IVD Technology
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Originally published March, 1998
Regulations and Standards
FDA's RUO/IUO Policy: A Small Step Forward
Jeffrey N. Gibbs
Over the past decade, the regulation of research use only (RUO) and investigational use only (IUO) products has been one of the most contentious compliance issues in the IVD arena. FDA has been trying to develop a policy for the regulation of RUO and IUO products for many years. This January, the agency took another step toward finalizing its regulatory approach by releasing its latest draft of an enforcement policy.
The new document is a compliance policy guide (CPG) entitled "Commercialization of In Vitro Diagnostic Devices (IVDs) Labeled for Research Use Only or Investigational Use Only."1 It represents a significant development not only because it supersedes the previous draft policy statement, issued in May 1996, but also because it is a step closer to whatever FDA's final policy may become.2
Because this document is a compliance policy guide rather than a regulation, it will never be legally binding. On the other hand, the final CPG will be an important expression of FDA policy. When finalized, it will provide manufacturers with a useful guidance to the agency's enforcement priorities with regard to RUO or IUO products that the agency believes are being commercialized improperly.
Background
Unapproved RUOs and IUOs are subject to FDA's requirements for IVD labeling and, potentially, to the agency's investigational device exemption (IDE) regulation.3,4 To be exempt from the IDE regulation, unapproved RUOs and IUOs must meet certain conditions specified by that regulation, and must also comply with the agency's labeling requirements for research and investigational devices.5,6
Over the past decade, however, FDA has frequently expressed its concern that many manufacturers are not following these requirements. The agency believes that unapproved products labeled for RUO or IUO are often distributed commercially, resulting in the widespread use of laboratory tests with unproven performance characteristics. In the latest draft of the CPG, the agency asserts—without citing any evidence—that the use of such tests can mislead providers of medical diagnoses and treatment, and cause serious adverse health consequences for patients.
Nevertheless, FDA recognizes that certain commercialized products have been in extensive clinical use for a significant period, and that immediate regulatory action against them might result in adverse public health consequences. Therefore, to avoid disrupting the beneficial uses of RUOs and IUOs, FDA proposes to prioritize its enforcement actions based on how long the product has been distributed.
Grace Period
According to the new draft of the CPG, manufacturers of unapproved RUOs and IUOs must take steps to obtain FDA approval or clearance for their products. Those steps include undertaking, within six months of the publication of the final CPG, any clinical investigations or studies necessary to enable the agency to determine the product's safety and effectiveness. Clinical studies must be conducted in accord with the informed consent and institutional review board (IRB) requirements. (An IRB can waive the informed consent requirement.)
This requirement to obtain product approval or clearance will not affect all products at the same time. FDA contends that companies whose RUOs and IUOs have been commercialized for relatively long periods should be able to generate data more quickly than those that have just begun commercializing their products. Thus, for products that have been in use for more than 10 years, the agency will permit a grace period of up to 18 months from the publication of the final CPG. For products that have been in use 5 to 10 years, the grace period is 24 months; for those in use less than 5 years, 30 months.
The 1996 version of the CPG provided a uniform 30-month grace period. In the latest version, FDA does not explain why it shortened the grace period or how it arrived at the staggered grace periods.
Although FDA maintains that 18 to 30 months is a reasonable period for gathering safety and effectiveness data and obtaining approval or clearance, for many premarket approval (PMA) devices this assertion is incorrect. And even for some premarket notification (510(k)) devices, 18 months may be insufficient to devise and conduct a clinical study, submit the data, answer FDA's questions, and gain clearance. Presumably, FDA will not take enforcement action against companies that are making good faith attempts to secure approval, even if the deadline has passed.
The grace periods apply only to products that are already in commercial distribution for diagnostic or prognostic purposes when the final CPG is published. New products "are required to have agency clearance or approval, as appropriate, prior to commercialization and the agency does not intend to exercise enforcement discretion with respect to these products."7
So long as manufacturers meet the requirements of 21 CFR 809 and 812, however, nothing in the draft CPG prohibits them from conducting clinical investigations with new IUO products prior to clearance or approval. In other words, the draft CPG should not be read as precluding research projects or clinical studies with new tests. Rather, FDA appears to be saying that new IUO products may not be commercialized for diagnostic or prognostic purposes, and that they must be labeled properly.
Enforcement Priorities
Investigational devices labeled as "Research Use Only" must be relabeled within three months of the publication of the final CPG, or the product will be placed into enforcement priority category I and be subject to immediate enforcement action. This policy is based on FDA's assertion that
devices labeled "For Research Use" are mislabeled if the device is being used for investigational purposes, i.e., in a clinical study, even if involving only one subject, where the diagnostic or prognostic measurement will be reported to the patient's physician or medical records or will be used to assess the patient's condition, regardless of whether confirmational tests or procedures are used.8
In effect, FDA is saying that even a single off-label use by a physician can determine a product's intended use. This is very different from the more traditional policy, in which a product's intended use is determined by the manufacturer's intent.
The draft CPG authorizes FDA district offices to prepare warning letters for companies that do not comply with its requirements. Before the letters are issued, however, the district offices must gain concurrence from the Office of Compliance at either the Center for Devices and Radiological Health (CDRH) or the Center for Biologics Evaluation and Research (CBER).
For some products, however, FDA intends to take much more direct action. The draft CPG states that the agency will take "immediate regulatory action" to remove from the market "high risk" categories of RUOs and IUOs identified as belonging to enforcement priority category I. An unapproved, commercialized RUO or IUO can fall into this highest enforcement category if the product
is being used as a stand alone test for diagnostic, monitoring, or screening procedures, and...the test result may lead to a significant medical decision or intervention (e.g., organ removal, surgery, radiation therapy, chemotherapy, drug treatment with potentially severe toxicity, or quarantine), and...there is a significant question as to the IVD's safety and effectiveness, as demonstrated by the review of scientific literature or by an assessment of standards of accepted medical practice.9
In keeping with this policy, the new draft CPG states that RUOs and IUOs "used for diagnosis or prognosis in humans for which there are no data on human use or only anecdotal data to support safety and effectiveness of the device, as determined by FDA" should be removed from the market immediately.9
Unfortunately, the agency did not provide any specific examples of products that might fall into this enforcement category. Presumably the group will be a small one, since RUO and IUO tests are rarely used as the stand-alone basis for a significant medical decision; other clinical information generally plays a large role. Moreover, by the time the final CPG is published, some of these products will have been on the market for years, and it is unclear how they could truly be considered high-risk diagnostics.
Products assigned to enforcement priority category II—that is, all products not in category I—are not necessarily immune from enforcement action. FDA will take action against any manufacturer that fails to comply with the labeling requirements within three months of the final CPG; any manufacturer that fails to commence, within six months of the final CPG, a valid study under a protocol sufficient to allow determination of the product's safety and effectiveness; or any manufacturer that fails to obtain clearance or approval within the relevant grace period.10
The CPG in Context
The new draft CPG differs from its 1996 predecessor in several respects. Already noted is the fact that it establishes staggered grace periods for implementation, whereas the 1996 draft prescribed only one 30-month grace period for all products. (An even earlier version listed specific products that would receive a grace period.)
Another difference involves the definition of high risk as it applies to the RUOs and IUOs that will be subject to "immediate regulatory action" upon publication of the final CPG. One criterion, specified in the 1996 draft, is "inadequate scientific proof of the IVD's safety and effectiveness, as determined by FDA."11 Attempting to clarify this term, the new CPG draft now says that high risk indicates that "there is a significant question as to the IVD's safety and effectiveness, as demonstrated by the review of scientific literature or by an assessment of standards of accepted medical practice."9
The new draft CPG does not explicitly acknowledge a citizen petition submitted by the Joint Council of Immunohistochemical Manufacturers (JCIM; Crestwood, MO) seeking to establish a category of products that would be labeled "For Experimental Use Only. Not Intended for Investigational, Diagnostic, or Therapeutic Use." The intent of such a category would be to distinguish in vitro products that are intended solely for basic scientific research, and therefore are not subject to FDA authority.
Nevertheless, the agency does acknowledge the concept that the CPG "does not pertain to in vitro products whose use is limited to laboratory research that is entirely unrelated to the development of IVDs." In the new CPG, FDA expands the definition of research use to include both "the initial research phase of product development that is necessary to identify test kit methods, components, and analytes to be measured," and "laboratory research that is entirely unrelated to product development."8 This definition recognizes that certain products never evolve beyond being laboratory research tools. Unfortunately, the draft CPG later confuses the issue by defining an RUO product as one "in the laboratory research phase of development."12 These two definitions are not entirely consistent with one another, and will need to be clarified for the final version of the CPG.
Like its predecessor, the new draft CPG encourages, but does not require, manufacturers, importers, and distributors of RUO and IUO products to develop user certification programs. According to FDA, such a program "will help . . . ensure that the distribution and use of their IVDs will be controlled and limited to use in scientifically sound research or investigations."13
This draft CPG does not cover analyte specific reagents (ASRs), which were recently defined in FDA's final rule on ASRs. These products are now separately regulated.14
Conclusion
Although FDA's policy on RUOs and IUOs has had a prolonged gestation, there is still uncertainty as to when it will be finalized. Given that the new draft CPG is very similar to its predecessor, one would assume that the final version will look much like this one. However, a number of questions and ambiguities still exist, and it remains to be seen whether FDA will use the next iteration to improve its policy.
References
1. "Commercialization of In Vitro Diagnostic Devices (IVDs) Labeled for Research Use Only or Investigational Use Only," draft compliance policy guide, chap. 3 devices, subchap. 300 general/processes, Rockville, MD, FDA, Office of Regulatory Affairs, January 5, 1998.
2. "Commercialization of In Vitro Diagnostic Devices (IVDs) Labeled for Research Use Only or Investigational Use Only," draft compliance policy guide, chap. 3 devices, subchap. 300 general/processes, Rockville, MD, FDA, Office of Regulatory Affairs, May 21, 1996.
3. Code of Federal Regulations, 21 CFR 809.
4. 21 CFR 812.
5. 21 CFR 812.2(c)(3)).
6. 21 CFR 809.10(c)(2).
7. January 1998 draft CPG, p 6.
8. January 1998 draft CPG, p 3.
9. January 1998 draft CPG, pp 4—5.
10. January 1998 draft CPG, pp 5—6.
11. May 1996 draft CPG, pp 3—4.
12. January 1998 draft CPG, p 10.
13. January 1998 draft CPG, p 7.
14. Gibbs JN, "ASRs: FDA Issues Final Rule," IVD Technol, 4(1):28—32, 1997.
Jeffrey N. Gibbs is a partner in the law firm of Hyman, Phelps & McNamara (Washington, DC). Judy Beach, PhD, an associate at the firm, assisted in the preparation of this article.
