Accelerating R&D for Emerging Infectious Diseases: Lessons Learnt From Ebola

Objective: The R&D explosion for Ebola virus disease (EVD) during the 2014-2016 outbreak led to the successful development of high-quality vaccines performed by China and the U.S. This study aims to compare the R&D activities of Ebola-related medical products in two countries, as a way to present the inuential factors of R&D for emerging infectious disease (EID) and to provide suggestions for timely and ecient R&D response to the COVID-19 pandemic. Methods: In this comparative study, R&D activities were analyzed in terms of research funding, scientic research outputs, R&D timeline, and government incentive and coordinated mechanisms. Quantitative analysis was performed using data retrieved from national websites, clinical trial registries and databases.Qualitative semi-structured interviews were conducted to explore perspectives of fteen key informants from EID eld, especially of those involved in Ebola product development. Findings: The funding gap between China and the U.S. was signicant before 2014 and narrowed after the Ebola outbreak. Both research teams started basic studies prior to the Ebola outbreak; however, the U.S. got FDA approval for clinical trials 5 months earlier than China. The underlying gap reveals the lack of participation and support by private sectors, the stagnant transformation platform, and the inadequate government incentives in China. Conclusion: and deployment mechanisms are crucial for and should allocated risks. Building collaboration, trials may accelerate basic


Background
The dreadful in uence of COVID-19 sounded alarm on the evolving emerging infectious disease (EID) challenge and the need for prompt and effective countermeasures research and development (R&D) [1].
Since the announcement of the outbreak, global community has been working collaboratively to uncover possible drug regimens, diagnostic tools, and vaccines for reducing case-fatality rate and halting transmission. , Ebola'sR&D experience has demonstrated the feasibility and success of accelerating more than 40 products to clinical phases under continuous and inclusive efforts [2]. To support the development of countermeasures for COVID-19 and future epidemic, global public health community needs to draw lessons from the top R&D contributors to Ebola response that re ect strengths and weaknesses.
As the leading force driving international pharmaceutical innovation, the U.S. government has worked closely with research institutions and biopharmaceutical companies during the 2014-2016 outbreak and provided strong support for developing the Ebola drug ZMapp [3]. It also contributed nearly half of the vaccine candidates to clinical trials, as reported by the WHO Ebola Response Roadmap [4].TherVSV-ZEBOV, also known as the Ebola Zaire vaccine, demonstrated highly effective performance in a phase III trial of Guinea and was approved for compassionate use in the 2018-2020 Kivu Ebola epidemic [5].
Meanwhile, as the second country bringing Ebola vaccine to market, China's rapid development and manufacture of medical products give hope to the developing world. After the lessons learnt from SARS, China has put intensi ed efforts and investment in rebuilding public health infrastructure, laboratory capacity and capability, as well as science and technology innovation for major EIDs [6]. It has successfully launched a portfolio of vaccines for SARS, H5N1 and H7N9, and become the rst country approved to mass-produce the H1N1 vaccine. Before the Ebola outbreak, China focused its R&D innovation on the main causes of domestic EID burden. With growing responsibility in global health and more multilateral engagement, China carried out its largest foreign health aid campaign in history and provided prompt and substantial nancial and technical support for Ebola R&D. As a result, China has independently developed a restructured Ebola vaccine named Ad5-EBOV, which got approved for emergency use by CFDA on Nov 2017.
Both China and the U.S. stepped up timely to offer Ebola vaccination for those who may have been exposed. As two great power representing the developing and developed world, the two countries' R&D practice should be compared and summarized in order to provide insights in accelerating R&D for global public health emergencies. Previous R&D studies mainly focused on parts of the R&D process, such as comparing the clinical trial progress, protective effect and e cacy, and funding ow for Ebola-related medical products in various countries [7,8,9]. While our study aims to draw a more comprehensive picture, for comparing the R&D activities of products, in regards to research funding, scienti c research outputs, R&D timeline, and government incentive and coordinated mechanisms. It will help present the in uential factors of R&D e ciency for EIDs, depict a proven R&D pathway of success in both developing and developed world contexts, thereby providing suggestions for timely and e cient R&D response to the COVID-19 pandemic.

Methods
Mixed methods were employed in this study, including a quantitative analysis for comparing R&D activities between China and the U.S.; and a qualitative analysis to explore the underlying gap in China and suggestions for accelerating the R&D process.

Research funding
The Chinese government's R&D research funding was sourced from the National Natural Science Foundation of China (NSFC) website. Relevant data in the U.S. was derived from the National Institutes of Health (NIH) Research Portfolio Online Reporting Tools (projectreporter.nih.gov). We included projects supported by individual governments between 2008 and 2016 using "Ebola" and "Ebola virus" as search terms, and excluded those irrelevant based on project summaries. For example, research on information platform, epidemic model, and clinical pharmacokinetics were excluded.

Scienti c research outputs
Clinical trial was extracted from the NIH web-based clinical trial resource (clinicaltrail.gov), which contains global trial data registered by study sponsors or principal investigators. Pipeline candidate information was extracted from the WHO Ebola R&D Landscape of Clinical Candidates and Trials Report.
The patent application data of China was mainly extracted from the Patent Search System of the State Intellectual Property O ce (sipo.gov.cn). We also searched the Patent Search and Analysis of SIPO database (pss-system.cnipa.gov.cn) for China and U.S.'s Ebola-related medical products patent application information. Patents were included based on their patent descriptions, and then classi ed into at least one category of "drugs", "vaccines" and "diagnostics". All the quantitative data was double-screened and cross-checked by two trained researchers to reach a consensus. Accordingly, data was double-entered into Microsoft Excel and checked for consistency. Microsoft Excel was also used for data description and analysis.

Qualitative Data
Participants Interviewees were mainly from three categories: professionals directly involved in Ebola pharmaceutical R&D; professionals involved in EID-related R&D; and policymakers and researchers who have been working in this eld and can provide policy recommendations for accelerating EID-related R&D process.

Sampling
The key informants were selected through non-random and purposeful snowball sampling. The sampling stopped until the obtained information was saturated. A total of 15 key informants were interviewed. Six were directly involved in the R&D of Ebola medical products; six engaged in the development of EIDrelated pharmaceutical products; and three contributed to providing relevant policy recommendations.

Interview Content and Analysis
A semi-structured qualitative outline was compiled before the interview. The content mainly focused on the in uential factors of R&D e ciency for EID, including coordination within government agencies, implementation barriers during the R&D cycle, R&D funding resources, as well as policy recommendations for accelerating R&D process. TNvivo software (version 11.0).

Quantitative Result for Comparing R&D Activities
Research funding According to the available data, U.S. had more government-funded projects on Ebola (n=187) from 2008 to 2016, which is 7.5 times of those in China (n=25). Meanwhile, U.S. input 180 million dollars for R&D, which is 17.5 times higher than that supported by the Chinese government. Both countries contributed consistent efforts between 2008 to 2015 and the gap was gradually narrowing, regarding the granted project number and research funding. However, the difference suddenly re-increased in 2016 (Fig. 1). As a result, CFDA has licensed six Ebola-related medical products, including ve diagnostic reagents and one vaccine products approved for emergency use. U.S. has licensed ten Ebola diagnostic tests for emergency use under FDA's Emergency Use Authorization (EUA) authority. On December 19, 2019, FDA approved the rVSV-ZEBOV, as the rst licensed vaccine for Ebola prevention [10].

R&D timeline
Our study focuses on comparing the R&D timeline of the rst two Ebola vaccines successfully developed by China and the U.S.: Ad5-EBOV and the rVSV-ZEBOV (Figure 3). Both China and the U.S. research teams started basic studies prior to the Ebola outbreak. The U.S. got FDA approval for clinical trials on Sept 2014, which is ve months earlier than China. However, the initial time of Phase I trials in two countries was only one month apart. For the preparation of oversea clinical trial sites, China spent ve months waiting for the approval by Sierra Leone, and another ve months for volunteer recruitment and laboratory preparation. Comparatively, the U.S. took only four months, in total, for going through all the process of resource allocation and preparation in Liberia. In the end, the Ad5-EBOV got CFDA approval for emergency use in China, whereas the rVSV-ZEBOV was adopted by the WHO as the only vaccine applied in the re-emerging Ebola outbreak in the Democratic Republic of the Congo [11].

Qualitative Result for Exploring the R&D Differences in China
Research funding According to interviewees, funding for basic research was su ciently supported by the NSFC programs. Meanwhile, funding for clinical trials mainly came from the Ministry of Science and Technology (MOST), and the R&D grants were only allocated after candidate products demonstrated promising. This funding process lagged the implementation of consistent scienti c research. Many teams had to use funding from other projects for Ebola before the government funding got approved. Our interviews suggested that the successful development of the Ad5-EBOV vaccine highlighted the signi cance of early research accumulation. China needs to establish R&D pre-planning and resource deployment mechanisms for EID preparedness and response.

Scienti c research outputs
Although China's basic research had achieved satisfying progress, most researchers found it challenging to transform results into applicable products. The underlying gap mainly attributed to the lack of participation and support by private sectors, the stagnant transformation platform, and the inadequate government incentives in China. The lack of economic and monetizing value of EID products disincentivizes biopharmaceutical enterprises to carry on studies and manufacture. Furthermore, academic institutions are incapable of translating basic research into clinical trial phases. Military a liated research institution seems as the rst choice for pushing forward oversea clinical trial; however, many things need to be coordinated under government support. Considering there is no existing department providing such guidance, the inadequate incentive mechanisms impede public and private sectors from transforming outputs into downstream timely and effectively.

R&D timeline
Interviewees agreed that the special review process established by CFDA and the technical guidance provided by its subsidiary evaluation center signi cantly accelerated the product licensing procedure.
Still, the government agencies should have enhanced regulatory support for promoting oversea clinical trials. The insu cient experience and lack of well-established coordination mechanisms placed signi cant workloads on individual research teams. Most interviewees expressed that the time spent on communication at work could have been shortened and more e cient.

Discussion
This study aims to compare the R&D activities between China and U.S. and to explore the underlying barriers to accelerating R&D process. Our research found that both countries put major efforts in Ebola countermeasures development. The difference in R&D activities implied diverse governmental support and regulatory environment. China has achieved substantial progress in basic research, patent application and vaccine licensing. However, U.S. government started funding for Ebola much earlier than China, and developed the rVSV-ZEBOV as the only vaccine adopted by WHO. The gap attributed to the lack of national R&D pre-planning, incentive and coordinated mechanisms in China before and during EID outbreak.
Our results indicated that a responsive and systematic pre-planning and resource deployment mechanism is crucial for achieving timely R&D. he U.S. government has a complicated coordinating body to assess the chemical and biological threats and enhance national health security through effective procurement and use of medical countermeasures [3,12]. It established the Public Health Emergency Medical Countermeasures Enterprise (PHEMCE) on Jul 2006 and determined that the EVD and related viral hemorrhagic fever viruses presented material threats to the U.S. population [12]. However, China's emergency response plan for EIDs was primarily based on emergency investigation, tracing and control of new infected cases [13]. The EVD had not been listed as a potential national security threat prior to the 2014 outbreak. Early Ebola projects started merely based on team's interests and most of the R&D projects initiated after the virus blasted. Funding for Ebola was further curtailed when outbreak got contained. The pivoted focus of Chinese scienti c research agencies neglected re-emerging risk of EIDs [14].
Furthermore, the rapid delivery of large-scale clinical trials within e cient and streamlined R&D process requires a set of incentive and coordinated mechanisms. For example, the public-private partnership plays an important role in linking upstream basic research and downstream manufacture [15], as well as in facilitating collaboration between agencies and private sectors [16]. It is widely used in the U.S. and leads to successful development of the vaccine Ad26.ZEBOV and the drug ZMapp [17,18]. China's current public-private partnerships were mainly driven by military research institutions, and the coordination and communication between companies and research institutions are still impeded due to the lack of e cient R&D partnership.Interviewees suggested that the lack of incentive and coordinated mechanisms in China has led to a considerable waste of time and resources. China needs to establish a unique government-led model that integrates participation from all sectors. For scienti c research institutions, bridges need to be established with private sectors for technical cooperation and communication. To ensure the pro tability of private sectors, government should provide tax support, procurement guarantees, and technical guidance to help enter the global market with labels that assure product quali cations in alliance with WHO standards.
The Chinese government has a unique advantage in promoting forceful and practical regulatory procedure, as exempli ed during the coordination for COVID-19 R&D, [19]. Besides emergency R&D response, the ongoing reform initiated by CFDA implies a consistent effort to address the lengthy review process for new drug development. It helps reduce the time and cost of clinical studies by minimizing regulatory and application backlogs and facilitating market access, [20]. However, the government agencies should continue enhancing regulatory support, especially for promoting oversea clinical trials.
Limited by insu cient participants and pivoted research priorities, the Ad5-EBOV vaccine is currently terminated on long-term e cacy studies and labelled for emergency use. The termination could bring potential risks for a timely and e cient R&D response to future Ebola outbreaks. Lessons learnt from Ebola highlighted the consistent government support through R&D life cycle and WHO's call for global collaboration to accelerate R&D and equitable access to COVID-19 countermeasures.
Although this study is the rst study to compare China's Ebola R&D process with developed countries, several limitations still existed. First, though we tried to include all the available o cial data for quantitative research, some of the data was not available, which might under-estimate the funding or outputs. Second, the possible differences of inclusion standards and categories between China and the U.S might impact the quantitative comparison. Third, in our analysis, qualitative study results were mainly represented by paraphrases or quotations, however a more thorough and systematic qualitative analysis should be conducted in future studies.
In conclusion,pre-planning and resource deployment mechanism for R&D on EID should be established to achieve a timely and more e cient R&D process. Funding should be allocated to support diversi ed R&D institutions for coping with the risks. Building private and public collaboration and communication, and strengthening government support in clinical trials may accelerate basic research translation.

Declarations
Ethics approval and consent to participate Not applicable.

Consent for publication
Not applicable.

Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.