False Negatives Still Common With COVID PCR Tests

 Taso and Megan Stefanidis of Manalapan, New Jersey, developed symptoms of COVID-19 a few days after gathering with their families for Christmas.

Other family members ended up testing positive for the disease. Megan also tested positive -- but Taso tested negative.

They were surprised by the negative result, especially since it came from the gold-standard PCR test, which has been hailed for its ability to detect even remnant viral genetic material.

Taso subsequently took a rapid antigen test, which turned up positive: "I knew I had it," he said.

False negatives with PCR testing are actually far more common than one might expect. Daniel Rhoads, MD, vice chair of the College of American Pathologists microbiology committee who is also at the Cleveland Clinic, said PCR sensitivity for detecting COVID-19 is actually around 80%.

That means "one in five people would be expected to test negative even if they have COVID," Rhoads told MedPage Today.

And that's a "best-case scenario" for sensitivity, he added, noting that it's likely to be different in a real-world scenario.

NPV, PPV, and the Real World

For his estimate, Rhoads cited data from a May 2020 study published in the Annals of Internal Medicine by researchers from Johns Hopkins and the National Institute of Allergy and Infectious Diseases. He said it's not likely that this sensitivity figure would be vastly different now.

Conversely, it's "reasonable to hypothesize that if shedding of virus is shorter duration or lower quantity in those with immunity, then it could decrease the sensitivity of tests," he added.

Disease prevalence also plays a role in the accuracy of test results. Although the sensitivity and specificity of a test remains static over time, the prevalence of disease in the community will impact the predictive value of a positive or negative result. Factoring prevalence into the mix determines positive predictive value (PPV) and negative predictive value (NPV).

"Sensitivity and specificity live in an ideal world," Gary Cornell, PhD, a retired mathematician who blogs about COVID-19, told MedPage Today. "PPV and NPV live in the real world."

Rhoads likened the sensitivity and specificity reported in a package insert of a test to the "miles per gallon" sticker advertised on a new car. "Everybody recognizes that the number is true but probably determined in an idealized setting that is not likely to be achieved in real life," he said.

As disease prevalence increases, PPV increases because there will be fewer false positives -- but NPV decreases because there will be more false negatives, Rhoads said.

"If everybody you know has COVID, you have symptoms of COVID, you test negative, the prevalence in your community is high, your clinical symptoms align with the disease ... you're at a high likelihood of having a falsely negative result," Rhoads explained, noting that the pre-test probability of disease is high.

On the other hand, if screening for influenza in the summer when disease prevalence is essentially zero, a positive result would be highly suspicious, he added. The post-test probability of having influenza would be low, and would need to be taken into account.

What Else Can Go Wrong?

There's no doubt that PCR testing is the best tool we have for detecting COVID-19, but "I'm comfortable recognizing that no test is perfect, and some tests are less perfect than others," Rhoads said.

"With respiratory viruses, we know PCR is the best laboratory test that we've been able to find, so we lean on that as our reference standard," he continued.

What else can impact the accuracy of tests? For starters, Rhoads said, "you have to get the virus in the sample." That's not just about good sample collection in terms of swabbing long enough, but also the renewed debate over whether oral versus nasal swabbing is better with Omicron. "It's a reasonable question, but I haven't seen good evidence yet" in favor of oral swabs, he noted.

Taso Stefanidis said that his PCR test involved self-swabbing. "In the beginning, they would shove it up your nose," he said. "Now they give you the swab and tell you to shove it up there so it's a little uncomfortable. I thought I did it right, but maybe I didn't."

Lester Layfield, MD, a pathologist with the University of Missouri Health Care, has studied ways to bring down rates of false positives. He's found that readouts generated by computers could be erroneous, but adding in human judgment can fix misinterpretations of positivity based on cycle thresholds, for instance.

Other issues include cross-contamination of sample wells inside the analyzer (a positive sample could spill over into a negative sample, for example), or a technologist could insert the wrong sample into the wrong well, according to Layfield.

He said it's fair to extrapolate his findings to false negatives as well, with some exceptions.

"You can have problems due to the technologist putting somebody else's negative sample in your well, and therefore you're a false negative," he explained. "Or it can be that the the cycling didn't actually work."

But "cross-contamination is not a problem there," he added.

Rhoads warned that antigen tests -- which the Biden administration began shipping to homes for free this week -- have even lower sensitivity, and highly suspicious negative results should be interpreted with extreme caution.

"If somebody is symptomatic, and there's a high prevalence of disease in the community, and they test negative on antigen testing, they need to be skeptical about that and consider taking another test," he said.

If it's positive, he noted, there's a very high likelihood that it is indeed a true positive, as these tests have upwards of 99% specificity.

https://www.medpagetoday.com/special-reports/exclusives/96789

Mirati's adagrasib scoring points where KRAS leader Amgen hasn't gone

 Mirati Therapeutics' KRAS drug adagrasib led to a 41% response rate in patients with pancreatic and other gastrointestinal tumors, the latest in the biotech's efforts to eke out an edge against the big winner in the drug class, Amgen. 

Rival Amgen beat Mirati into the KRAS-inhibitor market with Lumakras, which was approved in non-small cell lung cancer last May. Mirati is awaiting an FDA approval for adagrasib in NSCLC next quarter, which will set up a game of catch up. 

While Amgen may have crossed the regulatory finish line first in lung cancer, Lumakras hasn't fared as well as Mirati's adagrasib in colorectal cancer. Friday's data in pancreatic and GI tumors could pad adagrasib's stance, as it appears Amgen has no studies of Lumakras in those indications planned or ongoing. 

The data presented Friday gives the San Diego biotech confidence to "continue to aggressively evaluate adagrasib," said Charles Baum, M.D., Ph.D., founder, president and head of R&D, in a statement. 

The phase 2 KRYSTAL-1 study featured patients with cancers of the biliary tract, appendix, small bowel, gastro-esophageal junction, and esophagus, who have a mutation of the KRAS gene. Mirati disclosed the findings at the 2022 American Society for Clinical Oncology Gastrointestinal Cancers Symposium on Friday.

A specific breakdown of adagrasib's impact shows the drug worked better in patients with pancreatic cancer than those with other GI tumors in the subset of the Krystal-1 study. Patients with pancreatic cancer notched a 50% objective response, whereas others with GI cancers achieved a 35% response. Patients responded for a median of seven months and 7.9 months, respectively. 

The disease control rate was 100% across the 27 patients in the subset. Patients with pancreatic cancer did not see progression of their disease for a median of 6.6 months and for GI tumors, the duration was 7.9 months. 

The drug led to grade 3/4 treatment-related adverse events in 27% of patients, with none leading patients to stop treatment. 

“Adagrasib is going to be a very big drug for a very long time,” said David Meek, recently installed CEO, at last week's J.P. Morgan Healthcare Conference. 

Meek did not waste time reshuffling his team six weeks into his tenure as CEO last fall. He showed the exit to Chief Medical Officer Joseph Leveque, M.D., and Chief Operating Officer Daniel Faga in late October, causing shares to drop 15% to $161.40 apiece on Nov. 1. Shares have continued sliding since then, dropping slightly to $117.94 as of 11:25 a.m. ET on Friday.

https://www.fiercebiotech.com/biotech/mirati-s-very-big-drug-adagrasib-at-fda-s-doors-for-lung-cancer-leads-to-41-response-gi

FDA brushes off the pandemic with pick-up in novel drug approvals

 The US drugs regulator approved 58 novel drugs last year, the highest number for three years and well above the 10-year average of 48. With travel limitations blamed for decision delays in a number of cases, Novartis’s Leqvio and UCB’s Bimzelx included, this uptick could presumably have been steeper under more normal conditions. The only Covid product included in this count is Biontech and Pfizer’s Comirnaty; all the other pandemic-related projects are on the market under emergency use authorisations, rather than full approvals. The mRNA vaccine is almost certainly going to become last year’s biggest approval commercially speaking, though by 2026 sales are forecast to have dipped substantially. This time last year Biogen’s Aduhelm was looking like the class of 2021's biggest seller, according to fifth-year sales as predicted by sellside analysts. Should last week’s punitive US coverage decision hold consensus is likely to drop to close to zero. That still leaves plenty of potential future blockbusters that arrived on the market last year, according to Evaluate Pharma's consensus in the table below. That said, it is worth remembering that several of these projects need to win expanded labels, or carve out share in highly competitive therapy areas, to reach these lofty levels.

 FDA approval count: 49

Predicting great things: 2021's arrivals with blockbuster potential
Product	Company	Description	2026e US sales
Leqvio	Novartis	siRNA-based anti-PCSK9 for high cholesterol; approved in heterozygous familial hypercholesterolaemia and atherosclerotic cardiovascular disease.	$1.7bn
Abecma	Bristol Myers Squibb/Bluebird	Anti-BCMA Car-T cell therapy; approved for B-cell and follicular lymphomas	$1.4bn
Comirnaty	Pfizer	Covid-19 vaccine	$1.4bn
Tezspire	Amgen	Anti-TSLP MAb; approved in severe asthma	$1.2bn
Vyvgart	Argenx	Anti-FcRn MAb for IgG-mediated autoimmune diseases; approved in myasthenia gravis	$1.2bn
Lumakras	Amgen	Kras G12C inhibitor; approved in non-small cell lung cancer	$1.2bn
Lupkynis	Aurinia	Calcineurin inhibitor; approved in lupus nephritis	$1.1bn
Source: Evaluate Pharma. https://www.evaluate.com/vantage/articles/insights/nme-approvals-snippets/fda-brushes-pandemic-pick-novel-drug-approvals

'If we could make product, we could sell product': PPG details supply chain woes

 The hardest job at PPG today is being a plant manager.

“They wake up in the morning, check their phone to see how many people called off sick,” said Michael McGarry, PPG’s chairman and CEO, speaking to analysts during the company’s fourth quarter earnings call Friday morning.

“They get to work, they go through the dock area (to) see how many trucks didn't get picked up and then they go to the receiving areas and find out what didn't come in that was supposed to.”

Inside the plant, they must to decide what products will get made in smaller batches because of a lack of raw materials.

“And then the sales team is telling them, ‘If we don’t get paint out the door, here’s how many customers we’re going to impact.’”

All this before they sit down at their desk in the morning.

This, in a nutshell, is what Downtown-based coatings maker PPG is facing across its footprint.

The company reported net income of $1.4 billion, or $6.01 per share, for the full 2021 year. That’s an increase from the first year of the pandemic when PPG posted $1.1 billion in profit, or $4.45 per share, but less than the recovery expected based on demand for PPG’s products. Revenue was a record $16.8 billion in 2021, boosted by recent acquisitions including the $1.8 billion deal for Finnish paints-maker Tikkurila, which closed in June.

The virus continued to wreak havoc on manufacturing, with some plants reporting up to 40% of workers out at one time. Omicron increased COVID-related absenteeism four fold, Mr. McGarry said.

“What we’re really worried about is if omicron gets to China,” he said.

The world’s most populated country has had a restrictive zero-COVID policy since the beginning of the pandemic. During a recent small outbreak in Tianjin, the site of PPG’s largest manufacturing plant, China tested 14 million people in a matter of days, Mr. McGarry said. The country imposes severe restrictions on places with even a handful of cases.

“So if omicron were to get to China and they continue with their zero-COVID policy that could have a pretty disruptive effect,” he said.

But COVID isn’t the only thing disrupting the bottom line. Raw materials prices were up by 20% during in 2021 and up to 30% this quarter, PPG said, as the company raced to raise its own prices to offset them. Labor and utilities costs have also increased, with transportation being disrupted by a shortage of trucks and drivers, according to Mr. McGarry.

“Freight is the single biggest challenge we have right now — truck drivers not showing up,” he said.

These difficulties, which prompted PPG to pull its financial forecast in September, will continue in the first quarter this year, company leaders predicted. But they are expected to ease as 2022 rolls on and the coatings giant stands to benefit from a substantial order backlog, the ramp up of auto manufacturing, a return to the skies in the post-omicron period, and a push towards more sustainable, metal packaging products.

“If we could make product, we could sell product,” Vincent Morales, PPG’s CFO told analysts.

https://www.post-gazette.com/business/career-workplace/2022/01/21/PPG-paint-coatings-supply-chain-earnings-sickness-absenteeism-pandemic-covid-19-trucks-freight/stories/202201210102

Boston Doctors: COVID-19 Hospitalizations Cut in Half By New Reporting Guidelines

 The number of patients who are severely ill with COVID-19 is less than half of all those hospitalized with the virus, Boston doctors said Tuesday, but that doesn't mean there's any less strain on the health care system.

Hospitals have started to differentiate between patients they admit primarily for severe COVID-19 and those admitted to be treated for something else who end up testing positive. The change in reporting cut the number of what had been reported as COVID-19 hospitalizations in half.

The idea is to give the public a better understanding of how many people are in the hospital because of the virus. But while that data began to be collected last week, it won't be released by the Massachusetts Department of Public Health until sometime this week.

During NBC10 Boston's weekly "COVID Q&A" series Tuesday, Tufts Medical Center's hospital epidemiologist Dr. Shira Doron said in a week's worth of data, the number of patients being treated for severe COVID-19 was considerably below 50% of all COVID-19 hospitalizations.

She specified that under the new guidelines, hospitals are reporting the proportion of patients who received the drug Dexamethasone, a steroid used to reduce inflammation, at some point during their hospitalization vs. those who are COVID positive and in the hospital.

"One day was as low as 36%," Doron said of the data. "The state actually called and said, 'Are you sure that it's only 36%?' And so we took a look and indeed, none of those patients were receiving any supplemental oxygen."

The data indicates that although patients may have been in the hospital with COVID-19, the majority of them didn't need any oxygen, she explained. And Tufts Medical Center isn't the only hospital reporting lower numbers.

"We looked at what the other hospitals were reporting that day and we found that we weren't an outlier in that," Doron said. "And so I think that, you know, from Massachusetts, where again, we do mandatory testing of everybody on admission, we may find relatively lower than expected, I think, proportions of patients receiving that drug, which is the standard of care."

Dr. Daniel Kuritzkes, chief of infectious disease at Brigham and Women's Hospital, said his experience was "exactly the same," as Doron's.

"Most of the patients from I was seeing who happened to test positive for COVID were there for another reason and had very mild COVID or had already recovered but were still positive," he said.

Despite the fact that the number of patients with severe COVID-19 is far less than what was being reported previously, hospitals continue to struggle. COVID-19 hospitalizations have surged over the last month as the omicron variant has become dominant. Meanwhile, hospitals are dealing with staffing shortages that are further stressing the system and limiting bed capacity.

Health care providers still need the gown, glove and N95 masks to go in and see those patients, along with other safety protocols, even if they aren't severely ill.

"The problem for the hospitals is that those patients cause just as much inconvenience and disruption to normal hospital services because they still all need to be in a single, isolation room or cohorted with another COVID person," Kuritzkes said. "So despite the fact that it's good to see fewer people requiring care for their COVID, it's enormously disruptive and having a huge impact on provision of services in the hospital."

https://www.nbcboston.com/news/local/boston-doctors-covid-19-hospitalizations-cut-in-half-by-new-reporting-guidelines/2615433/

Lannett Up After FDA Gives OK For Biosimilar Insulin Trial

 Lannett Co. Inc. shares rose 4.5% to $1.62 premarket after the generic pharmaceutical company said the U.S. Food and Drug Administration said it could proceed with a proposed clinical investigation for biosimilar insulin glargine.

The company said it expects the pivotal clinical trial to start by March and be completed by early 2023.

If the trial is successful, the company said it anticipates filing the biologics license application in early 2023 and potentially launching the product by early 2024.

Glargine is a product the company is co-developing with its strategic alliance partners within the HEC Group of companies.

https://www.marketscreener.com/quote/stock/LANNETT-COMPANY-INC-15227635/news/Lannett-Up-After-FDA-Gives-OK-For-Biosimilar-Insulin-Trial-37607439/

Anti-abortion activists march in Washington, buoyed by waning U.S. abortion access

 

Anti-abortion advocates gathered in Washington on Friday for the annual "March for Life," their mood boosted by recent state abortion restrictions and the possibility that the U.S. Supreme Court could soon upend https://www.reuters.com/world/us/us-supreme-court-consider-rolling-back-abortion-rights-2021-12-01 the Roe v. Wade ruling that legalized abortion nationwide.

Despite freezing temperatures, tens of thousands of anti-abortion activists assembled on the National Mall, bearing signs that read "I am the post-Roe generation" and "The future is anti-abortion."

The event marks the 49th anniversary of Roe v. Wade. But Friday's activists were optimistic that this would be the last march to occur before the overturn of the landmark 1973 ruling that established a woman's right to terminate a pregnancy before the fetus is viable, at around 24 weeks.

Rachel Young, 19, came from northeastern Ohio with her fellow students at Franciscan University of Steubenville, a Roman Catholic school that sent several busloads of students on the 5-hour trip to Washington.

Young said it was her third time attending the March but that it was a uniquely exciting occasion because of how close the Supreme Court is to overturning Roe.

"I just can't even believe it," she said. "I am so thankful that God has brought us here. And that we are so, so close."

In December, the Supreme Court signaled its openness to overturning Roe during arguments for a case out of Mississippi. The conservative justices, like Samuel Alito and Brett Kavanaugh, indicated sympathy for Mississippi's 15-week abortion ban, which violates Roe's precedent.

If the conservative-leaning court rules in Mississippi's favor, it could overhaul abortion rights protected in the United States for nearly half a century. A ruling is expected by the end of June.

Jeanne Mancini, president of March for Life, the national anti-abortion group organizing Friday's event, said activists are hopeful "this year will bring us much closer to building the culture of life we have all marched for since Roe v. Wade was imposed on our nation nearly 50 years ago."

Abortion has long been a politically divisive issue in the United States, with abortion opponents concerned about preserving life from conception and abortion rights advocates standing for a woman's bodily autonomy.

In recent years, Republican-controlled states have advanced legislation and policies making it harder for women to get an abortion. The Guttmacher Institute, an abortion rights organization, found that 2021 saw the most restrictions of U.S. abortion rights in decades, with 108 abortion restrictions enacted in 19 states as of Dec. 31.

Liberate Abortion, a national coalition of more than 100 abortion rights advocacy groups, was not planning any in-person counterprotest at the March for Life because of the recent spike in COVID-19 cases, coalition campaign director Sharmin Hossain said. The coalition instead will hold a series of virtual events to mark the anniversary of Roe v. Wade this week.

"I think it's ironic that they call themselves March for Life because they ideologically do not support people living their best lives, lives filled without shame and stigma," Hossain said, adding that mobilizing large unmasked gatherings disregards public safety.

The anti-abortion movement also is celebrating a Texas law that banned abortion https://www.reuters.com/world/us/us-supreme-court-allows-challenge-texas-six-week-abortion-ban-2021-12-10 after six weeks and empowered private citizens to sue anyone who assists someone getting an abortion past that gestational limit. The Supreme Court has allowed that law, which took effect in September, to stand as it's challenged in lower courts.

Mark Lee Dickson, director of anti-abortion group Right to Life of East Texas, said he would attend the March for Life in Washington for the first time, inspired by the large crowds of anti-abortion protesters who gathered outside the Supreme Court for the oral arguments in the Mississippi case.

"There may not be another March for Life with Roe on the books, so I want to be a part of this," he said.

https://www.marketscreener.com/news/latest/Anti-abortion-activists-march-in-Washington-buoyed-by-waning-U-S-abortion-access--37606571/