- Update (3:06 p.m. ET) Johnson has officially announced the lockdown.
- The rules will come into effect on Thursday.
- The U.K. government will extend the furlough out-of-work payment system until December.
- Johnson says there will be a "massive expansion" of rapid COVID tests in a "matter of days".
- https://seekingalpha.com/news/3629328-boris-johnson-locks-down-u-k-for-month-updated
Saturday, October 31, 2020
Boris Johnson locks down U.K. for a month
Patient trials are the silent crisis in clinical research
The pharmaceutical industry is racing in unprecedented ways to develop therapies to treat Covid-19 and vaccines to prevent it. But outside of Covid-19, pharma has been slow to adopt technology that can speed new therapies of all types.
Well before December 2019, much of the world had adopted digital and mobile experiences — mobile banking, online grocery orders, on-demand video streaming, and more — for everyday life. The pharma industry, however, largely follows the same analog processes it did more than 40 years ago. Most clinical trials still require patients to attend in-person doctor visits, some lasting several hours, sometimes multiple times a week. They rely on patients writing in paper diaries to document how they are following their treatments. Recruitment is often done via primary care physicians.
As a result, the woman who works an hourly wage job with little paid time off or the single father who lives in a rural town and needs child care arrangements are unable to access clinical research as an option for care. The burden to participate is just too high, despite how critical the research may be to their health.
One solution is to increase the use of decentralized trials. Instead of depending solely on in-person visits, decentralized trials fully or partially use telehealth, connected devices, mobile apps, and other technology to aid patient participation. The industry had been slow and unwilling to embrace this model. Then Covid-19 happened.
During the height of the pandemic, clinical trial sites became inaccessible due to global shutdowns, which made recruitment difficult and prevented patients from making in-person visits. This forced pharma to temporarily reconsider decentralized trials as a means to continue some operations virtually from patients’ homes.
I applaud this agility. Yet I worry that the industry will see it as a temporary adaptation rather than widely embracing decentralized and hybrid trials for good because patient recruitment — the lifeline of clinical research — depends on it.
According to a survey by the Kaiser Family Foundation, 45% of millennials don’t have a regular primary care doctor, while 85% of those between the ages of 50 and 64 and 88% of those age 65 and older do have one. The low percentage among millennials is a problem for clinical trials because primary care doctors are the most relied-on source for recruiting participants. If many of those in the largest living adult generation have no trusted relationships with primary care physicians, where and how will pharma conduct recruitment for trials?
Even if they are recruited, how will clinical trial sponsors convince a demographic that relies on mobile solutions for everything from working, banking, and shopping to stay in a clinical trial that doesn’t use virtual or mobile technologies?
Add in the issue of diverse representation. The way diseases present themselves and the way drugs act can vary greatly by gender, race, and ethnicity. Diversity is not just a moral imperative but a scientific one that matters biologically. As treatments become more precise and address the molecular and genetic differences in people, it will become impossible to ignore diversity in clinical trials. Yet pharma continues glossing over the barriers that inherently preclude women, Black and Latino Americans, and people living in poor and rural communities from participating in clinical research.
Patient recruitment and retention is the longest, most difficult part of the clinical trial process. And shown by its inability to keep up with the way people use technology, the industry has become complacent and comfortable with spending billions of dollars and taking a decade or so to bring new treatments to market. More than 80% of clinical trials in the U.S. fail to meet their patient enrollment timelines and 30% of patients drop out.
Patients are rightfully expecting that health care be delivered more conveniently, but pharma is not listening. Unlike the pressures from Covid-19 that suddenly interrupted clinical trial operations, these challenges and others will slowly degrade recruitment one trial at a time and drive development costs to unsustainable heights.
But there’s a way forward.
It starts by resetting the definition of decentralized trials. The industry must move away from the paralyzing myth that decentralization means that everything becomes virtual. To be sure, some types of trials and diseases are appropriate for full decentralization. But many trials and diseases will still require some in-person visits for radiology procedures, biopsies, endpoints that must be evaluated by trained professionals, and the like.
A hybrid model that combines traditional and virtual components offers a new approach for designing clinical trials. Rather than copying and pasting old procedures, start with a clean slate and pose new questions: What is the minimum number of onsite visits needed? How can onsite visits be supplemented with telehealth visits? How much data can be collected from home through remote monitoring and connected medical devices? Can the data be collected accurately?
It’s helpful to start with technologies patients are already using. E-signatures, for example, can be applied to informed consent forms; text messaging can be used for medication reminders. Hybrid trials that deploy familiar technology in a new environment represent a stepwise approach to being intentionally flexible and patient-centric.
Although a decentralized strategy must start at the top of an organization, it must permeate into every level of it. I’ve had dozens of conversations with C-suite pharma executives who agree, “Decentralized trials are a fantastic idea,” but the intent breaks down once it reaches the operational level. Drug development culture is naturally risk averse, and teams generally shy away from being first adopters. Instead of fearing the unknown, establishing an agile, flexible culture that accepts obstacles as part of the change-management process can encourage teams to step up.
The decision to move forward with hybrid or fully decentralized trials must also be reinforced with investments. In the current environment, there is no immediate incentive or consequence to change how clinical trials are run. To foster thinking differently about problems, it can help to invest in training that shows teams how to be adaptable, nimble, and creative in their approach to designing hybrid clinical trials.
Finally, conducting a hybrid trial isn’t just about buying a product with patient-facing technology. To be successful, the trial needs the appropriate technology platform that can support and adhere to data privacy and security compliance. Pharma is highly regulated and laws like the General Data Protection Regulation and the Health Insurance Portability and Accountability Act exist to ensure patient privacy and protection.
How the trial reaches compliance is different in a decentralized or hybrid model. Every element of a trial must change in a hybrid or decentralized approach, down to the standard operating procedures that give instructions on how to run the trial properly. How a decentralized or hybrid model will create new implications and how to best address these changes in a highly regulated, global environment must be carefully considered.
The pharma industry is at an inflection point. Rather than solely using decentralized trials as a short-sighted business continuity response to Covid-19, it can resolve the silent problem of patient recruitment before it becomes the industry’s next crisis. This is the moment to make access to clinical research available to all, regardless of where they live or their gender, race, ethnicity, or financial status. Improving clinical trials must be done to advance clinical development and, most importantly, save more lives.
Kent Thoelke is the executive vice president and chief scientific officer at PRA Health Sciences, a global contract research organization and health care intelligence company headquartered in Raleigh, N.C.
https://www.statnews.com/2020/10/28/recruitment-retention-silent-crises-clinical-trials/
Teletherapy On the Rise: Tips to Make the Most of It
Even if you could attend an in-person therapy session — most were cancelled due to COVID-19 — sitting six feet apart with masks on makes it difficult to read each other's facial expressions.
Southern Cross University, with campuses across Australia, recently surveyed over 1,000 people on their experiences and perceptions of teletherapy and found 98% of respondents said COVID-19 has impacted their mental health care significantly. Over 65% participated in online therapy since the pandemic began and survey takers touted the top benefits as no commute, flexible schedules and an easy set-up.
"We're seeing a large increase in mental health services over video, and therapists and their clients are trying to adjust to it," says Jason Fierstein, licensed professional counselor at Phoenix Men's Counseling in Phoenix. "I think that people have started to get used to the idea of doing therapy over video, even if it's not ideal for either party. I do think that video will stay consistent for some time to come, even if COVID numbers go down, for the sheer usefulness of the platform."
Your Virtual Therapist Is In
While having a virtual therapy session may be new for you, some therapists have long offered the service, and many others ramped up to teletherapy quickly at the start of the pandemic. An American Psychiatric Association survey found that before the pandemic, only about 2% of providers offered tele-psych services. Now roughly 85% offer virtual treatment.
"At the beginning, it definitely took some getting used to, particularly for clients because it felt disconnected and less personal," says Leina Rodriguez, a licensed marriage and family therapist at Refresh Psychotherapy in New York City. As time goes by though, she says, clients seem more at ease.
"I would even say that there may be clients that feel even more comfortable being open because they are already in their safe space (their home)," says Rodriguez.
In fact, that's one advantage licensed clinical social worker Catherine McCallum at Coral Life Strategies in Bethesda, Md., touts when discussing teletherapy: "We get to see them in their home environments."
This can give important clues to how well a patient is really doing, whether their space is cluttered or tidy and whether they're dressed or out of bed. Even the art on their walls or what's on their nightstand can provide insight.
On the flip side, mental telehealth care may fall short in some ways, McCallum says, particularly without the ability to detect smells like alcohol or body odor, which can be warning signs of impaired functioning. Likewise, "Seeing body language not visible by video, particularly below the neck, may be indicators of anxiety, anger, problematic or repetitive behavior," says McCallum.
For example, not being able to see bouncing feet, clenched hands, scratching and self-injury through picking, could throw off a clinician's ability to assess for safety or a proper diagnosis.
Is Teletherapy as Good as it Gets?
While teletherapy has skyrocketed, whether it's right for everyone seeking therapy or as effective as in-person treatment remains unclear.
A Harmony Healthcare IT survey asked 2,042 Americans about virtual medical services and found 46% of boomers and 57% of Gen Xers were comfortable with online appointments. More than 40% of respondents have used telehealth for mental health and 70% would be more willing to speak with a mental health professional if they could do it virtually.
"I do think we need to investigate the outcomes of this grand teletherapy experiment so that we can determine evidence-based best treatments," says McCallum. "I have no doubt telemental health will be a bigger part now, but I do not think it will be the only modality for every client situation."
Making Teletherapy Work for You
Rodriguez notices that telehealth therapy appointment no-shows are very low because clients don't have to travel and it's much easier to attend a virtual session. "Also, many clients who suffer from depression are seeing that this is a great option for when they can't even get out of bed," she says.
What's more, during the pandemic, many health insurers as well as Medicare and Medicaid programs have waived co-pays or loosened restrictions to allow coverage for telehealth sessions. Check with your plan to be sure it's covered.
To have the most successful experience with teletherapy, Firestein recommends treating teletherapy sessions as you would a regular in-person visit. "Show up on time, make sure there aren't any distractions, such as kids, pets or other environmental noises. Find a private space in your home, or office," advises Firestein.
Some therapists say clients have connected from their parked car or tucked into a bathroom when there's nowhere else for a secluded session.
Also, get comfortable with how you look on video and adjust your computer for the best lighting and background. And if you're new to therapy or your virtual therapist, give it three to five sessions. It can be more difficult developing trust and rapport over screens with internet glitches and time lags.
McCallum says she worries about taking the human out of human connection. But for what it's worth, it has become normalized and accepted as the next best thing.
https://www.nextavenue.org/teletherapy-on-the-rise-tips-to-make-the-most-of-it/
The race to make COVID antibody therapies cheaper and more potent
When US President Donald Trump was ill with COVID-19, his physicians administered a bevy of medications — some proven, others experimental. But there is one that the president has hailed as a “cure”: a cocktail of coronavirus antibodies produced by Regeneron Pharmaceuticals in Tarrytown, New York.
The ‘curative’ power of this antibody treatment has yet to be proven. Although it has shown promise in small, early studies in people with mild COVID-19 symptoms, large clinical trials have not yet been completed. Meanwhile, researchers are already designing more-advanced antibody treatments that could be cheaper, easier to produce and more potent.
“What you really want is something that is so amazingly potent that you need barely any,” says biochemist Pamela Björkman of the California Institute of Technology in Pasadena. “You want to be able to give it to everybody in the house or the hospital or the school or the meat-packing plant that’s been exposed.”
Antibodies are a key component of the body’s natural immune response to SARS-CoV-2, and researchers have been racing to develop therapies that harness their ability to directly bind to viral proteins and prevent the virus from replicating. One way to do this is by using blood plasma from people who are recovering from COVID-19 to transfer the antibodies that they have produced to someone else. Another is to manufacture and mass-produce specific antibodies against the virus that could supplement the body’s immune response. This approach has proven successful against other diseases: on 14 October, the US Food and Drug Administration (FDA) approved a cocktail of three specific antibodies, also produced by Regeneron, as a treatment against the Ebola virus, after it was shown to reduce deaths from the virus in the Democratic Republic of Congo.
Early trial success
Regeneron and Eli Lilly in Indianapolis, Indiana, now lead the race in developing antibody treatments against COVID-19. Each is testing its own proprietary antibodies and has applied for an Emergency Use Authorization from the FDA on the back of promising early studies. Eli Lilly’s first antibody therapy reduced visits to the hospital, from 6% in the placebo group to 1.7% in those who received the drug; Regeneron’s combination of 2 antibodies reduced symptoms and viral loads.
The main hope is that antibody therapies could stop mild COVID-19 from becoming severe. There is less optimism that the treatments will be game-changing for severe COVID-19 cases — when damage is caused by not only the virus, but also the body’s immune response to it. “I can’t imagine how excited I would be if these drugs were available and proved reliable,” says infectious-disease physician Myron Cohen of the University of North Carolina at Chapel Hill.
At least ten COVID-19 antibodies are being tested in clinical trials; many more are under development. Considering how well these antibodies bind to SARS-CoV-2 proteins, many of these candidates are likely to offer some benefit to people with COVID-19, says chemist Zhiaqiang An at the University of Texas Health Science Center in Houston. “There might be differences in degree,” he says, “but most of these antibodies could have some kind of efficacy.”
And researchers are finding ways to minimize the chances of the virus becoming resistant to these treatments. When only one antibody is used, it might be possible for the virus to develop mutations — to the binding site, for example — that allow it to evade the antibody. Treatments that combine multiple antibodies, such as the Regeneron therapy that Trump received, can lessen the chance of this happening by targeting the virus with multiple antibodies that bind to different sites.
Still, there are drawbacks. Antibodies are expensive and difficult to make, and they are administered at relatively high doses. Several researchers who spoke to Nature highlighted the 8 grams of antibodies — the highest dosage tested in clinical trials — that Trump received. “It’s an enormous dose,” says virologist Gerald McInerney of the Karolinska Institute in Stockholm. “Even if it did work, at a dose of 8 grams, it would be incredibly expensive.” Even the lower doses being tested — Regeneron’s lowest is 2.4 grams — would be too high for widespread use as a preventative treatment, says Björkman.
Antibodies from alpacas
McInerney and others are working to develop small antibody-like molecules called nanobodies, based on a kind of antibody naturally produced by some camelids, including llamas and alpacas. Nanobodies are easier to make, and often can be produced in bacterial cells that are much cheaper to grow and maintain than are the mammalian cells required for normal antibody production. Last year, the FDA approved the first therapeutic nanobody, called caplacizumab, a treatment for a rare clotting disease.
But the technology is still relatively new, and COVID-19 nanobody treatments trail conventional antibodies in the clinic. McInerney’s team has isolated a nanobody against a crucial SARS-CoV-2 protein called Spike from an alpaca named Tyson. They engineered the antibody to improve its activity, stability and likelihood of working in people, but have not yet tested it in animals.
Some researchers are hoping to develop nanobodies that can be aerosolized and inhaled, to directly protect the key sites of coronavirus infection: the nose and the lungs. In Shanghai, China, Novamab Biopharmaceuticals was originally developing inhaled nanobodies to treat asthma, but switched to developing COVID-19 nanobodies. The company is now looking for international partners — particularly in regions where COVID-19 is prevalent — to help it to move into clinical trials, says Yakun Wan, founder and chief executive of the company.
Biochemist Peter Walter at the University of California, San Francisco, hopes that the inhalable approach will allow such nanobodies to be effective at far lower doses than are required for standard antibodies, which are injected and must travel through the blood to the site where they are needed. “We anticipate it being used as a prophylactic spray before you get on an airplane or go to a party,” says Walter, who is working on one such nanobody.
“We’re a long way off,” from moving such nanobodies into the clinic, says biophysicist Raymond Owens at the University of Oxford, UK. “But I’m cautiously optimistic.”
To Vaccinate Against Covid-19, U.S. Enlists Pharmacy Chains
More than a dozen retail pharmacy chains have agreed to partner with the federal government to serve as Covid-19 vaccination sites under a plan developed by the U.S. Centers for Disease Control and Prevention.
Walgreens Boots Alliance Inc., CVS Health Corp., Walmart Inc., Kroger Co., Publix Super Markets Inc. and Costco Wholesale Corp. are among the companies that have agreed to participate, according to the CDC plan issued Friday.
The pharmacies own more than 35,000 stores, the CDC said.
The information was contained in an updated "interim playbook" the CDC prepared for states, territories and local governments readying vaccination programs.
The playbook sketches out how Covid-19 shots would get to hospitals, clinics and other vaccination sites, starting with initial supplies for health-care workers and others at high risk of infection.
Pharmacies would become involved during a second phase of vaccine rollout. The pharmacies would order the Covid-19 vaccines from the federal government, which would then supply them, according to the CDC's plan.
The pharmacies' involvement would help expand and accelerate the public's access to the shots as supplies increase, the CDC said.
"Partnerships with retail chain pharmacies and networks of community pharmacists in the United States will increase the general population's access to COVID-19 vaccine," the interim playbook said.
A CVS spokesman said the company has been working with the U.S. government on Covid-19 vaccine-distribution plans but declined to provide specifics, while a Walgreens spokesman declined to comment.
The other pharmacy chains didn't immediately respond to requests for comment.
The government would provide the vaccines to the pharmacies free of charge. The government has said that vaccines will be free of charge to patients, though a person might have to pay a fee for the shot's administration.
The companies must sign agreements with the federal government detailing locations of their pharmacies and the capacity of each to store vaccines at subzero temperatures. The pharmacies must report daily to the CDC how many doses each store location orders and has on hand.
U.S. regulators haven't approved any Covid-19 vaccines but several are in late-stage testing.
Government officials and planning documents had earlier indicated that pharmacies would play some kind of role in vaccine distribution but have provided few details. Last week, the government said CVS and Walgreens would help with administering vaccines at long-term care facilities.
Under the plan, states have a say in whether pharmacies participate in the program. The states would have the authority to prevent pharmacies within their borders from getting vaccines directly from the federal government.
Pharmacies that aren't part of the program could still participate with Covid-19 vaccination and should work with local officials to do so, according to the CDC.
Merck sets ultra-high bar with development of Keytruda
- On Thursday, Sanofi announced an agreement with Merck (NYSE:MRK) under which the latter will supply Keytruda (pembrolizumab) for a mid-stage study evaluating the PD-1 inhibitor with THOR-707, a "not-alpha" interleukin-2 (long-acting version of the immune system-stimulating protein), in a range of cancers.
- The clinical trial collaboration is the latest addition to a long list of partnerships and studies involving pembrolizumab aimed at expanding its use. Merck's execution has been so effective that it became its top seller in Q1 2018 and accounted for almost 30% of its Q3 2020 revenues ($3,715M/12,551M).
- In the U.S., Keytruda was first approved in September 2014 for advanced melanoma. 28 subsequent FDA nods have followed in areas like lung, head and neck, bladder, kidney, endometrial and colorectal cancer and several blood malignancies including classical Hodgkin lymphoma.
- A search in ClinicalTrials.gov showed 1,139 active or planned clinical trials involving pembrolizumab including 137 sponsored by Merck, a subtotal that includes 73 Phase 3s and 41 Phase 2s.
- From a humble start of $55M in Q4 2014, quarterly sales have grown at a 22.1% compounded clip since then. On a yearly basis, the CAGR has been 153.5% (2020 estimated sales of $14,585M). Even at a more modest quarterly compounded growth rate of 6% (ytd 2020), Keytruda may overtake AbbVie's Humira (adalimumab) as the world's top-selling drug in four or five quarters.
- The company's impressive accomplishments represent a business school-caliber case study of how to successfully develop a biopharma asset.
- https://seekingalpha.com/news/3628459-merck-sets-ulta-high-bar-impressive-development-of-keytruda
Vax developers take varied approaches, may not improve much next gen
- As data readouts and expected regulatory nods approach for COVID-19 vaccines, a review of the platform technologies may be a timely refresher for healthcare investors since the next-generation approaches have yet to be approved for any use anywhere in the world and may not top the effectiveness of more traditional methods.
- Production scale-ups are well underway for rapid deployment, expected to begin in early 2021.
- Leading vaccine makers have inked supply deals in most major markets, led by the U.S.'s $18B Operation Warp Speed aimed at delivering 300M doses by January via supporting the development of eight candidates in parallel.
- Six of the eight vaccines are currently in clinical trials while two will enter studies soon.
- Traditional vaccines rely on a live-attenuated (weakened) virus [e.g., measles, mumps, rubella (MMR), rotavirus, smallpox, chickenpox, yellow fever] or whole-inactivated (killed) virus (e.g., hepatitis B, HPV, whooping cough, pneumonia, meningitis, shingles) to produce the desired immune response. The negatives include the potential to cause the disease it is designed to prevent (live-attenuated versions) and the need to deal with live virus in the development process.
- In COVID-19's case, researchers did not need the live virus since Chinese scientists sequenced the genome of SARS-CoV-2 and published the results online in January. Based on previous research on cousins SARS-CoV-1 and MERS, investigators knew to focus their attention of the coronavirus' spike protein that studs its surface and enables it to enter healthy human cells. Vaccines that expose the body to the spike protein alone, which is the antigen, should induce a protective immune response. This is the strategy behind most of the leading COVID-19 vaccine candidates.
- Moderna's (NASDAQ:MRNA) mRNA-1273 and Pfizer (NYSE:PFE)/BioNTech's (NASDAQ:BNTX) BNT162b2 are genetic vaccines which use messenger RNA (mRNA) to instruct the person's cells to make the spike protein which, in turn, activates the immune response. Since mRNA is a fragile rapidly degraded molecule that does not easily pass through the cell membrane, both candidates use carrier molecules called lipid nanoparticles to transport it into the cytoplasm of the cell.
- Other vaccines use a different (benign) virus, called a vector, to carry the spike protein coding sequence into cells. These are categorized as replication-defective (RD) or replication-competent (RC). The most popular RD choice for COVID-19 vaccines is adenoviruses, used in Johnson & Johnson's (NYSE:JNJ) Ad26.COV2.S and AstraZeneca (NASDAQ:AZN) (AZD1222) and Oxford University's candidate (ChAdOx1). The former uses human adenovirus 26 (Ad26) as the vector while the latter uses a chimpanzee adenovirus (ChAd). In both vaccines, the adenovirus carries DNA coding for the spike protein into the nucleus of the host cell where its machinery produces the spike protein. Since the viral vector is replication-defective, no more viruses are produced after the first cell is infected.
- Merck's (NYSE:MRK) candidate V590 uses a recombinant vesicular stomatitis virus (rVSV) vector while V591 uses the measles virus (Q3 earnings call presentation, slide #6). Wild-type VSV is usually asymptomatic or causes mild flu-like illness in humans. Company scientists replaced part of its RNA sequence with RNA coding for the spike. Unlike adenoviruses, this rVSV vector displays the spike on its surface. Since it is replication-competent, it more closely resembles a real viral attack. This is the same platform the company uses in its Ebola vaccine, Ervebo, approved by the FDA in December 2019, the first and only viral vector vaccine to earn a U.S. nod to date.
- Novavax's (NASDAQ:NVAX) NVX-CoV2373 is a stable prefusion protein based on its recombinant protein nanoparticle technology (uses a subunit of the spike protein) that includes its proprietary Matrix-M adjuvant. One of its advantages is that it is stable at cool temperatures (~36 - 46 degrees Fahrenheit) enabling distribution through standard vaccine channels.
- The FDA has yet to approve any adenovirus vector vaccine or DNA or mRNA vaccine.
- Data readouts from late-stage studies on Moderna and Pfizer/BioNTech's candidates should happen in the coming weeks.
- Presentation
- https://seekingalpha.com/news/3629098-vaccine-developers-take-varied-approaches-to-covidminus-19-next-gen-platforms-may-not-be
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