Enabling Faster Funding Timelines in the National Institutes of Health
概括
美国国立卫生研究院（NIH）为世界上一些最具创新性的生物医学研究提供了资金，但行政负担的上升和延长的等待时间（甚至在危机中）表明，其资金制度迫切需要现代化。存在有前途的替代模型的例子：在过去的两年中，私人“快速科学资金”举措（例如快速赠款和动力赠款）在响应冠状病毒大流行和衰老研究时给予了一个月的时间表，比一个月的时间表取得了突破NIH年度资金周期。为了应对19日的大流行，NIH实施了一项名为RADX的临时快速资金计划，表明愿意在急性危机期间采用这种做法。对衰老，阿片类药物流行和大流行准备等其他关键健康挑战的研究应受到类似的紧迫性。因此，我们认为，NIH必须正式并扩大其机构能力来快速资助高潜力研究，这一点至关重要。
使用这些快速资助计划的知识，本备忘录提出了NIH可以采取的行动来加速研究成果并减轻行政负担。具体而言，NIH董事应考虑采用以下方法之一，将更快的资金机制整合到其外壁外研究计划中：
- Reform the existing R21 grant mechanism to bring it more in line with its own goals of funding high-reward, rapid-turnaround research; and
- Direct NIH institutes and centers to independently develop and deploy new research programs with faster funding timelines.
NIH和其他联邦决策者的未来努力应对诸如Covid-19-19的大流行等危机的反应也将受益于对决策过程的影响以及NIH在大流行最早的几周内采取的行动的影响。为此，我们还建议国会启动政府责任局的报告，以阐明Covid-19期间的快速政府计划的结果和学习，例如RADX。
Challenge and Opportunity
Covid-19的大流行的紧迫性不仅在我们如何构建日常生活的方式上，而且在我们如何发展治疗和资助科学方面创造了适应。从2020年开始，公众看到了非政府计划的迅速出现，例如快速赠款，动力赠款和生殖补助金，以资助以前认为是不可能的时间表中的大型临床试验和概念证明的科学研究。在政府内部，NIH启动了RADX，这是一项针对冠状病毒诊断快速开发的计划，并具有明显的加速批准时间表。尽管大流行的突然发作是独一无二的，但我们认为，其他一系列生物医学危机值得同样的紧迫感和创新感。因此，至关重要的是，新的NIH董事将像RADX这样的快速资金计划永久整合到NIH中，以便更好地应对这些危机并加速未来的研究进度。
为了证明为什么，我们必须记住，冠状病毒远非离群值 - 在过去的20年中，人类已经经历了几种主要的大流行，尤其是猪流感，SARS COV-1和埃博拉病毒。基于感染悠久的传染病病史类似于Covid-19的影响的大流行者在任何一年中约为2％。天然发生的大流行的扩展是阿片类药物使用和成瘾的持续流行。阿片类药物使用的迅速变化的景观（随着过量的速度增长和合成的阿片类药物制剂变得越来越普遍），使适合该任务的缓慢，增量授予授予量变得越来越普遍。在这些情况下，通过更快的资金机制提供一些奖项的反事实是不言而喻的：进行测试，试验和干预措施较早地挽救了生命并挽救了金钱，而无需牺牲额外的资源。
除了急性危机外，还有强大的长期公共卫生动机来获得更快的科学资金。在大约10年的时间里，美国将拥有比儿童更多的老年人（65岁以上的人）。这将对美国的医疗保健系统产生重大压力，特别是考虑到三分之二的老年人患有多种慢性病。新的疾病治疗可能会有所帮助，但通常需要数年的时间才能将基础研究结果转化为认可的药物。药物发现和临床试验的特质使它们很难大规模加速，但是我们可以通过减少研究人员在写作和审查赠款方面花费的时间来可靠地加速前端的药物时间表，从而减轻对美国医疗保健的长期压力。
随着时间的推移，现有的科学资助系统以最佳意图发展，但由于各种原因 - 部分是因为联邦美元的供应没有满足需求 - 管理人员的要求已成为许多研究人员的主要挑战。根据调查，工作科学家现在花费44％的研究时间on administrative activities and compliance, with roughly half of that time spent on pre-award activities. Over60% of scientists说行政负担会损害研究生产力，许多人担心这会阻止学生从事科学职业。此外，等待资金可能是广泛的：一项主要的NIH赠款R01需要三个月以上的时间来写作8–20 months to receive（请参阅常见问题解答）。甚至概念证明的想法也面临着繁重的审查过程，至少需要一年的资金。这可以瓶颈有潜在的变革思想，就像卡塔琳·卡里科（Katalin Kariko）著名地努力为她的突破性mRNA疫苗工作获得资金而努力。这些问题对科金博宝正规网址学制定者一直引起了人们的关注，已有二十年多了，但几乎没有什么可展示的。
尽管几个非政府组织试图解决这一需求，但与NIH的影响相比，私人公民不断筹款以使快速科学既不可持续又足够实质。我们认为，需要进行协调的政府努力来振兴美国的研究生产力，并确保对国家和国际健康挑战的迅速反应，例如自然发生的大流行以及与年龄有关疾病的人口压力。新的NIH董事有机会通过将更快的资金计划作为其领导和遗产的基石来采取大胆行动。
政府通过此类计划的往绩为乐观提供了理由。除了NIH上述RADX计划外，国家科学基金会（NSF）还提供了探索性研究（急切）和快速响应研究（快速）计划的早期概念赠款，这些计划可以在几周内具有响应时间。在第二次世界大战期间，在历史上进一步回到国防研究委员会maintained a one-week review process.
Faster grant review processes can be either integrated into existing grant programs or rolled out by institutes in temporary grant initiatives responding to pressing needs, as the RADx program was. For example, when faced withdata falsification around the beta amyloid hypothesis国家老化研究所（NIA）可以利用快速的赠款审查基础设施来快速为关键论文提供复制研究，而无需等待下一个资金周期。如果威胁人类健康由于毒素国家环境健康科学研究所（NIEHS）可以迅速为风险评估和预防的研究提供资金，并毫不拖延地提供基于循证的建议。最后，赋予美国国家过敏和传染病研究所（NIAID）迅速为科学提供资金，这将为我们做好许多尚未到来的大流行的准备。
行动计划
The NIH is a decentralized organization, with institutes and centers (ICs) that each have their own mission and focus areas. While the NIH Office of the Director sets general policies and guidelines for research grants, individual ICs have the authority to create their own grant programs and define their goals and scope. The Center for Scientific Review (CSR) is responsible for the peer review process used to review grants across the NIH and recently publishednew guidelines简化审核标准。鉴于这种组织结构，我们建议董事的NIH办公室，尤其是校外研究办公室，评估NIH范围内和特定于研究所的特定快速资金机制的机会，并指导CSR，Institutes和Centers制定拟议的计划，以制定拟议的计划一年内的快速资金机制。董事办公室应考虑以下方法。
Approach 1.Develop an expedited peer review process for the existing R21 grant mechanism to bring it more in line with the NIH’s own goals of funding high-reward, rapid-turnaround research.
R21计划旨在支持高风险，高回报，快速转变的概念验证研究。但是，与NIH的传统研究机制R01相比，它在历史上一直在申请人中受欢迎。这部分是由于以下事实：尽管提供了不到一半的财务和时间支持，但已知它的应用和审查过程仅比R01少一些。因此，改革R21计划的应用程序和同行审查过程使其成为快速的赠款风格奖励，都将使它更符合其自己的目标，并可能使其对申请人更具吸引力。
All ICs follow identical yearly cycles for major grant programs like the R21, and the CSR centrally manages the peer review process for these grant applications. Thus, changes to the R21 grant review process must be spearheaded by the NIH director and coordinated in a centralized manner with all parties involved in the review process: the CSR, program directors and managers at the ICs, and the advisory councils at the ICs.
The track record of federal and private fast funding initiatives demonstrates that faster funding timelines can be feasible and successful (see FAQ). Among the key learnings and observations of public efforts that the NIH could implement are:
- 飞行员月度或每月学习部分或咨询委员会会议R21赠款审查。自从COVID-19大流行以来，CSR实际上已经改用了大部分会议，并发现面对面和虚拟会议的质量相同。企业社会责任应利用虚拟会议的便利性，通过较短，虚拟的月度或每两个月学习部分会议，以审查每年举行的三场常规会议之外的R21赠款。通过更频繁的会议，但时间较短，每次会议的个人时间承诺将减少，这可能会激励更多的研究人员参与研究部分，并防止审阅者疲劳从传统的一到两天的会议中。为了匹配这一变化，审查R21赠款申请的IC咨询委员会还应在相应的同行审查会议之后立即进行一次性虚拟会议。这些变化总之可以将R21赠款审查时间表从至少9个月减少到仅两个或三个月。
- Explore new approaches for reviewer participation.更快的资金时间的一个障碍是再保险cruitment of reviewers without a conflict of interest. Previously, the travel and financial burden of in-person study sections kept the standing body of reviewers small; this makes it difficult to find and gather a quorum of knowledgeable and unconflicted experts. With online study sections, the CSR could engage a larger committee of reviewers at lower cost. This would allow them to identify and address conflicts of interest dynamically and to select a small and varying subset of reviewers to meet each month. Scientists may also be more inclined to participate as potential reviewers, knowing that they may not be called upon for every round of reviews.
- 强调成功与风险的潜在价值。Reviewers should be explicitly instructed not to lower their scores for the Approach criterion (or the new Rigor and Feasibility criterion proposed by CSR) solely due to a lack of extensive prior literature or over differences in the applicant’s past area of expertise. (Reviewer suggestions could still be used to help inform the direction of the proposed work in these cases.) Instead, the Significance and Innovation criteria (or the new Importance of Research criterion) should be weighed much more heavily than other criteria in the overall score. The rationale for these changes is evident: novel areas will naturally have less extensive prior literature, while learnings from one area of research can cross-pollinate innovation in an entirely different area of research. Acceptance of high-risk, high-reward proposals could be further facilitated by piloting the “golden ticket” model, in which reviewers are provided the right to unilaterally fund one application per year that they believe holds the most innovation potential.
- Reduce the length of applications.The length of proposals for both Fast Grants and Impetus Grants did not exceed two pages, which, according to reviewers, was more than enough to make well-reasoned judgment calls. The NIH should reduce the page limit from six to three pages for the R21 grant program. This will reduce the administrative burden and save time for both applicants and peer reviewers.
在这些变化的成功之前，NIH应考虑对其他主要研究赠款计划应用类似的更改。
方法2。Direct NIH institutes and centers to independently develop and deploy programs with faster funding timelines using Other Transaction Authority (OTA).
Compared to reforming an existing mechanism, the creation of institute-specific fast funding programs would allow for context-specific implementation and cross-institute comparison. This could be accomplished using OTA—the same authority used by the NIH to implement COVID-19 response programs. Since 2020, all ICs at the NIH have hadthis authority并且可以在NIH董事批准的情况下使用OTA实施程序，尽管许多人尚未使用它。
As discussed previously, the NIA, NIDA, and NIAID would be prime candidates for the roll-out of faster funding. In particular, these new programs could focus on responding to time-sensitive research needs within each institute or center’s area of focus—such as health crises or replication of linchpin findings—that would provide large public benefits. To maintain this focus, these programs could restrict investigator-initiated applications and only issue funding opportunity announcements for areas of pressing need.
To enable faster peer review of applications, ICs should establish (a) new study section(s) within their Scientific Review Branch dedicated to rapid review, similar to how the RADx program had its own dedicated review committees. Reviewers who join these study sections would commit to short meetings on a monthly or bimonthly basis rather than meeting three times a year for one to two days as traditional study sections do. Additionally, as recommended above, these new programs should have a three-page limit on applications to reduce the administrative burden on both applicants and reviewers.
In this framework, we propose that the ICs be encouraged to direct at least one percent of their budget to establish new research programs with faster funding processes. We believe that even one percent of the annual budget is sufficient to launch initial fast grant programs funded through National Institutes. For example, the National Institute of Aging had an operating budget of $4 billion in the 2022 fiscal year. One percent of this budget would constitute $40 million for faster funding initiatives, which would be on the order of initial budgets of Impetus and Fast Grants ($25 million and $50 million accordingly).
NIH ICs should develop success criteria in advance of launching new fast funding programs. If the success criteria are met, they should gradually increase the budget and expand the scope of the program by allowing for investigator-initiated applications, making it a real alternative to R01 grants. A precedent for this type of grant program growth is the Maximizing Investigators’ Research Award (MIRA) (R35) grant program within the National Institute of General Medical Sciences (NIGMS), which set the goal of funding 60% of all R01 equivalent grants through MIRA by 2025. In the spirit of fast grants, we recommend setting a deadline on how long each institute can take to establish a fast grants program to ensure that the process does not extend for too many years.
其他建议。国会应启动政府问责办公室报告，以阐明Covid-19期间政府快速资助计划的结果和学习，例如RADX。
尽管许多已发表的论文引用了RADX资金，但该计划的整体影响和效率尚未得到评估。我们认为，该机构在大流行期间的反应尚未得到充分理解，但可能发挥了重要作用。阐明这些干预措施的学习将极大地使未来的紧急快速融资计划受益。
结论
The NIH should become a reliable agent for quickly mobilizing funding to address emergencies and accelerating solutions for longer-term pressing issues. As present, no funding mechanisms within NIH or its branch institutes enable them to react to such matters rapidly. However, both public and governmental initiatives show that fast funding programs are not only possible but can also be extremely successful. Given this, we propose the creation of permanent fast grants programs within the NIH and its institutes based on learnings from past initiatives.
The changes proposed here are part of a larger effort from the scientific community to modernize and accelerate research funding across the U.S. government. In the current climate of rapidly advancing technology and increasing global challenges, it is more important than ever for U.S. agencies to stay at the forefront of science and innovation. A fast funding mechanism would enable the NIH to be more agile and responsive to the needs of the scientific community and would greatly benefit the public through the advancement of human health and safety.
NIH发布了许多Notices of Special Interestto allow emergency revision to existing grants (e.g.,PA-20-135andPA-18-591)和一个更快的路径商业化的生活-saving COVID technologies (NOT-EB-20-008). Unfortunately, repurposing existing grants reportedly tookseveral months, significantly delaying impactful research.
NIH当前的科学审查过程涉及多个利益相关者。NIH有两个审查阶段，第一阶段由一个科学审查小组进行，主要由非联邦科学家组成。通常，科学审查委员会中心每年三次开会一两天。这样，最初的审查仅在提案提交后仅四个月就开始。由于小组招募和日程安排，特别强调的小组会议不再发生更长的时间。研究所和中心国家咨询委员会或董事会负责第二阶段的审查，通常在修订和上诉之后发生，将总时间表延长至大约一年。
Because of the困难在经验研究科学影响的驱动因素方面，几乎没有研究评估同伴评论对科学质量的影响。ACochrane系统评价从2007年开始，没有直接评估评论对科学质量的影响的研究，以及最近Rand reviewof the literature in 2018 found a similar lack of empirical evidence. A few morerecentstudieshave found modest associations between NIH peer review scores and research impact, suggesting that peer review may indeed successfully identify innovative projects. However, such a relationship still falls short of demonstrating that the current model of grant review reliably leads to更好的funding outcomes than alternative models. Additionally, some studies have demonstrated that the current model leads to多变的andconservative评估。综上所述，我们认为对申请人和审阅者的同行评审模型进行的实验不那么负担。
Intuitively, it seems that having longer grant applications and longer review processes ensures that both researchers and reviewers expend great effort to address pitfalls and failure modes before research starts. However,系统评价of the literature have found that reducing the length and complexity of applications has minimal effects on funding decisions, suggesting that the quality of resulting science is unlikely to be affected.
Historical examples have also suggested that the quality of an endeavor is largely uncorrelated from its planning times. It took Moderna 45 days from COVID-19 genome publication to submit the mRNA-1273 vaccine to the NIH for use in its Phase 1 clinical study. Such examples exist within government too: during World War II, National Defense Research Committee set a record by reviewing and authorizing grants within one week, which led to杜克,Project Pigeon,Proximity fuze， 和Radar。
Recent fast grant initiatives have produced high-quality outcomes. With its short applications and next-day response times, Fast Grants enabled:
- detection of new concerning COVID-19 variants before other sources of funding became available.
- 显示基于唾液的Covid-19测试的工作和使用鼻咽拭子一样起作用。
- 药物替代的临床试验，其中一项将仿制药从COVID-19减少了约40％。
- Research into “Long COVID,” which is now being followed up with a clinical trial on the ability of COVID-19 vaccines to improve symptoms.
Impetus Grants focused on projects with longer timelines but led to a number of important preprints in less than a year from the moment person applied:
- Aging Fly Cell Atlas
- Modular, programmable RNA sensing using ADAR editing in living cells
- 试管中自然复兴的机制
- Optogenetic rejuvenation of mitochondrial membrane potential to extend C. elegans lifespan
- 保守基因富集的证据证明了促态因素
- 试验neuroprotective effects of Canagliflozin
With the heavy toll that resource-intensive approaches to peer review take on the speed and innovative potential of science—and the early signs that fast grants lead to important and high-quality work—we feel that the evidentiary burden should be placed on current onerous methods rather than the proposed streamlined approaches. Without strong reason to believe that the status quo produces vastly improved science, we feel there is no reason to add years of grant writing and wait times to the process.
The adoption of faster funding mechanisms would indeed be valuable across a range of federal funding agencies. Here, we focus on the NIH because its budget for extramural research (over $30 billion per year) represents the single largest source of science funding in the United States. Additionally, the NIH’s umbrella of health and medical science includes many domains that would be well-served by faster research timelines for proof-of-concept studies—including pandemics, aging, opioid addiction, mental health, cancer, etc.
The space economy is enormous, but one of its biggest challenges is tiny: space debris.
到2050年，美国将需要65,000英里的管道才能实现净零排放。这是拜登政府可以扩大低排放，复合材料来支持零净愿景的方式。
氨基酸是重要的但昂贵的输入为洛杉矶rge-scale bioproduction. Federal funding can incentivize scalable production, cutting these costs in half.
通过按需基础设施将氧气作为公用事业，可以在全球范围内提高访问和死亡率。医疗保健专家提出，由美国国际开发署（USAID）领导的国际联盟如何改变低收入国家和中等收入国家的医疗氧气市场，以确保每个患者拥有所需的氧气。