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  • Californovation? California is Set to Become a Drug Manufacturer

    Californovation (sung to the tune of the Red Hot Chili Peppers’ Californication, obviously): the new portmanteau seems appropriate for California, who just keeps coming up with new ideas to address the many hurdles consumers face with respect to access to affordable medicines.  Last year, we wrote about California’s adoption of the controversial AB 824, designed to address anticompetitive agreements that may keep generic drugs from entering the market (thereby inflating drug prices for consumers), in an effort to control drug prices at the state level.  Now, California has passed another bill to address drug pricing – this time introducing additional competition at lower prices by supplementing the drug supply chain with state-sponsored drugs.

    The California legislature passed SB 852 in early September, and it may be the first legislation of its kind in the  U.S.  The bill essentially allows California to become a drug manufacturer.   It doesn’t quite nationalize drug manufacturing (or whatever the state version of nationalizing would be), but it requires the state of California to partner with industry to “produce or distribute generic prescription drugs and at least one form of insulin, provided that a viable pathway for manufacturing a more affordable form of insulin exists at a price that results in savings” in an effort to “increase patient access to affordable drugs.”  Specifically, California would engage in drug production only “to produce a generic prescription drug at a price that results in savings, targets failures in the market for generic drugs, and improves patient access to affordable medications.”

    SB 852 directs the California Health and Human Services Agency (“CHHSA”) to enter into partnerships “resulting in the production or distribution of generic prescription drugs” to be made available to both public and private purchasers.  Under the statutory definition, a “partnership” includes contracts or purchasing agreements for the procurement of generic prescription drug with a payer, state governmental agency, group purchasing organization, nonprofit organization or entity.  The statute doesn’t specify exactly how these partnerships will work, but it is clear that these partnerships must be for the “manufacturing or distribution of generic prescription drugs.”  Because any drug resulting from the CHHSA-led partnership must be produced or distributed by a drug company registered with FDA, at least one drug manufacturer will likely be a part of the partnership even if not explicitly called for under the “partnership” definition.

    The statute requires CHHSA to identify and prioritize the production of generic drugs that would have the greatest impact on lowering drug costs to patients or purchasers, increasing competition and addressing shortages, improving public health.  CHHSA must prioritize drugs for chronic or high-cost conditions, including an insulin.  For each top drug identified, CHHSA must determine whether a viable pathway exists for a partnership based on the relevant legal, market, policy, and regulatory factors.   Once the drugs have been identified, CHHSA then sets a price based on user fees, ANDA acquisition costs amortized over five years, mandatory rebates, contracting and production costs, research and development costs, and other initial start-up costs amortized over five years.  Once developed, the drugs will be made available to all purchasers at a transparent price and without rebates (unless federally required).  The statute requires CHHSA to report to the Legislature on the feasibility of directly manufacturing prescription drugs, as well as the drugs selected and activities undertaken.

    This is a really interesting approach to the drug affordability problem that FDA has been trying to address (even if it may be outside the Agency’s statutory mandate) for years.  But the mandated drug production and/or distribution partnership raises many questions, particularly if the partnership is executed from production.  The legislation requires CHHSA to select drugs based on priority and the need for competition, but often those high priority, expensive drugs are still subject to patents and exclusivity periods.  As a result, development costs could include potential Paragraph IV challenges, or, in the case of insulin and other biologics, the BPCIA patent dance.  Could those be included in the pricing calculations?  Or will this exercise instead be limited to the Off-Patent Off-Exclusivity list?

    Novel approaches often result in a myriad of legal challenges.  So while California continues to innovate and think outside the box in an effort to address drug pricing, surely someone in the industry is thinking of ways to challenge SB 852.  Governor Newsom has until September 30 to sign the bill. He proposed a similar plan in January 2020, so it’s unlikely that this will be a tough sell for him.

    Trump Embraces International Reference Pricing in Executive Order

    As we reported in a previous post, Donald Trump several weeks ago threatened drug manufacturers with the prospect of an Executive Order mandating international reference price limitations, unless the manufacturers put forward proposals to significantly reduce drug prices by August 24.  On Sunday, September 13, not having elicited the desired reaction from manufacturers, Trump issued the threatened Executive Order on Lowering Drug Prices by Putting America First.  The Order first directs the Secretary of the Department of Health and Human Services (HHS) to “immediately implement his rulemaking plan” to test a payment model under Medicare Part B, under which Medicare would pay no more than a “most favored nation price” for certain high-cost prescription drugs.   That price would be the lowest price for a drug that the manufacturer sells in a member country of the Organisation for Economic Co-operation and Development (OECD) that has a comparable per-capita gross domestic product, adjusted for volume differences and differences in national gross domestic product.  There is no further explanation of how these adjustments should be made.  In directing the HHS Secretary to “implement his rulemaking plan,” the Order presumably was referring to an Advance Notice of Proposed Rulemaking (ANPR) issued by HHS in November 2018 which proposed to implement an international reference pricing payment model under the auspices of the CMS Center for Medicare and Medicaid Innovation (CMMI).  See 42 U.S.C. § 1315a(b).  (Click here for our post on the ANPR.)  HHS has not taken any action on that ANPR to date.

    In addition, the Order extends the international reference pricing concept to Medicare Part D, which was not contemplated in HHS’s earlier ANPR.  Therefore, the Order directs HHS to “develop and implement a rulemaking plan,” again under the auspices of CMMI as authorized in 42 U.S.C. 1315a(b), to limit Medicare payment to the most favored nation price for Part D drugs where insufficient competition exits and seniors are faced with prices above those in comparable OECD countries.  The CMMI model would test whether limiting prices to the most favored nation price would mitigate poor clinical outcomes and increased expenditures on drugs.

    Ironically, both the Part B and Part D mandates of the Order rest on the authority of 42 U.S.C. 1315a(b) – which was enacted in 2010 as part of the Affordable Care Act.  In a case pending before the Supreme Court, the Trump Administration is seeking to invalidate the Affordable Care Act in its entirety on constitutional grounds.  See Brief for the Federal Respondents, State of California, et al. v. State of Texas, et al., Nos. 19-840 and 19-1019.  Oral argument is scheduled for November 10.  If the Administration prevails in that case, one of the more minor consequences will be the invalidation of this Executive Order.  In addition, a change of administration in January may result in the revocation of this Executive Order (among many others) and/or withdrawal of the mandated HHS proposed regulations, as often happens after a change in administration.  If final regulations are ever issued, there is a strong possibility of a legal challenge from the drug manufacturer industry, which is strenuously opposed to international reference pricing.

    Despite these uncertainties, the significance of this Executive Order should not be minimized.  International reference pricing was proposed by the Obama Administration in 2016 (see our post here), was reintroduced by this Administration in the HHS ANPR in 2018, and was incorporated into H.R. 3, the drug pricing bill passed by the House on December 12, 2019.  Although international reference pricing was not included in S. 4199, the Republican-sponsored Senate drug pricing bill introduced by Senator Grassley on July 2, it is now definitively being championed by Trump.  Regardless of the fate of this Executive Order or the result of the upcoming election, this bipartisan concept will not go away soon.

    How to Stay In Touch With Your Customers During the Coronavirus Pandemic

    On Tuesday, September 15, at 8:00 am, Hyman,Phelps & McNamara, P.C. Director Gail Javitt will moderate a one hour webinar sponsored by the Maryland Israel Development Center (MIDC), titled “How to Stay In Touch With Your Customers During the Coronavirus Pandemic.”  The webinar will feature a panel of experts who will share their strategies for navigating the “new normal” to continue to communicate meaningfully with customers and prospects and meet customer needs.


    • Steve Mensh, Senior Vice President, Textron Electronic Systems and Geospatial Solutions, a global aerospace and defense company, keeps his finger on the pulse of customers’ needs, sets the strategic path to provide solutions and executes all new product and business development programs.
    • Tim West, Vice President of Sales, Advance Business Systems, a managed IT services and document management company, leads new business development programs and services that keep the firm at the top of its industry.
    • David Warshawski, Founder and CEO of Warshawski, a full-service marketing, branding and communications firm, has worked with leading global companies to position them in front of their customers including Adidas, Black & Decker, Boeing, Credit Suisse, GlaxoSmithKline, Microsoft and the International Olympic Committee.

    See here for registration information.

    Categories: COVID19 |  Miscellaneous

    FDA Law Alert – September 2020

    During these unprecedented times, Hyman, Phelps & McNamara, P.C. is pleased to bring you the next 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 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.



    • Larry Houck deciphers the Drug Enforcement Administration’s (DEA) stated justification of its recent increase of registration and renewal fees affecting facilities handling controlled substances.  Houck analyzes the underlying fee calculation methodology as well as the conditions under which DEA will refund registration fees.

    Medical Devices

    • Gail JavittJeffrey GibbsRichard Lewis, and McKenzie Cato provide a “mid-mortem” analysis of FDA’s response to COVID-19 and propose potential areas of improvement.  The authors review FDA’s policy concerning laboratory developed tests, a lack of regulatory predictability for serological tests, unclear communication from the Agency regarding changing review priorities, and an over-extension of FDA’s capabilities leading to industry frustration over a lack of feedback.
    • Jeffrey Shapiro answers the difficult question of whether a company can lawfully advertise a device that has a pending Emergency Use Authorization (EUA).  Shapiro undertakes a close reading of the pertinent FDA policy, Compliance Policy Guide (CPG) 300.600, that has stood for over 40 years and, in the absence of FDA clarification, opines on whether such promotion is allowed.

    Food Labeling

    • Riëtte van Laack describes FDA’s temporary guidance providing flexibility to food manufacturers facing COVID-19-related supply chain issues, and permits manufacturers to substitute hard-to-get ingredients in food labeling.  This is FDA’s fifth announcement of flexibility regarding food labeling regulations.

    Drug Development

    • Deborah Livornese discusses FDA’s guidance as it applies to “compassionate use” determinations by investigational review boards (IRBs) and clinical investigators when reviewing individual patient access requests.  FDA issued this guidance in response to a substantial uptick in the number of requests for COVID-19 investigational drugs.
    • In this post, Mark Schwartz describes FDA’s proposed review standards for COVID-19 vaccines under the public-private partnership Operation Warp Speed.  Operation Warp Speed heralds questions and concerns such as undue political pressure as well as risks from a potentially abbreviated review cycle and novel technological platforms.
    • Larry Bauer and James Valentine detail their experiences with adapting externally led patient-focused drug development (EL-PFDD) meetings to adjust to the unprecedented disruptions presented by COVID-19.  In the face of social distancing, mask requirements, and other efforts to “flatten the curve,” HPM and several patient communities have successfully come together to represent and capture the voice of patients, as well as caregivers, regarding disease symptoms, the impacts of those symptoms on daily life, current treatments, and hopes for future treatments.  As of August 28, 2020, there have been five virtual EL-PFDD meetings.


    • Alan KirschenbaumMichelle Butler, and Faraz Siddiqui discuss a proposed rule published by the Centers for Medicare & Medicaid Services (CMS) that seeks to implement statutory amendments to the Medicaid Rebate Program statute while also including CMS’s own policy proposals concerning value-based purchasing arrangements and patient copay assistance.
    • In this post, Faraz Siddiqui and Alan Kirschenbaum describe litigation vacating a drug price transparency rule published by the CMS.  This rule would have required pharmaceutical manufacturers to disclose the Wholesale Acquisition Cost (WAC) in direct-to-consumer advertisements for certain prescription drugs and biological products.


    • Anne Walsh and John Fleder highlight a recent Supreme Court decision, Liu v. Securities and Exchange Commission, that may lead to future challenges to FDA’s and the Federal Trade Commission’s (FTC) presumed ability to secure disgorgement and restitution awards.  Indeed, since publication of the post, the Supreme Court granted the petition for a writ of certiorari in FTC v. Credit Bureau Center, so look for our next update on this litigation.
    • Karin Moore describes a D.C. Circuit Court decision striking down FDA’s regulations requiring extensive health warnings on packaging and in advertising for cigars and pipe tobacco.  The court found that FDA had violated both the Tobacco Control Act (TCA) and the Administrative Procedure Act (APA) by failing to study the effectiveness of such health warnings.


    Hyman, Phelps & McNamara, P.C. has its finger on the pulse of FDA law.  Our technical expertise and industry knowledge are exceptional in scope and depth.  Our professional team holds extensive experience with the myriad of issues faced by companies.  Please contact us with any questions you may have related to the issues described here or any other FDA-related issue affecting your industry.

    Regulation and Utilization of Digital Health in Clinical Trials

    Hyman, Phelps & McNamara, P.C. Director Jeff Shapiro will be moderating “Digital Health Session 1: Bonus Session – Regulation and Utilization of Digital Health in Clinical Trials” as part of the Food and Drug Law Institute’s Digital Health Conference on September 10.  Jeff’s panel will focus on the use of digital health tools in pharmaceutical clinical trials.  One of the speakers is FDA’s Dr. Leonard Sacks, MD, Office of Medical Policy, Center for Drug Evaluation and Research.

    Overall, this one-day all-virtual event will focus on developments in digital health regulation pre‑and post-COVID-19, including significant enforcement discretion policies and exemptions FDA has implemented over the past six months.

    Sign up for the Digital Health Conference with the discount code save15 for 15% off registration:  https://bit.ly/3iMcKa8.

    Categories: Medical Devices

    CDRH Issues Draft Guidance Regarding Patient Reported Outcomes

    In recent years, FDA has sought to increase the patient perspective in its regulatory decision making.  One way this is accomplished is through use of patient‑reported outcome (PRO) measures in clinical studies.  PROs can assess concepts that are unobservable to clinicians and are only know to the patient (e.g., pain intensity, anxiety, and how bothersome a condition is to a patient).  This concept can be particularly important for medical products that treat disease states primarily defined by patient perception/complaint.  PROs can be used in a wide range of manners in clinical studies including for example to assess inclusion/exclusion, and/or as primary endpoints, secondary endpoints, and/or exploratory endpoints.

    CDRH has, recently, sought to provide additional information regarding use and acceptance of PROs in regulatory decision making, including through publication of PRO case studies and a PRO Compendium outlining instances in which PROs were used in clinical studies in fiscal years 2014 through 2017 (both available here on CDRH’s PRO page).   Even with this recent focus on PROs in clinical studies, in our experience, it can still be challenging for sponsors to know whether PRO data may be accepted as a measure of safety and effectiveness.

    On August 31, CDRH published a new draft guidance, Principles for Selecting, Developing, Modifying, and Adapting Patient-Reported Outcome Instruments for Use in Medical Device Evaluation, aimed at giving sponsors some additional insight on this topic.  Importantly, the guidance notes that “information from well-defined and reliable PRO instruments can provide valuable evidence for benefit-risk assessments and can be used in medical device labeling to communicate the effect of a treatment on patient[s] . . . when the use is consistent with the PRO instrument’s documented and supported measurement properties.”

    The draft guidance describes overarching principles to consider when assessing whether a PRO meets these criteria, including recommendations about ensuring the PRO is fit-for-purpose and best practices for ensuring that “relevant, reliable, and sufficiently robust PRO instruments” are used in device clinical studies.  In order to demonstrate that a PRO is fit-for-purpose, the draft guidance lays out three factors:

    • Is the concept being measured by the PRO instrument meaningful to patients and would a change in the concept of interest be meaningful to patients?
    • What role (e.g., primary, key secondary, or exploratory) will the PRO instrument serve in the clinical study protocol and statistical analysis plan?
    • Does the evidence support its use in measuring the concept of interest as specified in the clinical study protocol and statistical analysis plan?

    These are important points, and while they may seem obvious, it is not always clear whether a PRO instrument will fulfill them to the Center’s satisfaction.  The draft guidance does not give any indication as to the level of evidence required for a PRO to be fit-for-purpose.  Indeed, in our experience, even when a disease-specific, validated PRO is used as a primary endpoint for its intended purpose, it can be met with resistance during premarket review, particularly when the PRO has not previously been used as a primary effectiveness measure.

    The draft guidance notes several times that sponsors should consider discussing novel (in that it has not previously been relied upon in premarket decision making) and modified PROs with the Center in a pre-submission prior to inclusion in a clinical study.  In such a pre-submission, sponsors should ensure they address each of the above‑described elements in as much detail as possible to convince the Center that the proposed PRO is fit-for-purpose.

    The draft guidance also provides practical considerations for PRO development including ensuring that PRO instruments are written in plain language easily understood by patients, and providing PRO instruments in multiple languages, where appropriate, to capture health outcomes from patients with limited English proficiency. If a PRO instrument is newly developed or modified from an existing instrument, it must be appropriately validated.  The draft guidance notes that while a PRO may be validated as part of a sponsor’s clinical study, the results of the PRO from such study cannot then be presented in the sponsor’s labeling.  An additional study of the device using the PRO would be necessary.  This approach is consistent with the Center’s view that separate development and validation data sets are necessary to ensure reliability of device and the tools used to assess their safety and effectiveness.

    Bottom line: the draft guidance provides helpful insight into understanding the Center’s thinking regarding use of PRO in medical device clinical studies.  In our view, it would be helpful to elaborate on how much evidence is necessary to establish that a PRO is fit-for-purpose and how the level of evidence changes depending on whether a PRO is being used as a primary endpoint as compared to a secondary or exploratory endpoint.  Even without this detail, however, the information in this draft guidance should help sponsors as they craft justifications for use of PRO measures in device clinical studies.

    Categories: Medical Devices

    Join Our Team: Hyman, Phelps & McNamara, P.C. Seeks Device and Drug Development Attorneys

    Device Attorney

    HP&M seeks to add an associate to its thriving device practice.  We assist medical device manufacturers with product development, FDA approval and clearance, and post-market compliance.  Qualified candidates should have familiarity with premarket strategies, including:

    • Investigation Device Exemption requirements
    • Premarket Notifications (510(k) clearances)
    • Premarket Approval Applications (PMAs)
    • De Novo Petitions
    • Pre-submissions
    • Product classification and reclassification

    The boutique, collaborative nature of this team allows attorneys to work closely with clients and in-house regulatory experts to bring exciting new technologies to market.  Strong verbal and writing skills are required.  The ideal candidate will have experience working at FDA or with a medical device company, and prior big law firm experience is helpful.

    Compensation is competitive and commensurate with experience.  HP&M is an equal opportunity employer.  Please send your curriculum vitae, transcript, and a writing sample to Anne K. Walsh (awalsh@hpm.com).  Candidates must be members of the DC Bar or eligible to waive in.

    Drug Development Attorney

    We are seeking an attorney to work with our drug development team. The attorney must possess at least two years of relevant experience in the drug development arena, either by working at FDA or by assisting companies develop product development strategy or navigate the regulatory process.  Strong verbal and writing skills are required.  Compensation is competitive and commensurate with experience.  HP&M is an equal opportunity employer.

    Please send your curriculum vitae, transcript, and a writing sample to Anne K. Walsh (awalsh@hpm.com).  Candidates must be members of the DC Bar or eligible to waive in.

    Categories: Jobs

    PTE Countdown (Or Not?!?): 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 (Read to a Funky Soundtrack and Vocals by The Pointer Sisters)

    For those of us of “a certain age,” the original “Sesame Street” recalls fond memories: Mr. Hooper, Mr. Snuffleupagus (when only Big Bird could see Snuffy), and those catchy songs like “C Is For Cookie” and, of course, “Pinball Countdown” – those animated segments with a funky soundtrack with vocals by The Pointer Sisters that teaches children to count to 12 by following the journey of a pinball through a fanciful pinball machine.

    “Pinball Countdown” is quite the earworm, and it rang in this blogger’s mind as I counted the number of Patent Term Extension (“PTE”) requests submitted – and still pending – based on the 2018 NDA approvals for Array Biopharma Inc.’s (“Array’s”) MEKTOVI (binimetinib) Tablets (NDA 210498) and BRAFTOVI (encorafenib) Capsules (NDA 210496).  Array filed six PTE applications in four U.S. Patent Nos. 7,777,050; 8,178,693; 8,193,229; and 8,513,293 based on the approval of MEKTOVI (two PTE applications were filed in each of the ‘050 and ‘229 patents), and six PTE applications in four U.S. Patent Nos. 8,501,758; 9,314,464; 9,593,099; and 9,593,100 based on the approval of BRAFTOVI) (two applications were filed in each of the ‘758 and ‘464 patents).  You can access those PTE applications at FDA-2019-E-3050; FDA-2019-E-3051; FDA-2019-E-3052; FDA-2019-E-3054; FDA-2019-E-3056; FDA-2019-E-3063; FDA-2019-E-3064; and FDA-2019-E-3073.

    While it is not unusual for a company to submit multiple PTE applications for multiple patents based on the approval of a marketing application and then make an election as to which patent term to extend based on a single Regulatory Review Period (“RRP”), or for a company to request (and be granted) multiple PTEs based on multiple NDA (or BLA) approvals, the PTE applications for MEKTOVI and BRAFTOVI raise an important matter of first impression: It is Array’s contention that both the BRAFTOVI and MEKTOVI approvals involved four non-same RRPs based on different INDs and NDAs, making four patents eligible for PTE for each approval.

    But before we delve into Array’s legal argument, some background on PTEs is in order . . . . because it’s going to be a bumpy ride from here . . .

    Under Title II of the Drug Price Competition and Patent Term Restoration Act of 1984, Pub. L. No. 98-417, 98 Stat. 1585 (1984) (“Hatch-Waxman Amendments”) and 35 U.S.C. § 156, certain patents related to products regulated by FDA are eligible for extension if patent life was lost during a period when the product was undergoing regulatory review.  The “regulatory review period” is composed of a “testing phase” and a “review phase.”  For a drug product, the “testing phase” begins on the effective date of an IND, and ends on the date a NDA is submitted to FDA.  The “review phase” is the period from NDA submission to the date of FDA’s approval of an NDA.  A patent term may be extended for a period of time that is the sum of one-half of the time in the “testing phase” (minus any time before patent issuance), plus all the time in the “review phase” (minus any time before patent issuance), including the time an applicant uses to respond to a Complete Response Letter.  The “regulatory review period” must be reduced by any time that the applicant “did not act with due diligence.”  The total (calculated) regulatory review period may not exceed five years, and the extended patent term may not exceed fourteen years after the date of approval of the marketing application.  In some cases, the term of a patent that is scheduled to expire before the PTO can issue a certificate of extension can be extended on an interim basis.  There are two types of interim PTEs: (1) interim patent extensions available during the “review phase” of the statutory “regulatory review period;” and (2) interim patent extensions available during the PTO’s review of an application for PTE.

    The PTE statute states (at 35 U.S.C. § 156(c)(4)) that “in no event shall more than one patent be extended . . . for the same regulatory review period for any product.”  For quite some time now, the PTO has interpreted 35 U.S.C. § 156(c)(4) to permit multiple PTEs under certain circumstances (as well as multiple interim PTEs).  Specifically, for a drug product covered by several patents PTO may extend a different patent for each NDA approved on the same first day (even when multiple NDAs share common “testing phase” and a “review phase” dates).  That is, the PTO considers each NDA “regulatory review period” to be distinct and for which a PTE is available.  We’ve posted on this issue several times over the years – see here, here, and here.

    Array presents a new twist on the multiple PTE argument.  The following is taken from one of the BRAFTOVI PTE applications, but the argument is the same for the MEKTOVI PTE applications:

    For many drug products, clinical testing and FDA approval involve a single IND and NDA. In these situations, only one RRP will exist and only one patent will be eligible for term extension. In other cases, however, due to the complexity of the clinical trials or for FDA’s “administrative convenience,” multiple INDs or NDAs may be required for FDA approval. For drug products reviewed under multiple INDs or NDAs, multiple RRPs will exist and multiple patents will be eligible for term extension.

    For example, if multiple NDAs for the same new drug product are approved simultaneously (to meet the statutory “first permitted commercial marketing” requirement discussed further below), non-same RRPs have been found to exist and multiple patent terms have been extended.  This has occurred where the NDAs reference the same underlying IND and even when the NDA and IND reviews occur over identical time frames.  Each IND/NDA combination was determined as not being the “same” RRP under§ 156(c)(4) and each provided the legal basis for a patent term extension.

    For this to happen, the Patent Office had to interpret “same regulatory review period” in 156(c)(4) as not referring to a same time period but rather, referring to a same substantive regulatory activities and review undertaken by FDA.  In other words, if the regulatory information produced and reviewed by FDA during any RRP is different from the regulatory information of any other RRP, they would be considered not to be the “same” even if the underlying IND and NDA time periods overlap or are identical.

    Under the Patent Office’s interpretation of the statute, non-same RRPs can be found to exist for the same product approval whether they are due to multiple NDAs and/or multiple INDs, as long as the underlying information reviews are different. Indeed, the statutory purpose of an RRP is to compensate a patentee for lost term associated with FDA review.  It should not matter, therefore, whether that term is lost due to multiple NDAs or multiple INDs as the outcome will be the same lost term due to regulatory delays in either event.

    In the case of BRAFTOVI™, four separate INDs were required for the clinical studies and investigations that went into FDA drug product approval.  Accordingly, each IND contributed to a regulatory delay represented by the following non-same RRPs:

    • RRP#l: IND 111003 + NDA 210496
    • RRP#2: IND 117085 + NDA 210496
    • RRP#3: IND 113850 + NDA 210496
    • RRP#4: IND 120738 + NDA 210496

    Based on these non-same RRPs for BRAFTOVI™, four separate patents are eligible for term extension.

    The PTO is already putting up a fight on the legal argument Array has raised.  In a letter to FDA, the PTO comments: “It would appear that contrary to there being four separate ‘non-same’ regulatory review periods which gave rise to the single approval, it is the combination of the information from the four INDs that provided sufficient data to support the approval of the single NDA for BRAFTOVI® (NDA 210496).”  To that end, the PTO requests that FDA confirm “that the product identified in the application, BRAFTOVI® (encorafenib), has been subject to a SINGLE regulatory review period within the meaning of 35 U.S.C. § 156(g) before its first commercial marketing or use as the term ‘regulatory review period’ has been interpreted and implemented by FDA.”

    Array responded to the PTO back in May 2019 in a 14-page letter stating, in part:

    In previous cases where a product approval involved multiple RRPs, FDA determined that two RRPs would not be considered the “same” if the first product approval involved separate NDA review periods, even if the NDAs relied on the same investigational new drug (IND) review period (see e.g., OMNICEF®, ADCETRIS®, MYCAMINE®).  Moreover, two RRPs were not considered to be the “same” even where the combined IND and NDA review periods were identical in time (see e.g. LYRICA®).  However, the only way to square these non-sameness determinations with Section 156(c)(4) is for FDA to construe the term “same” to mean the same information undergoing regulatory review and not the same period of time under which the regulatory review takes place.  Thus, FDA appears to consider multiple RRPs not to be the “same” as long as they involve the review of different regulatory information for product approval, even if some or all of the IND and/or NDA periods overlap.

    Consistent with this FDA precedent, the four RRPs identified in each of the Array PTE applications must also be determined as not being the “same” under Section 156(c)(4), because each involves the review of regulatory information that is different from the information under review in every other RRP. Accordingly, FDA must reject the recommendations in the USPTO’s advisory letter and make the determination that four non­same RRPs exist for each of the BRAFTOVI® and MEKTOVI® approvals.

    The Array PTE requests and dockets have been on our radar for some time.  Moreover, the same legal argument was raised for a second time in the context of PTE applications for VITRAKVI (larotrectinib) Capsules (NDA 210861) and Oral Solution (NDA 211710) (see Docket Nos. FDA-2019-E-5681FDA-2019-E-5682; FDA-2019-E-5663; and FDA-2019-E-5662), and for a third time in the context of PTE applications for patents covering a medical device, TherOx Downstream System, with multiple Investigational Device Exemptions and a single Premarket Approval (see the patent image file wrapper for each of U.S. Patent Nos. 8,246,564; 7,820,102; and 6,582,387).  So why are we blogging on the issue now?

    Well, there’s been a development that could not only throw Array’s arguments into . . . um . . . “disarray” . . . but that could call into question any multiple PTEs granted by the PTO.

    Earlier this week, when the non-Beta version of Regulations.gov was operational (because the new, and not too user-friendly, Beta version currently operates only on Tuesday and Thursday – see our previous post here – and searching is a pain), several new PTE dockets popped up in which Nabriva Therapeutics GMBH (“Nabriva”) requests multiple PTEs for different patents based on FDA’s August 19, 2019 approval of two NDAs for XENLETA: NDA 211672 for XENLETA (lefamulin) Tablets, and NDA 211673 for XENLETA (lefamulin) Injection.  You can access those PTE requests at Docket Nos. FDA-2020-E-1839; FDA-2020-E-1840; FDA-2020-E-1841; FDA-2020-E-1842; and FDA-2020-E-1843.

    OK . . . so a request for multiple PTEs based on different NDA approvals is nothing new.  But what’s shocking is a July 13, 2020 letter from the PTO to FDA contained in each XENLETA PTE docket.

    Styled as a “REQUIREMENT FOR INFORMATION PURSUANT TO 37 C.F.R. §1.750,” the PTO does an about-face on the availability of multiple PTEs:

    The issue is whether 35 U.S.C. § 156 permits a patent owner who owns more than one patent to obtain more than one patent term extension for the same FDA approved product.  Applicant has filed multiple PTE applications directed to the same product (lefamulin). If applicant contends that more than one patent may be extended based on the approval of lefamulin, then applicant is required to provide legal support pursuant to 35 U.S.C. § 156, expressly demonstrating that the statute permits multiple term extensions based on the same product.  Absent a convincing showing, the Office plans to issue only one PTE directed to XENLETA® (lefamulin), provided that the requirements of 35 U.S.C. § 156 are met. . . .

    Although both FDA approvals received the same date, they cannot both be considered as “first” approved under § 156(a)(5)(A) and they cannot both constitute distinct regulatory review periods under§ 156(a)(4).  These interpretations go against the plain statutory language, which states:

    “the first permitted commercial marketing or use of the product under the provision of law under which such regulatory review period occurred.”  There cannot be more than one “first permitted commercial marketing or use” of the product or more than “a” (single) regulatory review period of the product, subject to patent term extension.  Id.  Additionally,§ 156(c)(4) states that “in no event shall more than one patent be extended under subsection (e)(l) for the same regulatory review period for any product.”  Hence, subsection (c)(4) limits the right of a patent owner to obtain more than one extension based on time lost for the “same” regulatory review period for “any product.” See, 35 U.S.C. § 156(c)(4) and 37 C.F.R. § 1.785(b).

    The PTO goes on to cite Novartis AG v. Ezra Ventures LLC, 909 F.3d 1367 (Fed. Cir. 2018), Arnold Partnership v. Rogan, 246 F. Supp.2d 460 (E.D. Va. 2003), and even (curiously) Biogen lnt’l v. Banner Life Sciences LLC, 956 F.3d 1351 (Fed. Cir. 2020) as supposed legal support for its position.  PTO then concludes the letter with the following paragraph and footnote acknowledging a change in position:

    Section 156 does not allow for multiple extensions of patents beyond the one patent per one approved product.  The regulatory review period of XENLETA® (lefamulin) can be used as a basis for extension of only one patent.  See 35 U.S.C. § 156(c)(4) and 37 C.F.R. § 1.785(b).  Therefore, the Office plans to limit applicant to extending only one patent for the approved product (lefamulin).1

    1The Office acknowledges that in the past it has permitted more than one extension when multiple forms of administration of the same drug product were applied for and approved by the FDA on the same day.  However, the Office believes that the proper interpretation of the statute, especially in light of recent court decisions discussed in this requirement for information, mandates that only a single patent be extended for any given drug product, regardless of the number of forms of administration approved by the FDA.

    This is quite a bombshell!  We suspect the PTO will find itself in court trying to defend any final determination on multiple PTEs (maybe in the context of multiple PTE requests that were on the verge of being granted, such as for BAXDELA and BRIVIACT, but are now subject to letters like this).  And if the PTO is ultimately successful, then that decision could spawn litigation to invalidate previously-granted PTEs.  What a mess this could be!

    Tick Tock, Goes The Clock . . . October 1st is Fast-Approaching

    No, “Tick Tock, Goes The Clock” is not a reference to Doctor Who poetry, Ke$ha (TiK ToK), or to that “TikTok” destination for mobile videos that’s been in the news recently.  We’re talking about the countdown to October 1, 2020, when the Fiscal Year 2021 (“FY21”) Generic Drug User Fee Amendments of 2017 (“GDUFA II”) fees go into effect.

    FDA announced the FY21 fee rates in August.  That announcement usually triggers companies to consider what they can do to potentially lessen the effect of the annual user fee burden – and, in particular, the annual Program Fee.  That fee is based on the number of ANDAs owned by a company (including affiliates), which results in a company being placed into one of three tiers: a large size operation (20 or more ANDAs; $1,542,993 FY21 fee), a medium size operation (6-19 approved ANDAs; $617,197 FY21 fee), or a small business operation (1-5 approved ANDAs; $154,299 FY21 fee).

    The year-over-year up-and-down fluctuations in user fee rates we’ve seen thus far under GDUFA II continue for FY21 – especially for the annual Program Fee – as shown in the tables below.  Those fluctuations are attributable to several factors, including the changing landscape of generic drug manufacturers: there were 258, 177, 199, and 220 small size operations in FYs 2018, 2019, 2020, and 2021, respectively; 52, 49, 63, and 60  medium size operations in FYs 2018, 2019, 2020, and 2021, respectively; and 62, 57, 63, and 72 large size operations in FYs 2018, 2019, 2020, and 2021, respectively.

    In a post last week concerning ANDA consolidation we pointed out one way for generic drug manufacturers to potentially lessen the effect of the annual Program Fee burden.  A second way, as we’ve noted before, is to consider a system we dubbed “ANDA Arbitrage.”  It’s an effort undertaken by a company called ANDA Repository, LLC to help companies potentially decrease annual user fee liability under GDUFA II.  The company’s website explains how the system works (see here).  And it seems that they’ve been pretty successful in implementing that system.  According to our data, as of April 30, 2020, ANDA Repository LLC owned 130 ANDAs.

    ACI’s 14th Annual Paragraph IV Disputes (Virtual Conference)

    The American Conference Institute (“ACI”) is sponsoring its 14th Annual Paragraph IV Disputes Conference on October 6 – 7, 2020 (Eastern Daylight Time).  Like a lot of conferences this year, the ACI conference format has changed from a live, in-person event to an interactive, virtual conference.

    ACI’s Paragraph IV Disputes Conference provides invaluable professional development opportunities, meaningful networking, and vital “take-aways” for legal strategies and cost analysis for every aspect of this complex form of litigation

    A “Who’s Who of the Food Law Bar” will give you critical insights in sessions like:

    • “And Now a Word from the District of Delaware: A Conversation with Chief Judge Stark and Chief Magistrate Judge Thynge”
    • “Paragraph IV State of the Union: Developing a New Game Plan for the New Normal: Assessing Legal, Regulatory, and Jurisprudential Developments in the Era of COVID-19”
    • “Examining How New and Narrow Interpretations of the Scope of Patent Term Extension Will Affect Patent Rights and Generic Entry”
    • “FTC KEYNOTE: Antitrust Developments Impacting Brands and Generics”

    Hyman, Phelps & McNamara, P.C.’s Kurt R. Karst will be speaking at a session titled “FDA Think Tank on the Latest Regulatory Developments Impacting Hatch-Waxman.”

    FDA Law Blog is a conference media partner. As such, we can offer our readers a special 10% discount. The discount code is: D10-896-896CX13. You can access the conference brochure and sign up for the event here. We look forward to “seeing you at the conference.”

    In Support of the New HHS Policy Barring FDA from Premarket Review of LDTs

    On August 19, the Department of Health and Human Services (HHS) announced that FDA shall no longer conduct premarket review of laboratory developed tests (LDTs) under the Federal Food, Drug, and Cosmetic Act and implementing regulations (FDCA).  The crux of the statement is this:  “the department has determined that the Food and Drug Administration . . . will not require premarket review of laboratory developed tests . . . absent notice‑and‑comment rulemaking, as opposed to through guidance documents, compliance manuals, website statements, or other informal issuances.”  Others at our firm have summarized the policy here.

    To put the new HHS policy in context, the Centers for Medicare and Medicaid Services (CMS) regulates clinical laboratories under the Clinical Laboratory Improvement Amendments of 1988 and implementing regulations (CLIA).  CLIA requires laboratories to hire scientifically qualified personnel and to follow rigorous testing, analytical validation and record-keeping procedures.  These laboratories must obtain various CLIA certificates from CMS, depending on the complexity of the testing the laboratory performs.  According to CMS, CLIA applies to approximately 260,000 laboratory entities.  Under CLIA, these laboratories are regulated in the development and performance of in‑house developed assays, i.e., LDTs, as well as when they employ test kits manufactured outside the laboratory.

    FDA claims concurrent authority to regulate LDTs as medical devices under the FDCA.  The dirty little secret is that, during the past 40 years, FDA has only singled out a handful of LDTs for active regulation.  (This post explains why this selective enforcement is unlawful.)  The rest are left alone based upon “enforcement discretion.”  In this respect, therefore, the HHS policy change is not as dramatic as it might appear.  For almost all clinical laboratories, it will be largely business as usual.

    At the same time, the new HHS policy actually may have two potentially beneficial effects.  First, clinical laboratories will no longer have the sword of Damocles dangling over their LDTs, i.e., the threat that FDA may select their assays for regulation.  This type of legal uncertainty can have a chilling effect on innovation.  If the new policy remains firm, look for even greater technological progress in this space.

    Second, the new policy will allow FDA to better direct its resources against Corona Virus Disease 2019 (COVID‑19).  Even though few LDTs are regulated by FDA, the agency chose to regulate LDTs for the diagnosis of COVID‑19.  This post describes how FDA’s choice to do so led to critical delays in clinical testing in the early days of the pandemic when speed was paramount.  See also this Yale Law Journal article.

    Equally unfortunate, an inordinate share of FDA’s scarce resources have been directed toward these LDTs.  Just count the number of EUAs that FDA has issued for COVID‑19 LDTs in these past few months.  The laboratories offering these LDTs are already regulated under CLIA and well‑versed in validating assays.  FDA should have focused instead on manufacturers of test kits sold to laboratories and healthcare facilities.  These manufacturers are explicitly subject to FDA regulation.  The clinical laboratories are not.  Every EUA issued to a laboratory has diverted time and energy that FDA could have spent more productively.

    Now, thanks to the new HHS policy, FDA can better deploy its resources.  An example might be rapid asymptomatic screening that would allow safer congregation in places of work, worship, and schooling.  For obvious reasons, these rapid tests will generally not be offered by clinical laboratories.  If it turns out that this type of testing is a priority, FDA can now devote more resources to moving these tests through EUA review as quickly as possible.

    The new HHS policy requires FDA to follow notice and comment rulemaking before resuming premarket review of LDTs.  But, given the dubiousness of FDA’s legal authority over LDTs, and the complexity of harmonizing FDCA and CLIA requirements, an explicit act of Congress should be a prerequisite.  Indeed, FDA expressly stated two years ago that it would no longer seek to expand regulation of LDTs beyond the status quo but would await congressional action.  In a healthy republic, it is the legislature, not the regulatory agencies, that define the boundaries and nature of regulatory action.  FDA and CMS have each been entrusted with important regulatory schemes.  It is Congress, not FDA, that should define how these schemes should interact, if at all, with respect to clinical laboratory testing.

    An important issue not addressed in the HHS announcement is how to define LDTs that are no longer subject to FDA’s premarket review.  FDA’s LDT web page defines an LDT as follows:  “A laboratory developed test (LDT) is a type of in vitro diagnostic test that is designed, manufactured and used within a single laboratory. . . .  The FDA does not consider diagnostic devices to be LDTs if they are designed or manufactured completely, or partly, outside of the laboratory that offers and uses them.”

    Should HHS allow FDA to apply this definition under the new policy?  A concern here is that FDA may attempt to evade or weaken the new HHS policy by continuing to apply the portion of the definition positing that a test is not an LDT if any part of it is “designed” outside a clinical laboratory.  This requirement — that an LDT must have developed by a laboratory with autarkical self‑sufficiency — was invented by FDA.  It is ipse dixit with no statutory or regulatory basis.  It allows FDA unfettered latitude to decide how much “foreign aid” in the development of a test will lead to FDA’s premarket review.

    The new HHS policy now bars FDA from regulating LDTs based upon “guidance documents, compliance manuals, website statements, or other informal issuances.”  (The list does not mention enforcement correspondence such as untitled letters and warning letters, which FDA has deployed in the LDT space on occasion.  Nonetheless, these letters lack the force of law and therefore fall under the rubric of “other informal issuances.”)  In fact, FDA has only ever deployed informal issuances when regulating LDTs; there has never been a rulemaking.  Because FDA’s definition of an LDT was promulgated only in these informal issuances, the agency should be barred from applying it.

    Instead, HHS should simply preclude FDA from premarket review of any test offered by a clinical laboratory as the latter is defined by CLIA.  This facility‑based approach would at least be grounded in an existing statute.  Under CLIA, a clinical laboratory is defined as:

    a facility for the biological, microbiological, serological, chemical, immuno‑hematological, hematological, biophysical, cytological, pathological, or other examination of materials derived from the human body for the purpose of providing information for the diagnosis, prevention, or treatment of any disease or impairment of, or the assessment of the health of, human beings.

    If a test is offered by this type of facility, it is subject to CLIA requirements.  In such cases, HHS should preclude FDA from layering premarket review on top of the CLIA requirements.

    FDA might counter that the design activities, if performed outside the laboratory, mean that the laboratory has not actually developed the assay.  Hence, the assay is not be a “laboratory developed test.”  Rather, it is an in vitro diagnostic subject to FDA’s premarket review.  The reply to FDA is that this analytical framework would lose the forest for the trees.  The core legal dispute is that FDA claims that all tests performed in a clinical laboratory are subject to the FDCA.  The agency bases this claim on the definition of an in vitro diagnostic, which on its face encompasses tests performed in a clinical laboratory.  The contrary position is that CLIA is a more specific statute that was enacted after the FDCA to comprehensively regulate clinical laboratory testing.  Therefore, CLIA preempts the FDCA with regard to tests offered by clinical laboratories.

    The point of the new HHS policy is not to resolve the dispute but to instruct FDA to stand down for now.  Yet, if FDA continues to apply its longstanding definition of LDTs, it will not be required to stand down completely.  Rather, it will continue to pick and choose among LDTs offered by clinical laboratories, regulating some of them as “not true LDTs” as determined by FDA based upon subjective criteria not grounded in law.

    A facility‑based approach would more fully carry out the new HHS policy of precluding FDA from premarket review of LDTs.  At the same time, it would clearly permit FDA to continue regulating traditional test kits manufactured outside clinical laboratories (and typically shipped to laboratories for use).  It is uncontroversial that these kits are medical devices under section 201(h) of the FDCA and properly regulated by FDA.  If HHS were to apply this suggested approach, every test would be regulated either under CLIA or the FDCA.  With no test going entirely unregulated, Congress would have breathing room to sort out the proper harmonization of the FDCA and CLIA.

    Finally, another concern is that the new HHS policy says that FDA will abstain only from “premarket review.”  In the past, when FDA has chosen to regulate an LDT, it has said that all requirements of the FDCA apply.  (For example, see this warning letter from 2019.)  That would ordinarily include a panoply of post‑market requirements, such as the Quality System Regulation (QSR), Medical Device Reporting (MDR) and labeling requirements.  May FDA impose these even if premarket review is out of bounds?

    It would be illogical (and potentially ultra vires of the FDCA) for HHS to allow FDA to do so.  The new HHS policy is premised on FDA’s lack of authority to conduct premarket review of LDTs.  (Hence, the requirement for notice and comment rulemaking to support such review.)  That same concern applies to postmarket regulation.  The FDCA is a finely balanced statutory scheme in which premarket review and postmarket requirements are two sides of the same coin.  They work together to meet the FDCA’s mandate that all medical devices have “reasonable assurance of safety and effectiveness” (FDCA § 513(a)).  If FDA lacks authority to conduct premarket review, it also lacks authority to impose postmarket requirements.

    To sum up:  the new HHS policy is an excellent step to more rationally apply FDA’s resources during the pandemic.  In the bigger picture, it should take no less than an act of Congress to determine the proper scope of the FDCA and CLIA as applied to clinical laboratories.  Congress may decide that CLIA preempts the FDCA inside clinical laboratories.  Or, Congress may decide that developments in testing technology and business models warrants an overlay of FDA regulation.  If so, the new statute should supply the boundaries of such regulation and harmonize CLIA with the FDCA.

    Shifting Patient Engagement in the Era of COVID-19: HPM Facilitates the First Four Virtual Externally-Led PFDD Meetings, Moderating the Fifth Today

    We all have had to adapt to a world with COVID-19 concerns.  One of the challenges has been how to continue having Externally-Led Patient-Focused Drug Development (PFDD) meetings in these times of social distancing, travel restrictions, mask requirements, and other efforts to “flatten the curve”.

    On June 9, 2020, the first ever virtual Externally-Led Patient-Focused Drug Development (EL-PFDD) meeting took place for the Hepatitis B community.  This virtual format, rather than the usual face to face meetings, was planned to avoid social contact and possible health consequences for attendees due to the COVID-19 pandemic.  HPM’s James Valentine and Larry Bauer helped the Hepatitis B Foundation in the planning and leading of this meeting.  On the day of the meeting, James was the meeting moderator, working from a local studio, and Larry gave a virtual meeting summary.

    Since the success of that meeting, there have been three additional meetings for people living with Hypertrophic Cardiomyopathy (HCM); Facioscapulohumeral Muscular Dystrophy (FSHD); and, most recently, Pompe disease.  Today the National Kidney Foundation in partnership with NephCure hosts the fifth virtual meeting of its kind.  HPM helped in the planning and moderation of all these meetings.

    Leveraging HPM’s Longstanding Experience with PFDD

    PFDD meetings were a 2012 initiative originally conceived and sponsored by FDA to try to more systematically capture patients’ voices regarding their disease symptoms, the impacts of those symptoms on daily life, their current treatments, and their wishes for future treatments.  The goal of the meetings was to hear from patients and their caregivers to better incorporate their wishes and ideas throughout the drug development life cycle.  Information from these meetings is a valuable tool aiding FDA review staff when reviewing new drugs and treatments.  Part of each review is an evaluation of the potential benefits and risks from a new treatment.  Having direct patient input helps ensure that patients’ needs and wants are being considered.

    James and Larry were both working at FDA at the time of the creation of this program. James served as a patient liaison, helping create and launch the PFDD program, and Larry served on several FDA panels at these meetings on behalf of the Rare Diseases Program.

    Several years of success with these meetings followed; then, after conducting 24 such internal meetings, FDA decided to share the responsibility for PFDD meetings with patient organizations.  They encouraged interested groups to plan and conduct “externally-led” PFDD meetings with support from FDA.  These meetings typically follow a similar format to the original FDA meetings and result in a publicly available Voice of the Patient document that summarizes the meeting.

    The first externally-led meeting took place in November of 2015 and was for people with Amyloidosis.  Since then, there have been meetings for a variety of conditions, both common and rare, including Spinal Muscle Atrophy, Friedreich’s Ataxia, Barth Syndrome, Cystic Fibrosis, and others.  HPM has been very active in planning many of these meetings, aided in 27 out of 37 meetings (73%), and moderated all but one of those meetings (see a complete listing in table at end of post).  In addition to James and Larry, other HPM colleagues bring their regulatory expertise to aid in organizing these meetings (e.g., Frank Sasinowski helped organize the EL-PFDD meetings on epidermolysis bullosa and pachyonychia congenita).  This extensive experience with PFDD meetings, both FDA- and externally-led, was leveraged to reimagine the virtual PFDD format when confronted with the COVID-19 pandemic.

    Adapting the PFDD meeting format to a virtual environment

    When we first considered shifting EL-PFDD meetings to a virtual format, there were many questions and doubts.  Would the meeting have the same impact? Would FDA attend virtually? How would we manage all the technical aspects of having a virtual meeting? How would we deal with any kind of technical failures on the day of the meeting? Would the virtual meetings be as interesting as in-person meetings? A virtual meeting format was not entirely new to the HPM team.  On October 29, 2018, the Cystic Fibrosis (CF) community held an EL-PFDD meeting for their community with help in planning and moderating from James Valentine.  Due to the nature of CF and the potential for cross-infection between patients, it was decided that the patients would call into the meeting.  A tele-townhall style approach allowed the moderator and meeting attendees to engage with remote patients from an in-person style meeting.  This experimental hybrid meeting format was very successful and critical for this community.

    As the COVID-19 pandemic took ever greater hold on the country, it became clear that future EL-PFDD meetings would have to shift to virtual if the meetings were going to continue.  The Hepatitis B Foundation was the brave patient advocacy organization that decided to test the waters and planned a meeting for June 2020.  The Foundation enlisted the help of HPM as well as the media firm Dudley Digital Works to plan and produce the meeting.  When considering having a meeting, the Hepatitis B Foundation had these thoughts:

    We have only a limited understanding of the broad impact of chronic hepatitis B on affected individuals,” states Dr. Chari Cohen, DrPH, MPH, Senior Vice President of the Hepatitis B Foundation.  “Many aspects of the disease, including the experiences of living with and being treated for chronic hepatitis B infection, have not been formally captured in clinical trials or public health studies.

    The new virtual format gradually evolved.  It was decided that the patient panelists would pre-record their 5-minute statements to avoid any possibility of technical failure on the day of the meeting.  It also gave them the opportunity to practice their statements to ensure the best video quality.  For the first meeting, moderator James Valentine, was live in the Dudley Digital studio behind a desk to create the feeling of a news feature program.  For the subsequent meetings, James has had a co-host who was a representative from the patient advocacy community to provide additional commentary and moderate written comments.

    Communication with attendees was key.  This was primarily done through an enhanced landing page for attendees to register in advance and get information about how to access the meeting on the day of the event.  This helped capture information about who was watching and participating in the meeting.  Live polling of participants was very similar to in-person meetings with patients and caregivers being asked polling questions by the moderator and then responding from their cell phones or other web-enabled device to give feedback in real time.

    One of the biggest differences between in-person and virtual meetings was in how meeting attendees could participate in the live discussion part of the meeting.  During in-person meetings, the moderator asks questions and walks around the room with a microphone and people raise their hands to contribute to the meeting.

    In a virtual meeting, there were now three possible ways of getting attendee feedback.  The first was through a panel of five pre-chosen people with the specific disease or condition that were all participating simultaneously in a Zoom call.  We called these people ‘discussion starters,’ since the moderator could ask them specific questions related to the discussion topic while waiting for callers to enter the queue.  The second way to participate was through emailed, written comments.  Participants could respond to the moderator’s questions by sending in an email with their thoughts and responses.  The third way of participating was through calling into a call center that took calls in real time.  James could call on people by name and ask them to respond to the discussion question.  These meetings really feel like a documentary style news show with a variety of inputs including photographs and videos to be shown during patient testimony.  Many FDA staff have attended these meeting virtually, and each meeting has had an FDA representative give opening remarks.  The FDA’s Patient-Focused Drug Development Program staff in CDER were very helpful in guiding the planning of these meetings.

    This new virtual format has gone extremely well and put most of our doubts to rest.  Not unlike the in-person meetings, there have been few technical glitches, but the meetings have generally gone smoothly.  Some of the lessons learned have been to start planning early, make sure there are a lot of visuals to hold viewers’ attention, have the planning team communicate regularly, and to have two live meeting hosts instead of just one to balance the increased number of live inputs.

    Parting Thoughts

    COVID-19, unfortunately does not have any signs of going away soon.  It looks like virtual EL-PFDD meetings are the way for at least the near future and may remain a valuable option for patient communities that may have difficulty traveling or have other health risks.

    We look forward to today’s meeting and continuing to develop the virtual format to make it even better. In fact, several organizations are already planning meetings for the coming months.

    Table: 37 Externally-led PFDD meetings held to date (unofficial count)

    DiseasePatient OrganizationDate
    Amyloidosis*Amyloidosis Research ConsortiumNovember 15, 2015

    (prior to FDA guidelines)

    Myotonic Dystrophy*Myotonic Dystrophy FoundationSeptember 15, 2016
    Acute PorphyriasAmerican Porphyria FoundationMarch 1, 2017
    OsteoarthritisArthritis FoundationMarch 8, 2017
    Spinal Muscular Atrophy*Cure SMAApril 18, 2017
    Friedreich’s Ataxia*FA Research AllianceJune 2, 2017
    Tuberous Sclerosis (& LAM)*Tuberous Sclerosis AllianceJune 21, 2017
    C3G, a rare kidney disease*National Kidney FoundationAugust 4, 2017
    Lupus*LADA, LFA, & LRFSeptember 25, 2017
    HyperhidrosisInternational Hyperhidrosis SocietyNovember 13, 2017
    Duchenne Muscular DystrophyParent Project Muscular DystrophyMarch 5, 2018
    Hypereosinophilic SyndromesAm. Partnership for Eosinophilic DisordersMarch 23, 2018
    Pachyonychia Congenita*PC ProjectApril 6, 2018
    Epidermolysis Bullosa*debra of AmericaApril 6, 2018
    Sleep ApneaAmerican Sleep Apnea AssociationJune 8, 2018
    Barth Syndrome*Barth Syndrome FoundationJuly 18, 2018
    Juvenile Idiopathic ArthritisArthritis Foundation; CARRAAugust 2, 2018
    Alport Syndrome*National Kidney FoundationAugust 3, 2018
    Chemotherapy-induced hearing loss in pediatric cancers*Children’s Cause for Cancer AdvocacySeptember 13, 2018
    CMT & inherited neuropathies*Hereditary Neuropathy FoundationSeptember 28, 2018
    Chronic hypophosphatemias*XLH NetworkOctober 5, 2018
    Cystic Fibrosis*Cystic Fibrosis Research, Inc.October 29, 2018
    Major Depressive DisorderDepression and Bipolar Support AllianceNovember 16, 2018
    Niemann-Pick Type CAra Parseghian Medical Research FundMarch 18, 2019
    Mitochondrial Diseases*United Mitochondrial Disease FoundationMarch 29, 2019
    IgA Nephropathy*National Kidney FoundationAugust 19, 2019
    Myeloproliferative Neoplasms (MPN)*MPN Research FoundationSeptember 16, 2019
    Pyruvate Kinase Deficiency (PKD)*NORDSeptember 20, 2019
    Atopic Dermatitis*National Eczema Association

    Asthma & Allergy Foundation of America

    September 23, 2019
    CDKL5 Deficiency Disorder (CDD)*LouLou FoundationNovember 1, 2019
    Lennox-Gastaut SyndromeLGS FoundationNovember 1, 2019
    Pancreatitis*National Pancreas FoundationMarch 3, 2020
    Chronic Hepatitis B*Hepatitis B FoundationJune 9, 2020
    Adult Hypertrophic Cardiomyopathy*Hypertrophic Cardiomyopathy AssociationJune 26, 2020
    Facioscapulohumeral Muscular Dystrophy*FSHD SocietyJune 29, 2020
    Pompe Disease*Muscular Dystrophy AssociationJuly 13, 2020
    Focal segmental glomerulosclerosis (FSGS)*National Kidney FoundationAugust 28, 2020

    *Meetings HPM helped plan.  Aided with VOP report only.

    2 Become 1: MAPP on Consolidation of ANDAs

    Every so often, FDA revisits a policy set forth in FDA’s Manual of Policy and Procedures (“MAPP”) to reflect the Agency’s current practices.  Though MAPPs really only govern the actions of the Agency, their content is important to understanding how FDA will approach certain requests.  For example, FDA’s MAPP 5240.3, “Priority of Original ANDAs, Amendments, and Supplements,” sets forth the Office of Generic Drugs’ approach to Priority Review, which allows sponsors to understand when its ANDA or supplement may qualify for such Priority Review.  Last week, FDA revised MAPP 5241.2 , Consolidation of ANDAs by the Office of Generic Drugs (“OGD”), which, along with insights into FDA’s considerations when a sponsor requests to consolidate ANDAs, provides an important reminder that sponsors should be aware of and considering consolidation ANDAs when possible.

    MAPP 5241.2 explains that, historically, ANDA applicants would submit separate, original ANDAs for each strength of a generic drug for which the sponsor sought approval, resulting in multiple ANDA numbers for different strengths of the same drug product.  For a variety of reasons, including streamlining the postmarketing or transfer of ownership requirements, a sponsor might want to consolidate its ANDAs for different strength of the same product into one “parent” ANDA.  The parent ANDA is typically the ANDA for the strength used in bioequivalence testing and serves as the basis for bioequivalence waivers for the other strengths.  In such an instance, the sponsor submits a consolidation request, including information on the formulations of all ANDAs applicable to the requests, all listed drugs referenced, and all bioequivalence studies and bioequivalence waivers received, as well as a copy of the consolidation request as correspondence to each ANDA identified in the request.  Once a consolidation request is approved, the sponsor only needs to submit a Prior Approval Supplement or a Changes Being Effected supplement to implement the consolidation.  MAPP 5241.2 does little to impact this process other than removing a requirement to identify all inactive ingredients in the product formulations.

    While consolidation of ANDAs may not seem significant on its face, it is an important tool in managing user fee assessments.  Under the Generic Drug User Fee Act, sponsors must pay annual program fees based on the number of separate ANDAs held as of the fee due date, October 1 of each fiscal year.  A small business program fee is assessed for each entity, including its affiliates, that holds between 1 and 5 ANDAs; an entity that owns between 6 and 19 ANDAs is assessed a medium size operation generic drug applicant program fee; and an entity that owns 20 or more ANDAs is assessed a large size operation generic drug applicant program fee.  The small business program fee is equal to one-tenth of the large size operation generic drug applicant fee while a medium size is equal to two-fifths of the large size.  Consolidating ANDAs can help reduce the number of ANDAs that are considered in the calculation of the GDUFA program fee.

    As FDA explains on its GDUFA website, ANDA consolidation requests approved by October 1 can affect the program fee tier assessed:  a jump from the “medium size” program down to the “small size” – a reduction in ANDAs from 6 to 5 – could save a sponsor $500,000, and a jump from “large size” down to “medium” – 20 to 19 – can save a company over $900,000.  But the catch is that the consolidation request must be approved by October 1.  As FDA explains “if a company has 6 approved ANDAs and requests a consolidation of 2 ANDAs into 1, but the Office of Generic Drugs does not grant the consolidation request until after October 1, 2020, then the company’s tier would remain medium tier for FY 2021. (total remains 6 ANDAs).”  That’s $500,000 that a sponsor need not pay if it were just to consolidate its ANDAs in a timely fashion.  As such, MAPP 5241. 2 serves as a timely reminder as we approach the fall that companies considering consolidating ANDAs in an effort to address program fee assessments should get those requests in now!

    FDA, Testing, and COVID-19: A “Mid-Mortem”

    From the start of the COVID-19 pandemic, access to accurate and reliable testing to identify patients exposed to SARS-CoV-2 or infected with COVID-19 was identified as a critical element of an effective public health response.  Testing is needed to diagnose individuals with active symptoms, enable early identification (through contact tracing) and quarantine of individuals who may have been exposed, and determine whether an individual has developed antibodies to the disease.  And as we head into the Fall, testing is becoming integral to schools and universities seeking to safely resume in-person instruction, and to the health and safety of employees as they return to work.

    The Food and Drug Administration (FDA) is the government agency that has played the most pivotal role in determining what tests have been available in the United States.  Unfortunately, the issue of testing has too often been politicized, which has impeded a nuanced, rational assessment of FDA’s regulatory efforts and the extent to which FDA has succeeded in, on the one hand, facilitating widespread and timely access to accurate and reliable tests, while on the other, preventing poor quality tests from being disseminated.

    Although “post-mortems” are typically performed at the end of a project, the COVID-19 pandemic appears to be poised to continue for the foreseeable future.  This makes it all the more important to evaluate FDA’s response to date and to recommend any “mid-course corrections” that could improve the agency’s response during the pendency of this pandemic . . . let alone any future ones that may arise.  The list below is anything but exhaustive, but we believe it includes the key areas for improvement.

    As FDA regulatory practitioners who have worked with multiple companies trying to introduce COVID-19 tests, we have witnessed first-hand both the challenges faced by companies seeking to bring new tests to the market and the pernicious impact of “bad actors.”  With the end of summer approaching and states experimenting with “back to work” and “back to school” programs, this is an opportune time to reflect on the past five months and identify key lessons for regulators, policy makers, and the regulated industry, which we hope can inform the process going forward.

    Primum non nocere – First, do no harm

    The lack of adequate testing at the outset of the pandemic can be directly linked to FDA’s controversial laboratory-developed test (LDT) policy, which several FDA Law Blog contributors have addressed on numerous occasions.  See J. Gibbs, M. Cato & S. Schlanger, New FDA Policy Significantly Limits Serological Testing, FDA Law Blog (Apr. 13, 2020); J. Valentine, D. Clissold, & J. Shapiro, FDA Works Around the Clock, Provides More Detailed Guidance on the Conduct of Clinical Trials Amidst the COVID-19 Pandemic, FDA Law Blog (Apr. 1, 2020).  In short, FDA asserts jurisdiction to regulate clinical laboratory tests, but in most cases exercises “enforcement discretion,” allowing clinical laboratories to innovate and respond quickly to emerging clinical needs.  However, FDA did not elect to exercise general enforcement discretion for COVID-19 LDTs, meaning that clinical laboratories other than CDC were not permitted to offer testing for SARS-CoV-2 without prior authorization from FDA, either through an Emergency Use Authorization (EUA) or pursuant to an applicable FDA COVID-19 enforcement policy.  As was widely reported, CDC’s test – notwithstanding FDA authorization – had significant performance issues, but FDA’s prohibition on offering LDTs without FDA authorization meant there were no alternatives available for several crucial weeks at the beginning of the outbreak in the U.S.  Laboratories were ready, willing, and able to offer LDTs, but were blocked by FDA’s policy.  Michael Shear et al., The Lost Month: How a Failure to Test Blinded the U.S. to Covid-19, N.Y. Times, Mar. 28, 2020.

    FDA’s jurisdiction to regulate LDTs under the medical device provisions of the Federal Food, Drug, and Cosmetic Act (FD&C Act) has long been the subject of debate but has not yet been subject to legal challenge.  In a recent Yale Law Journal Forum essay, Barbara Evans and Ellen Wright Clayton present an additional jurisdictional argument based on Section 564 of the FD&C Act, which addresses FDA’s EUA authority specifically, and which FDA cited in guidance as the source for its authority to require clinical laboratories to obtain EUAs.  Barbara Evans & Ellen Wright Clayton, Deadly Delay: The FDA’s Role in America’s COVID-Testing Debacle, 130 Yale Law J Forum 78 (2020).  As Evans and Clayton note, Section 564 allows FDA to grant EUAs only for medical “products,” defined as drugs, devices, and biological products, but “grants no new powers for the FDA to regulate clinical laboratory services.”  Id. at 80.  Indeed, they note that the only mention of clinical laboratories under Section 564 occurs in the context of FDA’s authority to categorize the complexity of a “laboratory examination or procedure associated with such device.” Id.; FD&C Act § 564(m)(1).  By drawing a distinction between “laboratory examinations or procedures” that are not subject to Section 564 and “products,” which are subject to Section 564, the statutory language makes FDA’s assertion of jurisdiction to require EUAs for clinical laboratory tests highly suspect.

    In any event, FDA’s decision to prevent LDTs for SARS-CoV-2 testing was not dictated by decisions by the prior administration.  FDA did not have to prevent labs from running samples for SARS-CoV-2 using their LDTs.  FDA chose to take that approach.

    In short, FDA’s decision not to exercise enforcement discretion for use of LDTs for SARS-CoV-2 significantly delayed the availability of accurate and reliable tests.  The adverse consequences of FDA regulation of LDTs in the time of a pandemic was foreseeable.  This is not a case of hindsight is 20/20 – the need for LDTs during disease outbreaks had been foreseen in comments to FDA criticizing past FDA efforts to limit LDTs.  See, e.g., American Clinical Laboratory Association, Citizen Petition, Docket No. FDA-2013-P-0667-0001 (Jun. 17, 2013) at 15-16 (noting that LDTs allow for real-time response to emergent infectious diseases that is critical to the welfare of patients and the public health and that requiring FDA marketing authorization under such circumstances could have “potentially catastrophic consequences”).

    Remarkably, on August 19, 2020, the Department of Health and Human Services (HHS) issued a statement announcing that FDA could not regulate any LDTs – including those for SARS-CoV-2 – without first going through rulemaking (see our blog post here).  The HHS notice specifically stated that this position meant that laboratories did not need EUAs to offer LDTs.  As a consequence of this announcement, FDA’s policy requiring laboratories to obtain EUAs for LDTs for SARS-CoV-2 has been overridden.  This move, of course, cannot cure the damage caused by testing delays at the beginning of the pandemic.  But moving forward, laboratories will have significantly more flexibility to quickly offer appropriately validated LDTs for SARS-CoV-2 without FDA authorization as a rate-limiting step.

    Measure twice, cut once – The law of unintended consequences

    FDA’s requirements for serology (antibody) tests have changed multiple times in the space of a few short months.  We understand that FDA has needed to make changes to the regulatory requirements for serology tests as it learns more about the quality of the tests on the market and the data supporting their use, but making changes also imposes costs and confusion.  The lack of regulatory predictability has complicated matters for reviewers and companies.

    Initially, FDA announced that manufacturers of serology tests could begin marketing their tests without an EUA, so long as they had appropriate analytical and clinical test validation data on file and submitted a “notification” to FDA of their intent to distribute.  FDA, Guidance for Clinical Laboratories, Commercial Manufacturers, and FDA Staff, Policy for Diagnostic Tests for Coronavirus Disease-2019 during the Public Health Emergency, at 1 (Mar. 2020).  Companies rushed to validate their tests according to FDA’s recommendations and put distribution networks in place.

    FDA then abruptly shifted its notification policy in May, announcing that all serology test manufacturers would first need to prepare and submit an EUA, but could continue distribution pending FDA review.  FDA, Guidance for Clinical Laboratories, Commercial Manufacturers, and FDA Staff, Policy for Coronavirus Disease-2019 Tests During the Public Health Emergency (Revised) (May 2020).  FDA distributed a “template” EUA request disclosing the data required to be included in the submission.  Again, industry raced to meet the new requirements, since the penalty for not submitting an EUA by the stated deadline was to be placed on the list of companies not permitted to distribute in the U.S.  FDA was giving companies as little as 24 hours to respond to agency interactive review questions.

    FDA explained the change in policy was due in part to the improper promotional claims that companies made, as well as changes in understanding of the benefits and risks.  The document did not mention another factor that undoubtedly played a role: FDA was roundly criticized in the press and by Members of Congress for allowing serology test kits onto the market that it had not reviewed, some with low or inconsistent performance.  (While LDTs typically are not reviewed by FDA before being introduced, serology tests for new analytes ordinarily do require FDA review before commercial distribution.)  See Laurie McGinley, Dozens of coronavirus antibody tests on the market were never vetted by the FDA, leading to accuracy concerns, Washington Post, Apr. 19, 2020; Zachary Brennan & David Lim, FDA pushed through scores of inaccurate antibody tests without agency review, Politico, Apr. 27, 2020; Thomas Burton, FDA Sets Standards for Coronavirus Antibody Tests in Crackdown on Fraud, Wall Street J, May 4, 2020.

    While some reviewers, particularly in in the March-May timeframe, responded rapidly and substantively to serology EUA submissions, the collaborative nature of the interactions deteriorated, and response time and quality of reviews varied widely between submissions.  Some EUAs were issued fairly quickly, while others languished for weeks or months.  Eventually, FDA seemed to be overwhelmed by the influx of EUA submissions and would frequently reference its large “backlog” in submissions when companies requested status updates on FDA’s review of their EUA request.

    FDA also at some point made an internal decision to “deprioritize” serology tests, but this decision was never publicly announced or acknowledged.  FDA’s stated public rationale was that since, under the revised May policy, companies were permitted to begin distribution of their serology tests while the EUA submission was under review, FDA action on the EUA really was not that important, and FDA’s resources could be better utilized.  This perspective, though, ignored the real-world impact of lack of an EUA: in many cases, the product is not commercially viable without an EUA authorization because some customers (e.g., state governments and hospital systems) preferred to purchase tests that had completed the FDA review process.

    By design or inadvertently, FDA created two distinct marketplaces: some tests were being sold pursuant to FDA’s revised policy, which allowed distribution during the pendency of FDA’s review, while others had an EUA.  Another disadvantage to distribution of a test without an EUA is that there is a question of whether a test sold while an EUA request is under review, and not yet authorized, enjoys the strong liability protection available under the PREP Act, which is unquestionably available for tests that have an EUA.  See HHS, Advisory Opinion on the Public Readiness and Emergency Preparedness Act and the March 10, 2020 Declaration Under the Act, April 17, 2020 as modified on May 19, 2020.

    Transparency and Communication are Key

    The failure to acknowledge changes in review priorities is only one of many instances in which FDA has not clearly communicated with regulated industry.  The examples below are by no means exhaustive:

    • “Point-of-Care” serology tests: As noted above, FDA’s initial policy for COVID-19 tests allowed serology tests to be marketed pursuant to a notification only without prior FDA authorization. FDA’s written policy stated that such tests were intended for use by clinical laboratories and health care providers “at the point of care.”  On its face, this appeared to allow the tests to be sold to and used in point-of-care settings, such as doctors’ offices and drive-through testing facilities.  It made sense for this policy to apply to point-of-care health care settings, as these are the settings most suited to the use of these simple, rapid serological tests.  This interpretation would also have been consistent with broader access to tests.  However, in order for these tests to be used by non-laboratorians outside of a CLIA-certified clinical laboratory, FDA must classify them as “CLIA waived.”  Many readers of FDA’s policy reasonably inferred that FDA must mean these tests were CLIA waived, because that was the only way providers “at the point of care” could actually use them.  Nevertheless, FDA later issued an “FAQ” on its website stating that, in fact, the tests were not waived, and that manufacturers would need to conduct additional studies demonstrating that their tests could safely be used at the point of care and receive an EUA in order to market them to anyone other than a CLIA “high complexity” laboratory.  See Gibbs, M. Cato & S. Schlanger, New FDA Policy Significantly Limits Serological Testing, FDA Law Blog (Apr. 13, 2020).  Following this clarification, companies were forced to quickly cease distribution for point-of-care use and revise labeling and marketing materials to note the tests’ high-complexity status.  Companies that did not notice the clarification on FDA’s website continued distribution for point-of-care use.  There were several points in the process where FDA could have avoided the significant confusion over this issue. Procedurally, FDA’s delay allowed confusion to continue.  Substantively, FDA’s decision meant that tests could not be run at many sites where they would have been most useful.  FDA’s decision also directly clashed with a policy from the Centers for Medicare & Medicaid Services issued almost at the same time that permitted testing at pharmacies, which was not at the time possible because FDA has not yet authorized any serological tests for point-of-care use.
    • NCI testing pathway: On April 28, 2020, FDA issued an umbrella EUA, which was described as a “voluntary” program under which manufacturers could, at no cost, submit their tests to the National Cancer Institute for validation testing rather than conducting independent clinical validation testing and submitting an individual EUA. If the validation testing conducted by NCI showed that the test met minimum performance standards outlined by FDA, the test was authorized under the umbrella EUA.  This process was described by FDA as designed to cut down on FDA’s review burden, because FDA would not have to perform in-depth reviews of individual EUA submissions.  The NCI test data (whether favorable or unfavorable) would be made publicly available.

    While in concept this plan had merit – creating a central, standardized U.S. testing site in which FDA had confidence and for which manufacturers did not have to incur expense – the execution of the program was anything but smooth.  Companies that volunteered to have their tests evaluated by NCI were given priority in the form of continued communication with FDA.  NCI quickly (and foreseeably) became inundated with testing requests, and manufacturers experienced long delays for their results.

    At the same time, many companies chose not to pursue the “voluntary” NCI pathway (e.g., in favor of using a commercial testing laboratory).  There were some limitations to the umbrella EUA; for example, it only allowed for authorization for use in moderate- or high-complexity CLIA laboratories.  If companies wanted to pursue a point-of-care authorization, an individual EUA was required.  However, even though companies submitted robust clinical validation studies with their individual EUA, some were told by reviewers that they would need to submit test kits to NCI for testing to “confirm” their clinical validation results in order to obtain an EUA, while others found their EUAs inexplicably stalled while reviewers inquired repeatedly whether their tests had been submitted to NCI.  The de facto requirement to obtain NCI testing was never publicly announced or acknowledged, and companies were confused by requests to submit test kits to NCI for testing when they had not elected the umbrella pathway.

    Gating the review of serology tests through the NCI, which apparently stemmed from a lack of trust in data submitted by device manufacturers, has caused another host of problems for companies.  It was the expectation of FDA that the data generated by NCI would be consistent with the other data provided in the submission.  However, NCI data do not necessarily reflect performance in the field.  NCI uses a curated panel of specimens that, because of small sample size and limited range of titers, is not necessarily consistent with what might be observed in the real-world when evaluating “all-comers” as part of a clinical study.  The test report provided by NCI acknowledges these limitations, stating that the “[s]ensitivity and specificity estimates in this report may not be indicative of the real-world performance of the [Company] [Device Name].”  The report explains that the NCI results are “based on serum and plasma samples only and may not be indicative of performance with other sample types, such as whole blood, including finger stick blood.”  Additionally, the report states that the “number of samples in the panel is a minimally viable sample size that still provides reasonable estimates and confidence intervals for test performance, and the samples used may not be representative of the antibody profile observed in patient populations.”  Notwithstanding these acknowledged limitations by NCI, FDA has in practice treated NCI results as determinative and has rejected EUAs based on NCI data that failed to meet FDA’s threshold for sensitivity, even if the NCI test results conflicted with other data submitted by the manufacturer, often using much larger sample sizes compared to NCI testing.

    • Revocation of NCI umbrella EUA: Three months after announcing the “umbrella” pathway, on July 21, 2020, FDA announced without warning that the umbrella EUA was being revoked. (FDA explained that nobody had actually used this pathway it had created.  This was only partially true; many tests were in the pipeline awaiting authorization under the umbrella policy, but FDA not yet authorized any tests.)  FDA couched the decision as solely “administrative” in nature, but the implications of its actions seemed potentially far reaching, leaving applicants who had pursued the NCI testing pathway uncertain over the fate of their submissions and concerned about whether they needed to undertake costly independent clinical validation.  It took several days and multiple emails to regulators to clarify that pending submissions would not be adversely affected by the change.  This confusion could have been avoided had FDA more clearly communicated what the change meant.
    • Lack of industry input: FDA has three main resources for manufacturers looking to validate serology tests: “Policy for Coronavirus Disease-2019 Tests During the Public Health Emergency (Revised) Immediately in Effect Guidance for Clinical Laboratories, Commercial Manufacturers, and Food and Drug Administration Staff” (May 11, 2020); FAQs on Testing for SARS-CoV-2; and the Serology Template for Commercial Manufacturers. None of these resources mention FDA’s data expectations regarding shelf-life claims for EUAs. As it turns out, FDA will not accept the standard practice of providing accelerated aging studies that validate the full claimed shelf-life with real-time testing to be conducted post authorization.  Companies need real-time data in their EUAs, or they may find that they are left with a short-term shelf-life claim that presents commercial challenges or renders the product commercially non-viable.

    This specific example highlights another problem: the lack of industry input.  Under ordinary circumstances, FDA would be issuing draft guidances and receiving feedback from stakeholders.  The lack of a mechanism to receive comments has meant that FDA has been deprived of a critical outside perspective.  FDA may know what it is trying to communicate in its policies and FAQs, but sometimes it is not clear to the outside world.  For example, one of FDA’s early guidance documents referred to “at home” testing.  The ambiguous phrasing led companies reasonably to conclude that FDA’s policy applied to tests conducted at the home, not samples obtained from the home.  FDA then criticized companies for providing products where samples were collected at home, even though FDA’s phrasing was unclear.

    • Delays in providing guidelines on data expectations: While there have been occasions where FDA has been quick to provide feedback and clarifications to industry, such as through its list of FAQs and weekly “virtual town halls,” there have been occasions where FDA has been slow to provide public guidance on expectations for data supporting EUAs.  For example, for a period of about two months, FDA promised an EUA template for home testing “very soon” or by the “end of the week.”  Some companies delayed submission of EUAs for home tests, fearing that FDA would release a template with new requirements shortly after submission of an EUA application.  Similarly, following FDA’s clarification that an EUA was required to distribute a serology test for point-of-care use, companies requested information from FDA on the expectations for usability and flex studies.  FDA did not add these data expectations to the serology test EUA template until weeks later, but in the meantime, provided the usability and flex study expectations to companies individually upon request, leaving companies who did not know to request these guidelines at a disadvantage.  Given the unprecedented volume of work, we understand that developing these guidance documents and FAQs will take time.  It is important, however, for FDA to provide realistic estimates as to when these documents will be released.

    Dirty Harry had it right – An agency’s “got to know its limitations”

    During the early months of the pandemic, interactions between reviewers and test developers were, on the whole, collaborative and communicative.  Sadly, as the pandemic has dragged on to new heights, this situation has changed. Many companies have had their questions go unanswered by FDA for months. We at HPM have never had so many companies so frustrated by the lack of agency feedback.  Multiple companies have reported sitting in a queue for months, with no visible progress and no meaningful communications with FDA.  That same frustration clearly comes through in some of the calls to the weekly virtual town hall meeting on diagnostics.

    The reduction in collaborative discourse can be attributed in large measure to a sharp spike in submission volume for CDRH.  We are well aware that the agency has never faced such an onslaught of submissions.  We are sympathetic to the challenges FDA faces, not just with diagnostics but also with other pandemic-related products (e.g., vaccines, drugs, personal protective equipment, hand sanitizer).

    Even so, this lack of interaction has had a crippling impact on companies pursuing EUAs.  The regulatory landscape is still changing rapidly, and these changes are not always followed with appropriate communications by the Agency. And as applications languish, FDA’s standards can change, dooming companies whose submissions met the standards that had been in place at the time of submission. When emails are sent to FDA requesting updates on the status of a review one is very likely to hear nothing, or to receive this boilerplate response: “We appreciate your patience during this time.  Unfortunately, we are not able to provide estimates of review timelines.”  While the U.S. suffers from a shortage of tests, companies that raced to develop and validate tests are left in regulatory limbo.

    Again, this outcome was completely foreseeable.  FDA has received thousands of EUA requests since March – the equivalent of several years of work compressed into mere months.  Doing the math, it is physically impossible for FDA, with current staffing levels, to review these submissions in anywhere close to a timely manner.  Although FDA has not (and will not, we expect) publicly admit its capacity constraints, the reality is that some submissions will not get reviewed, and some products will not receive authorization because there are simply not enough people to do the work.

    However, FDA’s failure to acknowledge limitations in its capacity has significant adverse commercial consequences for test developers and public health consequences.  It also has created distrust and disillusionment.  For a number of companies, this has been their first experience with FDA – and it has not been a favorable one.

    Companies whose products have been rejected or criticized by FDA are also frustrated by their FDA interactions.  There is a recurring pattern reported by companies caught in these situations: that FDA has made up its mind and will not listen to any other perspective, and that when FDA communicates publicly its conclusions, the agency fails to provide the necessary context.  Once again, the result is a recurring perception that FDA has acted unfairly.

    Those Who Fail to Learn History Are Doomed to Repeat It

    This will almost certainly not be the last major outbreak of an infectious disease.  As Evans and Clayton note, “[w]hile nothing will buy back time already lost, the COVID-19 outbreak casts a useful light on flaws in recent laboratory-testing policy. . . . Lessons from the current pandemic might still help us in the next one.”  It is critical that a thorough, non-partisan, scientifically-based and objective review of FDA’s handling of COVID-19 testing be conducted to evaluate what went right and what needs to be improved.  FDA and all stakeholders need to learn from these experiences so that we are all more prepared.

    Lawsuit Challenges USDA’s BE Labeling Rule

    On July 27, 2020, the Natural Grocers, Citizens for GMO Labeling, Label GMOs, Rural Vermont, Good Earth Natural Foods, Puget Consumers Co-op, and the Center for Food Safety (“Plaintiffs”) filed a complaint against USDA challenging the final “BE labeling rule,” i.e., the final rule implementing the National Bioengineered Food Disclosure Standard (NBFDS).  According to Plaintiffs, the final BE labeling rule fails to provide meaningful labeling of, what Plaintiffs call, genetically engineered (GE) foods.   They allege that USDA “fell far short of fulfilling the promise of meaningful labeling of GE foods [and] in many ways, the [rule results] . . . in the direct or de facto concealment of these foods and avoidance of their labeling.”

    As readers of our blog know, Plaintiffs have been fighting for mandatory disclosure of the presence or use of genetically engineered ingredients in food for many years.  Congress passed the NBFDS in 2016 after several states had passed and several other states were poised to pass laws mandating certain statements on foods that were manufactured from or with the use of genetic engineering.  The Agricultural Marketing Service (AMS) of the USDA was tasked with the implementation of the law.   The final rule, setting a compliance date of Jan. 1, 2022, was issued in 2018.  (see our blog post here)

    Plaintiffs take issue with various aspects of the final regulation.

    1. The option of using a QR code only (i.e., without requiring additional on-package labeling) as method of disclosure. Plaintiffs allege that a study commissioned by AMS showed that it is not realistic to have customers scan barcodes for dozens of products in the store and the QR code would discriminate against people with lower smartphone ownership, with no or low ability to afford data, and people living in areas without general access to internet with the required bandwidth, i.e., the poor, elderly, rural and minorities.  According to Plaintiffs, AMS ignored the  study results and decided to allow the QR code as a method of disclosure anyway.
    2. The terminology used in the disclosure language . Congress used the new term “bioengineered” in the NBFDS.  However, Plaintiffs allege that NBFDS instructed USDA to also include “any similar term” in its new standard.  Nevertheless, the final rule prohibits the terms “genetically engineered” and “GMO,” on the label.  Plaintiffs allege that AMS’s decision was arbitrary and capricious and in contradiction to the plain language of the law.  According to Plaintiffs the use of “bioengineered” rather than “genetically engineered,”  or “GMO” will confuse and mislead consumers because for many decades, consumers, federal agencies, scientists and the marketplace have used the terms “genetically engineered” and “GMO.”
    3. The application of mandatory disclosure to foods that contain detectable modified genetic material only. Not surprisingly, Plaintiffs assert that the final rule is too limited because the mandatory disclosure applies only to foods that contain detectable modified genetic material and excludes highly refined products which do not contain any detectable modified genetic material.  As we reported previously, AMS considered the language of the definition of BE in the NBFDS and concluded that the term BE foods covers only those foods that contain detectable modified genetic material.
    4. The prohibition against the voluntary use of the terms “GMO” or “genetically engineered” on BE foods. The only voluntary labeling allowed is “derived from bioengineering” and only in certain circumstances.  Plaintiffs argue that this limitation is unconstitutional because “[m]anufacturers and retailers have a fundamental 1st Amendment Right to provide truthful commercial information to consumers, and consumers have a right to receive it.”  Therefore,  prohibiting manufacturers and retailers from labeling foods as produced through genetic engineering or as genetically engineered “violate[s] the statute’s text and purposes as well as the 1st Amendment’s guarantees.”

    Plaintiffs ask that the Court set aside or vacate all or portions of the final rule based on AMS/USDA’s violations of the NBFDS and Administrative Procedure Act, and set aside any portions of the rule and the NBFDS that violate the 1st Amendment.