On April 27, 2018, Petitioners Breckenridge Pharmaceutical, Inc. and Nexgen Pharma, Inc. filed a Petition for Review in the United States Court of Appeals for the District of Columbia Circuit. The Petition seeks review of a final FDA order published in the Federal Register on April 2, 2018 (the “Order”). The Order denied requests for a hearing and withdrew approval for ANDAs for prescription polyethylene glycol 3350 (PEG-3350). The Order was initially effective May 2, 2018 but was stayed by FDA in response to several petitions for stay to the Agency. Currently, the Order goes into effect on November 2, 2018 – but FDA may not have the final say on this issue. Breckenridge/Nexgen’s asks the D.C. Circuit to set aside the Order as clearly erroneous, arbitrary and capricious, an abuse of discretion, and not supported by substantial evidence.

The Petition for Review is not a surprise. Breckenridge/Nexgen was one of several Rx ANDA holders participating in the Agency proceedings. Additionally, it and the other Rx ANDA holders had included in their petitions for stay to the Agency arguments that a stay was required to permit judicial review.

While FDA granted a stay until November 2, 2018, the Agency rejected the Rx ANDA holders arguments that a stay was required under 21 U.S.C. § 10.35 (e), because the criteria in (e)(1)-(4) were met.. Instead, FDA reasoned that the Agency petitioners had established that a stay was “in the public interest and in the interest of justice,” and therefore a discretionary stay was warranted—but not required. Breckenridge/Nexgen challenge both FDA’s Order and FDA’s stay determination.

Because a Petition for Review only starts the process for judicial review, it does not set forth the substance of the arguments that Breckenridge/Nexgen will make to the D.C. Circuit. That said, the Agency proceedings have been pending for some time, so the arguments are not unfamiliar to dedicated FDA Law Blog readers (indeed, we blogged on these issues here, here, and here). For those of you who need a refresher on the regulatory history of laxatives, here’s a quick recap: in April 2007, FDA approved an NDA for an Rx-to-OTC switch for MiraLax. Five ANDAs based on MiraLax as the RLD had already been approved, so FDA issued a letter to the ANDA holders explaining that FDA believes their prescription products, which bear the “Rx only” symbol, are misbranded and may not be lawfully marketed. To lawfully market PEG-3350, according to the FDA letter, the ANDA holders must file new ANDAs referencing the OTC version of MiraLax and update the labeling to OTC labeling. FDA published a Notice of Opportunity for a Hearing in the Federal Register on October 24, 2008 (73 Fed. Reg. 63491) proposing to withdraw approval of the prescription PEG 3350 ANDAs. Four ANDA holders submitted timely requests for a hearing and supporting evidence, but FDA denied a hearing in both its proposed order of May 2014 and its final order of April 2018.

In a joint Petition for Stay at the agency level, Breckenridge/Nexgen argued that the final order irreparably harms their business and should be vacated. They explain that there is a meaningful difference between the Rx and OTC versions of PEG-3350 – duration of use, as well as reimbursement – and raise procedural errors and misstatements during the administrative process. Because the Order refused to consider all information submitted in 2014 and did not address Breckenridge/Nexgen’s arguments regarding outstanding factual issues with respect the scope of the Rx-to-OTC switch, those arguments may very well be made before the D.C. Circuit. Two Rx ANDA holders also filed petitions for stay with the Agency. Our firm represented one of those Rx ANDA holders.

As of the writing of this post, no briefing schedule has been set. The court has set May 31, 2018 as the date for Petitioner’s  procedural motions.

USDA announced the publication of its much awaited proposed rule establishing a National Bioengineered Food Disclosure standard as mandated by Congress almost two years ago (for more on that law, see our prior posting here).  The rule is scheduled to publish in the Federal Register on May 4, but for those who can’t wait, it’s available in prepublication form.  We’ll follow up with a posting on key aspects of the proposed rule, but one thing bears emphasis now: the deadline for comments is July 3, 2018, and USDA has stated that the comment period will not be extended.  It therefore behooves those with an interest in the rule to make the timely submission of comments a top priority.

In 2015, Senators D. Feinstein, R. Durbin and K. Gillibrand asked GAO to investigate the U.S. Department of Agriculture’s (USDA’s) Food Safety and Inspection Service (FSIS) pathogen standards for meat and poultry products and identify any steps that FSIS could make to address food safety. On April 18, 2018, GAO published its report of the two year investigation, Food Safety: USDA Should Take Further Action to Reduce Pathogens in Meat and Poultry Products.

Though the U.S. food supply is considered safe, the Centers for Disease Control and Prevention estimates that foodborne pathogens cause about 9 million illnesses each year. Two million of the illnesses are associated with Salmonella and Campylobacter.

GAO recognized that FSIS has taken a number of actions to address food safety, but concluded that it can do some things better. Among other things, FSIS has established performance standards for Salmonella and Campylobacter for some meat and poultry products. These standards are used to reduce contamination in meat and poultry before the products are sold. FSIS began setting these standards in 1996. At that time, the standards were set at industry-wide prevalence levels, not at levels that may protect human health. Since then, FSIS has changed its procedures and developed more science-based performance standards.

Over time, FSIS developed performance standards for Salmonella on beef carcasses, ground beef, pork carcasses, chicken carcasses and parts, comminuted chicken, turkey carcasses, and comminuted turkey. FSIS also developed performance standards for Campylobacter on chicken carcasses and parts, comminuted chicken, turkey carcasses, and comminuted turkey. Although some of the standards such as the standards for chicken have been updated, the standards for pork carcasses, beef carcasses and ground beef have not been updated since 1996 and there are no time frames for updating them. Moreover, for some commonly consumed products, such as turkey breasts, ground pork and pork chops, FSIS has never set standards. It was not clear to GAO how FSIS decides for which products it sets standards and when it updates standards.

The GAO made two recommendations regarding the performance standards: (1) document the process for deciding which products are considered for new standards (so as to better ensure that such decisions will be risk-based), and (2) set time frames for determining which updates or standards are needed for ground beef, beef carcasses, pork cuts, and ground pork.

Although FSIS agreed with the recommendations, its response included some comments. For example, FSIS indicated that it made a risk-based decision to not develop performance standards for turkey breast. Salmonella levels in turkey carcasses are typically low and consumption of turkey is relatively low, such that there appears minor exposure to pathogens from turkey parts.

As part of the audit, GAO also examined steps FSIS has taken to address challenges in reducing pathogen levels in meat and poultry that were identified in a 2014 GAO report. In that report, GAO found that the level of pathogens in poultry products can be affected by practices on farms where poultry are raised. Even though FSIS has no authority over such farm practices, GAO recommended that FSIS issue guidelines on the effectiveness of practices for controlling Salmonella and Campylobacter on farms. In response, FSIS did in fact revise its guidelines to include information on the effectiveness of on-farm practices for controlling pathogens in poultry and beef cattle. The draft guidelines for controlling Salmonella in pigs, however, do not contain such information. GAO recommends that FSIS include such information in the final guidance.

Senators Feinstein, Durbin, and Gillibrand sent the GAO report with four of their own questions (about timing of new performance standards and other actions recommended actions by GAO as well as a question about use of whole genome sequencing) in a letter to Secretary of Agriculture Sonny Perdue.

FDA is continuing the crackdown on the sale of tobacco products to minors (see our post here regarding recent FDA actions). On May 1, 2018, FDA and FTC issued 13 joint warning letters to manufacturers, distributors, and retailers for misleadingly labeling or advertising nicotine-containing e-liquids as kid-friendly food products, such as juice boxes, candies, and cookies.

The Federal Food, Drug, and Cosmetic Act (FDCA) provides that a tobacco product shall be deemed misbranded if, in relevant part:

1) its labeling is false or misleading (section 903(a)(1)), or

2) if, in the case of any tobacco product distributed or offered for sale in any State, its advertising is false or misleading in any particular (section 903(a)(7)(A)) or it is sold or distributed in violation of certain regulations, such as regulations prohibiting sale to minors (section 903(a)(7)(B)).

Section 201(rr)(4) of the FDCA prohibits a tobacco product from being marketed in combination with any other article or product regulated under the FDCA (including a drug, biologic, food, cosmetic, medical device, or a dietary supplement).

In terms of FTC authority, Section 5 of the FTC Act prohibits unfair or deceptive acts or practices in or affecting commerce. This prohibition includes practices that present unwarranted health or safety risks.

FDA and FTC found that companies violated the provisions outlined above by using false or misleading labeling and/or advertising that cause e-liquids to imitate food products, particularly ones that are marketed toward and appeal to minors. The batch of 13 warning letters all cited violations to both misbranding violations (under section 903(a)(1) of the FDCA) and unfair or deceptive acts or practices (Section 5 of the FTC Act). In addition, 6 warning letters also cited a violation of section 903(a)(7)(B) of the FDCA for sale of e-liquid products to minors and 1 warning letter cited a violation of section 201(rr)(4) of the FDCA for marketing a tobacco product in combination with a food product.

The warning letters mention that children are at particular risk for ingesting e-liquid products when the products have labeling and/or advertising that cause the product to imitate food products typically marketed toward and appealing to children. The warning letters also make the point that children are at particular risk because exposure to nicotine in the e-liquid can result in acute toxicity and, further, that severe harm can occur, including seizure, coma, respiratory arrest, and death from cardiac arrest.

The issuance of this batch of warning letters is just the most recent part of FDA’s ongoing efforts to enforce regulations specifically aimed at addressing youth access to tobacco products. We anticipate more FDA actions in the future and will continue to provide updates.

On April 24, 2018, FDA released a statement regarding new enforcement actions and a Youth Tobacco Prevention Plan aimed to help stop minors from using e-cigarette products.

Under the Family Smoking Prevention and Tobacco Control Act (“Tobacco Control Act”), a “tobacco product” is defined as “any product made or derived from tobacco that is intended for human consumption, including any component, part, or accessory of a tobacco product.” The Tobacco Control Act gave FDA the express authority to regulate cigarettes, cigarette tobacco, roll-your-own tobacco, and smokeless tobacco. Any other “tobacco product” could be regulated by FDA only if the Agency issued regulations “deeming” such products to be subject to the Tobacco Control Act. As discussed in our previous post, on May 10, 2016, FDA published the final “deeming regulation” asserting authority over all tobacco products meeting the broad statutory definition of a “tobacco product.” This authority extends to electronic nicotine delivery systems (ENDS), which may be described with terms such as vapes, vaporizers, vape pens, hookah pens, e-cigarettes, or e-pipes. ENDS products typically use a liquid (“e-liquid”) that contains nicotine. This e-liquid is heated into an aerosol that can be inhaled by the user. ENDS products may be manufactured to look like traditional tobacco products or may resemble items such as pens or USB drives.

FDA cites the following CDC statistics regarding the use of ENDS products by minors:

• More than 2 million middle and high school students were current users of e-cigarettes in 2016
• 11% of high school and 4.3% of middle school students were current users of e-cigarettes in 2016
• E-cigarette use rose from 1.5% to 16.0% among high school students and from 0.6% to 5.3% among middle school students from 2011 to 2015

We have previously discussed FDA’s comprehensive plan for tobacco and nicotine regulation announced last July (here). FDA’s most recent enforcement activity is more narrowly focused on the use of ENDS products by minors, and singles out one ENDS product in particular. In its April 24 statement, FDA outlined a series of enforcement and regulatory steps.

First, FDA announced that on April 6, 2018 it initiated a large-scale, undercover, nationwide blitz that will continue until the end of April 2018. This blitz focuses on the sale of e-cigarettes (specifically products under the JUUL brand) to minors at both brick-and-mortar and online retailers. The Agency’s efforts have already revealed numerous violations according to the FDA. This blitz, in addition to other compliance checks, has resulted in FDA issuing 40 warning letters for the illegal sale of e-cigarettes, specifically JUUL products, to minors.

Second, FDA contacted eBay regarding several listings for JUUL products on the website. According to FDA, eBay removed the listings and voluntarily implemented measures to prevent against re-listing of the items. It is possible that other online retailers with e-cigarette products, specifically JUUL products, may receive similar communications from the Agency.

Third, on April 24, 2018, FDA sent an official request for information to JUUL Labs, requesting the company submit information, such as documents related to product marketing; research on the health, toxicological, behavioral or physiologic effects of the products, including youth initiation and use; whether certain product design features, ingredients or specifications appeal to different age groups; and youth-related adverse events and consumer complaints associated with the products. FDA is planning on sending additional letters to other manufacturers and has asserted that companies that do not comply will be in violation of the law and subject to enforcement.

Fourth, the Agency announced that it is planning to take enforcement actions against companies that are marketing products in a way that is misleading to minors.

Finally, FDA is also continuing its efforts on science-based campaigns to educate minors about the dangers of all tobacco products, including e-cigarettes.

FDA Commissioner Gottlieb makes clear the focus of the Agency is ENDS products marketed and sold to minors. For adults, FDA believes that ENDS products may offer a potentially lower risk alternative for adult smokers, providing them with access to nicotine without the additional risks associated with the combustion of tobacco. However, the Agency states the viability of ENDS products serving this purpose is undermined if they attract minors.

The steps outlined above are just the first of those the FDA plans to pursue as part of the Youth Tobacco Prevention Plan, and additional steps will be announced in the future. FDA’s message to all tobacco product manufacturers and retailers is clear: the Agency is watching closely.

On April 13, 2018, FDA issued the final guidance documents “Considerations for Design, Development, and Analytical Validation of Next Generation Sequencing (NGS) – Based In Vitro Diagnostics (IVDs) Intended to Aid in the Diagnosis of Suspected Germline Diseases” (hereinafter the NGS Guidance, available here) and “Use of Public Human Genetic Variant Databases to Support Clinical Validity for Genetic and Genomic-Based In Vitro Diagnostics” (hereinafter the Databases Guidance, available here). We previously blogged on the draft guidance documents issued in July 2016 here. As we discussed in our earlier post, these guidances have the possibility to be incredibly important to the IVD industry given the tremendous potential that sequencing holds.

The two guidances could hardly have undergone more different degrees of revision since their drafts were issued. The Databases Guidance received no substantive changes as compared to the draft. On the other hand, the NGS Guidance has undergone significant changes as compared to its draft, including its name. The draft NGS Guidance was originally named the “Use of Standards in FDA Regulatory Oversight of Next Generation Sequencing (NGS)-Based In Vitro Diagnostics (IVDs) Used for Diagnosing Germline Diseases.” NGS test developers will want to ensure they closely read the final NGS guidance to understand the full extent of its changes. Below we discuss several of the significant substantive changes to the NGS Guidance.

It is important to note that FDA provided no explanation for the changes to the NGS Guidance. Unlike the case with regulations, where FDA describes the reasons for revisions, guidances keep readers guessing as to why FDA’s thinking has shifted.

One of the major changes to the scope of the guidance is that it now applies only to NGS-based IVDs intended to diagnose suspected germline diseases in symptomatic patients. The guidance specifically states that it “does not address tests intended for use in the sequencing of healthy individuals.” The original guidance did not limit the scope of the guidance to only symptomatic individuals. This is an important change that will limit the scope and impact of the guidance to industry.

The guidance does, however, include several new helpful sections, including one regarding recommendations for reviewing changes to device design and production. This section pertains to all changes, including those that may or may not require premarket review. The guidance provides general guidance regarding assessing changes, including revalidation. The guidance also includes a new Appendix A. This appendix includes illustrative examples to aid in the guidance’s recommendations regarding analytical tests.

Finally, the NGS Guidance includes a notably shorter discussion of the possible exemption of NGS-based tests for germline diseases as compared to the draft. The draft had a full section regarding the possibility of an exemption for such tests. The final NGS Guidance still leaves open the potential for NGS-based tests being exempt from premarket notification. But, with a much more limited discussion in the final guidance it may be a signal that the Agency believes it is less likely that these tests will actually be exempt once classified. The guidance continues to state that it anticipates that the de novo pathway is the appropriate premarket pathway for these IVDs.

The extent of changes to the final NGS Guidance likely reflect that the Agency’s understanding and view regarding these tests is continuing to evolve. That will almost certainly remain the case for years to come. This is an area we will continue to watch closely and look forward to seeing FDA’s first de novo authorization for an NGS test to diagnose a germline disease.

In 2014, the Center for Science in the Public Interest (CSPI) filed a Citizen Petition requesting that FDA ban the retail distribution of highly concentrated caffeine marketed as a dietary supplement and specify limits on the forms in which caffeine may be sold.   On April 16, 2018, on the same day that FDA issued guidance regarding highly concentrated caffeine in dietary supplements, FDA denied the petition.

FDA denied the Petition because, as explained in the denial, the Agency does not think that the requested actions (involving rulemaking) are necessary. It points to the guidance and “publication of information directed toward industry and consumers, through which [FDA] communicated about the legal status of” highly concentrated caffeine products.

In the guidance, FDA explained that it generally considers products containing potentially lethal amounts of pure or highly concentrated caffeine in powder or liquid form sold in bulk to be adulterated under FDC Act § 402(f)(1)(A). As discussed in the guidance, FDA’s concern relates to the difficulty of separating out a safe amount (serving) of caffeine. FDA has taken the position that labeling the product with instructions at to a safe serving size and warning statements do not mitigate the risk; notwithstanding the provision of a warning, directions, and dosing cups or other tools, the highly concentrated bulk caffeine product continues to present a significant or unreasonable risk of illness or injury.

The guidance also provides some examples of caffeine products that, according to FDA, do not present a significant or unreasonable risk of illness or injury. Assuming that the product otherwise complies with all applicable legal requirements, FDA likely will not consider caffeine supplement in solid dosage form or premeasured packets or containers that do not provide an excessive amount (not defined) of caffeine per dosage form adulterated. Even though such products may be highly concentrated, the dosage form eliminates the need to measure the serving and thus avoids the risk of inaccurate dosing. To avoid an adulteration charge for bulk powdered or liquid caffeine product, the caffeine concentration must be low so that a serving error or misunderstanding about dosing would not normally be expected to lead to a toxic/life threatening situation.

In the Federal Register notice, FDA justified issuing the guidance as final guidance; according to the Agency, the threat to public health posed by pure and highly concentrated caffeine products made prior public participation not feasible.

It is reasonable to expect that the Guidance will have the effect of discouraging the marketing of highly concentrated caffeine products sold in bulk form. Thus, it appears that even though FDA denied the Petition, CSPI effectively got what it requested and the Agency avoided having to go through notice and comment rulemaking.

Earlier this month, FDA issued a draft guidance: Expansion of the Abbreviated 510(k) Program: Demonstrating Substantial Equivalence through Performance Criteria. This draft guidance would expand use of the Abbreviated 510(k) pathway as follows: “The intent of the guidance is to describe an optional pathway for certain, well understood device types, where a submitter would demonstrate that a new device meets FDA-identified performance criteria to demonstrate that the device is as safe and effective as a legally marketed device.” Id. at 2.

The current Abbreviated 510(k) program allows a sponsor to demonstrate some of the performance characteristics necessary to support a finding of substantial equivalence by showing conformity to FDA-recognized consensus standards. In this guidance, FDA acknowledges that the current substantial equivalence analysis, which requires direct comparison testing can sometimes be very burdensome. For example, it is difficult to conduct comparison testing when a predicate device is not marketed or where it is prohibitively expensive. Another example is a device that relies on multiple predicate devices for different performance and technological characteristics may be required to conduct multiple comparative tests.

The draft guidance proposes an Expanded Abbreviated 510(k) program, in which sponsors would be able to utilize the same mechanisms available in the current Abbreviated 510(k) program to allow a demonstration of all performance characteristics. In some circumstances, no direct comparison testing would be required. A predicate device would still be identified, but testing of the proposed device would be conducted against objective performance criteria.

FDA plans to issue guidance documents to establish such performance criteria and identify the types of eligible devices. This guidance may include identification of products by product code, appropriate intended uses, appropriate indications for use, and expectations for technological characteristics.

This initiative should be considered a modest, but useful, tweak to the 510(k) program. While it may eventually ease testing burdens on well‑understood device types, FDA may require some time to issue a full panapoly of product-specific guidances. We suspect, though, that FDA has some devices in mind that it will address relatively quickly. Most device types will likely not be eligible for the program.

Anyone interested in submitting comments on the draft guidance must do so by July 11, 2018.

On April 12, 2018, the three FDA Centers jointly issued the draft guidance, “Investigational In Vitro Diagnostics in Oncology Trials: Streamlined Submission Process for Study Risk Determination” (draft available here). The draft guidance outlines a process for obtaining FDA’s feedback regarding whether an investigational IVD requires an approved Investigational Device Exemption (IDE) when used in the study of an Oncology therapeutic product. As we discussed in our earlier post (here), FDA’s December draft guidance regarding investigational IVDs includes an expansive definition, indicating that IVDs used in therapeutic product studies must be either investigational or cleared/approved. Thus, this guidance would apply to IVDs that are investigational or those that are currently marketed for non-diagnostic use (e.g., research use only).

The majority of IVD investigations have historically been exempt from the IVD studies pursuant to 21 C.F.R. § 812.2(c)(3). IVD investigations are exempt if the IVD is appropriately labeled as investigational pursuant to 21 C.F.R. Part 809, and it:

(i) Is noninvasive,

(ii) Does not require an invasive sampling procedure that presents significant risk,

(iii) Does not by design or intention introduce energy into a subject, and

(iv) Is not used as a diagnostic procedure without confirmation of the diagnosis by another, medically established diagnostic product or procedure.

Id. § 812.2(c)(3). FDA issued guidance regarding interpretation of these four criteria in 2010 (available here). The 2010 guidance does not, however, cover all possible IDE exemptions nor does it discuss when/if a companion diagnostic fits within the above criteria. In recent years, investigational IVDs used in therapeutic product clinical studies where the IVD will ultimately be a companion diagnostic have not been exempt from the IDE requirements.

Prior to issuance of the draft streamlined oncology study risk determination guidance, study sponsors could seek a determination from CDRH as to whether an IDE was required for an investigational IVD by submitting a study risk determination pre-submission. The new draft guidance indicates that oncology therapeutic study sponsors can now request this feedback via FDA Form 1571 when it submits an Investigation New Drug (IND) application. CDER or CBER will seek input from CDRH in providing its feedback. The guidance states that sponsors should include the following information on their form when seeking FDA feedback regarding the IDE requirements applicable to IVDs used in the planned study:

• How the results from the investigational IVD will be applied in the clinical trial;
• What is known about the prevalence of the biomarker (evaluated by the investigational IVD) in the patient population; and
• The specimen type that will be collected for investigational IVD testing (including the anatomical site) and whether any biopsy required for investigational IVD testing could present a potential for serious risk to the health, safety, or welfare of the subject.

With regard to the third bullet, FDA notes that this process does not apply “if an invasive biopsy that presents a potential for serious risk to health, safety, or welfare of the subject is required for investigational IVD testing for enrollment.” The guidance appears to suggest that such invasive biopsies automatically require an IDE, a position which would be consistent with § 812.2(c)(3)(ii).

The guidance explains that FDA will provide its feedback regarding whether an investigational IVD requires an IDE in a “May Proceed Letter.” This timing seems appropriate if an IDE is not required. However, if an IDE is required, it would not seem ideal for the drug or device sponsor to need to begin the IDE approval process after the IND has already been approved. Thus, this process seems as though it may be helpful for therapeutic and IVD manufacturers when the sponsor is seeking – and obtains – confirmation that the investigational IVD is exempt from the IDE requirements. In addition, depending on the parties’ (IVD manufacturer and therapeutic manufacturer) relationship, it may be challenging for only the therapeutic sponsor to communicate with FDA via the IND application regarding the proposed diagnostic test.

In our view, this process may be modestly helpful; however, it only addresses part of the IVD-therapeutic product question. The often more important question is whether FDA will view the IVD as a companion diagnostic. The draft guidance doesn’t touch that topic. In order to be truly helpful to study sponsors, we suggest that FDA expand the proposed program to also allow study sponsors to seek a determination as to whether the IVD will be viewed as a companion diagnostic. It is important to note that largely similar information required for the study risk determination also apply when assessing whether an IVD is a companion diagnostic.

Last week United States ex rel. Campie v. Gilead Sciences Inc. took one step closer to being the first FCA materiality case to be taken up by the Supreme Court since the Court’s seminal decision in Universal Health Services, Inc. v. United States ex rel. Escobar – or one step further away, if you read the tea leaves a different way. On April 16, the Supreme Court invited the U.S. Solicitor general to “file a brief. . . expressing the views of the United States” on Gilead’s petition for writ of certiorari.   It is not unusual for the Court to call for the views of the Solicitor General in a case where the United States is not a party (the United States declined to intervene in Gilead), but the government has a significant interest in the case. When the Supreme Court does call for the Solicitor General’s views on a petition for cert, it often acts in accordance with the Solicitor General’s recommendations (with respect to whether to grant certiorari, not necessarily with respect to the merits of the case).

We previously blogged about the Gilead case here, here, and here. Importantly, the Ninth Circuit’s decision Gilead is an outlier among the Circuits’ various interpretations of Escobar.  In its Gilead decision, the Ninth Circuit arguably seeks to either reverse or ignore Escobar’s emphasis on a rigorous standard for FCA materiality. For readers of this blog, in particular, Gilead is significant; the Ninth Circuit’s reasoning would allow FCA cases to proceed based on FDA regulatory infractions, because the government would have the option not to pay a claim based on the noncompliance—and even if FDA’s response to the infractions indicated that it did not view the regulatory issue as material. Gilead and several amici have urged the Supreme Court to take up the case, in part to avoid undermining FDA’s regulatory authority.

The Supreme Court may be inclined to grant certiorari in Gilead to address the Ninth Circuit’s misreading of Escobar and the FCA materiality standard. Escobar was decided by a unanimous Court in June 2016, and since then the Court’s composition has remained the same except for the addition of Justice Neil Gorsuch. The Court’s request for the Solicitor General’s views also suggests that the Court is willing to take up the Gilead case. But it seems too much to hope that the Solicitor General would recommend a course of action that could make it more difficult for the federal government to recover monies under the FCA, even if the government would welcome a case that revisits Escobar to clarify and/or limit that case’s materiality language. In fact, the government has previously expressed views on FCA materiality under Escobar that are similar to those expressed by the Ninth Circuit in Gilead. See, e.g., Statement of Interest of the United States, United States ex rel. Kolchinsky v. Moody’s Corp., 12-cv-1399 (S.D.N.Y May 8, 2017). The Solicitor General often takes months to file its brief in response a Supreme Court request, so we may have to wait some time to find out exactly what the government has to say.

Separately, on the same day that the Supreme Court made its request in Gilead, it announced the decision to deny certiorari in another significant FCA case, United States ex rel. Nargol v. DePuy Orthopeadics, Inc., relating to the pleading standards for an FCA case under Fed. R. Civ. P. 9(b). Justice Alito did not participate in the decision to deny cert. The Supreme Court’s denial in DePuy leaves in place a First Circuit ruling we blogged about here and here, which applied a relaxed pleading standard to a False Claims Act complaint that alleged indirect submission of false claims. The First Circuit took the position that it was possible for a plaintiff to adequately plead against defendant based on a statistical certainty that false claims were submitted as a result of the defendant’s alleged actions, rather than alleging the specifics of any actual false claims. This decision leaves defendants guessing about the courts’ application of 9(b) to indirect false claim cases, because the Circuits apply divergent pleading standards with respect to the use of statistics to establish the existence of false claims.

As we previously reported, the United States Cattlemen’s Association (USCA) filed a Petition with the Food Safety and Inspection Service (FSIS), asking that FSIS establish formal definitions of “meat” and “beef” that exclude what petitioners call lab grown meat and products prepared from plant or insect protein. Until April 17, the majority of comments submitted have been in support of the petition.

The National Cattlemen’s Beef Association, (NCBA), however, does not support the Petition. As described in its comment to the Petition, the NCBA does not believe that the action requested by USCA “will adequately provide meaningful protection for beef nomenclature.”  In contrast to the USCA, the NCBA wants FSIS to assert jurisdiction over foods produced from cell or tissue culture that are derived from livestock and poultry animals or their parts, so as to ensure a level playing field. NCBA takes the position that, since cell-cultured or lab-grown meat products are derived from parts of a carcass, in this case stem cells, these products fall squarely within the definition of meat food product.  Even if this were not the case, NCBA believes that “FSIS should assert jurisdiction as a means of ensuring regulatory equity.”

As to the labeling of the product, NCBA seems of two minds. It asserts that the cultured meat should not be permitted to be marketed as beef. Yet, it argues that, if the producers of lab-grown or cultured meat products wish to call these products meat, they must adhere to the same food safety inspection standards and comply with the same labeling standards as traditional meat food products; only in that way can “arbitrary marketing claims,” such as “clean meat,” be avoided.

As far as products that clearly fall outside USDA’s jurisdiction are concerned, such as products made from insects or plants, or other non-animal products, NCBA suggests that FSIS ask FDA to take appropriate and immediate enforcement action against allegedly mislabeled imitation beef products.

In a joint comment, the Good Food Institute, Field Roast Grain Meat Co., Finless Foods, Hungry Planet, Impossible Foods, Lightlife, Sweet Earth Enlightened Foods and the Tofurky Company (collectively GFI) also oppose the USCA Petition. GFI’s comments focus primarily on plant-based products.  GFI argues that FSIS lacks authority over the labeling of such products, and that any restriction to the truthful use of the terms “meat” or “beef” with appropriate qualifiers that accurately disclose the nature of the plant-based product would violate the First Amendment.

As far as cultured meat is concerned, GFI’s comments suggest that it believes that these products may be under FSIS jurisdiction. Referring to dictionary definitions for “meat,” GFI argues that meat does not require slaughter.  In a footnote, GFI requests that FSIS work closely with what it calls “clean meat companies” to determine the appropriate labeling for these products.  GFI opposes USCA’s request to limit the definition of beef to meat that comes from cattle “that have been raised and harvested in the traditional manner.”  GFI contends that FSIS does not have the authority to “prop up an industry or favor one production method over another,” and that such narrowing of the definition would inhibit innovation across the industry.  Moreover, GFI points out that what is traditional is subject to interpretation; arguably, current methods of cattle production are not traditional.

On April 13, FSIS announced that it was extending the comment period for the petition (which was set to close on April 17) by another 30 days. Comments submitted after April 13 are posted on regulations.gov.

Meanwhile, in a March 28, 2018 letter to GAO, U.S. Rep. Rosa DeLauro, D-CT requested that GAO “investigate what regulatory framework, if any exists for cell-cultured food products and how this framework compares to other international approaches,” e.g., those in Canada, Japan, and the European Union. According to the request, such information is needed for Congress to address this emerging issue and ensure that it is “properly overseen by the relevant . . . agencies” once these types of products becomes commercially available.

Declaring its intent to stand on the original complaint in FTC v. Shire ViroPharma, the FTC has appealed the District Court for the District of Delaware’s decision to dismiss the Commission’s unfair competition case against Shire without prejudice.  We previously blogged about this case here, and here.

Although District Court dismissals without prejudice are typically not subject to immediate appeal, the FTC seeks appellate jurisdiction by declaring that it will not amend its original Complaint despite the District Court’s grant of leave to do just that.  Rather, the FTC will risk abandoning its case in District Court in favor of seeking a review of the key legal issue by the Third Circuit. This speaks to the significance of the lower court’s ruling that the FTC had failed to meet its statutory burden in bringing the case – the Shire ruling has already been cited against the FTC in at least four other pending cases.

We will continue to follow this case as it develops.

As the breadth of the “patent safe harbor” continues to expand under the Federal Circuit’s growing body of relevant case law, some patent holders are looking to the Supreme Court to push back. In a Petition for Certiorari filed last week in Classen Immunotherapies v. Elan Pharmaceuticals (and sent to us by Alex MacCormick over at Center Lane, LLC), patent-holders challenge the District Court’s (as affirmed by the Federal Circuit) interpretation of routine and non-routine.

Codified in 35 U.S.C. § 271(e), the safe harbor exempts drug development and approval from patent infringement:

It shall not be an act of infringement to make, use, offer to sell, or sell within the United States or import into the United States a patented invention . . . solely for uses reasonably related to the development and submission of information under a Federal law which regulates the manufacture, use, or sale of drugs or veterinary biological products.

Over time, courts have held that the safe harbor applies to both drugs and devices and expanded the use of the patented technology to any activities “reasonably related” to FDA approval,” including data developed in clinical trials for FDA approval. As long as there is a reasonable basis to believe that a patented technology may be used for an FDA submission, the use is protected under the safe harbor.  Merck KGaA v. Integra Lifesciences, 545 U.S. 193 (2005).

In 2015, patent-holders were given a gift from the Federal Circuit when it held that ongoing post-approval commercial manufacturing activities do not fall under the safe harbor. But what the court giveth, it also taketh away.  For in 2016, the District Court held (and the Federal Circuit affirmed without input) in Classen Immunotherapies v. Elan Pharms that the safe-harbor protects data in a supplement to revise labeling.  In this case, Elan used Classen’s patented research tool to study the effect of food on the bioavailability of the already-approved drug Skelaxin.  The clinical data was then submitted to FDA in a citizen petition and an sNDA to revise its labeling.  The District Court concluded that Elan’s use of the research tool was protected by the safe harbor because the post-approval submissions were not routine and were necessary to update the Skelaxin product label regardless of the fact that the use was technically a post-approval commercial activity.

Classen filed this Cert Petition arguing that Elan’s use was outside the scope of the safe harbor because the use of the patented technology for post-marketing safety research was “routine.” Classen also complained that Elan not only used the data for submission to FDA, but also to patent a new use of the drug; protecting Elan under the safe harbor in spite of this additional use, Classen contends, means that the safe harbor will protect any data that is at some point submitted to FDA even if it is not the primary intent.  Classen argues that Elan’s clear commercial post-marketing purposes should play a role in a finding of infringement.

The Supreme Court has not granted cert yet – obvious, since Elan has not even filed its response – but it will be interesting to see if the Court decides to weigh in on the admittedly nebulous distinction between routine and not-routine. It seems that Classen wants to draw the line between pre-market commercial use and post-market commercial use.  But this raises a question of how much commercial use should be considered given that the statute clearly anticipates commercial use.  Is commercial use really the deciding factor, or is it actually routine vs. non-routine?  As recently as 2016, the Supreme Court adopted the routine test, so it’s unlikely that the Court will take the opportunity to further refine the distinction, but it seems like we’ll find out soon.

Last year, the President signed into law the Food and Drug Administration Reauthorization Act (FDARA) to revise and extend the user fee programs for drugs, medical devices and biosimilar biological products. Section 902 of FDARA requires FDA to publicly report, annually, information related to inspections of facilities necessary for approval of these medical products.

Not later than March 1 of each year, the Secretary of Health and Human Services shall post on the internet website of the Food and Drug Administration information related to inspections of facilities necessary for approval of a drug under section 505 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355), approval of a device under section 515 of such Act (21 U.S.C. 360e), or clearance of a device under section 510(k) of such Act (21 U.S.C. 360(k)) that were conducted during the previous calendar year. Such information shall include the following:

(1) The median time following a request from staff of the Food and Drug Administration reviewing an application or report to the beginning of the inspection, and the median time from the beginning of an inspection to the issuance of a report pursuant to section 704(b) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 374(b)).

(2) The median time from the issuance of a report pursuant to such section 704(b) to the sending of a warning letter, issuance of an import alert, or holding of a regulatory meeting for inspections for which the Secretary concluded that regulatory or enforcement action was indicated.

(3) The median time from the sending of a warning letter, issuance of an import alert, or holding of a regulatory meeting to resolution of the regulatory or enforcement action indicated for inspections for which the Secretary concluded that such action was indicated.

(4) The number of times that a facility was issued a report pursuant to such section 704(b) and approval of an application was delayed due to the issuance of a withhold recommendation.

Since this is the first report published under this statutory authority, we have nothing to compare it to. Nevertheless, the information is instructive. For example, in calendar year 2017, the median time between the issuance of a Form 483 for a cGMP inspection and the issuance of a Warning Letter was 191 days (or 6.4 months). For purposes of contrast, the agency’s own Regulatory Procedures Manual says that Warning Letters should be issued within four months of the appropriate reference date, which typically is the issuance of the Form 483:

To ensure the applicability of evidence to the present situation, the agency will strive to issue Warning Letters within four months from the appropriate reference date. Examples of the appropriate reference date are: the last day of the inspection, the date of sample analysis, or the date of evidence collection.

So, to summarize, in 2017, the median issuance time for an agency Warning Letter was 2.4 months longer (or 60% longer) than the goal set out in the agency’s own procedures. It is also well established that, not infrequently, the agency issues Warning Letters up to a year or more from the date of issuance of the Form 483. Clearly, there is room for significant improvement in the speed with which the agency issues Warning Letters.

In calendar year 2017, the median time between the issuance of a Form 483 and the occurrence of a Regulatory Meeting was 169 days (or 5.6 months). A Regulatory Meeting is a meeting requested by FDA management to inform responsible individuals or firms regarding how one or more products, practices, processes, or other activities are considered to be in violation of the law.

The Regulatory Procedures Manual does not provide timelines for the convening of a Regulatory Meeting. Nevertheless, the notion that a firm would need to wait, on average, close to half a year to discuss their Form 483 observations (or their responses to the Form 483) with agency regulators seems unduly limiting, particularly in situations where the Form 483 could be used as a basis to prevent the importation of the firm’s products (i.e., an import alert) or to prevent approval of a pending application (i.e., a compliance check).

In calendar year 2017, there were no resolutions for compliance actions for facilities that were issued a Form 483 in CY 2017, and that had resulted in a Warning Letter, Import Alert, or a Regulatory Meeting, and were named in a pending application.

As the agency states in this report, given the significant remediation efforts and re-inspection by FDA that would be required for resolution, it is unlikely that a site would be inspected, regulatory action taken, and resolution completed within a single calendar year. Perhaps that is part of the problem that Congress was attempting to point out or, more likely, Congress had no idea that it was entirely unrealistic that FDA, as it is currently run, would be able to resolve the compliance action in the same year in which the compliance action was initiated.

In addition, in calendar year 2017, 94 applications were denied approval solely due to a facility-related withhold recommendation because of the lack of compliance at a facility discovered during an inspection that had been completed in that calendar year.  (Biological products reviewed under section 351 of the Public Health Service Act were not included in this report.)  Also, in 2017, the median time between an inspection request from FDA staff to the beginning of an inspection was 102 days, and the median time between the beginning of a prior approval inspection and the issuance of a Form 483 was seven days.

In summary, it will be interesting to track how these timeframes change in the coming years. However, without the introduction of statutorily mandated incentives, such as currently exist under FDARA for review times of NDAs and BLAs, it is doubtful that we will see significant improvements in the issuance time of agency Warning Letters and in the convening of Regulatory Meetings.

This is all to the detriment of industry and the agency alike. After all, the longer it takes FDA to issue a Warning Letter or convene a Regulatory Meeting with non-compliant firms, the longer it will take the firms in question to resolve the issues at hand, bring the facilities back into cGMP compliance and, where relevant, bring the drug products back into distribution.

On Friday, April 13, 2018, the U.S. Court of Appeals for the Fourth Circuit ruled that Maryland’s law prohibiting “price gouging” by generic pharmaceutical manufacturers (HB 631) is unconstitutional because it violates the dormant commerce clause by directly regulating transactions that occur outside of Maryland. Circuit Judge Agee joined the majority opinion written by Circuit Judge Thacker; Circuit Judge Wynn wrote a dissenting opinion that HB 631 does not violate the commerce clause (both opinions are available here).

As discussed in our previous post on HB 631 (see here), this law sought to limit generic drug pricing by prohibiting a generic drug manufacturer or wholesale distributor from making unconscionable increases in the price of an “essential off-patent or generic drug.” To assist the Maryland Attorney General (AG) in identifying violations, the law authorized the Maryland Medical Assistance Program (“MMAP”) to notify the AG of a price increase when (1) the Wholesale Acquisition Cost (“WAC”) of a prescription drug increased by at least 50% within the preceding one-year period or when the price paid by MMAP would increase by at least 50% within the preceding one-year period, and (2) the WAC for either a 30-day supply or a full course of treatment exceeded $80. The law also provided the AG with civil remedies, including injunctive relief, monetary relief, and civil penalties, for violations of the law.

As we also previously reported, in July 2017 the Association for Accessible Medicines (“AAM”) filed suit seeking declaratory and injunctive relief against the implementation and enforcement of HB 631. AAM challenged HB 631 on two constitutional grounds: (1) that HB 631 violates the dormant Commerce Clause of the Federal Constitution because it regulates commerce wholly outside of Maryland; and (2) that HB 631 is impermissibly vague and therefore violates the Fourteenth Amendment Due Process Clause.

This case reached the Fourth Circuit after AAM appealed a decision by the U.S. District Court for the District of Maryland that granted the State of Maryland’s motion to dismiss AAM’s challenge based on the dormant commerce clause, but allowed the vagueness claim to proceed. The District Court also denied AAM’s motion for injunctive relief.

The Fourth Circuit relied on three determinations to find HB 631 unconstitutional:

1. The law focuses, not on the price that a Maryland consumer pays for a drug, but instead on the price initially charged by the manufacturer or wholesaler. Therefore, a violative price gouging transaction may occur outside of Maryland even if the transaction “did not result in a single pill being shipped into Maryland.”
2. Even if the Act did require a nexus to an actual sale in Maryland, a violation is triggered by the manufacturer’s or wholesaler’s initial sale. These “upstream” sales occur almost exclusively outside of Maryland.
3. If other states enacted similar laws, this would impose a significant burden on interstate commerce involving prescription drugs.

Because the Fourth Circuit found HB 631 unconstitutional based on AAM’s dormant commerce clause argument, the Court did not address whether the statute was also void for vagueness. However, the majority did acknowledge that the law’s “relatively subjective definition of what constitutes an unlawful price increase only exacerbates the problem[s]” that would occur if other states imposed similar laws. The majority stressed that, although Maryland could not constitutionally control prescription drug pricing in the manner utilized by HB 631, Maryland and other states could enact other legislation to secure lower prescription drug prices for their citizens.

Another commerce clause challenge has been brought by the Pharmaceutical Research and Manufacturers of America against a price increase transparency law in California (see our previous post here). We will continue to watch developments in the growing number of states that are seeking to limit drug costs through legislation, as well as legal challenges to those laws.