Keeping pace with the ever-changing life sciences industry, Morrison Foerster stays on top of the trends and political, legal, and economic drivers to support striking the balance between innovative discovery and purposeful business planning to assure our clients continued success. MoFo Life Sciences shares timely legal and business insights and in-depth analyses on trends and the complex technologies at the heart of the global pharmaceutical, biotechnology, diagnostics, medical devices, digital health, and AgTech fields.Learn more about our <a href="https://www.mofo.com/capabilities/life-sciences-healthcare" target="_self">Life Sciences practice</a>.<h2 dir="ltr">ABOUT MORRISON FOERSTER</h2>Morrison Foerster is a leading global law firm that transforms complexity into advantage for its clients. Our clients include some of the largest financial institutions, banks, consulting and accounting firms, and Fortune 100, technology, and life sciences companies. Highlighting the firm’s commitment to client service, leadership in market-changing deals and impact litigation, and values-based culture, Morrison Foerster has been repeatedly recognized as one of the top 10 firms on The American Lawyer’s A-List. Year after year, the firm receives significant recognition from Chambers and The Legal 500 across their various guides, including Global, USA, Asia‑Pacific, Europe, UK, Latin America, and FinTech Legal. Our lawyers passionately care about delivering legal excellence while living our values. Morrison Foerster has a long-standing commitment to creating a culture that respects and celebrates differences, while providing an inclusive environment. The firm has achieved Mansfield Certification Plus since 2018 as a result of successfully reaching at least 30 percent women, communities of color, and LGBTQ+ lawyer representation in a notable number of current leadership roles and committees. The firm also has a long history of commitment to the community and society through providing pro bono legal services, including litigating for civil rights and civil liberties, improving public education and fostering the wellbeing of children, advocating for veterans, promoting international human rights, enforcing the right to asylum, and safeguarding the environment.

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Dr. Meghan Poon counsels clients on patent preparation and prosecution, portfolio strategy, and IP due diligence in the areas of biotechnology and biologics. She has significant experience in diverse technologies including antibodies, cell therapies, gene therapies, diagnostics, and gene-edited plants. She represents clients ranging from large international pharmaceutical companies to midsized companies, startups, and universities.Meghan has filed numerous Patent Term Extension applications to secure additional term for her clients’ patents, which cover FDA-approved products. In addition, Meghan has extensive experience addressing complex obviousness-double patenting and subject matter eligibility issues impacting her clients’ patent portfolios. Meghan also represents clients in both investor-side and target-side due diligence, in deals from seed funding to initial public offerings.Prior to law school, Meghan attended graduate school at the University of California, Los Angeles, where she received a Ph.D. in biological chemistry based on her work on protein-protein and protein-DNA interactions at a molecular level. Meghan is the author of several scientific publications and has presented her research at international conferences.Meghan received her J.D. from the University of Southern California Law School and spent a year as a visiting student at Santa Clara University, where she focused on intellectual property.

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Dr. Meghan Poon counsels clients on patent preparation and prosecution, portfolio strategy, and IP due diligence in the areas of biotechnology and biologics. She has significant experience in diverse technologies including antibodies, cell therapies, gene therapies, diagnostics, and gene-edited plants.

Meghan Poon

Wolfgang advises clients on contentious and non-contentious matters involving their most valuable intellectual property assets in life sciences, digital, and high-tech industries.His subjects of focus include research and development collaborations, complex licensing agreements, and other technology transactions, as well as know-how protection strategies, and employee invention law. He also has substantial experience in litigating patents, trademarks, and other intellectual property assets, often in a multijurisdictional context. In addition, Wolfgang and his team frequently clear trademarks and ad campaigns and prosecute trademark applications.Wolfgang is co-editor of our <a href="https://lifesciences.mofo.com/" dir="ltr" target="_blank">MoFo Life Sciences Blog</a>.Wolfgang is a partner of Morrison Foerster based in our German office in Berlin.<h4 dir="ltr">Representative Transactional Matters</h4><ul dir="ltr"><li>U.S.-based BioTech fund on various research collaborations and other transactions with German start-ups or research institutions.</li><li>Negotiate multimillion-euro strategic partnership between two AgTech leaders concerning the development and commercialization of pest-resistant transgenic traits.</li><li>Craft global multi-million collaboration regarding AI-powered robotic MaaS.</li><li>UK-based digital health company on product roll-out of RPM applications in Germany; coordinate international expansion.</li><li>Advise numerous German start-ups on their U.S. expansion.</li><li>Draft diverse global patent and know-how license agreements in the areas of AgTech and life sciences—including gene licensing and licensing of genome editing technologies (e.g., CRISPR)—and medical devices; draft correlating supply and distribution agreements.</li><li>Structure IP rights in connection with joint ventures and other M&A transactions, including the carve-out of a patent-heavy semiconductor business comprising nine jurisdictions into a German–U.S. joint venture.</li><li dir="ltr">Advise on government-funded, multi-partner R&D projects and/or R&D projects with academic institutions, as well as on employee invention law.</li></ul><h4 dir="ltr">Representative Contentious IP Matters</h4><ul dir="ltr"><li>Lead counsel in an international dispute between software companies on rights and obligations following termination of a multi-million licensing and distribution arrangement; coordinate local counsel.</li><li>Defend Japanese chip manufacturer in high-profile SEP-litigation; advise on global settlement arrangement.</li><li>Represent leading internet retailer in patent infringement and concurrent invalidity proceedings in the context of a multijurisdictional dispute concerning touch-screen technology.</li><li>Represent diverse pharmaceutical and life sciences companies in national and cross-border patent infringement proceedings and other technology-related disputes, including preliminary injunctions as well as pre‑trial discovery and inspection proceedings, concerning, inter alia, drug-coating technologies, toner cartridges, medicinal gases, transgenic plants, and vaccines.</li><li dir="ltr">Conduct trademark, copyright, and false advertising litigation, including, most notably, a high-profile trademark litigation for a German bank, and a nine-country cross-border trademark litigation involving a famous pharmaceutical brand.</li></ul>

Dr. Wolfgang Schönig berät Mandanten zum Schutz des geistigen Eigentums sowohl in streitigen als auch nichtstreitigen Angelegenheiten, mit einem besonderen Fokus auf die IP-rechtliche Beratung von Unternehmen aus den Bereichen Life Sciences, Digitalwirtschaft und High-Tech.Zu seinen Beratungsschwerpunkten gehören Forschungs- und Entwicklungskooperationen, komplexe Lizenzvertragsgestaltungen und andereTechnologie-Transaktionen, sowie Know-how-Schutz-Strategien und das Arbeitnehmererfinderrecht. Er verfügt zudem über umfangreiche Prozesserfahrung zur Durchsetzung von Patenten, Marken- und anderen IP-Rechten, häufig auch in einem grenzüberschreitenden Kontext. Darüber hinaus bewertet Dr. Wolfgang Schönig zusammen mit seinem Team regelmäßig die Rechtskonformität von Werbekampagnen, prüft die Verfügbarkeit von Marken und entwickelt entsprechende Anmeldestrategien.Dr. Wolfgang Schönig ist Co-Editor des Life Sciences Blogs von Morrison Foerster.Er hat seinen Doktortitel an der Heinrich-Heine-Universität Düsseldorf und seinen LL.M. an der Fordham School of Law in New York erworben, jeweils mit Schwerpunkt im gewerblichen Rechtsschutz. Seinen MBA-Abschluss erhielt er von der European University in Barcelona.Dr. Wolfgang Schönig ist Partner des deutschen Büros von Morrison Foerster in Berlin.<h4 dir="ltr">Repräsentative Transaktionen</h4><ul><li dir="ltr">BioTech-Fonds mit Sitz in den USA bei verschiedenen Forschungskooperationen und anderen Transaktionen mit deutschen Start-ups oder Forschungseinrichtungen</li><li dir="ltr">Verhandlung einer hochvolumigen strategischen Partnerschaft zwischen zwei Technologieführern im Bereich Crop Science betreffend der Entwicklung und Kommerzialisierung von bestimmten Resistenzen</li><li dir="ltr">Gestaltung einer globalen Multi-Millionen-Zusammenarbeit für KI-gestützte Roboter</li><li dir="ltr">Ein in Großbritannien ansässiges Unternehmen für digitale Gesundheit bei der Markteinführung von RPM-Anwendungen in Deutschland; Koordination der internationalen Expansion</li><li dir="ltr">Beratung zahlreicher deutscher Start-ups bei deren US-Expansion</li><li dir="ltr">Strukturierung und Verhandlung diverser Patent- und Know-How-Lizenzen in den Bereichen Ag Tech und Life Sciences – einschließlich Fragen zu genome editing wie CRISPR-Medizingeräte, sowie Gestaltung von Softwarelizenzverträgen und Erstellung korrespondierender Liefer- und Vertriebsvereinbarungen</li><li dir="ltr">Strukturierung von IP-Rechten im Zusammenhang mit Joint Ventures und anderen M&A-Transaktionen, darunter die Koordination eines neun Länder umfassenden IP Carve-Outs im Rahmen eines Halbleiter-JVs</li><li dir="ltr">Beratung zu staatlich geförderten Multi-Partner F&E-Projekten und/oder F&E-Projekten mit akademischen Einrichtungen sowie zum Arbeitnehmererfindungsrecht</li></ul><h4 dir="ltr">Repräsentative IP-Streitigkeiten</h4><ul><li dir="ltr">Lead Counsel in einem internationalen Rechtsstreit zwischen Softwareunternehmen über Rechte und Pflichten nach Beendigung einer millionenschweren Lizenz- und Vertriebsvereinbarung; Koordinierung der lokalen Anwälte</li><li dir="ltr">Verteidigung eines japanischen Chipherstellers in einem prominenten Streitfall bezüglich Standardessentieller Patente (SEP); Beratung zu einer globalen Vergleichsregelung</li><li dir="ltr">Verteidigung einer führenden Internetplattform gegen Ansprüche eines Patenttrolls wegen vermeintlicher Verletzung von Patent bezüglich Touchscreen-Technologie sowie korrespondierende US-Streitigkeiten</li><li dir="ltr">Vertretung von Pharma- und Life Science-Unternehmen in nationalen und grenzüberschreitenden Patentverletzungsverfahren und anderen technologiebezogenen Streitigkeiten, einschließlich einstweiliger Verfügungsverfahren und vorprozessualer Beweissicherungs- und Besichtigungsverfahren, unter anderem in Bezug auf Arzneimittelbeschichtungstechnologien, Tonerkartuschen, medizinische Gase, transgene Pflanzen und Impfstoffe</li></ul>

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Wolfgang Schönig is a partner of Morrison Foerster (International) LLP based in our German office in Berlin. His practice specialty is advising on IP aspects relative to transactions in, among others, the life sciences, AgTech and pharmaceuticals industry, as well as legal representation in IP disputes. Wolfgang is specialized in research and development collaborations, complex licensing agreements, technology acquisitions, know-how protection strategies, and employee invention law.

Wolfgang Schönig focuses his practice on IP aspects relative to transactions in the digital, telecoms, high tech, life sciences, and pharmaceuticals industry, as well as legal representation in IP disputes.

Wolfgang Schönig advises clients on IP aspects relating to transactions in, among others, the life sciences, AgTech and pharmaceuticals industry, as well as legal representation in IP disputes. His additional focus areas include research and development collaborations, complex licensing agreements, technology acquisitions, know-how protection strategies, and employee invention law.

Wolfgang Schönig

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In Patent Prosecution, You Have the Right to Remain Silent. Anything You Say Can and Will Be Used Against You in the Court of Law

Federal Circuit Clarifies Requirements for Prior Art Under Pre-AIA 35 U.S.C. § 102(e)

AI Agent as a Service in Medtech: Key Considerations for Commercial Contracts

HHS Secretary to FDA: Consider Elimination of GRAS Self-affirmation Pathway

Federal Circuit Clarifies Patent Term Extension Calculation for Reissue Patents

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On March 2, 2022, FDA hosted a public Device Good Manufacturing Practice Advisory Committee meeting, where the Committee discussed the <a target="_blank" href="https://www.federalregister.gov/documents/2022/02/23/2022-03227/medical-devices-quality-system-regulation-amendments">proposed rule</a> titled "Medical Devices: Quality System Regulation Amendments."  If finalized, the proposed rule will rename the current 21 CFR Part 820 as the Quality Management System Regulation (QMSR).  In our previous <a href="https://lifesciences.mofo.com/topics/quality-management-system-regulation-qmsr--harmonizing-the-quality-system-regulation-qsr-with-iso-134852016.html">post</a>, we noted both the industry representatives and the Committee welcomed the proposed rule but agreed that it may have an overly ambitious implementation timeline, especially in light of the ambiguity in some key areas, such as inspection.  These concerns were echoed by FDA, which acknowledged the need to engage in a variety of implementation activities including personnel training, inspection approach finalization, and revising relevant regulations and other documents impacted by the rule.  Below we discuss some of the major concerns raised by both industry representatives and the Committee during the meeting.<ul><li>A one-year transition period would not give the industry sufficient time to be fully compliant with the new requirements.  QMSR proposes a one-year transition time after the final rule goes into effect.  Representatives from both the Advanced Medical Technology Association (“AdvaMed”) and the Medical Imaging and Technology Alliance (MITA) raised concerns about the short implementation timeline. Jamie Wolszon, Vice President of Technology and Regulatory Affairs at AdvaMed, stressed that “there must be a sufficiently long transition period to avoid disruption. We recommend at least a two-year transition period.”  She emphasized that the one-year transition period proposed by FDA would not give the industry enough time to adapt to the new requirements.  The Committee concurred with the industry’s concern that a one-year transition period would be “quite aggressive,” and a two- or three-year transition period would be more appropriate.</li></ul>Moreover, Committee members reminded FDA that the agency will also need a significant amount of transition time once the proposed rule is finalized.  Robert Phillips of Siemens Healthineers, who serves on the Committee, noted that a significant number of FDA guidance documents will all need to be updated to align with the new regulatory citations, definitions, and systems.  He further noted that these updates need to be worked out and made publicly available before a transition can be effected by device firms.  Committee members reminded the agency that when the current Quality System Inspection Technique (QSIT) was launched, it took two to three years for auditors to fully understand and work with QSIT.<ul><li>Industry representatives demand more clarity on the future inspectional approach.  The agency proposes to replace the current inspection approach for medical devices, the QSIT, with a new inspection model and manual to be determined and announced by FDA.  This regulatory vacuum will leave companies with no guidance on how to prepare for future inspections.  For example, it is unclear whether inspection programs under the current QSR, such as pre-approval, surveillance, and for-cause inspections, will survive.  Diane Wurzburger, Executive of Regulatory Affairs for GE Healthcare, speaking on behalf of MITA, also asked whether FDA’s process to inspect other requirements (e.g., medical device reporting and labeling) will change.  The industry also urged FDA to harmonize not only regulatory expectations, but also the actual procedures for inspections.  Specifically, the industry wants to avoid a “13485 plus type of approach,” where there could be “additional requirements over and above 13485 that are country-unique.”  These concerns were widely echoed across the industry.   </li><li>The industry demands clarity on whether ISO 13485 certification will be required.  Despite incorporating the ISO 13485 standard, FDA has stated that its inspections “will not result in certificates of conformance to ISO 13485 and manufacturers who have ISO 13485 certificates are not exempt from FDA inspections.”  However, the proposed rule did not clarify whether an ISO 13485 certificate will be required or expected.  Committee member Phillips of Siemens Healthineers noted that “topics about whether certification is required, or even expected … [are] something that needs to be clarified going forward.”  This regulatory uncertainty is particularly relevant for small firms that need to determine whether to apply for formal certification from an accredited auditing body.  Further, even if not explicitly required, questions remain about whether there will be preferential regulatory treatment for companies that are formally certified, which could put smaller firms without international presence at an unfair disadvantage.  AdvaMed’s Jamie Wolszon emphasized that the industry is interested in understanding how FDA intends to leverage existing ISO 13485 certifications, including whether there will be any “potential benefit(s)” for firms that are certified.</li></ul><ul><li>Risk management represents a significant change for small companies not previously subject to the ISO 13485 standard.  Harmonizing FDA regulations with the ISO 13485 standard means implementing risk management processes throughout the total product life-cycle.  Although FDA denies that the harmonization amounts to a policy shift, Melissa Torres, Associate Director for International Affairs at the Center for Devices and Radiological Health (CDRH), acknowledged during the meeting that compared to the current Part 820, ISO 13485 “has greater integration of risk management activities and stronger ties to ISO 14971, the risk management standard for medical devices.”  Committee member Scott Sardeson pointed out that the proposed change represents “a very big shift in mindset” for smaller companies that are not currently subject to the ISO 13485 standard and may not be aware of uncodified expectations from FDA.  These concerns add to the case for a longer transition period.</li></ul>The proposed rule may have a significant impact on device manufacturers, especially those not in compliance with the current ISO 13485 standard.  If the one-year proposed implementation timeline is not changed, device manufacturers will face a tight schedule to be in compliance with the new rule.  It is highly recommended that all device manufacturers, especially those without an international presence, review the proposed rule and identify any possible issues with compliance in order to address their challenges head-on.Comments on the proposed rule can be submitted in the Federal Register (<a target="_blank" href="https://www.federalregister.gov/documents/2022/02/23/2022-03227/medical-devices-quality-system-regulation-amendments">Docket No. FDA-2021-N-0507</a>) until May 24, 2022.

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Brigid is a food, drug, and medical device lawyer who counsels life sciences companies on a wide range of U.S. Food & Drug Administration pre- and post-market regulatory issues.

Brigid DeCoursey Bondoc

Brigid is a food, drug, and medical device lawyer who counsels life sciences companies on a wide range of U.S. Food & Drug Administration pre- and post-market regulatory issues.

Brigid Bondoc

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QMSR: Welcomed by the Industry, but Lacking in Practicality

QMSR: Welcomed by the Industry, but Lacking in Practicality

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On March 2, 2022, FDA hosted a public Device Good Manufacturing Practice Advisory Committee meeting, where the Committee discussed the proposed rule titled "Med

Owen Grayson Hosseinzadeh, Law Clerk in San Diego, contributed to the drafting of this post.On March 7, 2022, the Center for Veterinary Medicine (CVM) of the U.S. Food and Drug Administration (FDA) determined that <a href="https://recombinetics.com/acceligen/" target="_blank">Acceligen Inc.</a>’s genome-edited, heat-tolerant cattle, pose a “low risk to humans, animals, the food supply, and the environment.” This is the first such determination for a genetically engineered food-use animal and will allow the company to bypass many of the usual premarket approval requirements.These cattle, called PRLR-SLICK cattle, produce a short and slick hair coat due to a modification made to the prolactin receptor (PRLR) gene. This slick hair coat phenotype gives cattle the ability to regulate body temperature more effectively. This is important for raising cattle in tropical climates and might mitigate the predicted negative effects on livestock productivity associated with climate change.This intentional genomic alteration (IGA) was accomplished using CRISPR-Cas9 gene editing technology on in vitro fertilized calf embryos. Specifically, the IGA introduces a premature stop codon into the PRLR gene, and thereby truncates the encoded protein. IGAs like the alteration made to the PRLR gene in Acceligen’s cattle are intended to “affect the structure or function” of the altered animal, so FDA regulates them under its animal drug framework.Marketing an animal drug typically requires premarket approval, which entails a lengthy New Animal Drug Application (NADA) process through which FDA can evaluate the animal drug for efficacy, safety to the animal, and safety to the consumer. The only other FDA-approved food-use animals—Revivicor’s GalSafe pigs (2020) and the AquaBounty AquAdvantage salmon (2017)—went through the full NADA determination process.FDA discussed its intent to exercise enforcement discretion with respect to NADA requirements for IGA-containing animals as early as 2009, in guidance that has been updated several times, most recently in its 2017 <a href="https://www.fda.gov/regulatory-information/search-fda-guidance-documents/cvm-gfi-187-regulation-intentionally-altered-genomic-dna-animals" target="_blank">Guidance #187, “Regulation of Intentionally Altered Genomic DNA in Animals</a>.” But this is the first time that such enforcement discretion has been applied to an animal intended for food production.When FDA exercises its enforcement discretion over the NADA requirements, it does not also conduct a National Environmental Policy Act (NEPA) review, which can add significant costs and time to the application process. FDA instead considers the potential environmental risks when determining whether to exercise enforcement discretion.FDA examined four categories of risk factors in its risk assessment and concluded that PRLR-SLICK cattle pose a low risk to people, animals, the food supply, and the environment: 1. Molecular characterization<ul><li>PRLR-SLICK cattle have an IGA that mimics genomic sequences found in conventionally raised cattle</li><li>Analyses of the genomic data found evidence of unintended mutations, but based on their types and locations, they are not expected to result in changes to protein expression</li></ul><div> 2. Phenotypic data and animal safety</div><ul><li>PRLR-SLICK cattle have the same phenotype (i.e., short, slick hair coat) as conventionally raised cattle with naturally occurring slick mutations</li><li>PRLR-SLICK cattle appear healthy based on visual observations and animal health records</li></ul><div> 3. Human food safety</div><ul><li>Conventionally raised cattle with the slick phenotype are routinely consumed as human food </li><li>There is no expected change in the compositional or nutritional content of the edible tissues</li></ul><div> 4. Environmental risk</div><ul><li>The slick phenotype is a well-established trait in several breeds of conventionally raised domestic cattle in the United States</li><li>The likelihood of escape and establishment of PRLR-SLICK cattle in the U.S. environment is low due to the ability to rapidly recover escaped animals and the lack of feral cattle populations in the United States</li></ul>The “low-risk” decision is limited to products (e.g., live cattle, semen, embryos, and meat) derived from the existing two cattle reviewed by FDA and their progeny. FDA also intends to treat facilities or farms engaged in standard agricultural practices for PRLR-SLICK cattle the same as facilities or farms that are engaged in these practices for cattle without IGAs.According to FDA’s press release, meat products from PRLR-SLICK cattle are expected to be available for purchase by general consumers as early as 2024. PRLR-SLICK cattle meat and most other food products in which the cattle’s carcass is the predominant ingredient would not be subject to mandatory labeling under U.S. Department of Agriculture’s <a href="https://www.ams.usda.gov/resources/industry-fact-sheet-national-bioengineered-food-disclosure-standard" target="_blank">National Bioengineered Food Disclosure Standard</a>.

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Dr. Liz Freeman Rosenzweig focuses her practice on patent prosecution and intellectual property and regulatory counseling in the areas of life sciences and agricultural biotechnology, including AgTech

Liz Freeman Rosenzweig Ph.D.

Liz Freeman Rosenzweig

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FDA Clears CRISPR-Edited Cattle for Market Through Abbreviated Procedure: A First for Food-Use Animals

Last Week in the Federal Circuit (September 28 – October 2):  Product-by-Process Methods of Treatment

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Owen Grayson Hosseinzadeh, Law Clerk in San Diego, contributed to the drafting of this post.
On March 7, 2022, the Center for Veterinary Medicine (CVM) of the U

FDA Clears CRISPR-Edited Cattle for Market Through Abbreviated Procedure: A First for Food-Use Animals

On February 10, 2022, the U.S. Food and Drug Administration (FDA) held a public Oncologic Drugs Advisory Committee (ODAC) meeting to discuss the sintilimab application based on the ORIENT-11 trial conducted exclusively in China. Rather than following the traditional paradigm of assessing the risk-benefit profile of a single drug, the committee was, in a significant departure from typical Advisory Committee practice, asked to vote on a single question: Whether additional clinical trial(s) should be required to demonstrate applicability to the U.S. population and U.S. medical practice prior to a final regulatory decision. The committee ultimately voted 14–1 in support of the need for additional clinical trials, potentially delaying sintilimab’s approval in the United States by years. Yet, with more than 25 drug applications from China pending before the FDA, according to Dr. Richard Pazdur in his February 4, 2022 article in The Lancet, the more pressing question is whether the panel’s decision has any relevance beyond sintilimab. While there is no quick answer, the loud and clear message is that sponsors need to engage with the FDA early and formally if they seek FDA approval for their drugs.   ORIENT-11 is a randomized, double-blind, placebo-controlled phase 3 trial assessing the safety and efficacy of sintilimab in combination with pemetrexed and platinum chemotherapy as a first-line treatment for patients with advanced or metastatic nonsquamous non-small cell lung cancer (NSCLC). With trials exclusively in China, sintilimab’s review hinges on the FDA’s regulatory flexibility under <a target="_blank" href="https://www.ecfr.gov/current/title-21/chapter-I/subchapter-D/part-314/subpart-D/section-314.106">21 C.F.R. 314.106</a>, which stipulates that “[a]n application based solely on foreign clinical data meeting U.S. criteria for marketing approval may be approved if the foreign data are applicable to the U.S. population and U.S. medical practice.” After hearing presentations from both the FDA and the sponsor, the majority of the ODAC members decided that the study was not generalizable to the U.S. population because (1) the patient demographics in ORIENT-11 do not reflect the diverse U.S. population; (2) the study endpoint and comparator arm were not the standard of care for U.S. medical practice; (3) the consent forms should have been updated when pembrolizumab was approved by the Chinese regulatory agency seven months after study initiation; and (4) the inspections were too limited in scope to assess trial conduct and data integrity.Despite calling into question ORIENT-11’s trial design and conduct, the FDA did not conclude that trials conducted exclusively in a single foreign country could never be approved in the United States. Instead, the FDA indicates that the agency will apply 21 C.F.R. 314.106 in a flexible manner according to the nature of the drug and data considered. For “me-too” drugs that do not address unmet medical needs, rare diseases, or novel drug classes, the agency has to determine the applicability of the foreign data to the U.S. population, the recognized competence of the clinical investigators, and the FDA’s validation of the data. Sintilimab review provides valuable insights for sponsors that seek FDA approval based on a foreign-only clinical strategy.(1) Early engagement with the FDA. Regardless of the clinical strategy, sponsors should engage with the FDA formally and early if they want their drugs to be marketed in the United States. Relying on informal communication with the FDA can be a costly mistake. Eli Lilly and Innovent were reportedly prepared to launch sintilimab in the U.S. market when Dr. Richard Pazdur, director of the FDA’s Oncology Center of Excellence, openly welcomed Chinese sponsors to bring their PD-1/PD-L1 inhibitors to the U.S. market during the March 2019 American Association for Cancer Research (AACR) meeting. Yet, on February 4, 2022, less than one week before the committee meeting, Dr. Pazdur, writing for The Lancet, argued that drug applications seeking approval based on data from a “single foreign country” need to be representative of the U.S. population in order for regulators to be flexible. Defending his change of position, Dr. Pazdur declared that “I have a right to change my mind” in an interview with STAT News four days later. During the committee meeting, Dr. Pazdur emphasized again that “comments that were made at an AACR meeting should not be viewed as regulatory policy.”Sintilimab’s bumpy ODAC meeting sends a strong message that informal communication from the FDA should never be the basis for any business or regulatory decision. Additionally, if a product wants to enter the U.S. market, the sponsor needs to engage with the FDA during the early phases of drug development or early enough in advance of submission to have meaningful engagement with the FDA regarding the data development.The benefit of engaging the FDA early and formally is that the FDA can provide formal regulatory advice with regard to both study design and trial conduct. This can be particularly important when conducting trials in countries with different standards of care, or regulatory structures that are different from the ones in the United States. For ORIENT-11, the FDA has now indicated that it would have advised the sponsors to conduct a non-inferiority trial, comparing sintilimab with an FDA-approved anti-PD-(L)1/chemotherapy regimen with an overall survival (OS) endpoint, rather than a placebo arm with a progression-free survival (PFS) endpoint.  (2) Data Integrity. Data integrity is a critical underlying concern for all clinical trials, and is especially important for foreign sites. For ORIENT-11, the FDA conducted in-person inspections of two of the forty-eight clinical sites and one remote inspection of the sponsor. The inspections uncovered some minor issues, such as under-reporting of adverse events and the use of concomitant medications. However, the FDA cautioned that its inspections and data validation are limited in scope. The agency’s concerns, expressed during the ODAC meeting, are two-fold: first, most study investigators have limited experience conducting clinical trials, and second, historical data integrity problems in China make the agency less confident about clinical data generated locally. Citing a 2016 report by China’s State Food and Drug Administration that 80% of clinical trial data from China were “fraudulent or substandard,” Dr. Pazdur asked the sponsor during the ODAC meeting to clarify whether any site investigators were previously involved in data integrity scandals. To mitigate the potential or perceived issue of investigator competence and prevent fraudulent conduct in clinical trials, the FDA highlighted the need for international, multi-regional clinical trials (MRCTs) with “investigators who have gained experience in regulatory submissions to the FDA.” Further, MRCTs can enable regulators to “look at sites in different countries and take a look at differences . . . in adverse event reporting, in efficacy, and compare them and to see if there is any outlier.”(3)  Diversity. Both FDA officials and the committee members emphasized the need for trial subject diversity. Dr. Pazdur, responding to his comments at the 2019 AACR when recently questioned, stressed that “[t]he world has changed since those comments were made,” adding that the agency has to address ethnic and racial diversity concerns in clinical trials. The agency highlighted some known differences between the U.S. population with non-squamous NSCLC and the patient population enrolled in ORIENT-11, pointing out that ORIENT-11 enrolled only Chinese patients, while the U.S. racial/ethnic breakdown is 79% white, 15% Black, and 6% Asian. The FDA acknowledged that the majority of the studies approved by the agency do not reflect racial representation of the U.S. population. However, Dr. Pazdur avowed the agency’s commitment to “address ethnic and racial diversity,” adding that the agency cannot be deaf to the outcry even though it will require a major shift throughout the FDA.  (4) Human Subject Protections. Another area of focus by both the FDA and during the ODAC meeting was the troubling consent process. Seven months after ORIENT-11 was activated, pembrolizumab was approved by the Chinese regulatory agency as a first-line therapy for NSCLC. However, the consent form was not updated to reflect the change, a severe deviation from good clinical practice (GCP) requiring that patients be informed of any new and available treatment options for their conditions. The sponsor explained that, although the written consent form was not revised, all patients were informed by their treating physicians that another treatment option was available. Further, the sponsor pointed out that pembrolizumab was never a real option for ORIENT-11 patients due to its low availability and prohibitive cost.Informed consent is at the heart of modern clinical trials. Neither the agency nor the committee found the sponsor’s rationale reasonable. As pointed out by Dr. Ravi Madan, clinical director for the Genitourinary Malignancies branch at the National Cancer Institute, “while data integrity is of utmost importance in clinical research, moral integrity is of greater importance,” and regulatory agencies need to ensure in large studies like ORIENT-11 that “patients have the appropriate informed consent that is updated as needed over time.”The fate of sintilimab might be jeopardized, but its review process can provide insightful messages to future sponsors who plan to use foreign data when seeking FDA approval. The loud and clear message for sponsors is to engage with the FDA early and formally if the product is intended to be marketed in the United States. Informal communication can be a great way to learn the current thinking of the agency; however, it is critically important to follow up with a formal meeting to receive formal regulatory advice. Second, the FDA clearly favors MRCTs as a way to promote diversity and data integrity. It could be very beneficial to engage with study sites that have a known reputation with the FDA, such as prior involvement in FDA regulated clinical studies. Last, but not least, all clinical studies need to be conducted ethically, with informed consent as the cornerstone of all research ethics. Sponsors need to put in the utmost effort to ensure that patients are fully informed throughout the study.

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FDA’s Loud and Clear Message: Engage with FDA Early and Formally

Is 2021 the Value-Based and Shared Savings Revolution?

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On February 10, 2022, the U.S. Food and Drug Administration (FDA) held a public Oncologic Drugs Advisory Committee (ODAC) meeting to discuss the sintilimab appl

FDA’s Loud and Clear Message: Engage with FDA Early and Formally

Jianyuan (Yuan) Hua, FDA Regulatory and Compliance Associate in New York, contributed to the drafting of this post.The U.S. Food and Drug Administration (FDA) issued the much-anticipated <a target="_blank" href="https://www.federalregister.gov/documents/2022/02/23/2022-03227/medical-devices-quality-system-regulation-amendments">proposed rule</a> “Medical Devices: Quality System Regulation Amendments,” which will harmonize the current Quality System Regulation (QSR; 21 CFR Part 820) with the international standard specific for medical device quality management systems set by the International Organization for Standardization, ISO 13485:2016.  QSR has been the core regulation for device manufacturing in the United States since its implementation over 20 years ago.  Medical device establishments have come to have an increasingly international presence, necessitating significant efforts to comply with different requirements.  In order to reduce compliance costs for industry and harmonize domestic and international requirements, FDA first signaled its <a target="_blank" href="https://www.fda.gov/media/123488/download">intent</a> to align its QSR with the ISO 13485:2016 in December 2018, and estimated that a proposed rule would be issued in fall 2019.  After delays likely caused by FDA’s shift in priorities to focus on the COVID-19 response, the agency finally published the proposed rule last month.  The long-awaited and long-delayed proposed rule, if finalized, will rename 21 CFR Part 820 as “Quality Management System Regulation” (QMSR), and will harmonize the U.S. good manufacturing practices with international standards.  The proposal projects to save medical device establishments hundreds of millions of dollars in compliance costs. Many expected that FDA would rewrite QSR in order to align the U.S. regulatory framework with the ISO standard.  To the surprise of many, FDA performed a gap analysis and now proposes to incorporate ISO 13485 by reference rather than re-writing the regulation in its entirety.  ISO 13485 was first introduced in 1996, around the same time when FDA significantly revised Part 820, establishing the current QS regulation.  ISO 13485 went through many revisions since its first issuance, and its most current version has become more closely aligned with the requirements in part 820.  Notably, the 2016 updates to ISO 13485 included several requirements mandated by FDA under its QSR, such as document control and records management, particularly as both relate to protecting confidential information.  This alignment, as well as the agency’s commitment to global regulatory harmonization of medical device regulatory processes, prompted FDA to further explore incorporating the Quality Management System (QMS) requirements of ISO 13485:2016 into Part 820.  However, this “incorporation by reference” approach only applies to the current 2016 version of ISO 13485 and “[a]ny future revisions to this standard would need to be evaluated” before being incorporated.  As before, the proposed rule will only apply to finished devices, although FDA reiterates that it has the legal authority to apply the quality system requirements to manufacturers of components or parts of finished devices when needed.  The proposed QMSR, a nine-page document, is a “gap regulation” that is intended to be read in conjunction with ISO 13485.  Specifically, the proposed rule addresses FDA-specific requirements by adding necessary requirements and definitions that are absent from ISO 13485 and removing redundant or inconsistent regulations from Part 820.  For example, the proposed rule removed the term “device master record” (DMR) because (1) the concept is covered by ISO 13485’s Clause 4.2.3 on medical device files (MDF) and (2) under the QSR, the DMR is part of the design history file, which is inconsistent with the ISO standard.  Below are some key sections of the new proposed rule.Inspection.The proposed rule does not impact FDA’s authority to conduct inspections under section 704 of the Food Drug and Cosmetic Act (“FD&C Act”) (21 U.S.C. § 374).  However, FDA intends to replace its current inspection approach for medical devices, the Quality System Inspection Technique (QSIT), with an inspection approach that will be consistent with the requirements of the proposed Part 820 as finalized.  Similar to the current QSIT inspection approach, these inspections would involve the collection of information to support observations noted during the inspection and included on FDA Form 483, as appropriate and necessary.  FDA inspections will not result in the issuance of certificates of conformance to ISO 13485, nor is FDA developing a certification program for ISO 13485 or the revised Part 820.  In addition, manufacturers with a certificate of conformance to ISO 13485 are not exempt from FDA inspections.  Firms will need to participate in the Medical Device Single Audit Program (MDSAP) to avoid routine FDA inspections.Supplementary Provisions.  To fill the gap with ISO 13485, the proposed rule seeks to add (1) control of records (proposed section 820.35) and (2) device labeling and packaging controls (proposed section 820.45) to ensure consistency and alignment with other requirements in the FD&C Act and its implementing regulations.  For control of records, the agency plans to add the following requirements: <ul style="text-align: left;"><li>First, signature and date requirements will be required for records subject to Clause 4.2.5 of ISO 13485 (Control of Records).  </li><li>Second, information required by Part 803 (Medical Device Reporting) must be captured on certain records of complaints and servicing activities.  </li><li>Third, firms need to document in their records the Unique Device Identification (UDI) for each medical device or batch of medical devices in accordance with Part 830.  </li><li>Fourth, FDA proposes to retain the clarification from current Part 820 (section 820.180) about confidentiality of records FDA receives to remind firms that FDA protects such records in accordance with Part 20.</li></ul>For device labeling and packaging, ISO 13485 only states that “defined operations for labeling and packaging shall be implemented” without specifically addressing the inspection of labeling by the manufacturer.  Given that many device recalls are related to labeling and packaging, FDA proposes to supplement the ISO standard by retaining requirements from the current Part 820 (i.e., Subpart K).  If finalized, regulated industry must meet the requirements in ISO 13485 7.5.1 (Control of Production and Service) and the proposed section 820.45.Table 1—High-Level Summary of 21 CFR Part 820 Proposed Rule Differences and Additions<table style="text-align: left;" border="1" cellspacing="0" cellpadding="0"><tbody><tr><td width="165" valign="top" style="width: undefined%; height: auto;">Current part 820 </td><td width="229" valign="top" style="width: undefined%; height: auto;">ISO 13485 requirements </td><td valign="top">Proposed rule</td></tr><tr><td width="165" valign="top" style="width: undefined%; height: auto;">Subpart D—Document Controls</td><td width="229" valign="top" style="width: undefined%; height: auto;">Clause 4. Quality Management System</td><td valign="top">Differences addressed in 820.35</td></tr><tr><td width="165" valign="top" style="width: undefined%; height: auto;">Subpart M—Records</td><td width="229" valign="top" style="width: undefined%; height: auto;">Clause 4. Quality Management System</td><td valign="top">Differences addressed in 820.35</td></tr><tr><td width="165" valign="top" style="width: undefined%; height: auto;">Subpart K—Labeling and Packaging Control</td><td width="229" valign="top" style="width: undefined%; height: auto;">Clause 7. Product Realization</td><td valign="top">Differences addressed in 820.45</td></tr><tr><td width="165" valign="top" style="width: undefined%; height: auto;">Subpart N—Servicing</td><td width="229" valign="top" style="width: undefined%; height: auto;">Clause 7. Product Realization</td><td valign="top">Differences addressed in 820.35</td></tr></tbody></table>Risk Management.  Compared to the current QSR, which only explicitly addresses risk management activities in relation to design validation, the ISO standard has a greater emphasis on risk management activities and risk-based decision-making throughout the quality management system (QMS) processes.  Risk management for device manufacturers is the essential systematic practice of identifying, analyzing, evaluating, controlling, and monitoring risk throughout the product lifecycle to ensure that the devices they manufacture are safe and effective.  FDA expects the explicit integration of risk management throughout the clauses of ISO 13485 will send a clear message to manufacturers that it is necessary to “integrate risk management activities throughout their QMS and across the total product lifecycle.”On March 2, 2022, FDA hosted a public Device Good Manufacturing Practice Advisory Committee meeting.  While most industry stakeholders embraced the agency’s proposal, some have complained that the implementation period is too quick, saying that two years, rather than one, is a more appropriate timeframe.  Stay tuned for more detailed coverage about industry concerns in our next blog.Comments on the proposed rule can be submitted in the Federal Register (<a target="_blank" href="https://www.federalregister.gov/documents/2022/02/23/2022-03227/medical-devices-quality-system-regulation-amendments">Docket No. FDA-2021-N-0507</a>) until May 24, 2022, and the proposed rule is expected to be effective one year after finalization.<div style="position: absolute;left: -10000px;top: 0px;width: 1px;height: 1px;overflow-x: hidden;overflow-y: hidden;text-align: left;" id="_mcePaste"> <p style="background-image: initial;background-position-x: initial;background-position-y: initial;background-size: initial;background-repeat-x: initial;background-repeat-y: initial;background-attachment: initial;background-origin: initial;background-clip: initial;background-color: white;vertical-align: baseline;" class="MsoNormal"> </div>

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Quality Management System Regulation (QMSR) – Harmonizing the Quality System Regulation (QSR) with ISO 13485:2016

FDA Clinical Decision Support Software vs. EU’s Medical Device Regulation

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Jianyuan (Yuan) Hua, FDA Regulatory and Compliance Associate in New York, contributed to the drafting of this post.
The U.S. Food and Drug Administration (FDA) 

Quality Management System Regulation (QMSR) – Harmonizing the Quality System Regulation (QSR) with ISO 13485:2016

Earlier this month, the U.S. District Court for the Middle District of Alabama decided Method Pharmaceuticals, LLC v. H-2 Pharma, LLC, a dispute concerning labeling for fluoride products that raised a variety of issues with broader implications for industries regulated by the U.S. Food and Drug Administration (FDA).  Because the suit was brought pursuant to the private right of action provided by the Lanham Act, the case also called into question whether such a claim was precluded by the authority of the FDA (or U.S. Federal Trade Commission (FTC)) over the product’s labeling.  In particular, the case addressed whether fluoride is most appropriately classified as a drug or dietary supplement and whether product labeling, including the use of “Rx” in labeling for a purported dietary supplement is misleading. This is not the first case to address the propriety of labeling for “prescription” dietary supplements, and a prior case addressing prenatal vitamins reached the opposite result, finding that the Rx mark was not misleading.  While the cases are factually distinct, strident competition in the dietary supplement industry may lead other manufacturers to edge out the competition by implying that their products have undergone the rigorous review for prescription drugs or are eligible for medical coverage or reimbursement.  Without a definitive statement from the FDA regarding whether such claims are false or misleading, we expect to see more unfair competition and false advertising cases like this one.BackgroundMethod Pharmaceuticals LLC and H-2 Pharma LLC produce fluoride products.  Because excessive consumption of fluoride supplements may cause tooth damage, some manufacturers, like Method, require prescriptions for their fluoride supplement products.  H-2, on the other hand, offers its fluoride products either by prescription or by general purchase as dietary supplements.  The FDA has not yet determined if H-2’s fluoride supplements should be treated as drugs or as dietary supplements,<a href="file:///C:/Users/cxm41/Desktop/PROOF-Method%20H-2%20Blog%20Post%20DRAFT%2002.10.2022%20-%202332645%20(bb%20comments).DOCX#_ftn1">[1]</a> an important distinction, given the costs of complying with myriad drug regulations in the United States.  Method claimed that: (1) H-2’s use of the “Rx” mark on its fluoride products misleads consumers to believe they are prescription drugs; and (2) that H-2 uses the Rx mark to have its products linked to Method’s prescription drugs in pharmaceutical databases that track substitute drugs for use by physicians, effectively pricing them out of the market.  In an <a target="_blank" href="https://www.law360.com/articles/1461691/attachments/0">order</a> filed on February 3, 2022, Chief Judge Emily C. Marks found that all but one of the five claims brought by Method could go forward, as these claims adequately allege a false representation and do not circumvent FDA’s regulatory authority.Use of “Rx” on LabelingMethod argued that use of an “Rx” mark on non-prescription products is likely to be interpreted as misleading, and insufficiently distinguished from the official “Rx only” or “R only” labeling required for prescription products.  Judge Marks found H-2’s distinction between “Rx” and “Rx only” insufficient because H-2 marks its products with “Rx” regardless of whether they actually are prescription products.  Judge Marks wrote, “Indeed, if H-2 is correct that FDA regulations do require all prescription drugs to be marked with ‘Rx Only,’ that it marks its products with the similar ‘Rx’ appears to make it more likely that the market would be confused, not less.”  Judge Marks also pointed to allegations that H-2 knowingly omitted the customary disclaimer that products are not FDA approved, painting “a broader picture of H-2’s alleged misrepresentations than a mere ‘Rx’ on its labels.”There have been a few other recent cases touching on the use of “Rx” and “prescription only” labels for non-drug products.  For example, the Northern District of Illinois in Lupinetti v. Exeltis considered prenatal vitamins labeled with the “Rx” mark or phrase “prescription only” and the allegation that this labeling was intended to cause government coverage under Medicaid.<a href="file:///C:/Users/cxm41/Desktop/PROOF-Method%20H-2%20Blog%20Post%20DRAFT%2002.10.2022%20-%202332645%20(bb%20comments).DOCX#_ftn2">[2]</a>  The court rejected that claim, finding that it was objectively reasonable for the prenatal vitamin manufacturers to believe they could label their prenatal vitamins as “prescription only.”  In that case, the manufacturers’ “prescription only” labeling and statements were based on Centers for Medicare and Medicaid Services (CMS) guidance explaining that “prescription prenatal vitamins continue to meet the definition of a covered outpatient drug and are rebate-eligible” and issuance of a “covered outpatient drug” code for prescription prenatal vitamins.<a href="file:///C:/Users/cxm41/Desktop/PROOF-Method%20H-2%20Blog%20Post%20DRAFT%2002.10.2022%20-%202332645%20(bb%20comments).DOCX#_ftn3">[3]</a>FDCA Implications: Claim Preclusion and Federal PreemptionMethod also highlights apparent tension between Federal Food, Drug, and Cosmetic Act (FDCA) and the Lanham Act.  As the opinion explains, the FDCA proscribes misbranding of food and drugs and vests exclusive enforcement authority in the FDA, while the Lanham Act allows competitors to sue each other for false or misleading product descriptions.  It is clear from the Supreme Court’s decision in POM Wonderful LLC v. Coca-Cola Co., 573 U.S. 102, 120-21 (2014), that the FDCA does not preclude lawsuits concerning misleading labels between private competitors when it comes to food and beverage products.  Since then, courts across the country have grappled with whether Pom Wonderful extends to dietary supplements.<a href="file:///C:/Users/cxm41/Desktop/PROOF-Method%20H-2%20Blog%20Post%20DRAFT%2002.10.2022%20-%202332645%20(bb%20comments).DOCX#_ftn4">[4]</a>Method reaches a reasonable conclusion: if the Lanham Act claim does not require courts to contradict the FDA or make a determination committed to the FDA’s sole discretion, then it is permissible.  That rule allows companies to limit unfair competition, but respects the FDA’s authority and expertise with respect to safety.Along those lines, Method is relevant to the larger topic of FDA preemption of state law labeling claims.  This is an important issue because labeling claims are influential in driving consumer behavior.<a href="file:///C:/Users/cxm41/Desktop/PROOF-Method%20H-2%20Blog%20Post%20DRAFT%2002.10.2022%20-%202332645%20(bb%20comments).DOCX#_ftn5">[5]</a>  In this case, the court weighed whether private lawsuits were foreclosed by the FDCA but in other cases, courts have resolved conflicts between the FDA and state regulators enforcing state laws.<a href="file:///C:/Users/cxm41/Desktop/PROOF-Method%20H-2%20Blog%20Post%20DRAFT%2002.10.2022%20-%202332645%20(bb%20comments).DOCX#_ftn6">[6]</a>  A major theme in all of these cases is determining the proper role for the FDA.  On one hand, the FDCA vests sole enforcement authority for its regulations in the FDA for good reason—not only because of the FDA’s expertise, but also because complex national issues require dynamic federal solutions.  On the other hand, the FDA cannot possibly respond to every complaint from the industry regarding unfair or misleading labeling.  Moreover, reading the FDCA and its preemption provisions too broadly could jeopardize other vehicles for limiting misbranding and false advertising. <a href="file:///C:/Users/cxm41/Desktop/PROOF-Method%20H-2%20Blog%20Post%20DRAFT%2002.10.2022%20-%202332645%20(bb%20comments).DOCX#_ftnref1">[1]</a> Method Pharmaceuticals, LLC v. H-2 Pharma, LLC, 2:20-CV-753-ECM (M.D. Ala. February 3, 2022).<a href="file:///C:/Users/cxm41/Desktop/PROOF-Method%20H-2%20Blog%20Post%20DRAFT%2002.10.2022%20-%202332645%20(bb%20comments).DOCX#_ftnref2">[2]</a> See Lupinetti v. Exeltis USA Inc., 2021 WL 5407424 (N.D. Ill Nov. 19, 2021).<a href="file:///C:/Users/cxm41/Desktop/PROOF-Method%20H-2%20Blog%20Post%20DRAFT%2002.10.2022%20-%202332645%20(bb%20comments).DOCX#_ftnref3">[3]</a> CMS, Release No. 159 (Dec. 28, 2011). <a href="file:///C:/Users/cxm41/Desktop/PROOF-Method%20H-2%20Blog%20Post%20DRAFT%2002.10.2022%20-%202332645%20(bb%20comments).DOCX#_ftnref4">[4]</a> The Eleventh Circuit, which was binding on the Method court, has held that the FDCA does not preclude labeling claims under the Lanham Act.  Belcher Pharmaceuticals, LLC v. Hospira, Inc., 1 F.4th 1374, 1380-81 (11th Cir. 2021).  And the Ninth Circuit has reached a similar conclusion in ThermoLife Intern., LLC v. Gaspari Nutrition Inc., 648 Fed. App’x 609, 612 (9th Cir. 2016).  But in Amarin Pharma, Inc. v. International Trade Commission, 923 F.3d 959, 968-69 (Fed. Cir. 2019), the Federal Circuit held that the FDCA precluded that plaintiff’s particular Lanham Act claims.<a href="file:///C:/Users/cxm41/Desktop/PROOF-Method%20H-2%20Blog%20Post%20DRAFT%2002.10.2022%20-%202332645%20(bb%20comments).DOCX#_ftnref5">[5]</a> See Amanda Berhaupt-Glickstein, Neal H. Hooker, & William K. Hallman, Qualified Health Claim Language affects Purchase Intentions for Green Tea Products in the United States, 11 Nutrients 924 (Apr. 2019); Johann Steinhauser, Meike Janssen, & Ulrich Hamm, Who Buys Products With Nutrition and Health Claims? A Purchase Simulation with Eye Tracking on the Influence of Consumers’ Nutrition Knowledge and Health Motivation, 11 Nutrients 2199 (Sept. 2019).<a href="file:///C:/Users/cxm41/Desktop/PROOF-Method%20H-2%20Blog%20Post%20DRAFT%2002.10.2022%20-%202332645%20(bb%20comments).DOCX#_ftnref6">[6]</a> See, e.g., Johnson & Johnson v. Fitch ex rel. State, 315 So. 3d 1017 (Miss. 2021), cert. denied, 142 S. Ct. 732 (2021) (assessing whether the FDCA preempts labeling claims under the Mississippi Consumer Protection Act). Morrison & Foerster filed an amicus curiae brief on behalf of former FDA officials in support of Johnson & Johnson’s petition for certiorari.

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Fluoride Supplement Manufacturer Forced to Address Misleading Labeling Allegations

The EU General Court’s Ruling on Pay for Delay

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Earlier this month, the U.S. District Court for the Middle District of Alabama decided Method Pharmaceuticals, LLC v. H-2 Pharma, LLC, a dispute concerning labe

Fluoride Supplement Manufacturer Forced to Address Misleading Labeling Allegations

Special thanks to Morrison & Foerster Regulatory Analyst Brandy Guarda for contributing to this article. In response to COVID-19 pandemic, the U.S. Food and Drug Administration (FDA) continues to work in support of clinical investigation sponsors and an evolving environment in which they run their clinical trials while mitigating health risks. During the public health emergency, clinical trials have run into challenges ranging from quarantines to site closures, travel limitations, supply chain interruptions, and possible infection by either the site personnel or trial participants.[1] Throughout the pandemic, FDA has recognized that it may need to make modifications to protocol-specified procedures; and digital health technologies (DHTs) came to the rescue in clinical trials, assisting with remote data acquisition.On February 10, 2022, FDA held a webinar to discuss its draft guidance, Digital Health Technologies for Remote Data Acquisition in Clinical Investigations.[2] Presenters at this event included Leonard Sacks, MD (Center for Drug Evaluation and Research (CDER)), Elizabeth Kunkoski, MS (CDER), Matthew Diamond, MD, PhD (Center for Devices and Radiological Health (CDRH)), Christina Webber, PhD (CDRH), and Anindita Saha (CDRH).[3]Anindita Saha (CDRH) provided a few clinical scenarios to pull together the presented concepts and overarching objectives:<ul><li>DHTs have revolutionized the ability to remotely obtain and analyze clinically relevant information from individuals.</li><li>Compared to intermittent trial visits, the use of DHTs to remotely collect data from trial participants may allow for continuous or more frequent data collection.</li><li>DHTs provide opportunities to record data directly from trial participants (e.g., performance of activities of daily living and sleep) wherever the participants may be (e.g., home, school, work, or outdoors).</li><li>Some DHTs may also facilitate the direct collection of information from participants who are unable to report their experiences (e.g., infants or cognitively impaired individuals).</li></ul>As far as the rest of the program, Leonard Sacks, MD (CDER) introduced the definitions of patient-generated health data (PGHD) and DHTs. He discussed the benefits of using DHTs in a clinical investigation: (1) to obtain continuous measurements, (2) to document rare events, (3) to obtain real-world data from patients, and (4) to increase convenience of remote participation in trials. DHTs can also assist with obtaining correct measurements, finding suitable metrics, enhancing the ability to interpret continuous data, and ensuring proper use by patients.Matthew Diamond, MD, PhD (CDRH) discussed the regulatory considerations of DHTs and introduced the concept of a sponsor needing to find a DHT to be “fit for purpose.” FDA recommends the use of third-party verification to determine whether a DHT is fit for purpose and that sponsors engage frequently and early with the agency to discuss any use of a DHT in a specific clinical trial. Elizabeth Kunkoski, MS (CDER) further expanded on the concept of fit for purpose, while providing guidance on how to select DHTs for a clinical investigation. Fit-for-purpose considerations include DHT design and operation, ability to measure clinical events, and usability. The sponsor must also verify and validate the DHT to ensure that it is fit for purpose. In terms of regulation by FDA, those DHTs that meet the classification of a medical device are generally exempt from premarket clearance or approval when they are intended for use in clinical trials.  As far as communication with FDA regarding a DHT, the agency guidance documents on formal meetings, voluntary qualification programs (e.g., DDT, MMDT, and ISTAND), and CDRH’s Digital Health Center of Excellence (DHCoE) were suggested as additional support for sponsors considering the use of DHTs in a clinical trial. If a DHT has qualified for a specific context of use it may be used in multiple clinical trials.Furthermore, Elizabeth Kunkoski, MS (CDER) recommended that data from DHTs be treated as any other endpoint development (e.g., definition, justification, type, and positioning). FDA highlighted two types of risks with DHTs: clinical security risks (e.g., cybersecurity/hacking) and privacy-related risks to the data collected on the DHT (e.g., end-user agreements/terms of service). She also recommended a review of the guidance on record protection and retention.If you have any questions regarding the use of DHTs in a clinical trial, please contact a member of our FDA Regulatory Compliance team. [1] FDA Final Guidance, FDA Guidance on Conduct of Clinical Trials of Medical Products During the COVID-19 Public Health Emergency (Aug. 2021).[2] FDA Draft Guidance, Digital Health Technologies for Remote Data Acquisition in Clinical Investigations (Jan. 2022), available at <a target="_blank" href="https://www.fda.gov/regulatory-information/search-fda-guidance-documents/digital-health-technologies-remote-data-acquisition-clinical-investigations">https://www.fda.gov/regulatory-information/search-fda-guidance-documents/digital-health-technologies-remote-data-acquisition-clinical-investigations</a>.[3] FDA Webinar Slides, Digital Health Technologies for Remote Data Acquisition in Clinical Investigations (Feb. 10, 2022), available at <a target="_blank" href="https://sbiaevents.com/files2022/DHTs-Webinar-2022-02-10.pdf">https://sbiaevents.com/files2022/DHTs-Webinar-2022-02-10.pdf</a>.

FDA Releases Draft Guidance on Digital Health Technologies for Remote Data Acquisition in Clinical Investigations

FDA Releases Draft Guidance on Digital Health Technologies for Remote Data Acquisition in Clinical Investigations

Special thanks to Morrison & Foerster Regulatory Analyst Brandy Guarda for contributing to this article. 
In response to COVID-19 pandemic, the U.S. Food and Dr

Patent term extension (PTE) provides additional patent term for patents related to U.S. pharmaceutical products to compensate for the effective loss of patent term caused by delay during the drug approval process by the U.S. Food and Drug Administration (FDA). To be eligible for PTE, a patent must claim a drug product, a method of using a drug product, or a method of manufacturing a drug product, and PTE is only available for the first approval of an “active ingredient.”The Federal Circuit has addressed the question of what constitutes an active ingredient[1] several times in the context of small molecules. For example, claims directed to a metabolite do not cover the active ingredient,[2] enantiomers of the same compound are different active ingredients,[3] and different salts of the same compound are considered the same active ingredient for purposes of PTE.[4] Although the Federal Circuit case law on small molecules is more developed, it is not clear how the court will apply the current case law and statutory framework to biologics including cell-based therapies and gene therapies.Recent approval of a cell therapy, YESCARTA®, provides insight into considerations from the U.S. Patent & Trademark Office (USPTO) on what constitutes the active ingredient in the context of biologics. The YESCARTA PTE application illustrates two challenges for defining the active ingredient in cell-based therapies to meet the first approval requirement.[5] One challenge is how to define the active ingredient for certain cell-based therapies, where the product differs from patient to patient. Moreover, there is the related challenge of providing a detailed enough description of the active ingredient in the PTE application to allow the USPTO to distinguish the active ingredient of the product from previously approved active ingredients.YESCARTA (Axicabtagene ciloleucel) is an immunotherapy approved to treat B-cell lymphomas. YESCARTA comprises autologous T cells (a type of immune cell that plays a crucial role in detecting and killing cancer cells) derived from an individual patient and engineered specifically to target the patient’s cancer cells. The engineered T cells comprise: (1) T cells harvested from a patient and (2) a foreign protein (i.e., a chimeric antigen receptor (CAR)) specifically targeting a cell-surface protein. The T cells vary from patient to patient, but the CAR is the same for all patients. The T cells containing the CAR are responsible for the anti-tumor activity. All of this raises the question of whether the active ingredient is the T cells and/or the CAR.In the YESCARTA PTE application, applicant Cabaret Biotech Ltd. (“Cabaret”) defined the active ingredient as the engineered T cells. After reviewing the PTE application, the USPTO issued a letter to Cabaret, stating that (a) the cells could not be the active ingredient because the cells differ from patient to patient and (b) the CAR was not an active ingredient because it was not defined in the application as filed. Aside from the challenge surrounding the question “What is the active ingredient?” the USPTO also indicated that the applicant’s description of the structure of YESCARTA was insufficient. The USPTO requested that the applicant comment on whether an earlier approved antibody that targeted the same cell-surface protein was actually the first approval for the active ingredient in YESCARTA.The USPTO never squarely addressed what it considered the active ingredient of YESCARTA to be. After multiple communications between the USPTO and Cabaret, and between the USPTO and FDA, the USPTO approved the YESCARTA PTE application. The information the USPTO finally relied upon for determining that YESCARTA was eligible for PTE was the DNA sequence encoding the CAR. It appears that, based upon the differences in sequences between the YESCARTA CAR and the previously approved antibody, the USPTO determined that YESCARTA contained a new active ingredient.Interestingly, YESCARTA is not the first cell-based product with patient-to-patient variability to receive a grant of PTE. LAVIV® (Azficel-T) is an autologous cell product used for treating moderate to severe wrinkles. In its PTE application, Fibrocell Technologies, Inc. described the active ingredient of LAVIV as an autologous cellular product composed of fibroblasts suspended in a particular cell medium, and listed the active ingredient as “fibroblast cells.”[6] Although LAVIV shares the patient-to-patient variability seen in CAR T cells, the USPTO accepted this designation without further comment.The YESCARTA PTE application illustrates the challenges in applying the active ingredient analysis developed in the small molecule realm to biologics technologies. Precisely how the USPTO views the question of what constitutes an active ingredient in cell-based therapies remains an open question that will most likely be resolved by the courts. This uncertainty, however, has not impeded the grant of PTE for these cell-based therapies. Thus, patentees should not be deterred from filing PTE applications to secure an additional patent term for biologics products, but should keep these challenges in mind when drafting the description of the active ingredient in the PTE application.Follow us to stay up to date on developments regarding PTE. [1] Title 21 of the Code of Federal Regulations defines an “active ingredient” as any component that is “intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body of man or other animals.”[2] Glaxo Operations UK Ltd. v. Quigg, 894 F.2d 392 (Fed. Cir. 1990).[3] Ortho McNeil Pharm. v. Lupin Pharm., 603 F.3d 1377 (Fed. Cir. 2010).[4] Pfizer Inc. v. Dr. Reddy Labs. Ltd., 359 F.3d 1361 (Fed. Cir. 2004).[5] U.S. Patent No. 7,741,465; received at the USPTO on December 14, 2017.[6] U.S. Patent No. 5,591,444; received at the USPTO on August 17, 2011.