The ASAP Framework: A New Tool for Regulatory Agencies to Facilitate Adoption of Pandemic Approaches

Abstract

COVID-19 Lessons Learned

Urgency and a shared mission to identify and prevent transmission of SARS-CoV-2, as well as mitigate and treat COVID-19 disease, led regulatory agencies and innovating companies to change the way they work during the COVID-19 pandemic. The world watched as COVID-19 vaccines and treatments were developed and authorized for use in record time without compromising their quality, safety, or efficacy. The flexibility and ingenuity of the regulatory agencies tasked with reviewing and authorizing COVID-19 treatments and vaccines was critical to achieving this outcome while allowing the development of other products to continue during the pandemic.

During the COVID-19 pandemic, regulatory agencies across the globe developed new—and expanded or modified the use of known—tools, practices, and procedures, and collaborated across regions to an unprecedented degree.^1-3 For example, regulators reached decisions quickly and efficiently by using regulatory reliance (and related approaches), defined by the World Health Organization (WHO) as

the act whereby the regulatory authority in one jurisdiction takes into account and gives significant weight to assessments performed by another regulatory authority or trusted institution, or to any other authoritative information, in reaching its own decision. The relying authority remains independent, responsible and accountable for the decisions taken, even when it relies on the decisions, assessments and information of others. ⁴

For example, the Africa Vaccine Regulatory Forum held joint review workshops to enable participating African regulatory agencies to rely on WHO's emergency use listing without having to undertake full independent reviews of COVID-19 vaccines.⁵ Participating agencies could access the full vaccine dossiers and WHO assessment reports through a WHO portal and hear from and ask questions of WHO representatives during the workshops. Another example is the European Medicines Agency (EMA) OPEN pilot, in which regulators from Australia, Canada, Japan, Switzerland, as well as WHO, were invited to participate in EMA evaluations and discussions about COVID-19 vaccines and therapeutics to facilitate sharing of scientific expertise while retaining their independence in review decisions.⁶

Some regulators used rolling reviews, which enabled innovating companies to submit data as it was ready and regulators could start reviewing the data as it came in, rather than waiting for a complete application. For example, the UK Medicines and Healthcare products Regulatory Agency (MHRA) expanded the use of its rolling review program during the pandemic to support reviews of COVID-19 products.⁷ To inform regulatory decisions, regulators also accepted real-world data—defined by the US Food and Drug Administration (FDA) as

data relating to patient health status and/or the delivery of health care routinely collected from a variety of sources [including] data derived from electronic health records, medical claims data, data from product or disease registries, and data gathered from other sources (such as digital health technologies) that can inform on health status. ⁸

For example, both the EMA and FDA used real-world data to monitor the safety and effectiveness of authorized COVID-19 vaccines and treatments to inform their decisionmaking during the pandemic.^9-12

Many regulators allowed the use of remote tools during clinical trials to ensure the continuity of studies that were ongoing when the COVID-19 pandemic began. In some cases, such as when travel to clinical study sites was not possible or safe, regulators allowed researchers to use electronic informed consent, send investigational drugs to patients' homes, and collect safety and efficacy assessments through virtual visits with study participants. For example, MHRA issued guidance on managing clinical trials during the COVID-19 pandemic in March 2020,¹³ and the FDA issued guidance in August 2021, since updated in 2023, to address these issues.¹⁴

Many approaches used during the pandemic differed from typical procedures, magnitudes, or scopes of preexisting practices, which means that as the public health emergency ends, practices may “return to normal,” even though many of the pandemic practices have proven themselves valuable and potentially transferrable to routine (nonpandemic) practice.^12,15-29 Of course, regulatory agencies across the globe cannot, nor should they, simply continue to employ all pandemic practices in every postpandemic situation. Further, we recognize that regulator fatigue will continue as staff work to address backlogs of nonemergency work that accumulated during the pandemic. However, reverting to the old status quo is to be expected, and we risk losing ground if action is not taken now. We cannot assume that certain beneficial pandemic practices will continue without intentional action taken, regardless of how valuable they appear today. Instead, we need to address questions of sustainability to maximize the use of specific and beneficial pandemic practices in the long term.

Transforming Lessons Into Sustainable Change

In recognition of the need for a structured way to design, implement, and assess the sustainable retention of pandemic practices by regulatory agencies, we sought to identify factors that promote or limit the adoption of regulatory approaches. We found little in the literature on previous pandemics that described why regulators either adopted crisis-driven approaches as permanent ways of working or reverted to the status quo after the emergency ended, including what factors influenced decisionmaking and how were they weighed.

However, a robust body of literature on implementation science exists to address a similar but distinct question: What factors affect the uptake of health services research findings into routine practice to improve the quality and effectiveness of health services and care?^30,31 Various implementation science frameworks have been developed to help researchers study these factors and guide organizations in implementing or evaluating a new health delivery intervention. One of these, the Consolidated Framework for Implementation Research (CFIR),^30,32 is a comprehensive framework that collected and organized elements from many frameworks into general domains. The factors (“determinants”) within each domain are believed to influence implementation of new interventions. The CFIR has been applied in numerous contexts, including in 2020-2021 to assess implementation challenges in Iran related to “inter-sectoral efforts to improve COVID-19 pandemic response”³³ and has been applied to clinical trials.³⁴

Although adopting new interventions in healthcare delivery differs in some respects from making pandemic regulatory agency practices permanent, we hypothesized that many of the determinants in the CFIR would apply. We adapted the CFIR for our purposes by modifying or omitting determinants specific to healthcare delivery or otherwise less relevant to regulatory agency practice; in addition, using insights from public assessments of COVID-19 pandemic practices, we added factors related to how regulators work and the broader, global regulatory agency environment (for modifications made to the CFIR see the Supplemental Appendix, www.liebertpub.com/doi/suppl/10.1089/hs.2023.0023). In the next section, we describe a new conceptual framework that we developed for regulators, called the Adapted Sustainable Adoption of Pandemic Practices (ASAP) Framework, and how it can be used to structure thinking and guide strategic policy action. We outline 3 examples to illustrate potential tradeoffs that must be considered to ensure that retention of pandemic practices by regulatory agencies is sustainable and, finally, we offer a roadmap for practice adoption.

ASAP Framework: Determinants Influencing Adoption of Pandemic Practices

Table 1 describes the ASAP framework, adapted from the CFIR,³⁰ of key determinants that tend to either promote or limit the adoption of pandemic practices into routine regulatory agency practices. These determinants are organized under 4 domains: practice characteristics, outer setting, inner setting, and process.

Table 1.

ASAP Framework for Guiding the Sustainable Adoption of Pandemic Practices Into Routine Regulatory Agency Practice

I. Practice Characteristics
Topic	Determinant	Short Description
A	Evidence of impacts and outcomes of using the practice	Whether and to what extent the impact of using the practice—to the adopting regulator, other stakeholders (including other regulators), and public health—can be easily defined and assessed, evidence exists, and evidence is known by the adopting regulator and other stakeholders, including the public
	1. Impacts to the adopting regulator	Costs and benefits to the adopting regulator of using the practice (directly experienced during the pandemic and/or predicted postadoption). Benefits may include efficiencies gained, expanded capabilities, and increased stakeholder trust in regulators' decisions and process. Costs may include increased workload, opportunity costs related to other work, financial implications, workforce (number of staff and/or capabilities), and technology resources needed to use the practice. Does not include the costs of implementing or sustaining the practice (see Cost under Feasibility and sustainability).
	2. Impacts to other stakeholders	Costs and benefits (experienced during the pandemic and/or predicted postadoption) to other stakeholders—including innovating companies, patients, other regulators, academic researchers, clinical trial sites, and other actors—of the use of the practice by the adopting regulator
	3. Process and healthcare outcomes	Process and healthcare outcomes resulting from the use of the practice, which could include faster product approvals without compromising efficacy, safety, and quality, increased patient access to products and reduced risk of shortages, better patient outcomes, increased trust in products, and increased participation in clinical trials
B	Evidence strength and quality	The adopting regulator and other stakeholders' perceptions of the quality and validity of evidence supporting the belief that the practice will have desired impacts and/or outcomes
C	Relative advantage	The adopting regulator and other stakeholders' perceptions of the advantage of implementing the practice versus returning to the prepandemic status quo
D	Adaptability	The degree to which the practice can be trialed, adapted, tailored, refined, or reinvented to meet postpandemic and regulator needs
E	Feasibility and sustainability	Perceived difficulty of implementation, reflected by changes in policy required, alignment with regulatory priorities, level of modification of practice needed for use postpandemic, disruptiveness of incorporating practice into current workflows, and culture change required
	1. Authority	Legal (eg, statutory, regulatory) changes required for adoption of practice
	2. Other stakeholder action	Other stakeholder (eg, innovating companies, other regulators) action required for sustainable implementation and successful ongoing use of practice, which may include changes in culture and procedure; stakeholder support and commitment to take those actions with or without incentives
	3. Cost	Costs associated with implementing the practice and ensuring its sustainable use over time, including sustained investments in staffing and training; upgrading or obtaining new infrastructure, tools, and technology; and opportunity costs

II. Outer Setting
Topic	Determinant	Short Description
A	Cosmopolitanism	The degree to which the regulatory agency is networked with other external organizations such as the International Coalition of Medicines Regulatory Authorities
B	Stakeholder consensus and pressure	Stakeholder consensus and pressure to implement a practice
C	External policy and incentives	A broad construct that includes external strategies to encourage adoption of pandemic practices into routine regulatory agency action including government support and political will, legislative and regulatory mandates, recommendations and guidelines, collaboratives, and public or benchmark reporting

III. Inner Setting
Topic	Determinant	Short Description
A	Structural characteristics	The social architecture, age, maturity (including WHO maturity level 1-4), and size of the regulatory agency
B	Culture	Norms, values, and basic assumptions of the regulatory agency
C	Implementation climate	The regulatory agency's absorptive capacity for change, shared receptivity of agency staff to a practice, and the extent to which use of that practice will be supported and expected within the regulatory agency
D	Readiness for implementation	Tangible and immediate indicators of the regulatory agency's commitment to its decision to implement the practice
	1. Leadership engagement	Commitment, involvement, and accountability of leaders and managers with the implementation
	2. Available resources	The level of resources dedicated for implementation and ongoing operations including money, training, education, physical space, and time; staff bandwidth (given their need to clear pandemic backlogs of work); staff fatigue; and loss of staff during the pandemic

IV. Process
Topic	Determinant	Short Description
A	Planning	The degree to which a strategy and tasks for implementing the practice are developed in advance and the quality of those plans, including coordination and alignment across groups within the agency
B	Engaging	Attracting and involving appropriate individuals in the implementation and use of the practice through a combined strategy of education, training, workshops, issuing guidance, and other similar activities
	1. Internal opinion leaders	Individuals in the regulatory agency who have formal or informal influence on how the practice will be implemented and used
	2. Formally appointed internal implementation leaders	Individuals in the regulatory agency who have been formally appointed with responsibility for implementing the practice as a coordinator, project manager, team leader, or other similar role, including staff from across relevant groups within the agency
	3. Internal champions	Select individuals in the regulatory agency who dedicate themselves to supporting the implementation and sustained use of the practice, and who may also serve as a voice of the agency externally through publicly shared materials, presentations at external meetings, and participation in external workshops
	4. External stakeholders	Diverse stakeholder engagement to support successful adoption and sustainable use of the practice, which could include publishing guidance and soliciting public comments, presenting at conferences, posting on social media, issuing public announcements explaining how the practice will be implemented and used, participating in workshops and coalitions, and building collaborations with trusted community members to listen to, educate, and build trust in the practice, regulator, and approved products
C	Executing	Carrying out or accomplishing the implementation according to plan
D	Reflecting and evaluating	Collecting quantitative and qualitative feedback about the progress and quality of implementation and use of the practice from all relevant stakeholders through calls for comments, workshops, and other methods accompanied by regular internal debriefing about progress and experience and modification of the use of the practice, as needed

Abbreviation: WHO, World Health Organization.

The domain of practice characteristics relates to the pandemic practice itself. We changed the name of the CFIR domain “intervention characteristics” to “practice characteristics” and expanded it to include evidence of impacts (ie, benefits and costs) to stakeholders other than the regulator adopting the pandemic practice, which may include patients, innovating companies, other regulators, clinical trial participants and researchers, payers, or value assessors. Additional determinants include impacts on process timelines, patient access and outcomes, and overall global public health. The benefits and burdens, and who enjoys or bears them, are key factors in determining if and how a pandemic practice can be sustainably retained postpandemic. In fact, in recent assessment reports, regulators have cited benefits to other stakeholders as a reason for their plans to continue practices beyond the pandemic.^6,35

We also added specific determinants related to whether the pandemic practice aligns with the existing system of the regulatory agency (eg, legal frameworks in that jurisdiction, regulator priorities and workflows, organizational culture of the regulator). Pandemic practices that are more complex, do not align with regulatory priorities, or cannot be adopted without significant changes in law, culture, workflow, stakeholder action, or staff training face greater challenges in implementation than those practices that can fit easily into current work with little disruption or modification. This domain also includes determinants related to the resources required to retain the pandemic practice. Resources include not just funding, but also infrastructure, tools (existing, repurposed, or new), new staff or staff with different expertise leading to hiring or training needs, and opportunity costs to the adopting regulator, and also, potentially, to other stakeholders.

Outer setting determinants relate to the external environment and the regulator's relationships to external stakeholders. These include how networked the regulator is to other organizations and other regulators, whether stakeholder consensus and pressure exists to adopt the pandemic practice, and what external policies and incentives exist to adopt the pandemic practice, including any legislative mandates, recommendations, or benchmarking pressures.

Inner setting determinants refer to relevant characteristics of the adopting regulatory agency. These include structural characteristics such as agency size and maturity, culture, capacity and receptivity for change, and readiness for implementation, including available resources.

The last domain, process, relates to the stages of the implementation process itself, including planning, engaging, executing, and reflecting and evaluating. The success of implementing a practice depends, in part, on creating a thoughtful plan in advance, engaging the right internal and external individuals throughout, executing the implementation plan effectively, and assessing the process through feedback and evaluation.

The CFIR includes another domain related to the characteristics of individuals. For the ASAP framework, we omitted this domain and its determinants as they are less relevant to this context. The pandemic was addressed through rapid collective action, with the establishment of COVID-19 taskforces and working groups within and across regulatory agencies.^2,36 Even in less urgent times, and unlike healthcare networks in which individuals may choose whether to implement specific interventions, staff in government agencies must work as 1 organization (or center or division) and decisions regarding changing ways of working are made at the leadership level and adopted by staff as new standard operating procedures (SOPs). Although how regulatory staff implement and make choices within a new SOP can vary, implementation of a practice in these types of government organizations relies less on the characteristics of individuals than the decisionmaking of leadership.

We note that a pandemic practice used in nonpandemic periods needs to be designed to function in that different environment. The urgency of the pandemic drove the development and use of these practices; during “peace time” a different calculus of costs and benefits will exist. An assessment of the framework determinants should reflect the anticipated realities of a nonpandemic setting. In addition, such an assessment should be made through an equity lens, recognizing structural inequities.

We offer the ASAP framework as an organizing tool to help guide policy and implementation planning for regulators. Considering each adoption determinant for each pandemic practice and regulatory agency can help stakeholders identify potential challenges to adoption and direct policy action to address those challenges. However, the inquiry should not end there. The interconnectedness of the global regulatory ecosystem and the complexity of these pandemic practices leads to tradeoffs that should also be explored to ensure sustainable adoption of these practices.

Balancing Tradeoffs: 3 Examples

The tradeoffs that must be considered are essentially a function of the fact that most, if not all, pandemic practices have both beneficial and costly consequences for stakeholders. Importantly, the benefits and costs of a specific pandemic practice will almost certainly be shared unequally across these stakeholders. Further, some practices require significant regulatory agency staff resources, leading to burnout and backlogs of nonprioritized work. The sustainability of each pandemic practice depends on a precise understanding of the benefits and burdens to all relevant stakeholders so that the impacts can be deliberately balanced across stakeholders and, if necessary, offset by incentives or other accommodations. Overall, decisionmakers will have to weigh opposing determinants across all ASAP framework domains to decide if, when, and how to adopt a pandemic practice.

To do this successfully, it is critical to engage a diverse set of stakeholders to understand each of their unique views of and impacts from a pandemic practice, identify potential tradeoffs, and cocreate a vision for sustainable use of a practice. This can build support for adoption of the pandemic practice, identify stakeholder consensus, and challenge assumptions. For example, one may assume that the use of decentralized trial tools in clinical trials benefits all trial participants as easier, better, or more convenient for them. It seems reasonable that individuals will welcome fewer visits to a trial site because they can conduct visits with telehealth, can be monitored remotely, or can receive a study drug at their home. However, from asking and listening to potential and current study participants, we know that this is not necessarily the case.³⁷ For instance, while some individuals welcome home assessments, those less comfortable using the technology on their own may feel more burdened and might require additional at-home support to accurately conduct remote outcome assessments. Understanding these nuances can help ensure the sustainable use of decentralized trial tools in a context-specific way based on disease state, type of therapy, population of study participants, and individual participant needs.

To illustrate what tradeoffs can exist for the adoption of a pandemic practice, we explored 3 examples: (1) direct-to-patient investigational medicinal product (IMP) delivery, (2) rolling review of medical product licensure applications, and (3) remote inspections of product quality and supply. In Tables 2, 3, and 4, we assessed the practice characteristics domain determinants using insights from published perspectives and assessments of the COVID-19 pandemic. We note that these tables are neither comprehensive nor intended to imply that the same determinants or tradeoffs would apply in the same way to every global regulator.

Table 2.

Exploring Tradeoffs: Select ASAP Framework Determinant Assessment of Direct to Trial Participant Delivery of Investigational Product

	Direct to Participant/Patient Delivery of Investigational Product
Practice Characteristics	Tends to Promote Adoption	Tends to Limit Adoption
Evidence of impacts and outcomes of using the practice	Benefits to the adopting regulator: • Greater flexibility of IMP access allows better diversity and inclusion in clinical trials^26,38 • Under health emergencies with quarantine, ongoing clinical trials can progress^26,38 Benefits to innovating company: • Greater flexibility of IMP access allows better diversity and inclusion (including from rural and underserved areas)^26,27 • Under health emergencies with quarantine, ongoing clinical trials can progress^26,27 Benefits to trial investigators: • Greater flexibility of IMP access allows better diversity and inclusion in clinical trials²⁶ • Under health emergencies with quarantine, ongoing clinical trials can progress^26,40 Benefits to participants: • Allowed participation for some individuals not located near trial sites/not able to attend trial sites^26,27,38-40 • Under health emergencies with quarantine, ongoing clinical trials can progress²⁶	Burdens to the adopting regulator: • Impact of such measures on maintaining patient safety, good clinical practice, and trial integrity was largely unknown²⁶ • Self-administration of the IMP may be challenging for some technologies and incur additional risk, which will need management³⁸ Burdens to the innovating company: • Additional logistics costs and requirements^38,40 • Loss of informal direct oversight of participants and trial progress³⁸ • Self-administration of the IMP may be challenging for some technologies and incur additional risk, which will need management³⁸ Burdens to the trial investigators: • Loss of informal direct oversight of participants and trial progress^38,40 • Self-administration of the IMP may be challenging for some technologies and incur additional risk³⁸ Burdens to the participants: • Loss of informal and direct connections to the clinical trial staff and trial community³⁸ • Self-administration challenges may limit this practice for some participants³⁸
Evidence strength and quality	Peer-reviewed and published reviews from regulators, innovating companies, and others during the pandemic supporting adoption^26,27,38,40	Peer-reviewed and published reviews from regulators, innovating companies, and others during the pandemic noting challenges in adoption^38,40
Relative advantage	Allows widening participation in clinical trials, including from rural and underserved areas²⁶	More complex and potentially more expensive logistics arrangements⁴⁰
Adaptability	Can be used in times of health emergencies as well as all settings²⁶	Requires effective logistics, including appropriate cold chain, which may be a challenge in some countries⁴⁰ Self-administration challenges and ensuing risks may limit use for some novel technologies³⁸
Feasibility and sustainability	In many countries, can be feasible within existing legal and regulatory frameworks⁴⁰ Guidance and review of the clinical trial application should suffice for these countries Savings to participants in transport to clinical trial sites can be significant⁴⁰	In some countries, legal limitations of shipping unlicensed medical interventions may require additional review and certification^39,40 Even in countries where not prohibited, there can be potential national civil and criminal liability provisions that impact direct-to-participant/-patient delivery³⁹ Antitampering technologies may be required Additional logistics will require specific funding and organization⁴⁰

Note: Sources cited in the table are illustrative and are not meant to be a comprehensive list of relevant publications.

Abbreviation: IMP, investigational medicinal product.

Table 3.

Exploring Tradeoffs: Select ASAP Framework Determinant Assessment of Rolling Review

	Rolling Review
Practice Characteristics	Tends to Promote Adoption	Tends to Limit Adoption
Evidence of impacts and outcomes of using the practice	Benefits to the adopting regulator: • Earlier insights into the evidence in development for the candidate vaccine or therapeutic • Greater scrutiny over the development plan design and conduct • Ability to manage planning for access and use in partnership with payers and healthcare systems • Opportunity to advance regulatory science, particularly in addressing novel technologies and research design Benefits to the innovating company: • Iterative dialogue allows refinement of development plan and actions^27,28 • Submission of different data packages as soon as they become available^27,28 • Development timeline is compressed relative to standard filing milestones^27,28	Burdens to the adopting regulator: • Heavily resource- and time-intensive²⁸ • Variability across candidate medicines or vaccines, with the number of cycles and time for review conditional on outstanding questions and data development²⁸ • Because of resources and time burden, disruptive to other regulatory activities²⁸ Burdens to the innovating company: • Heavily resource- and time-intensive^27,28 • Because of resources and time burden, disruptive to other development activities²⁸ • Disruptive to existing regulatory functional procedures and standard operating practices
Evidence strength and quality	Peer-reviewed and published reviews from regulators, innovating companies, and others during the pandemic supporting adoption^27,28	Peer-reviewed and published reviews from regulators, innovating companies, and others during the pandemic noting challenges in adoption²⁸
Relative advantage	Recognized as a valuable—and even necessary—tool in addressing the development of novel medical interventions in a health emergency and for speeding review^27,28	Widely understood to have been a resource-heavy exercise that cannot become a standard practice for regulatory agencies or innovating companies for every review²⁸
Adaptability	Iterative dialogue can be adapted and introduced into other regulatory pathways^27,28 Rolling reviews could be redefined as “dynamic reviews,” with set stage points for engagement rather than the expectation for continuous review Could be prioritized for certain disease states/vulnerable populations^27,28	Not all regulators or developers globally will be able to undertake the resource and staffing commitment for these iterative procedures
Feasibility and sustainability	Aligns to regulatory paradigm of evaluation of vaccines and treatments as continuous, and not a point in time Within the current remit and responsibilities of regulatory authorities in many globally leading countries Existing regulatory staff skills will not require any change; this practice is about changing the ways of working Virtual meeting technologies can facilitate coordination and reduce cost burden to all parties	In some countries, a rolling-style review pathway would need to be introduced in the legal/regulatory framework Funding for specific regulatory milestones will need to be adapted to a “rolling-style” approach Additional resourcing and staffing are likely to be required if rolling reviews are used significantly Such additional resourcing will likely require additional fees from innovating companies

Note: Sources cited in the table are illustrative and are not meant to be a comprehensive list of relevant publications.

Direct-to-Patient Delivery of Investigational Medicinal Product

Our first example relates to the use of direct-to-patient delivery of IMP in clinical trials (Table 2).^26,27,38-40 Direct-to-participant or direct-to-patient delivery of IMPs has been discussed for some time, but until the pandemic, we had yet to fully experience its use in practice. Some health authorities raised concerns that there could be risks to the participants and impacts to the study that would go unaddressed.³⁸ In fact, as Table 2 demonstrates, the benefits of this flexibility accrue to the regulator, trial sponsor, trial investigators, and trial participants. In all cases, these benefits derive from eliminating the need for the participant to travel to a trial site. During the COVID-19 pandemic, quarantine requirements and overburdened healthcare systems made it impossible for normal travel to trial sites. However, even in normal settings, travel to a trial site has been long recognized as a burden to participants and likely limited the participation of individuals in rural areas and from vulnerable groups.^42,43

The challenges in using direct-to-participant delivery of IMPs are also well recognized. Logistics for clinical trial materials are closely controlled and monitored, and established lines for distribution to trial sites are already in place. Moving these arrangements to multiple delivery sites was no small feat. Moreover, there needed to be measures in place to reassure all stakeholders that the IMPs would arrive in correctly controlled conditions and that the trial participants would be in a position to manage self-administration of the IMP. During the pandemic, trial sponsors and investigators worked closely to meet these goals, and the results have been successful, so much so that there is renewed energy to advance the use of virtual or hybrid (virtual/onsite) trials. However, there is still room to explore how patients and trial participants have experienced this change in practice. In a recent COVID-19 lessons learned workshop, a view was offered that some patients did not like the direct delivery of IMP because they valued the exchange they had with their trial investigation team.⁴⁴

Rolling Reviews

Our second example refers to the use of rolling reviews (Table 3), the procedure in which an innovating company submits completed sections of its licensure (or authorization) application for regulator review when ready, rather than waiting until every section is complete to submit a full application for review. During the COVID-19 pandemic, some regulators allowed a rolling review procedure to be used for novel COVID-19 vaccines and therapeutics.^2,27,28 The use of rolling reviews precedes the pandemic, notably as a benefit of the FDA's fast track procedures, but its use was expanded and extended in other regions during the pandemic. Rolling reviews facilitate an earlier exchange of data to support not only licensure application reviews, but also dialogue between innovating companies and regulators. This interactive dialogue was highly valued by innovating companies during the pandemic, when decisions were constrained by information and time. Regulators were also able to gain earlier insights into trends and technologies, some of which were novel in their application (eg, mRNA vaccines).

The overwhelming concern about rolling reviews is that they are time- and resource-intensive for both regulators and innovating companies. After decades of very specific and limited points for exchange of views and evidence, having continuous dialogue procedures between regulatory agencies and innovating companies is daunting and disruptive for work planning. In practice, we may anticipate that elements of the much valued interactive discussions and real-time submission of evidence for review will be incorporated into regulatory procedures that are more sustainable and appreciated. This is particularly necessary when considering how to adapt these pandemic practices for regulators in resource-constrained settings. Moreover, the application review procedures would need to be well framed in law and in regulatory frameworks to ensure that a robust procedure is demonstrated and assured.

Remote Inspection Tools

The third and final example describes the use of remote inspection tools (Table 4).^{18,21,22,29,35,41} The use of remote inspection tools, such as touring a drug manufacturing facility by video or asking for and reviewing documentation electronically, can reduce the resource burden for regulators, enabling them to be more efficient and to direct limited resources to their best use. Hybrid inspections using in-person and remote tools can save time onsite because data can be reviewed remotely before the site visit, and remote tools can offer expanded opportunities for trainee inspectors to observe and learn from the process. At the same time, remote inspections limit the ability to train new inspectors for onsite inspections, and it is harder in remote interviews to get a full sense of what is going on at the site through assessment of body language and behaviors, alarms, or odors. Remote interactions may also reduce the free flow of information between parties, and some inspection techniques cannot be conducted remotely. Similarly, while remote inspections can offer more scheduling flexibility, the use of remote tools can be more burdensome for those inspected because they may, for example, have to redact and provide records in a suitable format for remote review or ensure sufficient internet and videoconferencing capabilities. Use of remote inspections may require, for 1 or both of the parties, new infrastructure and technology, including visual technologies, video streaming glasses, and/or hardware and software to provide appropriate videoconferencing.

Table 4.

Exploring Tradeoffs: Select ASAP Framework Determinant Assessment of Remote Inspection Tools

Practice Characteristics	Remote Inspection Tools
Practice Characteristics	Tends to Promote Adoption	Tends to Limit Adoption
Evidence of impacts and outcomes of using the practice	Benefits to the adopting regulator: • Increases efficiency⁴¹ • Allows regulator to make better use of limited agency resources^22,41 • Offers opportunities for inspector to observe for training purposes²¹ • Remote data review can save time to focus on other activities while onsite (hybrid inspection)²¹ Benefits to those inspected: • More scheduling flexibility⁴¹	Burdens to the adopting regulator: • Limits the ability to train new inspectors (remote inspection does not offer the same advantages as onsite inspection)²¹ • Conducting interviews remotely is not as effective as onsite (eg, harder to assess body language and behaviors, smell, hear alarms); meetings are “intrinsically less conducive to the free flow of information between parties, and within inspection teams.”²¹ • “Several key inspection techniques that cannot be replicated through the use of technology due to the restricted visual, auditory, and interactive abilities”²¹ • Increased (and less predictable before inspection) duration of cross-time zone remote inspections²¹ • Less experience and comfort with using remote tools can lead to challenges in accessing all areas and systems²¹ • IT challenges, dependent on the capabilities of the inspected organization to support communication²¹ Burdens to those inspected: • Increased burdens to prepare for remote inspections (eg, providing records in a suitable format for remote review)²¹ • Increased and less predictable duration of cross-time zone remote inspections²¹ • Possible administrative burden imposed on those inspected to redact source documents to safeguard privacy and confidentiality²¹ • Possible intrusion of remote inspection activities on the delivery of routine clinical care²¹ • Requires those inspected to allow access to relevant electronic systems, which can raise concerns²¹
Evidence strength and quality	Peer-reviewed and published reviews from regulators, innovating companies, and others during the pandemic supporting adoption²¹	Peer-reviewed and published reviews from regulators, innovating companies, and others during the pandemic noting challenges in adoption²¹
Relative advantage	Supportive regulator sentiment based on experience and assessment; remote inspection tool use can be beneficial in certain situations^21,22,41	Regulator sentiment that remote inspection tools are not appropriate or usable in all situations²¹
Adaptability	Combines well with risk-based approaches for inspection	Use of pandemic practice in routine practice needs additional work to ensure fit-for-purpose For example, to use remote tools for inspection, new infrastructure and technology may be required (eg, visual technologies, video streaming glasses, “hardware and software that can provide an appropriate field of vision, clarity and stabilization of the picture, while simultaneously facilitating conversation between the inspector and tour host”)²¹
Feasibility and sustainability	Aligns with current regulator priorities of increasing efficiency, but may fall short compared with other priorities Requires little new funding if needed technologies are already installed Requires no or few new staff or new staff expertise (can be trained on new approaches)	Current US law requires certain inspections be conducted in person. In addition, some countries have data protection laws that limit the use of remote tools (eg, use of cameras to film facilities) in inspections.^21,35 For some, local requirements regarding accessibility and data protection limit or prevent remote inspection of source documents²¹ Incorporation does not fit into or disrupts current workflow and processes in some situations Requires coordinated actions from numerous stakeholders, such as innovating companies and regulators, ensuring appropriate technologies are in place to allow remote inspection approaches²¹ Significant training of staff on new processes and some level of culture change may be required²¹ Requires new technology and software (eg, to enable virtual facility tours, facilitate remote data review) for some²¹ Availability of electronic systems to facilitate remote access to information²¹ Availability of sufficient IT capabilities to support communication (eg, share documents, share screen, network bandwidth, device battery life, camera image quality)²¹

Note: Sources cited in the table are illustrative and are not meant to be a comprehensive list of relevant publications.

Abbreviation: IT, information technology.

In addition, some regulators are legally restricted in when and how they can use remote inspection tools, and local data protection requirements may limit or prevent remote inspection of source documents. Successful remote inspections require coordinated action from both those being inspected and regulators to ensure that appropriate technologies and sufficient information technology capabilities are in place to allow remote inspection approaches.

Of note, balancing these tradeoffs can result in a hybrid model having both remote and in-person elements for inspections in certain circumstances. For example, based on its assessment of the practice, the FDA has stated that it will continue to use these remote inspection tools after the pandemic, using a risk-based approach to determine when and how to utilize them.³⁵ In addition, the International Coalition of Medicines Regulatory Authorities has stated that remote inspections are helpful but are unlikely to fully replace all onsite inspections, noting the diversity in working group members' views. Some regulators do not think remote inspections will fit in their regulatory framework, some plan to use it as a supplemental tool to onsite inspections, and some plan to replace onsite inspections for some purposes.²¹

Which benefits outweigh which burdens, and to whom, and how these tradeoffs are addressed, will be specific to each regulator and each pandemic practice, taking into account the practical realities and determinant assessments specific to their local setting.

Pathway for Pandemic Practice Adoption by Regulatory Agencies

Building on the ASAP framework, we offer a pathway for pandemic practice adoption in the Figure. As noted in the framework, process determinants—related to planning the implementation, engaging stakeholders, executing, and reflecting and evaluating—also impact the success of practice implementation. Analogously, our proposed pathway consists of 3 phases of implementation related to (1) pandemic practice adoption planning through stakeholder engagement and use of the ASAP framework to assess key determinants, (2) addressing contextual challenges and executing adoption of the pandemic practice, and (3) monitoring and adjusting, as needed, the use of the practice over time. Each phase has defining elements.

Figure. Iterative path for the adoption of pandemic practices into routine regulatory practices.

As discussed above, assessing ASAP framework determinants, including understanding the impacts of a pandemic practice on relevant stakeholders, informs how to design the practice to be used between pandemics. Making sure a diverse set of voices are at the table can challenge assumptions, elucidate a rich picture of varied experiences and potential tradeoffs, and create a spirit of cocreation and support for strategies to move forward.

Given the tradeoffs inherent for each pandemic practice and the differences in regulator priorities, legal frameworks, infrastructure, and resources, there is no 1-size-fits-all answer as to how to sustainably embed a pandemic practice into routine agency practice. Some weighing of the determinants must be done to arrive at a vision of practice use tailored to ensure sustainability and reflect the future global regulatory environment.

From a policy lens, assessing the ASAP framework determinants can reveal which policy levers will move determinants toward adoption and inform the development of directed policy strategies to, for example, address practical realities, identify potential hurdles, and ensure incentives are aligned and set up to reflect tradeoffs. Practical realities can include feasibility questions such as regulator workload and priorities, legal constraints, and available financial, technical, and staffing resources. Possible hurdles include challenges related to agency culture, lack of stakeholder alignment, and disruption to current processes.

Whenever possible, we should build on existing infrastructure, experience, use, tools, workflows, and ways of working to avoid duplication. Further, retention of pandemic practices must recognize that, even after a public health emergency ends, regulator workload will not immediately return to prepandemic levels. Importantly, we must (1) not just promise but demonstrate sufficient benefits to the regulatory agency, (2) ramp up slowly by starting with pilots in a subset of diseases or application types to track with increasing time and resource availability over time, and (3) increase regulator funding and workforce resources in a corresponding manner. Even when hurdles do not exist, we need to ensure that regulators are fully resourced to integrate and sustain use of the practice in the long term, including sufficient and sustainable funding, adequate workforce numbers and expertise, and information technology infrastructure.

It will be important to identify metrics to capture both quantitative impacts such as license application review timelines as well as stakeholder experience to show progress and demonstrate impacts of the retained pandemic practice. Where the data will come from and how it is generated and assessed should be part of an assessment plan, and this may require setting up data infrastructure to collect or report the data. Ideally, we should aim for a learning ecosystem that can solicit and assess feedback to evolve quickly. Given that guidelines, regulations, and laws take years to amend, starting with draft guidelines and using pilots can allow for trial, feedback, and adjustment in an iterative process. More permanent changes can then be made based on lessons from pilots. Furthermore, practice between pandemics will also make our systems better able to tackle the next pandemic.

Publicly sharing these assessments, adjustments, and lessons learned in the process of adopting a pandemic practice can increase public understanding about the nature of and reasons for changes made, building trust in regulatory agencies' work. Further, this information can be especially important for other regulatory agencies—both for informing their decisionmaking and facilitating greater coordination and alignment across the globe.

Conclusion

Lessons learned from the COVID-19 pandemic provided valuable experience for regulators around the world in using new ways of working, many of which hold great promise to advance the way things are done to benefit global public health. We have witnessed substantial gains in collaboration and trust among regulatory agencies and increases in comfort and acceptance of using innovative practices and tools. Continuing to use and refine pandemic practices so they become routine can make us better prepared when the next pandemic hits. However, stakeholders must work together to capitalize on this window of opportunity to maintain and build on these gains.

There appears to be good stakeholder consensus on which pandemic regulatory practices hold significant promise,² but little direction on how to enable their sustainable retention. For most pandemic practices, adoption will be complex. Understanding what factors tend to promote or limit adoption can guide both external policy efforts and regulatory agency implementation. To do this right, it will be important to engage a diverse set of stakeholders to understand the costs, benefits, and other impacts, as well as the associated tradeoffs.

The new ASAP framework we present here can organize thinking about each determinant to help regulators and other stakeholders (1) design a pandemic practice to make it “fit-for-purpose” for a nonpandemic environment, (2) identify potential challenges to sustainable adoption of the practice, and (3) direct strategic policy action to address those challenges. There is no 1-size-fits-all solution. Assessment of each determinant can reveal gaps and point to policy levers that might be used to shift these elements toward promoting adoption. Decisionmakers will need to weigh opposing factors to decide if, when, and how to adopt a pandemic practice. The ASAP framework can be applied to any area of regulatory practice, for example, to guide assessment and implementation of reliance approaches.

We must continue to assess, pilot, and refine. Regulatory agencies around the world stand to benefit from experiences during the COVID-19 pandemic, both to advance everyday practice and to prepare for the inevitable next public health emergency. Stakeholders must work together to ensure the promise of these pandemic practices is realized for the benefit of all. Achieving that vision of stronger, more efficient, and better prepared regulatory systems requires that learnings be retained and adopted—sustainably integrated into practice—and not just documented and filed away.

Footnotes

Acknowledgments

The authors would like to thank Denise de Villa for research support and Dorothee Grimald, Alexis Reisin Miller, Steve Morin, Leonardo Semprun, Mic McGoldrick, Elizabeth Blowers-Nyman, Joan Affleck, Mark A Marsico, Louis Macareo, Muazzam Nasrullah, and Julie Lowery for their guidance and helpful comments.

Supplementary Material

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