considered attention.

That however, is not always the case. IVD companies sometimes develop their proposed intended use after crafting the protocol or, even worse, without ensuring the intended use even matches the study data. Other times companies rewrite their proposed intended use just hours before meeting with the FDA to discuss the protocol or submission, leaving insufficient time to consider the ramifications of the new wording.

IVD companies and their investors lavish attention, time, and money on the biomarkers, technology, and physical materials comprising the IVD. Developing a proposed intended use does not require much money, however, the failure to thoughtfully consider and construct those words at an early point can prove costly in both time and money.

Jeffrey Gibbs ([email protected]) is director, Hyman, Phelps & McNamara. Web:

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