Medical Device Link.

REGULATIONS & STANDARDS

Jeffrey N. Gibbs, JD, is a director at Hyman, Phelps & McNamara (Washington, DC) and a member of IVD Technology’s editorial advisory board. He can be reached at jng@hpm.com.

In September 2006, FDA issued a draft document, “Guidance for Industry and FDA Staff—Commercially Distributed Analyte Specific Reagents (ASRs): Frequently Asked Questions.” Even though FDA issued the final guidance document one year later, its release has not ended the controversy over how ASRs should be regulated.¹

Since their creation in 1997, ASRs have presented more complex regulatory issues than any other medical device classification. Despite the lengthy classification regulations and associated special controls, questions have abounded from the outset as to what exactly constitutes an ASR. Such issues became more complex and pressing as technology changed significantly since 1997. With the IVD industry undergoing major technological changes, many of the products being offered today as ASRs were not commercially available in 1997.

In an effort to bring greater clarity to regulating ASRs, AdvaMed (Washington, DC) drafted a frequently asked questions (FAQ) document with proposed answers, which was forwarded to FDA for its review. The agency said it would respond by releasing a document in accordance with Good Guidance Practices.

The resulting FAQ document from FDA addresses various facets of ASR regulation. In many areas, the document does provide greater clarity. However, in a few key respects, the document has generated additional ambiguity or adopted positions that commenters have heavily criticized.

This article will summarize some of the substantive elements of the final ASR guidance document and their impact. The article will also discuss some of the procedural issues that have emerged.
 
Background

In 1997, FDA issued the final regulation that defined ASRs. The primary objective was to ensure laboratories received high quality building blocks for their in-house–developed tests. Most ASRs were classified as Class I, 510(k)-exempt devices.

The 1996 proposed regulation included a lengthy definition of ASRs. Responding to comments to the proposed regulation, FDA modified the definition in a number of respects. Subsequently, some questions were raised regarding what products fell within this definition. Other questions surfaced about other practical aspects, such as limits on interactions between ASR manufacturers and laboratories. Over time, the number of questions grew.

FDA’s 2006 ASR draft guidance document was intended to answer many of these questions.² Prior to issuing the draft guidance, FDA expressed its concerns about products that purported to be ASRs and contained multiple ingredients and defeated multiple conditions. However, once FDA released the draft guidance, the IVD industry was surprised when it said that products containing multiple moieties were not considered ASRs. The draft guidance also imposed greater limitations on communications between ASR manufacturers and laboratories than the ASR regulation.

Approximately 35 comments were submitted to the ASR draft guidance document. While many comments expressed appreciation for FDA’s efforts to articulate more precisely its ASR policies, they nearly uniformly expressed concerns about one or more aspects of the document. For example, some of the comments stated that additional clarifications were needed, the proposal would unduly limit the availability of tests, the proposed FAQ conflicted with the ASR regulation, and FDA should allow “multiple moieties.”

In August 2007, several interested parties, including members of Congress, asked FDA to publish revised draft policies for In Vitro Diagnostic and Multivariate Index Assays (IVDMIA) and ASRs and permit a new set of comments. FDA did issue a revised draft IVDMIA policy and permitted a second round of comments. However, the agency took a different approach with ASRs by releasing the final document with its effective date deferred by one year.

Final FAQ Document

Probably the single most contentious point of the final ASR guidance document is the continuing debate over what is an ASR. In the proposed FAQ document, FDA said that a product is not an ASR if it contains multiple moieties or multiple markers. The final FAQ followed by saying that for a product to be an ASR it must be “used to detect a single ligand or target (e.g., protein, single-nucleotide change, epitope).”¹ The IVD industry has disagreed, saying that ASRs used by a laboratory to detect, for example, multiple mutations associated with a single disease may still be considered ASRs.

To some extent, this debate stemmed from two fundamentally different perspectives regarding the nature of ASRs. ASRs have been characterized as the building blocks of laboratory-developed tests. Relying on this principle, many IVD companies believed that even if they supplied multiple ingredients in a single vial (e.g., multiple primers and probes that could be used to detect multiple single-nucleotide polymorphisms associated with one condition), they were still providing only one building block. The laboratory would need to obtain all of the other materials, secure all of the ancillary equipment, and develop and validate the assay. All of this work would fall on the laboratory’s shoulders. Viewed from this vantage point, supplying two primers and two probes in a vial does not diminish the laboratory’s central role in developing the assay.

In discussions with agency officials, it has become clear that FDA viewed ASRs differently. According to FDA, once an ASR manufacturer placed the primers and probes together, a laboratory no longer had complete control over the contents of the assay. Since the test has been preconfigured to some degree, it was no longer considered to be laboratory developed, so the ingredients are not ASRs. Since these products were not kits or ASRs, they were IVD devices subject to FDA clearance requirements.

FDA’s different views on ASRs can be illustrated by an analogy that agency officials have used. A store (representing an ASR manufacturer) can make available separately for sale each of the ingredients for a cake (e.g., eggs, flour, butter). While the customer (representing a laboratory) can pick and choose among the ingredients offered, the store cannot sell a cake mix. By extending the analogy to the final ASR guidance, a store could not sell flour as flour if it contains anything more than ground wheat. In other words, the flour must be only pure wheat in order to be sold as flour and cannot contain, for example, malted barley flour. The combination of malted barley flour and wheat flour (like the combination of a primer and a probe) means the user does not have complete control over the “recipe.” As such, according to FDA, the flour is no longer a single ingredient.

IVD companies have considered a product to be an ASR because it was far less than a complete test kit. However, that is not enough for FDA, as agency officials have explained. If a laboratory acquired materials that identified more than one target or a primer-probe pair identifying a single target, those materials are not ASRs and cannot be lawfully sold as ASRs, no matter how much development work the laboratory did or how many other products the lab independently sourced.

The final FAQ document illustrates how FDA’s perspective on ASRs has changed over the years. In the FAQ , FDA describes the dichotomy in the preamble to the ASR rule. The preamble contrasts ASRs, “the active ingredients of tests,” with the “kit or system for ‘in vitro diagnostic use’ that has a proposed intended use.”¹ It can strongly be argued that the two-primer, two-probe vials sold without any labeling are more akin to an “active ingredient” than a “kit or system.” Nevertheless, under the final ASR guidance, such vials fall on the “kit or system” end of the spectrum.

Such materials can be offered only by deconstructing the primers and probes into separate elements, or selling them as a kit. However, both options carry drawbacks. Separating the primers and probes into each constituent piece means more work for laboratories and more chances for error. Having to obtain FDA clearance for kits will add costs, delay the market entry of new products, and may not be economically feasible for products used to diagnose rare conditions. While these criticisms were raised in various comments, FDA did not address them in either the draft or final guidance documents.

FDA’s views on attaching ASRs to other materials are similar: attaching ASRs means the laboratory does not have unfettered control. For example, according to the FAQ document, reagents that are “arranged on beads” are not ASRs.¹ This limitation precludes offering as an ASR any product that is affixed to anything else. More broadly, such products that are intended to work with any other specific products, including instruments, do not qualify as ASRs.

Another important aspect of the final ASR guidance relates to communication between ASR suppliers and laboratories. The ASR regulation says that ASR companies cannot “make any statements regarding analytical or clinical performance.”³ However, the final guidance appears to be more restrictive. It says that ASR manufacturers may provide information “that establishes characteristics of the ASR itself.”¹ However, the company cannot supply any information, including peer-reviewed publications, that “describe the use of an ASR in a specific test.”¹ This limitation on providing peer-reviewed publications or responding to unsolicited requests is more restrictive than regulations for other medical devices, including diagnostic assays. In addition, whether this limitation is constitu­tional is open to debate.

Another factor contributed to narrowing the interpretation of ASRs. Some FDA officials have been concerned about kits masquerading as ASRs. Undoubtedly, some IVD companies have positioned products that did not meet the letter of the regulation as ASRs. However, as shown by the multiple FDA warning letters, the agency already had the ability to weed out such products. The new interpretation of the regulation, which introduced terms that modify the definition of an ASR, was not needed.

FDA officials suggested that issuing a new interpretation of the ASR regulation was motivated by the desire to “provide a bright line” and eliminate ambiguities. However, as evidenced by the comments submitted to the draft guidance, introducing new terms (e.g., moiety) created additional ambiguities, not all of which were resolved with the final guidance.

Guidance Document Procedure

The other aspect of the controversy over the FAQ document relates to the mechanisms FDA used to release this document. All regulations must be adopted in compliance with the Administrative Procedure Act (APA), which is designed to serve multiple objectives. Such goals include: giving adequate notice of the proposal and its basis to interested parties; providing a meaningful opportunity to comment on the proposal; and requiring the agency proposing the rule to respond to the principal comments and, if they were not accepted, to explain why.

Rules issued under APA must also be supported by the administrative record, which is open to public review. Compliance with APA will result in opportunities for meaningful public participation, and require a federal agency to articulate its rationale for the proposed action and the evidence supporting that action. Regulations can only be modified in compliance with APA. However, guidance documents are not subject to APA, so some requirements do not apply.

In addition, while FDA’s Good Guidance Practices regulation does require the agency to provide the public an opportunity to comment, FDA is not required to respond to the comments.⁴ FDA is also not obligated to explain why it adopted a particular approach, why it chose that approach over an alternative, or even why it is acting at all.

Consequently, even though under APA federal agencies must respond to the principal comments to a proposal, by using the guidance document route FDA was relieved of that obligation for the final ASR guidance. While many comments stated that FDA’s proposal would harm patients and reduce innovation, the final guidance was not required to, and did not, respond to those comments.

Although the ASR classification and definition were created by rulemaking, the 2006 proposal was deemed a draft guidance document. A number of commenters, including AdvaMed, the American Clinical Laboratory Association (Washington, DC), and some IVD manufacturers, asserted that the proposal conflicted with or changed the original ASR regulations. As noted above, a regulation can only be modified by complying with APA. However, by issuing the final guidance document, FDA rejected such comments. The agency also did not offer an explanation for using the guidance document route, instead of rulemaking, either in the proposal or the response to comments when issuing the final guidance.

In conversations with FDA officials, they have stated that using the guidance document route was faster, easier, and more flexible. While that is undoubtedly true, it raises the key question about whether doing so is lawful.

Under APA, federal agencies only need to follow rulemaking when they issue substantive rules and not interpretations. FDA concluded that including multiple moieties in the draft ASR guidance and multiple markers or targets in the final guidance did not substantively change the definition of ASRs as stated in the original regulation. FDA also concluded that the prohibition on attaching ASRs to physical materials and responding to requests for information from laboratories, as well as the restrictions on the naming of ASRs, were not substantive changes. Although FDA’s view that such elements of the ASR guidance document were interpretive is implicit, the agency never explained the basis for taking this view.

The distinction between an interpretive document and a substantive rule can be a fine one. Courts have often struggled to determine whether a federal agency correctly characterized its action as interpretive. Only a court can determine whether FDA is correct in terming the ASR guidance as interpretive.

Another major distinction between regulations and interpretations is that the former are legally binding while the latter are not. Violating a regulation can serve as the basis for an enforcement action, so FDA can assert that a company violated the Medical Device Reporting regulation. In contrast, interpretations or guidance documents create no binding legal norms, so FDA could not allege that a product was adulterated because it “violated” the ASR final guidance.

However, while legally significant, this distinction may be limited in its practical importance. Even though a guidance document does not create legal norms, in an enforcement action, FDA will ask a court to defer to the interpretation in a guidance document. While FDA could not assert the document itself creates legally enforceable standards, it could argue that its interpretation of the ASR regulation, which is legally binding, must be given deference.

Moreover, the final ASR guidance makes FDA’s views clear on several disputed points. An IVD company that engages in conduct that is inconsistent with FDA’s views on ASRs knows that it is taking a risk. For example, a company that may have believed its multiple-primer, single-condition product was a lawful ASR now knows that FDA disagrees. With that knowledge, a number of ASR companies have already discontinued selling some products, and others also plan to stop. Regardless of whether FDA’s characterization of the ASR final guidance as an interpretation is correct or whether the interpretation itself is correct, the final guidance will reshape ASRs and the IVD industry, particularly in molecular diagnostics.

What is also clear is that FDA’s decision to use the guidance document route was an important development for ASR companies and other IVD companies. The growing prevalence of guidance documents in lieu of rulemaking raises important questions about how regulatory requirements are imposed. It is impossible to know whether the outcome of the ASR guidance document would have been the same with rulemaking. However, the process would have unfolded differently. FDA’s rationale for the changes, its legal basis, its factual foundation, and its response to comments would have been placed on the record, providing more guidance and clarity. Even companies that wanted to see ASR use curbed should be concerned about the procedural shortcomings.

Conclusion

The final ASR guidance does not mean the end of the ASR controversy. Even though FDA delayed enforcement of its policy for one year, the publication of the document is already affecting the availability of ASRs.

However, the longer-term effect is unclear. Commenters criticized the potential impact of the draft guidance, particularly on molecular diagnostics and rare conditions. It remains to be seen to what extent tests for these criticisms will be borne out. From a broader perspective, it appears a more open exchange between FDA and interested parties during the guidance development process would have been beneficial and perhaps would have led to a better, clearer, and less contentious outcome.

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