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presented in a truthful and non-misleading manner in regulated promotional materials, FDA announced the release of the Draft Guidance for Industry: Promotional Labeling and Advertising Considerations for Prescription Biological Reference and Biosimilar Products – Questions and Answers and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  The draft guidance addresses various considerations, such as identifying reference products and biosimilars in promotional materials, presenting studies that were conducted in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

Under the Federal Food, Drug, and Cosmetic Act, FDA is authorized to hold advisory panel meetings for premarket approval applications (PMAs).  While FDA originally had to hold a panel meeting for all PMAs pursuant to the Medical Device Amendments of 1976, Congress liberalized the law in 1990 so that FDA panel meetings would only occur “on the Secretary of the Department of Health and Human Service’s own initiative” or “upon the request of an applicant unless the Secretary finds that the information in the application . . . substantially duplicates information which has previously been reviewed by a panel.”

As we have noted previously, the number of PMA advisory panels has declined significantly in recent years (see also our prior post here).  Whereas in 2010 there were 9 panel meetings, in 2017 there were only 2.  In 2019, this downward trend hit bottom: there was not a single PMA advisory panel meeting.

To connoisseurs of the device approval process, this was a sad loss.  The PMA panel process provided otherwise inaccessible insights into FDA’s thinking, as well as the ability to analyze the impact of policy changes on substantive decisions (see PMA Advisory Panels: The Impact of FDA’s Change in Policy on Voting Pattern).  And, they sometimes offered traits rarely associated with the application process: drama, excitement, tension, and even humor.

For those who crave device panel meetings, it was not a total loss.  FDA did hold 9 other panel meetings in 2019, on topics ranging from ethylene oxide sterilization to reclassification of surgical stapler devices.  And, there was one advisory panel meeting for a de novo request (the NeuroAD Therapy System for treatment of Alzheimer’s dementia).  One could have gotten good odds on a bet that the number of de novo panel meetings in 2019 (1) would exceed the number of PMA advisory panel meetings (0).

Of course, other types of applications are also subject to panel meetings.  For example, FDA convenes panels to consider applications for new molecular entities.  Still, an article published in the January 9 issue of the Pink Sheet (US FDA’s Breakneck Approval Pace Clashes With Advisory Committee Mandate) reports that number of advisory panel meetings for drugs has dropped significantly in recent years.  If these trends continue, advisory committee meetings to review individual product applications may eventually become extinct.

Over the years, we have blogged many times on FDA’s approach towards laboratory-developed tests (LDTs) (see, e.g., prior posts here, here, here, here, and here).  On October 31, 2018, FDA issued a Safety Communication relating to one particular type of LDT: pharmacogenomic (PGx) assays.  On November 1, 2018, the Center for Devices and Radiological Health and the Center for Drug Evaluation and Research issued a joint statement on the same topic.

Pharmacogenomics, or PGx, generally refers to testing and research related to the impact of genetic variants on drug response.  A growing body of evidence is emerging to support an association between certain genetic variants and patient response to medication.  Scientists and clinicians have been working to review and curate these data and rank the strength of the evidence for specific drugs and variants.  By knowing this information, physicians may be able to make more informed prescribing and dosing decisions

FDA has itself acknowledged that pharmacogenomics can play an important role in identifying responders and non-responders to medications, avoiding adverse events, and optimizing drug dose. See FDA, Table of Pharmacogenomic Biomarkers in Drug Labeling.  According to FDA, there are currently 385 known gene-drug interactions in FDA-approved prescribing information for hundreds of drugs; some but not all of these products include specific actions to be taken based on the biomarker information.

In the first quarter of 2019, FDA followed up on its Safety Communication by privately contacting various clinical laboratories and software companies that provide support services to laboratories asking them to cease including information about specific medications in laboratory reports for PGx tests.  During this same time period, FDA issued a Warning Letter to Inova Health Systems on April 4, 2019 after that entity refused to comply with FDA’s request.

Subsequently, FDA has continued its campaign of privately contacting companies and insisting that they stop providing physicians with any gene-drug association data (even if the data are included in the FDA-approved drug labeling.  For example, Tegretol (carbamazepine) has a black box warning about “serious and sometimes fatal” dermatologic reactions in patients with the HLA-B*15:02 allele.  However, complying with FDA’s recent directives would mean that a laboratory that detects the HLA-B*15:02 allele could not include in the test report information alerting the physician of the risk of a serious adverse reaction to Tegretol.

Thus, although FDA did not tell labs to stop performing PGx testing, the agency sought to prohibit labs from providing physicians any information about the potential clinical significance of test results.  In effect, FDA said it was up to doctors to sift through the FDA website, guidelines (there are numerous references to PGx data in treatment guidelines), articles, and other sources to try to figure out what the genetic information meant for patients.  Although FDA has asserted in the Safety Communication and elsewhere that providing PGx data to physicians poses risks to patients, the agency has not presented any supporting evidence for this assertion.

FDA’s actions here also have implications for the broader debate over regulations of LDTs.  FDA has historically said that it would exercise enforcement discretion over LDTs.  The agency’s attack on a broad category of LDTs – PGx – without notice or the opportunity for public discussion, and in the absence of a demonstrated risk to the public, is inconsistent with FDA’s long-standing policy of enforcement discretion for LDTs.

On January 9, 2020, Hyman, Phelps & McNamara, P.C. Directors Jeffrey N. Gibbs and Gail H. Javitt filed a citizen petition on behalf of the Coalition to Preserve Access to Pharmacogenomic (PGx) Information.  The Coalition is a group of stakeholders, including laboratories, companies that provide support to laboratories, and clinicians who utilize PGx information, committed to providing accurate PGx information to health care providers.

The citizen petition asserts that FDA’s actions violate the Administrative Procedure Act (APA) (both in relation to LDTs generally and PGx tests specifically) and are contrary to the First Amendment.  While FDA has repeatedly said that providing PGx information presents safety risks, the agency has provided neither corroboration nor details.  On the other hand, it is indisputable that FDA’s actions block the flow of information that can prevent harm and protect patient safety.  PGx information can help doctors avoid multiple risks, such as decreased or elevated serum levels, QT prolongation, weight gain, and undesired metabolic changes.  PGx information is especially important in the psychiatric field, where, according to the National Alliance on Mental Illness, prescribing that has been informed by PGx information has been shown to result in faster remission for conditions such as Major Depressive Disorder.

The citizen petition asks FDA to:

1. Issue a revised Safety Communication clarifying that clinical laboratories and software providers may communicate information about gene-drug interactions that is supported by adequate evidence and is not contraindicated by information in FDA-approved prescribing information.
2. Permit clinical laboratories to include medication-specific information in PGx test reports that is included in FDA-approved prescribing information or otherwise supported by adequate evidence without clearance or approval of a premarket submission.
3. Conduct any future policy development related to PGx tests in compliance with the APA, which allows for the participation of stakeholders through notice-and-comment rulemaking.

The citizen petition also requests a public hearing before the Commissioner pursuant to 21 C.F.R. Part 15.

All interested stakeholders can comment on the petition through the public docket on Regulations.gov (FDA-2020-P-0152).

On December 19, 2019, the Federal Trade Commission (“FTC” or the “Agency”) filed a petition for writ of certiorari in the Supreme Court seeking review of a ruling by the Seventh Circuit case FTC v. Credit Bureau Center, LLC.  A detailed overview of the background and reasoning in the appellate decision can be found in our prior post.  For present purposes what matters is that the FTC originally sought an injunction and restitution under section 13(b) of the Federal Trade Commission Act (“FTCA”).  Section 13(b) allows the FTC to seek an injunction whenever it has reason to believe one of its laws has been or may be violated.  After the FTC was initially successful in the district court, it suffered a setback on appeal when the Seventh Circuit held that section 13(b) allows the FTC to seek an injunction but does not allow for restitution as a remedy.  According to the Agency, the Seventh Circuit’s ruling “threatens the FTC’s ability to carry out its mission by eliminating one of its most important and effective enforcement tools.”  Petition for Writ of Certiorari at 1, FTC v. Credit Bureau Ctr., LLC, No. 19-825 (Dec. 19, 2019)

The Seventh Circuit’s holding created a circuit split on this issue, and, unsurprisingly, the FTC petitioned the Court to review.  If the Supreme Court grants cert. and on the merits agrees with the Seventh Circuit’s ruling, the FTC would be precluded from seeking restitution under section 13(b).  Instead, the Agency would only be able to obtain monetary relief in a court action following a successful administrative cease and desist order and  full administrative trial.

Notably, another case challenging the FTC’s ability to collect restitution has also sought Supreme Court review.  The petition in Publishers Business Services, Inc. v. FTC, filed in October of 2019, seeks review of a Ninth Circuit ruling upholding an award to the FTC of nearly $24 million in “equitable monetary relief” for a company’s operation of a telemarketing scheme.  See Petition for Writ of Certiorari, Publishers Business Services, Inc. v. FTC, No. 19-507 (Oct. 18, 2019).  Because the company did not raise the issue of whether section 13(b) allows for restitution during the proceedings below, the government argued that the issue could not be reviewed by the Supreme Court.  Brief for the Resp’t in Opp’n at 4, Publishers Business Services, Inc. v. FTC, No. 19-507 (Dec. 13, 2019).  The government’s brief described both the Ninth Circuit’s holding and the reasoning of the dissent, while acknowledging that the interpretation of section 13(b) has created a circuit split that may otherwise warrant review by the Supreme Court.  In the alternative, the government argued that this petition should be held pending the disposition of Liu v. SEC, cert. granted, No. 18-1501 (Nov. 1, 2019).  This case asks the Supreme Court to decide whether district courts may award disgorgement to the Securities and Exchange Commission under provisions of the securities laws analogous to the FTCA.  Publishers Business Services v. FTC was distributed for discussion at conference on January 10, 2020.

As always, we will continue to monitor these cases and keep our readers updated of new developments.

Hyman, Phelps & McNamara, P.C. (“HP&M”) is pleased to present its annual report highlighting the leading enforcement actions from 2019 that affect the FDA- and DEA-regulated industries.  As the largest boutique law firm dedicated to serving clients in this field, we are keenly aware of the hot button issues our clients are watching, and we carefully selected the cases highlighted in this report due to their potential broad implications.  We have first-hand involvement in several of these matters and are pleased to share our insights and successes with you.

We hope this report proves useful and interesting.

Too often, children are not included in clinical trials for new drugs, even though children may eventually be prescribed those very same drugs. This forces physicians who treat children to try and extrapolate information collected from adult trials to determine if and how to use that medicine in kids. Children deserve better than that. To help address this issue, the Food and Drug Administration (“FDA”) recently published a draft guidance titled: “FDARA Implementation Guidance for Pediatric Studies of Molecularly Targeted Oncology Drugs: Amendments to Sec. 505B of the FD&C Act Guidance for Industry.”

The purpose of this guidance is to facilitate the development of molecularly targeted therapies for the treatment of pediatric cancers. The guidance addresses the early planning needed for the eventual submission of New Drug Applications (NDAs) and Biologics License Applications (BLAs) expected to be submitted to the FDA on or after August 18, 2020 (and in accordance with section 505B of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (also referred to as the Pediatric Research Equity Act, or PREA) as amended by the FDA Reauthorization Act of 2017 (FDARA)).

There are now requirements for pediatric investigations to be conducted for certain targeted cancer drugs with new active ingredients, based on the molecular mechanism of action rather than clinical indication. In other words, products being developed that are directed towards a specific molecule in the cancer cells that may be involved in the growth, progression, or spread of the cancer.  These molecular targets may be related to numerous cancers rather than only a specific type of cancer. Original NDAs or BLAs for treatment of adult cancers and directed at a molecular target that is relevant to the growth or progression of a pediatric cancer must now include reports on the investigations of the molecularly targeted pediatric cancer.

The intent of this change is to accelerate early pediatric evaluation of these new products and help get these new products to market for kids with cancer. Many cancers that occur in children and adolescents may have the same molecular abnormalities that are seen in adult cancers. The guidance states:

Up to 50% of pediatric cancers have been reported to harbor a potentially druggable event, i.e. a molecular abnormality which can be potentially addressed by a targeted drug already approved for use in adults.

Gröbner SN, et al. The landscape of genomic alterations across childhood cancers. 2018. Nature, Mar 15;555(7696):321-327

The guidance defines several terms for regulatory purposes.  A molecular target is a “molecule in human cells (normal or cancer cells) that is intrinsically associated with a particular malignant disease process such as etiology, progression, and/or drug resistance.”  Relevance refers to the determination if a molecular target is substantially related to the growth or progression of pediatric cancer. The guidance outlines some of the criteria to determine if a molecular target is relevant. Categories include the following:

• Targets Related to Specific Gene Abnormalities
• Targets Associated with Cell Lineage Determinants
• Targets on Normal Immune Cells and Cellular Components of the Tumor Microenvironment
• Other Targets Associated with Specific Pathways or Functional Mechanisms of Normal and/or Malignant Cells

Additionally, FDA maintains two molecular target lists (relevant and non-relevant) for pediatric cancers.

The Pediatric Research Equity Act (PREA) had required that initial pediatric study plans (iPSP) were required prior to submission of an NDA or BLA. For oncology products, the iPSPs were frequently proposals to request waivers for pediatric assessments due to the type of cancer not occurring, or rarely occurring in children, which would make conducting pediatric studies impossible or highly impractical to conduct. After August 18, 2020 iPSPs, however, will require reports of pediatric cancer investigations if an adult cancer indication is directed at a molecular target relevant to pediatric cancer.  The guidance goes into detail about the content of an IPSP. Sponsors of these products can request a meeting with the Oncology COE Pediatric Oncology Program and Oncology Subcommittee of PeRC to assist with development of the iPSP.

The guidance offers additional considerations for Rare Cancers. These include considering including a pediatric cohort in adult trials. This can prevent the need for developing and conducting a separate pediatric trial. Another consideration is to imbed pediatric trials in an adult trial, especially if the molecular target is rare in the pediatric population. Increasing the enrollment of adolescent patients can be augmented by lowering the enrollment age for the trial. Tissue agnostic studies can help in development of treatment for multiple pediatric cancers that share the same genetic aberrations (e.g., MSI-H/dMMR tumors, NTRK-fusion positive tumors). Finally, master protocols (basket or umbrella trials) may be considered to minimize the number of pediatric patients exposed to therapies. These types of protocols will usually require a lot of planning and coordination.

Deferrals and waivers of doing pediatric studies are still appropriate in some cases such as when there is suspected serious toxicity in pediatric patients, when it may be prudent to wait until a clinical effect (in adults) is demonstrated, or if there are challenges in developing a pediatric formulation.

The guidance closes with a section on global implications and international collaboration which encourages drug developers to take a global approach when developing oncology treatments for pediatric patients.

Children with cancer may face additional risks when treated with drugs that were never specifically studied in pediatric clinical trials. Kids are way more complicated than being just small adults, and many things need to be considered when treating children e.g. age, rate of development and different metabolism. This new guidance is a great step in helping to see that new oncology drugs with molecular targets will be studied in children.

The docket for comments is open until February 20, 2020.

As we previously reported, in 2016, FDA issued significantly revised nutrition labeling regulations for foods and dietary supplements.  The compliance date is January 1, 2020 for all entities except those with less than 10 million dollars in annual sales.

The updated regulations resulted in many questions which FDA addressed in various guidances issued since 2016.  The development of guidance has been slow.  In fact, on December 30, two days before the compliance date, FDA issued the final guidance titled “Food Labeling: Serving Sizes of Foods That Can Reasonably Be Consumed at One Eating Occasion, Reference Amounts Customarily Consumed, Serving Size-Related Issues, Dual-Column Labeling, and Miscellaneous Topics.”  The final guidance differs from the draft guidance in only two substantive respects:

1. FDA modified the question and response regarding whether products sold in small packages eligible for the simplified nutrition facts may use the truncated statement “Not a significant source of other nutrients,” or must list all nutrient that are present in insignificant amounts to clarify that the statement “Not a significant source of other nutrients” is not limited to sugar free chewing gum but may be used on all products for which the package size may render it impracticable to include the long statement.
2. FDA modified the response to a question regarding the placement of the nutrition facts to clarify that it may not be placed on the bottom of packages (such as the bottom of boxes, cans, and bottles), unless they are visible during normal retail display and consumer handling.

FDA had issued the draft guidance in November 2018.  Even though the Agency received only forty comments, FDA took more than one year to finalize the guidance.  Fortunately, as we reported here, in October 2019, FDA announced that it intends “to work cooperatively with manufacturers” and “will not focus on enforcement actions” regarding the new nutrition labeling requirements until July 1, 2020, giving companies time to review this final guidance and adjust their labels accordingly.

The update to the nutrition labeling regulations has many consequences that have yet to be addressed, e.g., the impact on nutrient content claims and disqualifying nutrient levels.  We will continue monitoring FDA actions on this topic in 2020 (and beyond).