key: cord-0899174-4myb69bo authors: Marinus, Roelie; Mofid, Sarah; Mpandzou, Marya; Kühler, Thomas C. title: COVID-19 made the impossible possible - Rolling Reviews from a notion to reality – the EU experience put into a global context date: 2022-01-10 journal: Clin Ther DOI: 10.1016/j.clinthera.2022.01.001 sha: 7145129c93594be22742cafc9acfcee5189d3ffc doc_id: 899174 cord_uid: 4myb69bo Purpose Many regulators offered new ways of working to help combatting the COVID-19 pandemic and the rolling review procedure is one important and successful example. In rolling reviews, data are submitted and reviewed as they become available before the full data package is available. This approach is resource intensive but faster than standard review processes and therefor of benefit to society and patient during a health emergency. In this study we analyze the European Medicines Agency (EMA) rolling review process and extract learnings, based on the vaccines and treatments that have been approved to date (November 2021), and formulate three suggestions to be carried forward. Method Data and information on rolling reviews and similar related processes were collected from Health Authority websites across the globe with a focus on the EMA. Literature searches in PubMed® and checking company websites for additional information were conducted to complement and corroborate findings as required. Findings The duration of a rolling review cycle and the number of cycles before a conditional marketing authorization (CMA) differs between different applications. Through the rolling review process, COVID-19 vaccines could be approved in record times ranging from 17 to 36 days. The rolling review process is not limited to vaccines but is applied to promising treatments as well. Implications Our paper demonstrates that rolling reviews could be successfully conducted during a health emergency to meet an unmet medical need, namely the COVID-19 pandemic. Other critical conditions or life-threatening diseases with unmet needs exist and may be suitable to be addressed by a rolling review process to accelerate patient access to life-changing treatments. Indeed, we call for an evaluation of the rolling review process, its use, and efficiency, to capture learnings with the aim to build a novel, lean, and effective expedited review procedure that could be institutionalized and added to the regulatory toolbox. In 2020 the world was shocked by a pandemic. Unprecedented public measures were introduced, countries went into lockdown, and hospital emergency wards became overloaded with critically ill patients. The pandemic originated in the city of Wuhan, in China, which went into lockdown after they had confirmed the spreading of an unknown virus and warning the World Health Organization (WHO). 1 While the western world was convinced that they were prepared for the virus it turned out that they were not. Covid-19 started to spread across the globe and the fight against the virus started. Strategies were put in place and ranged from stopping the transmission and preventing it from spreading, through studying repurposed drugs in clinical trials, to developing de novo medicines and vaccines. According to the WHO, a pandemic is declared when a new disease for which people do not have immunity spreads across the globe beyond expectations, 1 and in March 2020, the WHO declared the COVID-19 outbreak as a pandemic. 2 This prompted health authorities and regulators around the globe to introduce extraordinary measures. A commitment to quickly address the public health emergency led to a (complete) rethink of the medicine and vaccine review processes and precipitated unprecedented regulatory ways of working. This included fast-track regulatory procedures, measures to ensure uninterrupted supply of medicines, and the accelerated adoption of electronic collaborative platforms, to name but a few examples. 3 Across the globe, regulatory agencies adopted agile and flexible ways of working resulting in new or adjusted policies and agency collaborations. 4 Although most of the procedures already existed in different jurisdictions, the pharmaceutical sector had never before experienced the way they were applied and adapted as during the pandemic. 3 One of the regulatory agilities offered during the pandemic is the rolling review procedure. In rolling reviews, data are submitted and reviewed as they become available before the full data package is available. This approach requires a closer collaboration and more intense interaction between the sponsor and the health authority. Although different regulatory jurisdictions approach and define rolling reviews differently, they are a variation of a common theme and have become a reality for a number health agencies. 3,5 The concept, however, is not new, but has been offered by the US Food and Drug Administration (US FDA) to fast-track designated products since 1988 and was used for vaccine reviews during the 2009 H1N1 pandemic by the European Medicine Agency (EMA). 6, 7 Indeed, the EMA developed a health threat management plan with four levels of emergency stages in the wake of the H1N1 pandemic, which defines the way of working in case of an emerging health threat. 8 The plan allows the agency to respond rapidly and efficiently to challenges caused by an outbreak even before a pandemic is officially declared by the WHO. Once a pandemic is declared, EMA can implement the highest level of the plan in response to the health crisis. In the health threat management plan, the rolling review procedure is one of the regulatory tools which can be deployed to speed up the assessment of a promising vaccine or treatment. Normally, the data on a medicine's effectiveness, safety, and quality must be collected and then submitted as a complete dossier before the review for approval of a marketing application can start. In the case of a rolling review, EMA's Committee for Medicinal Products for Human Use (CHMP) reviews data as they become available, before the full dossier is submitted. Once the CHMP decides that sufficient data are available, the complete dossier can be submitted by the company. By reviewing the data as they become available during the development process, the CHMP can reach its final opinion sooner on whether the application could be authorized or not. 9 In this paper we investigate the EMA rolling review process and analyze the European Public Assessment Reports (EPARs) of the different vaccines that have been approved to date (November 2021). This allows us to deduce learnings and propose ways on how to push the regulatory science envelope forward. General data and information on rolling reviews and similar or related processes, were collected from the official websites of the US FDA, 10 the UK Medicines and Healthcare products Regulatory Agency In addition, specific data on the approval of COVID-19 vaccines, was collected from official documents published by the EMA after approval, in particular the corresponding EPARs. Internal subject matter experts were consulted for input and experience. Searches in PubMed® (https://pubmed.ncbi.nlm.nih.gov/) and checking company websites for additional information were conducted to complement and corroborate findings as required. Figure 1 gives an overview of the different agencies around the globe that we could establish already used or introduced the rolling review concept as a result of the pandemic. Definitions and processes may differ between different regulatory jurisdictions, but they all have the same underlaying objectives; they aim at addressing an emergency health threat and meet an unmet medical need, offer procedural and timeline flexibilities, and stimulate the swift development of novel treatments and vaccines. Agencies that have introduced rolling reviews are the US FDA, 10 the MHRA, 11 Swissmedic, 12 EMA, 13, 14 Health Canada, 15 the HSA, 16,17 the PMDA, NMPA, the WHO, and ANVISA. The EMA has communicated how the rolling review process differs from accelerated assessment -a procedure that has been used for many years. 18 They stated that "[the rolling review] allows EMA to begin assessing data as they become available during the development process, to expedite the subsequent formal marketing authorization application assessment even further." 18 According to the EU pharmaceutical legislation, the standard timeline for the evaluation of a medicine is a maximum of 210 active days. However, for COVID-19 treatments, the EMA handled marketing authorization applications in an expedited manner reducing review timelines to less than 150 working days. A rolling review process consists of one or more review cycles where each cycle is pre-agreed between EMA and the applicant and questions from previous cycles must be addressed before the next cycle can begin. 19 In each of the rolling review cycles, EMA assesses the data and invites the applicant to submit the dossier for a Conditional Market Authorization (CMA) once they judge that the data package qualifies for a (final) review. Continuous dialogue and iterative reviews are integral elements of the rolling review process requiring significant mobilization of resources at both agency and sponsor levels. We observe that early and continuous dialogue between health authorities, scientific experts, and vaccine developers did increase during the COVID-19 pandemic. 3,18 Together with the strict timelines, this had an impact on resources on both sides. Working around the clock to assess the data, responding to outstanding questions, and meeting pre-agreed timelines led to additional workload for all stakeholders involved in the process. 20 Based on an analysis of the EPARs of Pfizer's Comirnaty, 21 Astra Zeneca's Vaxzevria, 22 Moderna's Spikevax, 23 and Janssen's Janssen COVID-19 Vaccine, 24 we were able to deduce the rolling review cycle timelines and identify what data were submitted and assessed during the different review cycles. The EMA has evaluated a total of 9 vaccines and 5 treatment to combat COVID-19 using the rolling review process. Out of the 9 vaccines, 5 applications have resulted in a submission for a CMA of which 4 have been approved to date (November2021). Even though rolling reviews are essential to speeding up the assessment, the data available at the beginning remains limited. To ensure a successful rolling review cycle, mature data packages should be submitted with each cycle. Inherent to a CMA, additional data can be submitted after the marketing authorization to further corroborate the safety, efficacy, or quality of the product. 25 The number of review cycles required by the COVID-19 vaccines approved so far are shown in figure 2 and vary between 1 and 3. For the vaccines that still are under rolling review, or have submitted a conditional market authorization application, the number of cycles are unknown, except for CureVac, which announced its withdrawal on October 12 shortly after the start of the sixth rolling review cycle. 26 Not only the number of cycles vary between the different vaccines, but also the length and duration of each individual cycle as shown in figure 3. Cycle timelines vary between a minimum of 16 to a maximum of 45 days. Ensuing CMA timelines hover around the 20 days mark with one outlier at 36 days. Review cycles also differed in terms of the data submitted, cf. table 1. There is no clear pattern, but nonclinical data seems to be submitted earlier while clinical and quality data is shared later -possibly reflecting inherent development processes of when the data type is generated. The number of extraordinary meetings range from 1 to 5, with Pfizer having the most which most likely is related to theirs being the first vaccine going through the rolling review process. Extraordinary meetings are used outside the planned schedule and used to review emergency measures, preparing the agency opinion, discuss the evaluation of an application, or to issue a recommendation. It is the Pharmacovigilance Risk Assessment Committee (PRAC) or the CHMP that call for such meetings when deemed necessary. 27, 28, 29 Table 1 Next to the approved vaccines with a CMA, there are 5 more vaccines to date (November 2021) which have entered the rolling review process. Submission dates for these vaccines fall between February and July 2021, with one withdrawal in the beginning of October 2021, 30 and one submission for a CMA in November 2021. 31 The first monoclonal antibodies evaluated through a rolling review process were approved with a CMA in November 2021 but there is no information on the number of cycles that were used. 32 There is one more COVID-19 treatment which started the rolling review process in October and 4 other treatments that have been submitted for CMA after completing the rolling review cycles with start dates between February and May 2021. 33 Next to de novo applications, rolling reviews can also be used for lifecycle management activities. It has been used for safety updates and for the line extension of Remdesivir. 34, 35 The processing of the line extension took less than 2 months and only one rolling review cycle, cf. From the start and throughout the pandemic, EMA has communicated extensively by issuing guidelines, and hosting press briefings and public stakeholder meetings on the approvals, safety monitoring, and impact of COVID-19 vaccines. This proactive and transparent way of communicating was also observed in the publication of the vaccine EPARs, they were published within 7 days of the approval of the COVID-19 vaccines instead of the normal 20 days. Other standard publication timelines were also significantly shortened, including timelines for Scientific Advice, Compassionate Use Opinion, Product information, the Risk Management Plan, the monthly safety updates for vaccines, and the assessment of safety signals amongst others. According to a joint Heads of Medicines Agency (HMA) and EMA statement on the approval of vaccines As part of the health threat management plan the EMA COVID-19 pandemic Task Force (ETF) was established. The purpose of the taskforce is to help EU Member States and the European Commission (EC) to take accelerated and coordinated regulatory actions on the development, authorization, and safety monitoring of treatments and vaccines for the COVID-19 virus by reviewing, available, scientific data of potential medicines and to identify promising candidates. 38, 39 The ETF is an expert group charged with assisting the CHMP, PRAC, and PDCO and to take part in early scientific discussions and reviews of development plans, identify promising candidates, approve the start of the rolling review process if scientific data is seen as sufficient, and interact with stakeholders and other regulators in and outside the EU as required. The ETF is accountable to the CHMP for all its activities. 40 The possibility for a rolling review with its cycles during the development of a treatment or vaccine is a prominent and important example of an exceptional regulatory agility offered in the EU during the pandemic. In comparison to the standard evaluation process, where the applicant does not submit the full dossier before all the required data is gathered, the rolling review allows the applicant to submit different data packages as soon as they become available. Depending on the nature of the data packages submitted, the number of rolling review cycles as well as the duration of each cycle can differ. To ensure the efficient use of each rolling review cycle, mature quality assured data packages should be submitted, and any outstanding questions from previous cycles (if any) be fully addressed. Once the EMA finds that the totality of data is sufficient, the applicant can submit a formal CMA application that the agency can assess. Altogether, this leads to a significantly reduction of timelines leading up to and including the final CMA-approval. After that the EMA reaches its conclusion of the assessment and issues their recommendation, the final decision on the marketing authorization is legalized and officially communicated by the EC. The vaccines we report on in this study were officially legalized by the EC within a day of the EMA recommendation. This contrasts with the 30 to 60 days it normally takes. 41, 42 These are important agilities offered that nicely respond to the shortened development timelines that have been demonstrated with the COVID-19 vaccines. An analysis of new drugs developed since 2000 shows that the mean development timeline from the start of clinical testing in Phase I to approval of the final product is almost ten years, contrasting with the development timelines of COVID-19 vaccines which all were less than a year. 43 Some clinical development phases were started before the prior phases had been fully completed. For instance, a phase II clinical development was started based on an interim readout from a Phase I clinical trial by one sponsor. 43 Such strategies may be justified in extraordinary circumstances, such as a pandemic of the COVID-19 magnitude, but we believe that they are unlikely to become a benchmark modus operandi in everyday drug development programs. Notwithstanding this, innovative measured risk taking could be considered also for other areas of medical need such as for oncology indications or for rare diseases for which there are no treatments available. Regulators took extraordinary steps on several fronts during the public-health emergency, including increasing the frequency and intensity of sponsor engagement. While this level of engagement would likely be difficult to sustain and replicate for every product being developed, the concept of regulatory collaboration has been applied by many agencies to facilitate alternate pathways in drug and medical- According to the EC, 53 two aspects are addressed by the rolling review in a post approval setting: the accelerated regulatory process and the ramping up of the production of vaccines. Firstly, the regulatory procedure is adjusted to accelerate the approval of COVID-19 vaccines to the new variants, as is currently done with human influenza vaccines. 54 This enables the swift approval of a modified vaccine with a smaller set of additional data submitted to EMA on a rolling basis. Secondly, early involvement of the regulatory authority in the certification process of the new production line is also essential. The early and rapid development of the necessary process control, validation, and stability data by companies is key to enable the review by the EMA on a rolling basis and rapid authorization of new production facilities/lines. 53 The EMA published a report on the use of the rolling review after the H1N1 2009 influenza Pandemic. 55 One recommendation put forward was to review the rolling review process from a logistics and resource perspective. Indeed, we believe that learnings from the COVID-19 rolling review process should be discussed by the vested parties in the pharma sector -regulators and industry -with the objective to agree on an optimized process that is less resource intensive, pragmatic, and robust, still reaming nimble and fast, while upholding normal scientific and regulatory standards. This is aligned with recommendations put forward in the WHO and ICMRA report on regulatory agilities and flexibilities where they call for an increased implementation of rolling submission procedures. 4 A foundation for such a dialogue has been put in place by a recent publication on Dynamic Regulatory Assessment (DRA) -a concept that seeks to re-imagine the regulatory review interactions across a product life cycle that calls for an iterative regulatory dialogue, data submission, and evidence assessment, enabled by contemporary IT and bringing significant efficiencies to the pharma sector for all product types. 56 As discussed in the DRA-paper, data for regulatory decision-making would be uploaded to a common (cloud-based) platform as it becomes available -as opposed to being submitted as a complete and validated dossier -very similar to what was observed in the situation of rolling reviews. Access to the (uploading and review) platform(s) can easily be granted to sponsors and regulators as adequate and on a need basis. Such a cloud-based platform lends itself, and is conducive to, international collaboration across multiple regulatory jurisdictions -a feature that we believe would be welcome, especially when global collaboration is required to mitigate the effects of a pandemic. The mobilization of extraordinary resources to assess data packages in a very limited time window as during the COVID-19 pandemic is acknowledged and understood by all parties concerned. However, digitalization, operational excellence, and innovation could seamlessly improve the rolling review procedure taking into account and preserving the good aspects of it. This would not only serve the pharma sector but be of benefit to society in general and patients in particular. The pandemic is by no means over yet, but the pharma sector is starting to debate which regulatory agilities did add the most value and extract lessons learned. 57, 58 Pharma companies, health authorities, and other vested stakeholders have an obligation to leverage these learnings and bring about transformations that will bring life-changing therapies much faster to patients. Learnings from this pandemic should not only be carried over to the next one but should, where appropriate, already now be applied also for other life-threatening diseases and conditions with unmet medical needs. We suggest that there are three areas that the pharma sector in the EU jointly should discuss and carry forward regarding rolling reviews. We propose that rolling reviews should become: Emer Cooke On The Future Of Rolling Reviews & The End Of Remote Meetings Comirnaty European Public assessment report Spikevax European Public assessment report Questions and Answers: Conditional Marketing Authorisation of COVID-19 Vaccines in the EU l What is the EU doing to accelerate the authorisation process for the COVID-19 vaccines? Announcement of withdrawal of CureVac Extraordinary meeting of the Pharmacovigilance Risk Assessment Committee (PRAC) Extraordinary meeting of the Committee for Medicinal Products for Human Use (CHMP) Extraordinary meeting of the Committee for Medicinal Products for Human Use (CHMP) EMA ends rolling review of CVnCoV COVID-19 vaccine following withdrawal by CureVac AG EMA receives application for conditional marketing authorisation of Novavax's COVID-19 vaccine COVID-19: EMA recommends authorisation of two monoclonal antibody medicines COVID treatments Assessment report Frequently Asked Questions for Velklury (remdesivir EMA ends rolling review of the antibodies bamlanivimab and etesevimab for COVID-19 following withdrawal by Lilly 39 EMA, «COVID-19 EMA pandemic Task Force «Dynamic Regulatory Assessment: evolving the European Regulatory Framework for the benefit of patients and public health -An EFPIA view Global COVID-19 Summit: Ending the Pandemic and Building Back Better Policy proposals to minimize medicine supply shortages in Europe Lessons from COVID-19 crisis, » COVID-19 Drug shortages EFPIA position paper Last accessed 26 Novemeber not become a benchmark beyond the COVID-19 pandemic. All authors designed the study, analysed the data, and wrote the whole manuscript. The views expressed in this research paper 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 company or any other affiliation. All authors are Sanofi employees and may hold shares and/or stock options in the company. All authors hold positions within the pharmaceutical industry, but they have not received any grant, honoraria, or other compensation to author this paper. The study was conceived of, executed on, and written up in the course of the authors' daily job. treatments and vaccines,» https://www.ema.europa.eu/en/documents/other/ema-initiatives-accelerationdevelopment-support-evaluation-procedures-covid-19-treatments-vaccines_en.pdf Last accessed 26