On March 23, 2017, DEA issued an Interim final rule “placing FDA-approved products of oral solutions containing dronabinol in schedule II of the CSA.” Schedules of Controlled Substances: Placement of FDA-Approved Products of Oral solutions Containing Dronabinol [(-)-delta-9-trans-tetrahydrocannabinol (delta-9-THC)] in Schedule II, 82 Fed. Reg. 14815 (Mar. 23, 2017) (“Interim final rule”). The action was based on FDA’s recent approval for marketing of Syndros, a drug product consisting of dronabinol in an oral solution. The action is effective as of publication; however, comments and/or a request for hearing may be filed by April 24, 2017.

As a result of the Interim final rule, Syndros, or any FDA-approved oral solution of dronabinol, will be controlled in Schedule II. DEA and HHS found that dronabinol has a high potential for abuse and for physical dependence requiring placement in Schedule II. The rule also distinguished Syndros from the only other FDA-approved dronabinol formulation, Marinol. In 1999, Marinol was rescheduled from Schedule II to III based on evidence that its formulation in a capsule in sesame oil would limit its abuse potential. Schedules of Controlled Substances: Rescheduling of the Food and Drug Administration Approved Product Containing Synthetic Dronabinol [(-)-D9-(trans)-Tetrahydrocannabinol] in Sesame Oil and Encapsulated in Soft Gelatin Capsules From Schedule II to Schedule III, 64 Fed. Reg. 35928 (July 2, 1999). In particular, HHS and DEA found that the sesame oil concentration would limit the ability to alter the concentration of the drug and affect its route of administration. In the present rule, both HHS and DEA noted that oral solutions of dronabinol can be manipulated to allow concentrations to be smoked, vaped or some other route of administration. 82 Fed. Reg. at 14817.   Thus, both agencies found that Syndros should be controlled in Schedule II rather than Schedule III because it has a greater abuse potential then Marinol.

While the control of Syndros in Schedule II was not unexpected for the reasons cited above, DEA’s interpretation of the recent amendment to the Controlled Substance Act (“CSA”) scheduling provisions raises other issues.

First, DEA declined to act on the HHS recommendation to reschedule all forms of dronabinol from Schedule I to Schedule II. As required under the CSA, 21 USC § 811(b), (c) and (f), on December 28, 2016, HHS provided DEA with its “eight-factor” analysis recommending to reschedule Syndros and dronabinol oral solutions from Schedule I to Schedule II. Id. at 14816.  HHS also recommended that all dronabinol formulations be rescheduled to Schedule II as well. However, DEA specifically declined to consider the HHS recommendation that all dronabinol products should be rescheduled to Schedule II. Instead, DEA limited the current Interim final rule to only FDA-approved products containing dronabinol in an oral solution. DEA characterized the HHS recommendation related to rescheduling of all forms of dronabinol as “outside the scope of the final rule.” Id. Nevertheless, HHS is now on record as recommending that DEA reschedule all formulations of dronabinol to Schedule II. It remains to be seen whether DEA believes it must now consider this recommendation in as separate rulemaking.

Second, DEA’s Interim final rule states that this action is a scheduling action while the HHS written recommendation viewed this as a rescheduling action. HHS recommended rescheduling of dronabinol and oral solutions containing dronabinol. However, DEA’s Interim final rule refers to the placement of oral solutions of dronabinol (Syndros) into Schedule II. DEA states that its legal authority for issuing the Interim final rule derives from the Improving Regulatory Transparency for New Medical Therapies Act, which requires DEA to initiate a scheduling action for new FDA-approved drugs within 90 days (see our previous post here). This requirement is codified at 21 U.S.C. § 811(j). DEA further states that the purpose of this law is to expedite scheduling of newly approved drugs that are currently in Schedule I or not controlled. In a footnote, the Agency stated that “in DEA’s view,” this law does not apply to the reformulation of a drug containing a substance already controlled in Schedule II-V. Id. at 14816, fan 1.

DEA takes a very narrow interpretation of the recent amendment to the CSA. The amended scheduling statute was intended to expedite the scheduling process but by referring to it as “expedited scheduling” DEA implies that it should be limited. However, the plain language of the law does not limit the 90 day scheduling requirement to drugs in Schedule I or drugs not currently scheduled. The law states that requirement to issue an interim rule not later than 90 days after transmission of the HHS recommendation shall apply to drugs with an abuse potential for which a new-drug application has been submitted to HHS, 21 USC § 811(f), and for which HHS recommends that DEA control such drug in schedules II-V, 21 U.S.C. § 811(j). Moreover, this section of the law specifically refers to § 811(a) which applies to actions to “transfer between such schedules”, or “ remove” a drug from any schedule. Thus, the statute does not support the apparent narrow scope of DEA’s interpretation for controlling a drug.

DEA’s characterization of this action as a drug “scheduling” and narrow interpretation of the 90 day requirement does not impact the “expedited” scheduling of Syndros. However, if DEA maintains this position, new drugs approved by FDA where HHS recommends rescheduling or descheduling, will not be subject to the 90 day rule which could mean scheduling delays of months if not years.

Not long ago, we recommended that the Food and Drug Administration (FDA) begin a new rulemaking to update the intended use regulation. We promised a blog post to get the ball rolling with suggestions for improvement. The time has arrived.

In the discussion below, the first section describes the shared role of the FDA and the medical profession in ensuring the safe and effective use of medical devices.  The second section outlines the chief problems with the device intended use regulation. The final section explains the actual proposal and marks up the text of the device intended use regulation to show how the language would change. (A similar approach could be applied to the drug regulations, albeit there are technical differences.)

We welcome comments on this blog post by email to jshapiro@hpm.com. If a critical mass of comments is received, we will publish a round‑up, including our responses and potential modifications to the proposal based upon the comments. (To protect privacy and to encourage free discussion, all comments are guaranteed to be summarized or quoted anonymously without reference to name or place of employment.) We hope that, with the help of our readers, the result will be a well‑vetted proposal that harmonizes FDA’s regulations with the First Amendment.

Such a proposal will be well‑timed, because FDA put a hold on the recent final rule amending the intended use regulation until March 19, 2018, to allow time for more consideration (see our previous post here).

The Statute: FDA’s Role

FDA’s authority to conduct premarket review of medical devices comes from the Federal Food, Drug, and Cosmetic Act of 1938, as amended (FDCA). The FDCA empowers FDA to exclude dangerous devices from the market to prevent tragedies from occurring, rather than removing dangerous devices after injuries occur. Additionally, FDA is empowered to bar ineffective or sham devices from the market.

Accordingly, the sponsoring firm has the burden to convince FDA that a device is labeled for safe use and has demonstrated effectiveness. The marketing of a device without FDA’s grant of 510(k) clearance or premarket approval causes it to be adulterated or misbranded. (Some low risk devices are 510(k)‑exempt if the sponsoring firm self-determines that their device is within the exempt category.) It is unlawful to introduce an adulterated or misbranded device into interstate commerce.

To conduct premarket review, FDA has a corps of professionals who perform careful multi‑disciplinary scientific evaluations of device safety and effectiveness:

FDA assigns review teams and primary reviewers who specialize in that scientific discipline to review . . . the application [for clearance or approval] and to generate a written evaluation. FDA then integrates the conclusions from these separate review activities to determine the appropriate outcome for the application. [Public Health Interests and First Amendment Considerations Related to Manufacturer Communications Regarding Unapproved Uses of Approved or Cleared Medical Products, pp. 8‑9 (Jan. 2017).

FDA generally approves a device with labeling for a specific intended use. Yet, many devices have more than one potential use in diagnosing or treating patients. The FDCA might have made FDA the sole gatekeeper for these additional uses. In this world, the burden would be on the sponsoring firm to return to FDA and obtain a separate approval of each additional use. Medical professionals, in turn, would be barred from deploying a device for any use other than those in the FDA‑authorized labeling.

The FDCA does not go down this road. The medical profession may lawfully utilize the same device for unlabeled additional uses in the practice of medicine. In fact, the FDCA expressly provides that it is not to be construed to limit or interfere with ability of the medical practitioner to use or prescribe a device off‑label in the practice of medicine (Section 1006).

The medical profession has developed an ecosystem for the evaluation of device performance. There are academic studies, journal articles, disease‑focused societies, symposia, conferences, case studies, clinical guidelines, talks by key opinion leaders, and a host of other mechanisms for weighing clinical evidence and reaching conclusions about the appropriate use of device technology. In addition, the medical professional has the benefit of clinical experience and knowledge of the individual patients they are treating. State licensure and malpractice exposure impose constraints on the use of devices as well.

The FDCA still gives FDA an important role to play after a device is legally marketed. FDA continues to provide premarket review of significant modifications to the device technology or its labeling. If a firm wishes to bring an additional use on label, it generally must seek clearance or approval.

In its postmarket role, FDA’s mandatory and voluntary reporting systems for malfunctions and adverse events apply to both on label and off‑label uses. Thus, FDA has good visibility into postmarket safety and performance. In fact, the Center for Devices and Radiological Health has an entire division, the Division of Postmarket Surveillance and Biometrics, which is responsible for ensuring the continued safety and effectiveness of medical devices after they have reached the marketplace.

Because the agency is not the gatekeeper for unlabeled uses, the medical profession and payors play a role in determining whether FDA’s approval of new uses in the labeling is worthwhile. In some situations, medical professionals and/or payors may demand that an unlabeled use be incorporated in the labeling before they will adopt it. In other cases, they may not. Firms will respond accordingly. There is a benefit to having this market‑based influence on whether a firm brings a use on label. FDA’s system of multi‑disciplinary review is excellent for ensuring robust, science-based labeling. Nevertheless, it tends to be relatively slow, cumbersome and resource‑intensive. Not all clinical uses of device technology require it.

There is a certain logic and balance to this system. On the one hand, FDA’s expert review provides a sophisticated screen against unsafe or wholly ineffective devices. On the other hand, FDA’s control over device labeling cannot possibly serve as a basis for directing all potential uses of medical devices across fifty states and 320 million people. It would require prodigious resources even to try to do so. The effort would be doomed to failure anyway, because crucial knowledge will always remain dispersed. It would not be possible for FDA to oversee the development of labeling for devices suited to the nuances inherent in all possible clinical uses and patient populations. Instead, the use of devices would be rigidly limited to fit the procrustean bed of FDA‑authorized labeling emanating from Washington, D.C. No one should desire this outcome.

To achieve the full potential of device technology, then, it is undeniable that the medical profession, including those in the front line treating patients, must play a significant role in determining the uses of medical devices, and they do. The reality of shared responsibilities between FDA and the medical profession for device safety and effectiveness is entirely consonant with the text, structure and history of the FDCA.

Problems with the Intended Use Regulation

The intended use of a new medical device is initially determined during FDA’s premarket review. FDA typically rests this determination upon information within the four corners of a 510(k) submission or premarket approval application, especially the draft labeling.

Once the device is legally marketed, FDA is authorized by the “intended use regulation” to base a determination of intended use on a much wider data set. The regulation states:

The intent is determined by such persons’ expressions or may be shown by the circumstances surrounding the distribution of the article. This objective intent may, for example, be shown by labeling claims, advertising matter, or oral or written statements by such persons or their representatives. It may be shown by the circumstances that the article is, with the knowledge of such persons or their representatives, offered and used for a purpose for which it is neither labeled nor advertised. [21 C.F.R. 801.4]

If FDA determines that the “circumstances surrounding the distribution” create a new intended use for the device, then FDA imputes the new intended use to all shipped units, even if their labeling complies with the existing clearance or approval. According to FDA, the device is now in the same legal position as if it had shipped without any clearance or approval at all. The device thus defined by FDA is adulterated and/or misbranded under the statute. The firm has now, according to FDA, committed a crime and/or incurred civil liability.

Last year, two criminal cases illustrated the extraordinary sweep of the intended use regulation. In United States v. Facteau, the prosecution invoked the intended use regulation in closing argument:

You’re going to hear from the judge, and you can look at all of the circumstances surrounding the distribution of the device to figure out what would be the intended use of the device. You can look at how the device was designed, you can look at how it was priced, you can look at how it was sold and you can look at what they say internally and what they say externally. And this is critical. [Tr., p. 26-78, emphasis added.]

FDA had cleared the device design in multiple 510(k) submissions between 2006 and 2011. Yet, in 2016, the jury was urged to consider the same design as evidence of an illegal new intended use. The jury also was urged to consider unpublished internal firm discussions of an unlabeled use as evidence of the creation of an illegal new intended use.

In another case, United States v. Vascular Solutions, in a pretrial motion, ruling the court interpreted the intended use regulation to allow FDA to infer “objective intent” from statements or claims not made public:

[N]owhere does the [intended use] regulation state that such statements or claims cannot be used to show objective intent unless they were published to the marketplace. To see the absurdity of defendants’ argument, consider a hypothetical in which a medical device manufacturer sells device D, which is approved for use A but frequently prescribed by doctors for off-label use B. If the firm creates a bumper sticker with the words `I intend D to be used for B: Prescribe D for B Today,’ by defendants’ logic that poster is inadmissible evidence of subjective intent so long as it sits in his briefcase, but admissible evidence of objective intent once he sticks it on his car. The Court is not persuaded that there is a legally relevant distinction here; in either scenario, the defendant has manifested into the physical world `oral or written statements’ that may be weighed as evidence of objective intent. [United States v. Vascular Solutions, Inc., 181 F. Supp. 3d 342, 347 (W.D. Tex. 2016).]

Following the court’s logic, a new intended use for a marketed device could be inferred from a secret diary, even if no one else in the world has seen it, because it also falls in the category of “oral or written statements” that have been “manifested into the physical world.” Id. at 347. Thus, objective evidence of subjective intent apparently may play a role in determining objective intent. This turns “objective intent,” an oxymoronic concept to begin with, into a hall of mirrors.

These court decisions did not break new ground. FDA has always taken the position that the regulation provides it the freedom to draw inferences based upon a virtually unlimited variety of evidence. Just last year, FDA provided this gloss:

In determining a product’s intended use, the Agency may look to “any . . . relevant source,” including but not limited to the product’ s labeling, promotional claims, and advertising . . . . For example, FDA may take into account any claim or statement made by or on behalf of a manufacturer that explicitly or implicitly promotes a product for a particular use . . . .

To establish a product’ s intended use, FDA is not bound by the manufacturer or distributor’s subjective claims of intent, but rather can consider objective evidence, which may include a variety of direct and circumstantial evidence. Thus, FDA may also take into account any circumstances surrounding the distribution of the product or the context in which it is sold . . . . In the context of medical products, generally, circumstantial evidence often ensures that FDA is able to hold accountable firms that attempt to evade FDA medical product regulation by avoiding making express claims about their products.   [80 Fed. Reg. 57756, 57757 (Sept. 25, 2015).]

The last sentence in this quotation addresses articles marketed without overt medical claims in order to evade FDA device regulation. It makes sense in such cases to look at all the circumstances surrounding distribution to ascertain the intended use.

It does not make sense in cases when a device is already legally marketed with FDA‑authorized labeling. There is a legal question about when additional uses for such devices should be treated as “intended uses” for regulatory purposes. Nevertheless, that implicates a different set of concerns compared to ferreting out hidden medical purposes for articles being marketed to evade regulation altogether. FDA frequently conflates the two cases to its own advantage when discussing the intended use regulation.

In so doing, FDA takes the position that promotion of an additional, unlabeled use for a cleared device creates a “new” intended use. FDA treats the new intended use as if it were the sole intended use while the cleared or approved intended use simply evaporates. Thus, FDA takes the position that if a firm engages in off‑label promotion of any kind, a violation springs into being even for devices shipped with FDA‑authorized labeling. FDA does not even concede that it must show that a purchaser saw the off‑label promotion prior to the sale.

The correct statutory analysis is that a device cleared for intended use X, and shipped with labeling matching that intended use, may be employed by a medical professional for additional use Y. It is true that use Y is not in the labeling and has not been evaluated by FDA. Yet, under the scheme of the FDCA, it is the medical professionals, not FDA, who are the gatekeepers as to this additional use. There is no illegality under the FDCA if a firm disseminates truthful and non‑misleading information to the medical profession about use Y outside of the labeling. The statute, in fact, is agnostic about whether a firm returns to FDA for an evaluation of use Y. There is no statutory requirement to do so. If a firm voluntarily seeks to add use Y to the labeling, FDA is authorized to grant the request if the statutory requirements are satisfied.

Nevertheless, FDA deploys the intended use regulation to threaten firms with criminal and civil liability for disseminating information about unlabeled uses. (There are certain narrow exceptions, such as responding to unsolicited requests and disseminating peer reviewed journal articles.) FDA justifies doing so as an “incentive” for firms to obtain bring additional uses on label.

This use of the intended use regulation appears to be unlawful under the Administrative Procedure Act, 5 U.S.C. § 706(2)(C) (agency action may be set aside if “in excess of statutory jurisdiction, authority, or limitations”). The statutory incentive for firms to seek supplemental clearance or approval is that it allows them to augment the device labeling with an additional use. FDA’s speech restrictions go beyond this quid pro quo to apply criminal and civil coercion not authorized by the FDCA. This additional measure of coercion is rooted in the intended use regulation. It is not rooted in the statute.

FDA is also interfering with the practice of medicine. It is incontrovertible that some off‑label uses are beneficial and some even represent the standard of care. As discussed, the medical profession has developed an ecosystem for the evaluation of device performance, both on label and off‑label, in order to make appropriate use of the technology. FDA’s evaluation (or lack thereof) certainly plays an important role in the decision‑making of the medical profession, but it is not always and everywhere determinative.

In the meantime, sponsoring firms often have significant knowledge about unlabeled uses and an economic incentive to disseminate the information. By suppressing this knowledge, FDA materially distorts the quality and quantity of information reaching the medical profession. For FDA, less information is better. But, under the statutory scheme, it is the medical profession that decides whether to employ legally marketed devices for unlabeled uses. FDA’s interference with the free flow of truthful and non‑misleading information pertinent to the lawful practice of medicine amounts to an interference with it.

Finally, as several courts have found, FDA’s application of the intended use regulation to stifle speech may conflict with the First Amendment by suppressing the free flow of truthful and non-misleading information to highly trained experts lawfully using devices off‑label. Moreover, it does so by targeting a class of “disfavored” speakers while other speakers may provide exactly the same information without sanction. The courts accept such content- and speaker-based restrictions only when narrowly tailored to directly advance a legitimate governmental interest. The courts have generally concluded that FDA’s use of the intended use regulation is not narrowly tailored and does not directly advance the FDA’s putative governmental interest in bringing additional uses on label.

One court has expressly found in a First Amendment context that FDA has a legitimate governmental interest in bringing all additional uses on label. Washington Legal Foundation v. Friedman, 13 F. Supp. 2d 51 (D.D.C. 1998). This conclusion was based upon misreading the FDCA to “require that manufacturers get all uses approved by the FDA.” Id. at 71. In fact, as discussed above, the FDCA is agnostic whether additional uses are brought on label, and it does not grant FDA authority to require it. It is difficult to see why FDA may claim a legitimate governmental interest in coercing an action that the statute makes voluntary. That is especially so in cases when the speech used for this coercion is not labeling, which is the locus of FDA’s statutory authority. FDA has never pointed to any provision in the FDCA that authorizes regulation of speech outside of labeling and restricted device advertising. (Restricted devices are Class III devices, hearing aids and analyte specific reagents.)

Proposal to Restore the Statutory Scheme

This section suggests specific changes to FDA’s device intended use regulation (21 C.F.R. § 801.4) as it stands after FDA’s recent amendment, although the amendment has been delayed for at least a year.

The easiest solution to the problems discussed above would be to restrict FDA to determining marketed intended use based upon a device’s labeling, just as it primarily does during premarket review. That way, FDA would simply make sure that the firm’s labeling in the marketplace matches the labeling that was cleared or approved. Advertising would not be part of the picture, because FDA does not have jurisdiction over most device advertising. Other speech would be excluded as completely outside the purview of the FDCA.

Unfortunately, FDA’s definition of labeling is so broad that it could easily encompass speech deserving of First Amendment protection. It is also so nebulous that it would still be too difficult for the regulated community to know in advance what communications will be the basis for determining intended use. Arguably, neither the breadth nor the nebulousness of FDA’s definition of labeling is faithful to the plain statutory language. Nonetheless, the dysfunction is deeply entrenched due to long‑ago court decisions and decades of administrative action. It grew up chiefly during the period from the 1930s to the 1960s, in the heat of a 30-year turf war between FDA and the FTC as to who would have jurisdiction over drug advertising. Origins of the Prohibition Against Off‑Label Promotion, 69 Food Drug L.J. 161 (2014).

Ideally, Congress would revisit the regulation of device (and drug) labeling and advertising and update the FDCA to make it a better fit for the age of electronic communications. That is too heavy a lift within the confines of this proposal. Our aim is simply to mitigate the worst excesses of FDA’s device intended use regulation. Two objectives underlie this proposal:

• Firms should have certainty about the labeling that will serve as the basis for an intended use determination. Providing this certainty will enable firms to resume their original statutory role as masters of their intended use. As the First Amendment requires, these firms can disseminate truthful and non‑misleading information about off‑label uses without fear of creating an unapproved new intended use.
• There is potential for FDA to apply an excessively broad definition of labeling when determining intended use, thereby chilling protected speech. Narrowing the subset of labeling that is the basis for intended use will mitigate this problem.

In light of these considerations, the specific proposal is as follows:

The preamble in the first sentence of the device intended use regulation is unchanged.

Subsection (a): This part of the intended use regulation continues to authorize FDA to determine intended use based upon a full consideration of the circumstances surrounding distribution of an article. This provision applies to any article not listed with FDA, i.e., the sponsoring firm has not conceded that device regulation applies. If FDA finds that the article actually has an intended use falling with the definition of a medical device, it may impose device regulation on that basis. Likewise, the existing approach to intended use determinations will continue for devices marketed over-the-counter (OTC) to lay users. The only change here is to remove from this approach the class of devices described in subsection (b).

Subsection (b): This new subsection governs the determination of intended use for articles meeting two requirements: (i) The article must be already listed with FDA as a legally marketed medical device; and (ii) the listed medical device must be sold for prescription use only by licensed medical practitioners under 21 C.F.R. § 801.109.

If requirements (i) and (ii) are both met, then FDA shall determine objective intended use exclusively from the labeling included per § 801.109(c) on or within the package from which the device is dispensed (or an electronic substitute as authorized under section 502(f) of the FDCA). FDA may not consider other labeling or advertising in making an intended use determination.

Subsection (b) does not alter FDA’s authority to require that all labeling and restricted device advertising be truthful and non-misleading in accordance with section 502(a) of the FDCA and various implementing regulations (e.g., 21 C.F.R. § 801.6). For the purpose of suppressing false and misleading labeling and advertising, these terms retain their current boundaries, even if overly expansive or nebulous.

Subsection (c): The first part is unchanged from the current regulation. The last sentence of subsection (c) was added by FDA in a final rule issued this year, although it will not be effective until 2018 at the earliest. The language we propose would ensure that the “totality of the evidence” ties back to the two different sources of evidence specified in (a) and (b). (An alternative would be to simply strike the last sentence, given that FDA says it merely reiterates existing requirements and therefore would seem to be unnecessary.)

Subsection (d): This provision would be added to establish that labeling or advertising stating or implying that a medical use has been cleared or approved by FDA (or is exempt), when that is not the case, is misleading and constitutes misbranding. The purpose of this provision is to require sponsors to be clear in labeling and advertising which uses have FDA’s imprimatur and which do not. This clarity may be important to the decision of medical professionals as to whether to employ the device for such use. The new provision is not necessarily a change in law, since the FDCA already prohibits false or misleading labeling and restricted device advertising, but it puts firms on notice and empowers FDA to focus on this particular issue.

Change to Sec. 801.109(c): Under the new provision in 801.4(b), a device’s intended use is determined based upon the labeling in or on the device package. Under this subsection, a device must ship with labeling that has adequate directions for all advertised uses. This provision would force the sponsor to include unapproved uses in the labeling shipped with the device, causing such uses to become “intended uses” under 801.4(b), and subjecting the sponsor to adulteration or misbranding charges due to lack of clearance or approval of the unapproved uses. This unwanted circularity is eliminated by removing this phrase.

Change to Sec. 801.109(d): This section refers to labeling “whether or not” on or within the device package, and so could be read to have the same circular effect as 801.109(c). A parallel change is made, striking the reference to advertised uses.

The following, then, is the mark up of the intended use regulation (new language in red italicized font, deletions in strike‑through):

Sec. 801.4 Meaning of intended uses.

The words intended uses or words of similar import in 801.5, 801.119, and 801.122 refer to the objective intent of the persons legally responsible for the labeling of devices.

(a) Except as provided in subsection (b), Tthe intent is determined by such persons’ expressions or may be shown by the circumstances surrounding the distribution of the article. This objective intent may, for example, be shown by labeling claims, advertising matter, or oral or written statements by such persons or their representatives. It may be shown by the circumstances that the article is, with the knowledge of such persons or their representatives, offered and used for a purpose for which it is neither labeled nor advertised.

(b) If a distributed article is listed as a device pursuant to 807.25 and purports to be sold for prescription use only pursuant to 809.109, then the intended use shall be determined from labeling on or within the package from which the device is to be dispensed (or equivalent labeling provided electronically pursuant to section 502(f) of the act). If there is no such labeling, then intended use shall be determined in accordance with subsection (a).

(c) The intended uses of an article may change after it has been introduced into interstate commerce by its manufacturer. If, for example, a packer, distributor, or seller intends an article for different uses than those intended by the person from whom he received the devices, such packer, distributor, or seller is required to supply adequate labeling in accordance with the new intended uses. And if the totality of the evidence in either (a) or (b), above, as applicable, establishes that a manufacturer objectively intends that a device introduced into interstate commerce by him is to be used for conditions, purposes, or uses other than ones for which it has been approved, cleared, granted marketing authorization, or is exempt from premarket notification requirements (if any), he is required, in accordance with section 502(f) of the Federal Food, Drug, and Cosmetic Act, or, as applicable, duly promulgated regulations exempting the device from the requirements of section 502(f)(1), to provide for such device adequate labeling that accords with such other intended uses.

(d) Any labeling or restricted device advertising that suggests a device has received agency clearance or approval (or is exempt) for a specific intended use, when that is not in fact the case, is misleading under section 201(n) of the Act and constitutes misbranding under section 502(a) or section 502(q)(1) as applicable.

Finally, 801.109(c) would have the following revision:

[A device is exempt from section 502(f) of the Act if, among other conditions:] Labeling on or within the package from which the device is to be dispensed bears information for use . . . under which practitioners licensed by law to administer the device can use the device safely and for the purpose for which it is intended, including all purposes for which it is advertised or represented. . . .

The same change would be made to 801.109(d), which parallels 801.109(c), except that it applies to labeling “whether or not on or within” a device package.

That is the proposal. We look forward to your comments (jshapiro@hpm.com).

The Interagency Food Safety Analytics Collaboration (IFSAC) has issued a strategic plan for the 5-year period beginning in 2017.  This is the second such plan issued by IFSAC, a collaboration between FDA, USDA/FSIS, and CDC that aims “to improve coordination of federal food safety analytic efforts and address cross-cutting priorities for food safety data collection, analysis, and use.”

The first strategic plan focused on foodborne illness source attribution.  The second plan appears geared to not only improve estimates of attribution, but also “develop methods to estimate how sources [of foodborne illness] change over time.”  In furtherance of those objectives, IFSAC intends to:

• “Incorporate additional sources of data into analyses, such as regulatory sampling data and whole genome sequencing (WGS) information”
• “Work internally with regulatory partners to identify and evaluate inspectional data and product and environmental sampling data to assess ways it could better inform attribution estimates”
• “Explore the possibility of incorporating existing sources of laboratory-based, non-human surveillance data into models to generate attribution estimates”
• “Evaluate existing microbial subtyping data of pathogens isolated from human, food, animal, and environmental samples relevant to foodborne illness”
• “Explore ways to incorporate genomic data and other novel data sources into models that generate attribution estimates”
• “Develop methods to assess changes in sources of illness over time”

The potential regulatory impact of these types of activities is obvious.  For example, the plan notes that analyses of “changes in the sources of illness caused by specific pathogens over time… can help in assessing the impact of specific policies, performance standards, regulations, and changes in industry practices.  These analyses could also help identify the emergence of historically uncommon food-pathogen pairs.”  The plan also notes that IFSAC has already contributed to food safety-related rulemaking activities, such as FDA’s 2010 egg safety rule.  It will be worth watching how IFSAC puts to use evidence gathered in the course of inspections, and in turn, how the member agencies draw on IFSAC’s output to refine their approaches to outbreak investigations, and to develop new regulations and guidance documents.

The American Conference Institute’s (“ACI’s”) 11th annual “Paragraph IV Disputes” conference is right around the corner! The conference will take place from April 24-26, 2017 at the Conrad New York in New York, NY. 

ACI has put together an excellent program for conference attendees that includes presentations from esteemed Judges and key representatives from the FDA, PTO, and the FTC. In addtion, attendees will get to hear from a virtual “who’s who” of Hatch-Waxman litigators and industry decision makers.  Hyman, Phelps & McNamara, P.C.’s Kurt R. Karst, along with Maryll W. Toufanian, Deputy Director of the Office of Generic Drug Policy, FDA, and Margaret J. Sampson, a Partner at Baker Botts L.L.P., will be speaking at a Q&A session on FDA’s October 2016 final rule implementing certain portions of the December 2003 Medicare Modernization Act (see our previous post here).

FDA Law Blog is a conference media partner. As such, we can offer our readers a special discount off the current price tier.  The discount code is: P10-999-FDAB17.  You can access the conference brochure and sign up for the event here.

 We look forward to seeing you at the conference. 

Cue up Neil Sedaka’s 1962 hit “Breaking Up Is Hard to Do,” or, for some of us younger-minded folk, take your pick from one of many Taylor Swift songs (“We Are Never Ever Getting Back Together,” “I Knew You Were Trouble,” and so many more).  What could break-up songs have to do with the Orange Book, you ask?  More than you think!

We try hard not to judge a book by its cover (though that can be difficult given the subject matter here). Instead, we try to look at the substance behind the cover.  And when you do, you realize that there’s a lot of information packed into the 1,400 pages of the current annual print edition of the Orange Book (and just as much information, though organized a bit differently, in the electronic and app versions of the publication).  But, despite all of that information, the Orange Book has her secrets.  During this blogger’s long relationship with the Orange Book, she has revealed (or let us discover) some of her hidden secrets.  Perhaps her biggest secret – and one that has frustrated us at times, sometimes causing a rift in the relationship, and delighted us at other times, bringing us closer together – is that some product listings are more than they appear.  It’s a result of historical baggage.

Beginning with the publication of the 23rd (2003) edition of the Orange Book, FDA clarified that certain injectable drug products should be identified in the publication on a strength-by-strength basis. This clarification (which we’ve noted before in the context of PDUFA user fees) states, in relevant part (in the current 37th [2017] edition of the Orange Book):

Consistent with the definition of strength included in Section 1.2,Therapeutic Equivalence-Related Terms, the strength of parenteral drug products generally is identified by both the total drug content and the concentration of drug substance in a container approved by FDA. In the past, the strength of liquid parenteral drug products in the Orange Book has not been fully displayed.  Rather, the strength of liquid parenteral drug products in the Orange Book has been displayed in terms of concentration, expressed as xmg/mL.  Generally, the amount of dry powder or lyophilized powder in a container is identified as the strength, expressed as xmg/vial.

With the finalization of the Hatch-Waxman Amendments that characterized each strength of a drug product as a listed drug, it became evident that the format of the Orange Book should be changed to reflect each strengthof a parenteral solution. To this end, the Orange Book now displays the strength of all new approvals of parenteral solutions.  Previously, we would have displayed only the concentration of an approved parenteral solution, e.g. 50mg/mL.  If this drug product had a 20 mL and 60 mL container approved, we would now display two product strengths for this product, listing both total drug content and concentration of drug substance in the relevant approved container, e.g. 1Gm / 20mL (50mg/mL) and 3Gm / 60mL (50mg/mL).

But while new products – injectables and other products, like those in metered doses – are broken out and displayed in the Orange Book on a strength-by-strength basis, older products generally are not . . . at least not until there’s a need for FDA to clarify the Orange Book. Let’s use an example:

Drug X was approved under NDA 999999 on January 2, 2000 in multiple strengths and was listed in the Orange Book as follows:

ACTIVE INGREDIENT

INJECTABLE; INJECTION

DRUG X

KK COMPANY

    2.5MG/ML    NDA 999999  001    Jan 2, 2000

    5MG/ML      NDA 999999  002    Jan 2, 2000

    10MG/ML    NDA 999999  003    Jan 2, 2000

    20MG/ML    NDA 999999  004    Jan 2, 2000

The “How Supplied” section of the prescribing information for Drug X describes each product identified above in terms of both concentration and container size (fill volume):

1. 25 mg/10 mL (2.5 mg/mL)
2. 50 mg/20 mL (2.5 mg/mL)
3. 250 mg/100 mL (2.5 mg/mL)
4. 500 mg/200 mL (2.5 mg/mL)
5. 50 mg/10 mL (5 mg/mL)
6. 100 mg/20 mL (5 mg/mL)
7. 500 mg/100 mL (5 mg/mL)
8. 1000 mg/200 mL (5 mg/mL)
9. 100 mg/10 mL (10 mg/mL)
10. 200 mg/20 mL (10 mg/mL)
11. 1000 mg/100 mL (10 mg/mL)
12. 2000 mg/200 mL (10 mg/mL)
13. 200 mg/10 mL (20 mg/mL)
14. 400 mg/20 mL (20 mg/mL)
15. 2000 mg/100 mL (20 mg/mL)
16. 4000 mg/200 mL (20 mg/mL)

Thus, despite the Orange Book showing only 4 separate drug products approved under NDA 999999, there are, in reality, 16 separate drug products approved under NDA 999999 as a result of FDA’s definition of the strength of an injectable drug product as both a function of concentration and container size (fill volume).

Under the scenario above, and depending on the patent estate for Drug X, there might be 16 different opportunities for 180-day exclusivity for an ANDA applicant. . . . or multiple opportunities for a subsequent ANDA applicant to be blocked by a first applicant’s eligibility for 180-day exclusivity. (And that’s why breaking up is hard to do, but sometimes it’s for the best.)  That means generic drug manufacturers need to carefully review not only the Orange Book, but also the “How Supplied” section of the prescribing information for a particular brand-name drug product still identified in the Orange Book with the old concentration-only strength nomenclature.

Time will usually cause the Orange Book to finally reveal the various drug products approved and bundled under a particular NDA. It may start with an entry on FDA’s ANDA Paragraph IV Patent Certifications List that does not appear to comport with an Orange Book drug product listing.  And then FDA may finally update the Orange Book to break-out and identify various sub-drug products when an ANDA for a particular concentration and fill volume is approved (or when a decision on 180-day exclusivity is made).  It’s a bit of a flawed system that probably should be revised so that ANDA applicants have the information necessary to make important drug product submission decisions sooner rather than later.  And FDA might just collect additional PDUFA drug product user fees along the way.

It never ceases to amaze this blogger how a law, like the Hatch-Waxman Amendments, can still generate new fact patterns and controversy after more than 30 years in existence! In today’s post, we look at how one of those new issues arose and how FDA resolved the controversy.

Like so many recent and interesting Hatch-Waxman controversies, the issue arose in the context of an abuse-deterrent drug product – here, Collegium Pharmaceuticals, Inc.’s (“Collegium’s”) NDA 208090 for XTAMPZA ER (oxycodone) Extended-release Capsules. But the controversy surrounding the approval of XTAMPZA ER didn’t concern (at least not initially) the existence of a potentially blocking period of non-patent exclusivity (which is where some new issues have arisen in the context of abuse-deterrent drug products – see our previous post here), but rather the existence of a 30-month patent litigation stay under FDC Act § 505(c)(3)(C). The stay stemmed from a Paragraph IV certification contained in the XTAMPZA ER 505(b)(2) NDA to patents listed in the Orange Book for the listed drug identified in NDA 208090 – i.e., Purdue Pharma L.P.’s (“Purdue’s”) NDA 022272 for OxyContin (oxycodone HCl controlled-release) Tablets.

By way of background, after FDA acknowledged the filing of NDA 208090, Collegium timely provided notice of its Paragraph IV certifications to Purdue and to the owners of certain patents listed in the Orange Book for OxyContin. Purdue and certain patent owners subsequently filed complaints in two district courts alleging patent infringement, and triggering a 30-month stay on the approval of NDA 208090. See Purdue Pharma LP et al. v. Colleaium Pharmaceutical Inc., Case 1:15-cv-00260 (D. Del. Mar. 24, 2015); Purdue Pharma L.P. et al. v. Collegium Pharmaceutical. Inc., Case 1:15-cv-l 1294 (D. Mass. Mar. 26, 2015).  On July 23, 2015, the action filed in Massachusetts was voluntarily dismissed by Purdue, thereby terminating the litigation.  On August 6, 2015, the U.S. District Court for the District of Delaware issued a Memorandum Opinion and Order dismissing the litigation in that jurisdiction for lack of personal jurisdiction.

But then, on October 7, 2015, a funny thing happened . . . . The Delaware District Court issued a Memorandum Order that appears to have vacated the court’s August 6, 2015 Order dismissing for lack of personal jurisdiction patent infringement litigation timely initiated by Purdue.  (We say “appears” because the court’s Order is not expressly characterized as vacating the earlier dismissal order.) The Delaware District Court’s apparent vacatur raised the question of whether or not the previously-terminated 30-month litigation stay was revived. Or, as FDA put it in a Memorandum included in the Approval Package for NDA 208090: “At issue is whether dismissal of a patent infringement action for lack of personal jurisdiction, which is later vacated and transferred to another venue, terminates a 30-month stay of approval of a 505(b)(2) application.”

Collegium (represented by Hyman, Phelps & McNamara, P.C.) argued that the stay was terminated and could not be revived by a subsequent reversal or vacatur. This result, argued Collegium, was dictated by:

(1)       The text of FDC Act § 505(c)(3)(C)(i) (“if before the expiration of [a 30-month stay] the district court decides that the patent is invalid or not infringed (including any substantive determination that there is no cause of action for patent infringement or invalidity), the approval shall be made effective on— (I) the date on which the court enters judgment reflecting the decision.”);

(2)       FDA guidance (“Neither a stay nor reversal of a district court decision finding the patent invalid, unenforceable, or not infringed will have an effect on the approval of the [generic application]. . . .”); and

(3)       FDA and court precedent.  Specifically, a case involving the approval of both an ANDA and a 505(b)(2) NDA for versions of Oxaliplatin Injection (ELOXATIN), which approvals the DC District Court affirmed notwithstanding vacatur of a district court decision of non-nfringement. See Sanofi-Aventis v. FDA, 725 F. Supp. 2d 92 (D.D.C. 2010) (see our previous post here).

FDA, however, disagreed in resolving this case of first impression, and affirmed that the 30-month stay remained in place:

The precise issue here is whether the Delaware district court’s dismissal of the infringement action for lack of personal jurisdiction terminated the 30-month stay, even though the district court later vacated that decision and the patent issues continue to be litigated. We conclude that the stay remains in effect.

As described in the MMA proposed rule, “the statute does not address whether a 30-month stay may be terminated and a 505(b)(2) application or ANDA approved if the court enters an order of dismissal without a finding of patent infringement.” FDA’s general policy has been that a court entry of an order of dismissal, with or without prejudice, of patent infringement litigation that was timely initiated in response to notice of a paragraph IV certification will terminate the 30-month period if the order does not state a finding of patent infringement. In the proposed MMA rule, FDA explained that “[i]t is appropriate that a 30-month stay terminates under these circumstances because the statutory purpose of the stay is to allow time for claims of patent infringement to be litigated prior to approval.”

To our knowledge, FDA has not addressed a case in which the order of dismissal (without a finding of patent infringement) was vacated, and the infringement action giving rise to the 30- month stay remains pending at the time FDA is ready to act on the 505(b)(2) application. Under the unique and specific facts at issue here, we have determined that the 30-month stay remains in effect. The purpose of the above-described general policy is to interpret the statutory ambiguity in section 505(c)(3)(C) in a manner that furthers Congress’ intent — to allow the parties time to litigate claims of patent infringement. As described in the MMA proposed rule, in the common example where the patent owner or exclusive patent licensee dismisses the patent infringement action voluntarily on terms that the court considers proper, and the litigation thereby ends, Congress’ intent is served by terminating the stay. In this case, because the Delaware district court ultimately determined that its dismissal was not proper and the order of dismissal was vacated, and the original infringement action giving rise to the stay remains pending, Congress’ intent is served by considering the stay to be in effect.

As a result of FDA’s decision, the Agency tentatively approved NDA 208090 for XTAMPZA ER, citing the unexpired stay as a basis for the approval action. At that time, there was also a period of unexpired 3-year non-patent exclusivity applicable to OxyContin; however, as FDA noted in the XTAMPZA ER tentative approval letter: “We need not determine at this time whether approval of your 505(b)(2) NDA for XTAMPZA ER would otherwise be blocked by any other drug’s marketing exclusivity expiring before termination of the 30-month stay.”). And that’s a topic we already covered (here).

Litigation between FDA and Ferring Pharmaceuticals Inc. (“Ferring”) over the availability of 5-year New Chemical Entity (“NCE”) exclusivity for Ferring’s colonoscopy preparation, PREPOPIK (sodium picosulfate, magnesium oxide, and citric acid) for Oral Solution (NDA 202535; approved on July 16, 2012), was recently – and quietly – settled by the parties. Although the terms of the settlement have not yet been made public, we think the settlement will have some pretty significant effects on FDA’s consideration of pending ANDAs for multiple drug products.

As we previously reported, in September 2016, Judge Rudolph Contreras of the U.S. District Court for the District of Columbia issued a Memorandum Opinion granting a Motion for Reconsideration filed by Ferring requesting reconsideration of the DC District Court’s March 2016 ruling that FDA’s pre-October 10, 2014 interpretation of the FDC Act’s NCE exclusivity provisions as applied to a newly approved Fixed-Dose Combination (“FDC”) drug product containing an NCE and a previously approved drug, such as PREPOPIK (see our previous post here), was not arbitrary and capricious. Although Judge Contreras initially backed FDA’s decision to deny NCE exclusivity for PREPOPIK, he reversed course after considering several precedents identified by Ferring in the company’s Motion for Reconsideration, and submitted in response to comments mande by Judge Contreras in his March 2016 ruling that “[i]f there were, in fact, situations in which a drug was eligible for five-year [NCE] exclusivity under the FDA’s prevailing interpretation but failed to receive it because of the order in which it was approved, those circumstances might render the FDA’s policy arbitrary and capricious.”  In addition to PREPOPIK, Ferring identified STRIBILD (elvitegravir, cobicistat, emtricitabine, tenofovir disoproxil fumarate) Tablets, NATAZIA (estradiol valerate and estradiol valerate/dienogest) Tablets, ANORO ELLIPTA (umeclidinium bromide; vilanterol trifenatate), and NUVARING (ethinyl estradiol; etonogestrel) as examples that “demonstrate that a single-entity drug substance’s ability to receive five-year exclusivity can turn arbitrarily on the order in which NDAs including that drug substance are approved.”  With those precedents, Judge Contreras had in hand the ammunition necessary to find FDA’s pre-October 2014 interpretation of NCE exclusivity, as applied to PREPOPIK, to be arbitrary and capricious and in violation of the Administrative Procedure Act.

In November 2016, FDA filed a Notice of Appeal with the U.S. Court of Appeals for the District of Columbia Circuit (Case No. 16-5326), and it seemed as though it would be in the hands of the DC Circuit to resolve the issue of NCE eligibility for PREPOPIK, as well as other drugs affected by the outcome of the case, such as Gilead Sciences, Inc.’s (“Gilead’s”) STRIBILD. (Meanwhile, in October 2016, and again in January 2017, Gilead petitioned FDA – see Docket Nos. FDA-2016-P-3312 and FDA-2017-P-1278 – to recognize NCE exclusivity for STRIBILD “and to apply such exclusivity to all subsequently approved drug products that contain any of the new active moieties (elvitegravir and cobicistat) approved” in STRIBILD.)

But then something unexpected happened. . . . On March 14, 2017, FDA filed with the DC Circuit an Unopposed Motion for Voluntary Dismissal.  The DC Circuit dismissed the case in a March 17, 2017 Order, and also issued its Mandate that same day.

Although we have not yet seen anything to indicate why, or under what terms, the case was voluntarily dismissed, we strongly suspect that FDA agreed to award Ferring 5-year NCE exclusivity for PREPOPIK. That also very likely means that any other similarly situated NDA holder will be awarded NCE exclusivity, such as Gilead for STRIBILD.  We should have confirmation soon, and perhaps in April with an update to the Orange Book.

But resetting the exclusivity periods for PREPOPIK, STRIBILD, and other drugs products is going to cause FDA’s Office of Generic Drugs (“OGD”) and affected ANDA applicants some big headaches. ANDAs under review for generic PREPOPIK have been in-house at OGD since May 2014, and ANDAs for generic versions of Gilead’s TYBOST (cobicistat) Tablets (NDA 203094) were first submitted to FDA in December 2015.  FDA even tentatively approved one ANDA – ANDA 205743 – for generic PREPOPIK on November 21, 2016.

Affected ANDA applicants will likely receive correspondence from OGD providing guidance on the path forward in light of FDA’s decision to recognize NCE exclusivity for affected FDC drug products. Presumably, ANDAs will need to be withdrawn and resubmitted to FDA. But will it be a race to resubmission for ANDA Paragraph IV applicants to secure first applicant status (and thus eligibility for 180-day exclusivity)? Or will FDA backdate ANDA submisions to the so-called NCE-1 dates (e.g., July 16, 2016 for generic PREPOPIK, and August 27, 2016 for generic TYBOST) so that previous first-filers don’t lose their place in line? We’ll see.

Antibiotic-resistant bacteria are claimed to be one of the biggest threats to global health, sickening an estimated 2 million people in the United States each year. There is evidence that some resistance in bacteria is caused by antibiotic use in food animals (cattle, poultry, swine). In the last decade, federal agencies including FDA and APHIS, have taken a number of actions addressing the use of medically important antibiotics in food animals.

Medically important antibiotics are antibiotics that are used in both animals and humans and that are important to treat human infections. Two federal departments are involved in ensuring the safe use of antibiotics in food animals, HHS (primarily FDA) and USDA (primarily APHIS and FSIS). FDA approves and regulates the manufacture and distribution of antibiotics use in food animals and FSIS and APHIS collect information about antibiotic use and resistance in food animals.

In 2011, GAO reported on antibiotic use and identified major gaps in data collection. On March 16, 2017, GAO issued an update. For the update, GAO examined actions by HHS (FDA) and USDA since 2011 to manage the use of antibiotics in food animals and to assess the impact of these actions, actions in other countries, and the extent to which HHS and USDA have conducted on-farm investigations regarding outbreaks from antibiotic-resistant pathogens in animal products.

GAO notes that HHS has made significant progress in veterinary oversight of medically important antibiotics. Actions by FDA include issuance of voluntary guidance to industry and revisions to the veterinary feed directive regulation (here, here, and here). According to FDA, as of January 2017, medically important antibiotics in feed and water of food animals may be used only under the supervision of a veterinarian. (FDA actions did not address oversight of antibiotics administered in injections or through other routes). However, data collection continues to be an issue. FDA has no measures to assess the impact of these actions. Thus, FDA cannot assess whether it is achieving its objective of ensuring judicious use of medically important antibiotics in food animals. Another “gap” identified by GAO is the use of long-term and open-ended use of medically important antibiotics for disease prevention.

In 2016, FDA issued a request for comments regarding the establishment of duration of medically important antimicrobial drugs that currently do not have a duration limitation. The comment period closed March 13, 2017, i.e., just before the GAO report was issued. FDA received a significant number of comments opposing a limit to duration of these drugs.

GAO noted improvements in collecting and reporting data on antibiotics. However, GAO believes that the agencies should have a joint effort to further assess the relationship between the use of antibiotics and antibiotic resistance. Although the agencies have developed a joint data collection plan, lack of funding may hinder the execution of this plan.

GAO reviewed programs to manage the use of antibiotics in food animals in the Netherlands, Canada, Denmark, and the European Union (EU). The programs in those countries and in the EU have resulted in a reduction in the use or sales of antibiotics. However, it is unclear whether the actions taken by those countries would be successful in the US. According to GAO, some U.S. federal officials and stakeholders believe that similar U.S. actions are not feasible because of production differences and other factors.

GAO makes a number of recommendations, including that HHS address oversight gaps, HHS and USDA develop measures to assess success or effectiveness and progress of the actions, and that USDA and HHS develop a framework to decide when to conduct on-farm investigations.

USDA agreed with GAO’s recommendations. HHS neither agreed nor disagreed because the incoming HHS transition personnel had insufficient time for review.

In response to the report, U.S. Senators Kirsten Gillibrand (D-N.Y.), Dianne Feinstein (D-Cal.), and Elizabeth Warren (D-Mass.) and U.S. Representatives Rosa DeLauro (D-Conn.) and Louise Slaughter (D-N.Y.) sent a letter to HHS and the USDA urging increased collaboration and oversight to reduce the inappropriate use of medically important antibiotics in food animal production. They ask for prompt answers to issues raised by GAO.

One and a half years since FDA first proposed changes, two months since the final rule was published, one month after objections threatening an Administrative Procedure Act challenge, and one day before the rules would have taken effect, FDA announced on Monday that it would delay its amendments to the regulations regarding “intended use.” Rather than implement the final rule by March 21, 2017, FDA announced it would delay the effective date until March 19, 2018, and even implied there might be a final rule issued “after” the 1-year delay.  82 Fed. Reg. 14319, 14323 (Mar. 20, 2017).

Why so much hubbub about what evidence can be used to discern “intended use”? Because FDA’s authority to regulate a product as a drug or device hinges on whether the product is intended to be used to diagnose, cure, mitigate, treat, or prevent disease.  A famous analogy is water.  If water is intended to quench thirst at mealtimes, it is not considered to be a drug.  If water is intended to cure cancer, then FDA believes it can regulate the claims being made by the water bottler, inspect the manufacturing facilities, take enforcement action, and potentially impose criminal penalties.  So a product’s “intended use” matters, and what evidence can be used to glean intended use can have a significant impact on whether the government can regulate the product and its manufacturer.

In 2015, FDA proposed revising the intended use regulations at 21 C.F.R. §§ 201.128 and 801.4, to remove objectionable language that imputed knowledge to a manufacturer of external uses: “But if a manufacturer knows, or has knowledge of facts that would give him notice, that a [drug or device] introduced into interstate commerce . . . is to be used for conditions, purposes, or uses other than the ones for which he offers it, he is required to provide adequate labeling for such a drug/device which accords with such other uses to which the article is to be put.”  This deletion was favorably received by companies who did not believe it fair to impose requirements on a manufacturer based on the uses of a product over which it did not have control.

Yet as reported here, rather than delete the standard in its final rule, FDA inserted new language that added a different standard to the calculus:  “And if the totality of the evidence establishes that a manufacturer objectively intends that a device [or drug] . . . is to be used for conditions, purposes, or uses other than ones for which it has been approved, . . . he is required . . . to provide for such device [or drug] adequate labeling that accords with such other intended uses.”  Pharmaceutical groups quickly filed a Citizen Petition asking FDA to reconsider the language in the final rule or indefinitely stay the rule.

On March 20, 2017, FDA acquiesced to the request for stay, and agreed to delay the effective date of the rule to invite public comment on the issues raised in the petition and the specific questions FDA posed in its notice.  Interestingly FDA asserted that it is “impracticable, unnecessary, and contrary to the public interest” to solicit public comment on the delay itself, but agreed to “accept public comments for a period of 60 days on whether this rule delaying the effective date should be modified or revoked.”  82 Fed. Reg. at 14321.  It is unknown on what grounds one could object to the delayed effective date of such a controversial rule given the important open issues that FDA admits remain in the final rule.

In addition to the issues raised by the Citizen Petition, FDA specifically solicits comments on the following issues:

1. How should FDA consider situations where companies distribute medical products without explicit promotional claims?
2. What are the potential public health consequences that should be evaluated in determining intended use?
3. How do First Amendment considerations apply to the use of non‑speech evidence in determining intended use, such as the circumstances surrounding the distribution of a product?
4. Is there a distinction between language permitting consideration of “any relevant source of evidence” and “the totality of the evidence”?

With respect to number 4, FDA claimed that the “totality of the evidence” standard is not a change in FDA’s approach regarding evidence of intended use. FDA cited to the preamble to the original proposal in which FDA claimed it set forth the standard that FDA may look to “any relevant source of evidence.”  82 Fed. Reg. at 14320, citing 80 Fed. Reg. 57756, 57757 (Sept. 25, 2015).  This clause, however, appears nowhere in the preamble.  Instead, there are citations to several court opinions that enumerate the types of information from which FDA can determine the objective intent of the person responsible for labeling the product.  All of the examples cited in the preamble already are specified in the intended use regulations (e.g., labeling, promotional claims and advertising, oral or written statements by a manufacturer or its representatives, and circumstances surrounding the distribution or sale of a product).  FDA’s addition of a sentence that includes an “any relevant source of evidence” standard or a “totality of evidence” standard renders the preceding language in the intended use regulations superfluous and unnecessary.

As FDA notes, these issues overlap with the parallel docket in which FDA is considering communications about unapproved uses of approved/cleared medical products, discussed here.  That docket is open until April 19, 2017; this docket will accept both substantive comments as well as comments on the decision to delay the rule until May 19, 2017.  Thus FDA encourages commenters to submit feedback in both dockets.

A final regulation implementing the 340B Drug Discount Program has been caught in the regulatory freeze. In the waning days of the Obama Administration, the Health Resources and Services Administration (“HRSA”) of HHS issued a final regulation describing the methodology for calculating the 340B ceiling price (including so-called penny pricing) and to establish civil monetary penalties for knowing and intentional overcharges of 340B covered entities.  We posted on that regulation here. It originally had a March 6, 2017 effective date, but the preamble stated that enforcement was not to begin until the beginning of the second quarter – i.e., April 1, 2017.

Pursuant to the new administration’s regulatory freeze (see our previous post here), HRSA postponed the effective date until March 21, 2017, but that postponement did not affect the April 1 enforcement date.  However, yesterday, HRSA issued an interim final rule further postponing the effective date until May 22, 2017, and inviting comment on whether the effective date should be even further delayed until October 1, 2017. Comments must be submitted by April 19, 2017.  HRSA explained that the additional delay was necessary to consider questions of fact, law, and policy raised in the rule, consistent with the regulatory freeze memorandum, and to provide regulated entities more time to implement changes necessary to comply with the Final Rule.

On Monday, March 27, FDA and the Society of Toxicology (SOT) will present a colloquium (chaired by Bernadene A. Magnuson, PhD, Health Science Consultants, Inc., and Sabine Francke, DVM, PhD, CFSAN FDA) on Considerations for the Determination of Adversity in Food Chemical Safety Evaluations, the seventh in a series of colloquia titled Emerging Toxicological Science: Challenges in Food and Ingredient Safety.  The colloquia are intended to inform the work of FDA employees, but are open to the public free of charge.  This colloquium begins at 8.30 a.m. featuring the following presentations, and concludes with a panel discussion at around 11:50 a.m. followed by lunch at 1 p.m.

• Adversity into Regulatory Science: Historical Perspective and Future Challenges – Nigel Walker, PhD, DABT, National Institute of Environmental Health Sciences, Research Triangle Park, NC
• When Is Adversity Legally Cognizable? – Ricardo Carvajal, JD, MS, Hyman, Phelps & McNamara PC, Washington, DC
• No Observed Adverse Effect Level: Sucralose As a Case Study – Bernadene A. Magnuson, PhD, Health Science Consultants, Inc., Mississauga, ON, Canada
• New Approaches to Adversity Assessment in Food Safety Evaluation – Daniel Krewski, PhD, MHA, University of Ottawa, Ottawa, ON, Canada

Although registration to attend the colloquium in person is now closed, registration for the webcast is still available here.

On March 15-17, 2017, the American Society for Experimental Neurotherapeutics (ASENT) held its 19th Annual Meeting in Rockville, MD. The meeting brought together clinical investigators, pharmaceutical industry sponsors, officials from drug regulatory agencies, and patient advocacy organizations to address and advance the science of neurotherapeutics.

On Wednesday, March 15th, Hyman Phelps, & McNamara’s (HP&M’s) Frank J. Sasinowski presented on regulatory innovations in neurological disorder therapies, including discussing the recent approvals of Spinraza for SMA and Exondys 51 for DMD. His presentation highlighted issues and opportunities related to:

• Role of patient advocates in the drug approval process;
• Reliance on historically-controlled trials in rare diseases;
• Cumulative distribution as a means to establish clinical meaningfulness; and
• Use of Accelerated Approval in neurological diseases.

Slides from Frank Sasinowski’s presentation are available here.

On Friday, March 17th, HP&M’s Kurt R. Karst presented on repurposing drugs, including providing an overview of the regulatory pathways for repurposed drugs, legislative attempts o address repurposing (e.g., the OPEN Act), and the current environment surrounding orphan drugs and drug repurposing. Late breaking topics discussed included the proposed OPEN Act and the recent Congressional inquiry into potential abuses of the Orphan Drug Act (see our previous post here).  Slides from Kurt Karst’s presentation are available here.

Oh Canada! Congress has decided that it’s once again time to start looking to our neighbors to the north for some help increasing accessibility and decreasing cost of prescription drugs.  With two new bills introduced in the last month, one in each chamber of Congress, it seems that congressional Democrats are hoping to import more than just hockey and Tim Horton’s from Canada.

On February 28, 2017, Senators Bernie Sanders, Cory Booker, and Bob Casey introduced S. 469, the “Affordable and Safe Prescription Drug Importation Act.” (A companion bill was introduced in the House of Representatives – H.R. 1245 – by Representative Elijah Cummings.) Designed to help lower the cost of prescription drugs by allowing Americans to import medicine from Canada, S. 469 would amend FDC Act § 804 to direct FDA to promulgate regulations facilitating the importation of “qualifying prescription drugs” from “certified foreign sellers” in Canada and other permitted countries into the U.S.  The bill has lengthy definitions of “qualifying prescription drugs” and “certified foreign sellers,” but in short, the bill allows importation of drugs approved in Canada that comply with FDA GMPs (other than controlled substances, inhaled drugs for surgery, and compounded drugs) to be imported foreign wholesale distributors or licensed pharmacy operators certified by FDA to meet certain conditions. Eventually, FDA may open up importation of drugs from OECD countries with comparable legal standards for approval.

H.R. 1480, introduced in the House of Representatives by Chellie Pingree of Maine as the “Safe and Affordable Drugs from Canada Act of 2017,” introduces similar, but much less detailed legislation. H.R. 1480 amends the FDC Act to permit for importation a 90 day or less supply of prescription drugs from Canada for personal use only.  The drugs must be purchased from an approved and certified Canadian pharmacy with a valid prescription from a health care provider licensed in the U.S.  More products are excluded under H.R. 1480 than S. 469, as H.R. 1480 explicitly excludes controlled substances, biologics, infused drugs, intravenously injected drugs, inhaled drugs for surgery, parenteral drugs, biotechnology-processed products (i.e. therapeutic DNA plasmid products, monoclonal antibody products, therapeutic synthide peptic products with fewer than 40 amino acids, and recombinant DNA-derived products), and refrigerated products from importation.  Senator John McCain’s S. 92, an almost identical bill, was introduced in the Senate in January 2017.

While both bills introduce some questions about supply chain accountability, they both reflect a fairly simple way to reduce drug prices while the rest of Congress fights it out over coverage. Similar efforts have failed in the past (see Sen. McCain’s version introduced in 2015 that went nowhere), but with the Congressional Budget Office projecting that millions of Americans may become uninsured with the repeal of the Affordable Care Act, this bill might see some action this year. Like we’ve had to say a lot this year: we’ll just have to wait and see what happens. . . . Eh?

There are many things that are unique to the 505(b)(2) NDA approval pathway. Some are good and some are . . . well, let’s just say that they have proven to be frustrating for  some 505(b)(2) applicants.   Perhaps one of the most nettlesome aspects of the 505(b)(2) NDA pathway arises by operation (or should we say by lack of operation?) of FDC Act § 505A(o), which is part of the Best Pharmaceuticals for Children Act (“BPCA”).

FDC Act § 505A(o), titled “Prompt approval of drugs under section 505(j) when pediatric information is added to labeling,” and also known as the “Anti-Glucophage Provision” (or Section 11 of the BPCA), allows an ANDA applicant to omit from its labeling certain patent- and/or exclusivity-protected information concerning the pediatric use of a drug, and to include a disclaimer with respect to the omitted information. (Such a disclaimer might state: “Pediatric use information is approved for [COMPANY’S BRAND-NAME DRUG]. However, due to [COMPANY’S] marketing exclusivity rights, this drug product is not labeled with that pediatric information.”)  Specifically, FDC Act § 505A(o) states:

(1) GENERAL RULE.— A drug for which an application has been submitted or approved under section 505(j) of this title shall not be considered ineligible for approval under that section or misbranded under section 502 of this title on the basis that the labeling of the drug omits a pediatric indication or any other aspect of labeling pertaining to pediatric use when the omitted indication or other aspect is protected by patent or by exclusivity under clause (iii) or (iv) of section 505(j)(5)(F) of this title.

(2) LABELING.— Notwithstanding clauses (iii) and (iv) of section 505(j)(5)(F) of this title [(concerning 3-year new clinical investigation exclusivity)], the Secretary may require that the labeling of a drug approved under section 505(j) of this title that omits a pediatric indication or other aspect of labeling as described in paragraph (1) include—

(A) a statement that, because of marketing exclusivity for a manufacturer—

(i) the drug is not labeled for pediatric use; or

(ii) in the case of a drug for which there is an additional pediatric use not referred to in paragraph (1), the drug is not labeled for the pediatric use under paragraph (1); and

(B) a statement of any appropriate pediatric contraindications, warnings, or precautions that the Secretary considers necessary.

(3) PRESERVATION OF PEDIATRIC EXCLUSIVITY AND OTHER PROVISIONS.— This subsection does not affect—

(A) the availability or scope of exclusivity under this section;

(B) the availability or scope of exclusivity under section 505 for pediatric formulations;

(C) the question of the eligibility for approval of any application under section 505(j) that omits any other conditions of approval entitled to exclusivity under clause (iii) or (iv) of section 505(j)(5)(F); or

(D) except as expressly provided in paragraphs (1) and (2), the operation of section 505.

We’ve seen FDC Act § 505A(o) come into play before, and sometimes in court. The provision was at issue in litigation over generic CRESTOR (rosuvastatin calcium) (here and here) and generic ABILIFY (aripiprazole) (see our previous post here).

At this point you may be asking: “Why are you discussing 505(b)(2) NDAs in the context of a provision that concerns only ANDAs?” After all, FDC Act § 505A(o) is titled “Prompt approval of drugs under section 505(j) when pediatric information is added to labeling” (emphasis added), and there’s no indication that FDA raised any concerns with the provision in a report submitted to Congress in July 2016.  But that’s precisely the point!  FDC Act § 505A(o) does not address 505(b)(2) NDAs.  The BPCA neither addresses the carve-out or retention of protected pediatric information from 505(b)(2) product labeling, nor does the BPCA address the use of disclaimers for protected pediatric use information that is carved-out of 505(b)(2) product labeling.

If FDA determines that the protected pediatric information is important safety information, and therefore, must be retained in 505(b)(2) product labeling for reasons of safe use, then a full approval for the affected 505(b)(2) product cannot be issued until pediatric exclusivity has expired. Instead, FDA could issue only a tentative approval, with final approval dependent on the expiration of exclusivity applicable to pediatric labeling information.  This is true regardless of how close a 505(b)(2) NDA product may be to an ANDA drug product (and which ANDA could be approved by operation of FDC Act § 505A(o)).  For example, a drug product that is essentially a generic version of a brand-name listed drug, but that is submitted under a 505(b)(2) NDA simply by virtue of the sponsor’s use of a so-called “non-exception excipient,” thus precluding ANDA submission (see our previous post here), may be blocked from obtaining final approval because FDC Act § 505A(o) does not accommodate 505(b)(2) NDAs.

With the growing popularity of 505(b)(2) NDAs, which the Tufts Center for the Study of Drug Development recently assessed, the inability of a 505(b)(2) NDA applicant to obtain final approval because of protected pediatric information is on the rise. We sifted through several 505(b)(2) NDA approval packages and found quite a few FDA assessments concerning the ability (or inability) of a 505(b)(2) applicant to omit protected pediatric information.  Sometimes FDA concluded that the 505(b)(2) NDA could be approved with a labeling carve-out, and sometimes FDA determined that only tentative approval could be granted because FDC Act § 505A(o) does not apply to 505(b)(2) NDAs.  Here’s a rundown of the FDA assessments we found:

• NDA 022312 – Docetaxel Injection (Approved on January 11, 2012)
• NDA 201811 – Argatroban Injection (Approved on March 23, 2015)
• NDA 207963 – Palonosetron HCl Injection (Approved on August 22, 2016)
• NDA 203049 – Argatroban Injection (Approved on January 5, 2012)
• NDA 201743 – Argatroban Injection (Approved on May 9, 2011)
• NDA 022485 – Argatroban Injection (Approved on May 9, 2011)
• NDA 022434 – Argatroban Injection (Approved on June 29, 2011)
• NDA 201635 – TROKENDI XR (topiramate) Extended-release Capsules (Approved on June 25, 2012)
• NDA 200795 – Gemcitabine Injection (Approved on August 4, 2011)

We also came across some 505(b)(2) NDA tentative approval letters containing the standard language regarding exclusivity (i.e., “The listed reference drug product upon which you based your application is subject to a period of exclusivity protection and therefore final approval of your application under section 505(c)(3) of the Act (21 U.S.C. 355(c)(3)) may not be made effective until the period has expired.”) that we suspect is related to a period of pediatric exclusivity and where FDA has determined that a carve-out is not permissible:

• NDA 022359 – Argatroban Injection (Tentatively Approved on July 28, 2010)
• NDA 205122 – QUDEXY XR (topiramate) Extended-release Capsules (Tentatively Approved on April 15, 2016)
• NDA 201635 – TROKENDI XR (topiramate) Extended-release Capsules (Tentatively Approved on August 18, 2016)
• NDA 208645 – Bortezomib Injection (Tentatively Approved on October 20, 2016)

Congress is currently debating reauthorization of the Prescription Drug User Fee Act. As part of that process, Congress will likely also consider other changes to the law, including changes to provisions applicable to pediatric drug development (see, e.g., S. 456/H.R. 1231, the Research to Accelerate Cures and Equity for Children Act). Should another one of those issues for consideration be whether or not FDC Act § 505A(o) should be amended to accommodate 505(b)(2) NDAs.

On March 14, in the Federal Register, FDA published a list of Class II devices that the agency proposes exempting from the 510(k) requirements. A copy of the Federal Register notice can be found here. As you may recall from our earlier post, Section 3054 of the 21^st Century Cures Act required FDA to publish such a list for public comment. Under this new law, FDA is required to publish such a list once every five years beginning this year.

The proposed list is quite extensive. However, many of the devices on the list are already informally exempt.  In 2015, FDA published a final guidance, “Intent to Exempt Certain Unclassified, Class II, and Class I Reserved Medical Devices from Premarket Notification Requirements,” listing numerous unclassified, Class I, and Class II devices that FDA believed qualified for 510(k) exemption.  The Class II devices from this final guidance now appear on FDA’s proposed list for public comment.  Thus, much of this proposed list is unenlightening.

There are, however, a number of new devices on the list including a large list of in vitro diagnostic (IVD) devices, such as gene expression profiling reagents and DNA genetic analyzers.  FDA has also proposed exempting high-throughput genomic sequence analyzer for clinical use.  All of these examples are relatively new devices.

Perhaps the most notable proposed exemption, however, relates to drugs of abuse tests. FDA has proposed exempting virtually all drugs-of-abuse testing including those performed by traditional screening methods such as enzyme immunoassay and radioimmunoassay, and newer confirmatory methods such as mass spectrometry and gas chromatography.  The proposed exemption includes not just professional use tests, but also some over-the-counter tests.

The proposed exemption for drugs-of-abuse test systems is limited to “test systems intended for employment and insurance testing and does not include test systems intended for Federal drug testing programs (e.g., programs run by the Substance Abuse and Mental Health Services Administration (SAMHSA), the Department of Transportation (DOT), and the U.S. military.)”

By regulation, FDA regulates drugs-of-abuse testing devices are intended for use “in the diagnosis and treatment of [drug] use or overdose” (see, e.g., 21 C.F.R. § 862.3250(a) (cocaine and cocaine metabolite test system)) and in some instances “in monitoring levels of [drug] to ensure appropriate therapy” (see, e.g., 21 C.F.R. §§ 862.3150(a) (barbiturate test system), 862.3170(a) (benzodiazepine test system)).

FDA has carved out a narrow exception to regulatory oversight of drugs-of-abuse test systems, in which FDA exercises enforcement discretion over tests used solely for forensic (law enforcement) purposes, “because there are protections to ensure sample integrity and test accuracy that are not generally available in the home, workplace, insurance and sports settings” including the rules of evidence in judicial proceedings.”  See 65 Fed. Reg. 18,230, 18,230 (Apr. 7, 2000) (here).

The regulatory scheme for drugs-of-abuse test systems have been a bit of a regulatory mystery for some over the years. Warning letters have asserted that test systems intended for workplace drug testing does not qualify as exempt forensic testing.  See, e.g., FDA, Warning Letter to American Bio Medica Corp. (July 30, 2009) (this warning letter also led to a 2013 Consent Decree relating to drugs-of-abuse tests for workplace testing requiring 510(k) clearance); and FDA, Warning Letter to Branan Medical Corp., Inc. (Dec. 28, 2009).  FDA’s proposal suggests that the Agency now considers employment and insurance testing to be of sufficiently low risk that they may warrant 510(k) exemption.

The proposed exemption for insurance and employment testing is separate from the forensic testing carve out. One notable difference is that forensic drugs-of-abuse tests are not subject to any FDA regulatory oversight under FDA’s enforcement discretion whereas the new proposal would only exempt workplace and insurance tests from the 510(k) requirements.  Workplace and insurance drugs-of-abuse tests (along with manufacturers of other devices on the proposed exemption list) will still be required to comply with all other applicable FDA regulatory requirements, including the design controls, to the extent applicable, MDR reporting, and reporting corrections and removals.  Manufacturers of such devices will also continue to be subject to FDA inspections.

If finalized, the exemptions, including the drugs-of-abuse tests would still be subject to the .9 limitations, which requires a manufacturer to obtain 510(k) clearance for an exempt device type, if (i) the device is intended for a use different from the intended use of a legally marketed device in that generic type of device, (ii) the device operates using a different fundamental scientific technology than a legally marketed device in that generic type of device, or (iii) if it falls within a certain category of IVDs. FDA will be accepting comments on the proposed list of devices for 510(k) exemption for the next 60 days.