Medical Breakthroughs Set to be Fast-Tracked by Innovative New Health Agency
Pippy Rogers, second from left, with her four siblings, who worry that they are at risk for Alzheimer's and are calling for an acceleration of research.
In 2007, Matthew Might's son, Bertrand, was born with a life-threatening disease that was so rare, doctors couldn't diagnose it. Might, a computer scientist and biologist, eventually realized, "Oh my gosh, he's the only patient in the world with this disease right now." To find effective treatments, new methodologies would need to be developed. But there was no process or playbook for doing that.
Might took it upon himself, along with a team of specialists, to try to find a cure. "What Bertrand really taught me was the visceral sense of urgency when there's suffering, and how to act on that," he said.
He calls it "the agency of urgency"—and patients with more common diseases, such as cancer and Alzheimer's, often feel that same need to take matters into their own hands, as they find their hopes for new treatments running up against bureaucratic systems designed to advance in small, steady steps, not leaps and bounds. "We all hope for a cure," said Florence "Pippy" Rogers, a 65-year-old volunteer with Georgia's chapter of the Alzheimer's Association. She lost her mother to the disease and, these days, worries about herself and her four siblings. "We need to keep accelerating research."
We have a fresh example of what can be achieved by fast-tracking discoveries in healthcare: Covid-19 vaccines.
President Biden has pushed for cancer moonshots since the disease took the life of his son, Beau, in 2015. His administration has now requested $6.5 billion to start a new agency in 2022, called the Advanced Research Projects Agency for Health, or ARPA-H, within the National Institutes of Health. It's based on DARPA, the Department of Defense agency known for hatching world-changing technologies such as drones, GPS and ARPANET, which became the internet.
We have a fresh example of what can be achieved by fast-tracking discoveries in healthcare: Covid-19 vaccines. "Operation Warp Speed was using ARPA-like principles," said Might. "It showed that in a moment of crisis, institutions like NIH can think in an ARPA-like way. So now the question is, why don't we do that all the time?"
But applying the DARPA model to health involves several challenging decisions. I asked experts what could be the hardest question facing advocates of ARPA-H: which health problems it should seek to address. "All the wonderful choices lead to the problem of which ones to choose and prioritize," said Sudip Parikh, CEO of the American Association for the Advancement of Science and executive publisher of the Science family of journals. "There is no objectively right answer."
The Agency of Urgency
ARPA-H will borrow at least three critical ingredients from DARPA: goal-oriented project managers, many from industry; aggressive public-private partnerships; and collaboration among fields that don't always interact. The DARPA concept has been applied to other purposes, including energy and homeland security, with promising results. "We're learning that 'ARPA-ism' is a franchisable model," said Might, a former principal investigator on DARPA projects.
The federal government already pours billions of dollars into advancing research on life-threatening diseases, with much of it channeled through the National Institutes of Health. But the purpose of ARPA-H "isn't just the usual suspects that NIH would fund," said David Walt, a Harvard biochemist, an innovator in gene sequencing and former chair of DARPA's Defense Science Research Council. Whereas some NIH-funded studies aim to gradually improve our understanding of diseases, ARPA-H projects will give full focus to real-world applications; they'll use essential findings from NIH research as starting points, drawing from them to rapidly engineer new technologies that could save lives.
And, ultimately, billions in healthcare costs, if ARPA-H lives up to its predecessor's track record; DARPA's breakthroughs have been economic game-changers, while its fail-fast approach—quickly pulling the plug on projects that aren't panning out—helps to avoid sunken costs. ARPA-H could fuel activities similar to the human genome project, which used existing research to map the base pairs that make up DNA, opening new doors for the biotech industry, sparking economic growth and creating hundreds of thousands of new jobs.
Despite a nearly $4 trillion health economy, "we aren't innovating when it comes to technological capabilities for health," said Liz Feld, president of the Suzanne Wright Foundation for pancreatic cancer.
Individual Diseases Ripe for Innovation
Although the need for innovation is clear, which diseases ARPA-H should tackle is less apparent. One important consideration when choosing health priorities could be "how many people suffer from a disease," said Nancy Kass, a professor of bioethics and public health at Johns Hopkins.
That perspective could justify cancer as a top objective. Cancer and heart disease have long been the two major killers in the U.S. Leonidas Platanias, professor of oncology at Northwestern and director of its cancer center, noted that we've already made significant progress on heart disease. "Anti-cholesterol drugs really have a wide impact," he said. "I don't want to compare one disease to another, but I think cancer may be the most challenging. We need even bigger breakthroughs." He wondered whether ARPA-H should be linked to the part of NIH dedicated to cancer, the National Cancer Institute, "to take maximum advantage of what happens" there.
Previous cancer moonshots have laid a foundation for success. And this sort of disease-by-disease approach makes sense in a way. "We know that concentrating on some diseases has led to treatments," said Parikh. "Think of spinal muscular atrophy or cystic fibrosis. Now, imagine if immune therapies were discovered ten years earlier."
But many advocates think ARPA-H should choose projects that don't revolve around any one disease. "It absolutely has to be disease agnostic," said Feld, president of the pancreatic cancer foundation. "We cannot reach ARPA-H's potential if it's subject to the advocacy of individual patient groups who think their disease is worse than the guy's disease next to them. That's not the way the DARPA model works." Platanias agreed that ARPA-H should "pick the highest concepts and developments that have the best chance" of success.
Finding Connections Between Diseases
Kass, the Hopkins bioethicist, believes that ARPA-H should walk a balance, with some projects focusing on specific diseases and others aspiring to solutions with broader applications, spanning multiple diseases. Being impartial, some have noted, might involve looking at the total "life years" saved by a health innovation; the more diseases addressed by a given breakthrough, the more years of healthy living it may confer. The social and economic value should increase as well.
For multiple payoffs, ARPA-H could concentrate on rare diseases, which can yield important insights for many other diseases, said Might. Every case of cancer and Alzheimer's is, in a way, its own rare disease. Cancer is a genetic disease, like his son Bertrand's rare disorder, and mutations vary widely across cancer patients. "It's safe to say that no two people have ever actually had the same cancer," said Might. In theory, solutions for rare diseases could help us understand how to individualize treatments for more common diseases.
Many experts I talked with support another priority for ARPA-H with implications for multiple diseases: therapies that slow down the aging process. "Aging is the greatest risk factor for every major disease that NIH is studying," said Matt Kaeberlein, a bio-gerontologist at the University of Washington. Yet, "half of one percent of the NIH budget goes to researching the biology of aging. An ARPA-H sized budget would push the field forward at a pace that's hard to imagine."
Might agreed. "It could take ARPA-H to get past the weird stigmas around aging-related research. It could have a tremendous impact on the field."
For example, ARPA-H could try to use mRNA technology to express proteins that affect biological aging, said Kaeberlein. It's an engineering project well-suited to the DARPA model. So is harnessing machine learning to identify biomarkers that assess how fast people are aging. Biological aging clocks, if validated, could quickly reveal whether proposed therapies for aging are working or not. "I think there's huge value in that," said Kaeberlein.
By delivering breakthroughs in computation, ARPA-H could improve diagnostics for many different diseases. That could include improving biowearables for continuously monitoring blood pressure—a hypothetical mentioned in the White House's concept paper on ARPA-H—and advanced imaging technologies. "The high cost of medical imaging is a leading reason why our healthcare costs are the highest in the world," said Feld. "There's no detection test for ALS. No brain detection for Alzheimer's. Innovations in detection technology would save on cost and human suffering."
Some biotech companies may be skeptical about the financial rewards of accelerating such technologies. But ARPA-H could fund public-private partnerships to "de-risk" biotech's involvement—an incentive that harkens back to the advance purchase contracts that companies got during Covid. (Some groups have suggested that ARPA-H could provide advance purchase agreements.)
Parikh is less bullish on creating diagnostics through ARPA-H. Like DARPA, Biden's health agency will enjoy some independence from federal oversight; it may even be located hundreds of miles from DC. That freedom affords some breathing room for innovation, but it could also make it tougher to ensure that algorithms fully consider diverse populations. "That part I really would like the government more involved in," Parikh said.
Might thinks ARPA-H should also explore innovations in clinical trials, which many patients and medical communities view as grindingly slow and requiring too many participants. "We can approve drugs for very tiny patient populations, even at the level of the individual," he said, while emphasizing the need for safety. But Platanias thinks the FDA has become much more flexible in recent years. In the cancer field, at least, "You now see faster approvals for more drugs. Having [more] shortcuts on clinical trial approvals is not necessarily a good idea."
With so many options on the table, ARPA-H needs to show the public a clear framework for measuring the value of potential projects. Kass warned that well-resourced advocates could skew the agency's priorities. They've affected health outcomes before, she noted; fundraising may partly explain larger increases in life expectancy for cystic fibrosis than sickle cell anemia. Engaging diverse communities is a must for ARPA-H. So are partnerships to get the agency's outputs to people who need them. "Research is half the equation," said Kass. "If we don't ensure implementation and access, who cares." The White House concept paper on ARPA-H made a similar point.
As Congress works on authorizing ARPA-H this year, Might is doing what he can to ensure better access to innovation on a patient-by-patient basis. Last year, his son, Bertrand, passed away suddenly from his disorder. He was 12. But Might's sense of urgency has persisted, as he directs the Precision Medicine Institute at the University of Alabama-Birmingham. That urgency "can be carried into an agency like ARPA-H," he said. "It guides what I do as I apply for funding, because I'm trying to build the infrastructure that other parents need. So they don't have to build it from scratch like I did."
Novel Technologies Could Make Coronavirus Vaccines More Stable for Worldwide Shipping
The vaccine from Pfizer will need to be stored at minus 70 degrees Celsius for worldwide distribution.
Ssendi Bosco has long known to fear the rainy season. As deputy health officer of Mubende District, a region in Central Uganda, she is only too aware of the threat that heavy storms can pose to her area's fragile healthcare facilities.
In early October, persistent rain overwhelmed the power generator that supplies electricity to most of the region, causing a blackout for three weeks. The result was that most of Mubende's vaccine supplies against diseases such as tuberculosis, diphtheria, and polio went to waste. "The vaccines need to be constantly refrigerated, so the generator failing means that most of them are now unusable," she says.
This week, the global fight against the coronavirus pandemic received a major boost when Pfizer and their German partner BioNTech released interim results showing that their vaccine has proved more than 90 percent effective at preventing participants in their clinical trial from getting COVID-19.
But while Pfizer has already signed deals to supply the vaccine to the U.S., U.K., Canada, Japan and the European Union, Mubende's recent plight provides an indication of the challenges that distributors will face when attempting to ship a coronavirus vaccine around the globe, particularly to low-income nations.
Experts have estimated that somewhere between 12 billion and 15 billion doses will be needed to immunize the world's population against COVID-19, a staggering scale, and one that has never been attempted before. "The logistics of distributing COVID-19 vaccines have been described as one of the biggest challenges in the history of mankind," says Göran Conradson, managing director of Swedish vaccine manufacturer Ziccum.
But even these estimates do not take into account the potential for vaccine spoilage. Every year, the World Health Organization estimates that over half of the world's vaccines end up being wasted. This happens because vaccines are fragile products. From the moment they are made, to the moment they are administered, they have to be kept within a tightly controlled temperature range. Throughout the entire supply chain – transportation to an airport, the flight to another country, unloaded, distribution via trucks to healthcare facilities, and storage – they must be refrigerated at all times. This is known as the cold chain, and one tiny slip along the way means the vaccines are ruined.
"It's a chain, and any chain is only as strong as its weakest link," says Asel Sartbaeva, a chemist working on vaccine technologies at the University of Bath in the U.K.
For COVID-19, the challenge is even greater because some of the leading vaccine candidates need to be kept at ultracold temperatures. Pfizer's vaccine, for example, must be kept at -70 degrees Celsius, the kind of freezer capabilities rarely found outsides of specialized laboratories. Transporting such a vaccine across North America and Europe will be difficult enough, but supplying it to some of the world's poorest nations in Asia, Africa and South America -- where only 10 percent of healthcare facilities have reliable electricity -- might appear virtually impossible.
But technology may be able to come to the rescue.
Making Vaccines Less Fragile
Just as the world's pharmaceutical companies have been racing against the clock to develop viable COVID-19 vaccine candidates, scientists around the globe have been hastily developing new technologies to try and make vaccines less fragile. Some approaches involve various chemicals that can be added to the vaccine to make them far more resilient to temperature fluctuations during transit, while others focus on insulated storage units that can maintain the vaccine at a certain temperature even if there is a power outage.
Some of these concepts have already been considered for several years, but before COVID-19 there was less of a commercial incentive to bring them to market. "We never felt that there is a need for an investment in this area," explains Sam Kosari, a pharmacist at the University of Canberra, who researches the vaccine cold chain. "Some technologies were developed then to assist with vaccine transport in Africa during Ebola, but since that outbreak was contained, there hasn't been any serious initiative or reward to develop this technology further."
In her laboratory at the University of Bath, Sartbaeva is using silica - the main constituent of sand – to encase the molecular components within a vaccine. Conventional vaccines typically contain protein targets from the virus, which the immune system learns to recognize. However, when they are exposed to temperature changes, these protein structures degrade, and lose their shape, making the vaccine useless. Sartbaeva compares this to how an egg changes its shape and consistency when it is boiled.
When silica is added to a vaccine, it molds to each protein, forming little protective cages around them, and thus preventing them from being affected by temperature changes. "The whole idea is that if we can create a shell around each protein, we can protect it from physically unravelling which is what causes the deactivation of the vaccine," she says.
Other scientists are exploring similar methods of making vaccines more resilient. Researchers at the Jenner Institute at the University of Oxford recently conducted a clinical trial in which they added carbohydrates to a dengue vaccine, to assess whether it became easier to transport.
Both research groups are now hoping to collaborate with the COVID-19 vaccine candidates being developed by AstraZeneca and Imperial College, assuming they become available in 2021.
"It's good we're all working on this big problem, as different methods could work better for different types of COVID-19 vaccines," says Sartbaeva. "I think it will be needed."
Next-Generation Vaccine Technology
While these different technologies could be utilized to try and protect the first wave of COVID-19 vaccines, efforts are also underway to develop completely new methods of vaccination. Much of this research is still in its earliest stages, but it could yield a second generation of COVID-19 vaccine candidates in 2022 and beyond.
"After the first round of mass vaccination, we could well observe regional outbreaks of the disease appearing from time to time in the coming years," says Kosari. "This is the time where new types of vaccines could be helpful."
One novel method being explored by Ziccum and others is dry powder vaccines. The idea is to spray dry the final vaccine into a powder form, where it is more easily preserved and does not require any special cooling while being transported or stored. People then receive the vaccine by inhaling it, rather than having it injected into their bloodstream.
Conradson explains that the concept of dry powder vaccines works on the same principle as dried food products. Because there is no water involved, the vaccine's components are far less affected by temperature changes. "It is actually the water that leads to the destruction of potency of a vaccine when it gets heated," he says. "We're looking to develop a dry powder vaccine for COVID-19 but this will be a second-generation vaccine. At the moment there are more than 200 first-generation candidates, all of which are using conventional technologies due to the timeframe pressures, which I think was the correct decision."
Dry powder COVID-19 vaccines could also be combined with microneedle patches, to allow people to self-administer the vaccine themselves in their own home. Microneedles are miniature needles – measured in millionths of a meter – which are designed to deliver medicines through the skin with minimal pain. So far, they have been used mainly in cosmetic products, but many scientists are working to use them to deliver drugs or vaccines.
At Georgia Institute of Technology in Atlanta, Mark Prausnitz is leading a couple of projects looking at incorporating COVID-19 vaccines into microneedle patches with the hope of running some early-stage clinical trials over the next couple of years. "The advantage is that they maintain the vaccine in a stable, dry state until it dissolves in the skin," he explains.
Prausnitz and others believe that once the first generation of COVID-19 vaccines become available, biotech and pharmaceutical companies will show more interest in adapting their products so they can be used in a dried form or with a microneedle patch. "There is so much pressure to get the COVID vaccine out that right now, vaccine developers are not interested in incorporating a novel delivery method," he says. "That will have to come later, once the pressure is lessened."
The Struggle of Low-Income Nations
For low-income nations, time will only tell whether technological advancements can enable them to access the first wave of licensed COVID-19 vaccines. But reports already suggest that they are in danger of becoming an afterthought in the race to procure vaccine supplies.
While initiatives such as COVAX are attempting to make sure that vaccine access is equitable, high and middle-income countries have already inked deals to secure 3.8 billion doses, with options for another 5 billion. One particularly sobering study by the Duke Global Health Innovation Center has suggested that such hoarding means many low-income nations may not receive a vaccine until 2024.
For Bosco and the residents of Mubende District in Uganda, all they can do is wait. In the meantime, there is a more pressing problem: fixing their generators. "We hope that we can receive a vaccine," she says. "But the biggest problem will be finding ways to safely store it. Right now we cannot keep any medicines or vaccines in the conditions they need, because we don't have the funds to repair our power generators."
Democratic U.S. presidential nominee and former Vice President Joe Biden puts his face mask back on after answering questions following a speech on the effects on the U.S. economy of the Trump administration's response to the coronavirus disease (COVID-19) pandemic during a campaign event in Wilmington, Delaware, U.S., September 4, 2020.
The response to the COVID-19 pandemic will soon become the responsibility of President-elect Biden. As is clear to anyone who honestly looks, the past 10+ months of this pandemic have been a disastrous litany of mistakes, wrong actions, and misinformation.
The result has been the deaths of 240,000 Americans, economic collapse, disruption of routine healthcare, and inability of Americans to pursue their values without fear of contracting or spreading a deadly infectious disease. With the looming change in administration, many proposals will be suggested for the path forward.
Indeed, the Biden campaign published their own plan. This plan encompasses many of the actions my colleagues and I in the public health and infectious disease fields have been arguing for since January. Several of these points, I think, bear emphasis and should be aggressively pursued to help the U.S. emerge from the pandemic.
Support More and Faster Tests
When it comes to an infectious disease outbreak the most basic question that must be answered in any response is: "Who is infected and who is not?" Even today this simple question is not easy to answer because testing issues continue to plague us and there are voices who oppose more testing -- as if by not testing, the cases of COVID cease to exist. While testing is worlds better than it was in March – especially for hospital inpatients – it is still a process fraught with unnecessary bureaucracy and delays in the outpatient setting.
Just this past week, friends and colleagues have had to wait days upon days to get a result back, all the while having to self-quarantine pending the result. This not only leaves people in limbo, it discourages people from being tested, and renders contact tracing almost moot. A test that results in several days is almost useless to contact tracers as Bill Gates has forcefully argued.
We need more testing and more actionable rapid turn-around tests. These tests need to be deployed in healthcare facilities and beyond. Ideally, these tests should be made available for individuals to conduct on themselves at home. For some settings, such as at home, rapid antigen tests similar to those used to detect pregnancy will be suitable; for other settings, like at a doctor's office or a hospital, more elaborate PCR tests will still be key. These last have been compromised for several months due to rationing of the reagent supplies necessary to perform the test – an unacceptable state of affairs that cannot continue. Reflecting an understanding of the state of play of testing, the President-elect recently stated: "We need to increase both lab-based diagnostic testing, with results back within 24 hours or less, and faster, cheaper screening tests that you can take right at home or in school."
Roll Out Safe and Effective Vaccine(s)
Biden's plan also identifies the need to "accelerate the development of treatments and vaccines" and indeed Operation Warp Speed has been one solitary bright spot in the darkness of the failed pandemic response. It is this program that facilitated a distribution partnership with Pfizer for 100 million doses of its mRNA vaccine -- whose preliminary, and extremely positive data, was just announced today to great excitement.
Operation Warp Speed needs to be continued so that we can ensure the final development and distribution of the first-generation vaccines and treatments. When a vaccine is available, it will be a Herculean task that will span many months to actually get into the arms (twice as a 2-dose vaccine) of Americans. Vaccination may begin for healthcare workers before a change in administration, but it will continue long into 2021 and possibly longer. Vaccine distribution will be a task that demands a high degree of competence and coordination, especially with the extreme cold storage conditions needed for the vaccines.
Anticipate the Next Pandemic Now
Not only should Operation Warp Speed be supported, it needs to be expanded. For too long pandemic preparedness has been reactive and it is long past time to approach the development of medical countermeasures for pandemic threats in a proactive fashion.
What we do for other national security threats should be the paradigm for infectious disease threats that too often are subject to a mind-boggling cycle of panic and neglect. There are an estimated 200 outbreaks of viral diseases per year. Luckily and because of hard work, for many of them we have tools at our hands to control them, but for the unknown 201st virus outbreak we do not –as we've seen this year. And, the next unknown virus will likely appear soon. A new program must be constructed guaranteeing that we will never again be caught blindsided and flatfooted as we have been with the COVID-19 pandemic.
A new dedicated "Virus 201" strategy, program, and funding must be created to achieve this goal. This initiative should be a specific program focused on unknown threats that emanate from identified classes of pathogens that possess certain pandemic-causing characteristics. For example, such a program could leverage new powerful vaccine platform technologies to begin development on vaccine candidates for a variety of viral families before they emerge as full-fledged threats. Imagine how different our world would be today if this action was taken after SARS in 2003 or even MERS in 2012.
Biden should remove the handcuffs from the Centers for Disease Control and Prevention (CDC) and allow its experts to coordinate the national response and to issue guidance in the manner they were constituted to do without fear of political reprisal.
Resurrect Expertise
One of the most disheartening aspects of the pandemic has been the denigration and outright attacks on experts in infectious disease. Such disgusting attacks were not for any flaws, incompetence, or weakness but for their opposite -- strength and competence – and emanated from a desire to evade the grim reality. Such nihilism must end and indeed the Biden plan contains several crucial remedies, including the restoration of the White House National Security Council Directorate for Global Health Security and Biodefense, a crucial body of experts at the White House that the Trump administration bafflingly eliminated in 2018.
Additionally, Biden should remove the handcuffs from the Centers for Disease Control and Prevention (CDC) and allow its experts to coordinate the national response and to issue guidance in the manner they were constituted to do without fear of political reprisal.
Shore Up Hospital Capacity
For the foreseeable future, as control of the virus slips away in certain parts of the country, hospital capacity will be the paramount concern. Unlike many other industries, the healthcare sector is severely constrained in its ability to expand capacity because of regulatory and financial considerations. Hospital emergency preparedness has never been prioritized and until we can substantially curtail the spread of this virus, hospitals must remain vigilant.
We have seen how suspensions of "elective" procedures led to alarming declines in vital healthcare services that range from childhood immunization to cancer chemotherapy to psychiatric care. This cannot be allowed to happen again. Hospitals will need support in terms of staffing, alternative care sites, and personal protective equipment. Reflecting these concerns, the Biden plan outlines an approach that smartly uses the Departments of Defense and Veterans Affairs assets and medical reserve corps, coupled to the now-flourishing telemedicine innovations, to augment capacity and forestall the need for hospitals to shift to crisis standards of care.
To these five tasks, I would add a long list of subtasks that need to be executed by agencies such as the Centers for Medicare and Medicaid, the Food and Drug Administration, and many other arms of government. But, to me, these are the most crucial.
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As COVID-19 has demonstrated, new deadly viruses can spread quickly and easily around the globe, causing significant loss of life and economic ruin. With nearly 200 epidemics occurring each year, the next fast-moving, novel infectious disease pandemic could be right around the corner.
The upcoming transition affords the opportunity to implement a new paradigm in pandemic response, biosecurity, and emerging disease response. The United States and President-elect Biden must work hard to to end this pandemic and increase the resilience of the United States to the future infectious disease threats we will surely face.
Dr. Adalja is focused on emerging infectious disease, pandemic preparedness, and biosecurity. He has served on US government panels tasked with developing guidelines for the treatment of plague, botulism, and anthrax in mass casualty settings and the system of care for infectious disease emergencies, and as an external advisor to the New York City Health and Hospital Emergency Management Highly Infectious Disease training program, as well as on a FEMA working group on nuclear disaster recovery. Dr. Adalja is an Associate Editor of the journal Health Security. He was a coeditor of the volume Global Catastrophic Biological Risks, a contributing author for the Handbook of Bioterrorism and Disaster Medicine, the Emergency Medicine CorePendium, Clinical Microbiology Made Ridiculously Simple, UpToDate's section on biological terrorism, and a NATO volume on bioterrorism. He has also published in such journals as the New England Journal of Medicine, the Journal of Infectious Diseases, Clinical Infectious Diseases, Emerging Infectious Diseases, and the Annals of Emergency Medicine. He is a board-certified physician in internal medicine, emergency medicine, infectious diseases, and critical care medicine. Follow him on Twitter: @AmeshAA