DeepMind AI cracks 50-year-old problem of protein folding

Source: The Guardian

(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 chessGoStarcraft 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.

Researchers engineer tiny machines that deliver medicine efficiently

Source: Medical Xpress

 (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.

 

 

Amazon is now a drug store. It will ship prescriptions to Prime members

Source: CNN Business

New York (CNN Business) — Amazon is making its biggest leap into the multi-billion-dollar health care industry with the launch of Amazon Pharmacy, a new digital drugstore.

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.

Pfizer and BioNTech’s coronavirus vaccine works. Here’s what we still don’t know.

(BioPharma Dive) – Pfizer and BioNTech’s experimental coronavirus vaccine works, possibly extremely well.

That’s the encouraging conclusion from the companies’ announcement Monday of early results from a large clinical trial of some 44,000 volunteers.

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.

Source: BioPharmaDive

Biogen Alzheimer’s drug closer to approval with U.S. FDA staff backing, shares jump 40%

Source: Reuters

(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.

Safety Tips for Trick-or-Treating and Other Halloween Activities

Source: The CDC

Steps to Take when Trick or Treating

Traditional Halloween activities are fun, but some can increase the risk of getting or spreading COVID-19 or influenza. Plan alternate ways to participate in Halloween.

Make trick-or-treating safer

  • Avoid direct contact with trick-or-treaters.
  • Give out treats outdoors, if possible.
  • Set up a station with individually bagged treats for kids to take.
  • Wash hands before handling treats.
  • Wear a mask.

Wear a mask

  • Make your cloth mask part of your costume.
  • A costume mask is not a substitute for a cloth mask.
  • Do NOT wear a costume mask over a cloth mask. It can make breathing more difficult.
  • Masks should NOT be worn by children under the age of 2 or anyone who has trouble breathing

Stay at least 6 feet away from others who do not live with you

  • Indoors and outdoors, you are more likely to get or spread COVID-19 when you are in close contact with others for a long time.

Wash your hands

  • Bring hand sanitizer with you and use it after touching objects or other people.
  • Use hand sanitizer with at least 60% alcohol.
  • Parents: supervise young children using hand sanitizer.
  • Wash hands with soap and water for at least 20 seconds when you get home and before you eat any treats.

Steps to Take for Other Halloween Activities

Enjoy Halloween activities and take steps to protect yourself from getting or spreading COVID-19.

illustration of a child in a bat costume carrying hand sanitizer

Remember to always

  • Wear a cloth mask
  • Indoors and outdoors, stay at least 6 feet away from others who do not live with you
  • Wash your hands or use hand sanitizer frequently

Decorate and carve pumpkins

  • Decorate your home for Halloween.
  • Carve pumpkins with members of your household or outside with neighbors or friends.
  • Walk from house to house, admiring Halloween decorations at a distance.

Visit an orchard, forest, or corn maze. Attend a scavenger hunt.

  • Go on an outdoor Halloween-themed scavenger hunt.
  • Visit a pumpkin patch or orchard. Remember to wash your hands or use hand sanitizer frequently, especially after touching frequently touched surfaces, pumpkins, or apples.
  • Go to a one-way, walk-through haunted forest or corn maze.

Other Ideas

  • Hide Halloween treats in and around your house. Hold a Halloween treat hunt with household members.
  • Hold an outdoor costume parade or contest so everyone can show off their costumes.
  • Host an outdoor Halloween movie night with friends or neighbors or an indoor movie night with your household members.

Are We Ready for Decentralized Clinical Trials?

Source: BioSpace

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.”

A Look Inside Clinical Trials During COVID-19

By: Sarah Hof

It’s no longer surprising to hear that many aspects of the pharmaceutical industry have been disrupted due to the far-reaching effects of COVID-19. Clinical trials are no exception, due to the myriad of moving parts it takes to conduct a clinical trial effectively. Hospital maintenance, doctor availability, and the willingness of patients to participate are areas impacted and if one of these factors is unreliable for whatever reason, a trial can be usurped and critically delayed.

We wanted to get an inside look at how clinical trials are running nowadays, so we invited Dr. Niaz Ausaf, the Principal Investigator of Auzmer Research in Lakeland, Florida to share some of his observations and insights.

Regarding his staff, Dr. Ausaf reported that in the spring everyone had to work remotely, and for a period of two weeks back in March his office was not permitted to see patients in the office. Now, approximately 80% of Dr. Ausaf’s staff are back in the labs resuming work.

Of the current workload in his office, Dr. Ausaf stated that “the flow of clinical trials is at the same ferocity as before.” Also, he notes that patient compliance in terms of completing diaries and attending onsite visits is close to 100%, reflecting the pre-pandemic rate.

A definitive change Dr. Ausaf has seen is the newly necessary budgeting for PPE, or personal protective equipment. He reported that his office now plans for six times the cost of PPE before COVID-19, and nearly all sponsors have been readily accommodating.

Another difference reflects the reluctance of some patients to leave their homes for unnecessary purposes, especially to spend time inside of a medical clinic. To be more accommodating towards patients, Dr. Ausaf sees the potential in new collaborations between sponsors and local pharmacies, allowing study subjects to pick up investigational product in a more convenient manner.

Of these collaborations, they are a new commonality offered for patients in clinical trials. A global survey conducted earlier this year by Medidata found that 45% of clinics and hospitals had transitioned near fully from in-person visits to virtual visits (source). 

As Dr. Ausaf looks to the future of clinical trials, he sees plenty of opportunity for innovation that have been made obvious by the new necessities brought by COVID-19. For example, he believes that the “virtual trial” model is not something that will go away, but rather will take hold in the space. In fact, the same survey found that a third of respondents have amended study protocols to include some degree of telemedicine (source).  

To that end, he sees sponsors potentially partnering with the home healthcare industry to facilitate different aspects of conducting a virtual trial. Sponsors may send nurses to patients’ homes when necessary, and team up with online recording software such as e-diaries, and consumer-facing medical devices such as Bluetooth-enabled stethoscopes. These devices and other home monitoring technologies would enable a patient to monitor and report his or her own vital signs.

Dr. Ausaf has helped forge a viable plan for his clinic, Auzmer Research, should these predictions come to fruition. He noted that his clinic has already been presented with two virtual trial opportunities.

On a macro scale, he believes that hospital networks with the means to do so will start buying independent research sites, which will mitigate the risks of using unknown or unverified sites. Sponsors have seen the negative effects of scrambling for doctors and clinics in the wake of COVID-19, and the experience is not one that sponsors would be willing to repeat.

It is clear that while the world of clinical research is evolving at a rapid pace, we must adopt innovative digital tools and collaborative platforms to be best positioned to meet these challenges and drive the best possible outcomes for patients.

To further your learning about the application of innovative technology in study start-up, please visit www.lineasystem.com.

Why is a Study Start-up Management System the vital tool sponsors need?

By: Sarah Hof

Countless industries are shifting to virtual and remote operations, and the realm of clinical trials is no exception. In fact, COVID-19 has only accelerated our industry’s dependence on technology to efficiently and successfully run trials. This shift has prompted the field to accept virtual or decentralized clinical trials as a trusted means to conduct research of such vital importance.

As teams become empowered to work from anywhere in the world, it is necessary for all stakeholders in a trial to have readily-available access to information on the clinical trial in real-time. The proper tools and technology to navigate a decentralized clinical trial ensures a successful outcome for the sponsor, and more importantly, an accelerated timeline for patients to gain access to life-changing medicines.

What is a Study Start-up Management System?

A Study Start-up Management System (SSMS) is an essential tool to efficiently accelerate clinical trial start-up. From all steps throughout the start-up process beginning with targeting the right sites, assessing site interest, conducting feasibility, collecting essential regulatory documents, obtaining approvals and contracts, and finally, enrolling patients, an SSMS ensures that a trial launches on-time and with the optimal sites.

There are three hallmark features of an SSMS:

  1. A built-in database of investigators. To deliver the optimal sites, every SSMS includes a built-in database of investigators.
  2. An automated workflow. By design, the system’s automated workflow enables a sponsor to quickly move from task to task and ensure that the start-up is progressing with no hold-ups.
  3. A cloud-based structure. The cloud-based nature of the system provides readily available access to data, metrics, and reporting anytime and anywhere.

Differing from other trial management software, an SSMS assists in the launch of a trial, while others such as a CTMS manage separate aspects of a trial after it has been launched and patients are being enrolled.

How can an SSMS help sponsors?

It is well-known that the most common source of delays to a trial is patient recruitment. This stems back to sponsors selecting initial sites that either prove unreliable once patients have been enrolled, or fail to enroll patients at all. In fact, according to the Tufts Center for the Study of Drug Development, 37 percent of sites selected under-enroll, and 11 percent fail to enroll a single patient. These routinely poor start-up metrics can lead to delayed trial timelines, and a 20 percent or higher increase in the originally projected trial budget.

When a sponsor selects the optimal sites first, patient recruitment is realized, the trial can proceed on-time, and the sponsor gains approval of vital medicines for patients in need. This efficient sequence of the events is possible using a Study Start-up Management System, with the built-in database of ranked investigators and an automated workflow to effectively launch the trial.

How does AcceleTrialdrive clinical trials forward?

AcceleTrial™ was created with the founding principle that nearly all clinical trials can avoid delays by selecting the right sites initially. Not only does AcceleTrial™ have a database of over 100,000 global expert investigators, those investigators are all ranked objectively. Its proprietary algorithm pulls hundreds of data points from multiple sources based on clinical expertise, access to patients, and former clinical trial experience, among other metrics. This powerful ranking system ensures that ultimately, the most effective and optimal investigators and sites are selected for the trial, thereby mitigating any chance of delay.

The “push and pull” workflow ensures a steady momentum, tracking each step and keeping the process seamless. To add transparency, both the sponsor and the sites and investigators are able to access the platform and complete their respective tasks while monitoring the full scope of the process. AcceleTrial™ is designed to be intuitive and make a significant and immediate impact on a trial’s launch time and operational costs.

When a trial progresses smoothly, the greatest value is the potential to make available life-changing medicines for patients who need them most.

COVID-19 & Clinical Trials: Understanding The Long-Term Impact

Like companies in all industry sectors, many biotechnology and pharmaceutical companies are struggling to understand and find strategies to address the challenges presented by the COVID-19 outbreak. For many, the impact of the pandemic on the conduct of clinical trials has forced both smaller biotechs and Big Pharma to make tough decisions to pause ongoing trials and reconsider timelines for data readouts, regulatory reviews, and product launches. Factors including impaired access to the healthcare system, travel restrictions, patient willingness to participate in trials, new guidance from regulatory agencies, and a shift in resources to fighting the pandemic are influencing the ability to advance many clinical research programs around the world. As companies focus on the immediate impact of COVID-19 on their development efforts, industry insiders are now starting to consider what the longer-term implications will be and how to address them.

The Life Sciences Practice at CRA recently reached out to a number of industry stakeholders, including regulatory and policy experts, venture capitalists, and contract research organizations (CROs), to better understand concerns about the impact of COVID-19 on clinical trials and how new challenges are likely to reverberate through the industry. Findings indicate that the impact on clinical development programs is already severe and will be broad and long-lasting, while the magnitude and nature of the impact will vary from trial to trial and company to company.

Addressing Short-Term Implications

In response to the pandemic, the FDA, EMA, and several national-level European governments have acted quickly to assess the impact and issued new recommendations related to clinical trials, including strategies for how companies can adapt to the current situation while reinforcing the essential need for any change to meet acceptable standards in patient safety and trial integrity. The agencies have also communicated their intention to remain flexible in evaluating protocol changes, deviations, and clinical efficacy and safety data. Industry insiders generally agree that the new guidelines provide a sufficient framework for trial sponsors to adapt their trial designs and protocols as needed at this stage.

As companies learn to adapt and consider implementing new strategies to keep clinical trials on track, in many cases the only option is to temporarily pause or delay development programs. For example, Provention Bio recently paused a Phase 3 trial in type 1 diabetes and Iveric Bio temporarily stopped a pivotal trial in geographic atrophy. But these decisions are not limited to smaller companies. Eli Lilly, Bristol-Myers Squibb, and Pfizer have announced pauses or delays in multiple development programs.

While consensus is that the impact of COVID-19 on clinical trials will be far-reaching, our analysis suggests that the level and duration of this impact will be especially severe in studies that have the following characteristics:

  • Enrolled vulnerable populations, including the elderly, the immunocompromised, and patients with pulmonary conditions (e.g., COPD)
  • Have primary or secondary endpoints that require in-person visits or hospital infrastructure and equipment (e.g., CT and PET scans) for assessment
  • Involve indications with minor safety or quality of life implications for patients (e.g., “lifestyle drugs”) and indications where a patient’s environment has a significant impact on therapeutic success (e.g., psychiatric and neurological indications)
  • Are currently in the patient recruitment stage or are in Phase 1 with healthy volunteers
  • Have trial sites located within hospitals or tertiary academic centers and in areas with high COVID-19 case density, potentially reducing the availability of staff to perform required activities and increasing the risk of adverse events and patient loss
  • Are evaluating immunosuppressive therapies or therapies that require complex and prolonged hospital visits (e.g., CAR-T cell and gene therapies)
  • Involve smaller patient populations where there are minimal margins of statistical power or people living with rare diseases (because patient accrual is already difficult, and the pandemic increases the risk for patient loss)

In the earliest stages of the pandemic, trial sponsors were primarily focused on essential decisions to pause or delay trials that were in the recruitment or pre-recruitment stages. Attention then shifted to trials in progress, where decisions related to protocols or timetables could have an impact on data integrity and statistical power.

The Longer-Term Impact

Looking ahead, organizations involved in clinical research are working to identify and assess financial, regulatory, and policy considerations that will affect their clinical programs in the longer term. Many are recognizing the need to plan for implementation of new and previously untried strategies to advance drug development programs.

In working to address the challenges of COVID-19, small biotechs could face potentially severe cash flow and financing issues as a result of trial delays. Companies with a single asset could be especially vulnerable. Delays in clinical trials may lead smaller companies to need additional funding at a time when their stock values have likely dropped and market conditions are not optimal. Many companies may be forced to make difficult cuts or prioritize development opportunities. Companies with potentially high-value products and platforms may be at risk of acquisition based on unfavorable terms.

Delays in clinical trials are likely to cause delays in projected launch timelines. This may in turn lead to shorter periods of patent exclusivity (barring patent term restoration) and lower near-term revenue forecasts. Changes in launch timelines also may shift the competitive landscape in many therapeutic areas, possibly presenting new opportunities for competitors that are able to adapt and act quickly in response.

From a regulatory standpoint, many stakeholders, including regulatory experts, trial site investigators, and CROs, anticipate that global agencies will require additional documentation and new protocols and procedures when considering new drug applications. The need for additional documentation can present significant challenges to trial sites and staffs. Processing this information also could cause delays in regulatory reviews and the ability of trial sponsors to quickly reply to follow-up inquiries from agencies.

Travel restrictions and social distancing measures will make protocol updates and deviations inevitable. Fortunately, per recent guidance from the FDA and EMA, trial sponsors will not be required to report protocol deviations prior to annual reports as long as the changes do not significantly impact the validity or safety of the trial. But sponsors and trial sites should meet with the appropriate institutional review boards (IRBs) to seek approval for protocol updates to reduce the risk that any changes could ultimately be rejected by the FDA or EMA.

The fact that trial participants cannot or will not attend in-person visits with investigators is a critical issue affecting many trials, but companies also should recognize the potential consequences if patients introduce COVID-19 to the trial itself. If patients contract the disease, it may impact clinical data by introducing elevated rates of related symptoms with a corresponding impact on endpoints. Any COVID-19-related fatalities would require these patients to be removed from data sets, potentially impacting the ability of trials to reach statistical significance. These consequences could be especially devastating for trials in rare diseases, where available patient populations are very small.

Based on our analysis, the impact of the pandemic on clinical trials will be felt on a policy level, including in drug pricing negotiations. The Pan-Canadian Pharmaceutical Alliance has already announced their intention to delay price negotiations for non-COVID-19 therapies. Pricing negotiations in Europe also could be impacted by the pandemic, especially for some non-COVID-19 therapies (e.g., the third or later drug to market in a class) where historically there has been a perception of low unmet need.

The Future

While most regulatory agencies have stated an intention to be flexible during these unprecedented times, it is critical that drug developers continue to monitor their risk diligently and develop contingency plans to adapt and respond to factors that affect their clinical development programs. Sponsors will need to balance patient safety, trial integrity, and statistical power considerations against funding and revenue issues on a trial-by-trial basis. In addition to reevaluating clinical development plans, companies may need to reassess their assumptions around pricing and revenue as well as the competitive landscape for both their pipeline and in-line products. There will not be a one-size-fits-all solution for the many short- and long-term challenges caused by COVID-19, but companies that are willing and able to rapidly adapt are likely to have the strongest chances for success.

Source: Clinical Leader