How ARPA-H’s Use-Inspired Research Can Accelerate Progress in Health

Introduction

The recently established Advanced Research Projects Agency for Health (ARPA-H) aims to accelerate breakthroughs in disease prevention, detection, and treatment. It’s modeled after the Defense Advanced Research Projects Agency (DARPA), which has contributed to groundbreaking innovations like the internet, GPS, and self-driving cars.

DARPA uses the Heilmeier Catechism, a guiding set of questions, to evaluate research proposals. The catechism asks questions like, “What are you trying to do? Articulate your objectives using absolutely no jargon,” and “Who cares? If you are successful, what difference will it make?”

Interestingly, ARPA-H has added two new questions to this classic catechism:

• “To ensure equitable access to all people, how will cost, accessibility, and user experience be addressed?“
• “How might this program be misperceived or misused (and how can we prevent that from happening)?“

Both of these questions get at the heart of ARPA-H’s mission. Many recent health advances are out of reach for the average American, and ARPA-H aims to change that. What’s more, agency leadership have said they want to safely bring disruptive technologies to fruition. ARPA-H’s role in helping develop cutting edge technology means the agency will be at the cutting edge of accompanying risks – whether they stem from accidents, misperceptions, or misuse.

Recommendations 

Creating a DARPA-style agency opens doors for transformative breakthroughs, but it does not guarantee them. DARPA clones like the Homeland Security (HS)ARPA have struggled to turn proofs-of-concept into widely deployed technologies. It will be no small feat for ARPA-H to provide revolutionary health solutions for all, especially given its limited budget of $1.5 billion in 2023.

We interviewed more than twenty experts from government, academia, and industry to discuss how ARPA-H can successfully commercialize technologies that benefit us all, while mitigating downside risks. Based on these conversations, we make the following recommendations:

Zero in on pandemic prevention

Many of the responses used to fight the COVID-19 pandemic would be familiar to our predecessors: cities under lockdown, flight out of urban areas, school cancellations. But much has changed since the great plagues of the past. It was mRNA vaccines, developed through support from DARPA, that helped transform society’s pandemic response to one worthy of the 21st century. What if we could go a step further and build technologies that prevent pandemics entirely?

ARPA-H has stated that its research pursuits will often begin with a similarly daring what-if question. This mandate to dream big, combined with a focus on solving concrete, real-world problems, is what makes the agency the ideal candidate to tackle pandemic prevention. 

COVID-19 has driven tens of millions into poverty, and those with the lowest incomes have had the largest financial losses. Protecting us from the risk of pandemics could be one of ARPA-H’s key strategies to address health inequities. 

Projects that prevent future pandemics will also have positive spillover effects on the day-to-day health of Americans. For instance, technologies that suppress indoor pathogen transmission would not only stop future pandemic pathogens from spreading, but would also reduce the disease burden from non-pandemic infectious diseases and even increase productivity. 

Finally, R&D advances in pandemic prevention align well with ARPA-H’s four strategic focus areas:

Explore novel avenues for technological transition

While DARPA has a deep-pocketed, obvious customer in the Department of Defense, ARPA-H lacks a clear counterpart. Many technologies nurtured by ARPA-H will eventually require private investors and users to transition from research and development to deployment and sustainment. Close interaction with the Centers for Medicare & Medicaid Services and the Food and Drug Administration (FDA) will be crucial for ARPA-H to streamline the regulatory process and identify users for its products.

Promisingly, ARPA-H has created a dedicated office for technology transition, the Project Accelerator Transition Innovation Office (PATIO). PATIO will be especially relevant for pandemic prevention technology, as the lack of commercial interest during “peaceful,” non-pandemic times often stalls R&D efforts. One expert told us that “true innovation will require innovation in transition models, too,” meaning technical innovation alone isn’t enough. By exploring innovative contracting models like prizes or advance market commitments, ARPA-H could ensure a sufficient demand-pull for its products.

Embrace the unique features of the ARPA model

To succeed at its mission of driving transformative breakthroughs, ARPA-H should leverage the many best practices of the ARPA model – most notably, its unique appetite for technical risk. Many DARPA technologies failed, but the ones that succeeded, like the internet, had vast pay-offs that sometimes extended far beyond the original use case. ARPA-H aims to replicate these successes in healthcare. 

Of course, ARPA-H will not single-handedly solve grand challenges like pandemic prevention. Instead, it can build on and accelerate existing efforts of governmental agencies that work in adjacent spheres. ARPA-H leadership have explicitly stated that they will pursue research that is currently not undertaken within the traditional health funding ecosystem due to its high technical risk. 

Here’s how ARPA-H can complement the efforts of other agencies and advance technically risky solutions for pandemic prevention:

• The National Institutes of Health (NIH) focuses on basic science, knowledge generation, and curiosity-driven research; for example, investigating the basic principles of virus biology and structure. ARPA-H differs from NIH because it aims to advance research with a problem-driven approach, which will rely on fundamental science as is done by NIH. While the NIH’s Center for Advancing Translational Sciences (NCATS) and Centers for Accelerated Innovations (NCAI) study the science of translation, only a modestly sized component within NCATS (the Cures Acceleration Network) is aligned with ARPA-H’s mission. What’s more, NIH’s methods are different from the high technical-risk, high-reward efforts ARPA-H can pursue. NIH grants are awarded by committees of peer scientists, whereas ARPA-H programs will be led by a single subject-matter program manager with autonomy over potentially risky funding decisions. Brief term times and rigorous performance evaluation will create a constant sense of urgency that NIH-funded projects lack.
• The Biomedical Advanced Research and Development Authority (BARDA) has been remarkably successful at developing and procuring medical countermeasures – for example, by investing in the Moderna mRNA vaccine. However, BARDA differs from ARPA-H in three important aspects:
  • First, its central mission is to develop medical countermeasures that address the public health and medical consequences of chemical, biological, radiological & nuclear incidents (CBRN). This includes influenza, COVID-19, and other emerging infectious diseases. To achieve this, BARDA works with the biomedical industry to help their products bridge the “valley of death,” the gap between the lab and the market where many promising biomedical innovations find their demise. This it does superbly: BARDA has a remarkable history of 80 FDA approvals, licensures, or clearances to date. But not all pandemic prevention and preparedness technologies will be “medical countermeasures” – government lingo for traditional product classes like vaccines or rapid tests. ARPA-H can thus complement BARDA’s efforts by enabling ancillary capabilities that don’t have clear pipelines for FDA approval. 
  • Second, BARDA focuses on pandemic preparedness and response rather than prevention. Their 2023 Broad Agency Announcement, which lays out R&D areas of interest, clearly states that pandemic prevention is outside of BARDA’s scope, and instead focuses on “a strategy of developing and acquiring medical countermeasures for post-event response[s].” By contrast, ARPA-H has dedicated one of its four focus areas to proactive health, in order to stop people from becoming patients in the first place.
  • Finally, BARDA’s narrow mandate to take medical countermeasures to FDA approval leaves little scope to take on the technical risk of an ARPA. ARPA-H, in contrast, intends to be “a safe place to fail.” Agency leadership are willing to take large technical bets, on the belief that a single breakthrough technology can justify many preceding failures. 
• DARPA’s Biological Technologies Office focuses on breakthrough, interdisciplinary applications of biology. Their portfolio includes life science applications in medicine, but also goes far beyond – investing in microbes as production platforms, for example. In fact, ARPA-H founding director Renee Wegrzyn previously worked as a program manager at DARPA BTO. However, BTO prioritizes the needs of the Department of Defense, whereas ARPA-H will focus on civilian health.
• The Centers for Disease Control and Prevention (CDC) leverages its epidemiological expertise to understand disease spread and to develop interventions, but is not well set up to adopt unexpected, engineering-led approaches from other disciplines. By deploying ARPA-H’s public health products, the CDC can increase demand-pull and ensure ARPA-H’s innovations reach their end customer, the American people.

Anticipate and mitigate downside risk

Disruptive technological innovation carries an inherent element of risk. Many technologies are “dual use,” meaning they can have both benevolent and malicious applications. For instance, while genome editing techniques like CRISPR offer the promise to heal once-incurable diseases, they have also sparked concerns about misuse, as evidenced by the case of the CRISPR babies. 

However, ARPA-H’s focus on disruptive innovations will not necessarily translate to unpredictable outcomes. In contrast to the curiosity-driven science often conducted at the NIH, ARPA-H will perform use-inspired research that is directed toward specific goals. In most cases, the outcomes of ARPA-H’s programs will be predictable – and so will the concomitant risks. 

ARPA-H employs a portfolio approach to identify the most promising technologies from a wide range of options. It would only be a small adjustment to include security risk considerations when deciding which technologies to pick. One approach could be to proactively steer the relative timing of technologies, a strategy sometimes referred to as “differential technological development.” For instance, scientists are currently developing post-quantum cryptography resistant to attacks by quantum computers before building actual quantum computers, as they anticipate the risks posed to our information security systems. 

In the course of each project’s R&D lifecycle, ARPA-H employees will be among the first to face the risks tied to the new technology they develop. However, given that program managers are among the very best in their fields, they are well-positioned to anticipate and mitigate these risks. 

What’s more, the agency has thus far prudently prepared to anticipate downside risk. It is hard to overstate the importance of its decision to update the near-canonical Heilmeier Catechism. However, to complete its forward-thinking biosafety and biosecurity framework, a few more steps should be taken:

• Establish a Research and Technology Protection Office. Like the intelligence ARPA (IARPA), ARPA-H could establish a Research and Technology Protection (RTP) Office to identify and mitigate accident and misuse risks.
• Foster collaboration with security agencies. As a civilian agency, ARPA-H may be more vulnerable to espionage or cyberattacks than DARPA, its defense counterpart. By granting staff security clearances and promoting collaboration between the RTP Office and security agencies, ARPA-H could decisively enhance its security posture.
• Include an addendum to the ARPA-(H)eilmeier Questions. ARPA-H should extend its informal guide to the Heilmeier Questions to include concrete strategies like differential technological development, thereby proactively mitigating misuse and unintended consequences of its technologies.

Technological progress is a deliberate choice. Over 97% of Americans have access to clean drinking water that will not sicken them with cholera or typhoid fever, thanks to technology that renders it pathogen-free. With the help of breakthrough technologies championed at ARPA-H, we could apply ourselves to a similarly ambitious goal: a future free from all pandemics.

By carrying out such use-inspired research, ARPA-H can revolutionize health and medicine for all Americans. And it can do so with foresight and prudence, paying close attention to the challenges and risks involved, thereby ensuring that its technologies change the world for the better, not the worse.

To read the articles this piece summarizes, see: (1) Zero in on pandemic prevention; (2) How ARPA-H can master the subtle art of risk-taking