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Regulatory Agilities in the Time of COVID-19: Overview, Trends, and Opportunities

Open AccessPublished:November 30, 2020DOI:https://doi.org/10.1016/j.clinthera.2020.11.015

      Abstract

      Purpose

      Crucial steps have been adopted by health and regulatory authorities around the world to respond to the COVID-19 pandemic. This review aims to highlight these steps by providing an overview of the regulatory approaches adopted during the onset of the pandemic, provide an assessment of observed trends, and offer some reflections and proposals to leverage learnings and opportunities from this current pandemic.

      Methods

      Documents and informational materials on regulating the development and management of medical products during the COVID-19 pandemic were collected and classified. These materials were sourced from official websites and press releases from health authorities and international bodies from selected markets across the globe, and covered the period between January and July 2020. Additional information to support this study was gathered through a literature review and analysis of related data available from the public domain, and was complemented with the authors' personal experience.

      Findings

      Communication has been vital in addressing the impact of COVID-19. A total of 1705 documents and informational materials related to health or regulatory response to the COVID-19 pandemic were gathered. Of these, 343 (around 20%) were identified as regulatory agilities. These agile approaches were classified into 3 categories, namely, where health and regulatory authorities had: (1) facilitated product management across the entire lifecycle, notably in expediting medical product use for COVID-19, ensuring the continuity of clinical trials, and addressing supply chain issues; (2) strengthened international cooperation; and (3) addressed regulatory burden with the adoption of electronic and digital tools.

      Implications

      While many regulatory measures have been introduced temporarily as a response to the COVID-19 crisis, there are opportunities for leveraging an understanding from these approaches in order to collectively achieve more efficient regulatory systems and to mitigate and address the impact of COVID-19 and further future-proof the regulatory environment.

      Key words

      Introduction

      A global pandemic of the magnitude of COVID-19 has a significant, even transformative, impact on health care, particularly on those involved in developing COVID-19–related treatments, medical devices, and vaccines, and on those who ensure that already-approved medical products remain available to patients.
      To address the effects of COVID-19 and to simultaneously ensure the continuity of development of non-COVID treatments, regulators have demonstrated significant regulatory agility while maintaining high standards of quality, tolerability, and effectiveness.
      • Stewart J.
      • Honig P.
      • Aljuburi L.
      • et al.
      COVID-19: a catalyst to accelerate global regulatory transformation.
      Regulators have adopted and made public crucial steps to raise awareness and to provide guidance to stakeholders on how to respond and navigate the current pandemic. In doing so, they have demonstrated tremendous agility. This review provides a comprehensive overview and assessment of these steps and of the approaches made available by regulatory authorities. Through this, we include reflections on some lessons learned and how to leverage solutions that continue to provide value-added, streamlined regulatory processes, or to address regulatory burden for the benefit of all stakeholders; from the medical-product developers through the regulators to health care practitioners for the ultimate benefit of patients.
      In this paper, we present several documents or informational materials related to the regulatory environment around the development and management of medical products concerning the COVID-19 pandemic. Some of these documents refer to actions, initiatives, or exceptional approaches where health or regulatory authorities have either: (1) advanced existing initiatives aimed at agile and responsive regulatory systems and processes; or (2) introduced new and innovative ways to expedite and improve such processes. For the purpose of this review, we refer to regulatory agility as the willingness of authorities to take quick action within the accepted regulatory framework to ensure that the regulatory ecosystem swiftly responds to the challenges imposed by the pandemic for the ultimate benefit of patients and society as a whole.

      Materials and Methods

      The data collected for this analysis were extracted by the authors from COVID-19–related information (eg, guidance, guidelines, notices, administrative communications) issued by health authorities in selected markets and regional and international bodies (the African Union, the European Commission, the International Coalition of Medicines Regulatory Authorities, the Organisation for Economic Co-operation and Development, the Pan American Health Organization, and the World Health Organization [WHO]) from January to July 2020 during the initial outbreak. These relate to information that has an impact on the policy environment around the development or lifecycle management of medical products. The information was sourced from the official websites of health authorities or bodies, when available, but excluded policies or information related to confinement and lockdown measures or to situational reports (eg, monitoring the number of cases in a region or country).
      The documents were then classified by zone, country, regulatory authority, information format, and topic area. These documents were also further classified into what we refer to as “regulatory agilities” by flagging those that explicitly indicate, within the text, the use of exceptional measures or flexible approaches of a regulation or regulatory process, which ultimately aim to facilitate the review, approval, and availability of medical products during the COVID-19 pandemic within the January to July 2020 time frame. We have then used these data as a basis for extracting trends, learnings, and potential ways forward. To put trends and learnings into perspective, additional information was gathered through a literature review and analysis of related data available from the public domain, as were the authors' experiences within the company.

      Results

       Figures on COVID-19–related Documents and Information

      As of July 2020, we collected 1705 documents and informational materials related to the policy environment affecting the development and management of COVID-19 medical products based on the aforementioned methodology. Fig. 1 presents an overview of the distribution of documents by month, which demonstrates a rapid increase in documents and information released by authorities and bodies in the March–April timeframe, followed by a gradual decline in new documents and information released from May onward. This finding shows the trend of COVID-19–management efforts across the world—more information was required at the onset of the pandemic, and subsequently less information was required in the later months as various approaches to better managing the situation were adopted.
      Figure 1
      Figure 1Number of COVID-19–related documents and information, by month. Source: Authors' elaboration, Sanofi COVID-19 regulatory guidance tracker, updated July 31, 2020.
      Figure 2 shows the distribution by zone, with Asia–Pacific having the highest number of documents issued. This number was driven by New Zealand and Australia, which respectively constituted 33% and 30% of the documents in the zone. China represented 13% of the total number of documents in the zone. The second-largest zone by number of documents came from Europe, of which 32% came from European Union–level authorities such as the European Commission and the European Medicines Agency. Fig. 3 provides a closer look at the distribution of these documents at the national level, hence excluding documents from regional (eg, African Union, European Medicines Agency) and/or global bodies.
      Figure 2
      Figure 2Distribution of COVID-19–related documents and information, by zone. AMEE = Africa, Middle East, and Eurasia; LATAM = Latin America. Source: Authors' elaboration, Sanofi COVID-19 regulatory guidance tracker, updated July 31, 2020.
      Figure 3
      Figure 3Heat map of COVID-19–related documents and information from authorities in selected countries, excluding regional or global organizations. Source: Authors' elaboration, Sanofi COVID-19 regulatory guidance tracker, updated July 31, 2020.
      These documents were further classified according to type (Fig. 4). Around 60% constituted documents that came in the form of communications (including announcement, notices, press releases, and circulars); 22%, guidance (including policies); 7% in the form of laws (including regulations, statutes, directives); and the rest as publications or “other.” In terms of topic area (Fig. 5), excluding the category “other,” most documents referred to information on clinical trials, safety, or multidisciplinary areas. The category “other” referred to documents and information that could not be otherwise classified (eg, agency operation and continuity, procurement, data protection, coordination mechanisms and platforms, meetings and response documents, among others).
      Figure 4
      Figure 4Type of COVID-19–related documents and information (in percentage). Other = documents or information that could not be classified elsewhere (eg, reports, meeting highlights or summary, or templates). Source: Authors' elaboration, Sanofi COVID-19 regulatory guidance tracker, updated July 31, 2020.
      Figure 5
      Figure 5Number of COVID-19–related documents and information, by topic area. Other = documents or information that could not be classified elsewhere (eg, agency operation and continuity, procurement, data protection, coordination mechanisms and platforms, meetings and response documents, among others). Source: Authors' elaboration, Sanofi COVID-19 regulatory guidance tracker, updated July 31, 2020.
      From these documents and materials, 343 (20%) that referred to regulatory agility or flexibility were identified. Figure 6, Figure 7 provide an overview of the distribution by zone and by type. Using these data, some information was extracted and coupled with information from public databases, literature reviews, and the authors' internal experiences and trends were identified and are described in the next section.
      Figure 6
      Figure 6Number of COVID-19–related documents and information that refer to regulatory agilities, by zone. AMEE = Africa, Middle East, and Eurasia; Global = the PAHO document on clinical trials
      Pan American Health Organization
      Clinical management of COVID-19 [PAHO website].
      ; LATAM = Latin America. Source: Authors' elaboration, Sanofi COVID-19 regulatory guidance tracker, updated July 31, 2020.
      Figure 7
      Figure 7Number of COVID-19–related documents and information that refer to regulatory agilities, by topic area. Other = documents or information that could not be classified elsewhere (eg, agency operation and continuity, procurement, data protection, co-ordination mechanisms and platforms, meetings and response documents, among others). Source: Authors' elaboration, Sanofi COVID-19 regulatory guidance tracker, updated July 31, 2020.

       Trends in Regulatory Approaches

       Facilitating Product Management Across the Entire Lifecycle

       Expedited Regulatory Reviews and Approvals

      To ensure that COVID-19–related medical products are rapidly assessed as potential treatments or vaccines, health authorities have considered expedited pathways,
      European Medicines Agency
      COVID-19: how EMA fast-tracks development support and approval of medicines and vaccines [EMA website].
      either through an already-existing pathway or as a new COVID-19–related emergency pathway.
      Centre for innovation in regulatory science. Emergency use pathways (EUPs): applying regulatory flexibility in the age of COVID-19 [CIRSCI website].
      Table I describes some examples of the various regulator-offered expedited pathways for COVID-19–related medical products.
      Table IExamples of expedited pathways offered for COVID-19–related medical products.
      PathwayDescription
      Rapid scientific adviceDevelopment of prompt guidance for sponsors on methods, study design, or robust data collection and generation for a medical product.
      European Medicines Agency
      COVID-19: how EMA fast-tracks development support and approval of medicines and vaccines [EMA website].
      On reviews
       Expedited reviewsReduction of timelines to the absolute minimum possible for products with major interest in public health. This encompasses priority reviews, fast track designations, and accelerated approvals.
      European Medicines Agency
      COVID-19: how EMA fast-tracks development support and approval of medicines and vaccines [EMA website].
      ,
      • Food and Drug Administration
      US dept of health and human services. Fast track [FDA website].
      Health Canada
      Priority review of drug submissions [Health Canada website].
      • Beninger P.
      COVID-19: regulatory landscape of medicinal and medical device products for human use.
       Rolling reviewsA procedure that allows the regulator to assess data on a particular medical product as they are made available on a rolling basis. In the case of the EMA, this review procedure involves appointed CHMP rapporteurs during the development phase and the agency reviewing the data on a rolling basis. This can be done through several review cycles. Each cycle lasts around two weeks depending on the data to be assessed until the data package is considered complete. Once complete, the sponsor can submit a formal marketing authorization application that is reviewed under a shorter timeline.
      European Medicines Agency
      COVID-19: how EMA fast-tracks development support and approval of medicines and vaccines [EMA website].
      On approvals
       Conditional approvalsRegulators can grant a conditional marketing authorization for medical products where the immediate benefit outweighs the risk for having less available data than normally available. These are valid for one year and can be renewed each year, following specific obligations.
      European Medicines Agency
      Conditional marketing authorisation [EMA website].
       Emergency useRegulators allow for the use of approved or unapproved medical products to diagnose, treat, or prevent serious and life-threatening diseases and conditions during an emergency when there are no adequate, approved, and available alternatives.
      • Beninger P.
      COVID-19: regulatory landscape of medicinal and medical device products for human use.
      ,
      • Food and Drug Administration
      US dept of health and human services. Emergency use authorization [FDA website].
      ,
      • World Health Organization
      Emergency Use Assessment and Listing (EUAL) procedure for IVDs [WHO website].
       Expanded accessAlso referred to as compassionate use, regulators allow for the use of an investigational medical product outside clinical trials for serious, immediately life-threatening diseases and conditions when no comparable, satisfactory alternative treatment is available.
      • Food and Drug Administration
      US dept of health and human services. Expanded access [FDA website].
      ,
      European Medicines Agency
      Compassionate use [EMA website].
      Special programs
       Coronavirus Treatment Acceleration Program (CTAP)The US FDA's special emergency program that aims to use every available method to facilitate the discovery and development of new treatments for COVID-19.
      • Food and Drug Administration
      US dept of health and human services. Coronavirus treatment acceleration program (CTAP) [FDA website].
       Operation Warp Speed (OWS)OWS is a partnership across the United States' bodies and agencies and private firms, with the aim of accelerating the development of COVID-19 vaccines and distributing 300 million doses of these safe and efficacious vaccines by January 2021.
      US Dept of Health and Human Services
      Fact sheet: explaining operation Warp speed [FDA website].
      CHMP = Committee for Medicinal Products for Human Use; EMA = European Medicines Agency; FDA = US Food and Drug Administration; OWS = Operation Warp Speed.
      In addition to those offered by regulators at the national or regional level, the WHO made available 2 global pathways for facilitating access to medical products in emergency situations: (1) the WHO Emergency Use and Listing, which aims to provide guidance to United Nations procurement agencies and regulators of WHO member states on the quality, tolerability, and performance of in vitro diagnostics
      • World Health Organization
      Emergency Use Assessment and Listing (EUAL) procedure for IVDs [WHO website].
      ; and (2) the WHO prequalification program, which aims to assess the quality, tolerability, and efficacy of medicinal products for priority diseases.
      Centre for innovation in regulatory science. Emergency use pathways (EUPs): applying regulatory flexibility in the age of COVID-19 [CIRSCI website].
      ,
      • World Health Organization
      Prequalification of medicines by WHO [WHO website].

       Streamlining Clinical Trials

      Flexible Approaches. Regulators have adopted approaches to facilitating the continuity of clinical trials of both COVID-19–related medical products and ongoing or planned studies outside of COVID-19.
      Danish Medicines Agency
      Danish medicines agency shortens the review time for applications for COVID-19 medicine trials [Danish medicines agency website].
      Guidance on conducting clinical trials during the pandemic have been offered by several regulators
      European Medicines Agency
      Guidance on the management of clinical trials during the COVID-19 (Coronavirus) pandemic [EMA website].
      • Food and Drug Administration
      US dept of health and human services. FDA guidance on conduct of clinical trials of medical products during COVID-19 public health emergency: guidance for industry, investigators, and institutional review boards [FDA website].
      Swissmedic & Swissethics
      Joint guidance of swissmedic and swissethics on the management of clinical trials with medicinal drug products in Switzerland during the COVID-19 pandemic [Swissmedic website].
      Health Canada
      Management of clinical trials during the COVID-19 pandemic: notice to clinical trial sponsors [Health Canada website].
      • Board Poisons
      Ministry of Health Pharmacy
      Guidance to sponsors and investigators for conduct of clinical trials during the COVID-19 pandemic in Kenya [Ministry of Health Pharmacy and Poisons Board website].
      —many of which are nonbinding and require effective monitoring from the sponsor and clinical investigators. These approaches ensure that patient safety remains paramount and that open communication is maintained across the various stakeholders involved in clinical trials. Some of these approaches are further described in Table II.
      Table IIFacilitating clinical trials during the COVID-19 pandemic.
      TopicDescription
      On changes in the conduct of clinical trialsSome protocol changes are permitted without the approval of institutional review boards or ethics committees
      • Food and Drug Administration
      US dept of health and human services. FDA guidance on conduct of clinical trials of medical products during COVID-19 public health emergency: guidance for industry, investigators, and institutional review boards [FDA website].
      or through a risk-based assessment from the sponsor.
      European Medicines Agency
      Guidance on the management of clinical trials during the COVID-19 (Coronavirus) pandemic [EMA website].


      Temporarily halting the trial, when it is not linked to the safety of the participant, to liberate resources to COVID-19 trials.
      European Medicines Agency
      Guidance on the management of clinical trials during the COVID-19 (Coronavirus) pandemic [EMA website].
      On the delivery investigational medicinal productsDelivery of investigational medicinal products directly to patients in case the trial participant has no access to the hospital or investigation site.
      European Medicines Agency
      Guidance on the management of clinical trials during the COVID-19 (Coronavirus) pandemic [EMA website].
      ,
      Swissmedic & Swissethics
      Joint guidance of swissmedic and swissethics on the management of clinical trials with medicinal drug products in Switzerland during the COVID-19 pandemic [Swissmedic website].


      Supplying larger amounts of Investigational Medicinal Products to trial participants, with the supervision of the investigator.
      European Medicines Agency
      Guidance on the management of clinical trials during the COVID-19 (Coronavirus) pandemic [EMA website].
      On monitoringAllowing for the use of alternative methods for safety assessment when in-person visits or on-site monitoring are unavailable, such as remote monitoring (phone contact, telemedicine, virtual visits) or use of alternative centers, as appropriate.
      European Medicines Agency
      Guidance on the management of clinical trials during the COVID-19 (Coronavirus) pandemic [EMA website].
      ,
      • Food and Drug Administration
      US dept of health and human services. FDA guidance on conduct of clinical trials of medical products during COVID-19 public health emergency: guidance for industry, investigators, and institutional review boards [FDA website].
      Collaboration and Harmonization Efforts. In August 2020, some 4800 clinical trials were being conducted worldwide, including those of COVID-19 treatments. Study types during this period were mostly either interventional or observational.
      • World Health Organization
      International clinical trials registry platform [WHO website].
      Significant efforts to ensure greater harmonization of clinical trials of COVID-19 treatments and vaccines are being made. These efforts include initiatives such as the WHO “Solidarity” Clinical Trial for COVID-19 Treatments,
      • World Health Organization
      the African Union's Consortium for COVID-19 Vaccine Clinical Trial
      • African Union
      African union commission launches Consortium for COVID-19 vaccine clinical trial [Africa CDC website].
      ; guiding principles provided by the International Coalition of Medicines Regulatory Authorities
      International Coalition of Medicines Regulatory Authorities
      ICMRA statement on clinical trials [ICMRA website]. June 24, 2020.
      ; and industry data-sharing efforts such as those facilitated by TransCelerate.
      TransCelerate. COVID-19
      Learn more about COVID-19 data sharing [TransCelerate website].

       Ensuring Continuous Supply of Medical Products and Avoiding Shortages

      Ensuring the supply of medical products remains essential, especially in emergency health situations, when the risk for shortages can be elevated. Simplified and exceptional management of regulatory processes have therefore been adopted by various regulators to maintain supply and to lower the risk for such shortages. These processes have complemented industry efforts, such as increasing production and donating medical products where needed. Expedited reviews have been offered (Table I) and have been useful, especially for post-approval changes, such as in the case of the European Union's use of the exceptional change management process.
      • European Commission, HMA & EMA
      Notice to stakeholders: questions and answers on regulatory expectations for medicinal products for human use during the COVID-19 pandemic [European commission website].
      With regard to ensuring good practices, regulators have offered to conduct inspections remotely
      Australia Therapeutic Goods Administration
      TGA expectations for overseas manufacturing sites hosting remote inspections during the COVID-19 pandemic [TGA website].
      or have granted sponsors existing marketing-authorization approval extensions, automatic recertifications, or temporary certifications.
      • European Commission, HMA & EMA
      Notice to stakeholders: questions and answers on regulatory expectations for medicinal products for human use during the COVID-19 pandemic [European commission website].
      ,
      National Health Surveillance Agency (Anvisa), Brazil Ministry of Health
      Resolution 346: Defines the Extraordinary and Temporary Criteria and Procedures for the Certification of Good Manufacturing Practices for the Purposes of Registration and Post-Registration Changes of Active Pharmaceutical Ingredient, Medication and Health Products Due to the International Public Health Emergency of the New Coronavirus [DO Online].
      The use of flexible approaches to labeling has also been widespread. For example, printed labels and packages adopted to a specific market may take a long time to be approved and then produced to ensure their availability during a pandemic. Some of the proposed regulatory approaches to address this issue have included extending the permitted implementation time of the labeling update (except for significant safety updates),
      Health Products Regulatory Authority
      Variation implementation times for labelling and leaflet updates to human medicines: update on regulatory flexibility during the COVID-19 pandemic. [HPRA website].
      allowing nonlocal-language labeling,
      • Swedish Medical Products Agency
      Temporary regulations regarding language requirements for medical devices [Swedish medical products agency website].
      using electronic submissions of packaging and leaflets instead of physical samples,
      National Institute of Pharmacy and Nutrition
      Information on the announcement and receipt of the final sample [national institute of pharmacy and nutrition website].
      and packing down of larger packs of medicinal products.
      • Medicines and Healthcare Products Regulatory Agency
      Guidance for manufacturers specials licence holders on 'packing down' medicines during the coronavirus (COVID-19) outbreak [MHRA website].
      In addition, open and transparent communication across stakeholders through virtual communication platforms and online notifications have proved useful in identifying any potential out-of-stock situations (eg, the US Food and Drug Administration's Drug Shortages database
      • Food and Drug Administration
      US dept of health and human services. FDA drug shortages: current and resolved drug shortages and discontinuations reported to FDA [FDA website].
      and mobile app
      • Food and Drug Administration
      US dept of health and human services. Drug shortages. United states Food and drug authority [FDA website].
      ), as well as the creation of industry–agency task forces and working groups that allow for regular interactions between industry and regulators on shortages (eg, the executive steering group on shortages and the industry single point–of-contact system in the European Union).

       Greater Work-sharing and Transversal Collaboration

      The COVID-19 crisis has also increased collaboration both across and between health authorities and industry. Various government-led partnerships and global consortia have been initiated to facilitate working together with industry and other stakeholders, such as academia, to accelerate the research and development of medical approaches to combatting COVID-19.
      National Institutes of Health
      NIH to launch public-private partnerships to speed COVID-19 vaccines and treatment options [NIH website].
      Institut Pasteur
      CEPI collaborates with the institut pasteur in a Consortium to develop COVID-19 vaccine [Institut Pasteur website].
      University of Oxford
      Oxford university announces landmark partnership with astrazeneca for the development of potential large-scale distribution of COVID-19 vaccine candidate [University of Oxford website].
      In addition to the various bilateral partnerships that have emerged at the government and industry levels, multilateral partnerships and initiatives have aimed to bring together efforts to building scientific knowledge and to pool resources to offer solutions to the pandemic (Table III).
      Table IIIExamples of partnerships leveraged to collectively combat COVID-19.
      PartnershipDescription
      Access to COVID-19 Tools (ACT) AcceleratorPools together various stakeholders (governments, businesses, civil society, and international actors) to support in the development and equitable distribution of medicinal products to lower mortality and severe COVID-19 cases.
      • Food and Drug Administration
      US dept of health and human services. Fast track [FDA website].
      COVID-19 Therapeutics AcceleratorLaunched by the Bill & Melinda Gates Foundation, Wellcome, and Mastercard, this platform aims to support the acceleration and evaluation of new and repurposed medicines and vaccines to treat patients with COVID-19, and ensure equitable access by making these available and affordable notably in low-resource settings.
      Bill & Melinda Gates Foundation
      Announcing the COVID-19 therapeutics accelerator [Bill & Melinda Gates foundation website].
      International Coalition of Medicines Regulatory Authorities (ICMRA)Serves as a forum for strategic co-ordination and international cooperation across regulatory authorities. In lieu of the COVID-19 pandemic, ICMRA members have aimed to expedite and streamline the research, development, and access of COVID-19 treatments and vaccines and ensure the effective and efficient approach to regulatory processes and decisions.
      International Coalition of Medicines Regulatory Authorities
      COVID-19 [ICMRA website].

       Addressing the Regulatory Burden

      Evidently, the current pandemic has also seen progress in the swift adoption of electronic platforms across many countries around the world—propelling stakeholders into a predominantly digital work mode. Based on information collected from our tracker and our experience when interacting with regulatory authorities, video calls have been used extensively, and even by default, to ensure regular interaction, while the use of the cloud and other online storage tools have been encouraged to store and share documents and information in real-time. Some countries have also opted for online submission of marketing-authorization applications, such as through an email-based or online platform, notably where they have not been previously or extensively used.
      While efforts to modernize regulatory processes through eliminating dated regulations and processes, and through the waiving of supplemental requirements, are not new, the pandemic has undoubtedly demonstrated that it is possible to reduce or even eliminate some unnecessary administrative steps and requirements that can often be burdensome for both regulators and stakeholders involved in the process. Some approaches that have been introduced to lower the bureaucratic burden include:
      Issuance of electronic Certificates of Pharmaceutical Products that are signed and authenticated electronically
      European Medicines Agency
      Information note on the format and validity features of electronic Certificates for medicines issues by the European Medicines Agency [EMA website].
      ;
      Acceptance of e-signatures
      • Ministry of Health Brazil & Anvisa
      Reolucao de Diretoria colegiada. RDC 355.
      ;
      Waiving of legalizations/notarizations,
      • Turkey Medicines
      • Medical Devices Agency
      To the attention of all pharmaceutical companies [TMMDA website]. April 22, 2020.
      ,
      Ministry of Public Health
      Circular 6: waiving off document legalization requirements [Ministry of Public Health website].
      with the condition of submitting legalized documents after the COVID-19 pandemic
      • Government of India
      Submission of notarized/apostilled documents for import and registration of cosmetics in view of COVID-19 regarding [Government of India website].
      ; and
      Waiving of physical-sample requirements
      Australia Therapeutic Goods Administration
      Physical samples for batch release not required: a reminder for sponsors of biosimilars and biological medicines [TGA website].
      ,
      • Food and Drug Administration Ghana
      Re-registration and variation applications during COVID-19 pandemic [Food and drugs authority Ghana website].

       Implications of COVID-19 on Health Authority Operations

      Many of the identified regulatory approaches have indeed been introduced temporarily to allow health authorities and stakeholders to manage the pandemic and to ensure the continuity of their respective operations. However, even with sustained operations, catching up on backlogs, delayed sponsor meetings, and other activities that had to be suspended during the pandemic constitute a challenge, as does resuming activities that have not yet been extensively tested in a virtual environment prior to the current pandemic (eg, remote inspections).
      Furthermore, new priorities emerging from the pandemic, such as ensuring supply-chain integrity and managing increasing fake medicines,
      Organisation for Economic Co-operation and Development
      Coronavirus (COVID-19) and the global trade in fake pharmaceuticals [OECD website].
      ,
      Interpol. Global
      Operation sees a rise in fake medical products related to COVID-19 [Interpol website].
      may require health authorities to seek additional tools and resources. In addition, the pandemic has affected the implementation of some new provisions, such as the EU Medical Device Regulation
      • Brennan Z.
      European commission proposes to delay MDR by a Year due to COVID-19 [RAPS regulatory focus].
      or Australia's adoption of TGO 91 labels,
      Australia Therapeutic Goods Administration
      COVID-19 delays to adoption of TGO 91 labels [TGA website]. TGA.
      to which resources have already been initially allocated.
      These new and/or emerging challenges can be addressed by continuously leveraging the agile approaches implemented during this pandemic. While these agile approaches have been triggered by COVID-19, there is indeed additional opportunity to expand them beyond the current pandemic and to adopt them to other services or products that could also benefit all stakeholders involved, notably patients.

       Leveraging Findings and Opportunities

      COVID-19 has precipitated several opportunities that could be sustained beyond the pandemic. Based on the trends discussed earlier and the adoption of such approaches to date, 5 considerations in moving forward can be proposed: (1) embedding regulatory agility and lessons learned; (2) accelerating the development process of innovative medical products; (3) address manufacturing and supply bottlenecks; (4) strengthening international cooperation, notably for clinical trials and vaccine development; and (5) committing to easing the regulatory burden and adopting the use of digital technologies.

       Embedding Regulatory Agility and Lessons Learned

      Regulators have reacted quickly with the expedited issuance of relevant guidance during the acute phase of the pandemic, while making sure that these remain to meet quality requirements. This reaction was especially useful for the industry's understanding of “current” agency thinking and aligning approaches toward addressing the impact of the pandemic. To fully benefit from the gains achieved in the United States of these agile regulatory approaches and extracted lessons for the future, it would be useful to conduct ex-post or postimplementation reviews. These reviews would allow regulators to determine which specific approaches resulted in the most gains across the sector and to identify those that can be introduced temporarily during emergency situations or permanently adopted. Reviewing such approaches can also help to identify best practices that can be shared across regulatory authorities globally and allow for a closer examination to ensure that regulatory mechanisms remain fit for purpose,
      • Mak T.K.
      • Lim J.C.W.
      • Thanaphollert P.
      • et al.
      Global regulatory agility during COVID-19 and other health emergencies.
      are increasingly harmonized, and take into account the possible risks and consequences in its application.
      Various ways of conducting ex-post evaluations can be pursued, such as in the form of programed review mechanisms or special-purpose reviews.
      • Allio L.
      Ex Post Evaluation of Regulation: An Overview of the Notion and of International Practices. Regulatory Policy in Perspective: A Reader's Companion to the OECD Regulatory Policy Outlook 2015.
      Effective stakeholder engagement throughout this process, through dialogue fora or other structured discussions and consultations, is essential for ensuring the uptake and implementation of any embedded regulatory approaches.

       Accelerating the Development Process of Innovative Medical Products

      In order to accelerate innovation of treatments and vaccines to meet (unmet) medical needs for the benefit of patients, expedited review and approval pathways continue to play an important role during the COVID-19 pandemic, especially among mature agencies. For example, the EMA implemented a rolling review tool to speed up the entire review process (Table I).
      To also stimulate the uptake of innovative medical products in emerging markets, where no expedited pathways are already available, regulatory agencies can consider the use of such pathways beyond COVID-19 and for a wider gamut of products or services, such as in the case of emergency situations or in allowing for an expedited approval of medical products for serious, life-threatening diseases. Nonetheless, any new expedited pathway introduced need to be carefully crafted, and experiences from other regulators that have implemented such pathways can be further leveraged.
      • Lexchin J.
      Health Canada's use of expedited review pathways and therapeutic innovation, 1995-2016: cross-sectional analysis.
      In addition, the use of existing expedited pathways during the pandemic also offers an opportunity for regulators to reflect on and review the effectiveness of them to identify challenges and solutions to eventually introduce improvements to the process.
      In cases in which the current system of a regulatory authority is still on the path to maturity, and in which resources for dedicated expedited pathways are limited, regulators can adopt reliance or work-sharing approaches that help facilitate the application of such approaches. For example, regulators can rely on trusted regulatory authorities according to the WHO-Listed Authority Interim List of National Regulatory Authorities.
      • World Health Organization
      A framework for evaluating and publicly designating regulatory authorities as WHO-listed authority (WLA) Interim list of national regulatory authorities [WHO website].
      They can also depend on available global pathways and guidance through the WHO Emergency Use Listing or Prequalification program.
      Centre for innovation in regulatory science. Emergency use pathways (EUPs): applying regulatory flexibility in the age of COVID-19 [CIRSCI website].
      ,
      • Lumpkin M.M.
      • Lim J.C.W.
      Pandemic best regulatory practices: an urgent need in the COVID-19 pandemic.

       Addressing Manufacturing and Supply Bottlenecks

      Medical products should be made available across their entire lifecycle. With the current pandemic affecting the availability across the globe, maintaining sustainable and resilient supply chains became even more important. Agile regulatory approaches related to manufacturing and supply chains, adopted to address some of the issues, have therefore been useful in providing guidance and complementing efforts carried out within industry. With careful review and analysis, such approaches can be broadly adopted and even improved.
      For example, the need for immediately available updated label or package information has resulted in agile approaches to the use of nonlocal language labeling or packed down versions of the product. While the waiving of labeling requirements can be useful for emergency purposes, developing the use of QR codes or adopting dynamic e-labeling can ensure that the most updated packaging and labeling information are made available and accessible to regulators, health care practitioners, and patients online or through pharmacies, even beyond the current pandemic.
      • Lumpkin M.M.
      • Lim J.C.W.
      Pandemic best regulatory practices: an urgent need in the COVID-19 pandemic.
      ,
      • Bolislis W.R.R.
      • Mortazavi C.
      • Riccioni R.
      • et al.
      From print to screen: regulatory considerations to adopting innovative approaches for patient information and safety.
      Broader application of remote inspections outside the pandemic, while risk-based approaches are maintained, may also be explored when both the regulatory authority and the manufacturers have an environment suitable for conducting the virtual inspection. Remote inspections can also help to ensure a smooth site transition, in cases of issues encountered with the current manufacturing site, or the possibility of utilizing multiple manufacturing sites.
      Furthermore, partnerships and platforms for discussion that have been leveraged or established during the COVID-19 pandemic, such as those that ensure efficient notification of medical product shortages, remain essential. These partnerships or platforms can play an important role when developing future guidance on the supply of essential medical products that need to be maintained beyond the pandemic (eg, life-saving medicines) or when introducing or enhancing tools for postmarketing surveillance or for the notification of supply shortages.
      • Scholz N.
      for the European Parliamentary Research Service
      Addressing shortages of medicines.
      ,
      European Federation Pharmaceutical Industries and Associations
      Policy proposals to minimise medicine supply shortages in Europe [EFPIA website].

       Strengthening International Cooperation, Notably for Clinical Trials and Vaccine Development

      The COVID-19 pandemic has demonstrated the increasing importance of working transversally across stakeholders to ensure that viable solutions are available for patients around the world. The benefits of different actors working close together is clearly evidenced by the various partnerships and platforms leveraged or initiated.
      For example, lesser-resourced regulatory authorities, whose operations have been greatly impaired by the pandemic, can also benefit from insights from better-resourced regulatory authorities, and facilitate data sharing and approaches more broadly across different jurisdictions, especially on product development, clinical trials, and marketing authorization.
      • Mak T.K.
      • Lim J.C.W.
      • Thanaphollert P.
      • et al.
      Global regulatory agility during COVID-19 and other health emergencies.
      ,
      • Pregelj L.
      • Hine D.C.
      • Oyola-Lozada M.G.
      • et al.
      Working hard or hardly working?.
      Reliance and work-sharing approaches can be further explored, as suggested by the WHO.
      • World Health Organization
      Regulatory collaboration: collaboration, not competition: developing new reliance models.
      A recently released WHO draft guidance on good reliance practices in regulatory decision-making provides some additional information and insights on how these practices can be implemented by regulators.
      • World Health Organization
      Draft working document for comments: good reliance practices in regulatory decision-making: high-level principles and recommendations. Working document QAS/20.851.
      As various approaches are being pursued to test medical products during the COVID-19 pandemic, consistency and harmonization on the oversight, review, and management of clinical trials are important.
      Organisation for Economic Co-operation and Development
      Greater harmonization of clinical trial regulations would help the fight against COVID-19. OECD policy responses to coronavirus (COVID-19) [OECD website].
      The Organisation for Economic Co-operation and Development offers some binding recommendations on the governance of clinical trials, including facilitating international cooperation, by which member states have agreed to abide.
      Organisation for Economic Co-operation and Development
      Recommendation of the council on the governance of clinical trials [OECD website].
      Approaches that facilitate the management and oversight of clinical trials, such as the use of remote clinical trials, can be further explored.
      • Izmailova E.S.
      • Ellis R.
      • Benko C.
      Remote monitoring in clinical trials during the COVID-19 pandemic.
      ,
      • TransCelerate
      Beyond COVID-19: modernizing clinical trial conduct [TransCelerate website].
      Maintaining international cooperation across all stakeholders will be especially important for vaccine research and development, which can be a rather lengthy and complex process.
      • Pregelj L.
      • Hine D.C.
      • Oyola-Lozada M.G.
      • et al.
      Working hard or hardly working?.
      ,
      • Mella K.
      • Mohan V.K.
      Coronavirus vaccine: light at the end of the tunnel.
      Various approaches are already being pursued to speed up and support the clinical-trial process, such as the use of remote clinical trials, e-consent, and direct-to-patient delivery of investigational medicinal products. However, strengthened international regulatory cooperation with stakeholders not only should be limited to the current pandemic but also must persist even postpandemic.

       Committing to Easing the Regulatory Burden and Adopting the Use of Digital Technologies

      Already-existing approaches that simplify or facilitate certain regulatory processes, such as the use of electronic submissions and payments, digital signatures, or online platforms for meetings, discussions, or information sharing are also some practices that can be retained or adopted more broadly.
      Opportunities to adopt innovative digital technologies, platforms, and tools can be further explored to propel the regulatory environment further into the future. These opportunities include data-sharing tools such as the use of a cloud-based data system to support a more agile regulatory decision-making process
      • Robertson A.S.
      • Malone H.
      • Bisordi F.
      • et al.
      Cloud-based data systems in drug regulation: an industry perspective.
      and processes facilitated by artificial intelligence.
      Organisation for Economic Co-operation and Development
      Using artificial intelligence to help combat COVID-19 [OECD website].
      These can also be further classified into those that facilitate the drug development or clinical trial process and those that can be broadly adopted as a way of working.
      Reducing the regulatory burden is a shared objective by all stakeholders, as it puts a strain on the limited resources available, and even more during emergency situations. This pandemic has provided an opportunity to look closely into regulatory tools and approaches that simplify operations and reduce unnecessary administrative steps to deliver more efficient, forward-looking regulatory systems.

      Discussion

      Significant efforts to manage and address the COVID-19 pandemic are being made and demonstrated by all stakeholders across the health sector. At the heart of the attention is the tremendous commitment from health authorities and regulators to ensure that communication channels remain open across stakeholders in order to collectively address the impact of the pandemic. Health authorities and regulators have responded promptly and communicated widely. They have provided guidance and demonstrated regulatory agility to complement efforts in the industry. These approaches have ensured that COVID-19 medical products are developed and made available to society, that new medical innovations under development continue to progress, and that existing medical products remain available to patients around the world. Such guidance and agile approaches remain valuable in addressing this crisis and in future situations, especially when they are consistent and aligned across regulatory authorities.
      The current pandemic has provided lessons learned in addressing global emergency situations, and these experiences—both the challenges and solutions adopted—can be leveraged for preparation for any future situations and can serve as an opportunity to reflect on current regulatory processes and tools. The authors propose that all relevant stakeholders work together to arrive at concrete proposals and actions in adopting learnings identified from agile approaches used during the COVID-19 crisis. Initiatives to review learnings are being undertaken by some health and regulatory authorities to embed enhancements into future regulatory processes. In some instances, it may help agencies to “leapfrog” into contemporary approaches (ie, maturing regulatory agencies looking into advancing their regulatory processes and systems and strengthening collaboration with other regulatory agencies and stakeholders).
      The use of digital tools during the pandemic has also been remarkable and has facilitated the continuity of business operations. It has provided the opportunity for the pharmaceutical sector to reevaluate the use of tools to ensure that they are able to facilitate the efficient functioning of regulatory processes and operations that ensure that medicines are developed and made available to patients. More importantly, this pandemic has underscored the importance and the benefit of working across all stakeholders, which can be continuously leveraged even postpandemic. A robust, coordinated approach will be beneficial, given the shared aims of ending the pandemic, ensuring a healthy population, and better managing emergency situations in the future.
      The deployment of digital-communication tools has seemingly lowered the barrier of communication and perhaps increased the frequency by which they have occurred, which has proven to be beneficial for all parties involved.

      Conclusions

      The use of agile regulatory approaches during the pandemic has helped to ensure that medical products have remained available, and that new ones could be effectively researched to address patients' needs. Nonetheless, many of these approaches have been introduced temporarily to mitigate the impact of the pandemic on patients and society. A number of learnings can be leveraged to further improve the regulatory environment. Proposals include: (1) embedding regulatory agility and lessons learned; (2) accelerating the development of innovative medical products; (3) addressing manufacturing and supply-chain bottlenecks using flexible labeling requirements or digital approaches such as remote inspections to facilitate site transfers or use of multiple sites; (4) strengthening international cooperation, notably in clinical trials and vaccines development; and (5) committing to easing regulatory burden and adopting digital tools. The use of these agile regulatory approaches that add value and have the potential to create opportunities to progress innovative research and development of medical products will be crucial for the future benefit of patients and society.

      Author Contributions

      All authors designed the commentary, analyzed the data, and wrote the manuscript.

      Disclosures

      All authors hold positions within the pharmaceutical industry, but did not receive any grant, honoraria, or other compensation to author this article. The study was conceived, executed, and written up in the course of the authors' daily jobs. The authors have indicated that they have no conflicts of interest with regard to the content of this article.

      Disclaimer

      The views expressed in this research are the independent views of the authors and should not be understood or quoted as being made on behalf of or reflecting of the position of their respective companies or any other affiliation.

      Acknowledgments

      We thank Sophie Miet-Eseverri, Sothavy Nguyen-Say, Camille Jackson, and Sara Ferragu for assistance in building part of the Sanofi COVID-19 regulatory guidance tracker. We also thank Lina Aljuburi for providing constructive feedback on the manuscript.

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