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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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.

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MoFo partners Kate Driscoll and Nate Mendell launched the MoFo life sciences podcast When Your Life Sciences Are on the Line this week, and Episode 1 is now <a href="https://soundcloud.com/user-496742723/03-27-lifescience-podcast01-v1" target="_blank">available</a>. The podcast features interviews with legal experts who share insights and advice you just might need when your life sciences are on the line.The special guest for Episode 1 was Jim Krenn, a MoFo partner whose practice is focused on major corporate transactions for emerging and established companies in the life sciences. Jim, Nate, and Kate discuss strategies to maximize and protect the value of trade secrets, how investing in compliance early pays dividends as companies mature, and where companies may face government scrutiny on the journey from startup to public company.Trade secrets play a central role in raising capital, selling a company, and going public, and the rise of cyber breaches and sophisticated intellectual property theft has pushed investors to look closely at how trade secrets are safeguarded. Jim maps out strategies for maximizing the value of trade secrets at key stages and discusses with Nate and Kate how to protect a critical asset for many life sciences companies.Early-stage companies often focus on development and growth, but an appropriate compliance function is important to control present and future downside risk. Jim explains the decision dynamics at play, and Kate discusses how increased scrutiny on life sciences companies makes good compliance a winning value proposition.Outside scrutiny on company systems peaks when the time comes to take a company public or consider a merger or acquisition. Interested parties pore over compliance functions at this stage, particularly in the highly regulated life sciences industry. Nate and Kate discuss corresponding risks for company insiders.

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Katherine (Kate) Driscoll, partner, focuses her practice on white collar defense, investigations and enforcement actions for companies and senior executives.

Kate Driscoll

Katherine (Kate) Driscoll is a partner in Morrison Foerster’s Investigations + White Collar Defense Practice Group. Kate focuses her practice on investigations, enforcement actions, and compliance, representing companies and senior business executives.

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Nathaniel (Nate) Mendell is a partner in Morrison Foerster’s Investigations + White Collar Defense and Privacy + Data Security practice groups and was the former Acting U.S. Attorney for the United States Attorney’s Office for the District of Massachusetts. 

Nathaniel Mendell

Nathaniel R. Mendell

Co-Chair of Emerging Companies + Venture Capital Practice

Jim has extensive experience representing private and public companies and investors in significant business transactions from formation through liquidity. His practice focuses on mergers and acquisitions, venture capital financings, and emerging company counseling. His clients span a broad range of industries, with a concentration in life science and technology companies.

Jim Krenn

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MoFo partners Kate Driscoll and Nate Mendell launched the MoFo life sciences podcast When Your Life Sciences Are on the Line this week, and Episode 1 is now available. 

When Your Life Sciences Are on the Line: Protecting Your Company’s Most Valuable Asset: Trade Secrets

The Beni Suef Economic Court in Egypt has recently ordered the removal of nearly five hectares of illegally grown Early Sweet™ grapevines, totaling 9000 vines and associated seedlings. The farm owner did not have a license to grow or commercialize the Early Sweet™ grapes and was found to be infringing the intellectual property (IP) rights held by Grapa Varieties Ltd. The case against the farm owner was won by Grapa, which specializes in breeding and licensing premium table grape varieties under the ARRA™ and Early Sweet™ brands. The particular IP right at issue was a plant breeders’ right (PBR) owned by Grapa.PBRs are similar to other forms of IP, such as patents, but are a sui generis form of IP protection available in many countries specifically for plant varieties. Egypt introduced its national plant variety protection system in 2002 under Law 82. Although negotiations regarding an association agreement for Egypt to be considered for membership in the International Union for the Protection of New Varieties of Plants (UPOV) began in 1995, Egypt did not accede to UPOV until 2019, after establishing compliance with the 1991 revised version of the UPOV Convention.  Grapa Varieties Ltd. previously dealt with illegal grape exports into Europe in June 2021 when illegally exported grapes were <a href="https://grapaes.com/the-power-of-enforcement/?utm_source=rss&utm_medium=rss&utm_campaign=the-power-of-enforcement">seized in a port and destroyed</a>. However, the new removal order is the first instance when enforcement has protected the PBRs at the origin of the fruit inside Egypt. The Beni Suef Economic Court ruling thus reflects a significant expansion in the industry protection of PBRs in Egypt, and comes as part of a wider crackdown on illegal fruit exports. This crackdown has been assisted by a decree issued last year by Egypt’s Minister of Agriculture, H.E. El-Sayed El-Quseir, which requires all farms to be registered and assessed before gaining the right to export. Infringements, such as from the propagation, sale, display, or export of the variety without a license, now result in a fine and the possibility of a custodial sentence.The order from the Beni Suef Economic Court demonstrates the commitment of Egypt’s phytosanitary authorities to protect the rights of plant breeders and their legitimate licensees within the country. The outcome of this case is likely to resonate throughout the export industry, as repeated incidents of export seizures incur significant financial losses for exporters, and negatively impact Egypt’s international reputation in the agricultural sector. Given that Egypt exports around 150,000 tonnes of grapes a year and has cornered the market as the world’s largest exporter of fresh oranges, relying on seizures at the export stage to protect plant IP would be worrying and expensive. The protection afforded through PBRs within Egypt is thus instrumental in ensuring that the IP holder does not experience a loss in revenue caused by illegal production and importation. <a href="https://grapaes.com/illegal-early-sweet-grapes-uprooted-in-egypt/">Sources</a> believe the citrus market is next in line for the IP shake-up.The <a href="https://www.freshfruitportal.com/news/2022/07/13/grapa-wins-legal-case-against-illegal-planting-in-egypt/">well-publicized protection</a> of Grapa’s PBRs by the Court will boost breeders’ confidence that pursuing illegal plantations, nurseries, and exporters in Egypt is not only achievable, but is expected of the phytosanitary authorities. This will have the additional benefit of strengthening Egypt’s image in international markets, thus improving Egypt’s ability to access new protected plants and create a healthy climate for breeders to invest in Egypt.

IN VINEIS VERITAS: NO SOUR GRAPES AS EGYPTIAN COURT ORDERS REMOVAL OF ILLEGAL VINES

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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

IN VINEIS VERITAS: NO SOUR GRAPES AS EGYPTIAN COURT ORDERS REMOVAL OF ILLEGAL VINES

The Beni Suef Economic Court in Egypt has recently ordered the removal of nearly five hectares of illegally grown Early Sweet™ grapevines, totaling 9000 vines and associated seedlings. The farm owner did not have a license to grow or commercialize the Early Sweet™ grapes and was found to be infringing the intellectual property (IP) rights held by Grapa Varieties Ltd. The case against the farm owner was won by Grapa, which specializes in breeding and licensing premium table grape varieties under the ARRA™ and Early Sweet™ brands. The particular IP right at issue was a plant breeders’ right (PBR) owned by Grapa.

Research assistant Nicole Gebert contributed to this article.<a href="https://lifesciences.mofo.com/topics/eu-in-vitro-diagnostic-regulation-entered-into-force--part-1-of-3.html">Part 1</a> of this article discussed the background and purpose of the <a href="https://eur-lex.europa.eu/eli/reg/2017/746/oj" target="_blank">EU In Vitro Diagnostic Regulation (EU) 2017/746</a> (IVDR), the definition of in vitro diagnostic medical devices (IVDs), the risk-based classification system, conformity assessments, and the role of notified bodies. This was followed by <a href="https://lifesciences.mofo.com/topics/eu-in-vitro-diagnostic-regulation-entered-into-force--part-2-of-3.html" target="_blank">part 2</a>, where we discussed clinical evidence, post-market surveillance, and transition periods. We will now focus specifically on requirements for medical device software (MDSW) as an IVD (IVD-MDSW) and the delimitation between the application of the <a target="_blank" href="https://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:32017R0745">EU Medical Device Regulation (EU) 2017/745</a> (MDR) and application of the IVDR to a software device.<h2>Qualification as IVD-MDSW</h2>As already mentioned in<a href="https://lifesciences.mofo.com/topics/eu-in-vitro-diagnostic-regulation-entered-into-force--part-1-of-3.html" target="_blank"> part 1</a> of this article, the expanded IVDR definition of “in vitro diagnostic medical devices” in Article 2 (2) now explicitly includes software.IVD-MDSW usually occurs in the following forms:<ul><li>Software itself as an IVD</li><li>Software as an accessory for an IVD</li><li>Software driving or influencing the use of an IVD</li></ul>The first stage in determining whether the software is an IVD-MDSW subject to the IVDR is to confirm that the software is a medical device (MDSW).<ul><li>The Medical Device Coordination Group (MDCG) guideline <a href="https://ec.europa.eu/docsroom/documents/37581?locale=en" target="_blank">MDCG 2019-11</a> clarifies that MDSW is software intended to be used alone, or in combination, for a purpose as specified in the definition of “medical device” in the MDR or IVDR (for more information on the intended purpose of MDSW under the MDR, see part 2 our <a href="https://lifesciences.mofo.com/topics/Software-as-Medical-Device-in-Eu--New-Reg-Enter-into-Force--Part-2-of-6.html" target="_blank">MDR blog series</a>). In general, software that processes, analyses, creates, or modifies medical information will qualify as MDSW if it is intended to have a medical purpose. Software for non-medical purposes, or for general purposes, even when used in a healthcare setting, or software intended for well-being purposes, is not covered by the MDR and IVDR. Software that merely used to store, archive, or performs simple searches on medical data does not qualify as MDSW.</li></ul>Second, the software must meet the following criteria to qualify as IVD-MDSW:<ul><li>The MDSW provides information within the scope of the definition of IVDs; </li><li>MDSW creates information based on data obtained by an IVD only; or</li><li>The intended purpose of the MDSW is substantially driven by data sources coming from IVDs.</li></ul>In accordance with the second step, an MDSW that analyses maternal parameters such as age, concentration of serum markers, and information obtained through various IVD assays, as well as fetal ultrasound examination to evaluate the risk of trisomy 21, may be considered an IVD-MDSW as the intended purpose is substantially driven by IVD data.MDSW that does not fulfill this second step is covered exclusively by the MDR. This includes, for example, MDSW that assesses the level of risk to initiate care processes that help reduce intensive care unit (ICU) transfers, readmissions, adverse events, and the duration of stay, by considering risk assessment parameters like respiratory rate, heart rate, blood pressure, and SpO2, by default, and can be configured by the user to include other parameters as well, including results from in vitro medical diagnostic devices. This MDSW would fall under the MDR as (i) the data is obtained from both IVDs and medical devices, and (ii) the data obtained from the IVD is not critical to the output, so the information derived from the medical device is more relevant to the intended purpose.<h2>Risk Classification of IVD-MDSW According to the IVDR</h2>In <a href="https://lifesciences.mofo.com/topics/eu-in-vitro-diagnostic-regulation-entered-into-force--part-1-of-3.html" target="_blank">part 1</a> of this article, we discussed the adoption of a new classification system. We also pointed out that the IVDR does not contain software-specific classification rules, like Rule 11 of Annex VIII to the MDR. Therefore, the classification of MDSW under the IVDR requires consideration of all classification and implementation rules of Annex VIII to the IVDR.The classification system of the IVDR considers the intended purpose of the device and the inherent risks, and groups devices into four different risk classes (classes A to D) in ascending order of their risk intensity. For example, software for the interpretation of automated readings of line immunoassay for the confirmation and determination of antibodies to HIV-1, HIV-1 group O, and HIV-2 in human serum and plasma, may be a device intended to be used for determining the infectious load of a life-threatening disease where monitoring is critical in the process of patient management under rule 1 of Annex VIII to the IVDR and would thus be classified in class D. At the same time, the IVD-MDSW referred to above, which uses maternal parameters and information obtained through fetal ultrasound examination to evaluate the risk of trisomy 21, may be considered a device that is intended for screening for congenital disorders in the embryo or fetus under Rule 3 (l) of Annex VIII to the IVDR and should thus be in class C.However, given the close nature of the MDR and the IVDR, there are of course similarities in the regulation of MDSW. Very similar to the risk assessment under the software-specific rule 11 of Annex VIII to the MDR (i.e., which effectively provides for class IIa ranking as a default result and therefore requires notified body review of most MDSW), the risk assessment of MDSW under the IVDR will in most cases result in a class B ranking (or higher) and therefore also require the IVD-MDSW to undergo an conformity assessment by a notified body. This is because IVDs, including IVD-MDSW, which are not covered by any specific classification rule, fall under class B by default (Rule 6 of Annex VIII of the IVDR).<h2>Technical Documentation for IVD-MDSW</h2>Before placing IVDs on the market, most manufacturers will need to get their technical documentation assessed by a notified body (see <a href="https://lifesciences.mofo.com/topics/eu-in-vitro-diagnostic-regulation-entered-into-force--part-1-of-3.html" target="_blank">part 1</a> of this article for IVDR conformity assessment routes). The IVDR stipulates several software-specific requirements for the technical documentation in Annex II:<ul><li>The device description and specification should include a description of any software that drives the device or influences use of the device (Annex II 1.1.k).</li><li>For IVDs that incorporate software, the design information should include a description of any software to be used with the device, as well as an overview of the entire system. If the IVD uses software for objective data interpretation, or if the software is independent of any other device, a description of the data interpretation methodology, namely the algorithm, should be included (Annex II 3.1).</li><li>The documentation should further contain evidence of software validation as used in the finished device, as well as address all hardware configurations and, where applicable, operating systems identified in the labeling (Annex II 6.4, EN ISO/IEC 62304 is considered the state of the art approach).</li></ul>Several guidelines for IVDR technical documentation submissions have been issued by notified bodies and should be taken into consideration when dealing with the respective notified body (e.g., TÜV Rheinland, BSI).<h2>Introduction of a Unique Device Identification Requirement for IVD-MDSW</h2>The IVDR, like the MDR, introduces the Unique Device Identification (UDI) system. Annex VI Part C 6.2 of the IVDR addresses the UDI assignment for software specifically. In accordance with the IVDR, software that is commercially available on its own (i.e., standalone IVD-MDSW), as well as software that constitutes an IVD device, shall be subject to UDI requirements. These requirements are identical for MDSW under the MDR and for IVD-MDSW under the IVDR. More details on how to identify software devices can be found in <a href="https://lifesciences.mofo.com/topics/Software-as-medical-device-in-Europe--New-Regulatory-Regime-About-To-Enter-Into-Force--Part-5-of-6.html" target="_blank">part 5</a> of our blog series on the MDR.<h2>IT Security</h2>Among the many novelties introduced, the IVDR and the MDR aim to ensure that devices placed on the EU market are suitable for the new technological challenges associated with cybersecurity risks.IVDs must thus be designed and manufactured in a way that removes or reduces risks associated with the possible negative interaction between software and the IT environment in which it operates and interacts (Annex I Chapter II 13.2.d). Manufacturers must establish, implement, document, and maintain a risk management system. Particularly with the complexity of software development, software configuration, and interdependencies between software components, IVD-MDSW is afflicted with security vulnerabilities. It is therefore considered more reasonable that software as such is subject to foreseeable misuse. Manufacturers should foresee or evaluate the potential exploitation of those vulnerabilities.Manufacturers must also develop and manufacture IVD-MDSW in accordance with the state of the art, while taking into account the principles of development lifecycle and risk management, including information security, verification, and validation. Manufacturers also need to set out minimum requirements concerning IT network characteristics and IT security measures, including protection against unauthorized access (Annex I Chapter II (16) IVDR).Further information can be found in the MDCG Guidance on Cybersecurity for medical devices (<a href="https://ec.europa.eu/health/system/files/2022-01/md_cybersecurity_en.pdf" target="_blank">MDCG 2019-16</a>).<h2>Performance Evaluation of IVD-MDSW</h2>Although the IVDD already required a performance assessment, it was only implied, not explicitly stated, and primarily concerned with the analytical performance of the device. Under the IVDR, any software that qualifies as an IVD must meet all clinical evidence and performance evaluation principles explicitly outlined in Article 56 (1) and Annex XIII of the IVDR. The MDCGs Guidance on Clinical Evaluation (MDR) / Performance Evaluation (IVDR) of Medical Device Software (<a href="https://ec.europa.eu/health/system/files/2020-09/md_mdcg_2020_1_guidance_clinic_eva_md_software_en_0.pdf" target="_blank">MDCG 2020-1</a>) aims to provide the framework for the determination of the appropriate level of clinical evidence required for MDSW to fulfill the requirements set out in the IVDR (and MDR).Although the definition of clinical evaluation in the MDR and performance evaluation in the IVDR are not identical, sufficient clinical evidence is expected in both cases to demonstrate compliance with the relevant general safety and performance requirements.When collecting clinical evidence for IVD-MDSW, three key elements should be taken into account:<ul><li>Scientific validity;</li><li>Analytical performance; and</li><li>Clinical performance.</li></ul>Part A of Annex XIII applies primarily to the pre-market phase and defines performance evaluation as a three-step process: (i) drafting a performance evaluation plan, (ii) collecting data to demonstrate scientific validity and analytical and clinical performance, and (iii) evaluating and documenting the data in a performance evaluation report.Part B of Annex XIII concerns the post-market phase and outlines the requirements for post-market performance follow-up. This concept was not included in the IVDD, but is in line with the practice of many manufacturers to conduct a periodic “state of the art” review.<h2>Concluding Remarks</h2>Under the IVDR, IVD-MDSW is subject to several software specific requirements. As most IVD-MDSW will likely end up in class B or higher, manufacturers will also need to undergo notified body review in order to be able to place IVD-MDSW on the market. Therefore, it can be expected that a number of manufacturers will make use of the transition periods discussed in <a href="https://lifesciences.mofo.com/topics/eu-in-vitro-diagnostic-regulation-entered-into-force--part-2-of-3.html" target="_blank">part 2</a> of this blog series. However, as discussed in more detail in <a href="https://lifesciences.mofo.com/topics/Software-as-medical-device-in-Europe-new-regulatory-regime-to-enter-into-force-part-6.html" target="_blank">part 4 of our blog series on MDSW under the MDR</a>, in particular MDSW manufacturers should be aware of the implications that come along with the use of transition periods as the IVD-MDSW may not undergo any significant changes to its design or intended purpose in order to benefit from such transition periods.

Wolfgang advises clients on contentious and non-contentious matters involving their most valuable intellectual property assets in the digital, high-tech, life sciences, and pharmaceutical industries.

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Counsel

Robert advises companies in the healthcare, pharmaceutical, medical device, and technology industries on all aspects of intellectual property law, primarily in connection with commercial life sciences, licensing, and technology transactions. His clients range from multinational companies to startups.

Robert Grohmann

Robert Grohmann is counsel at Morrison Foerster’s German office in Berlin. As a member of the technology transactions group, he focuses on advising domestic and foreign companies and startups in all areas of technology and IP law, including patent and software licensing, employee inventions law, as well as know-how protection. Moreover, Mr. Grohmann’s expertise encompasses the judicial and extra-judicial representation in matters of trademark law, design law, and competition law.

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EU: IN VITRO DIAGNOSTIC REGULATION ENTERED INTO FORCE (PART 3 OF 3)

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

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Research assistant Nicole Gebert contributed to this article.
Part 1 of this article discussed the background and purpose of the EU In Vitro Diagnostic Regulati

EU: IN VITRO DIAGNOSTIC REGULATION ENTERED INTO FORCE (PART 3 OF 3)

Research assistant Nicole Gebert contributed to this article. After having discussed the general purpose and background of the IVDR, the new definition of IVDs, and the conformity assessment in light of the new risk classification as well as the role of notified bodies in part 1 of our 3 part series on the entering into force of the <a href="https://eur-lex.europa.eu/legal-content/EN/TXT/?uri=CELEX%3A02017R0746-20220128 " target="_blank">EU In Vitro Diagnostic Regulation (EU) 2017/746</a> (IVDR), we will now (i) explore key changes regarding clinical evidence and post-market surveillance, and (ii) discuss applicable transition periods.<h2>Clinical Evidence, Performance Evaluation, and Performance Studies</h2>Ensuring that the clinical evidence can stand up to the scrutiny of the notified bodies will be one of the biggest challenges for manufacturers in IVDR compliance. It is the responsibility of the manufacturers to determine whether they have adequate clinical and performance data to demonstrate conformity with the relevant safety and performance requirements. According to the IVDR, clinical evidence must demonstrate a continuous process of performance evaluation and must support the intended purpose of the device as stated by the manufacturer. Gradually, the level of clinical evidence needed to demonstrate device conformity increases in line with the risk class. A manufacturer must document the clinical evidence in a performance evaluation report once they are satisfied they have all of the data needed to support compliance with the IVDR. The report must include the scientific validity report, the analytical performance report, the clinical performance report, and an assessment of those reports allowing demonstration of the clinical evidence. More detailed information on clinical evidence can be found in the <a target="_blank" href="https://ec.europa.eu/health/system/files/2022-01/mdcg_2022-2_en.pdf">MDCG Guidance on general principles of clinical evidence for In Vitro Diagnostic medical devices (IVDs)</a> from January 2022.<h2>Post-Market Surveillance</h2>Similar to the MDR, the IVDR too places a greater emphasis on life-cycle management and continuous product evaluation than the IVDD. In this context, manufacturers are required to have a quality management system (QMS) in place (Article 10 IVDR). As part of the QMS, manufacturers are obligated to plan, establish, document, implement, maintain, and update a post-market surveillance system for each device in a manner that is proportionate to the risk class and appropriate for the type of device (Article 78 (1) IVDR). The requirements for the post-market surveillance system are described in Articles 79-81, Annex III, and Annex XIII of the IVDR. The requirements vary according to the risk class. Many aspects of the IVDR post-market surveillance requirements resemble the requirements of the MDR (for more information on QMS and post-market surveillance under the MDR, please see our previous blog post <a href="https://lifesciences.mofo.com/topics/Software-as-a-Medical-Device-in-Europe--New-Regulatory-Regime-About-to-Enter-into-Force-Part-4-of-6.html">here</a>). Similar to the MDR’s post- market clinical follow-up, the IVDR stipulates that a post-market performance follow-up (PMPF) is required to ensure that an IVD’s safety, performance, and clinical evidence remain based on factual evidence throughout its expected lifespan and that its benefit-risk ratio remains acceptable. In some cases, PMPF can be justified as not required (see Annex III 1b and Annex XIII Part B 8).<h2>Unique Device Identification System</h2>The identification and traceability of IVDs will be improved under the IVDR with the introduction of unique device identifiers (UDI). As laid out in Article 24 IVDR, each IVD must have a UDI composed of two parts: a UDI that is specific to a manufacturer and a device that provides access to the information set forth in Part B of Annex VI IVDR, and a unique device production identifier that identifies the unit of device production and, if applicable, the packaged devices, as specified in Part C of Annex VI IVDR. Manufacturers are responsible for entering and maintaining the necessary data in a UDI database, which is part of the <a target="_blank" href="https://ec.europa.eu/tools/eudamed/#/screen/home">European Database on Medical Devices</a> (EUDAMED). The UDI requirements in the IVDR are in line with the requirements set out by the MDR, which we addressed in more detail in part 5 of our MDR blog series that can be found <a href="https://lifesciences.mofo.com/topics/Software-as-medical-device-in-Europe--New-Regulatory-Regime-About-To-Enter-Into-Force--Part-5-of-6.html">here</a>.<h2>Transition Periods</h2>As mentioned above, the Commission proposed a delayed, progressive roll-out of the IVDR in October 2021. The rationale behind this proposal is that due to the resources diverted to address the COVID-19 pandemic and the significant changes introduced by the IVDR, Member State authorities, healthcare facilities, notified bodies, and economic operators would not be able to fully comply with the requirements of the IVDR at the time of application on May 26, 2022. In particular, the inadequate number of notified bodies was highlighted, making it impossible to guarantee that the conformity assessments would be carried out in time. After immense stakeholder pressure, the Commission acknowledged that this situation could lead to a significant disruption in the supply of a multitude of IVDs on the market both for health institutions and for the public (<a target="_blank" href="https://eur-lex.europa.eu/legal-content/EN/TXT/?uri=CELEX%3A52021PC0627&qid=1634552565285">Commission proposal</a>, <a target="_blank" href="https://ec.europa.eu/commission/presscorner/detail/en/ip_21_5209">press release</a>, and <a target="_blank" href="https://ec.europa.eu/commission/presscorner/detail/en/qanda_21_5210">Questions & Answers</a> dated October 14, 2021). The proposal was adopted by the European Parliament in December 2021 (<a target="_blank" href="https://ec.europa.eu/commission/presscorner/detail/en/IP_21_6965">Commission press release</a>, <a target="_blank" href="https://www.europarl.europa.eu/doceo/document/TA-9-2021-0498_EN.html">EU Parliament Resolution</a> of December 15, 2021). Under the amended regulations, the dates on which certain requirements might apply are revised.The extended transition periods apply only to legacy IVDs, meaning devices that were certified or declared compliant before May 26, 2022. Therefore, all devices newly placed on the market after May 26, 2022, must be classified and certified in accordance with the IVDR rules.Furthermore, the IVDR will also immediately apply to any device for which an IVDD declaration of conformity was drawn up before May 26, 2022, and which must be reclassified as a class A non-sterile device under the IVDR. This is because such a device does not require a notified body review and, according to the rationale behind the transition periods, will thus not contribute to the notified bodies becoming a bottle neck that slows down market access or being subject to the same.If a manufacturer has drawn up an IVDD declaration of conformity without the involvement of a notified body before May 26, 2022, and if, under the IVDR reclassification, the device must be classified as a class A sterile device or higher and thus undergo conformity assessment with a notified body, according to the amended Article 110 (3) IVDR, the following new transition periods apply:<ul><li>May 26, 2025, for class D devices; </li><li>May 26, 2026, for class C devices;</li><li>May 26, 2027, for class B devices; and</li><li>May 26, 2027, for class A devices placed on the market in sterile condition. </li></ul>For IVDs which have been certified by an IVDD notified body before May 26, 2022, according to Article 110 (2), the following transition periods apply:<ul><li>Certificates issued by notified bodies under the IVDD prior to May 25, 2017, will remain valid until the date indicated on the certificate (with no amendment of the transition period). It should be noted, however, that IVDD certificates are usually valid for a maximum of five years according to Article 9 (10) IVDD.</li><li>Certificates issued by notified bodies in accordance with the IVDD from May 25, 2017, and certificates issued under the EC Verification in accordance with Annex VI of the IVDD, will become void at the latest by May 27, 2025. </li></ul>It should be noted that for the aforementioned transition periods to apply, the IVD needs to continue to comply with the IVDD requirements and must not undergo significant changes in its design or intended purpose after May 26, 2022, which in particular for IVD software can be challenging because changes in the intended user groups or changed indications, corrections of errors to minimize risks, changes in the user interface (like changed warning messages), or the use of a different runtime environment will likely be deemed significant according to <a href="https://ec.europa.eu/docsroom/documents/40301/attachments/1/translations/en/renditions/native" target="_blank">MDCG 2020-3 Guidance on Significant Changes</a>. Furthermore, according to Art. 110 (3) IVDR, the IVD manufacturer must comply with post-market surveillance, vigilance, UDI, and market surveillance rules of the IVDR.<h4>CONCLUDING REMARKS</h4> The IVDR brings about increased standards and requirements for IVDs in order for the devices to be placed on the market. Although it can be expected that many legacy IVDs, including IVD software, will benefit from the transition periods, manufacturers will need to assess on a case-by-case basis whether the respective device fulfills the criteria and whether the same can be maintained during the entire transition period (i.e., no significant changes can be made). Furthermore, the transition periods may bring some relief with respect to the certification of IVDs, but they do not necessarily mean that the IVDR requirements do not apply to these devices. Therefore, manufacturers should have adopted IVDR compliance measures by now and should seek. As it can be expected that the run on notified bodies will increase with the end of the transition periods approaching, it would also be advisable to start preparing the transition to IVDR certification and file for the same well in advance of the end of the applicable transition period.

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EU: IN VITRO DIAGNOSTIC REGULATION ENTERED INTO FORCE (PART 2 OF 3)

QMSR: Welcomed by the Industry, but Lacking in Practicality

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Research assistant Nicole Gebert contributed to this article. 
After having discussed the general purpose and background of the IVDR, the new definition of IVDs

EU: IN VITRO DIAGNOSTIC REGULATION ENTERED INTO FORCE  (PART 2 OF 3)

Research assistant Nicole Gebert contributed to this article.In vitro diagnostic medical devices (IVDs), hence devices used for medical tests on samples such as blood or tissue that have been taken from the human body, have become the center of attention in the public eye during the COVID-19 pandemic. But also apart from the pandemic, <a target="_blank" href="https://www.grandviewresearch.com/industry-analysis/in-vitro-diagnostics-ivd-market">the industry is seeing significant growth</a> with the software component of such devices becoming increasingly important with regard to in vitro testing.Similar to other medical devices, the regulatory framework for IVDs in Europe is undergoing significant changes. About a year ago, the <a target="_blank" href="https://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:32017R0745">EU Medical Device Regulation (EU) 2017/745</a> (MDR) entered into force and brought about significant challenges for medical device manufacturers with respect to obtaining medical device certification and post-market surveillance compliance (for more information on the MDR find our previous blog series <a target="_blank" href="https://lifesciences.mofo.com/topics/Software-as-a-Medical-Device-in-Europe--New-Regulatory-Regime-About-to-Enter-into-Force--Part-1-of-6.html">here</a>). Now the new <a target="_blank" href="https://eur-lex.europa.eu/eli/reg/2017/746/oj">EU In Vitro Diagnostic Regulation (EU) 2017/746</a> (IVDR) entered into full force and effect on May 26, 2022. Whereas certain legacy devices will benefit from transition periods, all new IVDs and certain low-risk IVDs already on the market are now subject to the IVDR requirements.Key changes that the IVDR brings about for stakeholders in the industry are the following:<ul><li>Broader definition of IVDs; </li><li>New risk-based classification system; </li><li>New conformity assessment procedures;</li><li>New requirements for clinical evidence, performance evaluation, and performance studies;</li><li>Post-market surveillance;</li><li>Introduction of a unique device identifier; and</li><li>Transition periods. </li></ul>This article is split into three parts. In this first part, we will discuss the general purpose and background of the IVDR, the new definition of IVDs, and the conformity assessment in light of the new risk classification as well as the role of notified bodies.In <a target="_blank" href="https://lifesciences.mofo.com/topics/eu-in-vitro-diagnostic-regulation-entered-into-force--part-2-of-3.html">part 2</a> of this article (to be published on June 6, 2022), we will discuss clinical evidence, post-market surveillance (including unique device identifiers (UDIs)), and transition periods.In <a target="_blank" href="https://lifesciences.mofo.com/topics/eu-in-vitro-diagnostic-regulation-entered-into-force-part-3-of-3.html">part 3</a> of this article (to be published on June 13, 2022), we will cast light specifically on software as an IVD and the delineation between the MDR and the IVDR.<h2>Background and Purpose of the IVDR</h2>In the European Union, before an IVD can be marketed, manufacturers must obtain a CE mark to certify that the device complies with applicable law. The former regulatory regime was based on the European Directive on In Vitro Diagnostic Medical Devices (<a href="https://eur-lex.europa.eu/legal-content/EN/ALL/?uri=CELEX%3A31998L0079">IVDD 98/79/EC</a> (IVDD)).The IVDR initially came into force on May 25, 2017, but contained a transition period that (after an extension during the COVID-19 pandemic) ended on May 26, 2022, and completely replaces the IVDD regime. As an EU Regulation, the IVDR does not need to be implemented into national legislation and will be applicable to all members of the EU and EFTA countries immediately. The regulation is designed to create a framework that sets out to improve clinical safety and establish fair market access for IVD manufacturers. The IVDR aims to bring EU legislation in line with technological advances, changes in medical science, and progress in law. Very similar to the MDR, the IVDR focuses on traceability throughout the supply chain, including the use of UDI systems and new clinical evidence standards. More stringent post-market surveillance is required, bringing the regulation of IVDs more closely in line with the requirements for medicines and other medical devices in the EU. It also sets new standards for the application of a CE mark on IVDs to ensure a higher level of quality, safety, and reliability.<h2>New Definition of IVD</h2>The definition of an IVD has been expanded and clarified to include tests intended to predict medical conditions or diseases, as well as companion diagnostics and software. Similar to the definition of a medical device under the MDR, the definition of an IVD is determined by the intended use of the device (more information on the MDR definition is available <a href="https://lifesciences.mofo.com/topics/Software-as-a-Medical-Device-in-Europe--New-Regulatory-Regime-About-to-Enter-into-Force--Part-1-of-6.html">here</a>). In accordance with MDR Article 2(2), the IVDR covers any IVD intended by the manufacturer to be used in vitro for the examination of specimens, including blood and tissue donations, derived from the human body for the purpose of providing information on one or more of the following:<ul><li>A physiological or pathological process or state;</li><li>Congenital physical or mental impairments;</li><li>A predisposition to a medical condition or a disease;</li><li>Safety and compatibility for potential recipients;</li><li>Predictions for treatment response or reactions; or </li><li>Definition or the monitoring of therapeutic measures.</li></ul>Furthermore, specimen receptacles are also deemed to be IVDs.Notably, the broadened IVDR definition explicitly includes software. While this is a reaction to the increasing use of software in the field (compared to the situation under the IVDD when it was established in 1998), it is also consistent with the general developments in EU legislation, which are also reflected in the definition of medical devices under the MDR, which explicitly includes software as well (for more information see part 2 of our <a href="https://lifesciences.mofo.com/topics/Software-as-Medical-Device-in-Eu--New-Reg-Enter-into-Force--Part-2-of-6.html">MDR blog series</a>). When software meets the above-mentioned criteria and serves a medical purpose, it qualifies as an IVD and must comply with the requirements of the IVDR. Examples of IVD software include (i) systems that support the process from patient sample to patient results, such as laboratory information systems and work area managers, (ii) expert systems that are intended to provide information by capturing and analyzing results obtained through in vitro examinations, and (iii) image management systems that incorporate functions to support post-processing of images for diagnostic purposes. A particular spotlight on these devices will be cast in part 3 of this article (to be published on June 13, 2022).<h2>New Risk-Based Classification System</h2>The IVDR adopts a new classification system that categorizes products into four classes according to their risk characteristics. Taking into account both patient and public health risks, these range from low to high:<ul><li>Class A - Low individual risk and low public health risk;</li><li>Class B - Moderate individual risk and/or low public health risk;</li><li>Class C - High individual risk and/or moderate public health risk; and</li><li>Class D - High individual risk and high public health risk.</li></ul><a target="_blank" href="https://eur-lex.europa.eu/legal-content/EN/TXT/HTML/?uri=CELEX:32017R0746&from=de#d1e32-304-1">Annex VIII</a> of the IVDR includes seven classification rules as well as a set of implementing rules, which are intended to aid IVD manufacturers in classifying products according to their risk levels. Additionally, the Medical Device Coordination Group (MDCG), issued its Guidance on Classification Rules for in vitro Diagnostic Medical Devices under Regulation (EU) 2017/746 in January 2022, which is a helpful tool for IVD manufacturers to use to self-assess the classification of their products.Under the IVDR, if IVD software is independent of any other device, it shall be classified in its own right (IVDR; Annex VIII 1.4). In contrast to the classification rules under the MDR which provide a specific rule governing the classification of standalone software as a medical device, the classification of software under the IVDR requires consideration of all classification and implementation rules of Annex VIII. Further guidance on the classification of software under the IVDR is provided by the <a target="_blank" href="https://ec.europa.eu/health/system/files/2020-09/md_mdcg_2019_11_guidance_qualification_classification_software_en_0.pdf">MDCG 2019-11 Guidance on Qualification and Classification of Software in Regulation (EU) 2017/745 – MDR and Regulation (EU) 2017/746 – IVDR</a>, which also contains valuable guidance on the delimitation of software as a medical device versus software as an IVD.<h2>New Conformity Assessment</h2>While the majority of IVDs were permitted to be self-certified by manufacturers under the IVDD, thereby evading the need for a notified body review in order to obtain their CE markings, this will be reversed under the IVDR. Due to the new classification system, the majority of IVDs will undergo a conformity assessment by a notified body, instead of self-certification by manufacturers, before they are deemed to be certified. As can be inferred from the graphic below, only conformity assessment procedures for non-sterile class A devices remain the responsibility of the manufacturer and don’t require the involvement of a notified body. The German notified body <a target="_blank" href="https://www.tuvsud.com/en/industries/healthcare-and-medical-devices/medical-devices-and-ivd/medical-device-market-approval-and-certification">TÜV Süd</a> estimates that 90 percent of all IVDs will have to be tested by a notified body under the IVDR, compared to less than 15 percent under the IVDD. In order for manufacturers to obtain the declaration of conformity and, where necessary, the CE mark certificate, the IVDR stipulates a conformity assessment route for each risk class.<h2>Notified Bodies</h2>As can be inferred from the above, notified bodies play a critical role in supporting manufacturers in their efforts to place only safe and compliant IVDs on the EU market. The IVDR requires notified bodies to be designated. Notified bodies will have to meet more stringent criteria than under the IVDD, particularly in terms of technical and scientific evaluation proficiency. After a notified body applies for designation, the process can take up to 12 months or more, with both national and European authorities involved in the assessment.The EU Commission maintains a <a target="_blank" href="https://ec.europa.eu/growth/tools-databases/nando/index.cfm?fuseaction=directive.notifiedbody&dir_id=35">list of all IVDR-certified notified bodies</a> on its New Approach Notified and Designated Organizations (NANDO) website. Including the <a target="_blank" href="https://www.3ec.sk/en/news/news/3ec-international-as-ziskalo-autorizaciu-a-notifikaciu-podla-ivdr/">latest designation of a notified body in Slovakia in May 2022,</a> there are only seven notified bodies designated under the IVDR, located in only four countries (Slovakia, France, Germany, and the Netherlands). In October 2021, the <a target="_blank" href="https://ec.europa.eu/commission/presscorner/detail/en/qanda_21_5210">EU Commission</a> already addressed this issue as “a grave shortage of notified body capacity” also saying it will be difficult “for manufacturers to conduct the legally required conformity assessment procedures in time.” Consequently, this led to the Commission’s proposal to extend the roll-out periods and introduce new transition periods.<h2>CONCLUDING REMARKS</h2>The IVDR will make a required careful assessment of the intended purpose of IVDs and IVD software inevitable, which must cover every part of their documentation and advertisement. As most IVDs will be reclassified in class B and higher, and therefore require notified body review, the importance of notified bodies within the EU regulatory regime for IVDs will increase significantly. At the same time, only a handful of notified bodies are currently accredited to review and certify IVDs, which creates a bottle neck for IVD manufacturers’ market access. Stakeholders will thus need to plan well in advance of a launch of new IVD products, and it can be expected that many manufacturers will need to rely on transition periods for legacy devices, which will be discussed in detail in part 2 of this series of consecutive articles.

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EU: IN VITRO DIAGNOSTIC REGULATION ENTERED INTO FORCE (PART 1 OF 3)

Is 2021 the Value-Based and Shared Savings Revolution?

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Research assistant Nicole Gebert contributed to this article.
In vitro diagnostic medical devices (IVDs), hence devices used for medical tests on samples such a

EU: IN VITRO DIAGNOSTIC REGULATION ENTERED INTO FORCE  (PART 1 OF 3)

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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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

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

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