The US Food and Drug Administration (FDA) has finalized a draft guidance on the distribution of investigational in vitro diagnostic (IVD) products, establishing the conditions under which the agency would not object to their dissemination and removing a highly controversial provision present in an earlier iteration of the guidance.
Under US federal law, products that have not been approved for use by FDA are barred from being distributed under the Federal Food, Drug and Cosmetic Act (FD&C Act). However, regulators are permitted to make exemptions to that ban on a case-by-case basis, and do so often. When a company submits an investigational new drug (IND) or investigational device exemption (IDE) application, it is actually not applying for approval for the trial, but rather for an exemption from interstate commerce law under the FD&C Act.
If an IDE is approved, it must bear the following statement: "CAUTION--Investigational device. Limited by Federal (or United States) law to investigational use." This is intended to warn patients and providers that though a device may be available, it has not necessarily been shown to be safe, effective or even manufactured to appropriate standards.
IVDs, however, are subject to exemptions from the IDE regulation. Under 21 CFR 809.10(c)(2)(i), IVDs "in the laboratory research phase of development, and not represented as an effective IVD" may be placed on the market so long as they bear the following labeling prominently:
"For Research Use Only. Not for use in diagnostic procedures."
This labeling requirement is also known by its acronym, RUO.
Under 21 CFR 809.10(c)(2)(ii), a second exemption for investigational devices seeking full marketing authorization (i.e. operating under an IDE) are also subject to unique labeling requirements. Products "being shipped or delivered for product testing prior to full commercial marketing" must be labeled with the following statement:
"For Investigational Use Only. The performance characteristics of this product have not been established."
This labeling requirement is also known by its acronym, IUO.
2011 Draft Guidance
In 2011, FDA published a draft guidance on the use of both terms-IUO and RUO-in which it said that some companies had been abusing the terms in order to market "unapproved and uncleared IVD products for purposes other than research or investigation has led in some cases to diagnostic use of laboratory tests with unproven performance characteristics and manufacturing controls that are inadequate to ensure consistent manufacturing of the finished product."
Some patients have been subject to testing using RUOs that could subject them to harm, FDA said.
The guidance went on to define the necessary qualifications of an RUO/IUO, which must:
- be non-invasive
- not require an invasive sampling procedure that presents a significant risk
- not by design or intention introduce energy into a subject
- not be used as a diagnostic procedure without confirmation of the diagnosis by another, medically established diagnostic product or procedure
- be clearly labeled as either RUO or IUO
Most Importantly (and Controversially)…
Most importantly, the draft guidance sought to bar companies from selling a RUO or IUO test to a customer who is known to use the product outside the parameters of the RUO/IUO statement.
The guidance has been subject to some controversy, as it was seen as dramatically expanding FDA's authority to go after companies based on the actual-rather than marketed-use of the device.
In August 2013, a legislator introduced the Medical Testing Availability Act (MTAA), which would have limited FDA's ability to prevent RUOs from being sold to end users who are known to use the product in a manner inconsistent with the RUO statement. The legislation has not yet passed the House of Representatives.
Changes in the Final Guidance
Now FDA is out with a revised final draft guidance that reflects both changes to the substance and the name of the guidance.
The guidance, now known as Distribution of In Vitro Diagnostic Products Labeled for Research Use Only or Investigational Use Only, was previous known as Commercially Distributed In Vitro Diagnostic Products Labeled for Research Use Only or Investigational Use Only: Frequently Asked Questions.
In the guidance, FDA appears to have removed all reference to actual use, and instead now only references the "objective intent" of those who label the product.
"Overt expressions by the manufacturer, such as those present in labeling and advertising, may be sufficient to show determine that an IVD product is inappropriately labeled RUO or IUO, when such expressions demonstrate that the device is actually intended for clinical use despite the RUO or IUO labeling," FDA wrote.
Absent are any major statements by FDA that the actual use of the device would be sufficient in and of itself to render a product misbranded. However, FDA maintains that the "totality of the circumstances surrounding the distribution and use [emphasis added] of an RUO or IUO products should be considered when assessing its intended use."
Manufacturers will be allowed to conduct maintenance and general non-diagnostic use-specific technical support, FDA added.