Alicia Ault

A review of the federal Open Payments database found that the pharmaceutical and medical device industry paid physicians $12.1 billion over nearly a decade.

Almost two thirds of eligible physicians — 826,313 doctors — received a payment from a drug or device maker from 2013 to 2022, according to a study published online in JAMA on March 28. Overall, the median payment was $48 per physician.

Orthopedists received the largest amount of payments in aggregate, $1.3 billion, followed by neurologists and psychiatrists at $1.2 billion and cardiologists at $1.29 billion.

Geriatric and nuclear medicine specialists and trauma and pediatric surgeons received the least amount of money in aggregate, and the mean amount paid to a pediatric surgeon in the top 0.1% was just $338,183 over the 9-year study period.

Excluding 2013 (the database was established in August that year), the total value of payments was highest in 2019 at $1.6 billion, up from $1.34 billion in 2014. It was lowest in 2020, the peak year of the COVID-19 pandemic, but dipped to $864 billion that year and rebounded to $1.28 billion in 2022, wrote the authors.

The Open Payments database, administered by the Centers for Medicare & Medicaid Services, requires drug and device makers and group purchasing organizations to report payments made to physicians, including for consulting services, speaking fees, food and beverages, travel and lodging, education, gifts, grants, and honoraria.

The database was created to shed light on these payments, which have been linked in multiple studies to more prescribing of a particular drug or more use of a particular device.

The JAMA review appeared to show that with the exception of the pandemic year, the relationships have more or less stayed the same since Open Payments began.

“There’s been no sea change, no massive shift in how these interactions are happening,” said Deborah C. Marshall, MD, assistant professor in the Department of Radiation Oncology at the Icahn School of Medicine at Mount Sinai in New York City, who has studied industry payments.

“There’s no suggestion that anything is really changing other than that’s there is transparency,” said Robert Steinbrook, MD, director of the Health Research Group at Public Citizen.

Still, Dr. Steinbrook told this news organization, “it’s better to know this than to not know this.”

The unchanging nature of industry-physician relationships “suggests that to reduce the volume and magnitude of payments, more would need to be done,” he said.

“Really, this should be banned. Doctors should not be allowed to get gifts from pharmaceutical companies,” said Adriane Fugh-Berman, MD, professor of pharmacology and physiology at Georgetown University, and director of PharmedOut, a Georgetown-based project that advances evidence-based prescribing and educates healthcare professionals about pharmaceutical marketing practices.

“The interactions wouldn’t be happening unless there was a purpose for them,” said Dr. Marshall. The relationships are “built with intention,” Dr. Marshall told this news organization.
 

Top Earners Range From $195,000 to $4.8 Million

Payments to the median physician over the study period ranged from $0 to $2339, but the mean payment to top earners — those in the top 0.1% — ranged from $194,933 for hospitalists to $4.8 million for orthopedic specialists.

Overall, the median payment was $48 per physician.

But small dollar amounts should not be discounted — even if it’s just a $25-catered lunch — said Aaron Mitchell, MD, a medical oncologist and assistant attending physician at Memorial Sloan Kettering Cancer Center in New York City who has studied industry-physician relationships. “The influence is not just in the dollar value,” Dr. Mitchell told this news organization. “It’s about the time listening to and the time in personal contact with industry representatives that these dollars are a marker for,” he said.

“There’s no such thing as a free lunch,” agreed Dr. Marshall. It’s “pretty well established” that lower-value payments do have influence, which is why academic institutions have established policies that limit gifts and meals and other payments from industry, she said.

Dr. Fugh-Berman said, “the size of the gift doesn’t really matter,” adding that research she conducted had shown that “accepting a meal increased not only the expense of the prescriptions that Medicare physicians wrote but also the number of prescriptions.”
 

Payments Mostly for High-Dollar Products

The top 25 drugs and devices that were related to industry payments tended to be high-cost brand-name products.

The top drug was Janssen’s Xarelto, an anticoagulant first approved in 2011 that costs about $600 a month, according to GoodRx. The drug has had annual sales of $4-$6 billion.

Xarelto was followed by Eliquis, another anticoagulant; Humira, used for a variety of autoimmune conditions including plaque psoriasis, rheumatoid arthritis, Crohn’s disease, and ulcerative colitis; Invokana, Jardiance, and Farxiga, all for type 2 diabetes.

The top medical devices included the da Vinci Surgical System, Mako SmartRobotics, CoreValve Evolut, Natrelle Implants, and Impella, a heart pump that received a US Food and Drug Administration (FDA) warning that it was associated with a heightened risk for death.
 

Industry Influence May Lead to Higher Cost, Poor Quality Care

Multiple studies have shown that payments to physicians tend to lead to increased prescribing and, often, higher costs for Medicare, a health system, or patients.

“I’m sure there are still a lot of physicians out there who think they’re getting away with something, that they can take meals, or they can take consulting fees and not be influenced, but there’s overwhelming data showing that it always influences you,” said Dr. Fugh-Berman.

One study in 2020 that used the Open Payments database found that physicians increase prescribing of the drugs for which they receive payment in the months just after the payment. The authors also showed that physicians who are paid prescribe lower-quality drugs following the payment, “although the magnitude is small and unlikely to be clinically significant.”

Dr. Marshall said that more studies are needed to determine whether quality of care is being affected when a physician prescribes a drug after an industry payment.

For now, there seems to be little appetite among physicians to give up the payments, said Dr. Marshall and others.

Physicians in some specialties see the payments as “an implicit statement about their value,” said Dr. Marshall.

In oncology, having received a lot of payments “gets worn more as a badge of honor,” said Dr. Mitchell.

The clinicians believe that “by collaborating with industry we are providing scientific expertise to help develop the next generation of technology and cures,” Dr. Mitchell said, adding that they see the payments “as a mark of their impact.”

Among the JAMA study authors, Joseph S. Ross, MD, reported that he is a deputy editor of JAMA but was not involved in decisions regarding acceptance of the manuscript or its review. Dr. Ross also reported receiving grants from the FDA, Johnson and Johnson, the Medical Devices Innovation Consortium, the Agency for Healthcare Research and Quality, and the National Heart, Lung, and Blood Institute. He was an expert witness in a qui tam suit alleging violations of the False Claims Act and Anti-Kickback Statute against Biogen that was settled in 2022. Dr. Steinbrook, Dr. Marshall, and Dr. Mitchell reported no relevant financial relationships. Dr. Fugh-Berman reported being an expert witness for plaintiffs in complaints about drug and device marketing practices.

A version of this article appeared on Medscape.com.

A review of the federal Open Payments database found that the pharmaceutical and medical device industry paid physicians $12.1 billion over nearly a decade.

Almost two thirds of eligible physicians — 826,313 doctors — received a payment from a drug or device maker from 2013 to 2022, according to a study published online in JAMA on March 28. Overall, the median payment was $48 per physician.

Orthopedists received the largest amount of payments in aggregate, $1.3 billion, followed by neurologists and psychiatrists at $1.2 billion and cardiologists at $1.29 billion.

Geriatric and nuclear medicine specialists and trauma and pediatric surgeons received the least amount of money in aggregate, and the mean amount paid to a pediatric surgeon in the top 0.1% was just $338,183 over the 9-year study period.

Excluding 2013 (the database was established in August that year), the total value of payments was highest in 2019 at $1.6 billion, up from $1.34 billion in 2014. It was lowest in 2020, the peak year of the COVID-19 pandemic, but dipped to $864 billion that year and rebounded to $1.28 billion in 2022, wrote the authors.

The Open Payments database, administered by the Centers for Medicare & Medicaid Services, requires drug and device makers and group purchasing organizations to report payments made to physicians, including for consulting services, speaking fees, food and beverages, travel and lodging, education, gifts, grants, and honoraria.

The database was created to shed light on these payments, which have been linked in multiple studies to more prescribing of a particular drug or more use of a particular device.

The JAMA review appeared to show that with the exception of the pandemic year, the relationships have more or less stayed the same since Open Payments began.

“There’s been no sea change, no massive shift in how these interactions are happening,” said Deborah C. Marshall, MD, assistant professor in the Department of Radiation Oncology at the Icahn School of Medicine at Mount Sinai in New York City, who has studied industry payments.

“There’s no suggestion that anything is really changing other than that’s there is transparency,” said Robert Steinbrook, MD, director of the Health Research Group at Public Citizen.

Still, Dr. Steinbrook told this news organization, “it’s better to know this than to not know this.”

The unchanging nature of industry-physician relationships “suggests that to reduce the volume and magnitude of payments, more would need to be done,” he said.

“Really, this should be banned. Doctors should not be allowed to get gifts from pharmaceutical companies,” said Adriane Fugh-Berman, MD, professor of pharmacology and physiology at Georgetown University, and director of PharmedOut, a Georgetown-based project that advances evidence-based prescribing and educates healthcare professionals about pharmaceutical marketing practices.

“The interactions wouldn’t be happening unless there was a purpose for them,” said Dr. Marshall. The relationships are “built with intention,” Dr. Marshall told this news organization.
 

Top Earners Range From $195,000 to $4.8 Million

Payments to the median physician over the study period ranged from $0 to $2339, but the mean payment to top earners — those in the top 0.1% — ranged from $194,933 for hospitalists to $4.8 million for orthopedic specialists.

Overall, the median payment was $48 per physician.

But small dollar amounts should not be discounted — even if it’s just a $25-catered lunch — said Aaron Mitchell, MD, a medical oncologist and assistant attending physician at Memorial Sloan Kettering Cancer Center in New York City who has studied industry-physician relationships. “The influence is not just in the dollar value,” Dr. Mitchell told this news organization. “It’s about the time listening to and the time in personal contact with industry representatives that these dollars are a marker for,” he said.

“There’s no such thing as a free lunch,” agreed Dr. Marshall. It’s “pretty well established” that lower-value payments do have influence, which is why academic institutions have established policies that limit gifts and meals and other payments from industry, she said.

Dr. Fugh-Berman said, “the size of the gift doesn’t really matter,” adding that research she conducted had shown that “accepting a meal increased not only the expense of the prescriptions that Medicare physicians wrote but also the number of prescriptions.”
 

Payments Mostly for High-Dollar Products

The top 25 drugs and devices that were related to industry payments tended to be high-cost brand-name products.

The top drug was Janssen’s Xarelto, an anticoagulant first approved in 2011 that costs about $600 a month, according to GoodRx. The drug has had annual sales of $4-$6 billion.

Xarelto was followed by Eliquis, another anticoagulant; Humira, used for a variety of autoimmune conditions including plaque psoriasis, rheumatoid arthritis, Crohn’s disease, and ulcerative colitis; Invokana, Jardiance, and Farxiga, all for type 2 diabetes.

The top medical devices included the da Vinci Surgical System, Mako SmartRobotics, CoreValve Evolut, Natrelle Implants, and Impella, a heart pump that received a US Food and Drug Administration (FDA) warning that it was associated with a heightened risk for death.
 

Industry Influence May Lead to Higher Cost, Poor Quality Care

Multiple studies have shown that payments to physicians tend to lead to increased prescribing and, often, higher costs for Medicare, a health system, or patients.

“I’m sure there are still a lot of physicians out there who think they’re getting away with something, that they can take meals, or they can take consulting fees and not be influenced, but there’s overwhelming data showing that it always influences you,” said Dr. Fugh-Berman.

One study in 2020 that used the Open Payments database found that physicians increase prescribing of the drugs for which they receive payment in the months just after the payment. The authors also showed that physicians who are paid prescribe lower-quality drugs following the payment, “although the magnitude is small and unlikely to be clinically significant.”

Dr. Marshall said that more studies are needed to determine whether quality of care is being affected when a physician prescribes a drug after an industry payment.

For now, there seems to be little appetite among physicians to give up the payments, said Dr. Marshall and others.

Physicians in some specialties see the payments as “an implicit statement about their value,” said Dr. Marshall.

In oncology, having received a lot of payments “gets worn more as a badge of honor,” said Dr. Mitchell.

The clinicians believe that “by collaborating with industry we are providing scientific expertise to help develop the next generation of technology and cures,” Dr. Mitchell said, adding that they see the payments “as a mark of their impact.”

Among the JAMA study authors, Joseph S. Ross, MD, reported that he is a deputy editor of JAMA but was not involved in decisions regarding acceptance of the manuscript or its review. Dr. Ross also reported receiving grants from the FDA, Johnson and Johnson, the Medical Devices Innovation Consortium, the Agency for Healthcare Research and Quality, and the National Heart, Lung, and Blood Institute. He was an expert witness in a qui tam suit alleging violations of the False Claims Act and Anti-Kickback Statute against Biogen that was settled in 2022. Dr. Steinbrook, Dr. Marshall, and Dr. Mitchell reported no relevant financial relationships. Dr. Fugh-Berman reported being an expert witness for plaintiffs in complaints about drug and device marketing practices.

A version of this article appeared on Medscape.com.

A review of the federal Open Payments database found that the pharmaceutical and medical device industry paid physicians $12.1 billion over nearly a decade.

Almost two thirds of eligible physicians — 826,313 doctors — received a payment from a drug or device maker from 2013 to 2022, according to a study published online in JAMA on March 28. Overall, the median payment was $48 per physician.

Orthopedists received the largest amount of payments in aggregate, $1.3 billion, followed by neurologists and psychiatrists at $1.2 billion and cardiologists at $1.29 billion.

Geriatric and nuclear medicine specialists and trauma and pediatric surgeons received the least amount of money in aggregate, and the mean amount paid to a pediatric surgeon in the top 0.1% was just $338,183 over the 9-year study period.

Excluding 2013 (the database was established in August that year), the total value of payments was highest in 2019 at $1.6 billion, up from $1.34 billion in 2014. It was lowest in 2020, the peak year of the COVID-19 pandemic, but dipped to $864 billion that year and rebounded to $1.28 billion in 2022, wrote the authors.

The Open Payments database, administered by the Centers for Medicare & Medicaid Services, requires drug and device makers and group purchasing organizations to report payments made to physicians, including for consulting services, speaking fees, food and beverages, travel and lodging, education, gifts, grants, and honoraria.

The database was created to shed light on these payments, which have been linked in multiple studies to more prescribing of a particular drug or more use of a particular device.

The JAMA review appeared to show that with the exception of the pandemic year, the relationships have more or less stayed the same since Open Payments began.

“There’s been no sea change, no massive shift in how these interactions are happening,” said Deborah C. Marshall, MD, assistant professor in the Department of Radiation Oncology at the Icahn School of Medicine at Mount Sinai in New York City, who has studied industry payments.

“There’s no suggestion that anything is really changing other than that’s there is transparency,” said Robert Steinbrook, MD, director of the Health Research Group at Public Citizen.

Still, Dr. Steinbrook told this news organization, “it’s better to know this than to not know this.”

The unchanging nature of industry-physician relationships “suggests that to reduce the volume and magnitude of payments, more would need to be done,” he said.

“Really, this should be banned. Doctors should not be allowed to get gifts from pharmaceutical companies,” said Adriane Fugh-Berman, MD, professor of pharmacology and physiology at Georgetown University, and director of PharmedOut, a Georgetown-based project that advances evidence-based prescribing and educates healthcare professionals about pharmaceutical marketing practices.

“The interactions wouldn’t be happening unless there was a purpose for them,” said Dr. Marshall. The relationships are “built with intention,” Dr. Marshall told this news organization.
 

Top Earners Range From $195,000 to $4.8 Million

Payments to the median physician over the study period ranged from $0 to $2339, but the mean payment to top earners — those in the top 0.1% — ranged from $194,933 for hospitalists to $4.8 million for orthopedic specialists.

Overall, the median payment was $48 per physician.

But small dollar amounts should not be discounted — even if it’s just a $25-catered lunch — said Aaron Mitchell, MD, a medical oncologist and assistant attending physician at Memorial Sloan Kettering Cancer Center in New York City who has studied industry-physician relationships. “The influence is not just in the dollar value,” Dr. Mitchell told this news organization. “It’s about the time listening to and the time in personal contact with industry representatives that these dollars are a marker for,” he said.

“There’s no such thing as a free lunch,” agreed Dr. Marshall. It’s “pretty well established” that lower-value payments do have influence, which is why academic institutions have established policies that limit gifts and meals and other payments from industry, she said.

Dr. Fugh-Berman said, “the size of the gift doesn’t really matter,” adding that research she conducted had shown that “accepting a meal increased not only the expense of the prescriptions that Medicare physicians wrote but also the number of prescriptions.”
 

Payments Mostly for High-Dollar Products

The top 25 drugs and devices that were related to industry payments tended to be high-cost brand-name products.

The top drug was Janssen’s Xarelto, an anticoagulant first approved in 2011 that costs about $600 a month, according to GoodRx. The drug has had annual sales of $4-$6 billion.

Xarelto was followed by Eliquis, another anticoagulant; Humira, used for a variety of autoimmune conditions including plaque psoriasis, rheumatoid arthritis, Crohn’s disease, and ulcerative colitis; Invokana, Jardiance, and Farxiga, all for type 2 diabetes.

The top medical devices included the da Vinci Surgical System, Mako SmartRobotics, CoreValve Evolut, Natrelle Implants, and Impella, a heart pump that received a US Food and Drug Administration (FDA) warning that it was associated with a heightened risk for death.
 

Industry Influence May Lead to Higher Cost, Poor Quality Care

Multiple studies have shown that payments to physicians tend to lead to increased prescribing and, often, higher costs for Medicare, a health system, or patients.

“I’m sure there are still a lot of physicians out there who think they’re getting away with something, that they can take meals, or they can take consulting fees and not be influenced, but there’s overwhelming data showing that it always influences you,” said Dr. Fugh-Berman.

One study in 2020 that used the Open Payments database found that physicians increase prescribing of the drugs for which they receive payment in the months just after the payment. The authors also showed that physicians who are paid prescribe lower-quality drugs following the payment, “although the magnitude is small and unlikely to be clinically significant.”

Dr. Marshall said that more studies are needed to determine whether quality of care is being affected when a physician prescribes a drug after an industry payment.

For now, there seems to be little appetite among physicians to give up the payments, said Dr. Marshall and others.

Physicians in some specialties see the payments as “an implicit statement about their value,” said Dr. Marshall.

In oncology, having received a lot of payments “gets worn more as a badge of honor,” said Dr. Mitchell.

The clinicians believe that “by collaborating with industry we are providing scientific expertise to help develop the next generation of technology and cures,” Dr. Mitchell said, adding that they see the payments “as a mark of their impact.”

Among the JAMA study authors, Joseph S. Ross, MD, reported that he is a deputy editor of JAMA but was not involved in decisions regarding acceptance of the manuscript or its review. Dr. Ross also reported receiving grants from the FDA, Johnson and Johnson, the Medical Devices Innovation Consortium, the Agency for Healthcare Research and Quality, and the National Heart, Lung, and Blood Institute. He was an expert witness in a qui tam suit alleging violations of the False Claims Act and Anti-Kickback Statute against Biogen that was settled in 2022. Dr. Steinbrook, Dr. Marshall, and Dr. Mitchell reported no relevant financial relationships. Dr. Fugh-Berman reported being an expert witness for plaintiffs in complaints about drug and device marketing practices.

A version of this article appeared on Medscape.com.

By this summer, state employees in Florida covered by state group health insurance plans should have access to free annual skin cancer screenings.

On March 1, 2024, legislation was unanimously passed by both chambers of the state legislature that will provide for the free screenings for this group as of July 1. Some 321,000 state employees would be eligible, at a cost of about $357,000 per year, according to a legislative analysis. Gov. Ron DeSantis (R) has received and is expected to sign the bill.

The analysis concluded that the bill would have a “significant negative fiscal impact on the state employee group health plan,” as screenings will ultimately reduce cancer incidence and related morbidity and mortality.

The screenings aim to provide access to patients who may think they might not be able to afford a visit or who may have other perceived or real barriers to going for a skin check, said Sima Jain, MD, president of the Florida Academy of Dermatology. “It’s really meant to give patients access who need it,” said Dr. Jain, a dermatologist in private practice in Orlando.

The goal is early detection. “If I do a simple excision on a melanoma and we catch it early, it’s done, it’s cured,” Dr. Jain told this news organization. “It’s a win-win. We catch it early and insurance companies pay less money,” she said.

An effort to have all insurers in the state provide free screenings failed in 2023. 

From 2016 to 2020, Florida had a higher overall incidence of melanoma at 25.4 per 100,000 than the national average of 22.5, according to the National Cancer Institute. The state had some 7500 cases of melanoma each year during that period. The incidence rate in some Florida counties is as high as 32.7-45.6 per 100,000.

The Florida legislation will allow physician assistants and advanced practice nurses who operate under the supervision of a dermatologist to conduct the screenings.

It’s not clear how many state employees will access the free skin checks. “I don’t expect to see a flood of skin cancer screenings,” said Dr. Jain, noting that she hopes that it attracts primarily those at highest risk.

Once the bill is signed by the governor, Florida will be the second state to cover skin cancer screenings in some way. Illinois has required free skin cancer screening for all insured residents since 2020.

A version of this article appeared on Medscape.com .

By this summer, state employees in Florida covered by state group health insurance plans should have access to free annual skin cancer screenings.

On March 1, 2024, legislation was unanimously passed by both chambers of the state legislature that will provide for the free screenings for this group as of July 1. Some 321,000 state employees would be eligible, at a cost of about $357,000 per year, according to a legislative analysis. Gov. Ron DeSantis (R) has received and is expected to sign the bill.

The analysis concluded that the bill would have a “significant negative fiscal impact on the state employee group health plan,” as screenings will ultimately reduce cancer incidence and related morbidity and mortality.

The screenings aim to provide access to patients who may think they might not be able to afford a visit or who may have other perceived or real barriers to going for a skin check, said Sima Jain, MD, president of the Florida Academy of Dermatology. “It’s really meant to give patients access who need it,” said Dr. Jain, a dermatologist in private practice in Orlando.

The goal is early detection. “If I do a simple excision on a melanoma and we catch it early, it’s done, it’s cured,” Dr. Jain told this news organization. “It’s a win-win. We catch it early and insurance companies pay less money,” she said.

An effort to have all insurers in the state provide free screenings failed in 2023. 

From 2016 to 2020, Florida had a higher overall incidence of melanoma at 25.4 per 100,000 than the national average of 22.5, according to the National Cancer Institute. The state had some 7500 cases of melanoma each year during that period. The incidence rate in some Florida counties is as high as 32.7-45.6 per 100,000.

The Florida legislation will allow physician assistants and advanced practice nurses who operate under the supervision of a dermatologist to conduct the screenings.

It’s not clear how many state employees will access the free skin checks. “I don’t expect to see a flood of skin cancer screenings,” said Dr. Jain, noting that she hopes that it attracts primarily those at highest risk.

Once the bill is signed by the governor, Florida will be the second state to cover skin cancer screenings in some way. Illinois has required free skin cancer screening for all insured residents since 2020.

A version of this article appeared on Medscape.com .

By this summer, state employees in Florida covered by state group health insurance plans should have access to free annual skin cancer screenings.

On March 1, 2024, legislation was unanimously passed by both chambers of the state legislature that will provide for the free screenings for this group as of July 1. Some 321,000 state employees would be eligible, at a cost of about $357,000 per year, according to a legislative analysis. Gov. Ron DeSantis (R) has received and is expected to sign the bill.

The analysis concluded that the bill would have a “significant negative fiscal impact on the state employee group health plan,” as screenings will ultimately reduce cancer incidence and related morbidity and mortality.

The screenings aim to provide access to patients who may think they might not be able to afford a visit or who may have other perceived or real barriers to going for a skin check, said Sima Jain, MD, president of the Florida Academy of Dermatology. “It’s really meant to give patients access who need it,” said Dr. Jain, a dermatologist in private practice in Orlando.

The goal is early detection. “If I do a simple excision on a melanoma and we catch it early, it’s done, it’s cured,” Dr. Jain told this news organization. “It’s a win-win. We catch it early and insurance companies pay less money,” she said.

An effort to have all insurers in the state provide free screenings failed in 2023. 

From 2016 to 2020, Florida had a higher overall incidence of melanoma at 25.4 per 100,000 than the national average of 22.5, according to the National Cancer Institute. The state had some 7500 cases of melanoma each year during that period. The incidence rate in some Florida counties is as high as 32.7-45.6 per 100,000.

The Florida legislation will allow physician assistants and advanced practice nurses who operate under the supervision of a dermatologist to conduct the screenings.

It’s not clear how many state employees will access the free skin checks. “I don’t expect to see a flood of skin cancer screenings,” said Dr. Jain, noting that she hopes that it attracts primarily those at highest risk.

Once the bill is signed by the governor, Florida will be the second state to cover skin cancer screenings in some way. Illinois has required free skin cancer screening for all insured residents since 2020.

A version of this article appeared on Medscape.com .

The US Food and Drug Administration (FDA) embraced the use of biomarkers and surrogate endpoints in its most recent guidance on developing therapeutics for early Alzheimer’s disease.

The agency’s draft guidance is the first update since 2018 for products aimed at the earliest stages of the disease, which the FDA defines as stages 1, 2, and 3. Such guidance — when it is made final, after public comment closes in mid-May — is considered a template that will guide discussions between the FDA and drug makers and help determine the structure of clinical trials.

It is considered the FDA’s “current thinking on the topic,” and should not be construed as “legally enforceable responsibilities,” the FDA document, which was published March 12, noted.

In a statement to this news agency, the Alzheimer’s Association said it “is fully supportive of the FDA’s revised draft guidance.”

The association is enthusiastic about the agency’s encouragement of “the use of biologically based diagnostic criteria that are grounded in a contemporary understanding of the pathophysiology and evolution” of Alzheimer’s disease, Rebecca M. Edelmayer, PhD, senior director of scientific engagement for the Alzheimer’s Association, said in the statement.

Dr. Edelmayer noted that an Alzheimer’s Association work group is “leading the process of defining and building consensus for biologically based diagnostic and staging criteria for Alzheimer’s disease.
 

A New POV

The FDA noted that “it is expected that biomarker evidence of disease will establish the reliable diagnosis of subjects in trials of early Alzheimer’s disease.” This is crucial when many individuals in the earliest phases of Alzheimer’s disease may have mild cognitive decline but no functional decline, the agency added.

In 2018, the FDA suggested that biomarker evidence of disease might only play a role in identifying trial participants but should not be a defining element. 

In another shift away from 2018 guidance, the FDA gave more credence to surrogate endpoints as measures of a drug’s efficacy for early disease.

“Surrogate endpoints or intermediate clinical endpoints that do not directly measure clinical benefit but that are considered reasonably likely to predict clinical benefit may support an accelerated approval,” the agency noted. 

The FDA added that it “has considered a reduction of the brain amyloid beta burden, as assessed by positron emission tomography, to be a surrogate endpoint that is ‘reasonably likely to predict clinical benefit,’ ” noting that this endpoint was used as a basis for accelerated approval for the monoclonal antibodies lecanemab (Leqembi) and aducanumab (Aduhelm).

“The FDA has determined there is substantial evidence that reduction of amyloid beta plaques in the brain is reasonably likely to predict important clinical benefits to patients,” said Dr. Edelmayer, adding the agency’s “determination is correct.”

However, she noted, “’reasonably likely’ is not a guarantee, and long-term, real-world data in representative populations is required to provide more conclusive evidence,” which is why the FDA requires post-approval studies for accelerated approvals. 
 

A Faster Pathway to Approval 

The agency noted that clinical outcomes should also be measured in trials of products seeking accelerated approval, “to assess early clinical changes that may potentially provide support for any changes observed on biomarkers.”

Indeed, it’s not always a slam-dunk for drugs that may show positive effects on biomarkers. The FDA is taking a closer look at donanemab for early symptomatic Alzheimer’s disease. Patients were enrolled based on PET-positive amyloid or tau, but efficacy was evaluated based on cognition and functional measures. 

Earlier this month the agency postponed an approval decision and instead will convene an advisory panel meeting to assess overall safety and efficacy and the unique trial design, which allowed patients to stop treatment based on amyloid levels.

The FDA emphasized throughout its guidance document that it is trying to find a faster pathway to approval for therapies for early Alzheimer’s disease. If conventional approaches for testing therapeutics were used in early disease it might “take longer to establish a clinically meaningful treatment effect” because of the “minimal or absent cognitive and functional deficits seen in those stages of the disease,” the agency wrote.

The use of surrogate endpoints “may allow for shorter trial durations,” the FDA added. 

Dr. Edelmayer applauded the agency’s efforts to shorten the process. “Finding ways to make the trials shorter and easier to conduct, without sacrificing scientific rigor or patient safety, is a very worthwhile thing to do,” she said.

The FDA noted that a key principle in developing guidance for early Alzheimer’s disease therapies is that treatment “must begin before there are overt clinical symptoms.” 

“We enthusiastically support this idea,” said Dr. Edelmeyer. “Prevention of Alzheimer’s dementia is possible through changing the course, stopping the progression, and eventually interrupting the causes of the disease, most likely through a combination of lifestyle/behavior choices and pharmaceutical intervention,” she added.

A version of this article appeared on Medscape.com.

The US Food and Drug Administration (FDA) embraced the use of biomarkers and surrogate endpoints in its most recent guidance on developing therapeutics for early Alzheimer’s disease.

The agency’s draft guidance is the first update since 2018 for products aimed at the earliest stages of the disease, which the FDA defines as stages 1, 2, and 3. Such guidance — when it is made final, after public comment closes in mid-May — is considered a template that will guide discussions between the FDA and drug makers and help determine the structure of clinical trials.

It is considered the FDA’s “current thinking on the topic,” and should not be construed as “legally enforceable responsibilities,” the FDA document, which was published March 12, noted.

In a statement to this news agency, the Alzheimer’s Association said it “is fully supportive of the FDA’s revised draft guidance.”

The association is enthusiastic about the agency’s encouragement of “the use of biologically based diagnostic criteria that are grounded in a contemporary understanding of the pathophysiology and evolution” of Alzheimer’s disease, Rebecca M. Edelmayer, PhD, senior director of scientific engagement for the Alzheimer’s Association, said in the statement.

Dr. Edelmayer noted that an Alzheimer’s Association work group is “leading the process of defining and building consensus for biologically based diagnostic and staging criteria for Alzheimer’s disease.
 

A New POV

The FDA noted that “it is expected that biomarker evidence of disease will establish the reliable diagnosis of subjects in trials of early Alzheimer’s disease.” This is crucial when many individuals in the earliest phases of Alzheimer’s disease may have mild cognitive decline but no functional decline, the agency added.

In 2018, the FDA suggested that biomarker evidence of disease might only play a role in identifying trial participants but should not be a defining element. 

In another shift away from 2018 guidance, the FDA gave more credence to surrogate endpoints as measures of a drug’s efficacy for early disease.

“Surrogate endpoints or intermediate clinical endpoints that do not directly measure clinical benefit but that are considered reasonably likely to predict clinical benefit may support an accelerated approval,” the agency noted. 

The FDA added that it “has considered a reduction of the brain amyloid beta burden, as assessed by positron emission tomography, to be a surrogate endpoint that is ‘reasonably likely to predict clinical benefit,’ ” noting that this endpoint was used as a basis for accelerated approval for the monoclonal antibodies lecanemab (Leqembi) and aducanumab (Aduhelm).

“The FDA has determined there is substantial evidence that reduction of amyloid beta plaques in the brain is reasonably likely to predict important clinical benefits to patients,” said Dr. Edelmayer, adding the agency’s “determination is correct.”

However, she noted, “’reasonably likely’ is not a guarantee, and long-term, real-world data in representative populations is required to provide more conclusive evidence,” which is why the FDA requires post-approval studies for accelerated approvals. 
 

A Faster Pathway to Approval 

The agency noted that clinical outcomes should also be measured in trials of products seeking accelerated approval, “to assess early clinical changes that may potentially provide support for any changes observed on biomarkers.”

Indeed, it’s not always a slam-dunk for drugs that may show positive effects on biomarkers. The FDA is taking a closer look at donanemab for early symptomatic Alzheimer’s disease. Patients were enrolled based on PET-positive amyloid or tau, but efficacy was evaluated based on cognition and functional measures. 

Earlier this month the agency postponed an approval decision and instead will convene an advisory panel meeting to assess overall safety and efficacy and the unique trial design, which allowed patients to stop treatment based on amyloid levels.

The FDA emphasized throughout its guidance document that it is trying to find a faster pathway to approval for therapies for early Alzheimer’s disease. If conventional approaches for testing therapeutics were used in early disease it might “take longer to establish a clinically meaningful treatment effect” because of the “minimal or absent cognitive and functional deficits seen in those stages of the disease,” the agency wrote.

The use of surrogate endpoints “may allow for shorter trial durations,” the FDA added. 

Dr. Edelmayer applauded the agency’s efforts to shorten the process. “Finding ways to make the trials shorter and easier to conduct, without sacrificing scientific rigor or patient safety, is a very worthwhile thing to do,” she said.

The FDA noted that a key principle in developing guidance for early Alzheimer’s disease therapies is that treatment “must begin before there are overt clinical symptoms.” 

“We enthusiastically support this idea,” said Dr. Edelmeyer. “Prevention of Alzheimer’s dementia is possible through changing the course, stopping the progression, and eventually interrupting the causes of the disease, most likely through a combination of lifestyle/behavior choices and pharmaceutical intervention,” she added.

A version of this article appeared on Medscape.com.

The US Food and Drug Administration (FDA) embraced the use of biomarkers and surrogate endpoints in its most recent guidance on developing therapeutics for early Alzheimer’s disease.

The agency’s draft guidance is the first update since 2018 for products aimed at the earliest stages of the disease, which the FDA defines as stages 1, 2, and 3. Such guidance — when it is made final, after public comment closes in mid-May — is considered a template that will guide discussions between the FDA and drug makers and help determine the structure of clinical trials.

It is considered the FDA’s “current thinking on the topic,” and should not be construed as “legally enforceable responsibilities,” the FDA document, which was published March 12, noted.

In a statement to this news agency, the Alzheimer’s Association said it “is fully supportive of the FDA’s revised draft guidance.”

The association is enthusiastic about the agency’s encouragement of “the use of biologically based diagnostic criteria that are grounded in a contemporary understanding of the pathophysiology and evolution” of Alzheimer’s disease, Rebecca M. Edelmayer, PhD, senior director of scientific engagement for the Alzheimer’s Association, said in the statement.

Dr. Edelmayer noted that an Alzheimer’s Association work group is “leading the process of defining and building consensus for biologically based diagnostic and staging criteria for Alzheimer’s disease.
 

A New POV

The FDA noted that “it is expected that biomarker evidence of disease will establish the reliable diagnosis of subjects in trials of early Alzheimer’s disease.” This is crucial when many individuals in the earliest phases of Alzheimer’s disease may have mild cognitive decline but no functional decline, the agency added.

In 2018, the FDA suggested that biomarker evidence of disease might only play a role in identifying trial participants but should not be a defining element. 

In another shift away from 2018 guidance, the FDA gave more credence to surrogate endpoints as measures of a drug’s efficacy for early disease.

“Surrogate endpoints or intermediate clinical endpoints that do not directly measure clinical benefit but that are considered reasonably likely to predict clinical benefit may support an accelerated approval,” the agency noted. 

The FDA added that it “has considered a reduction of the brain amyloid beta burden, as assessed by positron emission tomography, to be a surrogate endpoint that is ‘reasonably likely to predict clinical benefit,’ ” noting that this endpoint was used as a basis for accelerated approval for the monoclonal antibodies lecanemab (Leqembi) and aducanumab (Aduhelm).

“The FDA has determined there is substantial evidence that reduction of amyloid beta plaques in the brain is reasonably likely to predict important clinical benefits to patients,” said Dr. Edelmayer, adding the agency’s “determination is correct.”

However, she noted, “’reasonably likely’ is not a guarantee, and long-term, real-world data in representative populations is required to provide more conclusive evidence,” which is why the FDA requires post-approval studies for accelerated approvals. 
 

A Faster Pathway to Approval 

The agency noted that clinical outcomes should also be measured in trials of products seeking accelerated approval, “to assess early clinical changes that may potentially provide support for any changes observed on biomarkers.”

Indeed, it’s not always a slam-dunk for drugs that may show positive effects on biomarkers. The FDA is taking a closer look at donanemab for early symptomatic Alzheimer’s disease. Patients were enrolled based on PET-positive amyloid or tau, but efficacy was evaluated based on cognition and functional measures. 

Earlier this month the agency postponed an approval decision and instead will convene an advisory panel meeting to assess overall safety and efficacy and the unique trial design, which allowed patients to stop treatment based on amyloid levels.

The FDA emphasized throughout its guidance document that it is trying to find a faster pathway to approval for therapies for early Alzheimer’s disease. If conventional approaches for testing therapeutics were used in early disease it might “take longer to establish a clinically meaningful treatment effect” because of the “minimal or absent cognitive and functional deficits seen in those stages of the disease,” the agency wrote.

The use of surrogate endpoints “may allow for shorter trial durations,” the FDA added. 

Dr. Edelmayer applauded the agency’s efforts to shorten the process. “Finding ways to make the trials shorter and easier to conduct, without sacrificing scientific rigor or patient safety, is a very worthwhile thing to do,” she said.

The FDA noted that a key principle in developing guidance for early Alzheimer’s disease therapies is that treatment “must begin before there are overt clinical symptoms.” 

“We enthusiastically support this idea,” said Dr. Edelmeyer. “Prevention of Alzheimer’s dementia is possible through changing the course, stopping the progression, and eventually interrupting the causes of the disease, most likely through a combination of lifestyle/behavior choices and pharmaceutical intervention,” she added.

A version of this article appeared on Medscape.com.

Nearly 18 months after the US Food and Drug Administration (FDA) first acknowledged a national shortage of Adderall, the most common drug used to treat attention-deficit/hyperactivity disorder (ADHD), there is now a widespread scarcity of other stimulant medications — with no end in sight. How did this crisis develop and what measures are underway to address it?

The first shortage of immediate release formulations of amphetamine mixed salts (Adderall, Adderall IR) was reported by the FDA in October 2022. Now, the list includes Focalin, Ritalin, and Vyvanse, among others.

Adding to the ongoing crisis, the FDA announced in early February that Azurity Pharmaceuticals was voluntarily withdrawing one lot of its Zenzedi (dextroamphetamine sulfate) 30 mg tablets because of contamination with the antihistamine, carbinoxamine.

For the roughly 10 million adults and 6 million children in the United States grappling with ADHD, getting a prescription filled with the exact medication ordered by a physician is dictated by geographic location, insurance formularies, and pharmacy supply chains. It’s particularly challenging for those who live in rural or underserved areas with limited access to nearby pharmacies.

“Not a day goes by when I don’t hear from a number of unfortunately struggling patients about this shortage,” said Aditya Pawar, MD, a child and adolescent psychiatrist with the Kennedy Krieger Institute and an assistant professor of psychiatry and behavioral sciences at Johns Hopkins School of Medicine, Baltimore, Maryland.

The ADHD drug shortage is now well into its second year, and clinicians and advocates alike say there is no apparent end in sight.

How Did We Get Here?

Manufacturers and federal agencies blame the shortage on rising demand and each other, while clinicians say that insurers, drug distributors, and middlemen are also playing a role in keeping medications out of patients’ hands.

In August 2023, the Drug Enforcement Administration (DEA), which sets quotas for the production of controlled substances, and the FDA publicly blamed manufacturers for the shortages, claiming they were not using up their allocations.

At the time, the DEA said manufacturers made and sold only 70% of their quota, nearly 1 billion doses short of what they were allowed to produce and ship that year.

The agencies also noted a record-high number of prescriptions for stimulants from 2012 to 2021. Driven in part by telehealth, the demand intensified during the pandemic. One recent study reported a 14% increase in ADHD stimulant prescriptions between 2020 and 2022.

Insurers also play a role in the shortage, David Goodman, MD, an assistant professor of psychiatry and behavioral sciences also at Johns Hopkins University, told this news organization.

Stepped therapy — in which patients must try one, two, or three medications before they are authorized to receive a more expensive or newer drug — contributes to the problem, Dr. Goodman said. Demand for such medications is high and supply low. In addition, some insurers only provide coverage for in-network pharmacies, regardless of the ability of other providers outside such networks to fill prescriptions.

“If the insurance dictates where you get your pills, and that pharmacy doesn’t have the pills or that pharmacy chain in your area doesn’t have those pills, you’re out of luck,” Dr. Goodman said.

Patients as Detectives

To get prescriptions filled, patients must “turn into detectives,” Laurie Kulikosky, CEO of Children and Adults with Attention-Deficit/Hyperactivity Disorder, told this news organization. “It’s a huge stressor.”

Tracking which ADHD medications are available, on back order, or discontinued requires frequent checking of the FDA’s drug shortages website.

Some manufacturers of generic versions of mixed amphetamine salts are only fulfilling orders for existing contracts, while others say new product won’t be available until at least April or as late as September. All blame the delay on the shortage of active ingredients.

Teva, which makes both the brand and generic of Adderall, reported on the FDA’s site that its manufacturing and distribution is at record-high levels, but demand continues to rise.

The branded Concerta is available, but some makers of generic methylphenidate reported supplies won’t be available until July.

Lisdexamfetamine dimesylate in almost all dosages is either unavailable, available in restricted quantities, or on extended back order. However, the branded product Vyvanse is available.

Industry, Government Respond

In a November 2023 statement, the DEA reported that 17 of 18 drug manufacturers the agency contacted planned to use their full DEA quota and increase production for that year. The agency said it had made it easier for manufacturers to request changes in allocations and that periodically updating quotas was a possibility.

This news organization asked the DEA whether any manufacturers had not met their 2023 quotas, but an agency spokesperson said it would not comment.

An FDA spokesperson said it could help manufacturers ask for bigger quotas and to increase production, noting that in 2023, the DEA increased the quota for methylphenidate following an FDA request.

“The FDA is in frequent communication with the manufacturers of ADHD stimulant medications and the DEA, and we will continue to monitor supply,” the spokesperson said.

For 2024, the FDA told the DEA that it predicted a 3.1% increase in use of amphetamine, methylphenidate (including dexmethylphenidate), and lisdexamfetamine. The DEA took that into account when it issued its final quotas for 2024. Whether those amounts will be enough remains to be seen.

With many drugs — not just those for ADHD — in short supply, in February, the US Department of Health and Human Services (HHS) and the Federal Trade Commission opened an inquiry of sorts, seeking comments on how middlemen and others were influencing pricing and supply of generic drugs.

“When you’re prescribed an important medication by your doctor and you learn the drug is out of stock, your heart sinks,” HHS Secretary Xavier Becerra said in a statement. “This devastating reality is the case for too many Americans who need generic drugs for ADHD, cancer, and other conditions.”

On the comments site, which is open until April 15, many of the 4000-plus complaints filed to-date are from individuals with ADHD.

Dr. Pawar said clinicians can’t know what’s going on between the FDA, the DEA, and manufacturers, adding that, “they need to sit together and figure something out.”

Even Members of Congress have had trouble getting answers. In October, Rep. Abigail Spanberger (D-Virginia) and a dozen colleagues wrote to the FDA and DEA seeking information on how the agencies were responding to stimulant shortages. The DEA has still not replied.

Workarounds the Only Option?

In the past, physicians would prescribe the optimal medication for individual patients based on clinical factors. Now, one of the major factors in determining drug choice is the agent that has “the highest likelihood of benefit and the lowest likelihood of administrative demand or burden,” Dr. Goodman said.

With so many medications in short supply, clinicians have figured out workarounds to get prescriptions filled, but they don’t often pan out.

If a patient needs a 60-mg daily dose of a medication and the pharmacy doesn’t have any 60-mg pills, Dr. Goodman said he might write a prescription for a 30-mg pill to be taken twice a day. However, insurers often will cover only 30 pills for a month, which can thwart this strategy.

Dr. Pawar said he sometimes prescribes Journay PM in lieu of Concerta because it is often available. But insurers may deny coverage of Journay PM because it is a newer medication, he said. When prescribing ADHD medications, he also provides his patients with a list of potential substitutes so they can ask the pharmacist if any are in stock.

With no end to the shortage in sight, clinicians must often prescribe multiple medications until their patients are able to find one that’s available. In addition, patients are burdened with making calls and visits to multiple pharmacies until they find one that can fill their prescription.

Meanwhile, the ripple effects to the ADHD drug shortage continue to spread. Extended periods without treatment can lead to declining job performance or job loss, fractured relationships, and even financial distress, Dr. Goodman said.

“If you go without your pills for a month and you’re not performing, your work declines and you lose your job as a result, that’s not on you — that’s on the fact that you can’t get your treatment,” he noted. “The shortage is no longer an inconvenience.”

Dr. Goodman, Dr. Pawar, and Ms. Kulikosky reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

Nearly 18 months after the US Food and Drug Administration (FDA) first acknowledged a national shortage of Adderall, the most common drug used to treat attention-deficit/hyperactivity disorder (ADHD), there is now a widespread scarcity of other stimulant medications — with no end in sight. How did this crisis develop and what measures are underway to address it?

The first shortage of immediate release formulations of amphetamine mixed salts (Adderall, Adderall IR) was reported by the FDA in October 2022. Now, the list includes Focalin, Ritalin, and Vyvanse, among others.

Adding to the ongoing crisis, the FDA announced in early February that Azurity Pharmaceuticals was voluntarily withdrawing one lot of its Zenzedi (dextroamphetamine sulfate) 30 mg tablets because of contamination with the antihistamine, carbinoxamine.

For the roughly 10 million adults and 6 million children in the United States grappling with ADHD, getting a prescription filled with the exact medication ordered by a physician is dictated by geographic location, insurance formularies, and pharmacy supply chains. It’s particularly challenging for those who live in rural or underserved areas with limited access to nearby pharmacies.

“Not a day goes by when I don’t hear from a number of unfortunately struggling patients about this shortage,” said Aditya Pawar, MD, a child and adolescent psychiatrist with the Kennedy Krieger Institute and an assistant professor of psychiatry and behavioral sciences at Johns Hopkins School of Medicine, Baltimore, Maryland.

The ADHD drug shortage is now well into its second year, and clinicians and advocates alike say there is no apparent end in sight.

How Did We Get Here?

Manufacturers and federal agencies blame the shortage on rising demand and each other, while clinicians say that insurers, drug distributors, and middlemen are also playing a role in keeping medications out of patients’ hands.

In August 2023, the Drug Enforcement Administration (DEA), which sets quotas for the production of controlled substances, and the FDA publicly blamed manufacturers for the shortages, claiming they were not using up their allocations.

At the time, the DEA said manufacturers made and sold only 70% of their quota, nearly 1 billion doses short of what they were allowed to produce and ship that year.

The agencies also noted a record-high number of prescriptions for stimulants from 2012 to 2021. Driven in part by telehealth, the demand intensified during the pandemic. One recent study reported a 14% increase in ADHD stimulant prescriptions between 2020 and 2022.

Insurers also play a role in the shortage, David Goodman, MD, an assistant professor of psychiatry and behavioral sciences also at Johns Hopkins University, told this news organization.

Stepped therapy — in which patients must try one, two, or three medications before they are authorized to receive a more expensive or newer drug — contributes to the problem, Dr. Goodman said. Demand for such medications is high and supply low. In addition, some insurers only provide coverage for in-network pharmacies, regardless of the ability of other providers outside such networks to fill prescriptions.

“If the insurance dictates where you get your pills, and that pharmacy doesn’t have the pills or that pharmacy chain in your area doesn’t have those pills, you’re out of luck,” Dr. Goodman said.

Patients as Detectives

To get prescriptions filled, patients must “turn into detectives,” Laurie Kulikosky, CEO of Children and Adults with Attention-Deficit/Hyperactivity Disorder, told this news organization. “It’s a huge stressor.”

Tracking which ADHD medications are available, on back order, or discontinued requires frequent checking of the FDA’s drug shortages website.

Some manufacturers of generic versions of mixed amphetamine salts are only fulfilling orders for existing contracts, while others say new product won’t be available until at least April or as late as September. All blame the delay on the shortage of active ingredients.

Teva, which makes both the brand and generic of Adderall, reported on the FDA’s site that its manufacturing and distribution is at record-high levels, but demand continues to rise.

The branded Concerta is available, but some makers of generic methylphenidate reported supplies won’t be available until July.

Lisdexamfetamine dimesylate in almost all dosages is either unavailable, available in restricted quantities, or on extended back order. However, the branded product Vyvanse is available.

Industry, Government Respond

In a November 2023 statement, the DEA reported that 17 of 18 drug manufacturers the agency contacted planned to use their full DEA quota and increase production for that year. The agency said it had made it easier for manufacturers to request changes in allocations and that periodically updating quotas was a possibility.

This news organization asked the DEA whether any manufacturers had not met their 2023 quotas, but an agency spokesperson said it would not comment.

An FDA spokesperson said it could help manufacturers ask for bigger quotas and to increase production, noting that in 2023, the DEA increased the quota for methylphenidate following an FDA request.

“The FDA is in frequent communication with the manufacturers of ADHD stimulant medications and the DEA, and we will continue to monitor supply,” the spokesperson said.

For 2024, the FDA told the DEA that it predicted a 3.1% increase in use of amphetamine, methylphenidate (including dexmethylphenidate), and lisdexamfetamine. The DEA took that into account when it issued its final quotas for 2024. Whether those amounts will be enough remains to be seen.

With many drugs — not just those for ADHD — in short supply, in February, the US Department of Health and Human Services (HHS) and the Federal Trade Commission opened an inquiry of sorts, seeking comments on how middlemen and others were influencing pricing and supply of generic drugs.

“When you’re prescribed an important medication by your doctor and you learn the drug is out of stock, your heart sinks,” HHS Secretary Xavier Becerra said in a statement. “This devastating reality is the case for too many Americans who need generic drugs for ADHD, cancer, and other conditions.”

On the comments site, which is open until April 15, many of the 4000-plus complaints filed to-date are from individuals with ADHD.

Dr. Pawar said clinicians can’t know what’s going on between the FDA, the DEA, and manufacturers, adding that, “they need to sit together and figure something out.”

Even Members of Congress have had trouble getting answers. In October, Rep. Abigail Spanberger (D-Virginia) and a dozen colleagues wrote to the FDA and DEA seeking information on how the agencies were responding to stimulant shortages. The DEA has still not replied.

Workarounds the Only Option?

In the past, physicians would prescribe the optimal medication for individual patients based on clinical factors. Now, one of the major factors in determining drug choice is the agent that has “the highest likelihood of benefit and the lowest likelihood of administrative demand or burden,” Dr. Goodman said.

With so many medications in short supply, clinicians have figured out workarounds to get prescriptions filled, but they don’t often pan out.

If a patient needs a 60-mg daily dose of a medication and the pharmacy doesn’t have any 60-mg pills, Dr. Goodman said he might write a prescription for a 30-mg pill to be taken twice a day. However, insurers often will cover only 30 pills for a month, which can thwart this strategy.

Dr. Pawar said he sometimes prescribes Journay PM in lieu of Concerta because it is often available. But insurers may deny coverage of Journay PM because it is a newer medication, he said. When prescribing ADHD medications, he also provides his patients with a list of potential substitutes so they can ask the pharmacist if any are in stock.

With no end to the shortage in sight, clinicians must often prescribe multiple medications until their patients are able to find one that’s available. In addition, patients are burdened with making calls and visits to multiple pharmacies until they find one that can fill their prescription.

Meanwhile, the ripple effects to the ADHD drug shortage continue to spread. Extended periods without treatment can lead to declining job performance or job loss, fractured relationships, and even financial distress, Dr. Goodman said.

“If you go without your pills for a month and you’re not performing, your work declines and you lose your job as a result, that’s not on you — that’s on the fact that you can’t get your treatment,” he noted. “The shortage is no longer an inconvenience.”

Dr. Goodman, Dr. Pawar, and Ms. Kulikosky reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

Nearly 18 months after the US Food and Drug Administration (FDA) first acknowledged a national shortage of Adderall, the most common drug used to treat attention-deficit/hyperactivity disorder (ADHD), there is now a widespread scarcity of other stimulant medications — with no end in sight. How did this crisis develop and what measures are underway to address it?

The first shortage of immediate release formulations of amphetamine mixed salts (Adderall, Adderall IR) was reported by the FDA in October 2022. Now, the list includes Focalin, Ritalin, and Vyvanse, among others.

Adding to the ongoing crisis, the FDA announced in early February that Azurity Pharmaceuticals was voluntarily withdrawing one lot of its Zenzedi (dextroamphetamine sulfate) 30 mg tablets because of contamination with the antihistamine, carbinoxamine.

For the roughly 10 million adults and 6 million children in the United States grappling with ADHD, getting a prescription filled with the exact medication ordered by a physician is dictated by geographic location, insurance formularies, and pharmacy supply chains. It’s particularly challenging for those who live in rural or underserved areas with limited access to nearby pharmacies.

“Not a day goes by when I don’t hear from a number of unfortunately struggling patients about this shortage,” said Aditya Pawar, MD, a child and adolescent psychiatrist with the Kennedy Krieger Institute and an assistant professor of psychiatry and behavioral sciences at Johns Hopkins School of Medicine, Baltimore, Maryland.

The ADHD drug shortage is now well into its second year, and clinicians and advocates alike say there is no apparent end in sight.

How Did We Get Here?

Manufacturers and federal agencies blame the shortage on rising demand and each other, while clinicians say that insurers, drug distributors, and middlemen are also playing a role in keeping medications out of patients’ hands.

In August 2023, the Drug Enforcement Administration (DEA), which sets quotas for the production of controlled substances, and the FDA publicly blamed manufacturers for the shortages, claiming they were not using up their allocations.

At the time, the DEA said manufacturers made and sold only 70% of their quota, nearly 1 billion doses short of what they were allowed to produce and ship that year.

The agencies also noted a record-high number of prescriptions for stimulants from 2012 to 2021. Driven in part by telehealth, the demand intensified during the pandemic. One recent study reported a 14% increase in ADHD stimulant prescriptions between 2020 and 2022.

Insurers also play a role in the shortage, David Goodman, MD, an assistant professor of psychiatry and behavioral sciences also at Johns Hopkins University, told this news organization.

Stepped therapy — in which patients must try one, two, or three medications before they are authorized to receive a more expensive or newer drug — contributes to the problem, Dr. Goodman said. Demand for such medications is high and supply low. In addition, some insurers only provide coverage for in-network pharmacies, regardless of the ability of other providers outside such networks to fill prescriptions.

“If the insurance dictates where you get your pills, and that pharmacy doesn’t have the pills or that pharmacy chain in your area doesn’t have those pills, you’re out of luck,” Dr. Goodman said.

Patients as Detectives

To get prescriptions filled, patients must “turn into detectives,” Laurie Kulikosky, CEO of Children and Adults with Attention-Deficit/Hyperactivity Disorder, told this news organization. “It’s a huge stressor.”

Tracking which ADHD medications are available, on back order, or discontinued requires frequent checking of the FDA’s drug shortages website.

Some manufacturers of generic versions of mixed amphetamine salts are only fulfilling orders for existing contracts, while others say new product won’t be available until at least April or as late as September. All blame the delay on the shortage of active ingredients.

Teva, which makes both the brand and generic of Adderall, reported on the FDA’s site that its manufacturing and distribution is at record-high levels, but demand continues to rise.

The branded Concerta is available, but some makers of generic methylphenidate reported supplies won’t be available until July.

Lisdexamfetamine dimesylate in almost all dosages is either unavailable, available in restricted quantities, or on extended back order. However, the branded product Vyvanse is available.

Industry, Government Respond

In a November 2023 statement, the DEA reported that 17 of 18 drug manufacturers the agency contacted planned to use their full DEA quota and increase production for that year. The agency said it had made it easier for manufacturers to request changes in allocations and that periodically updating quotas was a possibility.

This news organization asked the DEA whether any manufacturers had not met their 2023 quotas, but an agency spokesperson said it would not comment.

An FDA spokesperson said it could help manufacturers ask for bigger quotas and to increase production, noting that in 2023, the DEA increased the quota for methylphenidate following an FDA request.

“The FDA is in frequent communication with the manufacturers of ADHD stimulant medications and the DEA, and we will continue to monitor supply,” the spokesperson said.

For 2024, the FDA told the DEA that it predicted a 3.1% increase in use of amphetamine, methylphenidate (including dexmethylphenidate), and lisdexamfetamine. The DEA took that into account when it issued its final quotas for 2024. Whether those amounts will be enough remains to be seen.

With many drugs — not just those for ADHD — in short supply, in February, the US Department of Health and Human Services (HHS) and the Federal Trade Commission opened an inquiry of sorts, seeking comments on how middlemen and others were influencing pricing and supply of generic drugs.

“When you’re prescribed an important medication by your doctor and you learn the drug is out of stock, your heart sinks,” HHS Secretary Xavier Becerra said in a statement. “This devastating reality is the case for too many Americans who need generic drugs for ADHD, cancer, and other conditions.”

On the comments site, which is open until April 15, many of the 4000-plus complaints filed to-date are from individuals with ADHD.

Dr. Pawar said clinicians can’t know what’s going on between the FDA, the DEA, and manufacturers, adding that, “they need to sit together and figure something out.”

Even Members of Congress have had trouble getting answers. In October, Rep. Abigail Spanberger (D-Virginia) and a dozen colleagues wrote to the FDA and DEA seeking information on how the agencies were responding to stimulant shortages. The DEA has still not replied.

Workarounds the Only Option?

In the past, physicians would prescribe the optimal medication for individual patients based on clinical factors. Now, one of the major factors in determining drug choice is the agent that has “the highest likelihood of benefit and the lowest likelihood of administrative demand or burden,” Dr. Goodman said.

With so many medications in short supply, clinicians have figured out workarounds to get prescriptions filled, but they don’t often pan out.

If a patient needs a 60-mg daily dose of a medication and the pharmacy doesn’t have any 60-mg pills, Dr. Goodman said he might write a prescription for a 30-mg pill to be taken twice a day. However, insurers often will cover only 30 pills for a month, which can thwart this strategy.

Dr. Pawar said he sometimes prescribes Journay PM in lieu of Concerta because it is often available. But insurers may deny coverage of Journay PM because it is a newer medication, he said. When prescribing ADHD medications, he also provides his patients with a list of potential substitutes so they can ask the pharmacist if any are in stock.

With no end to the shortage in sight, clinicians must often prescribe multiple medications until their patients are able to find one that’s available. In addition, patients are burdened with making calls and visits to multiple pharmacies until they find one that can fill their prescription.

Meanwhile, the ripple effects to the ADHD drug shortage continue to spread. Extended periods without treatment can lead to declining job performance or job loss, fractured relationships, and even financial distress, Dr. Goodman said.

“If you go without your pills for a month and you’re not performing, your work declines and you lose your job as a result, that’s not on you — that’s on the fact that you can’t get your treatment,” he noted. “The shortage is no longer an inconvenience.”

Dr. Goodman, Dr. Pawar, and Ms. Kulikosky reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

Alzheimer’s research is plagued with misconduct and fraud, undermining the progress toward understanding and treating the disease, say investigators who endeavor to expose errors and misleading practices.

The book is yet to be closed, for instance, on whether a 2006 paper by Sylvain Lesne positing amyloid as a major cause of Alzheimer’s was based on fraudulent data. Suspicions about the paper were first raised in late 2021 by Matthew Schrag, MD, PhD, an assistant professor of neurology at Vanderbilt University Medical Center, Nashville, Tennessee.

Dr. Schrag also queried the work of a City University of New York (CUNY) researcher who proposed PT-125 (now simufilam) as a potential anti-amyloid for Alzheimer’s disease. Even though CUNY recently found “egregious” and potentially deliberate misconduct by that researcher, Cassava Sciences is continuing phase 3 trials of simufilam.

Now questions are being raised about work from the lab of Berislav V. Zlokovic, PhD, a prominent neuroscientist at the University of Southern California (USC), Los Angeles, California, and also about studies conducted under the aegis of Domenico Pratico, MD, the director of the Alzheimer’s Center at Temple University in Philadelphia, Pennsylvania.

Alzheimer’s has been a notoriously hard puzzle to solve. Despite decades of research, there are still no effective therapies and disparate theories about potential causes.

Dr. Schrag said he wouldn’t “attribute all the ills in this field” to misconduct, but it “is absolutely a part of the equation.” Some of the papers flagged for integrity issues “have been hugely influential,” he said in an interview. “Some of the labs that we’re talking about have really shaped how we’ve thought about this disease,” he said. “It’s hard to un-ring the bell.”

The fallout from fraud has a wide impact. Taxpayer dollars are wasted in the creation of the fraud and in attempts to replicate the failed experiment. Grad students — the workhorses of labs — waste time trying to repeat studies or may be bullied or intimidated into misconduct, said Elisabeth Bik, PhD, a former Stanford microbiologist who is now a full-time fraud investigator.

And there’s potential harm to patients. “There’s a lot of false hope being given to these people and their families,” Dr. Bik said in an interview.
 

Alzheimer’s Tempts With Big Rewards

There are big rewards for those who publish important papers on Alzheimer’s: More grants, publication in higher-impact journals, larger labs, and potentially, personal enrichment from commercialization of therapies.

“I can see that people are driven to cut corners or even to make up results, or even anything in between, to reach that goal,” said Dr. Bik.

It’s unclear whether misconduct and fraud are on the rise or just being detected more frequently.

“It’s very hard to say,” said Mike Rossner, PhD, president of Image Data Integrity. Institutions hire Dr. Rossner to help ferret out research integrity issues. He told this news organization that it’s likely detection is on the rise, given the increasing number of sleuths like Dr. Bik.

In 2002, Dr. Rossner began to screen all images submitted to the Journal of Clinical Biology in response to the new phenomenon of digital images and the advent of PhotoShop. “Very early on, we started to see problems in digital images that we would not have seen on a glossy printout,” Dr. Rossner said of his time as managing editor of the journal.

From 2002 to 2014, at least 25% of papers had an image that violated guidelines that prohibited the removal of spots or other blemishes (called “beautification”) with PhotoShop, which did not necessarily indicate fraud. They withdrew acceptance for 1% of papers because of image manipulations that affected data interpretation.

Dr. Bik noted that even if there is not a greater percentage of fraudulent papers in Alzheimer’s, “it would still be in absolute numbers a lot of papers that could be fraudulent,” given that Alzheimer’s research is well-funded with federal agencies alone providing $3.7 billion a year.

Images Key to Spotting Issues

Investigative sleuths often use the online forum PubPeer to initially raise questions about papers. The format gives the original authors a chance to comment on or defend their work. While some critiques are about data, most hone in on alleged duplications or manipulations of images, primarily by Western Blots.

The images are key, because “the images are the data,” said Dr. Rossner. “The words are the author’s interpretation of what they see in the images,” he said.

It’s also easier to spot a problem in an image. The raw data or an investigator’s notebooks aren’t needed, and there are artificial intelligence-driven software programs such as Proofig and Image Twin that help investigators spot duplicated images or cases in which an image might have been flipped or otherwise manipulated to make results look better.

Science recently announced that it would be using Proofig to screen images in all papers submitted to its six journals.

Using a screening tool is better than nothing, said Dr. Rossner who still relies on visual inspection, employing contrast or other features in PhotoShop to spot inconsistencies or duplications. But “none of those companies have disclosed how effective they are relative to visual screening, and that to me is very problematic,” he said.

“The tools are not going to catch everything,” said Dr. Bik.

Dr. Schrag agreed. “One of the things that we’re worried about is that a lot of the journals will simply adopt these tools as a screener and assume that that’s going to de-risk their publication portfolio,” he said, noting the high rate of misses.

Artificial Intelligence a Growing Concern

Artificial intelligence (AI) may also accelerate the amount of fraud and add to the difficulty of ferreting it out, said the investigators.

“I’m very worried about AI,” said Dr. Bik. Although AI-generated images and content may be rudimentary today, “next year it’s going to be much better,” she said. Going forward, it may be hard to distinguish between a real dataset and one that has been generated by AI, she said.

“The more closely AI can mimic authentic content, the more difficult it will be for publications to detect intentionally fraudulent submissions,” wrote Dror Kolodkin-Gal, PhD, the founder of Proofig, in an article for the Council of Science Editors.

Dr. Kolodkin-Gal said that AI may be especially prone to misuse by paper mills. Those operations submit fake or shoddy manuscripts to a journal on behalf of researchers seeking publication who pay the mills a fee. The Committee on Publication Ethics reported in 2022 that 2%-46% of papers submitted to journals may be from paper mills.

While it’s unclear whether AI is having any impact now, Dr. Rossner said, “I think I can be pretty confident in saying it is going to be a growing problem” as the tools become more sophisticated.

He sees parallels with the rise of PhotoShop and cites data from the National Institute of Health’s Office of Research Integrity (ORI) showing that in 1990, when PhotoShop was still new, 2% of cases referred to ORI involved image manipulation. By 2007, 70% of cases had image manipulation issues.

Journals, Institutions Need to Step Up More

Fraud may continue apace in part because investigations drag on for years, and in many cases, with a lack of consequences for the perpetrators, said the investigators. And, they say, journals and institutions haven’t devoted enough resources to prevent or investigate misconduct.

“A lot of editors did not even want to investigate because they just didn’t want to believe that there could be fraud in science,” said Dr. Bik of her experiences. “I hope that by now most journals at least should have realized that some proportion of the manuscripts that get sent to their journals is going to be fraud,” she said.

“The bulk of the journals seem like they don’t want to be bothered by this,” agreed Dr. Schrag, adding that “some have gone to great lengths to try to discourage people from bringing forward complaints.”

A big issue is that journals “don’t answer to any higher authority,” said Dr. Schrag. He believes that journals that repeatedly refuse to address integrity issues should be barred from publishing research produced with funds from the National Institutes of Health.

All the investigators said institutions and journals should hire forensic investigators. Relying on unpaid peer reviewers or editors to root out fraud is unrealistic, they said.

“You want to have specialized people with experience and be paid to do that as a full-time job,” said Dr. Bik, who is funded by speaking engagements and receives about $2300 a month through donations to her Patreon account.

Once a potential integrity issue is flagged, there is “an incredible conflict of interest in how these investigations are run,” said Dr. Schrag. “Institutions are asked to investigate their own faculty; they’re asked to investigate themselves.” That “creates the disincentive to move expeditiously,” said Dr. Schrag.

With the space of time, people who have committed fraud can throw out notebooks, delete data from servers, or even PhotoShop original photos so they match the manipulated ones that were submitted, Dr. Bik said.

Institutions could show they are serious about fraud by offering a “central, systematic universal screening of all image data going out of their institutions before submission to a journal,” said Dr. Rossner. But he knows only of a handful that do so. “I think research integrity offices have historically been very reactive, and they need to pivot and become proactive,” said Dr. Rossner.

Dr. Schrag wants to see stronger values within the research enterprise. “You have to build a culture where it’s absolutely anathema at a core level to violate these standards of research integrity,” he said. “We have this notion that we can push the process along faster and get to a grant and get to a paper and get to some short-term goal,” he said. “But the long-term goal in most of these cases is to cure a disease or to understand some biological mysteries. There’s no shortcut to getting there,” said Dr. Schrag.

There have been some high-profile consequences for research integrity failures, such as the 2023 resignation of Stanford University President Marc Tessier-Lavigne in the wake of findings that members of his lab — but not Tessier-Lavigne — engaged in data manipulation.

The process is often opaque, with investigations done in secrecy. “Consequences are not usually revealed, either,” said Dr. Rossner.

Dr. Schrag acknowledges it’s a tough balancing act for institutions to root out bad actors while also ensuring there’s no harm to those who may simply have operated in error.

“But it doesn’t serve anyone’s interest including the people who are accused, in dragging these things out for 5, 6, 8, or 10 years,” he said.

Lesne and Cassava: The Long and Winding Road

The investigations into the Lesne papers and the work underpinning Cassava Sciences’ therapy point to the difficulty of policing integrity and the potential fallout.

Lesne’s signature paper published in Nature in 2006 has been cited some 2300 times and is the fourth most-accessed article of 81,612 articles of a similar age in all journals tracked by Altimetrics.

Dr. Schrag, Dr. Bik, and others wrote to multiple journals asking them to investigate some 25 papers related to simufilam, including a 2012 Journal of Clinical Investigation article by Hoau-Yan Wang, PhD, the CUNY scientist whose work on simufilam has been questioned.

JCI Editor Elizabeth McNally pushed back stating in an editorial in 2022 that they, as whistleblowers, had potential conflicts and that they could be assisting short sellers who were seeking to profit by depressing Cassava’s stock price. Indeed, Dr. Schrag was initially hired by a law firm that was representing short sellers. Ms. McNally said that JCI would start requiring disclosures by whistleblowers.

Dr. Bik urged CUNY to investigate Dr. Wang in 2021 but was rebuffed. Then, in November 2023, a copy of CUNY’s final report on the Wang inquiry was leaked to Science. The university reported that Dr. Wang did not provide any original data or notebooks and that it found “long-standing and egregious misconduct in data management and record keeping by Dr. Wang,” wrote Dr. Bik in a blog post summarizing the investigation.

As of late 2023, 42 papers by Dr. Wang have earned PubPeer posts, seven have been retracted, and five have been marked with an Expression of Concern, wrote Dr. Bik.

Some have called for Cassava to stop its phase 3 studies of simufilam, but the company is proceeding, announcing in November 2023 that they have completed enrollment.

Misconduct Queries Underway at USC and Temple

Meanwhile, Dr. Schrag and Dr. Bik continue sleuthing. They are among a small group of whistleblowers who have filed a complaint with NIH about irregularities in the Zlokovic lab at USC. They allege that images were manipulated in dozens of papers, including some that inform the development of a stroke drug in phase 2 trials.

The inquiry goes well beyond stroke, said Dr. Schrag. Dr. Zlokovic “is one of the most influential scientists on Alzheimer’s scientists in the country,” Dr. Schrag said. The USC scientist is a leader on blood-brain barrier research.

USC is investigating “at some level,” he said. In a statement to this news organization, USC said that it “takes any allegations about research integrity very seriously.” The statement added, “Consistent with federal regulations and USC policies, this review must be kept confidential. As a result, we are unable to provide any further information.”

Mu Yang, PhD, assistant professor of neurobiology at Columbia University Medical Center in New York City, is also working on the Zlokovic investigation.

She calls herself an “accidental sleuth” who fell into the hobby after a graduate student asked her to help replicate a study by Temple University, Philadelphia, Pennsylvania, researcher Dominco Pratico, MD, of Alzheimer’s-like phenotype mice in the Morris Water Maze test. Dr. Yang, who runs the “behavior core” at Columbia — teaching and advising on how to run assays and collect and report data — could see right away that the Pratico data were “too perfect.”

She enlisted maze inventor Richard Morris to join her in a letter of concern to the journals that published Dr. Pratico’s work, all under the aegis of Springer Nature.

The publisher’s integrity team has since retracted four Pratico papers. Three were because of image abnormalities pointed out by Dr. Bik, who worked with Dr. Yang. One was because of “self-plagiarism.”

“The official retraction notes didn’t mention anything about data abnormality being a concern,” said Dr. Yang who says that questionable data is harder to prove than an image duplication or manipulation. And the papers remain available, although dozens of Practico papers have been flagged on PubPeer.

To Dr. Yang, images are the canary in the coalmine. “People don’t just fake western blots but then give real behavior data or give you fake behavior data but give you the most authentic Western Blots,” she said.

Dr. Pratico has now sued a graduate student who was a coauthor on the papers, according to the Philadelphia Inquirer.

The NIH’s ORI has requested that Temple University conduct an investigation, Dr. Yang said.

In a statement to this news organization, Temple said it “does not comment on internal investigations or personnel issues,” but that “allegations of research misconduct are reviewed and investigated centrally through Temple’s Office of the Vice President for Research in accordance with university policy and applicable federal regulations.”

A version of this article appeared on Medscape.com.

Alzheimer’s research is plagued with misconduct and fraud, undermining the progress toward understanding and treating the disease, say investigators who endeavor to expose errors and misleading practices.

The book is yet to be closed, for instance, on whether a 2006 paper by Sylvain Lesne positing amyloid as a major cause of Alzheimer’s was based on fraudulent data. Suspicions about the paper were first raised in late 2021 by Matthew Schrag, MD, PhD, an assistant professor of neurology at Vanderbilt University Medical Center, Nashville, Tennessee.

Dr. Schrag also queried the work of a City University of New York (CUNY) researcher who proposed PT-125 (now simufilam) as a potential anti-amyloid for Alzheimer’s disease. Even though CUNY recently found “egregious” and potentially deliberate misconduct by that researcher, Cassava Sciences is continuing phase 3 trials of simufilam.

Now questions are being raised about work from the lab of Berislav V. Zlokovic, PhD, a prominent neuroscientist at the University of Southern California (USC), Los Angeles, California, and also about studies conducted under the aegis of Domenico Pratico, MD, the director of the Alzheimer’s Center at Temple University in Philadelphia, Pennsylvania.

Alzheimer’s has been a notoriously hard puzzle to solve. Despite decades of research, there are still no effective therapies and disparate theories about potential causes.

Dr. Schrag said he wouldn’t “attribute all the ills in this field” to misconduct, but it “is absolutely a part of the equation.” Some of the papers flagged for integrity issues “have been hugely influential,” he said in an interview. “Some of the labs that we’re talking about have really shaped how we’ve thought about this disease,” he said. “It’s hard to un-ring the bell.”

The fallout from fraud has a wide impact. Taxpayer dollars are wasted in the creation of the fraud and in attempts to replicate the failed experiment. Grad students — the workhorses of labs — waste time trying to repeat studies or may be bullied or intimidated into misconduct, said Elisabeth Bik, PhD, a former Stanford microbiologist who is now a full-time fraud investigator.

And there’s potential harm to patients. “There’s a lot of false hope being given to these people and their families,” Dr. Bik said in an interview.
 

Alzheimer’s Tempts With Big Rewards

There are big rewards for those who publish important papers on Alzheimer’s: More grants, publication in higher-impact journals, larger labs, and potentially, personal enrichment from commercialization of therapies.

“I can see that people are driven to cut corners or even to make up results, or even anything in between, to reach that goal,” said Dr. Bik.

It’s unclear whether misconduct and fraud are on the rise or just being detected more frequently.

“It’s very hard to say,” said Mike Rossner, PhD, president of Image Data Integrity. Institutions hire Dr. Rossner to help ferret out research integrity issues. He told this news organization that it’s likely detection is on the rise, given the increasing number of sleuths like Dr. Bik.

In 2002, Dr. Rossner began to screen all images submitted to the Journal of Clinical Biology in response to the new phenomenon of digital images and the advent of PhotoShop. “Very early on, we started to see problems in digital images that we would not have seen on a glossy printout,” Dr. Rossner said of his time as managing editor of the journal.

From 2002 to 2014, at least 25% of papers had an image that violated guidelines that prohibited the removal of spots or other blemishes (called “beautification”) with PhotoShop, which did not necessarily indicate fraud. They withdrew acceptance for 1% of papers because of image manipulations that affected data interpretation.

Dr. Bik noted that even if there is not a greater percentage of fraudulent papers in Alzheimer’s, “it would still be in absolute numbers a lot of papers that could be fraudulent,” given that Alzheimer’s research is well-funded with federal agencies alone providing $3.7 billion a year.

Images Key to Spotting Issues

Investigative sleuths often use the online forum PubPeer to initially raise questions about papers. The format gives the original authors a chance to comment on or defend their work. While some critiques are about data, most hone in on alleged duplications or manipulations of images, primarily by Western Blots.

The images are key, because “the images are the data,” said Dr. Rossner. “The words are the author’s interpretation of what they see in the images,” he said.

It’s also easier to spot a problem in an image. The raw data or an investigator’s notebooks aren’t needed, and there are artificial intelligence-driven software programs such as Proofig and Image Twin that help investigators spot duplicated images or cases in which an image might have been flipped or otherwise manipulated to make results look better.

Science recently announced that it would be using Proofig to screen images in all papers submitted to its six journals.

Using a screening tool is better than nothing, said Dr. Rossner who still relies on visual inspection, employing contrast or other features in PhotoShop to spot inconsistencies or duplications. But “none of those companies have disclosed how effective they are relative to visual screening, and that to me is very problematic,” he said.

“The tools are not going to catch everything,” said Dr. Bik.

Dr. Schrag agreed. “One of the things that we’re worried about is that a lot of the journals will simply adopt these tools as a screener and assume that that’s going to de-risk their publication portfolio,” he said, noting the high rate of misses.

Artificial Intelligence a Growing Concern

Artificial intelligence (AI) may also accelerate the amount of fraud and add to the difficulty of ferreting it out, said the investigators.

“I’m very worried about AI,” said Dr. Bik. Although AI-generated images and content may be rudimentary today, “next year it’s going to be much better,” she said. Going forward, it may be hard to distinguish between a real dataset and one that has been generated by AI, she said.

“The more closely AI can mimic authentic content, the more difficult it will be for publications to detect intentionally fraudulent submissions,” wrote Dror Kolodkin-Gal, PhD, the founder of Proofig, in an article for the Council of Science Editors.

Dr. Kolodkin-Gal said that AI may be especially prone to misuse by paper mills. Those operations submit fake or shoddy manuscripts to a journal on behalf of researchers seeking publication who pay the mills a fee. The Committee on Publication Ethics reported in 2022 that 2%-46% of papers submitted to journals may be from paper mills.

While it’s unclear whether AI is having any impact now, Dr. Rossner said, “I think I can be pretty confident in saying it is going to be a growing problem” as the tools become more sophisticated.

He sees parallels with the rise of PhotoShop and cites data from the National Institute of Health’s Office of Research Integrity (ORI) showing that in 1990, when PhotoShop was still new, 2% of cases referred to ORI involved image manipulation. By 2007, 70% of cases had image manipulation issues.

Journals, Institutions Need to Step Up More

Fraud may continue apace in part because investigations drag on for years, and in many cases, with a lack of consequences for the perpetrators, said the investigators. And, they say, journals and institutions haven’t devoted enough resources to prevent or investigate misconduct.

“A lot of editors did not even want to investigate because they just didn’t want to believe that there could be fraud in science,” said Dr. Bik of her experiences. “I hope that by now most journals at least should have realized that some proportion of the manuscripts that get sent to their journals is going to be fraud,” she said.

“The bulk of the journals seem like they don’t want to be bothered by this,” agreed Dr. Schrag, adding that “some have gone to great lengths to try to discourage people from bringing forward complaints.”

A big issue is that journals “don’t answer to any higher authority,” said Dr. Schrag. He believes that journals that repeatedly refuse to address integrity issues should be barred from publishing research produced with funds from the National Institutes of Health.

All the investigators said institutions and journals should hire forensic investigators. Relying on unpaid peer reviewers or editors to root out fraud is unrealistic, they said.

“You want to have specialized people with experience and be paid to do that as a full-time job,” said Dr. Bik, who is funded by speaking engagements and receives about $2300 a month through donations to her Patreon account.

Once a potential integrity issue is flagged, there is “an incredible conflict of interest in how these investigations are run,” said Dr. Schrag. “Institutions are asked to investigate their own faculty; they’re asked to investigate themselves.” That “creates the disincentive to move expeditiously,” said Dr. Schrag.

With the space of time, people who have committed fraud can throw out notebooks, delete data from servers, or even PhotoShop original photos so they match the manipulated ones that were submitted, Dr. Bik said.

Institutions could show they are serious about fraud by offering a “central, systematic universal screening of all image data going out of their institutions before submission to a journal,” said Dr. Rossner. But he knows only of a handful that do so. “I think research integrity offices have historically been very reactive, and they need to pivot and become proactive,” said Dr. Rossner.

Dr. Schrag wants to see stronger values within the research enterprise. “You have to build a culture where it’s absolutely anathema at a core level to violate these standards of research integrity,” he said. “We have this notion that we can push the process along faster and get to a grant and get to a paper and get to some short-term goal,” he said. “But the long-term goal in most of these cases is to cure a disease or to understand some biological mysteries. There’s no shortcut to getting there,” said Dr. Schrag.

There have been some high-profile consequences for research integrity failures, such as the 2023 resignation of Stanford University President Marc Tessier-Lavigne in the wake of findings that members of his lab — but not Tessier-Lavigne — engaged in data manipulation.

The process is often opaque, with investigations done in secrecy. “Consequences are not usually revealed, either,” said Dr. Rossner.

Dr. Schrag acknowledges it’s a tough balancing act for institutions to root out bad actors while also ensuring there’s no harm to those who may simply have operated in error.

“But it doesn’t serve anyone’s interest including the people who are accused, in dragging these things out for 5, 6, 8, or 10 years,” he said.

Lesne and Cassava: The Long and Winding Road

The investigations into the Lesne papers and the work underpinning Cassava Sciences’ therapy point to the difficulty of policing integrity and the potential fallout.

Lesne’s signature paper published in Nature in 2006 has been cited some 2300 times and is the fourth most-accessed article of 81,612 articles of a similar age in all journals tracked by Altimetrics.

Dr. Schrag, Dr. Bik, and others wrote to multiple journals asking them to investigate some 25 papers related to simufilam, including a 2012 Journal of Clinical Investigation article by Hoau-Yan Wang, PhD, the CUNY scientist whose work on simufilam has been questioned.

JCI Editor Elizabeth McNally pushed back stating in an editorial in 2022 that they, as whistleblowers, had potential conflicts and that they could be assisting short sellers who were seeking to profit by depressing Cassava’s stock price. Indeed, Dr. Schrag was initially hired by a law firm that was representing short sellers. Ms. McNally said that JCI would start requiring disclosures by whistleblowers.

Dr. Bik urged CUNY to investigate Dr. Wang in 2021 but was rebuffed. Then, in November 2023, a copy of CUNY’s final report on the Wang inquiry was leaked to Science. The university reported that Dr. Wang did not provide any original data or notebooks and that it found “long-standing and egregious misconduct in data management and record keeping by Dr. Wang,” wrote Dr. Bik in a blog post summarizing the investigation.

As of late 2023, 42 papers by Dr. Wang have earned PubPeer posts, seven have been retracted, and five have been marked with an Expression of Concern, wrote Dr. Bik.

Some have called for Cassava to stop its phase 3 studies of simufilam, but the company is proceeding, announcing in November 2023 that they have completed enrollment.

Misconduct Queries Underway at USC and Temple

Meanwhile, Dr. Schrag and Dr. Bik continue sleuthing. They are among a small group of whistleblowers who have filed a complaint with NIH about irregularities in the Zlokovic lab at USC. They allege that images were manipulated in dozens of papers, including some that inform the development of a stroke drug in phase 2 trials.

The inquiry goes well beyond stroke, said Dr. Schrag. Dr. Zlokovic “is one of the most influential scientists on Alzheimer’s scientists in the country,” Dr. Schrag said. The USC scientist is a leader on blood-brain barrier research.

USC is investigating “at some level,” he said. In a statement to this news organization, USC said that it “takes any allegations about research integrity very seriously.” The statement added, “Consistent with federal regulations and USC policies, this review must be kept confidential. As a result, we are unable to provide any further information.”

Mu Yang, PhD, assistant professor of neurobiology at Columbia University Medical Center in New York City, is also working on the Zlokovic investigation.

She calls herself an “accidental sleuth” who fell into the hobby after a graduate student asked her to help replicate a study by Temple University, Philadelphia, Pennsylvania, researcher Dominco Pratico, MD, of Alzheimer’s-like phenotype mice in the Morris Water Maze test. Dr. Yang, who runs the “behavior core” at Columbia — teaching and advising on how to run assays and collect and report data — could see right away that the Pratico data were “too perfect.”

She enlisted maze inventor Richard Morris to join her in a letter of concern to the journals that published Dr. Pratico’s work, all under the aegis of Springer Nature.

The publisher’s integrity team has since retracted four Pratico papers. Three were because of image abnormalities pointed out by Dr. Bik, who worked with Dr. Yang. One was because of “self-plagiarism.”

“The official retraction notes didn’t mention anything about data abnormality being a concern,” said Dr. Yang who says that questionable data is harder to prove than an image duplication or manipulation. And the papers remain available, although dozens of Practico papers have been flagged on PubPeer.

To Dr. Yang, images are the canary in the coalmine. “People don’t just fake western blots but then give real behavior data or give you fake behavior data but give you the most authentic Western Blots,” she said.

Dr. Pratico has now sued a graduate student who was a coauthor on the papers, according to the Philadelphia Inquirer.

The NIH’s ORI has requested that Temple University conduct an investigation, Dr. Yang said.

In a statement to this news organization, Temple said it “does not comment on internal investigations or personnel issues,” but that “allegations of research misconduct are reviewed and investigated centrally through Temple’s Office of the Vice President for Research in accordance with university policy and applicable federal regulations.”

A version of this article appeared on Medscape.com.

Alzheimer’s research is plagued with misconduct and fraud, undermining the progress toward understanding and treating the disease, say investigators who endeavor to expose errors and misleading practices.

The book is yet to be closed, for instance, on whether a 2006 paper by Sylvain Lesne positing amyloid as a major cause of Alzheimer’s was based on fraudulent data. Suspicions about the paper were first raised in late 2021 by Matthew Schrag, MD, PhD, an assistant professor of neurology at Vanderbilt University Medical Center, Nashville, Tennessee.

Dr. Schrag also queried the work of a City University of New York (CUNY) researcher who proposed PT-125 (now simufilam) as a potential anti-amyloid for Alzheimer’s disease. Even though CUNY recently found “egregious” and potentially deliberate misconduct by that researcher, Cassava Sciences is continuing phase 3 trials of simufilam.

Now questions are being raised about work from the lab of Berislav V. Zlokovic, PhD, a prominent neuroscientist at the University of Southern California (USC), Los Angeles, California, and also about studies conducted under the aegis of Domenico Pratico, MD, the director of the Alzheimer’s Center at Temple University in Philadelphia, Pennsylvania.

Alzheimer’s has been a notoriously hard puzzle to solve. Despite decades of research, there are still no effective therapies and disparate theories about potential causes.

Dr. Schrag said he wouldn’t “attribute all the ills in this field” to misconduct, but it “is absolutely a part of the equation.” Some of the papers flagged for integrity issues “have been hugely influential,” he said in an interview. “Some of the labs that we’re talking about have really shaped how we’ve thought about this disease,” he said. “It’s hard to un-ring the bell.”

The fallout from fraud has a wide impact. Taxpayer dollars are wasted in the creation of the fraud and in attempts to replicate the failed experiment. Grad students — the workhorses of labs — waste time trying to repeat studies or may be bullied or intimidated into misconduct, said Elisabeth Bik, PhD, a former Stanford microbiologist who is now a full-time fraud investigator.

And there’s potential harm to patients. “There’s a lot of false hope being given to these people and their families,” Dr. Bik said in an interview.
 

Alzheimer’s Tempts With Big Rewards

There are big rewards for those who publish important papers on Alzheimer’s: More grants, publication in higher-impact journals, larger labs, and potentially, personal enrichment from commercialization of therapies.

“I can see that people are driven to cut corners or even to make up results, or even anything in between, to reach that goal,” said Dr. Bik.

It’s unclear whether misconduct and fraud are on the rise or just being detected more frequently.

“It’s very hard to say,” said Mike Rossner, PhD, president of Image Data Integrity. Institutions hire Dr. Rossner to help ferret out research integrity issues. He told this news organization that it’s likely detection is on the rise, given the increasing number of sleuths like Dr. Bik.

In 2002, Dr. Rossner began to screen all images submitted to the Journal of Clinical Biology in response to the new phenomenon of digital images and the advent of PhotoShop. “Very early on, we started to see problems in digital images that we would not have seen on a glossy printout,” Dr. Rossner said of his time as managing editor of the journal.

From 2002 to 2014, at least 25% of papers had an image that violated guidelines that prohibited the removal of spots or other blemishes (called “beautification”) with PhotoShop, which did not necessarily indicate fraud. They withdrew acceptance for 1% of papers because of image manipulations that affected data interpretation.

Dr. Bik noted that even if there is not a greater percentage of fraudulent papers in Alzheimer’s, “it would still be in absolute numbers a lot of papers that could be fraudulent,” given that Alzheimer’s research is well-funded with federal agencies alone providing $3.7 billion a year.

Images Key to Spotting Issues

Investigative sleuths often use the online forum PubPeer to initially raise questions about papers. The format gives the original authors a chance to comment on or defend their work. While some critiques are about data, most hone in on alleged duplications or manipulations of images, primarily by Western Blots.

The images are key, because “the images are the data,” said Dr. Rossner. “The words are the author’s interpretation of what they see in the images,” he said.

It’s also easier to spot a problem in an image. The raw data or an investigator’s notebooks aren’t needed, and there are artificial intelligence-driven software programs such as Proofig and Image Twin that help investigators spot duplicated images or cases in which an image might have been flipped or otherwise manipulated to make results look better.

Science recently announced that it would be using Proofig to screen images in all papers submitted to its six journals.

Using a screening tool is better than nothing, said Dr. Rossner who still relies on visual inspection, employing contrast or other features in PhotoShop to spot inconsistencies or duplications. But “none of those companies have disclosed how effective they are relative to visual screening, and that to me is very problematic,” he said.

“The tools are not going to catch everything,” said Dr. Bik.

Dr. Schrag agreed. “One of the things that we’re worried about is that a lot of the journals will simply adopt these tools as a screener and assume that that’s going to de-risk their publication portfolio,” he said, noting the high rate of misses.

Artificial Intelligence a Growing Concern

Artificial intelligence (AI) may also accelerate the amount of fraud and add to the difficulty of ferreting it out, said the investigators.

“I’m very worried about AI,” said Dr. Bik. Although AI-generated images and content may be rudimentary today, “next year it’s going to be much better,” she said. Going forward, it may be hard to distinguish between a real dataset and one that has been generated by AI, she said.

“The more closely AI can mimic authentic content, the more difficult it will be for publications to detect intentionally fraudulent submissions,” wrote Dror Kolodkin-Gal, PhD, the founder of Proofig, in an article for the Council of Science Editors.

Dr. Kolodkin-Gal said that AI may be especially prone to misuse by paper mills. Those operations submit fake or shoddy manuscripts to a journal on behalf of researchers seeking publication who pay the mills a fee. The Committee on Publication Ethics reported in 2022 that 2%-46% of papers submitted to journals may be from paper mills.

While it’s unclear whether AI is having any impact now, Dr. Rossner said, “I think I can be pretty confident in saying it is going to be a growing problem” as the tools become more sophisticated.

He sees parallels with the rise of PhotoShop and cites data from the National Institute of Health’s Office of Research Integrity (ORI) showing that in 1990, when PhotoShop was still new, 2% of cases referred to ORI involved image manipulation. By 2007, 70% of cases had image manipulation issues.

Journals, Institutions Need to Step Up More

Fraud may continue apace in part because investigations drag on for years, and in many cases, with a lack of consequences for the perpetrators, said the investigators. And, they say, journals and institutions haven’t devoted enough resources to prevent or investigate misconduct.

“A lot of editors did not even want to investigate because they just didn’t want to believe that there could be fraud in science,” said Dr. Bik of her experiences. “I hope that by now most journals at least should have realized that some proportion of the manuscripts that get sent to their journals is going to be fraud,” she said.

“The bulk of the journals seem like they don’t want to be bothered by this,” agreed Dr. Schrag, adding that “some have gone to great lengths to try to discourage people from bringing forward complaints.”

A big issue is that journals “don’t answer to any higher authority,” said Dr. Schrag. He believes that journals that repeatedly refuse to address integrity issues should be barred from publishing research produced with funds from the National Institutes of Health.

All the investigators said institutions and journals should hire forensic investigators. Relying on unpaid peer reviewers or editors to root out fraud is unrealistic, they said.

“You want to have specialized people with experience and be paid to do that as a full-time job,” said Dr. Bik, who is funded by speaking engagements and receives about $2300 a month through donations to her Patreon account.

Once a potential integrity issue is flagged, there is “an incredible conflict of interest in how these investigations are run,” said Dr. Schrag. “Institutions are asked to investigate their own faculty; they’re asked to investigate themselves.” That “creates the disincentive to move expeditiously,” said Dr. Schrag.

With the space of time, people who have committed fraud can throw out notebooks, delete data from servers, or even PhotoShop original photos so they match the manipulated ones that were submitted, Dr. Bik said.

Institutions could show they are serious about fraud by offering a “central, systematic universal screening of all image data going out of their institutions before submission to a journal,” said Dr. Rossner. But he knows only of a handful that do so. “I think research integrity offices have historically been very reactive, and they need to pivot and become proactive,” said Dr. Rossner.

Dr. Schrag wants to see stronger values within the research enterprise. “You have to build a culture where it’s absolutely anathema at a core level to violate these standards of research integrity,” he said. “We have this notion that we can push the process along faster and get to a grant and get to a paper and get to some short-term goal,” he said. “But the long-term goal in most of these cases is to cure a disease or to understand some biological mysteries. There’s no shortcut to getting there,” said Dr. Schrag.

There have been some high-profile consequences for research integrity failures, such as the 2023 resignation of Stanford University President Marc Tessier-Lavigne in the wake of findings that members of his lab — but not Tessier-Lavigne — engaged in data manipulation.

The process is often opaque, with investigations done in secrecy. “Consequences are not usually revealed, either,” said Dr. Rossner.

Dr. Schrag acknowledges it’s a tough balancing act for institutions to root out bad actors while also ensuring there’s no harm to those who may simply have operated in error.

“But it doesn’t serve anyone’s interest including the people who are accused, in dragging these things out for 5, 6, 8, or 10 years,” he said.

Lesne and Cassava: The Long and Winding Road

The investigations into the Lesne papers and the work underpinning Cassava Sciences’ therapy point to the difficulty of policing integrity and the potential fallout.

Lesne’s signature paper published in Nature in 2006 has been cited some 2300 times and is the fourth most-accessed article of 81,612 articles of a similar age in all journals tracked by Altimetrics.

Dr. Schrag, Dr. Bik, and others wrote to multiple journals asking them to investigate some 25 papers related to simufilam, including a 2012 Journal of Clinical Investigation article by Hoau-Yan Wang, PhD, the CUNY scientist whose work on simufilam has been questioned.

JCI Editor Elizabeth McNally pushed back stating in an editorial in 2022 that they, as whistleblowers, had potential conflicts and that they could be assisting short sellers who were seeking to profit by depressing Cassava’s stock price. Indeed, Dr. Schrag was initially hired by a law firm that was representing short sellers. Ms. McNally said that JCI would start requiring disclosures by whistleblowers.

Dr. Bik urged CUNY to investigate Dr. Wang in 2021 but was rebuffed. Then, in November 2023, a copy of CUNY’s final report on the Wang inquiry was leaked to Science. The university reported that Dr. Wang did not provide any original data or notebooks and that it found “long-standing and egregious misconduct in data management and record keeping by Dr. Wang,” wrote Dr. Bik in a blog post summarizing the investigation.

As of late 2023, 42 papers by Dr. Wang have earned PubPeer posts, seven have been retracted, and five have been marked with an Expression of Concern, wrote Dr. Bik.

Some have called for Cassava to stop its phase 3 studies of simufilam, but the company is proceeding, announcing in November 2023 that they have completed enrollment.

Misconduct Queries Underway at USC and Temple

Meanwhile, Dr. Schrag and Dr. Bik continue sleuthing. They are among a small group of whistleblowers who have filed a complaint with NIH about irregularities in the Zlokovic lab at USC. They allege that images were manipulated in dozens of papers, including some that inform the development of a stroke drug in phase 2 trials.

The inquiry goes well beyond stroke, said Dr. Schrag. Dr. Zlokovic “is one of the most influential scientists on Alzheimer’s scientists in the country,” Dr. Schrag said. The USC scientist is a leader on blood-brain barrier research.

USC is investigating “at some level,” he said. In a statement to this news organization, USC said that it “takes any allegations about research integrity very seriously.” The statement added, “Consistent with federal regulations and USC policies, this review must be kept confidential. As a result, we are unable to provide any further information.”

Mu Yang, PhD, assistant professor of neurobiology at Columbia University Medical Center in New York City, is also working on the Zlokovic investigation.

She calls herself an “accidental sleuth” who fell into the hobby after a graduate student asked her to help replicate a study by Temple University, Philadelphia, Pennsylvania, researcher Dominco Pratico, MD, of Alzheimer’s-like phenotype mice in the Morris Water Maze test. Dr. Yang, who runs the “behavior core” at Columbia — teaching and advising on how to run assays and collect and report data — could see right away that the Pratico data were “too perfect.”

She enlisted maze inventor Richard Morris to join her in a letter of concern to the journals that published Dr. Pratico’s work, all under the aegis of Springer Nature.

The publisher’s integrity team has since retracted four Pratico papers. Three were because of image abnormalities pointed out by Dr. Bik, who worked with Dr. Yang. One was because of “self-plagiarism.”

“The official retraction notes didn’t mention anything about data abnormality being a concern,” said Dr. Yang who says that questionable data is harder to prove than an image duplication or manipulation. And the papers remain available, although dozens of Practico papers have been flagged on PubPeer.

To Dr. Yang, images are the canary in the coalmine. “People don’t just fake western blots but then give real behavior data or give you fake behavior data but give you the most authentic Western Blots,” she said.

Dr. Pratico has now sued a graduate student who was a coauthor on the papers, according to the Philadelphia Inquirer.

The NIH’s ORI has requested that Temple University conduct an investigation, Dr. Yang said.

In a statement to this news organization, Temple said it “does not comment on internal investigations or personnel issues,” but that “allegations of research misconduct are reviewed and investigated centrally through Temple’s Office of the Vice President for Research in accordance with university policy and applicable federal regulations.”

A version of this article appeared on Medscape.com.

For the first time, methamphetamines and cocaine have overtaken heroin and prescription opioids in illicit drug use involving fentanyl nationwide and in nearly every state, a new report suggested.

The use of methamphetamine among people who also use fentanyl reached a record high in 2023, urinary drug tests (UDTs) showed, while the use of prescription opioids in that same group reached an historic low. 

Investigators said the data offer further evidence that the US is experiencing a predicted “fourth wave” of the opioid crisis.

The report came on the heels of new data from the Centers for Disease Control and Prevention (CDC) that showed the preferred method of fentanyl-related illicit drug use shifted from intravenous injection to smoking.

“The rise in cocaine and methamphetamine nationally does not seem to be driven by one or even a few regions of the country,” authors of the 2024 Health Signals Report wrote. “Stimulants are a serious national challenge emphasizing the need for continued progress on the national plan to address methamphetamine supply, use, and consequences.”

The report, published online on February 22 by San Diego–based drug testing lab Millennium Health, is an analysis of urine specimens from 4.1 million unique patients aged ≥ 18 years, collected in all 50 states from 2013 to 2023. 
 

A Year of Firsts

Last year, 60% of specimens that contained fentanyl also contained methamphetamine, an increase of 875% since 2015, according to Millennium’s report. It’s the first time that methamphetamine and cocaine were detected more often in urine drug tests than heroin and prescription opioids.

About a quarter of fentanyl-positive specimens also contained cocaine, 17% heroin and just 7% prescription opioids.

Almost all the fentanyl-positive specimens were positive for at least one additional substance; almost half contained three or more. Xylazine, an animal sedative known as “tranq,” was detected in nearly 14% of fentanyl-positive specimens.

“These combinations increase overdose vulnerability and may lessen responses to overdose reversal agents, making treatment as challenging as any time in history,” Millennium Senior VP and Chief Clinical Officer, Angela G. Huskey, PharmD, CPE, said in a statement.

The Millennium data back up what has been increasingly reported by the CDC and others. As reported in September by this news organization, in 2010, stimulants were co-involved in less than 1% of fentanyl overdose deaths. By 2021, stimulant-fentanyl use accounted for 32% of all fatal fentanyl overdoses.

In July 2023, the CDC reported a significant spike in overdose deaths involving cocaine or other psychostimulants and opioids from 2011 to 2021. In 2021, 79% of overdose deaths involving cocaine also involved an opioid and 66% of overdose deaths involving psychostimulants also involved an opioid, according to the CDC.

There were more overdose deaths from stimulants combined with opioids than from opioids alone in 2022, according to the CDC’s State Unintentional Drug Overdose Reporting System, which includes reports from 30 jurisdictions.
 

Smoking Overtakes Injection

The route of administration for opioids and stimulants — whether used alone or in combination, has also changed, the CDC recently reported. In 2022, just 16% of overdose deaths involved injection drug use, down from 23% in 2020, according to the analysis, which included data from 28 jurisdictions. For deaths involving illegally manufactured fentanyl, just 12% of deaths involved IV drug use.

By 2022, “smoking was the most commonly documented route of use in overdose deaths,” CDC researchers wrote in their report. Almost a quarter of deaths that year involved smoking.

The increase in smoking was seen for all substances, including opioids, fentanyl and combinations of fentanyl and stimulants, reported the agency.

Users might be switching to smoking from injections because there is a perception of fewer adverse health effects such as abscesses, reduced cost and stigma, sense of more control over quantity consumed per use, and “a perception of reduced overdose risk,” the researchers wrote.

Smoking still “carries substantial overdose risk because of rapid drug absorption,” they added.

Some harm reduction programs are adapting to the change in use patterns by providing safer smoking supplies and by changing messaging to warn of the dangers associated with smoking drugs, the CDC report noted.
 

A version of this article appeared on Medscape.com.

For the first time, methamphetamines and cocaine have overtaken heroin and prescription opioids in illicit drug use involving fentanyl nationwide and in nearly every state, a new report suggested.

The use of methamphetamine among people who also use fentanyl reached a record high in 2023, urinary drug tests (UDTs) showed, while the use of prescription opioids in that same group reached an historic low. 

Investigators said the data offer further evidence that the US is experiencing a predicted “fourth wave” of the opioid crisis.

The report came on the heels of new data from the Centers for Disease Control and Prevention (CDC) that showed the preferred method of fentanyl-related illicit drug use shifted from intravenous injection to smoking.

“The rise in cocaine and methamphetamine nationally does not seem to be driven by one or even a few regions of the country,” authors of the 2024 Health Signals Report wrote. “Stimulants are a serious national challenge emphasizing the need for continued progress on the national plan to address methamphetamine supply, use, and consequences.”

The report, published online on February 22 by San Diego–based drug testing lab Millennium Health, is an analysis of urine specimens from 4.1 million unique patients aged ≥ 18 years, collected in all 50 states from 2013 to 2023. 
 

A Year of Firsts

Last year, 60% of specimens that contained fentanyl also contained methamphetamine, an increase of 875% since 2015, according to Millennium’s report. It’s the first time that methamphetamine and cocaine were detected more often in urine drug tests than heroin and prescription opioids.

About a quarter of fentanyl-positive specimens also contained cocaine, 17% heroin and just 7% prescription opioids.

Almost all the fentanyl-positive specimens were positive for at least one additional substance; almost half contained three or more. Xylazine, an animal sedative known as “tranq,” was detected in nearly 14% of fentanyl-positive specimens.

“These combinations increase overdose vulnerability and may lessen responses to overdose reversal agents, making treatment as challenging as any time in history,” Millennium Senior VP and Chief Clinical Officer, Angela G. Huskey, PharmD, CPE, said in a statement.

The Millennium data back up what has been increasingly reported by the CDC and others. As reported in September by this news organization, in 2010, stimulants were co-involved in less than 1% of fentanyl overdose deaths. By 2021, stimulant-fentanyl use accounted for 32% of all fatal fentanyl overdoses.

In July 2023, the CDC reported a significant spike in overdose deaths involving cocaine or other psychostimulants and opioids from 2011 to 2021. In 2021, 79% of overdose deaths involving cocaine also involved an opioid and 66% of overdose deaths involving psychostimulants also involved an opioid, according to the CDC.

There were more overdose deaths from stimulants combined with opioids than from opioids alone in 2022, according to the CDC’s State Unintentional Drug Overdose Reporting System, which includes reports from 30 jurisdictions.
 

Smoking Overtakes Injection

The route of administration for opioids and stimulants — whether used alone or in combination, has also changed, the CDC recently reported. In 2022, just 16% of overdose deaths involved injection drug use, down from 23% in 2020, according to the analysis, which included data from 28 jurisdictions. For deaths involving illegally manufactured fentanyl, just 12% of deaths involved IV drug use.

By 2022, “smoking was the most commonly documented route of use in overdose deaths,” CDC researchers wrote in their report. Almost a quarter of deaths that year involved smoking.

The increase in smoking was seen for all substances, including opioids, fentanyl and combinations of fentanyl and stimulants, reported the agency.

Users might be switching to smoking from injections because there is a perception of fewer adverse health effects such as abscesses, reduced cost and stigma, sense of more control over quantity consumed per use, and “a perception of reduced overdose risk,” the researchers wrote.

Smoking still “carries substantial overdose risk because of rapid drug absorption,” they added.

Some harm reduction programs are adapting to the change in use patterns by providing safer smoking supplies and by changing messaging to warn of the dangers associated with smoking drugs, the CDC report noted.
 

A version of this article appeared on Medscape.com.

For the first time, methamphetamines and cocaine have overtaken heroin and prescription opioids in illicit drug use involving fentanyl nationwide and in nearly every state, a new report suggested.

The use of methamphetamine among people who also use fentanyl reached a record high in 2023, urinary drug tests (UDTs) showed, while the use of prescription opioids in that same group reached an historic low. 

Investigators said the data offer further evidence that the US is experiencing a predicted “fourth wave” of the opioid crisis.

The report came on the heels of new data from the Centers for Disease Control and Prevention (CDC) that showed the preferred method of fentanyl-related illicit drug use shifted from intravenous injection to smoking.

“The rise in cocaine and methamphetamine nationally does not seem to be driven by one or even a few regions of the country,” authors of the 2024 Health Signals Report wrote. “Stimulants are a serious national challenge emphasizing the need for continued progress on the national plan to address methamphetamine supply, use, and consequences.”

The report, published online on February 22 by San Diego–based drug testing lab Millennium Health, is an analysis of urine specimens from 4.1 million unique patients aged ≥ 18 years, collected in all 50 states from 2013 to 2023. 
 

A Year of Firsts

Last year, 60% of specimens that contained fentanyl also contained methamphetamine, an increase of 875% since 2015, according to Millennium’s report. It’s the first time that methamphetamine and cocaine were detected more often in urine drug tests than heroin and prescription opioids.

About a quarter of fentanyl-positive specimens also contained cocaine, 17% heroin and just 7% prescription opioids.

Almost all the fentanyl-positive specimens were positive for at least one additional substance; almost half contained three or more. Xylazine, an animal sedative known as “tranq,” was detected in nearly 14% of fentanyl-positive specimens.

“These combinations increase overdose vulnerability and may lessen responses to overdose reversal agents, making treatment as challenging as any time in history,” Millennium Senior VP and Chief Clinical Officer, Angela G. Huskey, PharmD, CPE, said in a statement.

The Millennium data back up what has been increasingly reported by the CDC and others. As reported in September by this news organization, in 2010, stimulants were co-involved in less than 1% of fentanyl overdose deaths. By 2021, stimulant-fentanyl use accounted for 32% of all fatal fentanyl overdoses.

In July 2023, the CDC reported a significant spike in overdose deaths involving cocaine or other psychostimulants and opioids from 2011 to 2021. In 2021, 79% of overdose deaths involving cocaine also involved an opioid and 66% of overdose deaths involving psychostimulants also involved an opioid, according to the CDC.

There were more overdose deaths from stimulants combined with opioids than from opioids alone in 2022, according to the CDC’s State Unintentional Drug Overdose Reporting System, which includes reports from 30 jurisdictions.
 

Smoking Overtakes Injection

The route of administration for opioids and stimulants — whether used alone or in combination, has also changed, the CDC recently reported. In 2022, just 16% of overdose deaths involved injection drug use, down from 23% in 2020, according to the analysis, which included data from 28 jurisdictions. For deaths involving illegally manufactured fentanyl, just 12% of deaths involved IV drug use.

By 2022, “smoking was the most commonly documented route of use in overdose deaths,” CDC researchers wrote in their report. Almost a quarter of deaths that year involved smoking.

The increase in smoking was seen for all substances, including opioids, fentanyl and combinations of fentanyl and stimulants, reported the agency.

Users might be switching to smoking from injections because there is a perception of fewer adverse health effects such as abscesses, reduced cost and stigma, sense of more control over quantity consumed per use, and “a perception of reduced overdose risk,” the researchers wrote.

Smoking still “carries substantial overdose risk because of rapid drug absorption,” they added.

Some harm reduction programs are adapting to the change in use patterns by providing safer smoking supplies and by changing messaging to warn of the dangers associated with smoking drugs, the CDC report noted.
 

A version of this article appeared on Medscape.com.

The lifetime cost of the new topical gene therapy Vyjuvek (beremagene geperpavec, formerly known as B-VEC) could be as much as $15-$22 million per patient, a figure that may give payers, especially federal programs like Medicaid, pause, according to the authors of a new study.

The US Food and Drug Administration (FDA) approved Vyjuvek (Krystal Biotech) in May 2023 for the treatment of wounds in patients ages 6 months and older with dystrophic epidermolysis bullosa (DEB), which includes two types, the most severe form (autosomal recessive, or RDEB) and the autosomal dominant form of DEB (DDEB), which tends to be milder.

Raymakers_Adam_Boston_web.jpg

CMS Launching Gene Therapy Program

The Biden administration recently announced that it was launching a program aimed at increasing access, curbing costs, and ensuring value of gene therapies, starting with sickle cell disease. The program will begin in early 2025. Among other aspects, the federal government will negotiate the price of the product with the manufacturer.

“The goal of the Cell and Gene Therapy Access Model is to increase access to innovative cell and gene therapies for people with Medicaid by making it easier for states to pay for these therapies,” said Liz Fowler, CMS Deputy Administrator and Director of the CMS Innovation Center, in a statement announcing the program.

Whether the new program takes a look at Vyjuvek – and when – is not clear.

[embed:render:related:node:263130]

But the authors of the study noted that the lifetime costs of treating a patient with Vyjuvek “exceed the costs of all other one-time gene therapies for other diseases.” And they wrote, even at the most conservative estimates, Vyjuvek “will be the most expensive gene therapy currently marketed in the US.”

The study was funded by a grant from Arnold Ventures, grants from the Kaiser Permanente Institute for Health Policy, the Commonwealth Fund, and the National Heart, Lung, and Blood Institute. Dr. Raymakers and co-authors reported no financial relationships relevant to the work.

The lifetime cost of the new topical gene therapy Vyjuvek (beremagene geperpavec, formerly known as B-VEC) could be as much as $15-$22 million per patient, a figure that may give payers, especially federal programs like Medicaid, pause, according to the authors of a new study.

The US Food and Drug Administration (FDA) approved Vyjuvek (Krystal Biotech) in May 2023 for the treatment of wounds in patients ages 6 months and older with dystrophic epidermolysis bullosa (DEB), which includes two types, the most severe form (autosomal recessive, or RDEB) and the autosomal dominant form of DEB (DDEB), which tends to be milder.

Raymakers_Adam_Boston_web.jpg

CMS Launching Gene Therapy Program

The Biden administration recently announced that it was launching a program aimed at increasing access, curbing costs, and ensuring value of gene therapies, starting with sickle cell disease. The program will begin in early 2025. Among other aspects, the federal government will negotiate the price of the product with the manufacturer.

“The goal of the Cell and Gene Therapy Access Model is to increase access to innovative cell and gene therapies for people with Medicaid by making it easier for states to pay for these therapies,” said Liz Fowler, CMS Deputy Administrator and Director of the CMS Innovation Center, in a statement announcing the program.

Whether the new program takes a look at Vyjuvek – and when – is not clear.

[embed:render:related:node:263130]

But the authors of the study noted that the lifetime costs of treating a patient with Vyjuvek “exceed the costs of all other one-time gene therapies for other diseases.” And they wrote, even at the most conservative estimates, Vyjuvek “will be the most expensive gene therapy currently marketed in the US.”

The study was funded by a grant from Arnold Ventures, grants from the Kaiser Permanente Institute for Health Policy, the Commonwealth Fund, and the National Heart, Lung, and Blood Institute. Dr. Raymakers and co-authors reported no financial relationships relevant to the work.

The lifetime cost of the new topical gene therapy Vyjuvek (beremagene geperpavec, formerly known as B-VEC) could be as much as $15-$22 million per patient, a figure that may give payers, especially federal programs like Medicaid, pause, according to the authors of a new study.

The US Food and Drug Administration (FDA) approved Vyjuvek (Krystal Biotech) in May 2023 for the treatment of wounds in patients ages 6 months and older with dystrophic epidermolysis bullosa (DEB), which includes two types, the most severe form (autosomal recessive, or RDEB) and the autosomal dominant form of DEB (DDEB), which tends to be milder.

Raymakers_Adam_Boston_web.jpg

CMS Launching Gene Therapy Program

The Biden administration recently announced that it was launching a program aimed at increasing access, curbing costs, and ensuring value of gene therapies, starting with sickle cell disease. The program will begin in early 2025. Among other aspects, the federal government will negotiate the price of the product with the manufacturer.

“The goal of the Cell and Gene Therapy Access Model is to increase access to innovative cell and gene therapies for people with Medicaid by making it easier for states to pay for these therapies,” said Liz Fowler, CMS Deputy Administrator and Director of the CMS Innovation Center, in a statement announcing the program.

Whether the new program takes a look at Vyjuvek – and when – is not clear.

[embed:render:related:node:263130]

But the authors of the study noted that the lifetime costs of treating a patient with Vyjuvek “exceed the costs of all other one-time gene therapies for other diseases.” And they wrote, even at the most conservative estimates, Vyjuvek “will be the most expensive gene therapy currently marketed in the US.”

The study was funded by a grant from Arnold Ventures, grants from the Kaiser Permanente Institute for Health Policy, the Commonwealth Fund, and the National Heart, Lung, and Blood Institute. Dr. Raymakers and co-authors reported no financial relationships relevant to the work.

The patient had an advanced cutaneous squamous cell carcinoma (cSCC) on the face that seemed to be affecting the facial nerve, ruling out aggressive surgery. When Mohs surgery failed to clear the tumor, radiation was ordered. But the best option — an immune checkpoint inhibitor — could not be administered because the patient was a lung transplant recipient.

Although approved for metastatic cSCC, immune checkpoint inhibitors are associated with a higher potential for rejection of an organ transplant.

“The feeling is that the risk of rejection is just too great if we were to try to give an immune checkpoint inhibitor,” said Sean Christensen, MD, PhD, director of dermatologic surgery at Yale Dermatology–Branford, in Connecticut, who was treating the patient. Dr. Christensen consulted with the transplant team, and together they decided to switch the patient to sirolimus, an immunosuppressant that has been shown to have less risk of promoting skin cancer in those who take the medication. Sirolimus, however, is not as well tolerated as the usual first-line immunosuppressant, tacrolimus.

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Reducing Risk Factors

Dr. Bottomley said that there’s also been renewed effort to identify how to reduce cSCC risk in transplant recipients through recently developed consensus guidelines and a proposed decision framework developed by Dr. Bottomley and colleagues. The evidence will help clinicians have “greater confidence in making early interventions,” he said.

Currently, solid organ transplant patients are told to reduce sun exposure, in part because the majority of cSCCs occur in sun-exposed areas, such as the head and neck, and ultraviolet radiation leads to mutations. “Sun protection is critical,” Dr. Christensen said. That’s especially true in younger transplant recipients, who may have decades of sun exposure, he said.

The immunosuppressive medications also increase cancer risk, for a variety of reasons. One of the more-commonly used immunosuppressants in the past, azathioprine, is itself carcinogenic. Other antirejection medications, such as tacrolimus and mycophenolate, may also induce mutagenic changes that give rise to malignancies, according to the paper by Dr. Bibee, assistant professor of dermatology at Johns Hopkins, Baltimore.

Both Dr. Bibee, in her paper, and Dr. Arron, in an interview, noted that voriconazole, an antifungal used to prevent Aspergillus infection after lung transplant, has been associated with an increase in cSCC in lung transplant recipients.

Arron_Sarah_CA_2023_web.jpg

In addition, immunosuppression essentially “blocks the body’s immune system from recognizing that there are abnormal cancerous cells present,” Dr. Arron, a dermatologist in private practice in Burlingame, California, told this news organization.

Previously, while at the High-Risk Skin Cancer Program at University of California, San Francisco (UCSF), Dr. Arron and others studied whether human papillomavirus (HPV) might play a role in spurring the development of cSCC formation in the immunocompromised. HPV is highly prevalent on the skin, but the virus found on the skin tends to be composed of lower-risk strains.

“In our research, we did not find any biologic mechanism by which this virus might be driving these cancers,” said Dr. Arron, although she said that some researchers “feel very strongly that HPV must be in some way a driver.”

Dr. Bottomley believes that HPV’s role has not been completely determined. The excess incidence of cSCC suggests a virus might be involved, as has been seen with excess risk of lymphoma in patients with Epstein-Barr virus, he said.

Some of his research is focusing on whether advanced immune aging is an independent risk factor for subsequent cSCC development in solid organ transplant recipients. The immune system undergoes changes as people age, and the speed of this process varies from patient to patient, which means immune age can be different from chronological age, said Dr. Bottomley. “We’re still exploring why immune aging should predispose you to cSCC,” he said.
 

When to Intervene?

Transplant patients are followed by dermatologists at regular intervals. But guidelines are not consistent on the recommended timing of those intervals.

Dr. Arron and colleagues in 2019 created a risk prediction module that recommended frequency of follow-up based on low, medium, high, or very high risk. The tool is available to clinicians in an app called SUNTRAC, or the Skin and Ultraviolet Neoplasia Transplant Risk Assessment Calculator.

A question that Dr. Arron said dermatologists and transplant specialists have wrangled with: How early can they intervene to prevent further lesions?

In the 2022 decision framework paper in Transplant International, Dr. Bottomley and dermatology colleagues from around the world attempted to better delineate when and how clinicians should intervene when a cSCC is first detected. That first cSCC “should be regarded as a ‘red flag’ heralding an increased risk of further skin cancers and possibly internal malignancies,” the authors wrote. That moment is “a key opportunity to proactively consider secondary preventive strategies,” they wrote, but noted that the best interventions and “their sequencing remain unclear,” indicating the need for further research.
 

Coordinating With the Transplant Team

A key strategy to help prevent cSCC development — suggested in Dr. Bottomley’s paper, and by Dr. Arron and Dr. Christensen — is to consult with the transplant team on potentially changing a patient’s immunosuppressive medication or reducing the dose.

Dr. Arron said that a decade ago, it was somewhat of a novel concept, requiring data-sharing and making personal connections with the transplant team to forge trusting relationships. By the time she left UCSF a few years ago, she said, “the transplant program was very much on board with preventing and treating skin cancer and oftentimes they were making changes even before I would suggest them.”

Suggesting a change or dose reduction is not undertaken lightly. “Our transplant physician colleagues are balancing multiple problems in very sick patients, of which skin cancer might be one, but not the most pressing one in the setting of other transplant complications,” said Dr. Arron.

Dr. Bottomley said that “as transplant physicians, we very much respect and value the input of our dermatology colleagues,” but agreed that many factors “outside malignancy risk” must be weighed when considering changing an immunosuppressive regimen.

In a Delphi Consensus Statement on prevention of cSCC in organ transplant recipients, published in 2021 in JAMA Dermatology, the authors recommended having discussions about immunosuppression with transplant specialists, but did not make a recommendation on what strategy to use. The consensus panel said it preferred “to defer this decision to transplant physicians.”

[embed:render:related:node:254178]

Acitretin a Go, Nicotinamide Not So Much

Outside of changing an immunosuppressive regimen, among the interventions for secondary prevention are acitretin, the systemic retinoid, and nicotinamide, a form of niacin.

Dr. Christensen conducted a small retrospective investigation evaluating the effectiveness of acitretin in reducing cSCC in both immunocompromised and immunocompetent patients who had received care at Yale, which was recently published in the Journal of the American Academy of Dermatology. Acitretin reduced invasive cSCC by about 75% in both patient groups — a surprising result for the immunocompetent group, but well-established in patients who have had a solid organ transplant. But acitretin had no effect on cSCC in situ or basal cell carcinoma. “The benefit of acitretin is primarily in preventing the invasive SCC,” said Dr. Christensen, which is why he tends to reserve it for patients who have already had several cSCCs.

“It’s not a completely benign medication,” he said, noting the need for monitoring for cholesterol and liver function.

Several years ago, a study in immunocompetent patients, published in the New England Journal of Medicine, found that nicotinamide (also known as niacinamide) reduced the rate of nonmelonoma skin cancer by 23%, giving clinicians hope that it might also be a low-risk, low-cost cancer preventive for solid organ transplant patients. But enthusiasm has dampened since a 2023 study in the New England Journal of Medicine found that the vitamin did not reduce cSCCs in transplant recipients.

Dr. Christensen said he believes the most-recent study wasn’t powered to detect a 25% reduction in cancers. “It’s certainly possible that it still works exactly the same way in transplant patients that it does in immunocompetent patients,” he said. “There’s very little risk of recommending it to patients for general prevention. But it probably has a very modest effect in many,” he said.

Dr. Arron agreed, saying, “it may be that we simply need bigger studies to achieve that statistical significance.” Even so, she said she would not use the therapy “until there is more evidence supporting the use of nicotinamide in transplant recipients.”

Immune checkpoint inhibitors such as cemiplimab and pembrolizumab have been approved by the US Food and Drug Administration for advanced cSCC; nivolumab is another drug in the same class that has not yet been approved for cSCC. But “there’s always been a fear — and a legitimate fear — that if you gave those to organ transplant recipients they would reject their organ,” said Dr. Christensen.

Patients who take the checkpoint inhibitors may first have to stop taking their antirejection drugs, leaving them at risk. It also appears that the checkpoint inhibitors themselves contribute to organ rejection. Recent studies suggest that “the rate of organ rejection is only about 30% to 40%,” with the checkpoint inhibitors, said Dr. Christensen. “Obviously that’s still not an ideal outcome,” he said, but noted that with patients who have inoperable metastatic cSCC, “immune therapy can be a good option.”

Dr. Christensen reported no disclosures. Dr. Bottomley has previously received speaker fees and an educational grant from Astellas. Dr. Arron disclosed ties with Regeneron, Castle Biosciences, and Enspectra Health, not specific to transplantation.

The patient had an advanced cutaneous squamous cell carcinoma (cSCC) on the face that seemed to be affecting the facial nerve, ruling out aggressive surgery. When Mohs surgery failed to clear the tumor, radiation was ordered. But the best option — an immune checkpoint inhibitor — could not be administered because the patient was a lung transplant recipient.

Although approved for metastatic cSCC, immune checkpoint inhibitors are associated with a higher potential for rejection of an organ transplant.

“The feeling is that the risk of rejection is just too great if we were to try to give an immune checkpoint inhibitor,” said Sean Christensen, MD, PhD, director of dermatologic surgery at Yale Dermatology–Branford, in Connecticut, who was treating the patient. Dr. Christensen consulted with the transplant team, and together they decided to switch the patient to sirolimus, an immunosuppressant that has been shown to have less risk of promoting skin cancer in those who take the medication. Sirolimus, however, is not as well tolerated as the usual first-line immunosuppressant, tacrolimus.

Christensen_Sean_CONN_web.jpg

Bottomley_Matthew_UK_web.jpg

Reducing Risk Factors

Dr. Bottomley said that there’s also been renewed effort to identify how to reduce cSCC risk in transplant recipients through recently developed consensus guidelines and a proposed decision framework developed by Dr. Bottomley and colleagues. The evidence will help clinicians have “greater confidence in making early interventions,” he said.

Currently, solid organ transplant patients are told to reduce sun exposure, in part because the majority of cSCCs occur in sun-exposed areas, such as the head and neck, and ultraviolet radiation leads to mutations. “Sun protection is critical,” Dr. Christensen said. That’s especially true in younger transplant recipients, who may have decades of sun exposure, he said.

The immunosuppressive medications also increase cancer risk, for a variety of reasons. One of the more-commonly used immunosuppressants in the past, azathioprine, is itself carcinogenic. Other antirejection medications, such as tacrolimus and mycophenolate, may also induce mutagenic changes that give rise to malignancies, according to the paper by Dr. Bibee, assistant professor of dermatology at Johns Hopkins, Baltimore.

Both Dr. Bibee, in her paper, and Dr. Arron, in an interview, noted that voriconazole, an antifungal used to prevent Aspergillus infection after lung transplant, has been associated with an increase in cSCC in lung transplant recipients.

Arron_Sarah_CA_2023_web.jpg

In addition, immunosuppression essentially “blocks the body’s immune system from recognizing that there are abnormal cancerous cells present,” Dr. Arron, a dermatologist in private practice in Burlingame, California, told this news organization.

Previously, while at the High-Risk Skin Cancer Program at University of California, San Francisco (UCSF), Dr. Arron and others studied whether human papillomavirus (HPV) might play a role in spurring the development of cSCC formation in the immunocompromised. HPV is highly prevalent on the skin, but the virus found on the skin tends to be composed of lower-risk strains.

“In our research, we did not find any biologic mechanism by which this virus might be driving these cancers,” said Dr. Arron, although she said that some researchers “feel very strongly that HPV must be in some way a driver.”

Dr. Bottomley believes that HPV’s role has not been completely determined. The excess incidence of cSCC suggests a virus might be involved, as has been seen with excess risk of lymphoma in patients with Epstein-Barr virus, he said.

Some of his research is focusing on whether advanced immune aging is an independent risk factor for subsequent cSCC development in solid organ transplant recipients. The immune system undergoes changes as people age, and the speed of this process varies from patient to patient, which means immune age can be different from chronological age, said Dr. Bottomley. “We’re still exploring why immune aging should predispose you to cSCC,” he said.
 

When to Intervene?

Transplant patients are followed by dermatologists at regular intervals. But guidelines are not consistent on the recommended timing of those intervals.

Dr. Arron and colleagues in 2019 created a risk prediction module that recommended frequency of follow-up based on low, medium, high, or very high risk. The tool is available to clinicians in an app called SUNTRAC, or the Skin and Ultraviolet Neoplasia Transplant Risk Assessment Calculator.

A question that Dr. Arron said dermatologists and transplant specialists have wrangled with: How early can they intervene to prevent further lesions?

In the 2022 decision framework paper in Transplant International, Dr. Bottomley and dermatology colleagues from around the world attempted to better delineate when and how clinicians should intervene when a cSCC is first detected. That first cSCC “should be regarded as a ‘red flag’ heralding an increased risk of further skin cancers and possibly internal malignancies,” the authors wrote. That moment is “a key opportunity to proactively consider secondary preventive strategies,” they wrote, but noted that the best interventions and “their sequencing remain unclear,” indicating the need for further research.
 

Coordinating With the Transplant Team

A key strategy to help prevent cSCC development — suggested in Dr. Bottomley’s paper, and by Dr. Arron and Dr. Christensen — is to consult with the transplant team on potentially changing a patient’s immunosuppressive medication or reducing the dose.

Dr. Arron said that a decade ago, it was somewhat of a novel concept, requiring data-sharing and making personal connections with the transplant team to forge trusting relationships. By the time she left UCSF a few years ago, she said, “the transplant program was very much on board with preventing and treating skin cancer and oftentimes they were making changes even before I would suggest them.”

Suggesting a change or dose reduction is not undertaken lightly. “Our transplant physician colleagues are balancing multiple problems in very sick patients, of which skin cancer might be one, but not the most pressing one in the setting of other transplant complications,” said Dr. Arron.

Dr. Bottomley said that “as transplant physicians, we very much respect and value the input of our dermatology colleagues,” but agreed that many factors “outside malignancy risk” must be weighed when considering changing an immunosuppressive regimen.

In a Delphi Consensus Statement on prevention of cSCC in organ transplant recipients, published in 2021 in JAMA Dermatology, the authors recommended having discussions about immunosuppression with transplant specialists, but did not make a recommendation on what strategy to use. The consensus panel said it preferred “to defer this decision to transplant physicians.”

[embed:render:related:node:254178]

Acitretin a Go, Nicotinamide Not So Much

Outside of changing an immunosuppressive regimen, among the interventions for secondary prevention are acitretin, the systemic retinoid, and nicotinamide, a form of niacin.

Dr. Christensen conducted a small retrospective investigation evaluating the effectiveness of acitretin in reducing cSCC in both immunocompromised and immunocompetent patients who had received care at Yale, which was recently published in the Journal of the American Academy of Dermatology. Acitretin reduced invasive cSCC by about 75% in both patient groups — a surprising result for the immunocompetent group, but well-established in patients who have had a solid organ transplant. But acitretin had no effect on cSCC in situ or basal cell carcinoma. “The benefit of acitretin is primarily in preventing the invasive SCC,” said Dr. Christensen, which is why he tends to reserve it for patients who have already had several cSCCs.

“It’s not a completely benign medication,” he said, noting the need for monitoring for cholesterol and liver function.

Several years ago, a study in immunocompetent patients, published in the New England Journal of Medicine, found that nicotinamide (also known as niacinamide) reduced the rate of nonmelonoma skin cancer by 23%, giving clinicians hope that it might also be a low-risk, low-cost cancer preventive for solid organ transplant patients. But enthusiasm has dampened since a 2023 study in the New England Journal of Medicine found that the vitamin did not reduce cSCCs in transplant recipients.

Dr. Christensen said he believes the most-recent study wasn’t powered to detect a 25% reduction in cancers. “It’s certainly possible that it still works exactly the same way in transplant patients that it does in immunocompetent patients,” he said. “There’s very little risk of recommending it to patients for general prevention. But it probably has a very modest effect in many,” he said.

Dr. Arron agreed, saying, “it may be that we simply need bigger studies to achieve that statistical significance.” Even so, she said she would not use the therapy “until there is more evidence supporting the use of nicotinamide in transplant recipients.”

Immune checkpoint inhibitors such as cemiplimab and pembrolizumab have been approved by the US Food and Drug Administration for advanced cSCC; nivolumab is another drug in the same class that has not yet been approved for cSCC. But “there’s always been a fear — and a legitimate fear — that if you gave those to organ transplant recipients they would reject their organ,” said Dr. Christensen.

Patients who take the checkpoint inhibitors may first have to stop taking their antirejection drugs, leaving them at risk. It also appears that the checkpoint inhibitors themselves contribute to organ rejection. Recent studies suggest that “the rate of organ rejection is only about 30% to 40%,” with the checkpoint inhibitors, said Dr. Christensen. “Obviously that’s still not an ideal outcome,” he said, but noted that with patients who have inoperable metastatic cSCC, “immune therapy can be a good option.”

Dr. Christensen reported no disclosures. Dr. Bottomley has previously received speaker fees and an educational grant from Astellas. Dr. Arron disclosed ties with Regeneron, Castle Biosciences, and Enspectra Health, not specific to transplantation.

The patient had an advanced cutaneous squamous cell carcinoma (cSCC) on the face that seemed to be affecting the facial nerve, ruling out aggressive surgery. When Mohs surgery failed to clear the tumor, radiation was ordered. But the best option — an immune checkpoint inhibitor — could not be administered because the patient was a lung transplant recipient.

Although approved for metastatic cSCC, immune checkpoint inhibitors are associated with a higher potential for rejection of an organ transplant.

“The feeling is that the risk of rejection is just too great if we were to try to give an immune checkpoint inhibitor,” said Sean Christensen, MD, PhD, director of dermatologic surgery at Yale Dermatology–Branford, in Connecticut, who was treating the patient. Dr. Christensen consulted with the transplant team, and together they decided to switch the patient to sirolimus, an immunosuppressant that has been shown to have less risk of promoting skin cancer in those who take the medication. Sirolimus, however, is not as well tolerated as the usual first-line immunosuppressant, tacrolimus.

Christensen_Sean_CONN_web.jpg

Bottomley_Matthew_UK_web.jpg

Reducing Risk Factors

Dr. Bottomley said that there’s also been renewed effort to identify how to reduce cSCC risk in transplant recipients through recently developed consensus guidelines and a proposed decision framework developed by Dr. Bottomley and colleagues. The evidence will help clinicians have “greater confidence in making early interventions,” he said.

Currently, solid organ transplant patients are told to reduce sun exposure, in part because the majority of cSCCs occur in sun-exposed areas, such as the head and neck, and ultraviolet radiation leads to mutations. “Sun protection is critical,” Dr. Christensen said. That’s especially true in younger transplant recipients, who may have decades of sun exposure, he said.

The immunosuppressive medications also increase cancer risk, for a variety of reasons. One of the more-commonly used immunosuppressants in the past, azathioprine, is itself carcinogenic. Other antirejection medications, such as tacrolimus and mycophenolate, may also induce mutagenic changes that give rise to malignancies, according to the paper by Dr. Bibee, assistant professor of dermatology at Johns Hopkins, Baltimore.

Both Dr. Bibee, in her paper, and Dr. Arron, in an interview, noted that voriconazole, an antifungal used to prevent Aspergillus infection after lung transplant, has been associated with an increase in cSCC in lung transplant recipients.

Arron_Sarah_CA_2023_web.jpg

In addition, immunosuppression essentially “blocks the body’s immune system from recognizing that there are abnormal cancerous cells present,” Dr. Arron, a dermatologist in private practice in Burlingame, California, told this news organization.

Previously, while at the High-Risk Skin Cancer Program at University of California, San Francisco (UCSF), Dr. Arron and others studied whether human papillomavirus (HPV) might play a role in spurring the development of cSCC formation in the immunocompromised. HPV is highly prevalent on the skin, but the virus found on the skin tends to be composed of lower-risk strains.

“In our research, we did not find any biologic mechanism by which this virus might be driving these cancers,” said Dr. Arron, although she said that some researchers “feel very strongly that HPV must be in some way a driver.”

Dr. Bottomley believes that HPV’s role has not been completely determined. The excess incidence of cSCC suggests a virus might be involved, as has been seen with excess risk of lymphoma in patients with Epstein-Barr virus, he said.

Some of his research is focusing on whether advanced immune aging is an independent risk factor for subsequent cSCC development in solid organ transplant recipients. The immune system undergoes changes as people age, and the speed of this process varies from patient to patient, which means immune age can be different from chronological age, said Dr. Bottomley. “We’re still exploring why immune aging should predispose you to cSCC,” he said.
 

When to Intervene?

Transplant patients are followed by dermatologists at regular intervals. But guidelines are not consistent on the recommended timing of those intervals.

Dr. Arron and colleagues in 2019 created a risk prediction module that recommended frequency of follow-up based on low, medium, high, or very high risk. The tool is available to clinicians in an app called SUNTRAC, or the Skin and Ultraviolet Neoplasia Transplant Risk Assessment Calculator.

A question that Dr. Arron said dermatologists and transplant specialists have wrangled with: How early can they intervene to prevent further lesions?

In the 2022 decision framework paper in Transplant International, Dr. Bottomley and dermatology colleagues from around the world attempted to better delineate when and how clinicians should intervene when a cSCC is first detected. That first cSCC “should be regarded as a ‘red flag’ heralding an increased risk of further skin cancers and possibly internal malignancies,” the authors wrote. That moment is “a key opportunity to proactively consider secondary preventive strategies,” they wrote, but noted that the best interventions and “their sequencing remain unclear,” indicating the need for further research.
 

Coordinating With the Transplant Team

A key strategy to help prevent cSCC development — suggested in Dr. Bottomley’s paper, and by Dr. Arron and Dr. Christensen — is to consult with the transplant team on potentially changing a patient’s immunosuppressive medication or reducing the dose.

Dr. Arron said that a decade ago, it was somewhat of a novel concept, requiring data-sharing and making personal connections with the transplant team to forge trusting relationships. By the time she left UCSF a few years ago, she said, “the transplant program was very much on board with preventing and treating skin cancer and oftentimes they were making changes even before I would suggest them.”

Suggesting a change or dose reduction is not undertaken lightly. “Our transplant physician colleagues are balancing multiple problems in very sick patients, of which skin cancer might be one, but not the most pressing one in the setting of other transplant complications,” said Dr. Arron.

Dr. Bottomley said that “as transplant physicians, we very much respect and value the input of our dermatology colleagues,” but agreed that many factors “outside malignancy risk” must be weighed when considering changing an immunosuppressive regimen.

In a Delphi Consensus Statement on prevention of cSCC in organ transplant recipients, published in 2021 in JAMA Dermatology, the authors recommended having discussions about immunosuppression with transplant specialists, but did not make a recommendation on what strategy to use. The consensus panel said it preferred “to defer this decision to transplant physicians.”

[embed:render:related:node:254178]

Acitretin a Go, Nicotinamide Not So Much

Outside of changing an immunosuppressive regimen, among the interventions for secondary prevention are acitretin, the systemic retinoid, and nicotinamide, a form of niacin.

Dr. Christensen conducted a small retrospective investigation evaluating the effectiveness of acitretin in reducing cSCC in both immunocompromised and immunocompetent patients who had received care at Yale, which was recently published in the Journal of the American Academy of Dermatology. Acitretin reduced invasive cSCC by about 75% in both patient groups — a surprising result for the immunocompetent group, but well-established in patients who have had a solid organ transplant. But acitretin had no effect on cSCC in situ or basal cell carcinoma. “The benefit of acitretin is primarily in preventing the invasive SCC,” said Dr. Christensen, which is why he tends to reserve it for patients who have already had several cSCCs.

“It’s not a completely benign medication,” he said, noting the need for monitoring for cholesterol and liver function.

Several years ago, a study in immunocompetent patients, published in the New England Journal of Medicine, found that nicotinamide (also known as niacinamide) reduced the rate of nonmelonoma skin cancer by 23%, giving clinicians hope that it might also be a low-risk, low-cost cancer preventive for solid organ transplant patients. But enthusiasm has dampened since a 2023 study in the New England Journal of Medicine found that the vitamin did not reduce cSCCs in transplant recipients.

Dr. Christensen said he believes the most-recent study wasn’t powered to detect a 25% reduction in cancers. “It’s certainly possible that it still works exactly the same way in transplant patients that it does in immunocompetent patients,” he said. “There’s very little risk of recommending it to patients for general prevention. But it probably has a very modest effect in many,” he said.

Dr. Arron agreed, saying, “it may be that we simply need bigger studies to achieve that statistical significance.” Even so, she said she would not use the therapy “until there is more evidence supporting the use of nicotinamide in transplant recipients.”

Immune checkpoint inhibitors such as cemiplimab and pembrolizumab have been approved by the US Food and Drug Administration for advanced cSCC; nivolumab is another drug in the same class that has not yet been approved for cSCC. But “there’s always been a fear — and a legitimate fear — that if you gave those to organ transplant recipients they would reject their organ,” said Dr. Christensen.

Patients who take the checkpoint inhibitors may first have to stop taking their antirejection drugs, leaving them at risk. It also appears that the checkpoint inhibitors themselves contribute to organ rejection. Recent studies suggest that “the rate of organ rejection is only about 30% to 40%,” with the checkpoint inhibitors, said Dr. Christensen. “Obviously that’s still not an ideal outcome,” he said, but noted that with patients who have inoperable metastatic cSCC, “immune therapy can be a good option.”

Dr. Christensen reported no disclosures. Dr. Bottomley has previously received speaker fees and an educational grant from Astellas. Dr. Arron disclosed ties with Regeneron, Castle Biosciences, and Enspectra Health, not specific to transplantation.

Newly released documents show that the US Food and Drug Administration (FDA) has determined that cannabis has a legitimate medical use and that it should be moved from Schedule I to Schedule III on the controlled substances list.

The FDA’s recommendation was contained in a 252-page report that was sent to the US Drug Enforcement Administration (DEA) in August 2023. The report, which Bloomberg News reported on in late August and may have been leaked to that news outlet, was released to Houston attorney Matthew Zorn. He filed suit in September to pressure the FDA to make its recommendation public. The FDA responded days before a court-ordered deadline, said Zorn.

The attorney was not representing any client. “This document belongs in the public sphere,” Zorn told this news organization. “I found it farcical that public policy was being debated on the basis of a document recommendation that literally no one had seen,” he said.

The Bloomberg report ignited debate, but no other advocate, attorney, or news organization had been able to obtain an unredacted version of FDA’s recommendation. 

Now that the full report is public, the DEA may be under more pressure to act. However, it is not required to do anything, and there is no set timeline for any action. Still, lawyers expect to quickly see a rule proposing moving cannabis from Schedule I to III.

“I expect it to come fairly soon and the reason I expect that is because the President told the agencies to do this expeditiously,” said Shane Pennington, an attorney with Porter Wright who has worked with Zorn on cases challenging DEA’s scheduling process but was not involved in this suit.

In October 2022, President Joe Biden said that he was asking the Department of Health and Human Services and the US Attorney General “to review expeditiously how marijuana is scheduled under federal law.”

Howard Sklamberg, a lawyer with Arnold & Porter in Washington, DC, said that the Biden directive “certainly made the agencies reconsider” rescheduling cannabis but that it likely was going to happen anyway, given a wealth of supportive information generated since the DEA last rejected a rescheduling petition in 2016. 

Mr. Sklamberg told this news organization that he thought a proposed rule would be issued soon, with a final rule issued by mid-summer. 

“Agencies generally want to get their important rulemaking done before you get too much into the political season and the potential end of a presidency,” said Mr. Sklamberg, a former FDA deputy commissioner.
 

Credible Medical Use

The FDA said in its report that cannabis is a low-risk threat to public health and that it poses less potential for misuse than drugs in schedule I or II, such as heroin or cocaine.

Though the evidence showed that some people are using cannabis “in amounts sufficient to create a hazard to their health and to the safety of other individuals and the community evidence also exists showing that the vast majority of individuals who use marijuana are doing so in a manner that does not lead to dangerous outcomes to themselves or others,” the FDA noted. 

The agency stated that “the risks to the public health posed by marijuana are low compared to other drugs of abuse (e.g., heroin, cocaine, benzodiazepines), based on an evaluation of various epidemiological databases for [emergency department] visits, hospitalizations, unintentional exposures, and most importantly, for overdose deaths.”

The FDA assessed cannabis’s commonly accepted medical use in seven indications: anorexia, anxiety, epilepsy, inflammatory bowel disease, nausea and vomiting, pain, and posttraumatic stress disorder. It concluded that the strongest evidence existed for anorexia related to a medical condition, nausea and vomiting, and pain.

Of interest, the agency said that when it assessed the harms and benefits, it also used alcohol as a comparator even though it is not a controlled substance. The agency said that it did so because of alcohol’s extensive availability and use, “which is also observed for nonmedical use of marijuana.” 

Mr. Sklamberg found that interesting. A majority of adults have consumed cannabis or know someone who has, making it similar to alcohol, he said. And just as with alcohol, “those adults have formed their own conclusions about what marijuana is and what it isn’t,” he said.

“A lot of Americans make their judgment and think schedule I overstates the health risks,” he added.
 

Opposition in Congress 

It is not certain whether cannabis will be rescheduled; after the Bloomberg report in August, Republican members of Congress sent a letter to DEA Administrator Anne Milgram telling her that the agency should not reschedule the drug.

“The recommendation to remove cannabis from the DEA’s list of dangerous Schedule I drugs is not based on science — it’s based on an irresponsible pro-pot agenda,” said Oklahoma Senator James Lankford (R) on X, in September.

The letter contended that there is no accepted medical use for cannabis and that “the known facts about marijuana have not changed since 2016.”

The FDA, however, based its recommendations in part in looking at data from more than 30,000 healthcare providers and six million patients who have used medical marijuana in state programs, largely established since 2016. Congress has directed the agency to evaluate more of that kind of real-world evidence when evaluating products, said Mr. Sklamberg.

He said that the FDA report will be taken seriously: “It’s a thorough and impressive document.”

“It’s not a document that looks like it was just put together by policy people or political people,” Mr. Sklamberg added. “It’s heavily grounded in science and medicine.”

A version of this article appeared on Medscape.com.

Newly released documents show that the US Food and Drug Administration (FDA) has determined that cannabis has a legitimate medical use and that it should be moved from Schedule I to Schedule III on the controlled substances list.

The FDA’s recommendation was contained in a 252-page report that was sent to the US Drug Enforcement Administration (DEA) in August 2023. The report, which Bloomberg News reported on in late August and may have been leaked to that news outlet, was released to Houston attorney Matthew Zorn. He filed suit in September to pressure the FDA to make its recommendation public. The FDA responded days before a court-ordered deadline, said Zorn.

The attorney was not representing any client. “This document belongs in the public sphere,” Zorn told this news organization. “I found it farcical that public policy was being debated on the basis of a document recommendation that literally no one had seen,” he said.

The Bloomberg report ignited debate, but no other advocate, attorney, or news organization had been able to obtain an unredacted version of FDA’s recommendation. 

Now that the full report is public, the DEA may be under more pressure to act. However, it is not required to do anything, and there is no set timeline for any action. Still, lawyers expect to quickly see a rule proposing moving cannabis from Schedule I to III.

“I expect it to come fairly soon and the reason I expect that is because the President told the agencies to do this expeditiously,” said Shane Pennington, an attorney with Porter Wright who has worked with Zorn on cases challenging DEA’s scheduling process but was not involved in this suit.

In October 2022, President Joe Biden said that he was asking the Department of Health and Human Services and the US Attorney General “to review expeditiously how marijuana is scheduled under federal law.”

Howard Sklamberg, a lawyer with Arnold & Porter in Washington, DC, said that the Biden directive “certainly made the agencies reconsider” rescheduling cannabis but that it likely was going to happen anyway, given a wealth of supportive information generated since the DEA last rejected a rescheduling petition in 2016. 

Mr. Sklamberg told this news organization that he thought a proposed rule would be issued soon, with a final rule issued by mid-summer. 

“Agencies generally want to get their important rulemaking done before you get too much into the political season and the potential end of a presidency,” said Mr. Sklamberg, a former FDA deputy commissioner.
 

Credible Medical Use

The FDA said in its report that cannabis is a low-risk threat to public health and that it poses less potential for misuse than drugs in schedule I or II, such as heroin or cocaine.

Though the evidence showed that some people are using cannabis “in amounts sufficient to create a hazard to their health and to the safety of other individuals and the community evidence also exists showing that the vast majority of individuals who use marijuana are doing so in a manner that does not lead to dangerous outcomes to themselves or others,” the FDA noted. 

The agency stated that “the risks to the public health posed by marijuana are low compared to other drugs of abuse (e.g., heroin, cocaine, benzodiazepines), based on an evaluation of various epidemiological databases for [emergency department] visits, hospitalizations, unintentional exposures, and most importantly, for overdose deaths.”

The FDA assessed cannabis’s commonly accepted medical use in seven indications: anorexia, anxiety, epilepsy, inflammatory bowel disease, nausea and vomiting, pain, and posttraumatic stress disorder. It concluded that the strongest evidence existed for anorexia related to a medical condition, nausea and vomiting, and pain.

Of interest, the agency said that when it assessed the harms and benefits, it also used alcohol as a comparator even though it is not a controlled substance. The agency said that it did so because of alcohol’s extensive availability and use, “which is also observed for nonmedical use of marijuana.” 

Mr. Sklamberg found that interesting. A majority of adults have consumed cannabis or know someone who has, making it similar to alcohol, he said. And just as with alcohol, “those adults have formed their own conclusions about what marijuana is and what it isn’t,” he said.

“A lot of Americans make their judgment and think schedule I overstates the health risks,” he added.
 

Opposition in Congress 

It is not certain whether cannabis will be rescheduled; after the Bloomberg report in August, Republican members of Congress sent a letter to DEA Administrator Anne Milgram telling her that the agency should not reschedule the drug.

“The recommendation to remove cannabis from the DEA’s list of dangerous Schedule I drugs is not based on science — it’s based on an irresponsible pro-pot agenda,” said Oklahoma Senator James Lankford (R) on X, in September.

The letter contended that there is no accepted medical use for cannabis and that “the known facts about marijuana have not changed since 2016.”

The FDA, however, based its recommendations in part in looking at data from more than 30,000 healthcare providers and six million patients who have used medical marijuana in state programs, largely established since 2016. Congress has directed the agency to evaluate more of that kind of real-world evidence when evaluating products, said Mr. Sklamberg.

He said that the FDA report will be taken seriously: “It’s a thorough and impressive document.”

“It’s not a document that looks like it was just put together by policy people or political people,” Mr. Sklamberg added. “It’s heavily grounded in science and medicine.”

A version of this article appeared on Medscape.com.

Newly released documents show that the US Food and Drug Administration (FDA) has determined that cannabis has a legitimate medical use and that it should be moved from Schedule I to Schedule III on the controlled substances list.

The FDA’s recommendation was contained in a 252-page report that was sent to the US Drug Enforcement Administration (DEA) in August 2023. The report, which Bloomberg News reported on in late August and may have been leaked to that news outlet, was released to Houston attorney Matthew Zorn. He filed suit in September to pressure the FDA to make its recommendation public. The FDA responded days before a court-ordered deadline, said Zorn.

The attorney was not representing any client. “This document belongs in the public sphere,” Zorn told this news organization. “I found it farcical that public policy was being debated on the basis of a document recommendation that literally no one had seen,” he said.

The Bloomberg report ignited debate, but no other advocate, attorney, or news organization had been able to obtain an unredacted version of FDA’s recommendation. 

Now that the full report is public, the DEA may be under more pressure to act. However, it is not required to do anything, and there is no set timeline for any action. Still, lawyers expect to quickly see a rule proposing moving cannabis from Schedule I to III.

“I expect it to come fairly soon and the reason I expect that is because the President told the agencies to do this expeditiously,” said Shane Pennington, an attorney with Porter Wright who has worked with Zorn on cases challenging DEA’s scheduling process but was not involved in this suit.

In October 2022, President Joe Biden said that he was asking the Department of Health and Human Services and the US Attorney General “to review expeditiously how marijuana is scheduled under federal law.”

Howard Sklamberg, a lawyer with Arnold & Porter in Washington, DC, said that the Biden directive “certainly made the agencies reconsider” rescheduling cannabis but that it likely was going to happen anyway, given a wealth of supportive information generated since the DEA last rejected a rescheduling petition in 2016. 

Mr. Sklamberg told this news organization that he thought a proposed rule would be issued soon, with a final rule issued by mid-summer. 

“Agencies generally want to get their important rulemaking done before you get too much into the political season and the potential end of a presidency,” said Mr. Sklamberg, a former FDA deputy commissioner.
 

Credible Medical Use

The FDA said in its report that cannabis is a low-risk threat to public health and that it poses less potential for misuse than drugs in schedule I or II, such as heroin or cocaine.

Though the evidence showed that some people are using cannabis “in amounts sufficient to create a hazard to their health and to the safety of other individuals and the community evidence also exists showing that the vast majority of individuals who use marijuana are doing so in a manner that does not lead to dangerous outcomes to themselves or others,” the FDA noted. 

The agency stated that “the risks to the public health posed by marijuana are low compared to other drugs of abuse (e.g., heroin, cocaine, benzodiazepines), based on an evaluation of various epidemiological databases for [emergency department] visits, hospitalizations, unintentional exposures, and most importantly, for overdose deaths.”

The FDA assessed cannabis’s commonly accepted medical use in seven indications: anorexia, anxiety, epilepsy, inflammatory bowel disease, nausea and vomiting, pain, and posttraumatic stress disorder. It concluded that the strongest evidence existed for anorexia related to a medical condition, nausea and vomiting, and pain.

Of interest, the agency said that when it assessed the harms and benefits, it also used alcohol as a comparator even though it is not a controlled substance. The agency said that it did so because of alcohol’s extensive availability and use, “which is also observed for nonmedical use of marijuana.” 

Mr. Sklamberg found that interesting. A majority of adults have consumed cannabis or know someone who has, making it similar to alcohol, he said. And just as with alcohol, “those adults have formed their own conclusions about what marijuana is and what it isn’t,” he said.

“A lot of Americans make their judgment and think schedule I overstates the health risks,” he added.
 

Opposition in Congress 

It is not certain whether cannabis will be rescheduled; after the Bloomberg report in August, Republican members of Congress sent a letter to DEA Administrator Anne Milgram telling her that the agency should not reschedule the drug.

“The recommendation to remove cannabis from the DEA’s list of dangerous Schedule I drugs is not based on science — it’s based on an irresponsible pro-pot agenda,” said Oklahoma Senator James Lankford (R) on X, in September.

The letter contended that there is no accepted medical use for cannabis and that “the known facts about marijuana have not changed since 2016.”

The FDA, however, based its recommendations in part in looking at data from more than 30,000 healthcare providers and six million patients who have used medical marijuana in state programs, largely established since 2016. Congress has directed the agency to evaluate more of that kind of real-world evidence when evaluating products, said Mr. Sklamberg.

He said that the FDA report will be taken seriously: “It’s a thorough and impressive document.”

“It’s not a document that looks like it was just put together by policy people or political people,” Mr. Sklamberg added. “It’s heavily grounded in science and medicine.”

A version of this article appeared on Medscape.com.

Bromazolam, a street drug that has been detected with increasing frequency in the United States, has reportedly caused protracted seizures, myocardial injury, comas, and multiday intensive care stays in three individuals, new data from the US Centers for Disease Control and Prevention (CDC) showed.

The substance is one of at least a dozen designer benzodiazepines created in the lab but not approved for any therapeutic use. The Center for Forensic Science Research and Education (CFSRE) reported that bromazolam was first detected in 2016 in recreational drugs in Europe and subsequently appeared in the United States.

It is sold under names such as “XLI-268,” “Xanax,” “Fake Xanax,” and “Dope.” Bromazolam may be sold in tablet or powder form, or sometimes as gummies, and is often taken with fentanyl by users.

The CDC report, published in the Morbidity and Mortality Weekly Report (MMWR), described three cases of “previously healthy young adults,” two 25-year-old men and a 20-year-old woman, who took tablets believing it was alprazolam, when it was actually bromazolam and were found unresponsive.

They could not be revived with naloxone and continued to be unresponsive upon arrival at the emergency department. One of the men was hypertensive (152/100 mmHg), tachycardic (heart rate of 124 beats per minute), and hyperthermic (101.7 °F [38.7 °C]) and experienced multiple generalized seizures. He was intubated and admitted to intensive care.

The other man also had an elevated temperature (100.4 °F) and was intubated and admitted to the ICU because of unresponsiveness and multiple generalized seizures.

The woman was also intubated and nonresponsive with focal seizures. All three had elevated troponin levels and had urine tests positive for benzodiazepines.

The first man was intubated for 5 days and discharged after 11 days, while the second man was discharged on the fourth day with mild hearing difficulty.

The woman progressed to status epilepticus despite administration of multiple antiepileptic medications and was in a persistent coma. She was transferred to a second hospital after 11 days and was subsequently lost to follow-up.

Toxicology testing by the Drug Enforcement Administration confirmed the presence of bromazolam (range = 31.1-207 ng/mL), without the presence of fentanyl or any other opioid.

The CDC said that “the constellation of findings reported should prompt close involvement with public health officials and regional poison centers, given the more severe findings in these reported cases compared with those expected from routine benzodiazepine overdoses.” In addition, it noted that clinicians and first responders should “consider bromazolam in cases of patients requiring treatment for seizures, myocardial injury, or hyperthermia after illicit drug use.”
 

Surging Supply, Increased Warnings

In 2022, the CDC warned that the drug was surging in the United States, noting that as of mid-2022, bromazolam was identified in more than 250 toxicology cases submitted to NMS Labs, and that it had been identified in more than 190 toxicology samples tested at CFSRE.

In early 2021, only 1% of samples were positive for bromazolam. By mid-2022, 13% of samples were positive for bromazolam, and 75% of the bromazolam samples were positive for fentanyl.

The combination is sold on the street as benzo-dope.

Health authorities across the globe have been warning about the dangers of designer benzodiazepines, and bromazolam in particular. They’ve noted that the overdose reversal agent naloxone does not combat the effects of a benzodiazepine overdose.

In December 2022, the Canadian province of New Brunswick said that bromazolam had been detected in nine sudden death investigations, and that fentanyl was detected in some of those cases. The provincial government of the Northwest Territories warned in May 2023 that bromazolam had been detected in the region’s drug supply and cautioned against combining it with opioids.

The Indiana Department of Health notified the public, first responders, law enforcement, and clinicians in August 2023 that the drug was increasingly being detected in the state. In the first half of the year, 35 people who had overdosed in Indiana tested positive for bromazolam. The state did not test for the presence of bromazolam before 2023.

According to the MMWR, the law enforcement seizures in the United States of bromazolam increased from no more than three per year during 2016-2018 to 2142 in 2022 and 2913 in 2023.

Illinois has been an area of increased use. Bromazolam-involved deaths increased from 10 in 2021 to 51 in 2022, the CDC researchers reported.

A version of this article appeared on Medscape.com.

Bromazolam, a street drug that has been detected with increasing frequency in the United States, has reportedly caused protracted seizures, myocardial injury, comas, and multiday intensive care stays in three individuals, new data from the US Centers for Disease Control and Prevention (CDC) showed.

The substance is one of at least a dozen designer benzodiazepines created in the lab but not approved for any therapeutic use. The Center for Forensic Science Research and Education (CFSRE) reported that bromazolam was first detected in 2016 in recreational drugs in Europe and subsequently appeared in the United States.

It is sold under names such as “XLI-268,” “Xanax,” “Fake Xanax,” and “Dope.” Bromazolam may be sold in tablet or powder form, or sometimes as gummies, and is often taken with fentanyl by users.

The CDC report, published in the Morbidity and Mortality Weekly Report (MMWR), described three cases of “previously healthy young adults,” two 25-year-old men and a 20-year-old woman, who took tablets believing it was alprazolam, when it was actually bromazolam and were found unresponsive.

They could not be revived with naloxone and continued to be unresponsive upon arrival at the emergency department. One of the men was hypertensive (152/100 mmHg), tachycardic (heart rate of 124 beats per minute), and hyperthermic (101.7 °F [38.7 °C]) and experienced multiple generalized seizures. He was intubated and admitted to intensive care.

The other man also had an elevated temperature (100.4 °F) and was intubated and admitted to the ICU because of unresponsiveness and multiple generalized seizures.

The woman was also intubated and nonresponsive with focal seizures. All three had elevated troponin levels and had urine tests positive for benzodiazepines.

The first man was intubated for 5 days and discharged after 11 days, while the second man was discharged on the fourth day with mild hearing difficulty.

The woman progressed to status epilepticus despite administration of multiple antiepileptic medications and was in a persistent coma. She was transferred to a second hospital after 11 days and was subsequently lost to follow-up.

Toxicology testing by the Drug Enforcement Administration confirmed the presence of bromazolam (range = 31.1-207 ng/mL), without the presence of fentanyl or any other opioid.

The CDC said that “the constellation of findings reported should prompt close involvement with public health officials and regional poison centers, given the more severe findings in these reported cases compared with those expected from routine benzodiazepine overdoses.” In addition, it noted that clinicians and first responders should “consider bromazolam in cases of patients requiring treatment for seizures, myocardial injury, or hyperthermia after illicit drug use.”
 

Surging Supply, Increased Warnings

In 2022, the CDC warned that the drug was surging in the United States, noting that as of mid-2022, bromazolam was identified in more than 250 toxicology cases submitted to NMS Labs, and that it had been identified in more than 190 toxicology samples tested at CFSRE.

In early 2021, only 1% of samples were positive for bromazolam. By mid-2022, 13% of samples were positive for bromazolam, and 75% of the bromazolam samples were positive for fentanyl.

The combination is sold on the street as benzo-dope.

Health authorities across the globe have been warning about the dangers of designer benzodiazepines, and bromazolam in particular. They’ve noted that the overdose reversal agent naloxone does not combat the effects of a benzodiazepine overdose.

In December 2022, the Canadian province of New Brunswick said that bromazolam had been detected in nine sudden death investigations, and that fentanyl was detected in some of those cases. The provincial government of the Northwest Territories warned in May 2023 that bromazolam had been detected in the region’s drug supply and cautioned against combining it with opioids.

The Indiana Department of Health notified the public, first responders, law enforcement, and clinicians in August 2023 that the drug was increasingly being detected in the state. In the first half of the year, 35 people who had overdosed in Indiana tested positive for bromazolam. The state did not test for the presence of bromazolam before 2023.

According to the MMWR, the law enforcement seizures in the United States of bromazolam increased from no more than three per year during 2016-2018 to 2142 in 2022 and 2913 in 2023.

Illinois has been an area of increased use. Bromazolam-involved deaths increased from 10 in 2021 to 51 in 2022, the CDC researchers reported.

A version of this article appeared on Medscape.com.

Bromazolam, a street drug that has been detected with increasing frequency in the United States, has reportedly caused protracted seizures, myocardial injury, comas, and multiday intensive care stays in three individuals, new data from the US Centers for Disease Control and Prevention (CDC) showed.

The substance is one of at least a dozen designer benzodiazepines created in the lab but not approved for any therapeutic use. The Center for Forensic Science Research and Education (CFSRE) reported that bromazolam was first detected in 2016 in recreational drugs in Europe and subsequently appeared in the United States.

It is sold under names such as “XLI-268,” “Xanax,” “Fake Xanax,” and “Dope.” Bromazolam may be sold in tablet or powder form, or sometimes as gummies, and is often taken with fentanyl by users.

The CDC report, published in the Morbidity and Mortality Weekly Report (MMWR), described three cases of “previously healthy young adults,” two 25-year-old men and a 20-year-old woman, who took tablets believing it was alprazolam, when it was actually bromazolam and were found unresponsive.

They could not be revived with naloxone and continued to be unresponsive upon arrival at the emergency department. One of the men was hypertensive (152/100 mmHg), tachycardic (heart rate of 124 beats per minute), and hyperthermic (101.7 °F [38.7 °C]) and experienced multiple generalized seizures. He was intubated and admitted to intensive care.

The other man also had an elevated temperature (100.4 °F) and was intubated and admitted to the ICU because of unresponsiveness and multiple generalized seizures.

The woman was also intubated and nonresponsive with focal seizures. All three had elevated troponin levels and had urine tests positive for benzodiazepines.

The first man was intubated for 5 days and discharged after 11 days, while the second man was discharged on the fourth day with mild hearing difficulty.

The woman progressed to status epilepticus despite administration of multiple antiepileptic medications and was in a persistent coma. She was transferred to a second hospital after 11 days and was subsequently lost to follow-up.

Toxicology testing by the Drug Enforcement Administration confirmed the presence of bromazolam (range = 31.1-207 ng/mL), without the presence of fentanyl or any other opioid.

The CDC said that “the constellation of findings reported should prompt close involvement with public health officials and regional poison centers, given the more severe findings in these reported cases compared with those expected from routine benzodiazepine overdoses.” In addition, it noted that clinicians and first responders should “consider bromazolam in cases of patients requiring treatment for seizures, myocardial injury, or hyperthermia after illicit drug use.”
 

Surging Supply, Increased Warnings

In 2022, the CDC warned that the drug was surging in the United States, noting that as of mid-2022, bromazolam was identified in more than 250 toxicology cases submitted to NMS Labs, and that it had been identified in more than 190 toxicology samples tested at CFSRE.

In early 2021, only 1% of samples were positive for bromazolam. By mid-2022, 13% of samples were positive for bromazolam, and 75% of the bromazolam samples were positive for fentanyl.

The combination is sold on the street as benzo-dope.

Health authorities across the globe have been warning about the dangers of designer benzodiazepines, and bromazolam in particular. They’ve noted that the overdose reversal agent naloxone does not combat the effects of a benzodiazepine overdose.

In December 2022, the Canadian province of New Brunswick said that bromazolam had been detected in nine sudden death investigations, and that fentanyl was detected in some of those cases. The provincial government of the Northwest Territories warned in May 2023 that bromazolam had been detected in the region’s drug supply and cautioned against combining it with opioids.

The Indiana Department of Health notified the public, first responders, law enforcement, and clinicians in August 2023 that the drug was increasingly being detected in the state. In the first half of the year, 35 people who had overdosed in Indiana tested positive for bromazolam. The state did not test for the presence of bromazolam before 2023.

According to the MMWR, the law enforcement seizures in the United States of bromazolam increased from no more than three per year during 2016-2018 to 2142 in 2022 and 2913 in 2023.

Illinois has been an area of increased use. Bromazolam-involved deaths increased from 10 in 2021 to 51 in 2022, the CDC researchers reported.

A version of this article appeared on Medscape.com.