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Only 75% accelerated non-cancer drug approvals led to full approvals – study (NASDAQ:BIIB)

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Highlighting the drawbacks of the FDA’s accelerated approval, a newly published study has found that medications for only 75% of non-oncology conditions where drugs were cleared through the pathway were converted to regular approvals.

The accelerated approval program created in 1992 allows the FDA to clear drugs based on surrogate measures such as intermediate clinical endpoints and biomarkers, which can reasonably predict actual clinical endpoints.

It can take as little as five months or even a few weeks for the agency to greenlight a drug based on the accelerated path compared to the 10 months a formal approval can take.

As part of the accelerated approval, the manufacturer is required to conduct post-approval trials and add an official label to inform the public that the drug’s clinical benefit has not been established.

If the post-approval trial confirms clinical benefit, the label is revised, and the approval is converted to regular approval. If the FDA requirements are not met, or the post-approval trial fails, the drug may be pulled from the market.

The study published last week in The Journal of the American Medical Association evaluated 48 drugs that FDA greenlighted from June 1992 to May 2018 across 57 noncancer conditions based on data from 93 clinical trials.

However, drugs for only 75% of those indications went all the way to receive FDA’s full approval, researchers from Japan’s Fukushima Medical University and Kyoto University Graduate School of Medicine have found.

It took a median of 53.1 months to convert the accelerated approvals to regular approvals, while the median duration from the receipt of the manufacturer’s application to accelerated approval stood at 7.8 months.

Since the accelerated approval, 27 indications (47%) had required post-approval label modifications on boxed warnings. The labeling change that indicates a serious safety risk had taken effect after more than 20 years of median duration.

Out of 86 confirmatory trials required for accelerated approval, 20% did not meet the FDA requirements, and nine (10%) failed to prove clinical efficacy. While the median time to complete a confirmatory trial reached 39.4 months, only one out of eight indications (2%) were withdrawn, and that is also more than a decade after the approval.

“Once granted accelerated approval, delaying further testing could only benefit manufacturers while harming consumers,” the researchers wrote, arguing that patients with no therapeutic options will continue to rely on costly drugs despite the lack of evidence on their clinical benefit.

Researchers pointed to a 2018 FDA review which indicated that out of 93 oncology indications with accelerated approvals from December 1992 to May 2017, only 55% had met the post-approval requirements, while 5% were withdrawn due to unconfirmed clinical efficacy. They attributed the inferior post-approval performance in oncology drugs to poorly designed pre-approval cancer trials and longer follow-ups that allow sponsors to observe more events.

The researchers noted that the accelerated approval pathway expedited the regulatory clearance of noncancer drugs by nearly 4.5 years. However, they pointed to safety-related label changes and unconfirmed clinical efficacy to suggest that the full evaluation of such drugs could take more than a decade.

“These findings emphasize the importance of due diligence in conducting confirmatory trials within a reasonable time frame and withdrawing approval immediately if the trial does not demonstrate clinical benefits outweighing the risks,” the researchers added.

The study had several limitations, including insufficient information on the FDA drug database regarding label changes before July 1996.

FDA’s accelerated approval sparked debate in 2021 when the agency went against its own advisors and approved Aduhelm, the Alzheimer’s drug developed by Biogen (NASDAQ:BIIB) and Eisai (OTCPK:ESALY) (OTCPK:ESALF) based on surrogate endpoints. However, in May, Biogen (BIIB) pulled marketing support for the treatment amid payer pushback for its coverage while clinicians questioned its efficacy.

In June, the House passed a bill that would give explicit legal authority to the FDA to require that confirmatory trials are underway for a drug before its accelerated approval, and streamline the process for withdrawal if the drug is proved ineffective.

An upcoming FDA decision on Amylyx Pharma’s (AMLX) amyotrophic lateral sclerosis (ALS) therapy AMX-0035 will add further scrutiny on accelerated approval ahead of September 29 PDUFA date as patient advocates call for its approval.

Reversing an earlier decision, an independent panel of the FDA voted 7–2 in favor of AMX-0035 for ALS last week. The decision was based on data from a Phase 2 trial which met the primary endpoint but lacked evidence supporting the survival endpoints.

In a highly unusual move, AMLX Co-Chief Executive Justin Klee said during the meeting that after a potential approval, if the ongoing Phase 3 trial, which considers survival benefit of AMX-0035, fails, the company would voluntarily pull the drug from the market.

Meanwhile, bluebird bio (BLUE) became the latest to win FDA accelerated approval on Friday for its gene therapy Skysona (elivaldogene autotemcel) to slow the neurologic dysfunction in patients aged 4 – 17 years with early cerebral adrenoleukodystrophy.

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Wall Street hit with $2 billion in fines over employees using WhatsApp and other unauthorized messaging apps

U.S. regulators reached settlements with a dozen banks in a sprawling probe into how global financial firms failed to monitor employees’ communications on unauthorized messaging apps, bringing total penalties in the matter to more than $2 billion. 

The Securities and Exchange Commission announced $1.1 billion in fines and the Commodity Futures Trading Commission disclosed $710 million in penalties in separate statements Tuesday. Those levies — against firms including Bank of America Corp., Citigroup Inc. and Goldman Sachs Group Inc. — combined with JPMorgan Chase & Co.’s $200 million in fines from December, bring the total to $2.01 billion, making them the biggest penalties ever against US banks for record-keeping lapses. 

“Finance, ultimately, depends on trust. By failing to honor their record-keeping and books-and-records obligations, the market participants we have charged today have failed to maintain that trust,” SEC Chair Gary Gensler said in the agency’s statement. “As technology changes, it’s even more important that registrants appropriately conduct their communications about business matters within only official channels, and they must maintain and preserve those communications.”

Tuesday’s announcements cap months of discussions between regulators and the banks. Morgan Stanley said in July it was nearing a settlement that would see it pay a $200 million fine, with other major banks also disclosed setting aside similar figures as part of their second-quarter results without specifying the reason.

JPMorgan had been the only bank until now to reach a settlement with the regulators, and was the first to report the fines, in December. Even managing directors and other senior supervisors at the largest US bank had skirted regulatory scrutiny by using services such as WhatsApp or personal email addresses for work-related communication, regulators said at the time.

Finance firms are required to scrupulously monitor communications involving their business to head off improper conduct. That system, already challenged by the proliferation of mobile-messaging apps, was strained further as firms sent workers home shortly after the start of the Covid-19 outbreak.

In the SEC probe, eight firms agreed to penalties of $125 million each: Barclays Plc, Bank of America, Citigroup, Credit Suisse Group AG, Deutsche Bank AG, Goldman Sachs, Morgan Stanley and UBS Group AG. Jefferies Financial Group Inc. and Nomura Holdings Inc. agreed to pay $50 million apiece, and Cantor Fitzgerald LP agreed to pay $10 million.

Bank of America had the biggest CFTC penalty, at $100 million, followed by Barclays, Citigroup, Credit Suisse, Deutsche Bank, Goldman Sachs, Morgan Stanley and UBS at $75 million each. Nomura was fined $50 million, Jefferies $30 million and Cantor Fitzgerald $6 million.

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Ray Dalio says the U.K.’s policies ‘suggest incompetence’ and warns other governments not to make the same mistakes

Ray Dalio added his name to a growing list of critics of the U.K.’s new spending plan, unveiled last week by Prime Minister Liz Truss and Chancellor of the Exchequer Kwasi Kwarteng.

The billionaire investor—who founded what is now the world’s largest hedge fund, Bridgewater Associates, in 1975—argued the plan’s aggressive tax cuts will raise the U.K. debts to an unsustainable level and cripple the pound.

“Investors and policymakers: Heed the lesson of the UK’s fiscal blunder,” Dalio wrote in a Tuesday tweet. “The panic selling you are now seeing that is leading to the plunge of UK bonds, currency, and financial assets is due to the recognition that the big supply of debt that will have to be sold by the government is much too much for the demand.”

On Monday, in response to Truss’ new spending plan, the U.K.’s bond market experienced the largest one-day sell-off in its history, pushing the total losses in the country’s stock and bond markets since Truss’ appointment as prime minister on Sept. 5 to over $500 billion. Meanwhile, the pound sank to a record low of $1.05 against the U.S. dollar on Monday morning, and although it has since risen to $1.07, the currency remains near a 40-year low vs. the dollar. 

After the new Truss spending plan was announced, the U.K. Debt Management Office said that it will raise its debt issuance by 72.4 billion pounds for the current fiscal year to 234.1 billion pounds.

The new spending plan will also push the U.K.’s debt to GDP ratio to around 101%, the highest level of debt the U.K. has held since 1962, according to Deutsche Bank.

Deutsche Bank, UK Office of Debt Management

In Ray Dalio’s view, this rapid increase in debt, coupled with the lack of demand for the pound on the global stage, is a recipe for disaster.

“That makes people want to get out of the debt and currency. I can’t understand how those who were behind this move didn’t understand that. It suggests incompetence,” Dalio said. “Mechanistically, the U.K. government is operating like the government of an emerging country, it is producing too much debt in a currency that there is not a big world demand for.”

The investor went on to argue that this should be a teaching moment for governments around the world to not increase their debts to unsustainable levels.

“I hope, but doubt, that other policymakers who are doing similar things…will recognize that they are risking a similar outcome—and that investors will see this too,” he said.

Analysts are also worried that the U.K.’s new spending plan, which was designed to spur economic growth and help alleviate the effects of high energy prices in the short term, could end up exacerbating inflation in the U.K. overall. And consumer prices already jumped 9.9% from a year ago in August.

“The government is trying to balance support for consumers and businesses with measures that might trigger further inflation, whilst also trying to reinvigorate a stagflationary economy,” Giles Coghlan, chief market analyst at global Forex broker HYCM, told Fortune. “Such a large fiscal package could contribute to elevated prices in the medium to long term that could inflict further damage to an economy and currency that are already on their knees.” 

The potential inflationary impact of the new spending plan has increased calls for the Bank of England (BoE) to dramatically hike interest rates, with some economists even calling for the U.K.’s base interest rate to move from 2.25% to as high as 6% next year

That’s bad news for the U.K.’s homeowners. Monthly mortgage rates will increase immediately for 2 million people on tracker or variable interest rate plans if the BoE follows through with its next rate hike. And another 1.8 million homeowners with fixed-rate deals will also be forced to pay significantly higher rates next year, according to U.K. Finance.

With the U.K. facing more interest rate hikes ahead, rising government debts, a sinking pound, and a European energy crisis, Deutsche Bank’s chief economist, David Folkerts-Landau, said he now believes the country will experience a severe recession that lasts three to four quarters.

“We’re thinking in terms of a recession that will be deep and long,” he told Bloomberg on Tuesday. “It’s the price we have to pay for financial stability and for getting on the right track.”

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Artificial Intelligence: A.I. is solving traffic problems to get you where you’re going safely

“I haven’t met anyone that really loves traffic,” says Karina Ricks of the Federal Transit Administration.

Except, possibly, professionals like her who are tasked with reducing it.

Ricks has made her career out of caring about traffic patterns. Before her current role as the associate administrator for research, innovation, and demonstration at the FTA, she was the director of mobility and infrastructure for the City of Pittsburgh in Pennsylvania. She has spent countless hours thinking about cars, public transit, roads, and pedestrians—and how to make it all flow more smoothly.

“When you’re in the peak times for travel, when the system is so full, it only takes a small disruption to cause really big problems,” Ricks says. “The work is to quickly flag those disruptions and rapidly retool the system to operate around them.”

What Ricks aims to optimize affects anyone moving from point A to point B, especially in cities. She explained that congestion is the number one problem when it comes to traffic, and a common occurrence in metropolitan areas. Add to that the number of variables at any given time, including human operators of vehicles and geography, and it results in a mind-boggling puzzle to even attempt to solve.

If there were an easy way to reduce traffic, it would have been actioned in the past 50 years, she said. Instead, she, government organizations, and startups in the space, such as Lyt, are all looking at an immense amount of traffic data available—from traffic sensors to ride share data and even bike and scooter data from smartphones—and using it to inform decisions on how to get people to work, home, and the grocery store safely and quickly.

That solution involves artificial intelligence and machine learning.

“There are tasks that humans just aren’t good at that machinery is, and that’s recognizing patterns,” explains Tim Menard, founder and chief executive officer of Lyt, a software technology platform providing mobility solutions for cities. “A.I. is a great technology to use, because you’re looking at all parts of the system. You can start feeding it different information, and you can put that into a system that can make operational changes.”

Menard started Lyt after studying intelligent transportation systems for more than 13 years. His company uses vehicle data to solve traffic problems, especially when it comes to the efficiency of public transit options. For Menard, the end goal is to “make more cities equitable by making public transit reliable, predictable, and faster.”

Both Ricks and Menard believe that the way to reduce traffic is to get more people onto public transportation, such as buses, subways, and light rail systems. Public transportation is the safest surface transportation mode, with fewer injuries and fatalities. It’s also a speedier way to move a larger number of people.

Ricks explained that most of congestion is caused by “low-volume vehicles,” ie. single-occupant cars. Those drivers are human; some drive faster, some slower; some change lanes often, others stop abruptly when a traffic light flashes yellow before red. Because humans behave so differently, there is a level of unpredictability in the traffic system. Much of her work aims to make mass transit more enticing for commuters.

“You’re reducing the rate of crashes that might occur when you’re reducing the number of vehicles that are there,” Ricks added.

With that in mind, Menard started looking at the Internet of Things for his cloud platform, pulling data from smartphones, automotive sensors, public transportation logs, and delivery vehicles to understand traffic patterns at various times of the day as well as during special one-off events, such as a sports game at a local stadium. He said that the first hurdle was to operate from a place of known information rather than guessing; in the past, he explained, it took a human looking at a video screen for hours and hours to even begin to make an estimate on next steps.

He launched in San Jose, Calif., where for the past three years, he has collaborated with the city to optimize bus routes by 20%, thereby reducing fuel consumption by 14% and emissions at intersections by 12%. Using a predictive estimated time of arrival at each traffic light, his platform reduced the travel time between bus stops by optimizing bus lanes and traffic lights to ensure buses could move as effectively as possible without disrupting other traffic. He now works in other northern California cities, including additional Bay Area towns and Sacramento, as well as in the Pacific Northwest: Seattle and Portland, Ore.

Menard is also looking at bicycle and pedestrian traffic, something he says is of interest and priority to many transit authorities. He has worked to make bicycling safer by creating dedicated, curbed bike lanes with their own traffic signals synced with those of vehicle traffic to help avoid car-bicycle collisions. For pedestrians, Ricks explained that foot traffic uses sensors and adaptive controls to adjust settings in real time based on needs—a moment when the A.I. algorithm and real time data intersect.

Another benefit of A.I. technology for traffic patterns surrounds first responders. Menard employed machine learning to analyze data from emergency vehicles like ambulances and fire trucks to improve speed. He noted that in many urban environments, congestion and traffic patterns prohibit first responders from promptly arriving on scene or to a hospital with a life-or-death situation. In Sacramento, Calif., he tackled this problem.

“It was literally night and day better in under 15 minutes,” he said of taking a look at amassed data from all the relevant stakeholders in the city. There, he improved the slowest 10% of the emergency vehicles by more than 10 miles per hour, allowing them to arrive 70% faster on any response. Even the performing top 10% of vehicles saw an improvement of 6 miles per hour.

For every single-occupant car that swaps to public transit, there is one less vehicle on the road causing congestion. Menard regularly reminds people that when they are sitting in their car, stuck in traffic, they are surrounded by many other people doing the exact same thing. If they traded to a shared vehicle—a high-occupancy mode of transit—they may speed along very quickly.

But it’s always challenging to inspire commuters to change habits, so the new option needs to be compelling enough to motivate them to adjust the way they operate. “What you want in a transit system is to show up now [and] there’s a bus ready to get you in a timely fashion,” Ricks said. “We need to address traffic in order for transit to be that attractive alternative. There’s quite a bit of work to still do.”

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