As more biosimilars are approved (we’re up to 26 now!), FDA has been rolling out guidance documents under the Biosimilars Action Plan (“BAP”).  The most recent guidance has been long awaited.  While the Hatch-Waxman Act explicitly provides that an applicant can seek approval for only some of the uses for which the reference product is approved – ultimately resulting in a labeling “carve out” – the Biologics Price Competition and Innovation Act contains no such language.   However, back in 2018, then-Commissioner Gottlieb slipped into the BAP roll-out a reference to a guidance intended to “provide additional clarity to biosimilar applicants who seek approval for fewer than all conditions of use for which the reference product is licensed because, for example, one of the licensed conditions of use of the reference product is protected by a patent,” signaling to industry that FDA intended to permit carve-outs in biosimilar labeling.

At last, that guidance has arrived.  The new guidance, Biosimilars and Interchangeable Biosimilars: Licensure for Fewer Than All Conditions of Use for Which the Reference Product Has Been Licensed, makes it explicitly clear that carve-outs are permissible for biosimilars.  Like with NDAs, the guidance explains the situations in which a carve-out (or approval of fewer than all conditions of use for which the reference product is licensed) may occur when a condition of use is protected by exclusivity, such as Orphan drug Exclusivity, or by patent.  In such a case, FDA can license the biosimilar for any indications or conditions of use that are not protected by the relevant exclusivities or patents.

As with NDAs, aBLA sponsors seeking to carve-out an indication must submit draft labeling including all information from the reference product labeling to support the relevant (uncarved-out)  conditions of use.  As part of the aBLA review, FDA will consider whether the information carved out is essential scientific information needed for safe use of the product; if it is, FDA will not permit the carve-out.

Given the stark differences between the patent dance for NDAs and BLAs, the process for carving out conditions of use in these submissions is different.  Notably, the guidance explains that “FDA does not expect an applicant to submit a justification for the applicant’s decision not to seek licensure of a biosimilar for all of the reference product’s licensed conditions of use.”  This differs from a carve-out in an NDA, in which a section viii statement or exclusivity statement is necessary to justify the carve-out.  The lack of such a requirement for aBLAs is logical, as there is no requirement to certify to any reference product patents or discuss exclusivities in a given aBLA submission.  However, FDA will accept “information that is intended to inform FDA’s review of the draft labeling,” such a justification of why certain clinical trial information can be carved-out without raising safety or efficacy issues.

When ready to add such a carved-out condition of use into the labeling, the aBLA holder must submit a supplement to the aBLA containing all data and information needed to support licensure of the biosimilar with that condition of use.  FDA expects that it will review and act on aBLA supplements seeking licensure for additional conditions of use within 6 months.  Though the Biosimilar User Fee Act Goals Letter gives the agency 10 months to do so, FDA thinks that it can surpass this goal, assuming the supplement does not raise novel review issues.

While carve-outs for exclusivity purposes will prevent FDA from approving a supplement adding in a carved-out condition of use until the expiration of exclusivity, the same bar does not extend to carve-outs based on patents (or other reasons).  Indeed, FDA may license a product for conditions of use protected by patent as long as FDA determines that the requirements for licensure have met.  For that reason, FDA warns applicants in this guidance that it may review and act on a supplement early, and that an applicant should request that FDA refrain from acting on a supplement before a specified date that falls within the applicable goal date.  If the applicant requests a date beyond the applicable goal date, FDA will not honor the request.

FDA’s assertion about goal dates is important for purposes of infringement litigation.  Because the PHS Act provides that the submission of a BLA is an artificial act of infringement, the submission of the supplement to add a patented condition of use constitutes an act of infringement.  While the reference product sponsor would know about the supplement if the aBLA sponsor chooses to partake in the patent dance, the aBLA patent dance is optional; as such, a reference product sponsor may not know of the existence of an application or supplement to add a condition until FDA announces its approval.  If FDA announces a supplement approval adding a condition of use and that condition of use is still protected by patent (because FDA approved the supplement early or the applicant submitted the supplement early), the reference product sponsor will become aware and can immediately sue for infringement – even if there’s only a few days left on that patent.  Therefore, the exact date of approval of a supplement adding a carved-out condition of use could have a critical effect on infringement litigation.

The guidance also states, in a footnote, that FDA expects all applications for interchangeable products to include data to support that the product can produce the same clinical result as the reference product “in all of the reference product’s licensed conditions of use” (emphasis added).  While the interchangeable can still carve-out a condition of use, the expectation is that all data demonstrating that the product is interchangeable for that condition of use is submitted with the initial interchangeable application rather than in a supplement.  This too raises questions of infringement.  Again, because the PHS Act provides that the submission of a BLA is an artificial act of infringement, if there’s a patent protecting a condition of use and an interchangeable application is submitted with the intent to carve-out that condition of use, the act of submission is enough to allege patent infringement.  Therefore, FDA’s requirement that interchangeable applications include all data for all conditions of use, even those intended to be carved out, inherently requires interchangeable applicants to infringe patents for conditions of use that will be carved out.  In a way, it actually encourages applicants not to seek approval as an interchangeable product until all patents have run out.  In other words, because FDA’s requirement leaves interchangeable sponsors vulnerable to patent infringement allegations – even if the interchangeable is carving-out a condition of use – one might expect that aBLA sponsors would be hesitant to seek interchangeable status until all conditions of use can be included in the label.

As with all draft guidance documents, this document represents FDA’s current thinking on the matter.  There is always a chance that FDA hadn’t considered the ramifications of its requirements for interchangeable products carving out a patent.  Like always, FDA will accept comments on this guidance document.  Comments are due by April 7, 2020.

Congress enacted several priority review voucher (“PRV”) programs in the past fifteen or so years with the goal of incentivizing drug companies to develop new drugs for diseases that ordinarily may not be attractive because the potential market is small or otherwise unlikely to produce the desired rate of return.  These programs are the Neglected Tropical Disease Voucher Program, the Rare Pediatric Disease Voucher Program, and the Medical Countermeasures Program.  We have blogged on these programs multiple times since they each were enacted (e.g., here, here, and here) and won’t describe program details in this blogpost.  Of course, as it was before these programs, a significant incentive for drug companies to develop drugs for less prevalent diseases remains the seven years of marketing exclusivity available under the Orphan Drug Act.

What we will talk about today is the January 2020 report issued by the Government Accountability Office (“GAO”) entitled, “Drug Development – FDA’s Priority Review Voucher Programs”.  This isn’t the first time GAO has taken a look at these programs.  Five years ago, GAO issued a report in which it concluded that it was too early to gauge the effectiveness of the pediatric voucher program (see our blog here).

The current report was required under the provisions of the 21^st Century Cures Act and provides an update on the number of PRVs awarded by FDA to date (31).  Most were for drugs to treat Rare Pediatric Diseases (19).  Of the remainder, 10 PRVs were awarded for drugs to treat eligible tropical diseases and two were for medical countermeasures.  Based on the data available to GAO, 17 of the awarded PRVs were subsequently sold to another drug sponsor.  The prices for 14 of the 17 transferred PRVs were available, and ranged from $67.5 million for one sold in fiscal year (“FY”) 2014 to $350 million for one sold in FY 2015.  The reported range has narrowed considerably for those sold since February 2017 to $80 to $130 million.  The GAO report includes details on the PRV awards and transfers in Appendix I and Appendix II, respectively.

As of September 30, 2019, 16 of the 31 PRVs awarded had been redeemed – i.e., used to obtain priority review of a drug application for a drug that would not otherwise be eligible for priority review.  This number, too, is based on available data and it is possible others have been redeemed.  GAO noted that almost half of the PRVs awarded had not yet been redeemed as of the end of FY 2019 which it says FDA has noted “may affect FDA’s ability to forecast resources needed,” even though FDA receives at least 90 days’ notice of a PRV redemption.  Others GAO interviewed noted that uncertainty exists for every year and FDA receives additional user fees from the redemption of the PRVs to fund additional positions (almost $44 million for the 16 PRVs redeemed so far).  FDA has also noted that the demands of the PRV program may require it to shift priorities away from other public health priorities.

In order to assess the effect of the PRV programs on drug development, GAO performed a literature review and interviewed seven drug sponsors, seven academic researchers with expertise in drug development, drug pricing, or the PRV programs, and seven other stakeholder groups, including trade associations, patient advocates, and organizations that partner with or provide funding to drug sponsors.

The relevant literature available was limited.  For each of the three programs, GAO found one study that examined and drew conclusions about how the PRV programs affect drug development.  A 2019 study that looked at the rare pediatric disease voucher program found that the program was not associated with an increase in the number or rate of new pediatric disease drugs that started or completed clinical trials.  It did find, however, that after initiation of the program, drugs that the authors could identify as eligible for a rare pediatric disease PRV were “more likely to advance from phase I to phase II” compared to rare adult disease drugs (which are not eligible for this PRV program).  The study also found that the time it took for drugs to progress to the next stage of development was shorter among drugs eligible for this PRV compared to drugs for rare adult diseases.

For the tropical disease PRV program, the GAO identified a 2017 study that found that the PRV program was not associated with an increase in tropical disease drugs starting clinical testing.  The study found that the proportion of drugs in development for tropical diseases among all drugs decreased slightly after the program was created.  The authors suggested the small number of tropical disease products approved in the last decade indicates the program did not serve as a stimulus for completing late stage drug development.

For medical countermeasures, a 2018 study identified by the GAO reported that 25 of 26 medical countermeasures in clinical trials received direct or indirect public support such as funding by the Department of Defense.  The authors stated that the extent of federal funding for these programs suggests that alternatives other than a PRV program would better stimulate drug development in this area.

The drug sponsors GAO spoke with all reported that the PRV programs were an incentive and factor in their decision making.  The researchers and stakeholders had mixed views on the programs as incentives.  The drug sponsors, researchers and stakeholders contacted were mixed on whether the rare pediatric disease and medical countermeasures programs (due to expire in 2022 and 2023, respectively) should be reauthorized.  As of April 2019, FDA did not have a position of reauthorization of the programs.

Finally, GAO solicited thoughts about ways to improve the programs or other ways to incentivize drug development in these areas from the fairly small number of companies and individuals (7 drug companies, 7 researchers and 7 stakeholders).  The proposals for improvement included requiring innovation for PRV award (e.g., not awarding a voucher for drug that was already available outside the U.S.), requiring a plan to provide access to the drug if PRV was awarded in connection with its approval, limiting companies eligible for award to nonprofits or other sponsors that financially require it to develop their drug, and to making administrative changes to the program.  Potential alternatives identified included tax credits, direct federal funding or grants, and patent extensions.

Does this lackluster report foreshadow one or both of the rare pediatric disease and medical countermeasures programs expiring without reauthorization over the next several years?  Stay tuned.

Hyman, Phelps & McNamara, P.C. is pleased to publish the first FDA Law Alert of the new year. This is the fourth installment of our quarterly newsletter highlighting key postings from our nationally acclaimed FDA Law Blog.  Please subscribe to the FDA Law Blog to receive contemporaneous posts on government regulatory and enforcement activities affecting the broad cross-section of FDA-regulated industry.  As the largest dedicated FDA law firm, we are happy to help you or your clients navigate the nuances of the laws and regulations affecting them.

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Medical Devices

• Exportation: In November 2019, FDA issued final guidance on how device firms may request review of a decision to withhold issuance of a Certificate of Foreign Government (“CFG”).  A CFG provides official assurance that exported products comply with U.S. laws and regulations.  In his post, Jeff Shapiro explains the procedural rights and appeal options available through the Federal Food, Drug, and Cosmetic Act (“FD&C Act”) for companies denied a CFG.  He further explains how FDA’s final guidance implements these procedures.
• Enforcement: Sara Koblitz and Doug Farquhar discuss a recent success before the U.S. District Court for the District of Columbia.  The post describes a lawsuit filed by HPM on behalf of Genus Medical Technologies (“Genus”) challenging FDA’s attempt to regulate its device as a drug.  Koblitz and Farquhar provide detailed information on each parties’ arguments, the court’s reasoning for its decision in favor of Genus, and the future impact of this litigation on industry.

Drugs

• Drug Development: In this post, Larry Bauer describes FDA’s draft guidance, “FDARA Implementation Guidance for Pediatric Studies of Molecularly Targeted Oncology Drugs: Amendments to Sec. 505B of the FD&C Act.”  Check out the full blog post for a detailed explanation of the new requirement for pediatric investigations that involve these targeted therapies, FDA’s molecular target lists and additional considerations for rare cancers.

• Hatch-Waxman: In this post, Kurt Karst provides an overview of The Lower Health Care Costs Act of 2019 (the “Act”).  According to Karst, the Act looks strikingly similar to the BLOCKING Act of 2019.  His post describes how the Act would significantly alter the 180-day exclusivity provisions, the incentives for such exclusivity, as well as its potential to lead to higher drug prices.

Healthcare

• Qui Tam Litigation: Serra Schlanger describes the latest development in the United States ex rel. Campie v. Gilead Sciences, Inc. saga.  As False Claims Act litigators surely know, this case started back in 2010 based on allegations by two former employees that Gilead made false statements to FDA about the its anti-HIV drugs.  Schlanger details the U.S. District Court for the Northern District of California’s analysis and its ultimate decision to grant the government’s motion to dismiss.

Food & Dietary Supplements

• CBD in Dietary Supplements: Riëtte van Laack describes recent actions taken by four major trade associations, AHPA, CRN, CHPA and UNPA, in an effort to legalize hemp-derived CBD.  For example, one such action was a letter urging Congress to pass legislation that would make hemp-derived CBD a legal dietary ingredient for use in dietary supplements. The second was a citizen petition requesting swift action from FDA, including the establishment of a regulatory pathway to legally market dietary supplements containing hemp-derived CBD and to increase enforcement actions against “unscrupulous manufacturers” of CBD-containing products that use illegal drug claims.

Animal Drug Products

• Compounding: Karla Palmer discusses FDA’s latest revision to its draft guidance addressing compounding of animal drug products from bulk substances.  In her post, Palmer details the situations where FDA would exercise enforcement discretion, asserting that such discretion is an attempt by the Agency to expand its regulatory authority over animal drug compounding by pharmacies and veterinarians as well as veterinary medicine generally.

• Genetically Modified Animals: Also out of the Northern District of California, a Court upheld FDA’s authority to regulate genetic material used to modify an animal as a new animal drug.  Ricardo Carvajal outlines the Court’s basis for upholding such authority through the FD&C Act and Guidance #187.  Carvajal further analyzes the implications of the Court’s decision to defer the question of whether drug safety encompasses environmental risks.

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Hyman, Phelps & McNamara has its finger on the pulse of FDA. As the largest dedicated FDA law firm in the United States, our technical expertise and industry knowledge are exceptionally wide and deep. Our lawyers and non-lawyer experts possess extensive experience with the universe of issues faced by companies regulated by FDA.

Those familiar with the Hatch-Waxman Act and its various incentives to stimulate drug innovation know that New Chemical Entity (“NCE”) exclusivity is the holy grail of small molecule exclusivity.  Though orphan drug may give a sponsor two more years of exclusivity than NCE, it only applies to a specific indication and patient population, both of which can be designed around.  Other exclusivities, like three year or QIDP, can also be designed-around or are traditionally add-on exclusivities.  NCE exclusivity, on the other hand, blocks the submission of any 505(b)(2) application or ANDA for the same active moiety regardless of the indication.  NCE exclusivity, therefore, is coveted, as it forces any competitor seeking approval of the same active moiety to run its own expensive and time-consuming trials or wait at least four years to even submit an application—five years if the follow-on application does not include a Paragraph IV certification.  Specifically, the statute says:

. . . no application which refers to the drug for which the subsection (b) application was submitted . . . may be submitted under subsection (b) before the expiration of five years form the date of the approval of the application under subsection (b), except that such an application may be submitted under subsection (b) after the expiration of four years from the date of the approval of the subsection (b) application if it contains a certification of patent invalidity or noninfringement described in clause (iv) of subsection (b)(2)(A).

21 U.S.C. § 355(c)(3)(E)(ii), (j)(5)(F)(ii) (emphasis added).  Of course, the bar on the submission of a follow-on application for an NDA with NCE is great because it means that FDA cannot start reviewing the follow-on application until either the expiration of the five-year period (or, in the case of a follow-on application with a Paragraph IV certification, four years, subject to a 30-month stay), thereby providing a de facto extension of the five years of exclusivity.

Not so fast.  While NCE exclusivity is a major incentive, that submission provision in the statutory language provides a loophole.  While other periods of exclusivity block the approval of a follow-on application for the statutory period of exclusivity, the statutory language of the NCE provision blocks only the submission of a follow-on application.  FDA has long interpreted this provision to mean that applications submitted prior to approval of a product with NCE exclusivity are neither barred from approval, nor must they be withdrawn.  See FDA, Citizen Petition Response, Docket No. FDA-2011-P-0606 (May 17, 2011).FDA recognized this issue when adopting its regulations implementing NCE exclusivity back in 1989, noting that two applicants could submit and file 505(b)(2) applications for the same drug product, and one of the applications could subsequently be approved with an NCE exclusivity, leaving the question of what happens to the other application.  FDA decided “to interpret this phrase to mean that any 505(b)(2) application submitted to FDA before the approval of another new drug application that qualifies for [NCE exclusivity] is not affected by this exclusivity provision” other than when “the competing applicant amends its application to include the first applicant’s published data.  Where that data would be essential to the competing application, the second application will be deemed to refer to the first application.”    Abbreviated New Drug Application Regulations, 54 Fed. Reg. 28,872, 28,901 (July 10, 1989).

Last week, after several rounds of Citizen Petitions (here and here) Genus Lifesciences Inc. (“Genus”) sued FDA over its stance relating to dueling 505(b)(2)s.  In the suit, Genus accuses FDA of intentionally undermining its NCE exclusivity for its cocaine HCL nasal solution by accepting an incomplete 505(b)(2) application from a competitor mere weeks before it approved Genus’s 505(b)(2).  Genus received FDA approval for its cocaine product, called Goprelto and indicated for “the induction of local anesthesia of the mucous membranes” in certain diagnostic procedures and surgeries, on December 14, 2017.  Prior to December 2017, cocaine HCL products were on the market but only as unapproved drugs.  FDA required Genus to perform a battery of time-consuming and expensive testing prior to submission of its NDA, but Genus alleges that FDA admittedly required significantly less testing when its competitor, Lannett Company Inc. (“Lannett”), submitted its 505(b)(2) for its cocaine HCL nasal solution, Numbrino, on November 29, 2017.  Further, when Lannett received a Complete Response Letter for Numbrino in July 2018, FDA permitted Lannett to resubmit its application based on FDA’s position that a post-CRL resubmission is an amendment to the original 505(b)(2) rather than a submission.  This, Genus argues, amounts to allowing Lannett to submit an incomplete and inadequate “placeholder” application right before Goprelto’s five years of exclusivity took effect.

Genus sets forth three main arguments in its complaint: (1) That FDA’s acceptance of Lannett’s Numbrino 505(b)(2) application without the same rigorous data requirements FDA required for submission of Genus’s Goprelto 505(b)(2) treats similarly situated parties differently in violation of the Administrative Procedure Act; (2) That FDA’s acceptance of Lannett’s amendment and resubmission of its 505(b)(2) after its CRL, notwithstanding Genus’s NCE exclusivity, was arbitrary and capricious under the Administrative Procedure Act and in violation of the federal Food, Drug, and Cosmetic Act (“FDCA”); and (3) that approval of Genus’s NCE exclusivity is in violation of the NCE provisions of the FDCA.  Basically, Genus is accusing FDA  of letting the ends (approval of a competing cocaine HCL product) justify the means (disparate treatment and nullification of Genus’s NCE exclusivity), similar to litigation filed by Catalyst in its June 2019 suit against FDA challenging the approval of a Firdapse competitor.

Genus’s objections are compounded by the fact that cocaine HCL was, until Goprelto’s approval, a drug marketed without FDA approval.  Genus made a significant investment to meet FDA’s standards in an effort to voluntarily comply with FDA’s request that all unapproved drugs undergo the approval process.  As such, once a company obtains “approval of an NDA for a product that other companies are marketing without approval,” FDA is supposed to take enforcement action against “remaining unapproved drugs” because “they present a direct challenge to the drug approval system.”  FDA’s Compliance Policy Guide for Marketed Unapproved Drugs § 440.100.  Enforcement action is intended to “provide an incentive to firms to be the first to obtain approval to market a previously unapproved drug.”  Id.  Genus was in exactly this situation, but instead of exercising its enforcement authority with respect to cocaine HCL, Genus alleges that FDA held a competing product to a lower bar so that it could submit its 505(b)(2) prior to Goprelto approval and not be blocked by Goprelto’s 5-years of exclusivity.

This lawsuit is just the latest in a trend of suits against FDA, most of which have involved FDA trying to legally justify policies after-the-fact.  We saw this with Genus Medical Group (a different Genus), in which FDA tried to backfill its policy of regulating all contrast agents as devices regardless of the statutory text.   We also see this in the aforementioned Catalyst litigation, as well as the Eagle/Depomed litigation, in which FDA did not have statutory authority to require a demonstration of clinical superiority after granting orphan drug designation (the statute has since been changed to provide that authority).  Some of these recent challenges have been successful, but on Chevron Step 1 bases.  It looks like Genus will mostly be making a Step 2 arbitrary and capricious argument—though that won’t be clear until the inevitable Motion for Summary Judgment is filed—but industry has some success with Step 2 as well (e.g., Braeburn litigation).   It will be interesting to see how Genus frames these arguments in light of these recent rulings.

Hyman, Phelps & McNamara, P.C. is  pleased to announce that Sara Koblitz will be speaking in an upcoming Strafford live webinar, “Biologics and Biosimilars: FDA Initiatives and Guidance, Approvals and Exclusivity, Patent Prosecution, Litigation” scheduled for Thursday, February 13, 1:00pm-2:30pm EST. The panel will provide essential updates on FDA practice and patent law relating to biologics and biosimilars and discuss the current state of and recent changes to FDA initiatives, approvals, and exclusivities, as well as patent prosecution, post-grant proceedings, and litigation.

After the presentations, the speakers will engage in a live question and answer session with participants, so they can answer your questions about these issues directly.

As readers of our blog, you can participate in this program at half off.  Use this link, and the offer will be reflected automatically in your cart.  Alternatively, you can call 1-800-926-7926.  Ask for Biologics and Biosimilars: FDA Initiatives and Guidance on 2/13/2020, and mention code: ZDFCA.

Lately, FDA has been subject to criticism on almost every front.  A recent NY Times Op-Ed alleging political interference, the popular theory that FDA fueled the opioid crisis, and the quality and inspection concerns raised in the 2019 book Bottle of Lies are all emblematic of the recent and widespread criticism of FDA.  Through all of this criticism, FDA just keeps continuing on its mission of “advancing the public health by helping to speed innovations that make medical products more effective, safer, and more affordable.”  To that end, FDA approved 48 “novel drugs” in 2019—drugs never before approved or marketed in the United States.  But, as discussed in a recent Wall Street Journal article, a July 2019 study questions whether FDA should be touting all of these new approvals.  This is because, according to the study, FDA has routinely rushed approvals in an effort to meet an unofficial year-end deadline—and in doing so, has comprised patient safety.

The study, undertaken by professors from Harvard Business School, the University of Texas at Dallas, and the MIT Sloan School of Management, examines the global pattern of drug approvals in the last weeks of each year.  In the U.S., they found that there is a rush of drug approvals in December and the week before Thanksgiving.  And while this itself is not a problem, the concern arises from the significantly increased number of adverse events seen with these last-minute approvals.  According to the study abstract:

Drugs approved in December and at month-ends are associated with significantly more adverse effects, including more hospitalizations, life-threatening incidents, and deaths. This pattern is consistent with a model in which regulators rush to meet internal production benchmarks associated with salient calendar periods: this type of “desk-clearing” behavior results in more lax review, which leads both to increased output and increased safety issues.

The study notes that the “December drugs” phenomenon has been reported before, but findings that more adverse events are associated with these “December drugs” is novel to this paper.

The study evaluated FDA’s approval of new drug applications (both NDAs and BLAs) from 1980 to 2016 on a weekly and monthly basis with data derived from the Drugs@FDA database.  The authors found that there are roughly 80% more approvals in December than in any other month.  Further, more approvals occur at the end of the month than any other time during any given month.  Additionally, for each approved NDA, the authors identified and collected information on measures of post-market safety: reported adverse events, black box warnings, market withdrawal, and MedWatch reports.  They then compared the number of these safety issues arising from drugs approved in December to those approved throughout the year.

The study results showed that “drugs approved in December have higher adverse events.”   The authors found that 89% of their sample observations are associated with at least one reported adverse events.  They also found that 24 percent of their sample observations were included in Medwatch, 35 percent associated with a black-box warning, and 3.4% are withdrawn after reaching the market.  December drugs are 19% more likely to be included in Medwatch and 5.7% more likely to receive a black-box warning.

These results, in and of themselves, are not particularly concerning, but it’s not entirely clear how reflective they are of actual safety concerns.  Because the term “adverse events” is nebulous, and because it typically encompasses broad categories of events that are correlated with—rather than definitively caused by—a drug, it is not alarming that 89% of samples were associated with adverse events.  Further, as discussed below, the use of a black-box warning as a safety signal is a bit misplaced, as FDA has already assessed that safety concern.  Leading to additional questions, the authors manually determined whether reported adverse events were associated with a specific drug when multiple were listed and determined whether the events were life-threatening, led to hospitalization, disability, or death.  Additionally, the authors obtained information “on safety-related drug withdrawals following FDA approval” but provided little detail about this process.  But relying on market withdrawals to signify a safety risk is presumptuous: drugs can be withdrawn from the market for all sorts of reasons, so unless FDA has formally determined that a drug was withdrawn for reasons of safety or efficacy, this metric could skew results.  And because FDA typically makes such a determination in response to a request to do so, there are a whole host of products that have been withdrawn or discontinued for reasons that have not yet been fully assessed.  The use of this parameter, therefore, raises additional questions.

Nonetheless, taking efforts to control for drug popularity, complexity, and other circumstances, the study authors concluded that FDA may be biased towards approval for these “December drugs.”  The authors hypothesize that “informal performance benchmarks” focusing on quantity of drug approvals rather than quality, may bias FDA regulators toward approval.  Noting that the number of drugs that are approved is immediately visible and that industry and patient groups advocate for approval rather than rejection while adverse events may take years to be realized, the authors posit that internal pressure to approve drugs is high.

As the study authors themselves recognize, one major issue in the study is the inability to assess the benefits of the approved products in comparison to the risks.  But this assessment is a critical element of drug approval.  This is precisely the reason that the existence of a boxed warning should not be “counted” as a signal of safety issues with approved products.  Boxed warnings are the result of an assessment of the risk of the serious adverse event as compared to the benefit; indeed, in approving a product with a boxed warning, FDA is not only aware of the risks but has made an affirmative decision that the benefits of this potentially dangerous product outweigh the risks.  As such, using the existence of a boxed warning to suggest that FDA rushed approvals to meet an informal agency deadline inherently ignores the careful calculation that FDA undertakes when approving a product with a boxed warning.

In fact, the study’s omission of benefit analysis completely ignores the real-life context of a product’s approval.  While it is true that patient advocacy groups may be pushing FDA to approve a product that is associated with significant adverse events or risks, typically that signals that the patient benefit may outweigh the risks.  Therefore, FDA’s approval of such a product is not necessarily to meet some metric or because of internal pressure; it may approve a product with safety risks notwithstanding the risks or safety signals because of there is great patient need or benefit.  So while there may be more products approved in December and those products may be associated with more adverse events, the context in which these “less safe” products may be used is really important to why and how they got approval.  It’s too easy to say that adverse events suggest that the products are not safe enough if you discount the benefits that such products provide.

Further, the authors’ desk-clearing hypothesis seems to ignore the bureaucratic approval process.   They suggest delaying December approvals for reevaluation in January because December approvals are too rushed to make safe approval decisions, but this ignores the fact that the safety determinations required for approval may not even have occurred in December.  It’s not as though one FDA employee looks at an application for the first time in December and decides to send off an approval at Christmas break; there are several layers of approval necessary for each drug product.

This paper seems to surmise that FDA is just really focused on raising its approval statistics, and that the default stance of regulators has shifted to approval rather than rejection now that about 60% of all NDAs are approved.  But focusing on the publicly-available numbers alone is not enough to get the whole picture: the authors never discuss how many of this 60% of NDAs are approved in their second, third, fourth cycle of review.  This would suggest that the default is not necessarily approval but working with an NDA sponsor to ultimately get to approval.  And where the mission is to improve the public health and approve safe products, wouldn’t this approach make sense?  Though the study makes some really interesting points, the implied criticism, in which the authors seemingly link safety risks to rushed approvals, simply underestimates the rigorous risk/benefit analysis and bureaucratic process that each approval undergoes.  While no one is denying that more drugs may be approved in December or at the end of a given month, it’s definitely a leap to presume that the existence of additional adverse events for these products indicates a “rush” to approval comprising safety without at least a cursory review of the benefit-to-risk analysis.

On February 3rd, FDA announced several new actions as part of its Biosimilars Action Plan (BAP).  If you recall, back in July 2018 when FDA first unveiled the BAP, four key elements were identified:  improving efficiency of biosimilar and interchangeable product development; maximizing scientific and regulatory clarity for biosimilar development; developing effective communications to improve understanding of biosimilars among patients, clinicians, and payors; and supporting market competition by reducing gamesmanship or other attempts at unfairly delaying competition.  Each of these elements was associated with a number of priority deliverables, and, since then, FDA has been taking steps to meet those (for example, see our prior discussions here and here).

FDA’s most recent actions seek to address the biosimilar market competition element of the BAP.  First, FDA and FTC issued a lengthy joint statement that identified four goals to help combat anti-competitive practices in relation to biosimilars:  (1) coordinate to promote greater competition in biosimilar markets; (2) work together to deter behavior that impedes access to samples of the reference biological product that are required for testing and development of follow-on products; (3) take actions against false or misleading communications about biologics, including biosimilars; and (4) review patent settlements involving biologics, including biosimilars, for antitrust violations.  In particular, the agencies noted their concern with false or misleading statements comparing biological reference products and biosimilars, which may be hampering uptake of biosimilar therapies by creating negative misperceptions about the safety and efficacy of biosimilars.  The agencies “intend to take appropriate steps to address companies” who are engaged In such practices.

To further clarify how data and information about biosimilars should be presented in a truthful and non-misleading manner in regulated promotional materials, FDA announced the release of the Draft Guidance for Industry: Promotional Labeling and Advertising Considerations for Prescription Biological Reference and Biosimilar Products – Questions and Answers and invited comment by stakeholders in the docket.  The draft guidance addresses various considerations, such as identifying reference products and biosimilars in promotional materials, presenting studies that were conducted in support of reference product approval in biosimilar promotional materials, presenting data in promotional material derived from biosimilarity studies that are not part of the biosimilar labeling, and presenting  comparisons/comparative claims between reference products and their biosimilar, to name a few.

As part of their efforts to promote greater competition, FDA and FTC also announced that they would be holding a public workshop on March 9 at White Oak, with the goal of bringing together stakeholders from the government, industry, and academia to “discuss FDA and FTC’s collaborative efforts to support appropriate adoption of biosimilars, discourage false or misleading communications about biosimilars, and deter anticompetitive behaviors in the biologic product marketplace.”  The agencies are inviting written comments and in-person presentations.

And, unlike FTC’s November 2017 workshop on competition in prescription drug markets where FDA was a presenter, the upcoming biologics competition workshop is clearly an effort undertaken by the agencies in collaboration.  While FDA and FTC have not always seen eye to eye on all emerging biosimilar issues (such as naming conventions), the statement and workshop make clear their agreement that there will be increasing amounts of promotional activity relative to biosimilars, that such promotional activity could have a chilling affect on the uptake of biosimilars unless it is done in a truthful and non-misleading manner, and that they may be willing to take action sooner rather than later.

Only about 2 years after its last revision (which was only 5 months after its previous revision), FDA decided this week that MAPP 5240.3, Prioritization of Original ANDAs, Amendments, and Supplements, just wasn’t working.  With too many ANDA submissions designated as priority, and thereby entitled to 8 month review, FDA released version 5 of MAPP 5240.3 to try to more efficiently allocate its resources “to areas where priority review is most likely to meaningfully increase generic drug access and ensure fairness to applicants.”   As Dr. Choe shared in her statement announcing the revised MAPP:

Under the previous prioritization policy, roughly half of all ANDA submissions were designated as priority submissions, including many products that could not be marketed for several years as a result of blocking patents or exclusivities.

This practice strained the agency’s limited resources and did not support the agency’s goal of ensuring that ANDAs for those drugs with the greatest potential impact on public health are prioritized.

It seems that, despite FDA’s best efforts, the June and November 2017 versions created much more work for the Agency than anticipated.  For that reason, FDA has reconfigured its “prioritization factors and procedures.”

While the prioritization factors, generally speaking, have remained largely the same, the approach to granting Priority Review and prioritizing applications containing Paragraph IV certifications has changed a bit.  Firstly—and importantly—FDA will no longer prioritize review of an ANDA unless there is “an explicit request from the applicant at the time of submission” that includes the prioritization factors under which the applicant qualifies for priority review.  The only products that FDA will consider for priority review without such a request are products on FDA’s Drug Shortage list and products for which there are not more than 3 approved drug products in the Orange Book and for which there are no blocking patents or exclusivities listed for the RLD.  Any other type of drug product needs to explicitly state “Priority Review Requested,” include the basis for the request, and provide sufficient supporting documentation for the request.  Priority review applies to the entire application—not just an indication or strength that meets the priority review criteria.

Further, while FDA may still grant priority review after an ANDA has been submitted and received, it will not adjust a goal date for a submission even if the product later becomes eligible for priority review. If, for example, an already-submitted ANDA wouldn’t otherwise qualify for priority review but becomes subject to a drug shortage under section 506E of the FDCA at some time during the review process, FDA may still grant priority review, but it will not change the GDUFA goal date to reflect that priority status.  This means that once an ANDA receives a goal date, priority review basically just becomes expedited review, in which FDA will try to act on the ANDA as soon as possible but makes no actual commitment.

With respect to prioritization itself, FDA ditched the numerically-ranked Prioritization of Review in favor of “Prioritization Factors” that don’t appear to have a hierarchy.  The same categories as version 4 are still subject to priority review:

• Submissions with inadequate generic competition and no blocking patents or expired exclusivities listed in the Orange Book;
• Submissions with paragraph IV certifications and exclusivity considerations;
• Submissions related to drug shortages;
• Submissions subject to special review programs (like the President’s Emergency Plan for AIDS Relief);
• Submissions related to public health emergencies;
• Submissions related to certain government purchasing programs (like the Government-Wide Quality Assurance Program);
• Submissions subject to statutory mandates or other legal requirements;
• Supplements for public health reasons or supplements in which a delay would impose extraordinary hardship on the applicant (essentially resulting from catastrophic events); and
• Sole source products.

Only the considerations for Paragraph IV filers and ANDAs blocked by exclusivity appear to have actually changed.

Previously, FDA prioritized ANDAs containing paragraph IV certifications even if the ANDA would be blocked from marketing for years due to patents, 30-month stays, or exclusivity.  The revised ANDA limits priority review only to submissions ‘that will be ready for final approval at or before the goal date for that submission” and are from first-filers, from applicants blocked by a first-filer whose 180-day exclusivity has been triggered, or seek approval of a drug with limited competition (fewer than four therapeutically equivalent drug products listed in the Orange Book at the time of submission).  When approval for a noncomplex generic with limited competition is dependent on expiration of a patent or NDA exclusivity, the application will receive priority review if submitted between 24 and 36 months prior to expiration of the last applicable patent or exclusivity period; for complex products, priority is given to these applications submitted between 36 and 48 months prior to expiration of the last-expiring patent or exclusivity.

Importantly, FDA is now requiring documentation that the application will be eligible for final approval at or before the goal date for that submission.  For some of these factors, like a drug shortage, submitting this documentation is theoretically easy.  Or if you have tentative approval but are blocked by a first-filer’s 180-day exclusivity, documentation that the 180-day exclusivity period has started to run can be submitted without much challenge.  But for others—particularly paragraph IV filers—it presents a procedural challenge to get a priority review goal date.  Paragraph IV filers must wait to provide notice to the RLD sponsor until FDA receives its ANDA.  Once the ANDA filer provides its notice, the RLD sponsor has 45 days to sue the ANDA sponsor.  If the RLD sponsor doesn’t sue, then it will be easy to provide documentation that the product will be eligible for approval at goal date, but that can’t happen until at least 100 days after ANDA submission (60 days for FDA to “receive” the ANDA and 45 days to wait to see if the RLD holder will sue).  But FDA won’t assign a priority review goal date without that documentation.  So, presumably, FDA will have already assigned a non-priority review date to that ANDA upon receipt.  And even though it now meets the criteria for priority review, FDA won’t amend an already-assigned goal date and will only promise its best efforts to review quickly (expedited review).  And what about ANDAs for products with limited competition but will be blocked by  unapproved first-filers.  How do those applicants show  that they’ll be ready for approval at goal date?  Especially when FDA won’t make a determination about 180-day exclusivity forfeiture until another ANDA applicant is ready for approval.  And if you’re a first-filer subject to a 30-month stay, the revised MAPP means that you cannot get a priority review goal date because you won’t’ become eligible for priority review until the relevant litigation has been settled, dismissed, or completed.  For some, especially those going through an entire trial, it may not matter, but for those who settle quickly, ineligibility for a priority review date could delay market entry because the ANDA sponsor couldn’t provide documentation of a settlement before litigation even commenced.

Additionally, even though it’s implicit that the documentation FDA now requires to demonstrate that an application will be ready for final approval at the goal date is specific to applications subject to blocking patents or exclusivities, the MAPP could be interpreted to require documentation that the ANDA itself is robust enough for approval at the goal date.  If FDA decides for some reason that such documentation is needed, priority review assignment could become very subjective.  And even if FDA does not apply the policy this way, it is policy that FDA will not accelerate a goal date once an initial date is granted means that a lot of applicants are only entitled to vague promises of expedited review even if the ANDA meets the requirements for priority review.  Obviously, FDA is still working out some kinks in its priority review process.  Hopefully, the fifth time is the charm, but it remains to be seen how well this new documentation requirement will be enforced.

The American Conference Institute’s (“ACI’s”) popular “FDA Boot Camp” – now in its 35th iteration – is scheduled to take place from March 24- 25, 2020 at DoubleTree By Hilton Metropolitan, New York, NY.  The conference is billed as the premier event to provide folks with a roadmap to navigate the difficult terrain of FDA regulatory law.

ACI’s FDA Boot Camp will provide you not only with the essential background in FDA regulatory law to help you in your practice, but also key sessions that show you how this regulatory knowledge can be applied to situations you encounter in real life. A distinguished cast of presenters will share their knowledge and provide critical insights on a host of topics, including:

• The organization, jurisdiction, functions, and operations of FDA
• The essentials of the approval process for drugs and biologics, including: INDs, NDAs, BLAs, OTC Approval, the PMA process and the Expedited Approval Process
• Clinical trials for drugs and biologics
• Unique Considerations in the approval of combination products, companion diagnostics, and stem cell therapies
• The role of the Hatch-Waxman Amendments in the patenting of drugs and biologics
• Labeling in the drug and biologics approval process
• cGMPs, adverse events monitoring, risk management and recalls

In addition—and new for 2020—are special focus sessions on:

• FDA’s Digital Health Initiatives
• Opioid and Other Controlled Substances Classifications

Hyman, Phelps & McNamara, P.C.’s Suchira Ghosh will lead a workshop titled “Hatch-Waxman and BPCIA in the Trenches: Exclusivity and Bioequivalency Working Group.”

FDA Law Blog is a conference media partner. As such, we can offer our readers a special 10% discount. The discount code is: D10-874-874DX01.  You can access the conference brochure and sign up for the event here.  We look forward to seeing you at the conference.

In a letter dated January 9, 2020, the Center for Science in the Public Interest (CSPI) asked FDA to take immediate enforcement action to prevent what CSPI argues are misleading and unauthorized implied “low sugar” and “reduced sugar” claims, such as “lightly sweetened” and “less sweet,” on beverage products that are “high” in sugar.  In addition, CSPI asked FDA to issue regulations regarding “added sugar” claims.

In the letter, CSPI argues that claims such as “slightly sweetened,” “sorta sweet,” and “just a tad sweet” are implied nutrient content claims that the food is “low sugar” rather than a reference to the taste of the product.  Similarly, CSPI argues that a claim “less sweet” is a reduced sugar claim.  Nutrient content claims are claims that expressly or implicitly characterize the level of a nutrient.   Such claims may be made only if they are authorized by law.  FDA has not defined or authorized the nutrient content claim “low sugar.”  Moreover, although FDA regulations allows a “reduced sugar” claim, such a claim may be made only if the product meets certain requirements and the label includes specific disclosures.  CSPI identifies 19 products from five different brands that allegedly are misbranded because they use unauthorized implied low sugar or reduced sugar claims.  CSPI argues that the claims are not only violative but are “also particularly misleading” because the products contain 22-36% of the daily value for added sugars per Reference Amount Customarily Consumed.

In addition to requesting that FDA take enforcement action against companies marketing beverages with allegedly misleading unauthorized implied “low sugar” and “reduced sugar” claims, CSPI “encourages” the Agency to expeditiously issue regulations authorizing a “low added sugar” nutrient content claim.  As readers of this blog know, the updated nutrition labeling regulation requires the declaration of added sugars in addition to total sugars.  The updated regulation also established a daily value for added sugars (not for total sugars).  As a result, it would now be possible to define “low added sugars” similar to other “low” nutrient content claims.

It remains to be seen whether CSPI’s letter prompts a response from FDA.  In the interim, CSPI’s arguments could gain traction with the plaintiff’s bar.  In fact, on January 23, 2020, a complaint was filed against the Coca-Cola company in which plaintiffs allege that they were misled into believing that Honest tea beverages (among the products highlighted in the CSPI letter) labeled as “Just a Tad Sweet” were low in sugar and calories.  The action was filed in in New York federal court under various state laws for consumer protection, misrepresentation, breach of express and implied warranty, fraud, and unjust enrichment.

Back in September 2019, California passed AB 824: Preserving Access to Affordable Drugs.  That law sought to discourage “reverse-payment agreements” in which a brand manufacturer enters into a patent settlement agreement with a potential generic sponsor that involves a transfer of value from the brand to the generic without authorizing immediate generic market entry.  As we explained in our last post, AB 824 does not ban these types of agreement per se, but instead presumes that such agreements are anticompetitive where the ANDA sponsor receives “anything of value” from the brand manufacturer as part of a Paragraph IV litigation settlement.  As a result, AB 824 effectively shifts the government’s usual burden of proving anticompetitive effect to the drug sponsors, who now must show that a given settlement is not anticompetitive.  This shift is significant: It not only requires pharmaceutical companies to prove a negative, but will require the affected parties to disclose substantial proprietary information about these settlements to the California Attorney General.  At the time AB 824 was passed, we asked whether AB 824 would actually have any effect on these types of settlements (or whether California was merely dreaming).   And given the considerable impact AB 824 likely would have on the pharmaceutical industry, we also suggested that AB 824 likely would be subject to a constitutional challenge from industry.

Industry did not disappoint.  In November 2019, the Association for Accessible Medicines (“AAM”) sued the California Attorney General and sought both preliminary and permanent injunctions staying the implementation of AB 824 on January 1, 2020.  AAM is no stranger to this type of litigation: it successfully sued the Maryland Attorney General’s Office back in 2017 over a Maryland law addressing generic drug pricing.  Like its suit against Maryland, AAM’s challenge to AB 824 alleges that AB 824 violates the dormant Commerce Clause because it extends far beyond California entities and agreements.  Further, AAM alleged that federal law preempts AB 824—specifically alleging that the state law is inconsistent with the federal patent laws, federal antitrust law as set forth in FTC v. Actavis, and the delicate balance between innovation and competition that Congress established in the Hatch-Waxman Amendments and Biologic Price Competition and Innovation Act.  AAM also argued that AB 824’s imposition of a minimum penalty of $20 million violates the Excessive Fines Clause in the Eighth Amendment of the U.S. Constitution.  Finally, AAM maintained that AB 824 contravenes the basic notions of procedural due process because the presumption that any settlement is anticompetitive provides no meaningful opportunity for rebuttal.

On December 31, 2019, the U.S. District Court for the Eastern District of California denied AAM’s request for preliminary injunctive relief “due to the nature of Plaintiff’s pre-enforcement attack on AB 824.”  But despite this headline “loss” for the industry challengers, the district court all but agreed with AAM’s central constitutional challenge by making clear that the enforcement of AB 824 to settlements executed outside of California and between non-California entities almost would certainly be unconstitutional:

if the [California] Attorney General were to enforce the terms of AB 824 against two out of state parties that entered into a settlement agreement outside of California, having nothing to do with California, such conduct would likely violate the Dormant Commerce Clause.

Nevertheless, the Court explained, “invaliding or even preliminarily enjoining the law on this basis would force the Court to not only assume the Attorney General will apply the law unconstitutionally, but also make a constitutional determination before it is necessary to do so.” The Court refused to presume that California would apply AB 824 in such clearly unconstitutional fashion, and therefore found that AAM could not establish the elements necessary for an as-applied pre-enforcement challenge—namely, the existence of a concrete plan to violate AB 824, a communicated threat of prosecution under AB 824, and/or a history of past prosecution or enforcement of AB 824.  In short, while the Court effectively held that AAM likely would prevail if California applied AB 824 to the vast majority of patent settlements (which are executed outside of California, by companies domiciled outside of California), the Court simply found it premature to enjoin the statute given uncertainty about whether the State would attempt to apply the statute in such an unconstitutional fashion.

The Court also opined on AAM’s likelihood of success under the three other cited causes of action: field preemption, the Excessive Fines Clause, and procedural due process.  Because AB 824 does not address the validity of patent law, the Court determined that federal patent law does not preempt AB 824.  The Court also explained that because Actavis permits enforcement of antitrust law on patent settlements rather than foreclosing enforcement, federal antitrust law does not preempt state antitrust law.  And because the effect of AB 824 on generic drug applications cannot be discerned until AB 824 has been implemented, the Court determined that it was impossible to know whether AB 824 actually conflicts with the Hatch-Waxman Amendments, stating:

Because AB 824 has not been enacted, nor has any other similar law been enacted in another state, it is impossible to know if this law will have its intended effect, or as Plaintiff argues, will backfire, causing generic drug companies to cease filing ANDA applications and challenging patents held by brand-name drug companies. The Court is not in a position to predict the future impacts of AB 824 before it is enacted and enforced. At this time, it is too speculative for the Court to find one way or another that AB 824 will frustrate or further the aims of the Hatch-Waxman Act.

The Court further determined that AAM’s Excessive Fine Clause and procedural due process counts suffered from the same speculation issue.  Noting that the imposition of $20 million penalties (or three times the value at issue in the settlement agreement) could be appropriate in certain circumstances, the Court determined that AAM’s facial attack on the penalty failed.  And because an as-applied analysis requires a balance of the penalty against the infraction, the as-applied pre-enforcement challenge on the penalty provision was too fact-specific to address in the abstract.  Similarly, the procedural due process challenge was also premature because AB 824 provides a mechanism by which a party can rebut the anticompetitive presumption of a Paragraph IV settlement, which the Court cannot assess for meaningfulness until it has been employed.

The Court briefly addressed the other elements necessary for an injunction—irreparable harm, public interest, and balance of harms.  With respect to irreparable harm, the Court stated that AAM failed to establish that irreparable harm is both likely and imminent.  Further, the Court explained that “the question of balance of harms and public interest are too speculative at this point for the Court to find that either factor favors Plaintiff, sharply or otherwise.”

While this decision is a procedural setback for AAM, who has already submitted its Notice of Appeal, it is one that AAM has faced before.  In its Maryland challenge, the U.S. District Court for the District of Maryland dismissed AAM’s dormant Commerce Clause claim and denied AAM’s motion for injunctive relief (while allowing a vagueness claim to proceed).  AAM appealed, and the Fourth Circuit reversed the district court, holding that the Maryland provision was unconstitutional under the dormant Commerce Clause “because it directly regulates transactions that take place outside of Maryland.”  There’s no reason, therefore, for AAM to give up hope just yet.  As we noted, the District Court agreed that the same issue arises here.

Clearly, AAM has signaled its intent to fight here.  However, while the appeal is pending, AB 824 technically already has gone into effect.  So while we wait to see if how the Ninth Circuit reacts to the pre-enforcement challenge argument, we will also be waiting to see how California actually does enforce AB 824.  Given the Court’s strong warning about AB 824’s constitutionality in the mine run of cases, we suspect that any enforcement actions taken under AB 824 will be subject to further litigation.  But like we said back in September: we will have to wait to see whether AB 824 will survive pre-enforcement litigation, whether it will be considered constitutional when actually applied, and whether it will have any effect on pay-for-delay settlements—or whether California is only dreaming.

Hyman, Phelps & McNamara, P.C. is pleased to announce that Serra Schlanger will present at this year’s Drug Pricing Transparency Congress, to be held in Philadelphia, PA on March 30-31, 2020.  This conference gathers stakeholders to examine the evolving landscape of state drug price reporting and transparency efforts.  Serra will speak about the state laws that require price disclosures to be made directly to health care providers, as well as join a panel of experts to discuss recent developments and practical tips for compliance with the various state requirements.

As a sponsor of the event, we can offer our readers a special $500 discount off the registration.  The discount code is DPC500, which expires on February 7.  We look forward to seeing you at this conference.

Lystn, LLC (also doing business as Answers Pet Food; Lystn) is a pet food manufacturer of raw pet food.  Lystn has been in a battle with FDA and the Colorado Department of Agriculture (CDA) since 2018 when CDA collected a sample of Lystn’s Straight Beef Formula for Dogs that allegedly tested positive for Salmonella and Listeria monocytogenes.  On January 9, 2019, FDA issued a Public Warning Notice cautioning consumers about Lystn’s Straight Beef Formula for Dogs because, according to FDA, the product represented a serious threat to human and animal health due to the presence of Salmonella.

CDA pursued action against the Company in the Colorado Office of Administrative Courts based on the positive sample.  Lystn attributed CDA’s enforcement action to FDA, alleging that FDA “through the CDA, ha[d] chosen to prosecute [the Company] for alleged violations” of FDA’s compliance policy guide, Salmonella in Food for Animals (CPG).  This CPG states that “FDA considers a pet food to be adulterated under . . . 21 U.S.C. 342(a)(1) when it is contaminated with Salmonella and will not subsequently undergo a commercial heat step or other commercial process that will kill the Salmonella” and identifies criteria for determining whether such pet food should be subject to seizure. The Association of American Feed Control Officials’ (AAFCO) model bill and regulations and the CDA definition of “adulteration” mirror, or are similar to, FDA’s definition of “adulteration” in the CPG.

In July 2019, Lystn sued FDA, AAFCO, the CDA, three CDA employees, and HHS, in the U.S. District Court for the District of Colorado seeking a declaratory judgment that Lystn had been denied its due process rights and an injunction against FDA and AAFCO from applying and enforcing the CPG against Lystn.  Specifically, Lystn sought to enjoin FDA and AAFCO from pursuing any pending enforcement action based on the CPG, preventing the reintroduction of similar CPGs, and expunging all claims and references related to Lystn’s distribution of an adulterated product related to the CPG.  Defendants moved to dismiss plaintiff’s action alleging lack of subject matter jurisdiction (Federal and State defendants) and personal jurisdiction (AAFCO).

The Court granted all motions to dismiss.  It dismissed the action against federal defendants because, according to the Court, the CPG does not constitute final agency action.  Instead, the CPG “simply provides information to staff members concerning the interpretation of 21 C.F.R. § 342(a)(1)” to determine if administrative actions are necessary; the CPG does not create a legal right, instead “FDA’s enforcement power stems from 21 U.S.C. § 334.”  The Court compared  FDA’s public warning to a warning letter, which, as the Court noted does not constitute final agency action either.

Plaintiff’s argument that CDA’s enforcement action was a “thinly-veiled enforcement attempt by . . . FDA” because FDA compels states regulatory agencies to enforce the CPG (a “shadow regulation”) in exchange for FDA funding, also failed because, according to the Court, Plaintiff did not provide evidence that CDA’s action was at the behest of FDA.  Moreover, even if it had done so, CDA’s acts of collecting samples and initiation of an investigation did not constitute final agency action.

The action against the State Defendants also was dismissed because the Administrative Procedure Act (APA) does not create a private cause of action against State Agencies.  Plaintiff claimed that the State agencies were a vehicle of FDA, but the Court determined that there was insufficient evidence of a connection between the State Agencies and FDA to create subject matter jurisdiction.  Thus, the State agencies could not be sued for a violation of the federal APA.

The Court dismissed the case with prejudice.  As suggested by the title, this action concerned a company suing FDA pre-enforcement, not a company defending against FDA’s final action.

Hyman, Phelps & McNamara, P.C. (“HP&M”) is pleased to announce that Gail Javitt has become its newest Director.   Many leading companies have turned to Gail for her deep knowledge, skills, experience and thought leadership on the complex regulatory issues they face while looking to innovate and comply with existing and emerging FDA regulations.

As a Director at HP&M, Gail will provide strategic FDA regulatory advice for leading medical device, diagnostics, pharmaceutical, biological products, human cellular and tissue-based products (HCT/Ps) throughout the product lifecycle. Gail has successfully resolved disputes for these types of entities both at the pre-and post-market stages. She also has significant experience advising clinical laboratories on FDA and Clinical Laboratory Improvement Amendments (CLIA) requirements for laboratory developed tests.

In addition, Gail has published and spoken widely on issues at the intersection of law, science, ethics and policy, including FDA regulation of clinical trials, genetic testing, precision medicine and next generation sequencing.  Early in her career, Gail worked at the Genetics and Public Policy Center (part of Johns Hopkins University), as a law and policy director.  In this role, she was responsible for developing policy options to guide the development and use of reproductive and other genetic technologies.

Gail’s academic experience has included serving as a faculty member at the Berman Institute of Bioethics at Johns Hopkins University and as an adjunct professor at the Georgetown University Law Center, American University’s Washington College of Law and the University of Maryland School of Law.  She earned her J.D., cum laude, from Harvard Law School; her Master’s in Public Health from Johns Hopkins University and her B.A., phi beta kappa, magna cum laude, from Columbia College.

“Joining a firm known specifically for its intentional focus on the FDA and the needs of the health care and life sciences industry is important to me because of the exceptional resources that they can offer its clients. Combining my experience with the firm’s exceptional bench is an exciting opportunity, and I look forward to the many collaborative successes we will achieve together,” said Ms. Javitt.

About eighteen months ago, the government accused former Theranos founder Elizabeth Holmes and former Theranos president Ramesh “Sunny” Balwani of wire fraud and conspiracy, a scheme that fooled investors into providing more than $700 million to the then-promising blood-testing startup.

In the latest development in US vs. Elizabeth Holmes et al., federal prosecutors have asked Judge Davila to extend a December 31, 2019 court-ordered discovery deadline for FDA to produce documents, which the agency failed to meet.  FDA says it needs until April 30, 2020.  We blogged about the prior court order here.  In the January 13 hearing on FDA’s extension request, the agency’s Chief Counsel, Stacy Amin, participated by phone to describe the Agency’s efforts to respond.

Ms. Amin argued that time frame had been too short to comply with the large request.  She reported that the Agency had multiple employees working at 200% of their normal capacity in an attempt to meet the court’s initial deadline of December 31, 2019.  Ms. Amin said that several employees and significant resources had been redirected to meet the demand of the court’s discovery request. These strains, she said, have caused FDA to place other regulatory activities on pause, making it difficult for the Agency to meet its public mission to protect public health.  Remarkably, she indicated that even FDA enforcement efforts have taken a backseat to this discovery, including reduced resources for the issuance of warning letters and reduced resources for seeking court injunctions in other cases.  On net, Ms. Amin indicated FDA believes document production can be completed by April 30.

In light of the trial date of August 4, 2020 (mark your calendars!), Holmes’ and Balwani’s counsel argued that April 30 still would not give them enough time to review the material prior to trial.  The prosecution blamed the defense counsel for their predicament, suggesting that the complexity of the search requests had contributed to FDA’s inability to meet the December 31 deadline.

Judge Davila did not make a ruling during the hearing and has not yet issued a written order.  Since FDA has already missed the original deadline, the judge will have to either grant the motion for an extention until April 30 or deny the motion and set a different deadline.

We will continue to provide updates on the Theranos saga as developments occur.  The next court date is February 10, 2020 where the defense’s motions to dismiss will be heard.

*Work supervised by the Firm while DC Bar application is pending