(The Guardian) — Having risen to fame on its superhuman performance at playing games, the artificial intelligence group DeepMind has cracked a serious scientific problem that has stumped researchers for half a century.
With its latest AI program, AlphaFold, the company and research laboratory showed it can predict how proteins fold into 3D shapes, a fiendishly complex process that is fundamental to understanding the biological machinery of life.
Independent scientists said the breakthrough would help researchers tease apart the mechanisms that drive some diseases and pave the way for designer medicines, more nutritious crops and “green enzymes” that can break down plastic pollution.
DeepMind said it had started work with a handful of scientific groups and would focus initially on malaria, sleeping sickness and leishmaniasis, a parasitic disease.
“It marks an exciting moment for the field,” said Demis Hassabis, DeepMind’s founder and chief executive. “These algorithms are now becoming mature enough and powerful enough to be applicable to really challenging scientific problems.”Advertisement
Venki Ramakrishnan, the president of the Royal Society, called the work “a stunning advance” that had occurred “decades before many people in the field would have predicted”.
DeepMind is best known for its run of human-trouncing programs that achieved supremacy in chess, Go, Starcraft II and old-school Atari classics. But superhuman gameplay was never the primary aim. Instead, games provided a training ground for programs that, once powerful enough, would be unleashed on real-world problems.
Protein folding has been a grand challenge in biology for 50 years. An arcane form of molecular origami, its importance is hard to overstate. Most biological processes revolve around proteins and a protein’s shape determines its function. When researchers know how a protein folds up, they can start to uncover what it does. How insulin controls sugar levels in the blood and how antibodies fight coronavirus are both determined by protein structure.
Scientists have identified more than 200m proteins but structures are known for only a fraction of them. Traditionally, the shapes are discovered through meticulous lab work that can take years. And while computer scientists have made headway on the problem, inferring the structure from a protein’s makeup is no easy task. Proteins are chains of amino acids that can twist and bend into a mind-boggling variety of shapes: a googol cubed, or 1 followed by 300 zeroes.
To learn how proteins fold, researchers at DeepMind trained their algorithm on a public database containing about 170,000 protein sequences and their shapes. Running on the equivalent of 100 to 200 graphics processing units – by modern standards, a modest amount of computing power – the training took a few weeks.
DeepMind put AlphaFold through its paces by entering it for a biennial “protein olympics” known as Casp, the Critical Assessment of Protein Structure Prediction. Entrants to the international competition are given the amino acid sequences for about 100 proteins and challenged to work them out. The results from teams that use computers are compared with those based on lab work.
AlphaFold not only outperformed other computer programs but reached an accuracy comparable to the laborious and time-consuming lab-based methods. When ranked across all proteins analysed, AlphaFold had a median score of 92.5 out of 100, with 90 being the equivalent to experimental methods. For the hardest proteins, the median score fell, but only marginally to 87.
Hassabis said DeepMind had started work on how to give researchers access to AlphaFold to help with scientific research. Andrei Lupas, the director of the Max Planck Institute for Developmental Biology in Tübingen, Germany, said he had already used the program to solve a protein structure that scientists had been stuck on for a decade.
Janet Thornton, a director emeritus of EMBL’s European Bioinformatics Institute near Cambridge, who was not involved in the work, said she was excited to hear the results. “This is a problem that I was beginning to think would not get solved in my lifetime,” she said. “Knowing these structures will really help us to understand how human beings operate and function, how we work.”
John Jumper, a researcher on the team at DeepMind, said: “We really didn’t know until we saw the Casp results how far we had pushed the field.” It is not the end of the work, however. Future research will focus on how proteins combine to form larger “complexes” and how they interact with other molecules in living organisms.
(Medical Xpress) -- Inspired by a parasitic worm that digs its sharp teeth into its host's intestines, Johns Hopkins researchers have designed tiny, star-shaped microdevices that can latch onto intestinal mucosa and release drugs into the body.
David Gracias, Ph.D., a professor in the Johns Hopkins University Whiting School of Engineering, and Johns Hopkins gastroenterologist Florin M. Selaru, M.D., director of the Johns Hopkins Inflammatory Bowel Disease Center, led a team of researchers and biomedical engineers that designed and tested shape-changing microdevices that mimic the way the parasitic hookworm affixes itself to an organism's intestines.
Made of metal and thin, shape-changing film and coated in a heat-sensitive paraffin wax, "theragrippers," each roughly the size of a dust speck, potentially can carry any drug and release it gradually into the body.
The team published results of an animal study this week as the cover article in the journal Science Advances.
Gradual or extended release of a drug is a long-sought goal in medicine. Selaru explains that a problem with extended-release drugs is they often make their way entirely through the gastrointestinal tract before they've finished dispensing their medication.
"Normal constriction and relaxation of GI tract muscles make it impossible for extended-release drugs to stay in the intestine long enough for the patient to receive the full dose," says Selaru, who has collaborated with Gracias for more than 10 years. "We've been working to solve this problem by designing these small drug carriers that can autonomously latch onto the intestinal mucosa and keep the drug load inside the GI tract for a desired duration of time."
Thousands of theragrippers can be deployed in the GI tract. When the paraffin wax coating on the grippers reaches the temperature inside the body, the devices close autonomously and clamp onto the colonic wall. The closing action causes the tiny, six-pointed devices to dig into the mucosa and remain attached to the colon, where they are retained and release their medicine payloads gradually into the body. Eventually, the theragrippers lose their hold on the tissue and are cleared from the intestine via normal gastrointestinal muscular function.
Gracias notes advances in the field of biomedical engineering in recent years.
"We have seen the introduction of dynamic, microfabricated smart devices that can be controlled by electrical or chemical signals," he says. "But these grippers are so small that batteries, antennas and other components will not fit on them."
Theragrippers, says Gracias, don't rely on electricity, wireless signals or external controls. "Instead, they operate like small, compressed springs with a temperature-triggered coating on the devices that releases the stored energy autonomously at body temperature."
The Johns Hopkins researchers fabricated the devices with about 6,000 theragrippers per 3-inch silicon wafer. In their animal experiments, they loaded a pain-relieving drug onto the grippers. The researchers' studies found that the animals into which theragrippers were administered had higher concentrates of the pain reliever in their bloodstreams than did the control group. The drug stayed in the test subjects' systems for nearly 12 hours versus two hours in the control group.
(AP) — Drugmaker AstraZeneca said Monday that late-stage trials showed its COVID-19 vaccine is highly effective, buoying the prospects of a relatively cheap, easy-to-store product that may become the vaccine of choice for the developing world.
The results are based on an interim analysis of trials in the U.K. and Brazil of a vaccine developed by Oxford University and manufactured by AstraZeneca. No hospitalizations or severe cases of COVID-19 were reported in those receiving the vaccine.
AstraZeneca is the third major drug company to report late-stage data for a potential COVID-19 vaccine as the world waits for scientific breakthroughs that will end a pandemic that has pummeled the world economy and led to 1.4 million deaths. But unlike the others, the Oxford-AstraZeneca vaccine doesn’t have to be stored at freezer temperatures, making it potentially easier to distribute, especially in developing countries.
“I think these are really exciting results,” Dr. Andrew Pollard, chief investigator for the trial, said at a news conference. “Because the vaccine can be stored at fridge temperatures, it can be distributed around the world using the normal immunization distribution system. And so our goal … to make sure that we have a vaccine that was accessible everywhere, I think we’ve actually managed to do that.”
The Oxford-AstraZeneca vaccine was 90% effective in preventing COVID-19 in one of the dosing regimens tested; it was less effective in another. Earlier this month, rival drugmakers Pfizer and Moderna reported preliminary results from late-stage trials showing their vaccines were almost 95% effective.
While the AstraZeneca vaccine can be stored at 2 degrees to 8 degrees Celsius (36 degrees to 46 degrees Fahrenheit), the Pfizer and Moderna products must be stored at freezer temperatures. In Pfizer’s case, it must be kept at the ultra-cold temperature of around minus-70 degrees Celsius (minus-94 Fahrenheit).
The AstraZeneca vaccine is also cheaper.
AstraZeneca, which has pledged it won’t make a profit on the vaccine during the pandemic, has reached agreements with governments and international health organizations that put its cost at about $2.50 a dose. Pfizer’s vaccine costs about $20, while Moderna’s is $15 to $25, based on agreements the companies have struck to supply their vaccines to the U.S. government.
All three vaccines must be approved by regulators before they can be widely distributed.
Oxford researchers and AstraZeneca stressed they weren’t competing with other projects and said multiple vaccines would be needed to reach enough of the world’s population to end the pandemic.
“We need to be able to make a lot of vaccine for the world quickly, and it’s best if we can do it with different technologies so that if one technology runs into a roadblock, then we’ve got alternatives, we’ve got diversity,″ professor Sarah Gilbert, a leader of the Oxford team, told The Associated Press. “Diversity is going to be good here, but also in terms of manufacturing, we don’t want to run out of raw materials.”
AstraZeneca said it will immediately apply for early approval of the vaccine where possible, and it will seek an emergency use listing from the World Health Organization, so it can make the vaccine available in low-income countries.
The AstraZeneca trial looked at two different dosing regimens. A half-dose of the vaccine followed by a full dose at least one month later was 90% effective. Another approach, giving patients two full doses one month apart, was 62% effective.
That means that, overall, when both ways of dosing are considered, the vaccine showed an efficacy rate of 70%.
Gilbert said researchers aren’t sure why giving a half-dose followed by a larger dose was more effective, and they plan to investigate further. But the answer is probably related to providing exactly the right amount of vaccine to get the best response, she said.
“It’s the Goldilocks amount that you want, I think, not too little and not too much. Too much could give you a poor quality response as well …,″ she said. “I’m glad that we looked at more than one dose because it turns out to be really important.”
The vaccine uses a weakened version of a common cold virus that is combined with genetic material for the characteristic spike protein of the virus that causes COVID-19. After vaccination, the spike protein primes the immune system to attack the virus if it later infects the body.
Peter Openshaw, professor of experimental medicine at Imperial College London, said the finding that a smaller initial dose is more effective than a larger one is good news because it may reduce costs and mean more people can be vaccinated with a given supply of the vaccine.
“The report that an initial half-dose is better than a full dose seems counterintuitive for those of us thinking of vaccines as normal drugs: With drugs, we expect that higher doses have bigger effects, and more side-effects,” he said. “But the immune system does not work like that.”
The results reported Monday come from trials in the U.K. and Brazil that involved 23,000 people. Of those, 11,636 people received the vaccine — while the rest got a placebo.
Overall, there were 131 cases of COVID-19. Details on how many people in the various groups became ill weren’t released Monday, but researchers said they will be published in the next 24 hours.
Late-stage trials of the vaccine are also underway in the U.S., Japan, Russia, South Africa, Kenya and Latin America, with further trials planned for other European and Asian countries.
Researchers said they expect to add the half dose-full dose regimen to the U.S. trial in a “matter of weeks.” Before doing so they must discuss the changes with the U.S. Food and Drug Administration.
The AstraZeneca trials were paused earlier this year after a participant in the U.K. study reported a rare neurological illness. While the trials were quickly restarted in most countries after investigators determined the condition wasn’t related to the vaccine, the FDA delayed the U.S. study for more than a month before it was allowed to resume.
AstraZeneca has been ramping up manufacturing capacity, so it can supply hundreds of millions of doses of the vaccine starting in January, Chief Executive Pascal Soriot said earlier this month.
Soriot said Monday that the Oxford vaccine’s simpler supply chain and AstraZeneca’s commitment to provide it on a nonprofit basis during the pandemic mean it will be affordable and available to people around the world.
“This vaccine’s efficacy and safety confirm that it will be highly effective against COVID-19 and will have an immediate impact on this public health emergency,” Soriot said.
British Health Secretary Matt Hancock said he felt “a great sense of relief” at the news from AstraZeneca.
Britain has ordered 100 million doses of the vaccine, and the government says several million doses can be produced before the end of the year if it is approved by regulators.
Just months ago, “the idea that by November we would have three vaccines, all of which have got high effectiveness … I would have given my eye teeth for,” Hancock said.
From the beginning of their collaboration with AstraZeneca, Oxford scientists have demanded that the vaccine be made available equitably to everyone in the world so rich countries can’t corner the market as has happened during previous pandemics.
Leaders of the world’s most powerful nations on Sunday agreed to work together to ensure “affordable and equitable access” to COVID-19 drugs, tests and vaccines.
“If we don’t have the vaccine available in many, many countries, and we just protect a small number of them, then we can’t go back to normal because the virus is going to keep coming back and causing problems again,” Gilbert said. “No one is safe until we’re all safe.”
The US-based service, which became available to customers Tuesday, works just like a traditional drugstore with special added perks for Prime members. Amazon Pharmacy accepts most major insurance with the ability to manage orders on its website. Prime members can get free two-day delivery.
There’s also a savings benefit plan for those without insurance or people who don’t want to pay with their insurance plans. Amazon Pharmacy is offering an 80% discount on generic medications and 40% off brand names. Amazon (AMZN) said its new service makes it “simple for customers to compare prices and purchase medications for home delivery,” adding that the tedious task is now “as convenient as any other purchase” on Amazon.
“As more and more people look to complete everyday errands from home, pharmacy is an important and needed addition to the Amazon online store,” Doug Herrington, senior vice president of North American Consumer for Amazon, said in a statement.
Amazon Pharmacy is an extension of PillPack, the drugstore startup Amazon bought for more than $700 million in 2018. PillPack has pharmacy licenses in all 50 states and delivers medications to customers in pre-sorted doses designed to make it easier for people to take multiple medications a day.
That same year, Amazon announced a health care venture with Berkshire Hathaway (BRKA) and JPMorgan Chase (JPM), but nothing substantial has come from that yet.
Hints of an Amazon drug store launch appeared in 2019 when Amazon tweaked the branding from “PillPack, an Amazon company” to “PillPack by Amazon Pharmacy.” PillPack will still exist as a “distinct service for customers managing multiple daily medications for chronic conditions,” noted Amazon.
Shares of Rite Aid (RAD), Walgreens (WBA) and CVS Health (CVS) all tumbled — between 8% to 12% — in early trading following Amazon’s announcement. GoodRx, a discount drug program that doesn’t require insurance, also fell 15%.Pharmacies have been squeezed as people have filled fewer prescriptions in stores during the pandemic. Some doctor’s offices closed, while many elective procedures have been put on hold and some shoppers have switched to mail-order drug delivery.
Preparing for the future, Rite Aid and CVS have recently revealed store remodels with a greater emphasis on health services that is more challenging to be replicated online, including appointments with health care professionals and minor procedures with licensed clinicians.
Walmart (WMT) doesn’t appear to be alarmed by Amazon’s launch. Its US CEO John Furner said during Tuesday’s earnings call with analysts that its health and wellness had a “great quarter” and its one of its “best businesses.” He added that the company has “really broad coverage on the ability to deliver prescriptions around the country.
“The nation’s largest retailer reported in $37.5 billion in sales during its latest fiscal last year from its pharmacies, optical services and revenue from over-the-counter drugs and other medical products.
(Vox) — The epic global effort to develop a Covid-19 vaccine has been unmatched in its scale, speed, and scientific advances. And recent announcements about the high efficacy of two leading vaccine candidates — one from Moderna and one developed by Pfizer and BioNTech — have raised hopes that an end to the pandemic might be in sight.
But the vaccine’s potential to provide immunity to the broader population is now threatened by a massive logistical hurdle in actually getting it to people safely: keeping the vaccine doses cold.
Vaccines are fragile drugs that demand strict temperature controls lest they spoil. And they spoil a lot. According to the World Health Organization, about half of the vaccines distributed around the world go to waste, in large part because of a failure to properly control storage temperatures. That in turn undermines efforts to contain and eradicate disease.
“They lose effectiveness and their potency if they’re exposed to temperatures outside of the range that they’re supposed to be kept in,” said Michelle Seidel, UNICEF’s immunization supply chain specialist.
This vulnerability stands to be an even bigger problem for the campaign against Covid-19, where just about everyone in the world is vulnerable so just about everyone will need the shot. Containing the disease will require billions of people to be immunized around the world — likely with two doses — and fast.
Pfizer and BioNTech have reported that their vaccine is more than 90 percent effective at preventing the disease in a preliminary analysis. Moderna’s candidate was reported to be 94.5 percent effective in early data.
But these vaccines, which use strands of genetic material known as mRNA, also have some stringent temperature requirements. Moderna’s vaccine requires long-term storage at minus 20 degrees Celsius (minus 4 degrees Fahrenheit) and is stable for 30 days between 2 degrees to 8 degrees Celsius (36 degrees to 46 degrees Fahrenheit). Pfizer and BioNTech’s vaccine, however, requires some of the coldest temperatures of any vaccine under consideration: minus 70 degrees Celsius (minus 94 degrees Fahrenheit) or lower.
Pfizer, BioNTech, and other companies whose vaccine candidates require very cold storage say they are already preparing for this challenge, investing in freezers, transportation, and temperature-tracking devices. But with so many moving parts, there’s a lot that can go wrong. With recent struggles in the United States to maintain adequate supply chains for Covid-19 tests, masks, and personal protective equipment, the concern is that the same mistakes could be repeated in a high-stakes vaccination effort.
While full approval of a Covid-19 vaccine may still be months away, the foundation for getting it to people has to be laid now.
The vaccine cold chain, explained
Getting a vaccine through clinical trials and approved by the Food and Drug Administration is a tedious, expensive, and time-consuming process. But it’s not the finish line for a Covid-19 immunization campaign. It’s just one of the first hurdles.
“There’s almost an assumption that once a vaccine is created and approved, then everyone is healthy and fine, but the operational component is pretty complex,” said Caesar Djavaherian, an ER physician and chief clinical innovation officer at Carbon Health. “We’ve never tried to administer vaccines to 100 million Americans in a short period of time.”
To prepare for that, Covid-19 vaccine production is already underway. The idea is that once a vaccine does get the green light, doses are ready to roll out right away. Operation Warp Speed, the $10 billion US government vaccine development effort, is aiming to have 300 million doses of a Covid-19 vaccine produced by January 2021.
But at that point, vaccines have to go from factories to shipping facilities to trucks to hospitals, clinics, and pharmacies, and, eventually, into the arms of people — all while without budging from narrow, specific temperature ranges.
This series of handoffs under strict temperature controls is known as the cold chain. It’s this chain — between the manufacturer and the clinic — that represents one of the biggest challenges of the vaccine distribution effort, and each step could potentially become a weak link.
It’s particularly challenging because vaccines are only manufactured in a handful of facilities around the world, demanding a sprawling international network of transportation and storage sites in order to get immunizations to wherever they’re needed.
Many major hospitals may have the specialized cold storage facilities needed to stockpile vaccines, but smaller clinics and pharmacies don’t. And even some of the big hospitals may not have the specialized ultra-cold freezers needed to store a vaccine like the one developed by Pfizer and BioNTech, especially in large quantities.
That’s why vaccines are typically sent from factories to regional warehouses. These facilities often have sophisticated freezers for long-term storage, as well as a reliable electricity supply and backup generators. They aren’t set up to administer the vaccine to people, however, so the vials still have to be delivered to the final users.
But every time a vaccine moves, it introduces yet another risk. Bad weather can delay delivery flights. Freezers can fail on refrigerator trucks. Vaccine shipping containers can end up stuck on the tarmac. Coolers can leak. Even opening freezers repeatedly to move things in and out can harm vaccines stored inside. Every breach in temperature control degrades the vaccine, and every time the vaccine moves, the chances of this happening increase, so health officials need to plan carefully to ensure the absolute minimum amount of movement.
Once a clinic receives a vaccine shipment, health workers can thaw out the vials in a refrigerator as they prepare to give injections to patients. But once a vaccine is warmed up, it’s only viable for a few days. For clinics without their own cold-storage facilities, the clock starts ticking as soon as they receive their doses. So getting everyone vaccinated requires a precisely coordinated series of complex events spanning the globe, and any break therein could derail an effort to control a deadly disease.
Why supply chains are even more complicated for the Covid-19 pandemic
All that said, health systems in the United States and around the world have been administering vaccines for decades, and there is plenty of experience and know-how for effectively bringing vaccines to people.
But again, the Covid-19 vaccination effort has to happen at an even larger scale than just about any other vaccination effort to date. And it can’t seize infrastructure from existing vaccines since immunizations for illnesses like measles, influenza, polio, and meningitis are still needed at the same time.
That means many of the things needed to distribute a Covid-19 vaccine have to be additional to what’s already on the market; freezers, refrigeratedshipping containers, and remote temperature-monitoring systems can’t simply be cannibalized from other vaccine supply chains.
The scale of a Covid-19 vaccination campaign could also create other bottlenecks. Vaccine vials require a specific type of glass that can tolerate low temperatures and remain sterile, and there may not be enough of this glass to go around right away. Even the self-sealing rubber stoppers on the vials could face a shortfall. Syringes, personal protective equipment, and trained personnel to administer vaccines are already facing a crunch from dealing with the ongoing pandemic.
Then there are complications that arise from the Covid-19 vaccines themselves. Covid-19 vaccine development has allowed researchers to showcase new technologies that have never been tried before at scale. In particular, multiple companies are developing vaccines based on the genetics of the SARS-CoV-2 virus, the virus that causes Covid-19, rather than the classical approach of using the structure or pieces of the virus itself.
The problem is that these fragments of DNA and RNA are delicate. They can degrade quickly on their own, even at refrigerated temperatures. That’s why freezing them is so important for keeping them intact.
But that’s hard to do for vaccines like Pfizer and BioNTech’s vaccine candidate, which requires storage at such extreme temperatures. Some experts are concerned these cold requirements could end up being a deal breaker for widely distributing these vaccines. “These mRNA vaccines, which are stored at minus 80°C, from a practical perspective are showstoppers right now,” said Vijay Samant, the former chief operating officer at Merck Vaccines.
Ultra-cold freezers that can reach the requisite temperatures cost between $10,000 and $15,000 each. That’s out of the budget for many clinics and hospitals. With these logistical and storage constraints, that may mean that people will have to travel to centralized locations like regional hospitals to get vaccinated instead of to their local clinics and pharmacies.
But Pfizer and BioNTech said they have a solution.
“We have specially designed, temperature-controlled thermal shippers utilizing dry ice to maintain recommended temperature conditions for up to 10 days,” said Jerica Pitts, a spokesperson for Pfizer, in an email. “The intent is to utilize Pfizer-strategic transportation partners to ship by air to major hubs within a country/region and by ground transport to dosing locations.”
According to the Wall Street Journal, Pfizer’s vaccine shipping system can hold up to 5,000 doses of its vaccine at minus 70°C for those10 days. The company is also spending more than $2 billion to create its own distribution network, aiming to ship these containers on a just-in-time basis to the places that need them, bypassing the need for warehouses.
However, this strategy could run into its own supply chain constraints. There may be shortages in critical components for Pfizer and BioNTech’s containers, like the dry ice required to keep those super-cold temperatures.
Many of the Covid-19 vaccine candidates, including the one from Pfizer and Moderna, also require two doses, spaced several weeks apart. “It does mean double the capacity requirements, so yes, there is an additional complication,” Seidel said. Ensuring there is the right number of doses available at just the right time for everyone’s second dose will require even more storage capacity and precise tracking and timing of shipments.
The Covid-19 vaccination campaign has to be global
One stark lesson of the Covid-19 pandemic is that an outbreak anywhere in the world can ripple across the whole planet. So the effort to contain the disease has to reach every country, in every circumstance.
Some health systems do have experience with keeping finicky vaccines frigid, even in places with limited resources. The Ebola vaccine, for instance, had to be stored at minus 80°C in remote areas of Guinea and the Democratic Republic of the Congo.
But the looming question is whether limited resources can also be stretched to accommodate a Covid-19 vaccination effort. “We are leveraging our experience in Ebola-prone countries to develop guidance on that, but that is something where we do lack funding,” Seidel said.
And ensuring distribution is seamless and also fast is critical. Every day, thousands of people are dying from Covid-19, so there is intense pressure to get people vaccinated as quickly as possible. That would require a simultaneous effort, in the United States and around the world.
However, if governments and private companies make the investments now, the weaker links in the supply chain can be strengthened and ideally avoid the same mistakes made in the earlier stages of the Covid-19 pandemic that left many scrounging for vital masks, gloves, gowns, and tests. The true test of the vaccine supply chain will come when vaccine vials start leaving factories, which could start before the end of the year.
After examining 94 cases of COVID-19 in the late-stage study, a data monitoring committee concluded Pfizer and BioNTech’s vaccine was more than 90% effective in preventing disease — a better-than-expected outcome and an extraordinary scientific achievement for researchers that 10 months ago were just learning of SARS-CoV-2.
“Everybody is just smiling with delight, knowing what an accomplishment of science this is,” said Larry Corey, a virologist at Fred Hutchinson Cancer Research Center and co-head of the National Institutes of Health’s COVID-19 Prevention Trials Network.
Beyond the headline, however, Pfizer and BioNTech had little information to share. That’s expected, given the monitoring committee only performed its analysis Sunday. The companies said they plan to disclose and publish their data.
“Their outcome is essentially that the vaccine arm was protected from developing disease,” said Akiko Iwasaki, an immunologist at Yale University. “That’s really all we know now.”
For a beleaguered world facing a resurgent pandemic, that’s enough right now. But there are many missing details that could matter greatly, not least of which is a detailed look at how safe the shot was for the participants enrolled in the Phase 3 trial.
Earlier, smaller studies have shown vaccination with Pfizer and BioNTech’s shot led to side effects like injection site pain, fever, fatigue or chills — most of which were mild or moderate in nature and are typical signs of an immune response to a vaccine. The companies’ statement Monday noted no serious adverse reactions had been reported to date.
A fuller reporting will likely come around when Pfizer and BioNTech ask the Food and Drug Administration for an emergency approval, for which the regulator has requested that companies to provide a median of at least two months follow-up for their study participants.
The two-month requirement is meant to capture rarer, more serious side effects that typically emerge between 40 to 60 days after vaccination. Pfizer expects to have those data as early as next week, after which it would formally ask the FDA for an emergency authorization.
Emergency approval is just a first step, made necessary by the urgent need for a coronavirus vaccine. For a full approval of a vaccine, the FDA typically requires at least six months of safety data.
Safety results aren’t the only data points scientists and public health officials need to more fully assess Pfizer and BioNTech’s vaccine.
Vaccines can be more or less protective due to factors like age or underlying medical conditions. In Pfizer and BioNTech’s early studies, for instance, older individuals had somewhat weaker immune responses to vaccination than younger people.
Breakdowns by age from Pfizer’s trial, which enrolled individuals older than 12 years, will be critical, as will reporting on whether there were differences between participants who identified as Black, Hispanic or Latino, Asian or Native American.
It’s also unclear from the companies’ announcement whether the shot is equally protective against mild and more severe COVID-19, or whether vaccination protected against infection as well as disease.
If the vaccine can’t block transmission of the virus, prevention guidelines like wearing masks or social distancing will remain critical even after inoculation.
Those questions will only become more important if the vaccine is authorized, and people start to receive the shot outside of the close monitoring of a clinical trial.
“The bottom line is we have much to learn about what’s needed to make vaccine policy and to answer the questions that people want about vaccination,” Corey said.
Key to any such policy will be information on how long any protective benefit conferred by a vaccine lasts. Pfizer and BioNTech’s claim of greater than 90% effectiveness was based on an analysis done one week after the second of two doses. Under a revised plan, the companies will also analyze the vaccine’s efficacy at 14 days following the second dose — similar to what other developers’ are doing.
Looking further out to months or years post-vaccination, however, “only time can tell whether long-term protection is conferred,” said Yale’s Iwasaki.
Indeed, at this point, vaccine experts can only guess. Antibodies, the immune cell defenders key to battling foreign pathogens, naturally wane over time, and scientists still aren’t certain what levels of antibodies are needed to confer protection in the first place.
“It’s always better to have higher efficacy,” said Corey, but he added that higher initial effectiveness doesn’t necessarily mean longer durability.
(Reuters) – Biogen Inc has shown “exceptionally persuasive” evidence that its experimental Alzheimer’s disease drug is effective, U.S. Food and Drug Administration staff said on Wednesday, elevating its chances of a swift approval and sending company shares soaring.
An FDA approval could come by March, which would make the drug, aducanumab, the first new treatment for the disease in decades and the first that appears to be able to slow progression of the fatal, mind-wasting condition that affects millions of people.
Shares of Biogen and its partner Eisai Co Ltd both jumped 40%. The FDA staff comments also buoyed shares of other Alzheimer’s drug developers, including a 15% rise in shares of Eli Lily and Co.
The agency’s documents were released ahead of a meeting on Friday of outside experts who will review, and decide whether to recommend approval of, aducanumab, an antibody designed to remove amyloid plaques from the brain.
“Briefing documents suggests a positive Advisory Committee vote, which bodes well for approval,” Guggenheim analyst Yatin Suneja said in a research note. Mizuho Securities analyst Salim Syed called it “almost a best-case scenario” for Biogen.
FDA drug reviewers said results from one pivotal trial of aducanumab were persuasive and strongly positive. They acknowledged that a second large trial did not succeed, but maintained it did not detract from the findings of the positive study. The FDA is not obligated to abide by its expert panel recommendations, but typically does.
One statistical reviewer at the FDA said another study is needed to confirm whether aducanumab is effective. “There is no compelling substantial evidence of treatment effect or disease slowing,” FDA staffer Tristan Massie wrote in the review.
Alzheimer’s disease afflicts nearly 6 million Americans and millions more worldwide. Biogen estimates about 1.5 million people with early Alzheimer’s in the United States could be candidates for its drug.
Patient advocacy groups have argued that aducanumab needs to be approved due to that large unmet medical need.
“If a third trial is recommended then years could go by … while people aren’t granted access to the drug,” said Dr. Howard Fillit, chief science officer at the Alzheimer’s Drug Discovery Foundation.
Biogen and its investors also need an aducanumab approval after the company recently lost a patent fight over its big-selling multiple sclerosis drug Tecfidera. If approved, annual sales are forecast to reach $5.3 billion by 2025, according to Refinitiv.
Cambridge, Massachusetts-based Biogen in October last year revived its plans to seek approval for aducanumab, months after it had said that an independent futility analysis of its two pivotal studies showed they were unlikely to succeed.
Biogen said it changed course after a new analysis showed a high dose of the drug could slow disease progression.
The FDA staff said data from one of the trials “provides the primary evidence of effectiveness as a robust and exceptionally persuasive study demonstrating” a clinically meaningful treatment effect.
Shares of Biogen were up $99.57 at $346.58, and shares of Eisai were up $30.82 at $110.12.
The Food and Drug Administration said on Thursday that it had formally approved remdesivir as the first drug to treat Covid-19, a move that indicated the government’s confidence in its safe and effective use for hospitalized patients.
The F.D.A. said the drug had been approved for adults and pediatric patients 12 years of age and older and weighing at least 40 kilograms (about 88 pounds) who require hospitalization for Covid-19, the disease caused by the coronavirus, which has killed more than 220,000 people in the United States.
The F.D.A. had granted remdesivir emergency authorization in May after a trial by the National Institutes of Health found that it modestly reduced the recovery time in hospitalized patients. President Trump received the antiviral drug after he began showing symptoms earlier this month. The drug does not prevent death from Covid-19.
The formal approval by the F.D.A. indicated that the drug had cleared more rigorous regulatory hurdles involving a more thorough review of clinical data and manufacturing quality since it was given emergency authorization in May.
“The FDA is committed to expediting the development and availability of Covid-19 treatments during this unprecedented public health emergency,” Dr. Stephen M. Hahn, the agency’s commissioner, said in a statement. “Today’s approval is supported by data from multiple clinical trials that the agency has rigorously assessed and represents an important scientific milestone in the Covid-19 pandemic.”
Remdesivir, which was originally developed as a treatment for Ebola and hepatitis C, interferes with the reproduction of viruses by jamming itself into new viral genes. A study of more than 11,000 people in 30 countries sponsored by the World Health Organization found that the drug failed to prevent deaths in patients with Covid-19.
The drug did not go through an outside panel of experts, called an advisory committee, before being approved.
Dr. Peter Lurie, a former associate commissioner with the F.D.A. and now president of the Center for Science in the Public Interest, said that was not unusual.
“The F.D.A. tends to pick for advisory committees those drugs that are most novel and those that present safety issues, and those that are close calls with respect to effectiveness,” Dr. Lurie said. “This is not a blockbuster drug. This is not some massive breakthrough. It’s a drug that appears convincingly to benefit patients, but it’s not some kind of miracle cure.”
Thursday’s approval did not cover the entire population that was covered under the agency’s emergency authorization in May.
That emergency authorization allows doctors to use the drug on hospitalized pediatric patients weighing between 3.5 kilograms (not quite 8 pounds) and 40 kilograms or hospitalized pediatric patients less than 12 years of age who weigh at least 3.5 kilograms. Clinical trials assessing the safety and efficacy of the drug in this pediatric patient population are ongoing, the F.D.A. said.
The drug was approved less than two weeks before Election Day, as Mr. Trump has been promising a “cure” for Covid-19. Shares of Gilead Sciences, the company that makes remdesivir, rose on Thursday amid news of the F.D.A. action.
“As part of the FDA’s Coronavirus Treatment Acceleration Program, the agency will continue to help move new medical products to patients as soon as possible, while at the same time determining whether they are effective and if their benefits outweigh their risks,” Dr. Hahn said.
Decentralized clinical trials gained a foothold in the pharmaceutical industry amidst the COVID-19 pandemic and will continue to be used once the pandemic ends, according to panelists at BIO 2020, speaking Thursday in a virtual session.
The chief benefit of decentralized clinical trials is the options it brings to patients. “There is a lot of opportunity for more of us to participate in trials that are decentralized,” said Valerie Paradiz, VP, services and supports at Autism Speaks, and an autism patient herself.
Autistic patients, as well as those with other conditions, experience a range of characteristics that affect patients’ lives. They include varying degrees of communication issues, responses to sensory input and focused interests that can impede relationships or fulfill lives, Paradiz explained.
In a clinical setting, distributed trials could open the door to people who can’t leave home easily or as frequently as needed for them to participate in traditional clinical trials. “Distributed trials, therefore, could capture new kinds of data” by including those populations. “The keyword is ‘options,’” she said.
The “all hands on deck” approach to the pandemic by Congress and the FDA set the stage for clinical trial innovation. “It has set up a lot of conversations about where telehealth is, and where it will be six months from now,” Wade Ackerman, partner at Covington & Burling, said. “When the new Congress convenes in January, it will have an 18-month runway to the next FDA user fee authorization, so there will be significant policy discussion on the Hill about these issues.”
Not surprisingly, defining the terms around decentralized trials is foundational. “People often use the terms decentralized, remote, virtual and hybrid interchangeably,” moderator Rasika Kalamegham, group director, US regulatory policy at Genentech, noted.
In actuality, their meanings are quite different. Isaac Rodriguez-Chavez, officer for clinical research methodology, regulatory compliance & policy development within FDA’s, Center for Drug Evaluation and Research, explained. “At the Agency, ‘decentralized trials’ refers to the decentralization of technologies. These clinical trials use digital technologies to have remote interactions with real participants. In contrast, virtual trials are preclinical trials conducted in silico or on models. Both examples use digital technology, but their application is different.
“Hybrid trials combine elements of traditional and centralized approaches,” Rodriguez-Chavez continued. Here, some patient consultations or tests may be performed remotely and others in person at a trial site. Which trial design may be best used depends on the trial’s goals, the patient population and the available technology.
The technology itself is a major consideration. “For a simple example, having to go to a trial site for a blood draw rather than having the option to have blood drawn at home could be a deal-breaker for some individuals,” Paradiz said. In autism, reducing a person’s anxiety by their not having to process the additional information of a clinical setting, reducing wait times (and, thus unstructured time) and communicating in multiple ways are simple elements that have great impacts on trial participants.
What can be measured during trials depends on the wearables selected for the study. “Wearing a device for the duration of a trial can be intrusive. Even playing a game or using an app on a regular basis takes a lot of effort, so it’s challenging to identify the right technology to use. When integrating technology into a study, you want to consider the comfort level of the patient,” Kalamegham said.
Paradiz recommended getting input not just from the intended trial participants, but also from industrial or cognitive engineers to optimize the experience and ensure the right data is obtained at the right quality.
Patient education should play a role, too, panelists advised. “It’s important to educate study participants about the study’s purpose, how to use the technology and how to get used to it.” To do this, Paradiz recommended consulting real-world evidence showing how your particular population consumes and retains information. That could mean developing a social narrative or step-by-step videos, like task analyses, she added.
As decentralized trials become more necessary, pharma sponsors are looking for guidance. “There’s an inertia in the FDA and in the industry,” Ackerman acknowledged. “There’s already a tried and true pathway for clinical trials, so does any sponsor want to take risks (by using decentralized trials)?”
Normalization will be more likely after the FDA issues its decentralized guidance, tentatively scheduled for later this year. “It represents an expansion of clinical research from traditional to decentralized trials,” Rodriguez-Chavez said. It will include hybrid trials, as well. “The whole Agency is engaged in this topic.
“The technology must make sense for the context in which it is used,” he continued. “For us, it comes down to following 21CFR Part 11 guidelines.” He defined that as having an audit trail for the technology and for everything that occurs, as well as robust and reliable data.
For instance, the sensors and wearable devices used in the trial must be customized, verified and validated – in addition to the verification and validation studies conducted by their manufacturer. “This is to ensure you are measuring what you intend to measure,” Rodriguez-Chavez explained.
“Because of a public health crisis, the industry has pushed to adopt technology that otherwise would have been adopted in a step-wise approach,” Ackerman noted. “The promise is there, but there are cautions, too. There are a lot of layers to work through, and a lot of thought must be given to each step.
“I encourage people to collaborate with the FDA in evolving areas,” Ackerman concluded. “Keep a positive mindset and be engaged as you hit the gray areas.”