The 100h clinical trial

At Alvea we thought a lot about how to run faster clinical trials. At one point, we even considered whether we could fit an animal testing facility, a manufacturing pipeline, a lab and a clinical trial site into one big aircraft. While you may think this sounds ludicrous, humanity is capable of crazy things when we decide we want to achieve something, including having burger kings in overseas military bases. (I haven’t fact checked this twitter post, but it illustrates well that humanity can get even much more mundane things done)

The Nucleic acids On-demand Worldwide (NOW) program by DARPA is one of the only efforts to fund a manufacturing platform to rapidly produce medical countermeasures (MCM). However, rapid manufacturing is insufficient: we also need to evaluate the efficacy and safety of the MCMs, and administer the MCMs to the relevant populations. Completing this is an immense operational challenge, and isn’t addressed by NOW. To illustrate, a recent Ebola outbreak had two vaccine candidates, but was too slow to get the testing started and recruited no one, despite >100 cases. 

Bill Gates outlines in his GERM (Global Epidemic Response and Mobilization) team proposal the importance of an international team that has fire-fighter spirit when new pathogens with pandemic potential emerge. To my knowledge GERM is not pursued with any seriousness at this point.

Within days of detecting an outbreak, I believe a small team could distribute ~1,000 doses of any stockpiled vaccine candidate and set up ring-vaccination trials to evaluate the effectiveness of the candidates. They’d operate with pre-approved documents and no dependencies to external vendors, reducing timelines to days or weeks, rather than months. And of course, we’d put everything into an A380 aircraft. If the US had ice cream ships during WW2, we should have vaccine airplanes in the 2020s.

Here is the blueprint we developed at Alvea for how to make this a reality. Our “local emergency response” approach is complementary to CEPI’s 100 Days Mission, which is focused on having vaccines ready to be produced at scale in <100 days after a dangerous pathogen is detected.

100h Pharmaceutical Response and Preparedness Teams

Ambulances, firefighters, and police benchmark themselves to take less than 15 minutes to arrive at an emergency scene. Substantial investments in decentralized and mobile preparedness, structured and repeated training, algorithmic execution, and extensive technology R&D enable this. 

Humanity needs an equivalent pharmaceutical preparedness and response ability to stop pandemics in their tracks: with an exponentially growing threat, speed is the decisive factor.

When a pathogen attacks the human body, the innate immune system rapidly provides the first response, buying time and suppressing pathogenicity before the more specific processes of the adaptive immune system become effective. For humanity to be prepared for a new pandemic threat, development is needed in two analogous areas: 

1. Broadly effective vaccines and therapeutics that are stockpiled for immediate deployment and evaluation when an outbreak begins
2. Extremely rapid targeted product development and deployment after the outbreak starts

Here we argue that a 100h timeline is an audacious, but realistic goal for a first-response to an outbreak. Within 100h of identification of a potential outbreak (T₀ ), stockpiled broad pharmaceutical medical countermeasures (MCMs) should be deployed in pre-approved clinical trials and targeted candidate vaccines and therapeutics produced for testing, with scaled-up manufacture beginning in parallel. Nucleic-acid medicines represent a highly promising technology available currently for pharmaceutical pandemic preparedness and response. Unlike any other modality, nucleic-acids like RNA and DNA can form the basis of therapeutics, vaccines, and combination products, enabling a great diversity of medicines to be created from a single manufacturing process. Crucially, it is a ‘plug and play’ technology with extensive safety data and enormous manufacturing capacity globally, which could be adopted in disaster scenarios to quickly manufacture effective vaccines. 

A 100h Pharmaceutical Response and Preparedness (PREP) team needs to be established with the mission to contain outbreaks and save lives. It would be available 24/7 to manufacture, deploy and evaluate the efficacy of medicines against pathogens, at the site of the outbreak. A 100h timeline for pharmaceutical emergency response could be the difference between a prospering society and millions of deaths.

Broadly effective vaccines and therapeutics that are stockpiled for immediate deployment and evaluation when an outbreak begins 

We argue that the optimal approach for pandemic suppression requires many different MCMs to cover a range of threats. These must be accessible quickly and ready for human use. Many currently stockpiled vaccines target specific strains of pathogens and will either not be useful or need to be updated in the event of a pandemic. Existing stockpiles contain large quantities of few vaccines (until recently, around half of the US national stockpile budget on anthrax vaccines) and therapies.

Broad pharmaceutical MCMs that cover ten or more strains of a viral family have the potential to be an effective immediate response at the earliest stages of an outbreak, enabling suppression or buying valuable time  in combination with other non-pharmaceutical interventions (NPIs) until more targeted approaches are available.

Extremely rapid targeted product development after the outbreak starts

Targeted product development needs to begin as soon as a threat is identified. End-to-end integrated and automated drug development and manufacturing processes can generate experimental batches suitable for human use within days rather than weeks or months.

Pre-approved, virus agnostic manufacturing processes, batch release specifications and analytical rather than preclinical testing would facilitate this. Development needs to be independent of external service providers, supply chains, and not reliant on slow biological processes (such as cell-based manufacture). In peace-time, a constant state of readiness will be maintained with regular equipment testing and process validation. Notably it is far more viable to store ingredients to produce the first 1,000 doses of a drug then tens of millions.

Other ambitious proposals to accelerate pandemic product development exist. CEPI’s 100d timeline for a vaccine ready for authorisation allows ~30 days to develop and manufacture pathogen specific vaccines for clinical use, with design being possible in as little as 2 days. In COVID-19 we were not far from this: Moderna manufactured the first batches of their vaccine in 42 days after the sequence was released. With current technology it only takes ~ a week to produce an experimental batch of mRNA vaccine from the vaccine sequence. This timeline can be compressed to days by stacking and automating existing technologies.

100h Pharmaceutical Response and Preparedness (PREP) Team / Special forces

Even within hospitals and despite being health care experts themselves non-emergency doctors and nurses hand off patients who need CPR quickly to specialized teams to ensure best possible care. Time and expertise matter. Similarly, the value of pharmaceutical response is exponentially greater, the closer to T₀  it is available. Every hour of exponential growth reduces the probability of containment. The full value of broad pharmaceutical MCMs and rapid development will therefore only be realized with resources dedicated to deploying and developing MCMs at the earliest signals of outbreaks. The Pharmaceutical Response and Preparedness (PREP) Team will fulfill this function having the following capabilities:

• Deployment of stockpiled broad pharmaceutical MCMs against all viral families: immediate access to decentralized stockpiles of pre-approved pharmaceutical MCMs and capacity to deploy and evaluate them in pre-approved studies at the outbreak location via plane and helicopter 
• End-to-end sequencing, automated drug design and development systems: technology to allow ‘point of care’ design and development of novel RNA medicines with minimal human involvement
• Ultra-rapid cell-free GMP-grade mRNA manufacturing: fully automated manufacture including process control and batch release, allowing manufacture of any stockpiled RNA MCM in an approved process remotely (in case e.g. transport fails) and manufacture of targeted MCMs produced by AI-guided design and development process for immediate testing in humans
• Containerized infrastructure deployment to the outbreak: containerized full infrastructure stack (sequencing technology, manufacturing equipment, stockpiled MCM and ingredients depot, clinical trial site, software stacks etc.) ready for transport 24/7 via plane, boat, or road 
• Comprehensively trained and certified execution algorithms: the full “new pathogen to first-in-human” process codified in standard operating procedures and algorithms, similar to those used by CPR professionals
• Deliver on the 100h timeline: A high-level sequence of events in the first 100h of deployment is listed in the below table.

Milestones of the 100h timeline

Hour 1	Reception and verification of outbreak signal. Alert to PREP team members.
Hour 2	Confirmation of outbreak and immediate deployment of on-call scouting team carrying an Ilumina NextSeq (or similar) metagenomic sequencing device by airA battery of rapid PCR/lateral flow tests for known pathogen and pathogen families. Activation of additional staff members. Coordination and remote instructions for local non-PREP staff (sampling, contact tracing, etc.)
Hour 5	Scouting team arrives at outbreak center and conducts further confirmation steps incl. comprehensive battery of rapid tests and sets up local headquarter. Deployment of first PREP sub-unit team to the outbreak center. Continued remote training of local non-PREP staff on upcoming procedures.
Hour 10	First sub-unit team starts enrolment in pre-approved ring-vaccination and therapeutic trial with suspected infected individuals using stockpiled MCMs based on early characterization of pathogen. Early characterization communicated to global RNA manufacturing sites to begin scaled manufacture of stockpiled relevant MCM. Automated drug-development process begins. In case of false positive operations are adjusted and teams called back.
Hour 20	Deployment of second PREP subunit team delivering further specialized equipment. Local headquarter in outbreak location established. Start of GMP manufacturing of first targeted candidate.
Hour 30	Ring vaccination with stockpiled vaccines & therapeutics completed for all known (contact) cases in pre-approved trial.
Hour 50	Vaccination of all local health care personnel with stockpiled therapeutics completed. Start of GMP manufacturing second targeted candidate drug.
Hour 75	Start of GMP manufacturing third targeted candidate drug. First results of ring vaccination trial published in continuously updated open access database.
Hour 100	Early outcome data from stockpiled efforts available. 1000 doses of first targeted candidate available for administration and use in local trial. Technology transfer to scaled up manufacturing sites. Vaccination center set up with local authorities.