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Califf on accelerated approvals: Companies need to do more work before FDA says OK

As he awaits a tight Senate vote, Rob Califf, President Joe Biden’s nominee to be the next FDA commissioner, is signaling where the agency may move on accelerated approvals if he takes over at FDA.
Building off comments from his Senate confirmation…

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As he awaits a tight Senate vote, Rob Califf, President Joe Biden’s nominee to be the next FDA commissioner, is signaling where the agency may move on accelerated approvals if he takes over at FDA.

Building off comments from his Senate confirmation hearing, in which Califf said that he’s “a fan of accelerated approval” but the US needs a better system to evaluate these drugs once they’re on the market, the nominee raised questions about how well the current structure serves patients.

There’s been “failure to produce confirmatory evidence quickly and in a way that really gives us the information we need as patients and clinicians to decide which treatments are most effective and in which order,” he said at the CERSI Summit last week.

Comparing the accelerated approval pathway to a relay race — potentially poking at the controversial situation where the FDA granted an accelerated approval to Biogen’s Alzheimer’s drug but CMS is requiring an additional randomized clinical trial — Califf argued the “FDA runs the first lap, gets to the end, drops the baton down on the ground, and someone else like CMS has to figure out where the baton is, pick it up and start all over.”

“I think one of the most important things I learned from my time [as FDA commissioner under the Obama administration] is the power of federal agencies working together with common purpose,” Califf said. “In a relay race, you have a number of yards where the second runner is running alongside the first, and we just don’t have that.”

He also lamented the fact that the US is “losing life expectancy in the US and relatively faster than the rest of the world. We’re innovating in the US in a way that’s helping the entire world, but there’s something we’re not doing right in implementing those innovations. That’s the way I see it.”

Julia Beaver

Julia Beaver, chief of medical oncology at the FDA’s Oncology Center of Excellence, also spoke on the CERSI panel with Califf, noting that overall, OCE’s work in accelerated approvals has been “a success” by providing years of early access to “transformative, life-prolonging therapies.”

She noted that half of all accelerated approval indications have confirmed benefit in a median of 3 years, and the remainder of those that have not yet confirmed benefit have been those granted AA in the last few years. Less than 10% of these indications have been withdrawn either due to failed trials or because the trials weren’t conducted, she said.

“The situation and framework we’re in now is that although we can’t require this, we are stressing the need for the confirmatory trial to be well underway, if not fully enrolled, at the time of the accelerated approval action to avoid these delays and get the evidence,” Beaver said. “But in terms of our confidence in getting that confirmatory evidence, that does now play into our overall risk/benefit decision. So if we have confidence or early agreement on evidence needed for confirmatory trial, that’s the ideal.”

Such earlier agreements between FDA and companies seeking accelerated approvals, “potentially even on confirmatory metrics,” Beaver noted, would allow for greater confidence in the approval pathway.

Hal Barron, who recently made the leap from CSO at GlaxoSmithKline to CEO of startup Altos Labs, also noted on the panel that there a number of surrogates where the benefit of an accelerated approval is a “smart risk to take.” But “in terms of where it’s failed,” he stressed that there needs to be more rigor in designing the confirmatory trials, “so you believe” the results when they’re positive or negative.

Hal Barron

Some of these trials are taking an “enormously long time to convert” to full approval, Barron noted, and he said there’s been a lot of talk about using RWE to satisfy confirmatory trial results. “But I’m not as convinced that that will help as much as randomized trials,” he said.

Califf, a longtime fan of using RWE when randomized, stressed, “Nothing about RWE excludes randomization, which is one of the most powerful tools we have.” He pointed to the UK-based Recovery trial, which quickly tested a number of different Covid-19 therapeutics, and which “beat the socks off” the US trials.

“If the trials are mostly enrolled before the [accelerated] approval comes, you’re going to get the answer,” Califf said.

Barron, meanwhile, noted the push toward doing more observational studies and using those to conclude a drug works when compared to untreated patients: “You can use all these sophisticated techniques, but I’m just not confident. Given that these drugs are going to be used for a long, long time, we’ve got to get it right and not skimping on the randomization, and understanding efficacy and effectiveness is critical.”

Barron also stressed that for a smaller company, it can be a big risk to initiate a confirmatory trial before an approval is granted or before the survey trials are unblinded. He also called for more companies to work in a pre-competitive way to define the utility around the surrogates on which the accelerated approvals are based.

“Whatever legislative framework is inserted, think hard about how every group has skin in the game. Incentivize approvals to get to patients faster but incentivize to quickly figure out if you made a smart decision that was wrong or a smart decision that was right,” he added when asked how Congress could improve the accelerated pathway.

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Economics

New Work Foundation Index reveals UK workers suffering most from insecure employment

New in-depth analysis of UK job market data reveals women, disabled people, ethnic minorities and young workers have been consistently trapped in insecure…

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New in-depth analysis of UK job market data reveals women, disabled people, ethnic minorities and young workers have been consistently trapped in insecure employment over the last twenty years.

Credit: Work Foundation

New in-depth analysis of UK job market data reveals women, disabled people, ethnic minorities and young workers have been consistently trapped in insecure employment over the last twenty years.

The Work Foundation, a leading think-tank dedicated to improving work in the UK, today launches its new ‘UK Insecure Work Index’ that details the prevalence of in-work insecurity felt by workers across the UK, and reveals how this insecurity has changed over the last two decades.

Using ONS labour market data from 2000 to 2021, the Work Foundation index focuses on three elements that can constitute insecurity at work – employment contracts, personal finances and access to workers’ rights.

Results reveal four groups of workers consistently trapped in the most severe category of in-work insecurity over the last twenty years, which has affected 20-25% of workers every year on average and an estimated 6.2 million employees just last year:

  • Young workers who are two and half times more likely to be in severely insecure work than those in the middle of their working lives (43% of 16-24-year olds vs. 17% of 25-65-year olds)
  • Women who are 10% more likely to be in severely insecure work than men (25% compared to 15%)
  • Ethnic minority workers are more likely to be in severely insecure work than white workers (24% versus 19%). Men from ethnic minority backgrounds are 10% more likely to experience severely insecure work compared to white men (23% versus 13%)
  • Disabled workers who are 6% more likely to suffer severely insecure work, compared to non-disabled workers (25% compared to 19%).

Data also reveals the sectors most at risk of severe in-work insecurity are hospitality, services and agriculture, which see one in three workers affected, compared to one in five nationally.

Ben Harrison, Director of the Work Foundation at Lancaster University, said, “At a time of a cost of living crisis, those in insecure and low paid work are among the groups at most risk. Wages have stagnated and while millions more people may be in employment, the quality and security of the jobs they are in often means they are unable to make ends meet.”

Job market data captured during the pandemic demonstrates that those in severely insecure work face the biggest risks in a crisis. During Covid-19, these workers were at greater risk of losing their jobs, were ten times more likely to receive no sick pay, were more likely to lose out on support through furlough or other schemes.

 “Our analysis shows that job insecurity is impacting certain groups more than others – in particular if you are a young person, a woman in work, from an ethnic minority background or have disabilities, you are more likely to experience severe insecurity in work,” Harrison continues. “With the Bank of England predicting inflation could potentially rise to 10% by the end of 2022, workers may be facing the largest real-term wage cut we’ve seen in generations.”

Former Chair of the Social Mobility Commission, Rt Hon. Alan Milburn, said: “The challenges facing millions of UK families due to job insecurity, low pay and lack of full-time work shouldn’t be underestimated. As the country faces the worst cost of living crisis in living memory, it is clear that more urgently needs to be done.

 “Social mobility has stagnated over recent decades and the UK Insecure Work Index confirms that severely insecure work significantly reduces people’s chances of escaping poverty. It is a stark reminder of the need to focus on access to more secure, better paid and higher quality jobs if we are to truly level-up the UK.”

TUC General Secretary, Frances O’Grady, welcomed the UK Insecure Work Index. She said: “Up and down the country, millions are trapped in jobs that have wildly unpredictable hours, low pay, and limited rights.

“For years working people were promised improved rights and protections. But ministers have now shelved the Employment Bill, which they said would help make Britain the best place in the world to work. 

 “Instead of tackling insecure work, ministers have sat on their hands and allowed it to flourish. In the midst of a cost-of-living emergency, it’s more important than ever that the government clamps down on low-paid precarious work.

“The time for excuses is over. We need to see government action to boost workers’ rights and end exploitative practices like zero hours contracts.”

Lord Gavin Barwell, Chief of Staff to the Prime Minister (2017-19) said: “Today for the first time ever, we have fewer people out of work than job vacancies. But, if low unemployment is a UK success story, the government and employers now face two challenges. First, how do we encourage people back into the market to meet the demand for labour? And second, how do we improve the security of those jobs and thereby level up the country?

“This timely report provides recommendations for what the government can do to improve security while maintaining the benefits of the UK’s current approach. The government is on the search for ways to use the regulatory freedom we now enjoy outside the EU: building on the success of the UK economy in creating jobs by ensuring those jobs are secure in the broadest sense of the word would be a great place to start.”

Ben Harrison adds: “In the immediate term, the Chancellor must raise Universal Credit in line with predicted inflation to ensure support through this cost of living crisis is targeted to those in low-paid and insecure work.

“And while plans for an Employment Bill that could have addressed many of these issues appear to have been shelved, the fact remains Government cannot hope to deliver on its ambition to Level Up the country without driving up employment standards and increasing the number of higher quality, better paid and more secure jobs on offer.”

The launch of the UK Insecure Work Index is the benchmark for the Work Foundation’s Insecure Work Research Programme, which aims to produce timely insights on insecure work in the UK going forward.

The UK Insecure Work Index report is published and available in full on the Work Foundation’s website on 26 May 2022: www.theworkfoundation.com.             

Ends


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International

The State of Democracy In Each Region Of the World

The state of democracy has dropped from an average global score of 5.37 to 5.28, the biggest drop since 2010 after the global financial crisis which translates…

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The world’s (almost) eight billion people live under a wide variety of political and cultural circumstances…[that] can be measured and presented on a sliding scale between “free” (democracy) and “not free” (authoritarian) and the…Democracy Index report by the Economist Intelligence Unit (EIU), is one such attempt to apply a score to countries based on how closely they measure up to democratic ideals.

According to EIU, the state of democracy is at its lowest point since the index began in 2006, dropping from an average global score of 5.37 to 5.28, the biggest drop since 2010 after the global financial crisis….[which] translates into the sobering fact that only 46% of the population is living in a democracy “of some sort.”

Below is a look at the democratic state of each region in the world:

The Americas

Europe

map showing democracy index measuring political regimes in europe

Africa

map showing democracy index measuring political regimes in africa

Middle East and Central Asia

map showing democracy index measuring political regimes in the middle east

East Asia and Oceania

map showing democracy index measuring political regimes in east asia and oceania

Decline in Global Democracy Levels

Two years after the world got hit by the pandemic, we can see that global democracy is in a downward trend with very region’s global score experiencing  a drop, with the exception of Western Europe, which remained flat. Out of the 167 countries, 74 (44%) experienced a decline in their democracy score.

Editor’s Note: The above article is an edited and abridged version of the original post on visualcapitalist.com by Raul Amoros with article editing by Nick Routley and graphics design by Sabrina Fortin.

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Government

After mass shootings like Uvalde, national gun control fails – but states often loosen gun laws

After mass shootings, politicians in Washington have failed to pass new gun control legislation, despite public pressure. But laws are being passed at…

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A girl cries outside the Willie de Leon Civic Center in Uvalde, Texas, on May 24, 2022. Allison Dinner/AFP via Getty Images

Calls for new gun legislation that previously failed to pass Congress are being raised again after the May 24, 2022, mass shooting at an elementary school in the small town of Uvalde, Texas.

An 18-year-old shooter killed at least 19 fourth grade students and two teachers at Robb Elementary School, marking the deadliest school shooting in the U.S. in a decade.

The U.S. has been here before – after shootings in Tucson, Aurora, Newtown, Charleston, Roseburg, San Bernardino, Orlando, Las Vegas, Parkland, El Paso, Boulder, and 12 days earlier at a grocery store in Buffalo, N.Y.

Gun production and sales in the U.S. remain high, following a purchasing surge during the COVID-19 pandemic. In 2021, the firearms industry sold about six guns for every 100 Americans.

Senator Chris Murphy of Connecticut was among the Democratic politicians who pleaded for action on gun control as horrifying details of the Uvalde school shooting unfolded.

“What are we doing?” Murphy asked other lawmakers, speaking from the Senate floor on the day of the shooting. “Why are you here if not to solve a problem as existential as this?”

Congress has declined to pass significant new gun legislation after dozens of shootings, including those that occurred during periods like this one, with Democrats controlling the House of Representatives, Senate and presidency.

This response may seem puzzling given that national opinion polls reveal extensive support for several gun control policies, including expanding background checks and banning assault weapons.

In October 2021, 52% of people polled by Gallup said that they thought firearm sales laws should be made more strict.

But polls do not determine policy.

I am a professor of strategy at UCLA and have researched gun policy. With my co-authors at Harvard University, I’ve studied how gun laws change following mass shootings.

Our research on this topic finds there is legislative activity following these tragedies, but it’s at the state level.

A Democratic senator and Sandy Hook parents and teachers at a press conference in the US Capitol in 2013.
U.S. Senator Richard Blumenthal (D-Conn.) speaks to the media as teachers, parents and residents from Newtown, Conn. – where the Sandy Hook school massacre happened – listen after a Capitol Hill hearing on Feb. 27, 2013, on the Assault Weapons Ban of 2013. Alex Wong/Getty Images

Restrictions loosened

Stricter gun laws at the national level are more popular among Democrats than Republicans, and major new legislation would likely need votes from at least 10 Republican senators. Many of these senators represent constituencies opposed to gun control.

Despite national polls showing majority support for an assault weapons ban, not one of the 30 states with a Republican-controlled legislature has such a policy.

U.S. Texas Senator Ted Cruz said on May 24 that more gun control laws could not have prevented the Uvalde attack, explaining “that doesn’t work, it’s not effective, it doesn’t prevent crime.”

The absence of strict control policies in Republican-controlled states shows that senators crossing party lines to support gun control would be out of step with the views of voters whose support they need to win elections.

But a lack of action from Congress doesn’t mean gun laws are stagnant after mass shootings.

To examine how policy changes, we assembled data on shootings and gun legislation in the 50 states between 1990 and 2014. Overall, we identified more than 20,000 firearm bills and nearly 3,200 enacted laws. Some of these loosened gun restrictions, others tightened them, and still others did neither or both – that is, tightened in some dimensions but loosened in others.

We then compared gun laws before and after mass shootings in states where mass shootings occurred, relative to all other states.

Contrary to the view that nothing changes, state legislatures consider 15% more firearm bills the year after a mass shooting. Deadlier shootings – which receive more media attention – have larger effects.

In fact, mass shootings have a greater influence on lawmakers than other homicides, even though they account for less than 1% of gun deaths in the United States.

As impressive as this 15% increase in gun bills may sound, gun legislation can reduce gun violence only if it becomes law. And when it comes to enacting these bills into law, our research found that mass shootings do not regularly cause lawmakers to tighten gun restrictions.

In fact, we found the opposite. Republican state legislatures pass significantly more gun laws that loosen restrictions on firearms after mass shootings.

In 2021, Texas Governor Greg Abbott signed a new law that eliminated a requirement for Texans to obtain a license or receive training to carry handguns. This came two years after a 2019 mass shooting at a Walmart in El Paso.

That’s not to say Democrats never tighten gun laws – there are prominent examples of Democratic-controlled states passing new legislation following mass shootings.

California, for example, enacted several new gun laws following a 2015 mass shooting in San Bernardino. Our research shows, however, that Democrats don’t tighten gun laws more than usual following mass shootings.

After the Buffalo shooting in early May 2022, New York Governor Kathy Hochul said that she would work to increase the age for legal gun purchasing from 18 to 21 “at a minimum.”

'Change gun laws or change Congress' reads a sign at a 2018 rally in New York City.
In August 2018, Moms Demand Action hosted a rally at New York City’s Foley Square to call upon Congress to pass gun safety laws. Erik McGregor/LightRocket via Getty Images

Ideology governs response

The contrasting response from Democrats and Republicans is indicative of different philosophies regarding the causes of gun violence and the best ways to reduce deaths.

While Democrats tend to view social factors as contributing to violence, Republicans are more likely to blame the individual shooters.

Cruz, for example, has said that stopping individuals with criminal records from committing violence could help prevent mass shootings.

Politicians favoring looser restrictions on guns following mass shootings frequently argue that more people carrying guns would allow law-abiding citizens to stop perpetrators.

In fact, gun sales often surge after mass shootings, in part because people fear being victimized.

Democrats, in contrast, typically focus more on trying to solve policy and societal problems that contribute to gun violence.

For both sides, mass shootings are an opportunity to propose bills consistent with their ideology.

Since we wrote our study of gun legislation following mass shootings, which covered the period through 2014, several additional tragedies have energized the gun control movement that emerged following the December 2012 shooting at Sandy Hook Elementary School in Connecticut. These include the May 2022 shooting at the Tops grocery store in Buffalo, as well as the Uvalde school massacre.

While President Joe Biden issued executive orders in 2021 with the goal of reducing gun violence, action in Congress remains elusive. States, meanwhile, have been more active on the issue.

Student activism following the 2018 shooting at Marjory Stoneman Douglas High School in Parkland, Florida, did not result in congressional action but led several states to pass new gun control laws.

With more funding and better organization, this new movement is better positioned than prior gun control movements to advocate for stricter gun policies following mass shootings. Public outcry and devastation over the Uvalde shootings will likely provide fuel to this advocacy work.

But with states historically more active than Congress on the issue of guns, both advocates and opponents of new restrictions should look beyond Washington for action on gun policy.

This is an updated version of an article originally published on March 21, 2021.

Christopher Poliquin does not work for, consult, own shares in or receive funding from any company or organization that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.

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