However, using this approach solely in a time of crisis is an enormous error.
Tenacity and innovation / Prior to Operation Warp Speed, the fastest vaccine to be developed—a mumps vaccine back in the 1960s—took four years. For COVID-19, it took less than one. This success was in large part due to the tenacity and innovation of the FDA’s Center for Biologics Evaluation and Research (CBER). In recognition of the urgent need to deploy vaccines and the dire consequences of delay, CBER adopted a streamlined regulatory approach and identified bureaucratic hurdles that could be removed with little detrimental effect on safety and efficacy.
Developing a vaccine is usually a cumbersome process, taking on average 10 years to go from initial vaccine research and development through preclinical and clinical trials. Under Operation Warp Speed, CBER greenlit initial Phase I human testing of vaccine candidates on an accelerated basis (often in the absence of animal data) and enabled large-scale Phase II and III human testing to begin before a full readout of Phase I results became available. Also, CBER quickly issued guidance for pharmaceutical companies that established the evidentiary threshold for demonstrating the suitability of their candidates for Emergency Use Authorization (EUA). By doing so, CBER provided clear expectations to developers regarding the safety and efficacy standards they were required to meet, which reduced regulatory uncertainty for developers and eased the review process by standardizing evidence packages.
To ensure data from vaccine developers were reviewed as quickly as possible, CBER exercised rolling review, examining the data as they became available instead of waiting for the trials to conclude and having the developers submit all their results as a complete package. CBER expanded its review capability, with staff working around the clock to review submissions in real time. These efforts allowed CBER to authorize the Pfizer vaccine within 21 days of its EUA request and Moderna within eight. In comparison, the FDA’s existing Priority Review designation aims for action on an application within six months.
Using regulatory acceleration to promote medical innovation isn’t unique to COVID-19 vaccines. Other FDA accelerated programs have shown promising results. Its Breakthrough Therapy Designation, which accelerates the development and evaluation of medications that show significant enhancements over existing therapies, has cut clinical development times by 23 percent without any statistical effect on safety or efficacy. However, CBER’s handling of the COVID-19 vaccines completely eclipses the existing accelerated programs, with huge implications for medical innovation.
Despite its results, Operation Warp Speed’s legacy is barely noticeable within the FDA today and stories of stagnating approvals have begun to reappear. A particularly frustrating example is the new interferon drug to treat COVID-19 patients that has been shown to cut hospitalizations in half in a large clinical trial. Despite its promise, it’s likely to take years until the drug receives FDA approval.
Making Warp Speed permanent / To reverse this, the FDA should create an Office of Preparedness and Response within CBER. This office would embrace the Warp Speed approach to authorizing vaccines and other biologics by fostering an expedited and flexible approach toward the authorization of medical countermeasures and other socially valuable medical products. In ordinary times, this office would support developers of medical countermeasures against potential emerging threats through the publication of proactive guidance, an expedited review of proposed clinical studies to prepare “prototype” countermeasures that can be quickly adapted and deployed if a pandemic starts, and undertaking rapid review of medical products whose social value appears to greatly exceed their market value.
As with Operation Warp Speed, where CBER insisted that “the general safety evaluation of COVID-19 vaccines […] should be no different than for other preventive vaccines for infectious diseases,” this office would make no tradeoff between safety and speed. On the contrary, additional safety and efficacy measures would be implemented to complement expediency. For the COVID-19 vaccines, CBER increased the usual number of required clinical trial participants to 30,000. In the new office, additional safety measures could take the form of stricter deadlines on developers for conducting confirmatory trials following initial authorization and concrete plans for the collection of real-world evidence to verify a product’s safety and effectiveness.
Public acceptance / Regardless of additional safety measures, a challenge facing any accelerated approach to authorization is the effect it could have on vaccine hesitancy. Whereas the FDA’s earlier accelerated programs drew far less attention from vaccine skeptics prior to the pandemic, vaccine hesitancy has increased substantially in the wake of COVID-19.
At root, this skepticism is the product of miscommunication. By socializing accelerated approval during ordinary times and dedicating resources to improving post-market data generation, this new office’s normalization of accelerated research and testing could make great headway in building public confidence in advance of the next pandemic. By improving standards of verifiability through the better collection of real-world evidence, it could create better information to address skeptics’ concerns.
This new office could also function as a proving ground for innovative approaches to enhance the FDA’s regulatory framework, surpassing the measures used by CBER during Operation Warp Speed. One pathway for improvement would be the integration of alternative clinical trial designs, such as the human challenge trials that my organization advocates, in which compensated volunteers are deliberately exposed to an infectious disease as part of a clinical trial. Human challenge trials are uniquely positioned to accelerate vaccine development: challenge models can help researchers gain a better understanding of how diseases work and establish correlates of protection for clinical trials to allow for rapid regulatory approval. While challenge studies have been used historically for developing treatments and vaccines for a range of pathogens (including malaria, influenza, typhoid, and cholera), their use to accelerate vaccines has been sporadic and no regulatory incentives exist to advance their effective utilization. An Office of Preparedness and Response would be perfectly suited to build the FDA’s experience with using human challenge trials, creating the necessary regulatory structures to best utilize challenge studies for accelerated approval.
By practicing rapid review, this office would create a template for Warp Speed decision-making across the FDA. This rollout could take place in the form of a new type of FDA award, analogous to its current Priority Review Voucher (PRV) program for neglected and rare diseases. Under standard review times, the FDA aims to make a decision on a new drug application within 10 months, while priority review decreases this to six. If a developer secures approval, it is awarded a sellable voucher that can be applied to another new drug that becomes eligible for priority review, buying four months’ faster decision time. When first offered, the vouchers typically sold for about $300 million, though subsequent wider availability has reduced the price to around $100 million—still a valuable incentive.
The new office could also develop a discovery award for developers that make discoveries or develop tools that advance their respective fields. The award would be a sellable voucher that would make a product eligible for “warp speed” treatment by the FDA. In doing so, discovery awards could one day potentially disseminate process improvements throughout the FDA while incentivizing the improvement of regulatory science.
Conclusion / Recent events have reinforced the urgency of establishing this office. The upcoming reauthorization of the Pandemic and All-Hazards Preparedness Act is instigating a reevaluation of the U.S. pandemic strategy in light of the lessons learned from COVID-19. The FDA’s proposal for an Emerging Pathogens Preparedness Program to “enhance regulatory capabilities and readiness to respond to emerging pathogens” parallels this proposal. It is precisely the kind of change we should be seeking because it would institutionalize the successes of Operation Warp Speed for the benefit of future medical products.
Also, the Biden administration’s recent launch of Project Next-Gen—a $5 billion program to accelerate next-generation coronavirus vaccines and monoclonals—offers a perfect case study for a new FDA program. Details regarding the program are scarce, leading to calls for Project Next-Gen to replicate the Operation Warp Speed model, especially its speeding up of regulatory processes. Allocating just 1 percent of the Project Next-Gen budget to fund the FDA’s proposed Emerging Pathogens Preparedness Program to authorize these next-generation vaccines at a similar pace to Operation Warp Speed could be critical to the program’s success.
After years of calls for regulatory process reform at the FDA, the COVID-19 pandemic has expanded the realm of possibilities and provided a glimpse of what can be achieved through regulatory innovation.
