CHEST Physician

SAN DIEGO — Patients with idiopathic pulmonary fibrosis (IPF) had significant improvements in lung function and reversal of lung fibrosis measures after 12 weeks of therapy with an investigational inhibitor of the Hedgehog signaling pathway.

Early efficacy data from a phase 2a safety trial suggest that the novel oral agent, dubbed ENV-101, is associated with improvements in forced vital capacity (FVC) and other measures of lung function, and may be a disease-modifying therapy for IPF, according to Toby M. Maher, MD, PhD, director of the interstitial lung disease program at Keck School of Medicine, University of Southern California, Los Angeles. Dr. Maher presented the results at the American Thoracic Society’s international conference.

“Historically we’ve not been seeing improvements in FVC, which is what we’ve been seeing [with ENV-101], and I think it’s conceivable that you can get remodeling of early areas of fibrosis in the lung,” Dr. Maher said in an interview with Chest Physician.

“We know from histology studies that if you look at IPF lungs you’ll see areas of end-stage fibrosis, but even in advanced disease you’ll see areas where the lung is relatively well preserved and there’s early fibrosis, so I think it’s conceivable that there is remodeling of some of those early areas of fibrosis,” he said.
 

Vital pathway

The Hedgehog pathway is highly conserved in evolution. The cell-signaling pathway is active embryogenesis, tissue proliferation, and organ development. There is also evidence to suggest that in adult the pathway becomes reactivated following tissue injury, as can occur in lung epithelia, Dr. Maher explained.

Although as the word “idiopathic” in IPF indicates the etiology of the disease is unknown, investigators have found that in IPF repetitive epithelial injury to lung tissue leads to activation of the Hedgehog pathway. Hedgehog signaling in turn induces formation and activation of myofibroblasts that lay down fibrotic matrix and contract lung tissue, leading to significant impairments in gas exchange, Dr. Maher said.

ENV-101 blocks Hedgehog from binding to the PTCH1 receptor, preventing release of the zinc-finger protein GLI1 from the kinase complex into the cell cytoplasm. With signaling blocked, myofibroblasts undergo apoptosis instead of initiating wound repair as they normally would, thereby eliminating an evident mechanism of IPF pathology, he explained.
 

Study details

In the phase 2a trial, investigators enrolled patients with IPF who were not taking antifibrotic agents and who had a percent predicted FVC greater than 50%, percent predicted diffusing capacity for carbon monoxide (DLCO) of at least 35%, and life expectancy of more than 1 year.

The patients were randomized to receive 200 mg oral ENV-101 daily (18 patients) or placebo (15 patients) for 12 weeks.

The primary endpoint of the trial was safety of the experimental agent. A previous phase 1b study of a different Hedgehog inhibitor — vismodegib (Erivedge), in combination with the antifibrotic agent pirfenidone (Pirespa) — in patients with IPF was discontinued because of poor tolerability.

In the current study, the most common treatment-related adverse events were dysgeusia in 57% of patients who received the drug, alopecia in 52%, and muscle spasms in 43%. The spasms were generally less severe than those seen in the vismodegib/pirfenidone trial mentioned above.

Seven patients (33%) had treatment-emergent events leading to dose interruption. Five patients discontinued treatment: one who withdrew because of taste alterations, one who was lost to follow-up after an IPF exacerbation, and three who withdrew consent.

There were no treatment-related deaths, and no clinically significant findings on labs, vital signs, electrocardiograms, or physical exam.
 

Efficacy endpoints

An analysis of the secondary efficacy endpoints showed a 1.9% mean improvement in FVC from baseline among patients assigned to ENV-101, compared with a mean decline of 1.3% of patients assigned to placebo (P = .035).

Patients on the active drug also had a 200-mL mean increase in total lung capacity, compared with a mean decline of 56 mL for patients on placebo (P = .005).

In addition, high-resolution CR studies showed a 9.4% absolute decrease from baseline in quantitative interstitial lung disease with ENV-101, vs. a 1.1% increase among controls, a 2% absolute decline from baseline in quantitative lung fibrosis compared with a 0.87% increase with placebo, and a 4.6% absolute decrease from baseline in quantitative ground glass, compared with an increase of 0.29% with placebo.
 

Bad taste a good sign?

Reinoud Gosens PhD, University of Groningen, the Netherlands, who co-moderated the session but was not involved in the study, questioned whether the dysgeusia seen in patients who received ENV-101 might be related to the dysgeusia seen in clinical trials of P2X3 receptor antagonists for cough.

“I was wondering if there would be a mechanistic overlap between Hedgehog inhibition and cough, which would be quite relevant for IPF,” he said in an interview.

The increase in FVC seen with ENV-101 and with the investigational agent buloxibutid, a novel angiotensin II type 2 receptor agonist described in a separate presentation by Dr. Maher, suggests that these drugs may have the ability to help remodel damaged lungs, Dr. Gosens said.

Investigators are currently planning a phase 2 dose-ranging trial (WHISTLE-PF) in patients with IPF or progressive pulmonary fibrosis.

The phase 2a trial was supported by Endeavor BioMedicines. Dr. Maher disclosed consultancy or speaker fees from Endeavor and others. Dr. Gosens had no relevant disclosures.

SAN DIEGO — Patients with idiopathic pulmonary fibrosis (IPF) had significant improvements in lung function and reversal of lung fibrosis measures after 12 weeks of therapy with an investigational inhibitor of the Hedgehog signaling pathway.

Early efficacy data from a phase 2a safety trial suggest that the novel oral agent, dubbed ENV-101, is associated with improvements in forced vital capacity (FVC) and other measures of lung function, and may be a disease-modifying therapy for IPF, according to Toby M. Maher, MD, PhD, director of the interstitial lung disease program at Keck School of Medicine, University of Southern California, Los Angeles. Dr. Maher presented the results at the American Thoracic Society’s international conference.

“Historically we’ve not been seeing improvements in FVC, which is what we’ve been seeing [with ENV-101], and I think it’s conceivable that you can get remodeling of early areas of fibrosis in the lung,” Dr. Maher said in an interview with Chest Physician.

“We know from histology studies that if you look at IPF lungs you’ll see areas of end-stage fibrosis, but even in advanced disease you’ll see areas where the lung is relatively well preserved and there’s early fibrosis, so I think it’s conceivable that there is remodeling of some of those early areas of fibrosis,” he said.
 

Vital pathway

The Hedgehog pathway is highly conserved in evolution. The cell-signaling pathway is active embryogenesis, tissue proliferation, and organ development. There is also evidence to suggest that in adult the pathway becomes reactivated following tissue injury, as can occur in lung epithelia, Dr. Maher explained.

Although as the word “idiopathic” in IPF indicates the etiology of the disease is unknown, investigators have found that in IPF repetitive epithelial injury to lung tissue leads to activation of the Hedgehog pathway. Hedgehog signaling in turn induces formation and activation of myofibroblasts that lay down fibrotic matrix and contract lung tissue, leading to significant impairments in gas exchange, Dr. Maher said.

ENV-101 blocks Hedgehog from binding to the PTCH1 receptor, preventing release of the zinc-finger protein GLI1 from the kinase complex into the cell cytoplasm. With signaling blocked, myofibroblasts undergo apoptosis instead of initiating wound repair as they normally would, thereby eliminating an evident mechanism of IPF pathology, he explained.
 

Study details

In the phase 2a trial, investigators enrolled patients with IPF who were not taking antifibrotic agents and who had a percent predicted FVC greater than 50%, percent predicted diffusing capacity for carbon monoxide (DLCO) of at least 35%, and life expectancy of more than 1 year.

The patients were randomized to receive 200 mg oral ENV-101 daily (18 patients) or placebo (15 patients) for 12 weeks.

The primary endpoint of the trial was safety of the experimental agent. A previous phase 1b study of a different Hedgehog inhibitor — vismodegib (Erivedge), in combination with the antifibrotic agent pirfenidone (Pirespa) — in patients with IPF was discontinued because of poor tolerability.

In the current study, the most common treatment-related adverse events were dysgeusia in 57% of patients who received the drug, alopecia in 52%, and muscle spasms in 43%. The spasms were generally less severe than those seen in the vismodegib/pirfenidone trial mentioned above.

Seven patients (33%) had treatment-emergent events leading to dose interruption. Five patients discontinued treatment: one who withdrew because of taste alterations, one who was lost to follow-up after an IPF exacerbation, and three who withdrew consent.

There were no treatment-related deaths, and no clinically significant findings on labs, vital signs, electrocardiograms, or physical exam.
 

Efficacy endpoints

An analysis of the secondary efficacy endpoints showed a 1.9% mean improvement in FVC from baseline among patients assigned to ENV-101, compared with a mean decline of 1.3% of patients assigned to placebo (P = .035).

Patients on the active drug also had a 200-mL mean increase in total lung capacity, compared with a mean decline of 56 mL for patients on placebo (P = .005).

In addition, high-resolution CR studies showed a 9.4% absolute decrease from baseline in quantitative interstitial lung disease with ENV-101, vs. a 1.1% increase among controls, a 2% absolute decline from baseline in quantitative lung fibrosis compared with a 0.87% increase with placebo, and a 4.6% absolute decrease from baseline in quantitative ground glass, compared with an increase of 0.29% with placebo.
 

Bad taste a good sign?

Reinoud Gosens PhD, University of Groningen, the Netherlands, who co-moderated the session but was not involved in the study, questioned whether the dysgeusia seen in patients who received ENV-101 might be related to the dysgeusia seen in clinical trials of P2X3 receptor antagonists for cough.

“I was wondering if there would be a mechanistic overlap between Hedgehog inhibition and cough, which would be quite relevant for IPF,” he said in an interview.

The increase in FVC seen with ENV-101 and with the investigational agent buloxibutid, a novel angiotensin II type 2 receptor agonist described in a separate presentation by Dr. Maher, suggests that these drugs may have the ability to help remodel damaged lungs, Dr. Gosens said.

Investigators are currently planning a phase 2 dose-ranging trial (WHISTLE-PF) in patients with IPF or progressive pulmonary fibrosis.

The phase 2a trial was supported by Endeavor BioMedicines. Dr. Maher disclosed consultancy or speaker fees from Endeavor and others. Dr. Gosens had no relevant disclosures.

SAN DIEGO — Patients with idiopathic pulmonary fibrosis (IPF) had significant improvements in lung function and reversal of lung fibrosis measures after 12 weeks of therapy with an investigational inhibitor of the Hedgehog signaling pathway.

Early efficacy data from a phase 2a safety trial suggest that the novel oral agent, dubbed ENV-101, is associated with improvements in forced vital capacity (FVC) and other measures of lung function, and may be a disease-modifying therapy for IPF, according to Toby M. Maher, MD, PhD, director of the interstitial lung disease program at Keck School of Medicine, University of Southern California, Los Angeles. Dr. Maher presented the results at the American Thoracic Society’s international conference.

“Historically we’ve not been seeing improvements in FVC, which is what we’ve been seeing [with ENV-101], and I think it’s conceivable that you can get remodeling of early areas of fibrosis in the lung,” Dr. Maher said in an interview with Chest Physician.

“We know from histology studies that if you look at IPF lungs you’ll see areas of end-stage fibrosis, but even in advanced disease you’ll see areas where the lung is relatively well preserved and there’s early fibrosis, so I think it’s conceivable that there is remodeling of some of those early areas of fibrosis,” he said.
 

Vital pathway

The Hedgehog pathway is highly conserved in evolution. The cell-signaling pathway is active embryogenesis, tissue proliferation, and organ development. There is also evidence to suggest that in adult the pathway becomes reactivated following tissue injury, as can occur in lung epithelia, Dr. Maher explained.

Although as the word “idiopathic” in IPF indicates the etiology of the disease is unknown, investigators have found that in IPF repetitive epithelial injury to lung tissue leads to activation of the Hedgehog pathway. Hedgehog signaling in turn induces formation and activation of myofibroblasts that lay down fibrotic matrix and contract lung tissue, leading to significant impairments in gas exchange, Dr. Maher said.

ENV-101 blocks Hedgehog from binding to the PTCH1 receptor, preventing release of the zinc-finger protein GLI1 from the kinase complex into the cell cytoplasm. With signaling blocked, myofibroblasts undergo apoptosis instead of initiating wound repair as they normally would, thereby eliminating an evident mechanism of IPF pathology, he explained.
 

Study details

In the phase 2a trial, investigators enrolled patients with IPF who were not taking antifibrotic agents and who had a percent predicted FVC greater than 50%, percent predicted diffusing capacity for carbon monoxide (DLCO) of at least 35%, and life expectancy of more than 1 year.

The patients were randomized to receive 200 mg oral ENV-101 daily (18 patients) or placebo (15 patients) for 12 weeks.

The primary endpoint of the trial was safety of the experimental agent. A previous phase 1b study of a different Hedgehog inhibitor — vismodegib (Erivedge), in combination with the antifibrotic agent pirfenidone (Pirespa) — in patients with IPF was discontinued because of poor tolerability.

In the current study, the most common treatment-related adverse events were dysgeusia in 57% of patients who received the drug, alopecia in 52%, and muscle spasms in 43%. The spasms were generally less severe than those seen in the vismodegib/pirfenidone trial mentioned above.

Seven patients (33%) had treatment-emergent events leading to dose interruption. Five patients discontinued treatment: one who withdrew because of taste alterations, one who was lost to follow-up after an IPF exacerbation, and three who withdrew consent.

There were no treatment-related deaths, and no clinically significant findings on labs, vital signs, electrocardiograms, or physical exam.
 

Efficacy endpoints

An analysis of the secondary efficacy endpoints showed a 1.9% mean improvement in FVC from baseline among patients assigned to ENV-101, compared with a mean decline of 1.3% of patients assigned to placebo (P = .035).

Patients on the active drug also had a 200-mL mean increase in total lung capacity, compared with a mean decline of 56 mL for patients on placebo (P = .005).

In addition, high-resolution CR studies showed a 9.4% absolute decrease from baseline in quantitative interstitial lung disease with ENV-101, vs. a 1.1% increase among controls, a 2% absolute decline from baseline in quantitative lung fibrosis compared with a 0.87% increase with placebo, and a 4.6% absolute decrease from baseline in quantitative ground glass, compared with an increase of 0.29% with placebo.
 

Bad taste a good sign?

Reinoud Gosens PhD, University of Groningen, the Netherlands, who co-moderated the session but was not involved in the study, questioned whether the dysgeusia seen in patients who received ENV-101 might be related to the dysgeusia seen in clinical trials of P2X3 receptor antagonists for cough.

“I was wondering if there would be a mechanistic overlap between Hedgehog inhibition and cough, which would be quite relevant for IPF,” he said in an interview.

The increase in FVC seen with ENV-101 and with the investigational agent buloxibutid, a novel angiotensin II type 2 receptor agonist described in a separate presentation by Dr. Maher, suggests that these drugs may have the ability to help remodel damaged lungs, Dr. Gosens said.

Investigators are currently planning a phase 2 dose-ranging trial (WHISTLE-PF) in patients with IPF or progressive pulmonary fibrosis.

The phase 2a trial was supported by Endeavor BioMedicines. Dr. Maher disclosed consultancy or speaker fees from Endeavor and others. Dr. Gosens had no relevant disclosures.

Tell someone you’re a doctor, and the reaction is often: “You must be rich.” But physicians who are just finishing medical school or are in their early careers might feel far from it. The average medical school debt is more than $200,000, with total debts including undergrad climbing well north of $250,000.

That leaves house-hunting physicians in a predicament. A key factor for lending institutions is the “debt to income” ratio, a calculation which indicates if you already have too much debt to pay your mortgage. That single equation could eliminate you from lenders’ mortgage requirements.

But young doctors are also in a unique situation. Yes, they carry above-average levels of debt, but they are on a path to substantial income in future years. That’s where the physician mortgage loan (PML) becomes a useful option. 

What Is a Physician Mortgage Loan?

A PML is designed to help physicians access mortgages despite large amounts of debt. They are also sometimes available to dentists, veterinarians, podiatrists, and others, according to Stephen Chang, MD, a radiologist, and a managing director at Acts Financial Advisors in McLean, Virginia.

The key features, according to James M. Dahle, MD, an emergency physician and founder of The White Coat Investor, include:

• No required down payment, which is typically 20% with a conventional loan.
• No private mortgage insurance (PMI). This is often a requirement of traditional loans, designed to protect the lender if the buyer misses payments. PMLs don’t involve PMI even if you don’t put down 20%.
• No pay stubs. With a conventional loan, pay stubs are often required to prove income level and reliability. PMLs will often allow an employment contract in place of those. 
• Different consideration of the student loan burden.

Those are the upsides, of course, but there may be downsides. Dr. Dahle said a PML might involve slightly higher rates and fees than a conventional mortgage does but not always.

Who Is Best Suited for a Physician Mortgage Loan?

Financial advisers caution that everyone should first consider their full financial picture before applying for a mortgage, PML or otherwise. “If you don’t have the money saved for a down payment, one can ask if you are financially prepared to purchase a home,” says Cobin Soelberg, MD, an anesthesiologist and owner of Greeley Wealth Management, a financial planning firm serving physician families in Bend, Oregon. 

If your savings are slim, you might need to build those accounts further before pursuing home ownership and the expenses that come along with it.

Your credit score can contribute to the equation. “With any loan product, we always recommend working to optimize your personal credit score as soon as possible before applying for a loan,” said Mark P. Eid, MD, a dermatologist and co–managing director (with Dr. Chang) at Act Financial Advisors. “Once you get into the high 700s, you’ve typically qualified for the best interest rates, so while that perfect 850 is nice to achieve, it’s by no means necessary.”

Also, assess your reasons for purchasing a home and whether it will fit your lifestyle in the coming years. “The main reason that [my wife and I] wanted to buy a home was for stability,” said Jordan Frey, MD, founder of The Prudent Plastic Surgeon. “After living in apartments for years, we wanted a place that was truly our own. We definitely felt disappointed and frustrated when worrying that our student debt may limit our ability to do this.”

Like many physicians, Dr. Frey had taken on a huge amount of debt, to the tune of half a million dollars in student loans and credit card debt when he finished training in 2020. The question Dr. Frey and his wife wrestled with was: “How much debt should we take on in addition to what we already have?”

What Are the Risks? What’s in the Fine Print?

The eased limitations of PMLs come with potential pitfalls, and physicians should not imagine that they have unlimited buying power.

“Many physicians buy more expensive or bigger houses than they need simply because banks are willing to lend physicians money,” Dr. Soelberg warns. “So, the doctor gets locked into a large mortgage and cannot build wealth, save for retirement, and repay their student loans.” 

As you shop around, beware of omissions and scams. When meeting with lenders, Dr. Frey recalled that some didn’t even present PMLs as an option, and others presented them with unfavorable terms. He was careful to look for disadvantages hidden in the fine print, such as a potential “big hike in the rate a year later.” 

But sometimes, a scam is not outright deception but is more like temptation. So it’s important to have your own best interests in mind without relying on lenders’ advice. 

“When we were shopping around, some mortgage lenders would [offer] $1.5 million, and we thought ‘that makes no sense,’ ” said Dr. Frey. “[Physicians] have big future income, which makes us attractive to these lenders. No one in their right mind would give a mortgage like this to anyone else. They aren’t worried about whether it’s a smart decision for you or not.” 

What Other Red Flags Should You Look Out for?

Dr. Frey recommends medical professionals beware of these red flags when shopping for PMLs:

• A request for any type of collateral, including your medical practice
• A rate that is much higher than others
• A lender is pushing you to borrow a higher amount than you’re comfortable with 
• A lender attempts to influence your decision about the size of your down payment

Remember, if you are choosing an adjustable-rate mortgage (ARM), your rate will recalibrate on the basis of the market’s rates — for better or worse. This means that your payment might be higher or lower, taking current interest rates into account, based on the market.

Looking back, Dr. Frey said he might reconsider his decision to use a 10-year ARM. He and his wife chose it because the rate was low at the time, and they planned to pay off the mortgage quickly or move before it went up. But the uncertainty added an element of pressure. 

How Can PMLs Contribute to Overall Financial Health?

Dr. Frey says his physician mortgage was “a huge advantage,” allowing him and his wife to put 0% down on their home without PMI. But most importantly, it fit within their overall financial plan, which included investing. “The money that we would have potentially used for a down payment, we used to buy a rental property, which then got us more income,” he says. 

Of course, buying a rental property is not the only path to financial health and freedom. Many people approach a home as an investment that will eventually become fully their own. Others might put that down payment toward building a safety net of savings accounts. 

Used strategically and intentionally, PMLs can put you on a more predictable financial path. And with less money stress, buying a home can be an exciting milestone as you plan your future and put down roots in a community.

A version of this article appeared on Medscape.com.

Tell someone you’re a doctor, and the reaction is often: “You must be rich.” But physicians who are just finishing medical school or are in their early careers might feel far from it. The average medical school debt is more than $200,000, with total debts including undergrad climbing well north of $250,000.

That leaves house-hunting physicians in a predicament. A key factor for lending institutions is the “debt to income” ratio, a calculation which indicates if you already have too much debt to pay your mortgage. That single equation could eliminate you from lenders’ mortgage requirements.

But young doctors are also in a unique situation. Yes, they carry above-average levels of debt, but they are on a path to substantial income in future years. That’s where the physician mortgage loan (PML) becomes a useful option. 

What Is a Physician Mortgage Loan?

A PML is designed to help physicians access mortgages despite large amounts of debt. They are also sometimes available to dentists, veterinarians, podiatrists, and others, according to Stephen Chang, MD, a radiologist, and a managing director at Acts Financial Advisors in McLean, Virginia.

The key features, according to James M. Dahle, MD, an emergency physician and founder of The White Coat Investor, include:

• No required down payment, which is typically 20% with a conventional loan.
• No private mortgage insurance (PMI). This is often a requirement of traditional loans, designed to protect the lender if the buyer misses payments. PMLs don’t involve PMI even if you don’t put down 20%.
• No pay stubs. With a conventional loan, pay stubs are often required to prove income level and reliability. PMLs will often allow an employment contract in place of those. 
• Different consideration of the student loan burden.

Those are the upsides, of course, but there may be downsides. Dr. Dahle said a PML might involve slightly higher rates and fees than a conventional mortgage does but not always.

Who Is Best Suited for a Physician Mortgage Loan?

Financial advisers caution that everyone should first consider their full financial picture before applying for a mortgage, PML or otherwise. “If you don’t have the money saved for a down payment, one can ask if you are financially prepared to purchase a home,” says Cobin Soelberg, MD, an anesthesiologist and owner of Greeley Wealth Management, a financial planning firm serving physician families in Bend, Oregon. 

If your savings are slim, you might need to build those accounts further before pursuing home ownership and the expenses that come along with it.

Your credit score can contribute to the equation. “With any loan product, we always recommend working to optimize your personal credit score as soon as possible before applying for a loan,” said Mark P. Eid, MD, a dermatologist and co–managing director (with Dr. Chang) at Act Financial Advisors. “Once you get into the high 700s, you’ve typically qualified for the best interest rates, so while that perfect 850 is nice to achieve, it’s by no means necessary.”

Also, assess your reasons for purchasing a home and whether it will fit your lifestyle in the coming years. “The main reason that [my wife and I] wanted to buy a home was for stability,” said Jordan Frey, MD, founder of The Prudent Plastic Surgeon. “After living in apartments for years, we wanted a place that was truly our own. We definitely felt disappointed and frustrated when worrying that our student debt may limit our ability to do this.”

Like many physicians, Dr. Frey had taken on a huge amount of debt, to the tune of half a million dollars in student loans and credit card debt when he finished training in 2020. The question Dr. Frey and his wife wrestled with was: “How much debt should we take on in addition to what we already have?”

What Are the Risks? What’s in the Fine Print?

The eased limitations of PMLs come with potential pitfalls, and physicians should not imagine that they have unlimited buying power.

“Many physicians buy more expensive or bigger houses than they need simply because banks are willing to lend physicians money,” Dr. Soelberg warns. “So, the doctor gets locked into a large mortgage and cannot build wealth, save for retirement, and repay their student loans.” 

As you shop around, beware of omissions and scams. When meeting with lenders, Dr. Frey recalled that some didn’t even present PMLs as an option, and others presented them with unfavorable terms. He was careful to look for disadvantages hidden in the fine print, such as a potential “big hike in the rate a year later.” 

But sometimes, a scam is not outright deception but is more like temptation. So it’s important to have your own best interests in mind without relying on lenders’ advice. 

“When we were shopping around, some mortgage lenders would [offer] $1.5 million, and we thought ‘that makes no sense,’ ” said Dr. Frey. “[Physicians] have big future income, which makes us attractive to these lenders. No one in their right mind would give a mortgage like this to anyone else. They aren’t worried about whether it’s a smart decision for you or not.” 

What Other Red Flags Should You Look Out for?

Dr. Frey recommends medical professionals beware of these red flags when shopping for PMLs:

• A request for any type of collateral, including your medical practice
• A rate that is much higher than others
• A lender is pushing you to borrow a higher amount than you’re comfortable with 
• A lender attempts to influence your decision about the size of your down payment

Remember, if you are choosing an adjustable-rate mortgage (ARM), your rate will recalibrate on the basis of the market’s rates — for better or worse. This means that your payment might be higher or lower, taking current interest rates into account, based on the market.

Looking back, Dr. Frey said he might reconsider his decision to use a 10-year ARM. He and his wife chose it because the rate was low at the time, and they planned to pay off the mortgage quickly or move before it went up. But the uncertainty added an element of pressure. 

How Can PMLs Contribute to Overall Financial Health?

Dr. Frey says his physician mortgage was “a huge advantage,” allowing him and his wife to put 0% down on their home without PMI. But most importantly, it fit within their overall financial plan, which included investing. “The money that we would have potentially used for a down payment, we used to buy a rental property, which then got us more income,” he says. 

Of course, buying a rental property is not the only path to financial health and freedom. Many people approach a home as an investment that will eventually become fully their own. Others might put that down payment toward building a safety net of savings accounts. 

Used strategically and intentionally, PMLs can put you on a more predictable financial path. And with less money stress, buying a home can be an exciting milestone as you plan your future and put down roots in a community.

A version of this article appeared on Medscape.com.

Tell someone you’re a doctor, and the reaction is often: “You must be rich.” But physicians who are just finishing medical school or are in their early careers might feel far from it. The average medical school debt is more than $200,000, with total debts including undergrad climbing well north of $250,000.

That leaves house-hunting physicians in a predicament. A key factor for lending institutions is the “debt to income” ratio, a calculation which indicates if you already have too much debt to pay your mortgage. That single equation could eliminate you from lenders’ mortgage requirements.

But young doctors are also in a unique situation. Yes, they carry above-average levels of debt, but they are on a path to substantial income in future years. That’s where the physician mortgage loan (PML) becomes a useful option. 

What Is a Physician Mortgage Loan?

A PML is designed to help physicians access mortgages despite large amounts of debt. They are also sometimes available to dentists, veterinarians, podiatrists, and others, according to Stephen Chang, MD, a radiologist, and a managing director at Acts Financial Advisors in McLean, Virginia.

The key features, according to James M. Dahle, MD, an emergency physician and founder of The White Coat Investor, include:

• No required down payment, which is typically 20% with a conventional loan.
• No private mortgage insurance (PMI). This is often a requirement of traditional loans, designed to protect the lender if the buyer misses payments. PMLs don’t involve PMI even if you don’t put down 20%.
• No pay stubs. With a conventional loan, pay stubs are often required to prove income level and reliability. PMLs will often allow an employment contract in place of those. 
• Different consideration of the student loan burden.

Those are the upsides, of course, but there may be downsides. Dr. Dahle said a PML might involve slightly higher rates and fees than a conventional mortgage does but not always.

Who Is Best Suited for a Physician Mortgage Loan?

Financial advisers caution that everyone should first consider their full financial picture before applying for a mortgage, PML or otherwise. “If you don’t have the money saved for a down payment, one can ask if you are financially prepared to purchase a home,” says Cobin Soelberg, MD, an anesthesiologist and owner of Greeley Wealth Management, a financial planning firm serving physician families in Bend, Oregon. 

If your savings are slim, you might need to build those accounts further before pursuing home ownership and the expenses that come along with it.

Your credit score can contribute to the equation. “With any loan product, we always recommend working to optimize your personal credit score as soon as possible before applying for a loan,” said Mark P. Eid, MD, a dermatologist and co–managing director (with Dr. Chang) at Act Financial Advisors. “Once you get into the high 700s, you’ve typically qualified for the best interest rates, so while that perfect 850 is nice to achieve, it’s by no means necessary.”

Also, assess your reasons for purchasing a home and whether it will fit your lifestyle in the coming years. “The main reason that [my wife and I] wanted to buy a home was for stability,” said Jordan Frey, MD, founder of The Prudent Plastic Surgeon. “After living in apartments for years, we wanted a place that was truly our own. We definitely felt disappointed and frustrated when worrying that our student debt may limit our ability to do this.”

Like many physicians, Dr. Frey had taken on a huge amount of debt, to the tune of half a million dollars in student loans and credit card debt when he finished training in 2020. The question Dr. Frey and his wife wrestled with was: “How much debt should we take on in addition to what we already have?”

What Are the Risks? What’s in the Fine Print?

The eased limitations of PMLs come with potential pitfalls, and physicians should not imagine that they have unlimited buying power.

“Many physicians buy more expensive or bigger houses than they need simply because banks are willing to lend physicians money,” Dr. Soelberg warns. “So, the doctor gets locked into a large mortgage and cannot build wealth, save for retirement, and repay their student loans.” 

As you shop around, beware of omissions and scams. When meeting with lenders, Dr. Frey recalled that some didn’t even present PMLs as an option, and others presented them with unfavorable terms. He was careful to look for disadvantages hidden in the fine print, such as a potential “big hike in the rate a year later.” 

But sometimes, a scam is not outright deception but is more like temptation. So it’s important to have your own best interests in mind without relying on lenders’ advice. 

“When we were shopping around, some mortgage lenders would [offer] $1.5 million, and we thought ‘that makes no sense,’ ” said Dr. Frey. “[Physicians] have big future income, which makes us attractive to these lenders. No one in their right mind would give a mortgage like this to anyone else. They aren’t worried about whether it’s a smart decision for you or not.” 

What Other Red Flags Should You Look Out for?

Dr. Frey recommends medical professionals beware of these red flags when shopping for PMLs:

• A request for any type of collateral, including your medical practice
• A rate that is much higher than others
• A lender is pushing you to borrow a higher amount than you’re comfortable with 
• A lender attempts to influence your decision about the size of your down payment

Remember, if you are choosing an adjustable-rate mortgage (ARM), your rate will recalibrate on the basis of the market’s rates — for better or worse. This means that your payment might be higher or lower, taking current interest rates into account, based on the market.

Looking back, Dr. Frey said he might reconsider his decision to use a 10-year ARM. He and his wife chose it because the rate was low at the time, and they planned to pay off the mortgage quickly or move before it went up. But the uncertainty added an element of pressure. 

How Can PMLs Contribute to Overall Financial Health?

Dr. Frey says his physician mortgage was “a huge advantage,” allowing him and his wife to put 0% down on their home without PMI. But most importantly, it fit within their overall financial plan, which included investing. “The money that we would have potentially used for a down payment, we used to buy a rental property, which then got us more income,” he says. 

Of course, buying a rental property is not the only path to financial health and freedom. Many people approach a home as an investment that will eventually become fully their own. Others might put that down payment toward building a safety net of savings accounts. 

Used strategically and intentionally, PMLs can put you on a more predictable financial path. And with less money stress, buying a home can be an exciting milestone as you plan your future and put down roots in a community.

A version of this article appeared on Medscape.com.

BASEL, SWITZERLAND — Early reduction of blood pressure has a beneficial effect in hemorrhagic stroke but a detrimental effect in ischemic stroke, new trial data show. The findings could shake up recommendations on control of blood pressure in acute stroke patients. 

“This is the first time that we have randomized evidence of blood pressure control prior to reperfusion in ischemic stroke patients, and our data will challenge the current guidelines that recommend lowering blood pressure to below 180 mm Hg systolic in these patients,” said study coauthor Craig Anderson, MD, George Institute for Global Health, Sydney, Australia. 

“And this study also clearly shows for the first time that getting blood pressure under control in hemorrhagic stroke patients in the first couple of hours has definitive benefits,” he added.

The findings were presented on May 16 at the European Stroke Organization Conference (ESOC) annual meeting and published online simultaneously in The New England Journal of Medicine. 

A Test of Early BP Control

The trial was conducted to test the strategy of very early blood pressure control during patient transport in an ambulance after acute stroke, which investigators suspected could benefit patients with both types of stroke. 

The hypothesis was that this would reduce bleeding in the brain for those with hemorrhagic stroke. For ischemic stroke patients, it was thought this strategy would speed up administration of thrombolysis, because guidelines recommend bringing blood pressure under control before thrombolysis. 

For the INTERACT4 trial, which was conducted in China, 2404 patients with suspected acute stroke and elevated systolic blood pressure (≥ 150 mm Hg) who were assessed in the ambulance within 2 hours after symptom onset were randomized to receive immediate treatment with intravenous urapidil to lower the systolic blood pressure or usual blood pressure management (usual care group).

The median time between symptom onset and randomization was 61 minutes, and the mean blood pressure at randomization was 178/98 mm Hg. 

Stroke was subsequently confirmed by imaging in 2240 patients, of whom 46% had a hemorrhagic stroke and 54% an ischemic stroke. 

At the time of arrival at the hospital, the mean systolic blood pressure in the intervention group was 158 mm Hg, compared with 170 mm Hg in the usual care group. 

The primary efficacy outcome was functional status as assessed by modified Rankin scale score at 90 days. 

Overall, there was no difference between the two groups in terms of functional outcome scores (common odds ratio [OR], 1.00; 95% CI, 0.87-1.15), and the incidence of serious adverse events was similar. 

But the study showed very different results in patients with hemorrhagic stroke vs those with ischemic stroke. 

Prehospital reduction of blood pressure was associated with a decrease in the odds of a poor functional outcome among patients with hemorrhagic stroke (common OR, 0.75; 95% CI, 0.60-0.92) but an increase in poor outcomes among patients with cerebral ischemia (common OR, 1.30; 95% CI, 1.06-1.60).

‘Slam-Dunk’ Effect 

Anderson has led several previous trials of blood pressure control in stroke patients, some of which have suggested benefit of lowering blood pressure in those with hemorrhagic stroke, but he says the results of the current trial are more clear-cut.

“We have never seen such a slam-dunk effect as there was in INTERACT4,” Dr. Anderson said. “Not only did we show that early reduction of blood pressure in hemorrhagic stroke patients improved functional outcome, it also reduced bleeding in the brain, improved survival and quality of life, and reduced surgery and infection complications. That’s quite remarkable.”

The findings offer “clear evidence that for patients with hemorrhagic stroke, we must get the blood pressure under control as soon as possible and introduce systems of care to ensure this happens,” he added.

The reason for the clear findings in the current trial is probably the treatment time, Dr. Anderson said. 

“This is the first trial in which blood pressure has been controlled in the ambulance and occurred much earlier than in the previous trials.” 

Challenging Ischemic Stroke Guidelines

The INTERACT4 results in ischemic stroke patients are likely to be more controversial. 

“Our results are clearly challenging longstanding beliefs around blood pressure control in ischemic stroke prior to thrombolysis,” Dr. Anderson said. 

Current guidelines recommend a blood pressure < 185 mm Hg systolic before initiation of thrombolysis because of concerns about intracerebral hemorrhage, he noted. Often, blood pressure is lowered rapidly down to much lower levels in order give thrombolysis quickly. 

“Our results suggest this may not be a good idea,” Dr. Anderson said. “I think these data will shake us up a bit and make us more cautious about reducing blood pressure in these patients. Personally, I wouldn’t touch the blood pressure at all in ischemic stroke patients after these results.” 

He said the mechanisms behind the different stroke types would explain the results. 

“If a patient is bleeding, it makes sense that higher blood pressure would make that worse,” Dr. Anderson said. “But when a patient has a blocked artery and ischemia in the brain, it seems likely that the extra pressure is needed to keep oxygen delivery to the ischemic tissue.”

Accurate Diagnosis Necessary

Because it is not possible to make an accurate diagnosis between ischemic and hemorrhagic stroke without a CT scan, Dr. Anderson stressed that at the present time, no action on blood pressure can be taken in the ambulance. 

“There is a lot of interest in developing a lightweight brain scanner to be used in ambulances, but this won’t be routinely available for several years,” he said. “So for now, quick diagnosis of the type of stroke that is occurring on the patient’s arrival at the emergency department and, for hemorrhagic stroke patients, swift action to control blood pressure at this point is critical to preserving brain function.”

Commenting on the INTERACT4 results at the ESOC meeting, Simona Sacco, MD, professor of neurology at the University of L’Aquila, Italy, said this was a very important trial that would impact clinical practice. 

“The data really reinforce that hemorrhagic stroke patients must have their blood pressure reduced as soon as possible,” she stated. 

Dr. Sacco said the trial emphasizes the need to be able to distinguish between a hemorrhagic and ischemic stroke in a prehospital setting and supports the introduction of more mobile stroke units carrying CT scanners and calls for the development of biomarkers that can allow rapid differentiation between the two conditions. 

In an accompanying editorial, Jonathan Edlow, MD, Department of Emergency Medicine, Beth Israel Deaconess Medical Center, Boston, points out several aspects of the trial that may potentially limit the generalizability of the findings. These include use of urapidil as the antihypertensive agent, which is unavailable in the United States; all patients being of Han Chinese ethnicity; and an unusually high sensitivity of initial CT scans in detecting visible signs of ischemia or infarction in patients in acute ischemic stroke. 

“These findings should be considered hypothesis-generating, and they make the case for validation of the trial results in other settings,” Dr. Edlow wrote. 

The INTERACT4 trial was funded by the National Health and Medical Research Council of Australia, the George Institute for Global Health, several Chinese healthcare institutions, and Takeda Pharmaceuticals China. Disclosures for study and editorial authors are provided in the original articles.

A version of this article appeared on Medscape.com.

BASEL, SWITZERLAND — Early reduction of blood pressure has a beneficial effect in hemorrhagic stroke but a detrimental effect in ischemic stroke, new trial data show. The findings could shake up recommendations on control of blood pressure in acute stroke patients. 

“This is the first time that we have randomized evidence of blood pressure control prior to reperfusion in ischemic stroke patients, and our data will challenge the current guidelines that recommend lowering blood pressure to below 180 mm Hg systolic in these patients,” said study coauthor Craig Anderson, MD, George Institute for Global Health, Sydney, Australia. 

“And this study also clearly shows for the first time that getting blood pressure under control in hemorrhagic stroke patients in the first couple of hours has definitive benefits,” he added.

The findings were presented on May 16 at the European Stroke Organization Conference (ESOC) annual meeting and published online simultaneously in The New England Journal of Medicine. 

A Test of Early BP Control

The trial was conducted to test the strategy of very early blood pressure control during patient transport in an ambulance after acute stroke, which investigators suspected could benefit patients with both types of stroke. 

The hypothesis was that this would reduce bleeding in the brain for those with hemorrhagic stroke. For ischemic stroke patients, it was thought this strategy would speed up administration of thrombolysis, because guidelines recommend bringing blood pressure under control before thrombolysis. 

For the INTERACT4 trial, which was conducted in China, 2404 patients with suspected acute stroke and elevated systolic blood pressure (≥ 150 mm Hg) who were assessed in the ambulance within 2 hours after symptom onset were randomized to receive immediate treatment with intravenous urapidil to lower the systolic blood pressure or usual blood pressure management (usual care group).

The median time between symptom onset and randomization was 61 minutes, and the mean blood pressure at randomization was 178/98 mm Hg. 

Stroke was subsequently confirmed by imaging in 2240 patients, of whom 46% had a hemorrhagic stroke and 54% an ischemic stroke. 

At the time of arrival at the hospital, the mean systolic blood pressure in the intervention group was 158 mm Hg, compared with 170 mm Hg in the usual care group. 

The primary efficacy outcome was functional status as assessed by modified Rankin scale score at 90 days. 

Overall, there was no difference between the two groups in terms of functional outcome scores (common odds ratio [OR], 1.00; 95% CI, 0.87-1.15), and the incidence of serious adverse events was similar. 

But the study showed very different results in patients with hemorrhagic stroke vs those with ischemic stroke. 

Prehospital reduction of blood pressure was associated with a decrease in the odds of a poor functional outcome among patients with hemorrhagic stroke (common OR, 0.75; 95% CI, 0.60-0.92) but an increase in poor outcomes among patients with cerebral ischemia (common OR, 1.30; 95% CI, 1.06-1.60).

‘Slam-Dunk’ Effect 

Anderson has led several previous trials of blood pressure control in stroke patients, some of which have suggested benefit of lowering blood pressure in those with hemorrhagic stroke, but he says the results of the current trial are more clear-cut.

“We have never seen such a slam-dunk effect as there was in INTERACT4,” Dr. Anderson said. “Not only did we show that early reduction of blood pressure in hemorrhagic stroke patients improved functional outcome, it also reduced bleeding in the brain, improved survival and quality of life, and reduced surgery and infection complications. That’s quite remarkable.”

The findings offer “clear evidence that for patients with hemorrhagic stroke, we must get the blood pressure under control as soon as possible and introduce systems of care to ensure this happens,” he added.

The reason for the clear findings in the current trial is probably the treatment time, Dr. Anderson said. 

“This is the first trial in which blood pressure has been controlled in the ambulance and occurred much earlier than in the previous trials.” 

Challenging Ischemic Stroke Guidelines

The INTERACT4 results in ischemic stroke patients are likely to be more controversial. 

“Our results are clearly challenging longstanding beliefs around blood pressure control in ischemic stroke prior to thrombolysis,” Dr. Anderson said. 

Current guidelines recommend a blood pressure < 185 mm Hg systolic before initiation of thrombolysis because of concerns about intracerebral hemorrhage, he noted. Often, blood pressure is lowered rapidly down to much lower levels in order give thrombolysis quickly. 

“Our results suggest this may not be a good idea,” Dr. Anderson said. “I think these data will shake us up a bit and make us more cautious about reducing blood pressure in these patients. Personally, I wouldn’t touch the blood pressure at all in ischemic stroke patients after these results.” 

He said the mechanisms behind the different stroke types would explain the results. 

“If a patient is bleeding, it makes sense that higher blood pressure would make that worse,” Dr. Anderson said. “But when a patient has a blocked artery and ischemia in the brain, it seems likely that the extra pressure is needed to keep oxygen delivery to the ischemic tissue.”

Accurate Diagnosis Necessary

Because it is not possible to make an accurate diagnosis between ischemic and hemorrhagic stroke without a CT scan, Dr. Anderson stressed that at the present time, no action on blood pressure can be taken in the ambulance. 

“There is a lot of interest in developing a lightweight brain scanner to be used in ambulances, but this won’t be routinely available for several years,” he said. “So for now, quick diagnosis of the type of stroke that is occurring on the patient’s arrival at the emergency department and, for hemorrhagic stroke patients, swift action to control blood pressure at this point is critical to preserving brain function.”

Commenting on the INTERACT4 results at the ESOC meeting, Simona Sacco, MD, professor of neurology at the University of L’Aquila, Italy, said this was a very important trial that would impact clinical practice. 

“The data really reinforce that hemorrhagic stroke patients must have their blood pressure reduced as soon as possible,” she stated. 

Dr. Sacco said the trial emphasizes the need to be able to distinguish between a hemorrhagic and ischemic stroke in a prehospital setting and supports the introduction of more mobile stroke units carrying CT scanners and calls for the development of biomarkers that can allow rapid differentiation between the two conditions. 

In an accompanying editorial, Jonathan Edlow, MD, Department of Emergency Medicine, Beth Israel Deaconess Medical Center, Boston, points out several aspects of the trial that may potentially limit the generalizability of the findings. These include use of urapidil as the antihypertensive agent, which is unavailable in the United States; all patients being of Han Chinese ethnicity; and an unusually high sensitivity of initial CT scans in detecting visible signs of ischemia or infarction in patients in acute ischemic stroke. 

“These findings should be considered hypothesis-generating, and they make the case for validation of the trial results in other settings,” Dr. Edlow wrote. 

The INTERACT4 trial was funded by the National Health and Medical Research Council of Australia, the George Institute for Global Health, several Chinese healthcare institutions, and Takeda Pharmaceuticals China. Disclosures for study and editorial authors are provided in the original articles.

A version of this article appeared on Medscape.com.

BASEL, SWITZERLAND — Early reduction of blood pressure has a beneficial effect in hemorrhagic stroke but a detrimental effect in ischemic stroke, new trial data show. The findings could shake up recommendations on control of blood pressure in acute stroke patients. 

“This is the first time that we have randomized evidence of blood pressure control prior to reperfusion in ischemic stroke patients, and our data will challenge the current guidelines that recommend lowering blood pressure to below 180 mm Hg systolic in these patients,” said study coauthor Craig Anderson, MD, George Institute for Global Health, Sydney, Australia. 

“And this study also clearly shows for the first time that getting blood pressure under control in hemorrhagic stroke patients in the first couple of hours has definitive benefits,” he added.

The findings were presented on May 16 at the European Stroke Organization Conference (ESOC) annual meeting and published online simultaneously in The New England Journal of Medicine. 

A Test of Early BP Control

The trial was conducted to test the strategy of very early blood pressure control during patient transport in an ambulance after acute stroke, which investigators suspected could benefit patients with both types of stroke. 

The hypothesis was that this would reduce bleeding in the brain for those with hemorrhagic stroke. For ischemic stroke patients, it was thought this strategy would speed up administration of thrombolysis, because guidelines recommend bringing blood pressure under control before thrombolysis. 

For the INTERACT4 trial, which was conducted in China, 2404 patients with suspected acute stroke and elevated systolic blood pressure (≥ 150 mm Hg) who were assessed in the ambulance within 2 hours after symptom onset were randomized to receive immediate treatment with intravenous urapidil to lower the systolic blood pressure or usual blood pressure management (usual care group).

The median time between symptom onset and randomization was 61 minutes, and the mean blood pressure at randomization was 178/98 mm Hg. 

Stroke was subsequently confirmed by imaging in 2240 patients, of whom 46% had a hemorrhagic stroke and 54% an ischemic stroke. 

At the time of arrival at the hospital, the mean systolic blood pressure in the intervention group was 158 mm Hg, compared with 170 mm Hg in the usual care group. 

The primary efficacy outcome was functional status as assessed by modified Rankin scale score at 90 days. 

Overall, there was no difference between the two groups in terms of functional outcome scores (common odds ratio [OR], 1.00; 95% CI, 0.87-1.15), and the incidence of serious adverse events was similar. 

But the study showed very different results in patients with hemorrhagic stroke vs those with ischemic stroke. 

Prehospital reduction of blood pressure was associated with a decrease in the odds of a poor functional outcome among patients with hemorrhagic stroke (common OR, 0.75; 95% CI, 0.60-0.92) but an increase in poor outcomes among patients with cerebral ischemia (common OR, 1.30; 95% CI, 1.06-1.60).

‘Slam-Dunk’ Effect 

Anderson has led several previous trials of blood pressure control in stroke patients, some of which have suggested benefit of lowering blood pressure in those with hemorrhagic stroke, but he says the results of the current trial are more clear-cut.

“We have never seen such a slam-dunk effect as there was in INTERACT4,” Dr. Anderson said. “Not only did we show that early reduction of blood pressure in hemorrhagic stroke patients improved functional outcome, it also reduced bleeding in the brain, improved survival and quality of life, and reduced surgery and infection complications. That’s quite remarkable.”

The findings offer “clear evidence that for patients with hemorrhagic stroke, we must get the blood pressure under control as soon as possible and introduce systems of care to ensure this happens,” he added.

The reason for the clear findings in the current trial is probably the treatment time, Dr. Anderson said. 

“This is the first trial in which blood pressure has been controlled in the ambulance and occurred much earlier than in the previous trials.” 

Challenging Ischemic Stroke Guidelines

The INTERACT4 results in ischemic stroke patients are likely to be more controversial. 

“Our results are clearly challenging longstanding beliefs around blood pressure control in ischemic stroke prior to thrombolysis,” Dr. Anderson said. 

Current guidelines recommend a blood pressure < 185 mm Hg systolic before initiation of thrombolysis because of concerns about intracerebral hemorrhage, he noted. Often, blood pressure is lowered rapidly down to much lower levels in order give thrombolysis quickly. 

“Our results suggest this may not be a good idea,” Dr. Anderson said. “I think these data will shake us up a bit and make us more cautious about reducing blood pressure in these patients. Personally, I wouldn’t touch the blood pressure at all in ischemic stroke patients after these results.” 

He said the mechanisms behind the different stroke types would explain the results. 

“If a patient is bleeding, it makes sense that higher blood pressure would make that worse,” Dr. Anderson said. “But when a patient has a blocked artery and ischemia in the brain, it seems likely that the extra pressure is needed to keep oxygen delivery to the ischemic tissue.”

Accurate Diagnosis Necessary

Because it is not possible to make an accurate diagnosis between ischemic and hemorrhagic stroke without a CT scan, Dr. Anderson stressed that at the present time, no action on blood pressure can be taken in the ambulance. 

“There is a lot of interest in developing a lightweight brain scanner to be used in ambulances, but this won’t be routinely available for several years,” he said. “So for now, quick diagnosis of the type of stroke that is occurring on the patient’s arrival at the emergency department and, for hemorrhagic stroke patients, swift action to control blood pressure at this point is critical to preserving brain function.”

Commenting on the INTERACT4 results at the ESOC meeting, Simona Sacco, MD, professor of neurology at the University of L’Aquila, Italy, said this was a very important trial that would impact clinical practice. 

“The data really reinforce that hemorrhagic stroke patients must have their blood pressure reduced as soon as possible,” she stated. 

Dr. Sacco said the trial emphasizes the need to be able to distinguish between a hemorrhagic and ischemic stroke in a prehospital setting and supports the introduction of more mobile stroke units carrying CT scanners and calls for the development of biomarkers that can allow rapid differentiation between the two conditions. 

In an accompanying editorial, Jonathan Edlow, MD, Department of Emergency Medicine, Beth Israel Deaconess Medical Center, Boston, points out several aspects of the trial that may potentially limit the generalizability of the findings. These include use of urapidil as the antihypertensive agent, which is unavailable in the United States; all patients being of Han Chinese ethnicity; and an unusually high sensitivity of initial CT scans in detecting visible signs of ischemia or infarction in patients in acute ischemic stroke. 

“These findings should be considered hypothesis-generating, and they make the case for validation of the trial results in other settings,” Dr. Edlow wrote. 

The INTERACT4 trial was funded by the National Health and Medical Research Council of Australia, the George Institute for Global Health, several Chinese healthcare institutions, and Takeda Pharmaceuticals China. Disclosures for study and editorial authors are provided in the original articles.

A version of this article appeared on Medscape.com.

For years, researchers and medical companies have explored low-field MRI systems (those with a magnetic field strength of less than 1 T) — searching for a feasible alternative to the loud, expensive machines requiring special rooms with shielding to block their powerful magnetic field.

Most low-field scanners in development are for brain scans only. In 2022, the US Food and Drug Administration (FDA) cleared the first portable MRI system — Hyperfine’s Swoop, designed for use at a patient’s bedside — for head and brain scans. But the technology has not been applied to whole-body MRI — until now.

In a new study published in Science, researchers from Hong Kong described a whole-body, ultra low–field MRI.

“This is a big breakthrough,” said Kevin Sheth, MD, director of the Yale Center for Brain & Mind Health, who was not involved in the study. “It is one of the first, if not the first, demonstrations of low-field MRI imaging for the entire body.”

The device uses a 0.05 T magnet — one sixtieth the magnetic field strength of the standard 3 T MRI model common in hospitals today, said lead author Ed Wu, PhD, professor of biomedical engineering at The University of Hong Kong.

Because the field strength is so low, no protective shielding is needed. Patients and bystanders can safely use smart phones . And the scanner is safe for patients with implanted devices, like a cochlear implant or pacemaker, or any metal on their body or clothes. No hearing protection is required, either, because the machine is so quiet.

If all goes well, the technology could be commercially available in as little as a few years, Dr. Wu said.

But first, funding and FDA approval would be needed. “A company is going to have to come along and say, ‘This looks fantastic. We’re going to commercialize this, and we’re going to go through this certification process,’ ” said Andrew Webb, PhD, professor of radiology and the founding director of the C.J. Gorter MRI Center at the Leiden University Medical Center, Leiden, the Netherlands. (Dr. Webb was not involved in the study.)
 

Improving Access to MRI

One hope for this technology is to bring MRI to more people worldwide. Africa has less than one MRI scanner per million residents, whereas the United States has about 40.

While a new 3 T machine can cost about $1 million, the low-field version is much cheaper — only about $22,000 in materials cost per scanner, according to Dr. Wu.

A low magnetic field means less electricity, too — the machine can be plugged into a standard wall outlet. And because a fully shielded room isn’t needed, that could save another $100,000 in materials, Dr. Webb said.

Its ease of use could improve accessibility in countries with limited training, Dr. Webb pointed out.

“To be a technician is 2-3 years training for a regular MRI machine, a lot of it to do safety, a lot of it to do very subtle planning,” said Webb. “These [low-field] systems are much simpler.”
 

Challenges and the Future

The prototype weighs about 1.5 tons or 3000 lb. (A 3 T MRI can weigh between 6 and 13 tons or 12,000 and 26,000 lb.) That might sound like a lot, but it’s comparable to a mobile CT scanner, which is designed to be moved from room to room. Plus, “its weight can be substantially reduced if further optimized,” Dr. Wu said.

One challenge with low-field MRIs is image quality, which tends to be not as clear and detailed as those from high-power machines. To address this, the research team used deep learning (artificial intelligence) to enhance the image quality. “Computing power and large-scale data underpin our success, which tackles the physics and math problems that are traditionally considered intractable in existing MRI methodology,” Dr. Wu said.

Dr. Webb said he was impressed by the image quality shown in the study. They “look much higher quality than you would expect from such a low-field system,” he said. Still, only healthy volunteers were scanned. The true test will be using it to view subtle pathologies, Dr. Webb said.

That’s what Dr. Wu and his team are working on now — taking scans to diagnose various medical conditions. His group’s brain-only version of the low-field MRI has been used for diagnosis, he noted.
 

A version of this article appeared on Medscape.com.

For years, researchers and medical companies have explored low-field MRI systems (those with a magnetic field strength of less than 1 T) — searching for a feasible alternative to the loud, expensive machines requiring special rooms with shielding to block their powerful magnetic field.

Most low-field scanners in development are for brain scans only. In 2022, the US Food and Drug Administration (FDA) cleared the first portable MRI system — Hyperfine’s Swoop, designed for use at a patient’s bedside — for head and brain scans. But the technology has not been applied to whole-body MRI — until now.

In a new study published in Science, researchers from Hong Kong described a whole-body, ultra low–field MRI.

“This is a big breakthrough,” said Kevin Sheth, MD, director of the Yale Center for Brain & Mind Health, who was not involved in the study. “It is one of the first, if not the first, demonstrations of low-field MRI imaging for the entire body.”

The device uses a 0.05 T magnet — one sixtieth the magnetic field strength of the standard 3 T MRI model common in hospitals today, said lead author Ed Wu, PhD, professor of biomedical engineering at The University of Hong Kong.

Because the field strength is so low, no protective shielding is needed. Patients and bystanders can safely use smart phones . And the scanner is safe for patients with implanted devices, like a cochlear implant or pacemaker, or any metal on their body or clothes. No hearing protection is required, either, because the machine is so quiet.

If all goes well, the technology could be commercially available in as little as a few years, Dr. Wu said.

But first, funding and FDA approval would be needed. “A company is going to have to come along and say, ‘This looks fantastic. We’re going to commercialize this, and we’re going to go through this certification process,’ ” said Andrew Webb, PhD, professor of radiology and the founding director of the C.J. Gorter MRI Center at the Leiden University Medical Center, Leiden, the Netherlands. (Dr. Webb was not involved in the study.)
 

Improving Access to MRI

One hope for this technology is to bring MRI to more people worldwide. Africa has less than one MRI scanner per million residents, whereas the United States has about 40.

While a new 3 T machine can cost about $1 million, the low-field version is much cheaper — only about $22,000 in materials cost per scanner, according to Dr. Wu.

A low magnetic field means less electricity, too — the machine can be plugged into a standard wall outlet. And because a fully shielded room isn’t needed, that could save another $100,000 in materials, Dr. Webb said.

Its ease of use could improve accessibility in countries with limited training, Dr. Webb pointed out.

“To be a technician is 2-3 years training for a regular MRI machine, a lot of it to do safety, a lot of it to do very subtle planning,” said Webb. “These [low-field] systems are much simpler.”
 

Challenges and the Future

The prototype weighs about 1.5 tons or 3000 lb. (A 3 T MRI can weigh between 6 and 13 tons or 12,000 and 26,000 lb.) That might sound like a lot, but it’s comparable to a mobile CT scanner, which is designed to be moved from room to room. Plus, “its weight can be substantially reduced if further optimized,” Dr. Wu said.

One challenge with low-field MRIs is image quality, which tends to be not as clear and detailed as those from high-power machines. To address this, the research team used deep learning (artificial intelligence) to enhance the image quality. “Computing power and large-scale data underpin our success, which tackles the physics and math problems that are traditionally considered intractable in existing MRI methodology,” Dr. Wu said.

Dr. Webb said he was impressed by the image quality shown in the study. They “look much higher quality than you would expect from such a low-field system,” he said. Still, only healthy volunteers were scanned. The true test will be using it to view subtle pathologies, Dr. Webb said.

That’s what Dr. Wu and his team are working on now — taking scans to diagnose various medical conditions. His group’s brain-only version of the low-field MRI has been used for diagnosis, he noted.
 

A version of this article appeared on Medscape.com.

For years, researchers and medical companies have explored low-field MRI systems (those with a magnetic field strength of less than 1 T) — searching for a feasible alternative to the loud, expensive machines requiring special rooms with shielding to block their powerful magnetic field.

Most low-field scanners in development are for brain scans only. In 2022, the US Food and Drug Administration (FDA) cleared the first portable MRI system — Hyperfine’s Swoop, designed for use at a patient’s bedside — for head and brain scans. But the technology has not been applied to whole-body MRI — until now.

In a new study published in Science, researchers from Hong Kong described a whole-body, ultra low–field MRI.

“This is a big breakthrough,” said Kevin Sheth, MD, director of the Yale Center for Brain & Mind Health, who was not involved in the study. “It is one of the first, if not the first, demonstrations of low-field MRI imaging for the entire body.”

The device uses a 0.05 T magnet — one sixtieth the magnetic field strength of the standard 3 T MRI model common in hospitals today, said lead author Ed Wu, PhD, professor of biomedical engineering at The University of Hong Kong.

Because the field strength is so low, no protective shielding is needed. Patients and bystanders can safely use smart phones . And the scanner is safe for patients with implanted devices, like a cochlear implant or pacemaker, or any metal on their body or clothes. No hearing protection is required, either, because the machine is so quiet.

If all goes well, the technology could be commercially available in as little as a few years, Dr. Wu said.

But first, funding and FDA approval would be needed. “A company is going to have to come along and say, ‘This looks fantastic. We’re going to commercialize this, and we’re going to go through this certification process,’ ” said Andrew Webb, PhD, professor of radiology and the founding director of the C.J. Gorter MRI Center at the Leiden University Medical Center, Leiden, the Netherlands. (Dr. Webb was not involved in the study.)
 

Improving Access to MRI

One hope for this technology is to bring MRI to more people worldwide. Africa has less than one MRI scanner per million residents, whereas the United States has about 40.

While a new 3 T machine can cost about $1 million, the low-field version is much cheaper — only about $22,000 in materials cost per scanner, according to Dr. Wu.

A low magnetic field means less electricity, too — the machine can be plugged into a standard wall outlet. And because a fully shielded room isn’t needed, that could save another $100,000 in materials, Dr. Webb said.

Its ease of use could improve accessibility in countries with limited training, Dr. Webb pointed out.

“To be a technician is 2-3 years training for a regular MRI machine, a lot of it to do safety, a lot of it to do very subtle planning,” said Webb. “These [low-field] systems are much simpler.”
 

Challenges and the Future

The prototype weighs about 1.5 tons or 3000 lb. (A 3 T MRI can weigh between 6 and 13 tons or 12,000 and 26,000 lb.) That might sound like a lot, but it’s comparable to a mobile CT scanner, which is designed to be moved from room to room. Plus, “its weight can be substantially reduced if further optimized,” Dr. Wu said.

One challenge with low-field MRIs is image quality, which tends to be not as clear and detailed as those from high-power machines. To address this, the research team used deep learning (artificial intelligence) to enhance the image quality. “Computing power and large-scale data underpin our success, which tackles the physics and math problems that are traditionally considered intractable in existing MRI methodology,” Dr. Wu said.

Dr. Webb said he was impressed by the image quality shown in the study. They “look much higher quality than you would expect from such a low-field system,” he said. Still, only healthy volunteers were scanned. The true test will be using it to view subtle pathologies, Dr. Webb said.

That’s what Dr. Wu and his team are working on now — taking scans to diagnose various medical conditions. His group’s brain-only version of the low-field MRI has been used for diagnosis, he noted.
 

A version of this article appeared on Medscape.com.

For decades, physicians and nurses who ventured across state lines to practice, particularly in locum tenens roles, have reaped the benefits of medical licensure compacts. Yet, the same courtesy has eluded physician assistants (PAs), until now. The introduction of the PA Licensure Compact (PA Compact) marks a long-awaited and significant step forward for the PA community.

In April, Virginia Governor Glenn Youngkin signed the bill enacting the PA Compact making Virginia the seventh state to join. The legislation opens a cross-state agreement with seven states and finally allows locum tenens PAs to practice across these state’s borders.

How the PA Compact Works

The interstate arrangement recognizes valid, unencumbered PA licenses issued by other states in the compact. PAs working within the seven states won’t need a separate license from any of those states to practice.

The states include Delaware, Nebraska, Utah, Washington, West Virginia, Wisconsin, and Virginia. While the compact has been approved, the American Academy of Physician Associates said it could take an additional 18-24 months for the states to execute it, giving PAs the access they need to work in the compact states.

How the PA Compact Helps

The PA Compact holds the promise of alleviating some of the travel barriers that PAs often encounter, especially when they work locum tenens or in telehealth and must traverse state lines to deliver essential healthcare. This agreement not only enhances healthcare access but also empowers facilities to recruit new PAs, thereby bridging gaps in their healthcare staffing and addressing public health emergencies more effectively.

PAs will also gain increased flexibility and additional opportunities to earn and benefit from the right to practice in more states without requiring a time-consuming and expensive licensure from each state.

One motivating factor behind developing an interstate compact for physician assistants is that the same types of compacts for physicians and nurses are highly successful. The Nurse Licensure Compact and the Interstate Medical Licensure Compact for physicians encompass 37 and 41 states, respectively. While the seven-state PA Compact is in its earliest stages, it will likely be equally beneficial for PAs.

A survey by Barton Associates found that 95% of PAs said they would be more likely to consider working in a different state if the PA Compact made it more accessible.

Other states have begun legislation to enact a PA Compact, including Colorado, New Hampshire, Maine, Michigan New York, Ohio, Oklahoma, Rhode Island, Tennessee, and Vermont. 

If your state still needs to enact a compact or file for compact legislation, let your elected officials know that the PAs in your state want to join a compact. 
 

A version of this article appeared on Medscape.com .

For decades, physicians and nurses who ventured across state lines to practice, particularly in locum tenens roles, have reaped the benefits of medical licensure compacts. Yet, the same courtesy has eluded physician assistants (PAs), until now. The introduction of the PA Licensure Compact (PA Compact) marks a long-awaited and significant step forward for the PA community.

In April, Virginia Governor Glenn Youngkin signed the bill enacting the PA Compact making Virginia the seventh state to join. The legislation opens a cross-state agreement with seven states and finally allows locum tenens PAs to practice across these state’s borders.

How the PA Compact Works

The interstate arrangement recognizes valid, unencumbered PA licenses issued by other states in the compact. PAs working within the seven states won’t need a separate license from any of those states to practice.

The states include Delaware, Nebraska, Utah, Washington, West Virginia, Wisconsin, and Virginia. While the compact has been approved, the American Academy of Physician Associates said it could take an additional 18-24 months for the states to execute it, giving PAs the access they need to work in the compact states.

How the PA Compact Helps

The PA Compact holds the promise of alleviating some of the travel barriers that PAs often encounter, especially when they work locum tenens or in telehealth and must traverse state lines to deliver essential healthcare. This agreement not only enhances healthcare access but also empowers facilities to recruit new PAs, thereby bridging gaps in their healthcare staffing and addressing public health emergencies more effectively.

PAs will also gain increased flexibility and additional opportunities to earn and benefit from the right to practice in more states without requiring a time-consuming and expensive licensure from each state.

One motivating factor behind developing an interstate compact for physician assistants is that the same types of compacts for physicians and nurses are highly successful. The Nurse Licensure Compact and the Interstate Medical Licensure Compact for physicians encompass 37 and 41 states, respectively. While the seven-state PA Compact is in its earliest stages, it will likely be equally beneficial for PAs.

A survey by Barton Associates found that 95% of PAs said they would be more likely to consider working in a different state if the PA Compact made it more accessible.

Other states have begun legislation to enact a PA Compact, including Colorado, New Hampshire, Maine, Michigan New York, Ohio, Oklahoma, Rhode Island, Tennessee, and Vermont. 

If your state still needs to enact a compact or file for compact legislation, let your elected officials know that the PAs in your state want to join a compact. 
 

A version of this article appeared on Medscape.com .

For decades, physicians and nurses who ventured across state lines to practice, particularly in locum tenens roles, have reaped the benefits of medical licensure compacts. Yet, the same courtesy has eluded physician assistants (PAs), until now. The introduction of the PA Licensure Compact (PA Compact) marks a long-awaited and significant step forward for the PA community.

In April, Virginia Governor Glenn Youngkin signed the bill enacting the PA Compact making Virginia the seventh state to join. The legislation opens a cross-state agreement with seven states and finally allows locum tenens PAs to practice across these state’s borders.

How the PA Compact Works

The interstate arrangement recognizes valid, unencumbered PA licenses issued by other states in the compact. PAs working within the seven states won’t need a separate license from any of those states to practice.

The states include Delaware, Nebraska, Utah, Washington, West Virginia, Wisconsin, and Virginia. While the compact has been approved, the American Academy of Physician Associates said it could take an additional 18-24 months for the states to execute it, giving PAs the access they need to work in the compact states.

How the PA Compact Helps

The PA Compact holds the promise of alleviating some of the travel barriers that PAs often encounter, especially when they work locum tenens or in telehealth and must traverse state lines to deliver essential healthcare. This agreement not only enhances healthcare access but also empowers facilities to recruit new PAs, thereby bridging gaps in their healthcare staffing and addressing public health emergencies more effectively.

PAs will also gain increased flexibility and additional opportunities to earn and benefit from the right to practice in more states without requiring a time-consuming and expensive licensure from each state.

One motivating factor behind developing an interstate compact for physician assistants is that the same types of compacts for physicians and nurses are highly successful. The Nurse Licensure Compact and the Interstate Medical Licensure Compact for physicians encompass 37 and 41 states, respectively. While the seven-state PA Compact is in its earliest stages, it will likely be equally beneficial for PAs.

A survey by Barton Associates found that 95% of PAs said they would be more likely to consider working in a different state if the PA Compact made it more accessible.

Other states have begun legislation to enact a PA Compact, including Colorado, New Hampshire, Maine, Michigan New York, Ohio, Oklahoma, Rhode Island, Tennessee, and Vermont. 

If your state still needs to enact a compact or file for compact legislation, let your elected officials know that the PAs in your state want to join a compact. 
 

A version of this article appeared on Medscape.com .

Over the past few decades, the US Food and Drug Administration (FDA) has increasingly relied on surrogate measures such as blood tests instead of clinical outcomes for medication approvals. But critics say the agency lacks consistent standards to ensure the surrogate aligns with clinical outcomes that matter to patients — things like improvements in symptoms and gains in function.

Sometimes those decisions backfire. Consider: In July 2021, the FDA approved aducanumab for the treatment of Alzheimer’s disease, bucking the advice of an advisory panel for the agency that questioned the effectiveness of the medication. Regulators relied on data from the drugmaker, Biogen, showing the monoclonal antibody could reduce levels of amyloid beta plaques in blood — a surrogate marker officials hoped would translate to clinical benefit.

The FDA’s decision triggered significant controversy, and Biogen in January announced it is pulling it from the market this year, citing disappointing sales.

Although the case of aducanumab might seem extreme, given the stakes — Alzheimer’s remains a disease without an effective treatment — it’s far from unusual.

“When we prescribe a drug, there is an underlying assumption that the FDA has done its due diligence to confirm the drug is safe and of benefit,” said Reshma Ramachandran, MD, MPP, MHS, a researcher at Yale School of Medicine, New Haven, Connecticut, and a coauthor of a recent review of surrogate outcomes. “In fact, we found either no evidence or low-quality evidence.” Such markers are associated with clinical outcomes. “We just don’t know if they work meaningfully to treat the patient’s condition. The results were pretty shocking for us,” she said.

The FDA in 2018 released an Adult Surrogate Endpoint Table listing markers that can be used as substitutes for clinical outcomes to more quickly test, review, and approve new therapies. The analysis found the majority of these endpoints lacked subsequent confirmations, defined as published meta-analyses of clinical studies to validate the association between the marker and a clinical outcome important to patients.

In a paper published in JAMA, Dr. Ramachandran and her colleagues looked at 37 surrogate endpoints for nearly 3 dozen nononcologic diseases in the table.

Approval with surrogate markers implies responsibility for postapproval or validation studies — not just lab measures or imaging findings but mortality, morbidity, or improved quality of life, said Joshua D. Wallach, PhD, MS, assistant professor in the department of epidemiology at the Emory Rollins School of Public Health in Atlanta and lead author of the JAMA review.

Dr. Wallach said surrogate markers are easier to measure and do not require large and long trials. But the FDA has not provided clear rules for what makes a surrogate marker valid in clinical trials.

“They’ve said that at a minimum, it requires meta-analytical evidence from studies that have looked at the correlation or the association between the surrogate and the clinical outcome,” Dr. Wallach said. “Our understanding was that if that’s a minimum expectation, we should be able to find those studies in the literature. And the reality is that we were unable to find evidence from those types of studies supporting the association between the surrogate and the clinical outcome.”

Physicians generally do not receive training about the FDA approval process and the difference between biomarkers, surrogate markers, and clinical endpoints, Dr. Ramachandran said. “Our study shows that things are much more uncertain than we thought when it comes to the prescribing of new drugs,” she said.
 

Surrogate Markers on the Rise

Dr. Wallach’s group looked for published meta-analyses compiling randomized controlled trials reporting surrogate endpoints for more than 3 dozen chronic nononcologic conditions, including type 2 diabetes, Alzheimer’s, kidney disease, HIV, gout, and lupus. They found no meta-analyses at all for 59% of the surrogate markers, while for those that were studied, few reported high-strength evidence of an association with clinical outcomes.

The findings echo previous research. In a 2020 study in JAMA Network Open, researchers tallied primary endpoints for all FDA approvals of new drugs and therapies during three 3-year periods: 1995-1997, 2005-2007, and 2015-2017. The proportion of products whose approvals were based on the use of clinical endpoints decreased from 43.8% in 1995-1997 to 28.4% in 2005-2007 to 23.3% in 2015-2017. The share based on surrogate endpoints rose from 43.3% to roughly 60% over the same interval.

A 2017 study in the Journal of Health Economics found the use of “imperfect” surrogate endpoints helped support the approval of an average of 16 new drugs per year between 2010 and 2014 compared with six per year from 1998 to 2008.

Similar concerns about weak associations between surrogate markers and drugs used to treat cancer have been documented before, including in a 2020 study published in eClinicalMedicine. The researchers found the surrogate endpoints in the FDA table either were not tested or were tested but proven to be weak surrogates.

“And yet the FDA considered these as good enough not only for accelerated approval but also for regular approval,” said Bishal Gyawali, MD, PhD, associate professor in the department of oncology at Queen’s University, Kingston, Ontario, Canada, who led the group.

The use of surrogate endpoints is also increasing in Europe, said Huseyin Naci, MHS, PhD, associate professor of health policy at the London School of Economics and Political Science in England. He cited a cohort study of 298 randomized clinical trials (RCTs) in JAMA Oncology suggesting “contemporary oncology RCTs now largely measure putative surrogate endpoints.” Dr. Wallach called the FDA’s surrogate table “a great first step toward transparency. But a key column is missing from that table, telling us what is the basis for which the FDA allows drug companies to use the recognized surrogate markers. What is the evidence they are considering?”

If the agency allows companies the flexibility to validate surrogate endpoints, postmarketing studies designed to confirm the clinical utility of those endpoints should follow.

“We obviously want physicians to be guided by evidence when they’re selecting treatments, and they need to be able to interpret the clinical benefits of the drug that they’re prescribing,” he said. “This is really about having the research consumer, patients, and physicians, as well as industry, understand why certain markers are considered and not considered.”

Dr. Wallach reported receiving grants from the FDA (through the Yale University — Mayo Clinic Center of Excellence in Regulatory Science and Innovation), National Institute on Alcohol Abuse and Alcoholism (1K01AA028258), and Johnson & Johnson (through the Yale University Open Data Access Project); and consulting fees from Hagens Berman Sobol Shapiro LLP and Dugan Law Firm APLC outside the submitted work. Dr. Ramachandran reported receiving grants from the Stavros Niarchos Foundation and FDA; receiving consulting fees from ReAct Action on Antibiotic Resistance strategy policy program outside the submitted work; and serving in an unpaid capacity as chair of the FDA task force for the nonprofit organization Doctors for America and in an unpaid capacity as board president for Universities Allied for Essential Medicines North America.
 

A version of this article appeared on Medscape.com.

Over the past few decades, the US Food and Drug Administration (FDA) has increasingly relied on surrogate measures such as blood tests instead of clinical outcomes for medication approvals. But critics say the agency lacks consistent standards to ensure the surrogate aligns with clinical outcomes that matter to patients — things like improvements in symptoms and gains in function.

Sometimes those decisions backfire. Consider: In July 2021, the FDA approved aducanumab for the treatment of Alzheimer’s disease, bucking the advice of an advisory panel for the agency that questioned the effectiveness of the medication. Regulators relied on data from the drugmaker, Biogen, showing the monoclonal antibody could reduce levels of amyloid beta plaques in blood — a surrogate marker officials hoped would translate to clinical benefit.

The FDA’s decision triggered significant controversy, and Biogen in January announced it is pulling it from the market this year, citing disappointing sales.

Although the case of aducanumab might seem extreme, given the stakes — Alzheimer’s remains a disease without an effective treatment — it’s far from unusual.

“When we prescribe a drug, there is an underlying assumption that the FDA has done its due diligence to confirm the drug is safe and of benefit,” said Reshma Ramachandran, MD, MPP, MHS, a researcher at Yale School of Medicine, New Haven, Connecticut, and a coauthor of a recent review of surrogate outcomes. “In fact, we found either no evidence or low-quality evidence.” Such markers are associated with clinical outcomes. “We just don’t know if they work meaningfully to treat the patient’s condition. The results were pretty shocking for us,” she said.

The FDA in 2018 released an Adult Surrogate Endpoint Table listing markers that can be used as substitutes for clinical outcomes to more quickly test, review, and approve new therapies. The analysis found the majority of these endpoints lacked subsequent confirmations, defined as published meta-analyses of clinical studies to validate the association between the marker and a clinical outcome important to patients.

In a paper published in JAMA, Dr. Ramachandran and her colleagues looked at 37 surrogate endpoints for nearly 3 dozen nononcologic diseases in the table.

Approval with surrogate markers implies responsibility for postapproval or validation studies — not just lab measures or imaging findings but mortality, morbidity, or improved quality of life, said Joshua D. Wallach, PhD, MS, assistant professor in the department of epidemiology at the Emory Rollins School of Public Health in Atlanta and lead author of the JAMA review.

Dr. Wallach said surrogate markers are easier to measure and do not require large and long trials. But the FDA has not provided clear rules for what makes a surrogate marker valid in clinical trials.

“They’ve said that at a minimum, it requires meta-analytical evidence from studies that have looked at the correlation or the association between the surrogate and the clinical outcome,” Dr. Wallach said. “Our understanding was that if that’s a minimum expectation, we should be able to find those studies in the literature. And the reality is that we were unable to find evidence from those types of studies supporting the association between the surrogate and the clinical outcome.”

Physicians generally do not receive training about the FDA approval process and the difference between biomarkers, surrogate markers, and clinical endpoints, Dr. Ramachandran said. “Our study shows that things are much more uncertain than we thought when it comes to the prescribing of new drugs,” she said.
 

Surrogate Markers on the Rise

Dr. Wallach’s group looked for published meta-analyses compiling randomized controlled trials reporting surrogate endpoints for more than 3 dozen chronic nononcologic conditions, including type 2 diabetes, Alzheimer’s, kidney disease, HIV, gout, and lupus. They found no meta-analyses at all for 59% of the surrogate markers, while for those that were studied, few reported high-strength evidence of an association with clinical outcomes.

The findings echo previous research. In a 2020 study in JAMA Network Open, researchers tallied primary endpoints for all FDA approvals of new drugs and therapies during three 3-year periods: 1995-1997, 2005-2007, and 2015-2017. The proportion of products whose approvals were based on the use of clinical endpoints decreased from 43.8% in 1995-1997 to 28.4% in 2005-2007 to 23.3% in 2015-2017. The share based on surrogate endpoints rose from 43.3% to roughly 60% over the same interval.

A 2017 study in the Journal of Health Economics found the use of “imperfect” surrogate endpoints helped support the approval of an average of 16 new drugs per year between 2010 and 2014 compared with six per year from 1998 to 2008.

Similar concerns about weak associations between surrogate markers and drugs used to treat cancer have been documented before, including in a 2020 study published in eClinicalMedicine. The researchers found the surrogate endpoints in the FDA table either were not tested or were tested but proven to be weak surrogates.

“And yet the FDA considered these as good enough not only for accelerated approval but also for regular approval,” said Bishal Gyawali, MD, PhD, associate professor in the department of oncology at Queen’s University, Kingston, Ontario, Canada, who led the group.

The use of surrogate endpoints is also increasing in Europe, said Huseyin Naci, MHS, PhD, associate professor of health policy at the London School of Economics and Political Science in England. He cited a cohort study of 298 randomized clinical trials (RCTs) in JAMA Oncology suggesting “contemporary oncology RCTs now largely measure putative surrogate endpoints.” Dr. Wallach called the FDA’s surrogate table “a great first step toward transparency. But a key column is missing from that table, telling us what is the basis for which the FDA allows drug companies to use the recognized surrogate markers. What is the evidence they are considering?”

If the agency allows companies the flexibility to validate surrogate endpoints, postmarketing studies designed to confirm the clinical utility of those endpoints should follow.

“We obviously want physicians to be guided by evidence when they’re selecting treatments, and they need to be able to interpret the clinical benefits of the drug that they’re prescribing,” he said. “This is really about having the research consumer, patients, and physicians, as well as industry, understand why certain markers are considered and not considered.”

Dr. Wallach reported receiving grants from the FDA (through the Yale University — Mayo Clinic Center of Excellence in Regulatory Science and Innovation), National Institute on Alcohol Abuse and Alcoholism (1K01AA028258), and Johnson & Johnson (through the Yale University Open Data Access Project); and consulting fees from Hagens Berman Sobol Shapiro LLP and Dugan Law Firm APLC outside the submitted work. Dr. Ramachandran reported receiving grants from the Stavros Niarchos Foundation and FDA; receiving consulting fees from ReAct Action on Antibiotic Resistance strategy policy program outside the submitted work; and serving in an unpaid capacity as chair of the FDA task force for the nonprofit organization Doctors for America and in an unpaid capacity as board president for Universities Allied for Essential Medicines North America.
 

A version of this article appeared on Medscape.com.

Over the past few decades, the US Food and Drug Administration (FDA) has increasingly relied on surrogate measures such as blood tests instead of clinical outcomes for medication approvals. But critics say the agency lacks consistent standards to ensure the surrogate aligns with clinical outcomes that matter to patients — things like improvements in symptoms and gains in function.

Sometimes those decisions backfire. Consider: In July 2021, the FDA approved aducanumab for the treatment of Alzheimer’s disease, bucking the advice of an advisory panel for the agency that questioned the effectiveness of the medication. Regulators relied on data from the drugmaker, Biogen, showing the monoclonal antibody could reduce levels of amyloid beta plaques in blood — a surrogate marker officials hoped would translate to clinical benefit.

The FDA’s decision triggered significant controversy, and Biogen in January announced it is pulling it from the market this year, citing disappointing sales.

Although the case of aducanumab might seem extreme, given the stakes — Alzheimer’s remains a disease without an effective treatment — it’s far from unusual.

“When we prescribe a drug, there is an underlying assumption that the FDA has done its due diligence to confirm the drug is safe and of benefit,” said Reshma Ramachandran, MD, MPP, MHS, a researcher at Yale School of Medicine, New Haven, Connecticut, and a coauthor of a recent review of surrogate outcomes. “In fact, we found either no evidence or low-quality evidence.” Such markers are associated with clinical outcomes. “We just don’t know if they work meaningfully to treat the patient’s condition. The results were pretty shocking for us,” she said.

The FDA in 2018 released an Adult Surrogate Endpoint Table listing markers that can be used as substitutes for clinical outcomes to more quickly test, review, and approve new therapies. The analysis found the majority of these endpoints lacked subsequent confirmations, defined as published meta-analyses of clinical studies to validate the association between the marker and a clinical outcome important to patients.

In a paper published in JAMA, Dr. Ramachandran and her colleagues looked at 37 surrogate endpoints for nearly 3 dozen nononcologic diseases in the table.

Approval with surrogate markers implies responsibility for postapproval or validation studies — not just lab measures or imaging findings but mortality, morbidity, or improved quality of life, said Joshua D. Wallach, PhD, MS, assistant professor in the department of epidemiology at the Emory Rollins School of Public Health in Atlanta and lead author of the JAMA review.

Dr. Wallach said surrogate markers are easier to measure and do not require large and long trials. But the FDA has not provided clear rules for what makes a surrogate marker valid in clinical trials.

“They’ve said that at a minimum, it requires meta-analytical evidence from studies that have looked at the correlation or the association between the surrogate and the clinical outcome,” Dr. Wallach said. “Our understanding was that if that’s a minimum expectation, we should be able to find those studies in the literature. And the reality is that we were unable to find evidence from those types of studies supporting the association between the surrogate and the clinical outcome.”

Physicians generally do not receive training about the FDA approval process and the difference between biomarkers, surrogate markers, and clinical endpoints, Dr. Ramachandran said. “Our study shows that things are much more uncertain than we thought when it comes to the prescribing of new drugs,” she said.
 

Surrogate Markers on the Rise

Dr. Wallach’s group looked for published meta-analyses compiling randomized controlled trials reporting surrogate endpoints for more than 3 dozen chronic nononcologic conditions, including type 2 diabetes, Alzheimer’s, kidney disease, HIV, gout, and lupus. They found no meta-analyses at all for 59% of the surrogate markers, while for those that were studied, few reported high-strength evidence of an association with clinical outcomes.

The findings echo previous research. In a 2020 study in JAMA Network Open, researchers tallied primary endpoints for all FDA approvals of new drugs and therapies during three 3-year periods: 1995-1997, 2005-2007, and 2015-2017. The proportion of products whose approvals were based on the use of clinical endpoints decreased from 43.8% in 1995-1997 to 28.4% in 2005-2007 to 23.3% in 2015-2017. The share based on surrogate endpoints rose from 43.3% to roughly 60% over the same interval.

A 2017 study in the Journal of Health Economics found the use of “imperfect” surrogate endpoints helped support the approval of an average of 16 new drugs per year between 2010 and 2014 compared with six per year from 1998 to 2008.

Similar concerns about weak associations between surrogate markers and drugs used to treat cancer have been documented before, including in a 2020 study published in eClinicalMedicine. The researchers found the surrogate endpoints in the FDA table either were not tested or were tested but proven to be weak surrogates.

“And yet the FDA considered these as good enough not only for accelerated approval but also for regular approval,” said Bishal Gyawali, MD, PhD, associate professor in the department of oncology at Queen’s University, Kingston, Ontario, Canada, who led the group.

The use of surrogate endpoints is also increasing in Europe, said Huseyin Naci, MHS, PhD, associate professor of health policy at the London School of Economics and Political Science in England. He cited a cohort study of 298 randomized clinical trials (RCTs) in JAMA Oncology suggesting “contemporary oncology RCTs now largely measure putative surrogate endpoints.” Dr. Wallach called the FDA’s surrogate table “a great first step toward transparency. But a key column is missing from that table, telling us what is the basis for which the FDA allows drug companies to use the recognized surrogate markers. What is the evidence they are considering?”

If the agency allows companies the flexibility to validate surrogate endpoints, postmarketing studies designed to confirm the clinical utility of those endpoints should follow.

“We obviously want physicians to be guided by evidence when they’re selecting treatments, and they need to be able to interpret the clinical benefits of the drug that they’re prescribing,” he said. “This is really about having the research consumer, patients, and physicians, as well as industry, understand why certain markers are considered and not considered.”

Dr. Wallach reported receiving grants from the FDA (through the Yale University — Mayo Clinic Center of Excellence in Regulatory Science and Innovation), National Institute on Alcohol Abuse and Alcoholism (1K01AA028258), and Johnson & Johnson (through the Yale University Open Data Access Project); and consulting fees from Hagens Berman Sobol Shapiro LLP and Dugan Law Firm APLC outside the submitted work. Dr. Ramachandran reported receiving grants from the Stavros Niarchos Foundation and FDA; receiving consulting fees from ReAct Action on Antibiotic Resistance strategy policy program outside the submitted work; and serving in an unpaid capacity as chair of the FDA task force for the nonprofit organization Doctors for America and in an unpaid capacity as board president for Universities Allied for Essential Medicines North America.
 

A version of this article appeared on Medscape.com.

The US Food and Drug Administration has granted accelerated approval to tarlatamab-dlle (Imdelltra) for extensive-stage small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy.

Tarlatamab is a first-in-class bispecific T-cell engager (BiTE) that binds delta-like ligand 3 on the surface of cells, including tumor cells, and CD3 expressed on the surface of T cells. It causes T-cell activation, release of inflammatory cytokines, and lysis of DLL3-expressing cells, according to labeling. 

Approval was based on data from 99 patients in the DeLLphi-301 trial with relapsed/refractory extensive-stage SCLC who had progressed after platinum-based chemotherapy. Patients with symptomatic brain metastases, interstitial lung disease, noninfectious pneumonitis, and active immunodeficiency were excluded. 

The overall response rate was 40%, and median duration of response 9.7 months. The overall response rate was 52% in 27 patients with platinum-resistant SCLC and 31% in 42 with platinum-sensitive disease. 

Continued approval may depend on verification of clinical benefit in a confirmatory trial.

Labeling includes a box warning of serious or life-threatening cytokine release syndrome and neurologic toxicity, including immune effector cell–associated neurotoxicity syndrome. 

The most common adverse events, occurring in 20% or more of patients, were cytokine release syndrome, fatigue, pyrexia, dysgeusia, decreased appetite, musculoskeletal pain, constipation, anemia, and nausea. 

The most common grade 3 or 4 laboratory abnormalities included decreased lymphocytes, decreased sodium, increased uric acid, decreased total neutrophils, decreased hemoglobin, increased activated partial thromboplastin time, and decreased potassium.

The starting dose is 1 mg given intravenously over 1 hour on the first day of the first cycle followed by 10 mg on day 8 and day 15 of the first cycle, then every 2 weeks until disease progression or unacceptable toxicity.

M. Alexander Otto is a physician assistant with a master’s degree in medical science and a journalism degree from Newhouse. He is an award-winning medical journalist who worked for several major news outlets before joining Medscape. Alex is also an MIT Knight Science Journalism fellow. Email: [email protected]

A version of this article appeared on Medscape.com.

The US Food and Drug Administration has granted accelerated approval to tarlatamab-dlle (Imdelltra) for extensive-stage small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy.

Tarlatamab is a first-in-class bispecific T-cell engager (BiTE) that binds delta-like ligand 3 on the surface of cells, including tumor cells, and CD3 expressed on the surface of T cells. It causes T-cell activation, release of inflammatory cytokines, and lysis of DLL3-expressing cells, according to labeling. 

Approval was based on data from 99 patients in the DeLLphi-301 trial with relapsed/refractory extensive-stage SCLC who had progressed after platinum-based chemotherapy. Patients with symptomatic brain metastases, interstitial lung disease, noninfectious pneumonitis, and active immunodeficiency were excluded. 

The overall response rate was 40%, and median duration of response 9.7 months. The overall response rate was 52% in 27 patients with platinum-resistant SCLC and 31% in 42 with platinum-sensitive disease. 

Continued approval may depend on verification of clinical benefit in a confirmatory trial.

Labeling includes a box warning of serious or life-threatening cytokine release syndrome and neurologic toxicity, including immune effector cell–associated neurotoxicity syndrome. 

The most common adverse events, occurring in 20% or more of patients, were cytokine release syndrome, fatigue, pyrexia, dysgeusia, decreased appetite, musculoskeletal pain, constipation, anemia, and nausea. 

The most common grade 3 or 4 laboratory abnormalities included decreased lymphocytes, decreased sodium, increased uric acid, decreased total neutrophils, decreased hemoglobin, increased activated partial thromboplastin time, and decreased potassium.

The starting dose is 1 mg given intravenously over 1 hour on the first day of the first cycle followed by 10 mg on day 8 and day 15 of the first cycle, then every 2 weeks until disease progression or unacceptable toxicity.

M. Alexander Otto is a physician assistant with a master’s degree in medical science and a journalism degree from Newhouse. He is an award-winning medical journalist who worked for several major news outlets before joining Medscape. Alex is also an MIT Knight Science Journalism fellow. Email: [email protected]

A version of this article appeared on Medscape.com.

The US Food and Drug Administration has granted accelerated approval to tarlatamab-dlle (Imdelltra) for extensive-stage small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy.

Tarlatamab is a first-in-class bispecific T-cell engager (BiTE) that binds delta-like ligand 3 on the surface of cells, including tumor cells, and CD3 expressed on the surface of T cells. It causes T-cell activation, release of inflammatory cytokines, and lysis of DLL3-expressing cells, according to labeling. 

Approval was based on data from 99 patients in the DeLLphi-301 trial with relapsed/refractory extensive-stage SCLC who had progressed after platinum-based chemotherapy. Patients with symptomatic brain metastases, interstitial lung disease, noninfectious pneumonitis, and active immunodeficiency were excluded. 

The overall response rate was 40%, and median duration of response 9.7 months. The overall response rate was 52% in 27 patients with platinum-resistant SCLC and 31% in 42 with platinum-sensitive disease. 

Continued approval may depend on verification of clinical benefit in a confirmatory trial.

Labeling includes a box warning of serious or life-threatening cytokine release syndrome and neurologic toxicity, including immune effector cell–associated neurotoxicity syndrome. 

The most common adverse events, occurring in 20% or more of patients, were cytokine release syndrome, fatigue, pyrexia, dysgeusia, decreased appetite, musculoskeletal pain, constipation, anemia, and nausea. 

The most common grade 3 or 4 laboratory abnormalities included decreased lymphocytes, decreased sodium, increased uric acid, decreased total neutrophils, decreased hemoglobin, increased activated partial thromboplastin time, and decreased potassium.

The starting dose is 1 mg given intravenously over 1 hour on the first day of the first cycle followed by 10 mg on day 8 and day 15 of the first cycle, then every 2 weeks until disease progression or unacceptable toxicity.

M. Alexander Otto is a physician assistant with a master’s degree in medical science and a journalism degree from Newhouse. He is an award-winning medical journalist who worked for several major news outlets before joining Medscape. Alex is also an MIT Knight Science Journalism fellow. Email: [email protected]

A version of this article appeared on Medscape.com.

Large language models (LLM) such as ChatGPT have shown mixed results in the quality of their responses to consumer questions about cancer.

One recent study found AI chatbots to churn out incomplete, inaccurate, or even nonsensical cancer treatment recommendations, while another found them to generate largely accurate — if technical — responses to the most common cancer questions.

While researchers have seen success with purpose-built chatbots created to address patient concerns about specific cancers, the consensus to date has been that the generalized models like ChatGPT remain works in progress and that physicians should avoid pointing patients to them, for now.

Yet new findings suggest that these chatbots may do better than individual physicians, at least on some measures, when it comes to answering queries about cancer. For research published May 16 in JAMA Oncology (doi: 10.1001/jamaoncol.2024.0836), David Chen, a medical student at the University of Toronto, and his colleagues, isolated a random sample of 200 questions related to cancer care addressed to doctors on the public online forum Reddit. They then compared responses from oncologists with responses generated by three different AI chatbots. The blinded responses were rated for quality, readability, and empathy by six physicians, including oncologists and palliative and supportive care specialists.

Mr. Chen and colleagues’ research was modeled after a 2023 study that measured the quality of physician responses compared with chatbots for general medicine questions addressed to doctors on Reddit. That study found that the chatbots produced more empathetic-sounding answers, something Mr. Chen’s study also found. The best-performing chatbot in Mr. Chen and colleagues’ study, Claude AI, performed significantly higher than the Reddit physicians on all the domains evaluated: quality, empathy, and readability.
 

Q&A With Author of New Research

Mr. Chen discussed his new study’s implications during an interview with this news organization.

Question: What is novel about this study?

Mr. Chen: We’ve seen many evaluations of chatbots that test for medical accuracy, but this study occurs in the domain of oncology care, where there are unique psychosocial and emotional considerations that are not precisely reflected in a general medicine setting. In effect, this study is putting these chatbots through a harder challenge.



Question: Why would chatbot responses seem more empathetic than those of physicians?

Mr. Chen: With the physician responses that we observed in our sample data set, we saw that there was very high variation of amount of apparent effort [in the physician responses]. Some physicians would put in a lot of time and effort, thinking through their response, and others wouldn’t do so as much. These chatbots don’t face fatigue the way humans do, or burnout. So they’re able to consistently provide responses with less variation in empathy.



Question: Do chatbots just seem empathetic because they are chattier?

Mr. Chen: We did think of verbosity as a potential confounder in this study. So we set a word count limit for the chatbot responses to keep it in the range of the physician responses. That way, verbosity was no longer a significant factor.



Question: How were quality and empathy measured by the reviewers?

Mr. Chen: For our study we used two teams of readers, each team composed of three physicians. In terms of the actual metrics we used, they were pilot metrics. There are no well-defined measurement scales or checklists that we could use to measure empathy. This is an emerging field of research. So we came up by consensus with our own set of ratings, and we feel that this is an area for the research to define a standardized set of guidelines.

Another novel aspect of this study is that we separated out different dimensions of quality and empathy. A quality response didn’t just mean it was medically accurate — quality also had to do with the focus and completeness of the response.

With empathy there are cognitive and emotional dimensions. Cognitive empathy uses critical thinking to understand the person’s emotions and thoughts and then adjusting a response to fit that. A patient may not want the best medically indicated treatment for their condition, because they want to preserve their quality of life. The chatbot may be able to adjust its recommendation with consideration of some of those humanistic elements that the patient is presenting with.

Emotional empathy is more about being supportive of the patient’s emotions by using expressions like ‘I understand where you’re coming from.’ or, ‘I can see how that makes you feel.’



Question: Why would physicians, not patients, be the best evaluators of empathy?

Mr. Chen: We’re actually very interested in evaluating patient ratings of empathy. We are conducting a follow-up study that evaluates patient ratings of empathy to the same set of chatbot and physician responses,to see if there are differences.



Question: Should cancer patients go ahead and consult chatbots?

Mr. Chen: Although we did observe increases in all of the metrics compared with physicians, this is a very specialized evaluation scenario where we’re using these Reddit questions and responses.

Naturally, we would need to do a trial, a head to head randomized comparison of physicians versus chatbots.

This pilot study does highlight the promising potential of these chatbots to suggest responses. But we can’t fully recommend that they should be used as standalone clinical tools without physicians.

This Q&A was edited for clarity.

Large language models (LLM) such as ChatGPT have shown mixed results in the quality of their responses to consumer questions about cancer.

One recent study found AI chatbots to churn out incomplete, inaccurate, or even nonsensical cancer treatment recommendations, while another found them to generate largely accurate — if technical — responses to the most common cancer questions.

While researchers have seen success with purpose-built chatbots created to address patient concerns about specific cancers, the consensus to date has been that the generalized models like ChatGPT remain works in progress and that physicians should avoid pointing patients to them, for now.

Yet new findings suggest that these chatbots may do better than individual physicians, at least on some measures, when it comes to answering queries about cancer. For research published May 16 in JAMA Oncology (doi: 10.1001/jamaoncol.2024.0836), David Chen, a medical student at the University of Toronto, and his colleagues, isolated a random sample of 200 questions related to cancer care addressed to doctors on the public online forum Reddit. They then compared responses from oncologists with responses generated by three different AI chatbots. The blinded responses were rated for quality, readability, and empathy by six physicians, including oncologists and palliative and supportive care specialists.

Mr. Chen and colleagues’ research was modeled after a 2023 study that measured the quality of physician responses compared with chatbots for general medicine questions addressed to doctors on Reddit. That study found that the chatbots produced more empathetic-sounding answers, something Mr. Chen’s study also found. The best-performing chatbot in Mr. Chen and colleagues’ study, Claude AI, performed significantly higher than the Reddit physicians on all the domains evaluated: quality, empathy, and readability.
 

Q&A With Author of New Research

Mr. Chen discussed his new study’s implications during an interview with this news organization.

Question: What is novel about this study?

Mr. Chen: We’ve seen many evaluations of chatbots that test for medical accuracy, but this study occurs in the domain of oncology care, where there are unique psychosocial and emotional considerations that are not precisely reflected in a general medicine setting. In effect, this study is putting these chatbots through a harder challenge.



Question: Why would chatbot responses seem more empathetic than those of physicians?

Mr. Chen: With the physician responses that we observed in our sample data set, we saw that there was very high variation of amount of apparent effort [in the physician responses]. Some physicians would put in a lot of time and effort, thinking through their response, and others wouldn’t do so as much. These chatbots don’t face fatigue the way humans do, or burnout. So they’re able to consistently provide responses with less variation in empathy.



Question: Do chatbots just seem empathetic because they are chattier?

Mr. Chen: We did think of verbosity as a potential confounder in this study. So we set a word count limit for the chatbot responses to keep it in the range of the physician responses. That way, verbosity was no longer a significant factor.



Question: How were quality and empathy measured by the reviewers?

Mr. Chen: For our study we used two teams of readers, each team composed of three physicians. In terms of the actual metrics we used, they were pilot metrics. There are no well-defined measurement scales or checklists that we could use to measure empathy. This is an emerging field of research. So we came up by consensus with our own set of ratings, and we feel that this is an area for the research to define a standardized set of guidelines.

Another novel aspect of this study is that we separated out different dimensions of quality and empathy. A quality response didn’t just mean it was medically accurate — quality also had to do with the focus and completeness of the response.

With empathy there are cognitive and emotional dimensions. Cognitive empathy uses critical thinking to understand the person’s emotions and thoughts and then adjusting a response to fit that. A patient may not want the best medically indicated treatment for their condition, because they want to preserve their quality of life. The chatbot may be able to adjust its recommendation with consideration of some of those humanistic elements that the patient is presenting with.

Emotional empathy is more about being supportive of the patient’s emotions by using expressions like ‘I understand where you’re coming from.’ or, ‘I can see how that makes you feel.’



Question: Why would physicians, not patients, be the best evaluators of empathy?

Mr. Chen: We’re actually very interested in evaluating patient ratings of empathy. We are conducting a follow-up study that evaluates patient ratings of empathy to the same set of chatbot and physician responses,to see if there are differences.



Question: Should cancer patients go ahead and consult chatbots?

Mr. Chen: Although we did observe increases in all of the metrics compared with physicians, this is a very specialized evaluation scenario where we’re using these Reddit questions and responses.

Naturally, we would need to do a trial, a head to head randomized comparison of physicians versus chatbots.

This pilot study does highlight the promising potential of these chatbots to suggest responses. But we can’t fully recommend that they should be used as standalone clinical tools without physicians.

This Q&A was edited for clarity.

Large language models (LLM) such as ChatGPT have shown mixed results in the quality of their responses to consumer questions about cancer.

One recent study found AI chatbots to churn out incomplete, inaccurate, or even nonsensical cancer treatment recommendations, while another found them to generate largely accurate — if technical — responses to the most common cancer questions.

While researchers have seen success with purpose-built chatbots created to address patient concerns about specific cancers, the consensus to date has been that the generalized models like ChatGPT remain works in progress and that physicians should avoid pointing patients to them, for now.

Yet new findings suggest that these chatbots may do better than individual physicians, at least on some measures, when it comes to answering queries about cancer. For research published May 16 in JAMA Oncology (doi: 10.1001/jamaoncol.2024.0836), David Chen, a medical student at the University of Toronto, and his colleagues, isolated a random sample of 200 questions related to cancer care addressed to doctors on the public online forum Reddit. They then compared responses from oncologists with responses generated by three different AI chatbots. The blinded responses were rated for quality, readability, and empathy by six physicians, including oncologists and palliative and supportive care specialists.

Mr. Chen and colleagues’ research was modeled after a 2023 study that measured the quality of physician responses compared with chatbots for general medicine questions addressed to doctors on Reddit. That study found that the chatbots produced more empathetic-sounding answers, something Mr. Chen’s study also found. The best-performing chatbot in Mr. Chen and colleagues’ study, Claude AI, performed significantly higher than the Reddit physicians on all the domains evaluated: quality, empathy, and readability.
 

Q&A With Author of New Research

Mr. Chen discussed his new study’s implications during an interview with this news organization.

Question: What is novel about this study?

Mr. Chen: We’ve seen many evaluations of chatbots that test for medical accuracy, but this study occurs in the domain of oncology care, where there are unique psychosocial and emotional considerations that are not precisely reflected in a general medicine setting. In effect, this study is putting these chatbots through a harder challenge.



Question: Why would chatbot responses seem more empathetic than those of physicians?

Mr. Chen: With the physician responses that we observed in our sample data set, we saw that there was very high variation of amount of apparent effort [in the physician responses]. Some physicians would put in a lot of time and effort, thinking through their response, and others wouldn’t do so as much. These chatbots don’t face fatigue the way humans do, or burnout. So they’re able to consistently provide responses with less variation in empathy.



Question: Do chatbots just seem empathetic because they are chattier?

Mr. Chen: We did think of verbosity as a potential confounder in this study. So we set a word count limit for the chatbot responses to keep it in the range of the physician responses. That way, verbosity was no longer a significant factor.



Question: How were quality and empathy measured by the reviewers?

Mr. Chen: For our study we used two teams of readers, each team composed of three physicians. In terms of the actual metrics we used, they were pilot metrics. There are no well-defined measurement scales or checklists that we could use to measure empathy. This is an emerging field of research. So we came up by consensus with our own set of ratings, and we feel that this is an area for the research to define a standardized set of guidelines.

Another novel aspect of this study is that we separated out different dimensions of quality and empathy. A quality response didn’t just mean it was medically accurate — quality also had to do with the focus and completeness of the response.

With empathy there are cognitive and emotional dimensions. Cognitive empathy uses critical thinking to understand the person’s emotions and thoughts and then adjusting a response to fit that. A patient may not want the best medically indicated treatment for their condition, because they want to preserve their quality of life. The chatbot may be able to adjust its recommendation with consideration of some of those humanistic elements that the patient is presenting with.

Emotional empathy is more about being supportive of the patient’s emotions by using expressions like ‘I understand where you’re coming from.’ or, ‘I can see how that makes you feel.’



Question: Why would physicians, not patients, be the best evaluators of empathy?

Mr. Chen: We’re actually very interested in evaluating patient ratings of empathy. We are conducting a follow-up study that evaluates patient ratings of empathy to the same set of chatbot and physician responses,to see if there are differences.



Question: Should cancer patients go ahead and consult chatbots?

Mr. Chen: Although we did observe increases in all of the metrics compared with physicians, this is a very specialized evaluation scenario where we’re using these Reddit questions and responses.

Naturally, we would need to do a trial, a head to head randomized comparison of physicians versus chatbots.

This pilot study does highlight the promising potential of these chatbots to suggest responses. But we can’t fully recommend that they should be used as standalone clinical tools without physicians.

This Q&A was edited for clarity.

A few months ago, I posted a column on continuous positive airway pressure (CPAP) with the title, “CPAP Oversells and Underperforms.” To date, it has 299 likes and 90 comments, which are almost all negative. I’m glad to see that it’s generated interest, and I’d like to address some of the themes expressed in the posts.

Most comments were personal testimonies to the miracles of CPAP. These are important, and the point deserves emphasis. CPAP can provide significant improvements in daytime sleepiness and quality of life. I closed the original piece by acknowledging this important fact. Readers can be forgiven for missing it given that the title and text were otherwise disparaging of CPAP.

But several comments warrant a more in-depth discussion. The original piece focuses on CPAP and cardiovascular (CV) outcomes but made no mention of atrial fibrillation (AF) or ejection fraction (EF). The effects of CPAP on each are touted by cardiologists and PAP-pushers alike and are drivers of frequent referrals. It›s my fault for omitting them from the discussion.

AF is easy. The data is identical to all other things CPAP and CV. Based on biologic plausibility alone, the likelihood of a relationship between AF and obstructive sleep apnea (OSA) is similar to the odds that the Celtics raise an 18th banner come June. There’s hypoxia, intrathoracic pressure swings, sympathetic surges, and sleep state disruptions. It’s easy to get from there to arrhythmogenesis. There’s lots of observational noise, too, but no randomized proof that CPAP alters this relationship.

I found four randomized controlled trials (RCTs) that tested CPAP’s effect on AF. I’ll save you the suspense; they were all negative. One even found a signal for more adverse events in the CPAP group. These studies have several positive qualities: They enrolled patients with moderate to severe sleep apnea and high oxygen desaturation indices, adherence averaged more than 4 hours across all groups in all trials, and the methods for assessing the AF outcomes differed slightly. There’s also a lot not to like: The sample sizes were small, only one trial enrolled “sleepy” patients (as assessed by the Epworth Sleepiness Score), and follow-up was short.

To paraphrase Carl Sagan, “absence of evidence does not equal evidence of absence.” As a statistician would say, type II error cannot be excluded by these RCTs. In medicine, however, the burden of proof falls on demonstrating efficacy. If we treat before concluding that a therapy works, we risk wasting time, money, medical resources, and the most precious of patient commodities: the energy required for behavior change. In their response to letters to the editor, the authors of the third RCT summarize the CPAP, AF, and CV disease data far better than I ever could. They sound the same words of caution and come out against screening patients with AF for OSA. 

The story for CPAP’s effects on EF is similar though muddier. The American College of Cardiology (ACC)/American Heart Association (AHA) guidelines for heart failure cite a meta-analysis showing that CPAP improves left ventricular EF. In 2019, the American Academy of Sleep Medicine (AASM) CPAP guidelines included a systematic review and meta-analysis that found that CPAP has no effect on left ventricular EF in patients with or without heart failure.

There are a million reasons why two systematic reviews on the same topic might come to different conclusions. In this case, the included studies only partially overlap, and broadly speaking, it appears the authors made trade-offs. The review cited by the ACC/AHA had broader inclusion and significantly more patients and paid for it in heterogeneity (I2 in the 80%-90% range). The AASM analysis achieved 0% heterogeneity but limited inclusion to fewer than 100 patients. Across both, the improvement in EF was 2%- 5% at a minimally clinically important difference of 4%. Hardly convincing.

In summary, the road to negative trials and patient harm has always been paved with observational signal and biologic plausibility. Throw in some intellectual and academic bias, and you’ve created the perfect storm of therapeutic overconfidence. The cemetery for discarded medical therapies is crowded, but there’s room for CPAP, at least when it comes to using it to improve CV outcomes. 
 

Dr. Holley is a professor in the department of medicine, Uniformed Services University, Bethesda, Maryland, and a physician at Pulmonary/Sleep and Critical Care Medicine, MedStar Washington Hospital Center, Washington. He disclosed ties to Metapharm Inc., CHEST College, and WebMD.

A version of this article appeared on Medscape.com .

A few months ago, I posted a column on continuous positive airway pressure (CPAP) with the title, “CPAP Oversells and Underperforms.” To date, it has 299 likes and 90 comments, which are almost all negative. I’m glad to see that it’s generated interest, and I’d like to address some of the themes expressed in the posts.

Most comments were personal testimonies to the miracles of CPAP. These are important, and the point deserves emphasis. CPAP can provide significant improvements in daytime sleepiness and quality of life. I closed the original piece by acknowledging this important fact. Readers can be forgiven for missing it given that the title and text were otherwise disparaging of CPAP.

But several comments warrant a more in-depth discussion. The original piece focuses on CPAP and cardiovascular (CV) outcomes but made no mention of atrial fibrillation (AF) or ejection fraction (EF). The effects of CPAP on each are touted by cardiologists and PAP-pushers alike and are drivers of frequent referrals. It›s my fault for omitting them from the discussion.

AF is easy. The data is identical to all other things CPAP and CV. Based on biologic plausibility alone, the likelihood of a relationship between AF and obstructive sleep apnea (OSA) is similar to the odds that the Celtics raise an 18th banner come June. There’s hypoxia, intrathoracic pressure swings, sympathetic surges, and sleep state disruptions. It’s easy to get from there to arrhythmogenesis. There’s lots of observational noise, too, but no randomized proof that CPAP alters this relationship.

I found four randomized controlled trials (RCTs) that tested CPAP’s effect on AF. I’ll save you the suspense; they were all negative. One even found a signal for more adverse events in the CPAP group. These studies have several positive qualities: They enrolled patients with moderate to severe sleep apnea and high oxygen desaturation indices, adherence averaged more than 4 hours across all groups in all trials, and the methods for assessing the AF outcomes differed slightly. There’s also a lot not to like: The sample sizes were small, only one trial enrolled “sleepy” patients (as assessed by the Epworth Sleepiness Score), and follow-up was short.

To paraphrase Carl Sagan, “absence of evidence does not equal evidence of absence.” As a statistician would say, type II error cannot be excluded by these RCTs. In medicine, however, the burden of proof falls on demonstrating efficacy. If we treat before concluding that a therapy works, we risk wasting time, money, medical resources, and the most precious of patient commodities: the energy required for behavior change. In their response to letters to the editor, the authors of the third RCT summarize the CPAP, AF, and CV disease data far better than I ever could. They sound the same words of caution and come out against screening patients with AF for OSA. 

The story for CPAP’s effects on EF is similar though muddier. The American College of Cardiology (ACC)/American Heart Association (AHA) guidelines for heart failure cite a meta-analysis showing that CPAP improves left ventricular EF. In 2019, the American Academy of Sleep Medicine (AASM) CPAP guidelines included a systematic review and meta-analysis that found that CPAP has no effect on left ventricular EF in patients with or without heart failure.

There are a million reasons why two systematic reviews on the same topic might come to different conclusions. In this case, the included studies only partially overlap, and broadly speaking, it appears the authors made trade-offs. The review cited by the ACC/AHA had broader inclusion and significantly more patients and paid for it in heterogeneity (I2 in the 80%-90% range). The AASM analysis achieved 0% heterogeneity but limited inclusion to fewer than 100 patients. Across both, the improvement in EF was 2%- 5% at a minimally clinically important difference of 4%. Hardly convincing.

In summary, the road to negative trials and patient harm has always been paved with observational signal and biologic plausibility. Throw in some intellectual and academic bias, and you’ve created the perfect storm of therapeutic overconfidence. The cemetery for discarded medical therapies is crowded, but there’s room for CPAP, at least when it comes to using it to improve CV outcomes. 
 

Dr. Holley is a professor in the department of medicine, Uniformed Services University, Bethesda, Maryland, and a physician at Pulmonary/Sleep and Critical Care Medicine, MedStar Washington Hospital Center, Washington. He disclosed ties to Metapharm Inc., CHEST College, and WebMD.

A version of this article appeared on Medscape.com .

A few months ago, I posted a column on continuous positive airway pressure (CPAP) with the title, “CPAP Oversells and Underperforms.” To date, it has 299 likes and 90 comments, which are almost all negative. I’m glad to see that it’s generated interest, and I’d like to address some of the themes expressed in the posts.

Most comments were personal testimonies to the miracles of CPAP. These are important, and the point deserves emphasis. CPAP can provide significant improvements in daytime sleepiness and quality of life. I closed the original piece by acknowledging this important fact. Readers can be forgiven for missing it given that the title and text were otherwise disparaging of CPAP.

But several comments warrant a more in-depth discussion. The original piece focuses on CPAP and cardiovascular (CV) outcomes but made no mention of atrial fibrillation (AF) or ejection fraction (EF). The effects of CPAP on each are touted by cardiologists and PAP-pushers alike and are drivers of frequent referrals. It›s my fault for omitting them from the discussion.

AF is easy. The data is identical to all other things CPAP and CV. Based on biologic plausibility alone, the likelihood of a relationship between AF and obstructive sleep apnea (OSA) is similar to the odds that the Celtics raise an 18th banner come June. There’s hypoxia, intrathoracic pressure swings, sympathetic surges, and sleep state disruptions. It’s easy to get from there to arrhythmogenesis. There’s lots of observational noise, too, but no randomized proof that CPAP alters this relationship.

I found four randomized controlled trials (RCTs) that tested CPAP’s effect on AF. I’ll save you the suspense; they were all negative. One even found a signal for more adverse events in the CPAP group. These studies have several positive qualities: They enrolled patients with moderate to severe sleep apnea and high oxygen desaturation indices, adherence averaged more than 4 hours across all groups in all trials, and the methods for assessing the AF outcomes differed slightly. There’s also a lot not to like: The sample sizes were small, only one trial enrolled “sleepy” patients (as assessed by the Epworth Sleepiness Score), and follow-up was short.

To paraphrase Carl Sagan, “absence of evidence does not equal evidence of absence.” As a statistician would say, type II error cannot be excluded by these RCTs. In medicine, however, the burden of proof falls on demonstrating efficacy. If we treat before concluding that a therapy works, we risk wasting time, money, medical resources, and the most precious of patient commodities: the energy required for behavior change. In their response to letters to the editor, the authors of the third RCT summarize the CPAP, AF, and CV disease data far better than I ever could. They sound the same words of caution and come out against screening patients with AF for OSA. 

The story for CPAP’s effects on EF is similar though muddier. The American College of Cardiology (ACC)/American Heart Association (AHA) guidelines for heart failure cite a meta-analysis showing that CPAP improves left ventricular EF. In 2019, the American Academy of Sleep Medicine (AASM) CPAP guidelines included a systematic review and meta-analysis that found that CPAP has no effect on left ventricular EF in patients with or without heart failure.

There are a million reasons why two systematic reviews on the same topic might come to different conclusions. In this case, the included studies only partially overlap, and broadly speaking, it appears the authors made trade-offs. The review cited by the ACC/AHA had broader inclusion and significantly more patients and paid for it in heterogeneity (I2 in the 80%-90% range). The AASM analysis achieved 0% heterogeneity but limited inclusion to fewer than 100 patients. Across both, the improvement in EF was 2%- 5% at a minimally clinically important difference of 4%. Hardly convincing.

In summary, the road to negative trials and patient harm has always been paved with observational signal and biologic plausibility. Throw in some intellectual and academic bias, and you’ve created the perfect storm of therapeutic overconfidence. The cemetery for discarded medical therapies is crowded, but there’s room for CPAP, at least when it comes to using it to improve CV outcomes. 
 

Dr. Holley is a professor in the department of medicine, Uniformed Services University, Bethesda, Maryland, and a physician at Pulmonary/Sleep and Critical Care Medicine, MedStar Washington Hospital Center, Washington. He disclosed ties to Metapharm Inc., CHEST College, and WebMD.

A version of this article appeared on Medscape.com .

TOPLINE:

Cutaneous manifestations of cystic fibrosis (CF) include palmar wrinkling, nutrient deficiency dermatitis, vascular disorders, and reactions to CF treatments.

METHODOLOGY:

• Patients with CF, caused by a mutation in the CF Transmembrane Conductance Regulator (CFTR) gene, can develop diverse dermatologic manifestations.
• Researchers reviewed the literature and provided their own clinical experience regarding dermatologic manifestations of CF.
• They also reviewed the cutaneous side effects of CFTR modulators and antibiotics used to treat CF.

TAKEAWAY:

• Aquagenic wrinkling of the palm is common in individuals with CF, affecting up to 80% of patients (and 25% of CF gene carriers), and can be an early manifestation of CF. Treatments include topical medications (such as aluminum chloride, corticosteroids, and salicylic acid), botulinum toxin injections, and recently, CFTR-modulating treatments.
• CF nutrient deficiency dermatitis, often in a diaper distribution, usually appears in infancy and, before newborn screening was available, was sometimes the first sign of CF in some cases. It usually resolves with an adequate diet, pancreatic enzymes, and/or nutritional supplements. Zinc and essential fatty acid deficiencies can lead to acrodermatitis enteropathica–like symptoms and psoriasiform rashes, respectively.
• CF is also associated with vascular disorders, including cutaneous and, rarely, systemic vasculitis. Treatment includes topical and oral steroids and immune-modulating therapies.
• CFTR modulators, now the most common and highly effective treatment for CF, are associated with several skin reactions, which can be managed with treatments that include topical steroids and oral antihistamines. Frequent antibiotic treatment can also trigger skin reactions.

IN PRACTICE:

“Recognition and familiarity with dermatologic clinical manifestations of CF are important for multidisciplinary care” for patients with CF, the authors wrote, adding that “dermatology providers may play a significant role in the diagnosis and management of CF cutaneous comorbidities.”

SOURCE:

Aaron D. Smith, BS, from the University of Virginia (UVA) School of Medicine, Charlottesville, and coauthors were from the departments of dermatology and pulmonology/critical care medicine at UVA. The study was published online in the Journal of the American Academy of Dermatology.

LIMITATIONS:

The authors did not make a comment about the limitations of their review.

DISCLOSURES:

No funding was received for the review. The authors had no disclosures.

A version of this article first appeared on Medscape.com.

TOPLINE:

Cutaneous manifestations of cystic fibrosis (CF) include palmar wrinkling, nutrient deficiency dermatitis, vascular disorders, and reactions to CF treatments.

METHODOLOGY:

• Patients with CF, caused by a mutation in the CF Transmembrane Conductance Regulator (CFTR) gene, can develop diverse dermatologic manifestations.
• Researchers reviewed the literature and provided their own clinical experience regarding dermatologic manifestations of CF.
• They also reviewed the cutaneous side effects of CFTR modulators and antibiotics used to treat CF.

TAKEAWAY:

• Aquagenic wrinkling of the palm is common in individuals with CF, affecting up to 80% of patients (and 25% of CF gene carriers), and can be an early manifestation of CF. Treatments include topical medications (such as aluminum chloride, corticosteroids, and salicylic acid), botulinum toxin injections, and recently, CFTR-modulating treatments.
• CF nutrient deficiency dermatitis, often in a diaper distribution, usually appears in infancy and, before newborn screening was available, was sometimes the first sign of CF in some cases. It usually resolves with an adequate diet, pancreatic enzymes, and/or nutritional supplements. Zinc and essential fatty acid deficiencies can lead to acrodermatitis enteropathica–like symptoms and psoriasiform rashes, respectively.
• CF is also associated with vascular disorders, including cutaneous and, rarely, systemic vasculitis. Treatment includes topical and oral steroids and immune-modulating therapies.
• CFTR modulators, now the most common and highly effective treatment for CF, are associated with several skin reactions, which can be managed with treatments that include topical steroids and oral antihistamines. Frequent antibiotic treatment can also trigger skin reactions.

IN PRACTICE:

“Recognition and familiarity with dermatologic clinical manifestations of CF are important for multidisciplinary care” for patients with CF, the authors wrote, adding that “dermatology providers may play a significant role in the diagnosis and management of CF cutaneous comorbidities.”

SOURCE:

Aaron D. Smith, BS, from the University of Virginia (UVA) School of Medicine, Charlottesville, and coauthors were from the departments of dermatology and pulmonology/critical care medicine at UVA. The study was published online in the Journal of the American Academy of Dermatology.

LIMITATIONS:

The authors did not make a comment about the limitations of their review.

DISCLOSURES:

No funding was received for the review. The authors had no disclosures.

A version of this article first appeared on Medscape.com.

TOPLINE:

Cutaneous manifestations of cystic fibrosis (CF) include palmar wrinkling, nutrient deficiency dermatitis, vascular disorders, and reactions to CF treatments.

METHODOLOGY:

• Patients with CF, caused by a mutation in the CF Transmembrane Conductance Regulator (CFTR) gene, can develop diverse dermatologic manifestations.
• Researchers reviewed the literature and provided their own clinical experience regarding dermatologic manifestations of CF.
• They also reviewed the cutaneous side effects of CFTR modulators and antibiotics used to treat CF.

TAKEAWAY:

• Aquagenic wrinkling of the palm is common in individuals with CF, affecting up to 80% of patients (and 25% of CF gene carriers), and can be an early manifestation of CF. Treatments include topical medications (such as aluminum chloride, corticosteroids, and salicylic acid), botulinum toxin injections, and recently, CFTR-modulating treatments.
• CF nutrient deficiency dermatitis, often in a diaper distribution, usually appears in infancy and, before newborn screening was available, was sometimes the first sign of CF in some cases. It usually resolves with an adequate diet, pancreatic enzymes, and/or nutritional supplements. Zinc and essential fatty acid deficiencies can lead to acrodermatitis enteropathica–like symptoms and psoriasiform rashes, respectively.
• CF is also associated with vascular disorders, including cutaneous and, rarely, systemic vasculitis. Treatment includes topical and oral steroids and immune-modulating therapies.
• CFTR modulators, now the most common and highly effective treatment for CF, are associated with several skin reactions, which can be managed with treatments that include topical steroids and oral antihistamines. Frequent antibiotic treatment can also trigger skin reactions.

IN PRACTICE:

“Recognition and familiarity with dermatologic clinical manifestations of CF are important for multidisciplinary care” for patients with CF, the authors wrote, adding that “dermatology providers may play a significant role in the diagnosis and management of CF cutaneous comorbidities.”

SOURCE:

Aaron D. Smith, BS, from the University of Virginia (UVA) School of Medicine, Charlottesville, and coauthors were from the departments of dermatology and pulmonology/critical care medicine at UVA. The study was published online in the Journal of the American Academy of Dermatology.

LIMITATIONS:

The authors did not make a comment about the limitations of their review.

DISCLOSURES:

No funding was received for the review. The authors had no disclosures.

A version of this article first appeared on Medscape.com.