The World Health Organization is set to list the artificial sweetener aspartame as a possible carcinogen.

The move, reported by multiple media sources, is expected during a July 14 meeting of WHO research experts – the International Agency for Research on Cancer. Reuters cited two unnamed sources “with knowledge of the process,” noting that aspartame is one of the world’s most commonly used sweeteners. 

Aspartame is 200 times sweeter than sugar and was first approved by the Food and Drug Administration in 1974 for use as a tabletop sweetener and in chewing gum and cold breakfast cereals, as well as instant coffee, gelatins, puddings and fillings, and dairy products. Up to 95% of carbonated soft drinks that have a sweetener use aspartame, and the substance is often added by consumers to beverages (it’s the blue packet of sweetener in the array of packets that appear on diner and restaurant tables),  The Washington Post  reported. 

The WHO currently lists 126 agents as known to be carcinogenic to humans, ranging from alcohol and tobacco to outdoor air pollution. The WHO also lists 94 agents as “probably” carcinogenic to humans and 322 agents as “possibly” carcinogenic to humans. Aspartame would join the “possibly” group, which includes gasoline engine exhaust and working as a dry cleaner.

Earlier this year, the WHO warned that people should not use nonsugar sweeteners to control their weight because of potential health risks. 
 

A version of this article originally appeared on WebMD.com.

The World Health Organization is set to list the artificial sweetener aspartame as a possible carcinogen.

The move, reported by multiple media sources, is expected during a July 14 meeting of WHO research experts – the International Agency for Research on Cancer. Reuters cited two unnamed sources “with knowledge of the process,” noting that aspartame is one of the world’s most commonly used sweeteners. 

Aspartame is 200 times sweeter than sugar and was first approved by the Food and Drug Administration in 1974 for use as a tabletop sweetener and in chewing gum and cold breakfast cereals, as well as instant coffee, gelatins, puddings and fillings, and dairy products. Up to 95% of carbonated soft drinks that have a sweetener use aspartame, and the substance is often added by consumers to beverages (it’s the blue packet of sweetener in the array of packets that appear on diner and restaurant tables),  The Washington Post  reported. 

The WHO currently lists 126 agents as known to be carcinogenic to humans, ranging from alcohol and tobacco to outdoor air pollution. The WHO also lists 94 agents as “probably” carcinogenic to humans and 322 agents as “possibly” carcinogenic to humans. Aspartame would join the “possibly” group, which includes gasoline engine exhaust and working as a dry cleaner.

Earlier this year, the WHO warned that people should not use nonsugar sweeteners to control their weight because of potential health risks. 
 

A version of this article originally appeared on WebMD.com.

The World Health Organization is set to list the artificial sweetener aspartame as a possible carcinogen.

The move, reported by multiple media sources, is expected during a July 14 meeting of WHO research experts – the International Agency for Research on Cancer. Reuters cited two unnamed sources “with knowledge of the process,” noting that aspartame is one of the world’s most commonly used sweeteners. 

Aspartame is 200 times sweeter than sugar and was first approved by the Food and Drug Administration in 1974 for use as a tabletop sweetener and in chewing gum and cold breakfast cereals, as well as instant coffee, gelatins, puddings and fillings, and dairy products. Up to 95% of carbonated soft drinks that have a sweetener use aspartame, and the substance is often added by consumers to beverages (it’s the blue packet of sweetener in the array of packets that appear on diner and restaurant tables),  The Washington Post  reported. 

The WHO currently lists 126 agents as known to be carcinogenic to humans, ranging from alcohol and tobacco to outdoor air pollution. The WHO also lists 94 agents as “probably” carcinogenic to humans and 322 agents as “possibly” carcinogenic to humans. Aspartame would join the “possibly” group, which includes gasoline engine exhaust and working as a dry cleaner.

Earlier this year, the WHO warned that people should not use nonsugar sweeteners to control their weight because of potential health risks. 
 

A version of this article originally appeared on WebMD.com.

The American Medical Association is considering whether to study alternatives to the current residency matching program in an effort to improve residents’ compensation and other job-related issues. A recent call-to-action resolution by the AMA’s House of Delegates is the latest in a long string of debates about whether to change the annual process that matches future doctors with compatible residency programs.

AMA’s Resident and Fellow Section introduced the resolution in March, and the delegates approved it earlier in June at AMA’s annual meeting. The resolution states that the match process of the National Resident Matching Program (NRMP) “poses significant anticompetition concerns.” Those include preventing residents from negotiating for higher wages, better benefits, and improved working conditions, according to the approved resolution.

The full AMA board still has to consider the resolution and hasn’t set a date for that review, though it’s expected to be in the next few months, according to Jennifer Sellers, AMA’s public information officer. She said in an interview that the organization declined to comment, wanting to hold off until the board decides how to proceed.

The NRMP, which oversees the matching process, told this news organization that the AMA doesn’t play a role in the Match.

The organization doesn’t believe studying alternative placement methods benefits applicants and residents, and returning to a pre-Match environment, would harm applicants and programs, according to Donna Lamb, DHSc, MBA, BSN, president and CEO.

“The NRMP has no role in determining, publishing, or setting resident salaries nor does the NRMP have a role in the contracting or employment of residents, and it never has.”

Dr. Lamb said changing the Match would “subject applicants to undue pressure and coercion to accept an offer of training. This will exacerbate disparities in candidate selection already evident in medical education and potentially result in salary reductions in more competitive specialties and in more desirable geographic locations.”

The latest push to reform the match process dates back two decades to a 2002 class action antitrust lawsuit by residents and doctors against the NRMP and other organizations involved in the Match.

The residents argued at that time that by restraining competition among teaching hospitals, the matching system allowed hospitals to keep residents’ wages artificially low. The defendants, which included large teaching hospitals, successfully lobbied Congress for an exemption to the antitrust laws, and the case was subsequently dismissed.

The AMA was one of the defendants, so if it moves forward to review the match process, it likely would pit the organization against the NRMP.

Sherman Marek, the attorney who represented the residents, said in an interview that he was not surprised by the latest AMA resolution. “Maybe the AMA leadership has come around to the idea that it’s better for young physicians to not have the match in place,” he says. “I would applaud that sort of evolution.”

Tyler Ramsey, DO, an internal medicine resident and AMA member, said he believes the group’s current president, Jesse Ehrenfeld, MD, MPH, empathizes with doctors in training. “I think he understands [our] views and is more progressive.”

The NRMP also has considered ways to improve the match process to make it easier and more equitable for applicants. In its latest effort, the organization is studying whether programs should certify their rank order list in advance of applicants. This change would give applicants more flexibility to visit residency locations before the programs consider changing their rankings, Dr. Lamb explained. The NRMP also is mulling the possibilities of a two-phase match after deciding in 2022 not to move forward with a previous version of the proposal.

The recent House of Delegates resolution states that “residents are using other means to obtain fair wages, safe working conditions, and other benefits that are unable to be negotiated within the current system.”

Dr. Ramsey, who trains in North Carolina, said the “other means” may include negotiating through a union. “The AMA realizes that there is a problem and that people are unionizing,” he said. “Obviously, as an organization, we’re not doing something correctly, to the point where people are feeling the need to get their rights a different way.”

The Committee of Interns and Residents, which represents 30,000 members, reported a rise in medical trainee unions across the country in 2022.

Not everyone believes that ditching the Match would benefit applicants and residents. Sam Payabvash, MD, assistant professor of radiology at Yale, New Haven, Conn., School of Medicine, tweeted about the resolution as part of a larger Twitter discussion that alternatives are likely to be “more onerous and expensive for applicants.”

An advantage of the match program, Dr. Lamb argued, is that it “improves the reach of applicants into medically underserved communities through widespread program participation.”

Dr. Ramsey agreed that the match program has benefits and drawbacks, but he believes it favors programs over residents. “It comes as no surprise that numerous residents suffer from depression and our suicide rates are the highest amongst all professions due to the lack of control or negotiation of fair salary and working conditions. Overall, the way things are now, residents just do not have a lot of rights.”

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

The American Medical Association is considering whether to study alternatives to the current residency matching program in an effort to improve residents’ compensation and other job-related issues. A recent call-to-action resolution by the AMA’s House of Delegates is the latest in a long string of debates about whether to change the annual process that matches future doctors with compatible residency programs.

AMA’s Resident and Fellow Section introduced the resolution in March, and the delegates approved it earlier in June at AMA’s annual meeting. The resolution states that the match process of the National Resident Matching Program (NRMP) “poses significant anticompetition concerns.” Those include preventing residents from negotiating for higher wages, better benefits, and improved working conditions, according to the approved resolution.

The full AMA board still has to consider the resolution and hasn’t set a date for that review, though it’s expected to be in the next few months, according to Jennifer Sellers, AMA’s public information officer. She said in an interview that the organization declined to comment, wanting to hold off until the board decides how to proceed.

The NRMP, which oversees the matching process, told this news organization that the AMA doesn’t play a role in the Match.

The organization doesn’t believe studying alternative placement methods benefits applicants and residents, and returning to a pre-Match environment, would harm applicants and programs, according to Donna Lamb, DHSc, MBA, BSN, president and CEO.

“The NRMP has no role in determining, publishing, or setting resident salaries nor does the NRMP have a role in the contracting or employment of residents, and it never has.”

Dr. Lamb said changing the Match would “subject applicants to undue pressure and coercion to accept an offer of training. This will exacerbate disparities in candidate selection already evident in medical education and potentially result in salary reductions in more competitive specialties and in more desirable geographic locations.”

The latest push to reform the match process dates back two decades to a 2002 class action antitrust lawsuit by residents and doctors against the NRMP and other organizations involved in the Match.

The residents argued at that time that by restraining competition among teaching hospitals, the matching system allowed hospitals to keep residents’ wages artificially low. The defendants, which included large teaching hospitals, successfully lobbied Congress for an exemption to the antitrust laws, and the case was subsequently dismissed.

The AMA was one of the defendants, so if it moves forward to review the match process, it likely would pit the organization against the NRMP.

Sherman Marek, the attorney who represented the residents, said in an interview that he was not surprised by the latest AMA resolution. “Maybe the AMA leadership has come around to the idea that it’s better for young physicians to not have the match in place,” he says. “I would applaud that sort of evolution.”

Tyler Ramsey, DO, an internal medicine resident and AMA member, said he believes the group’s current president, Jesse Ehrenfeld, MD, MPH, empathizes with doctors in training. “I think he understands [our] views and is more progressive.”

The NRMP also has considered ways to improve the match process to make it easier and more equitable for applicants. In its latest effort, the organization is studying whether programs should certify their rank order list in advance of applicants. This change would give applicants more flexibility to visit residency locations before the programs consider changing their rankings, Dr. Lamb explained. The NRMP also is mulling the possibilities of a two-phase match after deciding in 2022 not to move forward with a previous version of the proposal.

The recent House of Delegates resolution states that “residents are using other means to obtain fair wages, safe working conditions, and other benefits that are unable to be negotiated within the current system.”

Dr. Ramsey, who trains in North Carolina, said the “other means” may include negotiating through a union. “The AMA realizes that there is a problem and that people are unionizing,” he said. “Obviously, as an organization, we’re not doing something correctly, to the point where people are feeling the need to get their rights a different way.”

The Committee of Interns and Residents, which represents 30,000 members, reported a rise in medical trainee unions across the country in 2022.

Not everyone believes that ditching the Match would benefit applicants and residents. Sam Payabvash, MD, assistant professor of radiology at Yale, New Haven, Conn., School of Medicine, tweeted about the resolution as part of a larger Twitter discussion that alternatives are likely to be “more onerous and expensive for applicants.”

An advantage of the match program, Dr. Lamb argued, is that it “improves the reach of applicants into medically underserved communities through widespread program participation.”

Dr. Ramsey agreed that the match program has benefits and drawbacks, but he believes it favors programs over residents. “It comes as no surprise that numerous residents suffer from depression and our suicide rates are the highest amongst all professions due to the lack of control or negotiation of fair salary and working conditions. Overall, the way things are now, residents just do not have a lot of rights.”

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

The American Medical Association is considering whether to study alternatives to the current residency matching program in an effort to improve residents’ compensation and other job-related issues. A recent call-to-action resolution by the AMA’s House of Delegates is the latest in a long string of debates about whether to change the annual process that matches future doctors with compatible residency programs.

AMA’s Resident and Fellow Section introduced the resolution in March, and the delegates approved it earlier in June at AMA’s annual meeting. The resolution states that the match process of the National Resident Matching Program (NRMP) “poses significant anticompetition concerns.” Those include preventing residents from negotiating for higher wages, better benefits, and improved working conditions, according to the approved resolution.

The full AMA board still has to consider the resolution and hasn’t set a date for that review, though it’s expected to be in the next few months, according to Jennifer Sellers, AMA’s public information officer. She said in an interview that the organization declined to comment, wanting to hold off until the board decides how to proceed.

The NRMP, which oversees the matching process, told this news organization that the AMA doesn’t play a role in the Match.

The organization doesn’t believe studying alternative placement methods benefits applicants and residents, and returning to a pre-Match environment, would harm applicants and programs, according to Donna Lamb, DHSc, MBA, BSN, president and CEO.

“The NRMP has no role in determining, publishing, or setting resident salaries nor does the NRMP have a role in the contracting or employment of residents, and it never has.”

Dr. Lamb said changing the Match would “subject applicants to undue pressure and coercion to accept an offer of training. This will exacerbate disparities in candidate selection already evident in medical education and potentially result in salary reductions in more competitive specialties and in more desirable geographic locations.”

The latest push to reform the match process dates back two decades to a 2002 class action antitrust lawsuit by residents and doctors against the NRMP and other organizations involved in the Match.

The residents argued at that time that by restraining competition among teaching hospitals, the matching system allowed hospitals to keep residents’ wages artificially low. The defendants, which included large teaching hospitals, successfully lobbied Congress for an exemption to the antitrust laws, and the case was subsequently dismissed.

The AMA was one of the defendants, so if it moves forward to review the match process, it likely would pit the organization against the NRMP.

Sherman Marek, the attorney who represented the residents, said in an interview that he was not surprised by the latest AMA resolution. “Maybe the AMA leadership has come around to the idea that it’s better for young physicians to not have the match in place,” he says. “I would applaud that sort of evolution.”

Tyler Ramsey, DO, an internal medicine resident and AMA member, said he believes the group’s current president, Jesse Ehrenfeld, MD, MPH, empathizes with doctors in training. “I think he understands [our] views and is more progressive.”

The NRMP also has considered ways to improve the match process to make it easier and more equitable for applicants. In its latest effort, the organization is studying whether programs should certify their rank order list in advance of applicants. This change would give applicants more flexibility to visit residency locations before the programs consider changing their rankings, Dr. Lamb explained. The NRMP also is mulling the possibilities of a two-phase match after deciding in 2022 not to move forward with a previous version of the proposal.

The recent House of Delegates resolution states that “residents are using other means to obtain fair wages, safe working conditions, and other benefits that are unable to be negotiated within the current system.”

Dr. Ramsey, who trains in North Carolina, said the “other means” may include negotiating through a union. “The AMA realizes that there is a problem and that people are unionizing,” he said. “Obviously, as an organization, we’re not doing something correctly, to the point where people are feeling the need to get their rights a different way.”

The Committee of Interns and Residents, which represents 30,000 members, reported a rise in medical trainee unions across the country in 2022.

Not everyone believes that ditching the Match would benefit applicants and residents. Sam Payabvash, MD, assistant professor of radiology at Yale, New Haven, Conn., School of Medicine, tweeted about the resolution as part of a larger Twitter discussion that alternatives are likely to be “more onerous and expensive for applicants.”

An advantage of the match program, Dr. Lamb argued, is that it “improves the reach of applicants into medically underserved communities through widespread program participation.”

Dr. Ramsey agreed that the match program has benefits and drawbacks, but he believes it favors programs over residents. “It comes as no surprise that numerous residents suffer from depression and our suicide rates are the highest amongst all professions due to the lack of control or negotiation of fair salary and working conditions. Overall, the way things are now, residents just do not have a lot of rights.”

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

The recent Food and Drug Administration approval of colchicine 0.5 mg (Lodoco) for use in atherosclerotic cardiovascular disease (ASCVD) prevention will possibly create opportunities to use the drug to treat residual risk for ASCVD in some patients with immune-mediated inflammatory diseases, particularly in rheumatology.

Potential in rheumatology

The 0.5-mg dose is just a shade under the 0.6-mg, twice daily dosing rheumatologists typically prescribe for gout, Christie Bartels, MD, MS, chief of rheumatology at the University of Wisconsin–Madison, said in an interview. Clinicians also use the 0.6-mg dose off-label for pseudogout or calcium pyrophosphate deposition disease (CPPD), Dr. Bartels noted.

University of Wisconsin

The new formulation opens the consideration for using colchicine more in patients with psoriatic arthritis, lupus, and rheumatoid arthritis, she said. “I think we could certainly discuss it, particularly, in secondary prevention patients who already had an event or who are at the highest risk and already on optimal traditional agents,” she said.

She cited previous comments by Paul Ridker, MD, director of the center for cardiovascular disease prevention at Brigham and Women’s Hospital in Boston, and developer of the high-sensitivity C-reactive protein (hsCRP) test for measuring inflammatory markers. “We might not know the answer because Dr. Ridker pointed out he used colchicine 0.5 mg in patients that had a high-sensitivity CRP that was high; we need patients who have had inflammation of unknown origin, so those patients presumably weren’t already on another anti-inflammatory,” she said, noting that hydroxychloroquine, methotrexate, and some biologics provide some protection from cardiovascular risks.

However, a potential role for long-term colchicine 0.5 mg in ASCVD prevention may cause consideration for changing the drug’s role in gout treatment, Dr. Bartels said. “In gout, where we do have an FDA-approved indication for colchicine, we used to use it only for the first 6 months while we were getting patients to goal on allopurinol, which was usually then monotherapy after the first 6 months,” she said. “I think this will likely change how I treat gout patients in that I may also offer to continue both medications [colchicine and allopurinol] if they are tolerating them well.

“And then in patients where I’m using it off-label in CPPD, I might again share with them that in addition to possibly helping their CPPD, there may be this added benefit to reduce inflammation just in discussing the risks and benefits of the medicine.”

However, rheumatologists must be careful in using colchicine beyond the typical 6-month cycle, Dr. Bartels said. “One of the tricky things with colchicine, and part of the reason we did not traditionally continue it specifically past the first 6 months, was that it can cause myopathies or cytopenias, so we still have to counsel patients regarding these risks and monitor that,” she said.

Additionally, colchicine can have drug interactions with statins or calcium channel blockers that can change colchicine levels. “I think the dose here is so low, the 0.5 mg, that it’s probably still safe, but again, it’s something that we have to take a look at in the patient’s whole picture and the rest of their burden of their meds in order to make a decision with them,” Dr. Bartels said.

Possibilities in dermatology

The LoDoCo2 trial one of two major randomized trials that supported approval of colchicine 0.5 mg, reported that treated patients had a 60% lower rate of gout than the placebo group (1.4% vs. 3.4%). Joel Gelfand, MD, MSCE, the James J. Leyden professor of dermatology and epidemiology at the University of Pennsylvania, Philadelphia, pointed to this in evaluating the dermatologic implications of the drug’s approval. “This may be of particular interest as people with psoriasis have an increased risk of gout,” he said in emailed comments.

University of Pennsylvania

Colchicine’s mechanism of action to reduce inflammation parallels that of tumor necrosis factor (TNF) inhibitors used for dermatologic indications, namely by inhibiting leukocyte adhesion to disrupt the downregulation of TNF receptors, Dr. Gelfand said.

“Interestingly, observational data suggests biologics that target TNF such as adalimumab, etanercept, etc., are associated with a reduction in CV events, and in placebo-controlled trials we conducted in psoriasis patients, it reduced key inflammatory mediators of cardiovascular disease, including IL [interleukin]-6,” he said. “Randomized clinical trials to evaluate the ability of TNF inhibitors, which are now available as biosimilars, to prevent cardiovascular events in high-risk patients, should be conducted, and more work is needed to identify which additional immune-targeted treatments may lower CV risk with an acceptable safety profile.”

Colchicine currently has few indications for rare conditions in dermatology, Dr. Gelfand said, including Sweets syndrome, subcorneal pustular dermatosis, and cutaneous vasculitis. “There are some reports to suggest it may help psoriatic disease, but current data are limited and insufficient to recommend its use for psoriasis and/or psoriatic arthritis,” he said.

The approval of colchicine 0.5 mg for ASCVD could be meaningful for people with psoriasis who are also being treated for CV risk factors, Dr. Gelfand said. “Additional considerations such as signs of residual inflammation (elevated hsCRP) and CV imaging findings may be used to further guide shared decision-making for optimal use,” he said.

Another consideration he noted: “This is also a novel 0.5-mg formulation, and thus cost may be an issue.”
 

Would side effects bar use in gastroenterology?

Colchicine 0.5 mg may not move the needle much for expanding treatment of ASCVD in patients with inflammatory bowel disease (IBD) and potentially other gastrointestinal conditions, Edward Loftus Jr., MD, the Maxine and Jack Zarrow Family professor of gastroenterology specifically for IBD at the Mayo Clinic in Rochester, Minn., told MDEdge in emailed comments. “Given the GI side effect profile [of colchicine], I am not sure I would go there,” he said.

Mayo Clinic

“Hopefully, the prescribers of this low-dose formulation are aware of the gastrointestinal side effects, such as diarrhea and nausea, and educate patients about these side effects so that a proper risk-benefit discussion can ensue,” he said.

Dr. Bartels reporting a previous financial relationship with Pfizer. Dr. Gelfand said he has financial relationships with AbbVie, Amgen, Bristol-Myers Squibb, Boehringer Ingelheim, Celldex, GlaxoSmithKline, Twill, Lilly, Leo, Moonlake, Janssen Biologics, Novartis, Pfizer, UCB, Neuroderm, and Veolia North America. Dr. Loftus disclosed relationships with AbbVie, Alvotech, Amgen, Arena, Avalo, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene/Receptos, Celltrion Healthcare, Eli Lilly, Fresenius Kabi, Genentech, Gilead, GlaxoSmithKline, Gossamer Bio, Iterative Health, Janssen, KSL Diagnostics, Morphic, Ono, Pfizer, Sun, Surrozen, Takeda, Theravance, and UCB.
 

The recent Food and Drug Administration approval of colchicine 0.5 mg (Lodoco) for use in atherosclerotic cardiovascular disease (ASCVD) prevention will possibly create opportunities to use the drug to treat residual risk for ASCVD in some patients with immune-mediated inflammatory diseases, particularly in rheumatology.

Potential in rheumatology

The 0.5-mg dose is just a shade under the 0.6-mg, twice daily dosing rheumatologists typically prescribe for gout, Christie Bartels, MD, MS, chief of rheumatology at the University of Wisconsin–Madison, said in an interview. Clinicians also use the 0.6-mg dose off-label for pseudogout or calcium pyrophosphate deposition disease (CPPD), Dr. Bartels noted.

University of Wisconsin

The new formulation opens the consideration for using colchicine more in patients with psoriatic arthritis, lupus, and rheumatoid arthritis, she said. “I think we could certainly discuss it, particularly, in secondary prevention patients who already had an event or who are at the highest risk and already on optimal traditional agents,” she said.

She cited previous comments by Paul Ridker, MD, director of the center for cardiovascular disease prevention at Brigham and Women’s Hospital in Boston, and developer of the high-sensitivity C-reactive protein (hsCRP) test for measuring inflammatory markers. “We might not know the answer because Dr. Ridker pointed out he used colchicine 0.5 mg in patients that had a high-sensitivity CRP that was high; we need patients who have had inflammation of unknown origin, so those patients presumably weren’t already on another anti-inflammatory,” she said, noting that hydroxychloroquine, methotrexate, and some biologics provide some protection from cardiovascular risks.

However, a potential role for long-term colchicine 0.5 mg in ASCVD prevention may cause consideration for changing the drug’s role in gout treatment, Dr. Bartels said. “In gout, where we do have an FDA-approved indication for colchicine, we used to use it only for the first 6 months while we were getting patients to goal on allopurinol, which was usually then monotherapy after the first 6 months,” she said. “I think this will likely change how I treat gout patients in that I may also offer to continue both medications [colchicine and allopurinol] if they are tolerating them well.

“And then in patients where I’m using it off-label in CPPD, I might again share with them that in addition to possibly helping their CPPD, there may be this added benefit to reduce inflammation just in discussing the risks and benefits of the medicine.”

However, rheumatologists must be careful in using colchicine beyond the typical 6-month cycle, Dr. Bartels said. “One of the tricky things with colchicine, and part of the reason we did not traditionally continue it specifically past the first 6 months, was that it can cause myopathies or cytopenias, so we still have to counsel patients regarding these risks and monitor that,” she said.

Additionally, colchicine can have drug interactions with statins or calcium channel blockers that can change colchicine levels. “I think the dose here is so low, the 0.5 mg, that it’s probably still safe, but again, it’s something that we have to take a look at in the patient’s whole picture and the rest of their burden of their meds in order to make a decision with them,” Dr. Bartels said.

Possibilities in dermatology

The LoDoCo2 trial one of two major randomized trials that supported approval of colchicine 0.5 mg, reported that treated patients had a 60% lower rate of gout than the placebo group (1.4% vs. 3.4%). Joel Gelfand, MD, MSCE, the James J. Leyden professor of dermatology and epidemiology at the University of Pennsylvania, Philadelphia, pointed to this in evaluating the dermatologic implications of the drug’s approval. “This may be of particular interest as people with psoriasis have an increased risk of gout,” he said in emailed comments.

University of Pennsylvania

Colchicine’s mechanism of action to reduce inflammation parallels that of tumor necrosis factor (TNF) inhibitors used for dermatologic indications, namely by inhibiting leukocyte adhesion to disrupt the downregulation of TNF receptors, Dr. Gelfand said.

“Interestingly, observational data suggests biologics that target TNF such as adalimumab, etanercept, etc., are associated with a reduction in CV events, and in placebo-controlled trials we conducted in psoriasis patients, it reduced key inflammatory mediators of cardiovascular disease, including IL [interleukin]-6,” he said. “Randomized clinical trials to evaluate the ability of TNF inhibitors, which are now available as biosimilars, to prevent cardiovascular events in high-risk patients, should be conducted, and more work is needed to identify which additional immune-targeted treatments may lower CV risk with an acceptable safety profile.”

Colchicine currently has few indications for rare conditions in dermatology, Dr. Gelfand said, including Sweets syndrome, subcorneal pustular dermatosis, and cutaneous vasculitis. “There are some reports to suggest it may help psoriatic disease, but current data are limited and insufficient to recommend its use for psoriasis and/or psoriatic arthritis,” he said.

The approval of colchicine 0.5 mg for ASCVD could be meaningful for people with psoriasis who are also being treated for CV risk factors, Dr. Gelfand said. “Additional considerations such as signs of residual inflammation (elevated hsCRP) and CV imaging findings may be used to further guide shared decision-making for optimal use,” he said.

Another consideration he noted: “This is also a novel 0.5-mg formulation, and thus cost may be an issue.”
 

Would side effects bar use in gastroenterology?

Colchicine 0.5 mg may not move the needle much for expanding treatment of ASCVD in patients with inflammatory bowel disease (IBD) and potentially other gastrointestinal conditions, Edward Loftus Jr., MD, the Maxine and Jack Zarrow Family professor of gastroenterology specifically for IBD at the Mayo Clinic in Rochester, Minn., told MDEdge in emailed comments. “Given the GI side effect profile [of colchicine], I am not sure I would go there,” he said.

Mayo Clinic

“Hopefully, the prescribers of this low-dose formulation are aware of the gastrointestinal side effects, such as diarrhea and nausea, and educate patients about these side effects so that a proper risk-benefit discussion can ensue,” he said.

Dr. Bartels reporting a previous financial relationship with Pfizer. Dr. Gelfand said he has financial relationships with AbbVie, Amgen, Bristol-Myers Squibb, Boehringer Ingelheim, Celldex, GlaxoSmithKline, Twill, Lilly, Leo, Moonlake, Janssen Biologics, Novartis, Pfizer, UCB, Neuroderm, and Veolia North America. Dr. Loftus disclosed relationships with AbbVie, Alvotech, Amgen, Arena, Avalo, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene/Receptos, Celltrion Healthcare, Eli Lilly, Fresenius Kabi, Genentech, Gilead, GlaxoSmithKline, Gossamer Bio, Iterative Health, Janssen, KSL Diagnostics, Morphic, Ono, Pfizer, Sun, Surrozen, Takeda, Theravance, and UCB.
 

The recent Food and Drug Administration approval of colchicine 0.5 mg (Lodoco) for use in atherosclerotic cardiovascular disease (ASCVD) prevention will possibly create opportunities to use the drug to treat residual risk for ASCVD in some patients with immune-mediated inflammatory diseases, particularly in rheumatology.

Potential in rheumatology

The 0.5-mg dose is just a shade under the 0.6-mg, twice daily dosing rheumatologists typically prescribe for gout, Christie Bartels, MD, MS, chief of rheumatology at the University of Wisconsin–Madison, said in an interview. Clinicians also use the 0.6-mg dose off-label for pseudogout or calcium pyrophosphate deposition disease (CPPD), Dr. Bartels noted.

University of Wisconsin

The new formulation opens the consideration for using colchicine more in patients with psoriatic arthritis, lupus, and rheumatoid arthritis, she said. “I think we could certainly discuss it, particularly, in secondary prevention patients who already had an event or who are at the highest risk and already on optimal traditional agents,” she said.

She cited previous comments by Paul Ridker, MD, director of the center for cardiovascular disease prevention at Brigham and Women’s Hospital in Boston, and developer of the high-sensitivity C-reactive protein (hsCRP) test for measuring inflammatory markers. “We might not know the answer because Dr. Ridker pointed out he used colchicine 0.5 mg in patients that had a high-sensitivity CRP that was high; we need patients who have had inflammation of unknown origin, so those patients presumably weren’t already on another anti-inflammatory,” she said, noting that hydroxychloroquine, methotrexate, and some biologics provide some protection from cardiovascular risks.

However, a potential role for long-term colchicine 0.5 mg in ASCVD prevention may cause consideration for changing the drug’s role in gout treatment, Dr. Bartels said. “In gout, where we do have an FDA-approved indication for colchicine, we used to use it only for the first 6 months while we were getting patients to goal on allopurinol, which was usually then monotherapy after the first 6 months,” she said. “I think this will likely change how I treat gout patients in that I may also offer to continue both medications [colchicine and allopurinol] if they are tolerating them well.

“And then in patients where I’m using it off-label in CPPD, I might again share with them that in addition to possibly helping their CPPD, there may be this added benefit to reduce inflammation just in discussing the risks and benefits of the medicine.”

However, rheumatologists must be careful in using colchicine beyond the typical 6-month cycle, Dr. Bartels said. “One of the tricky things with colchicine, and part of the reason we did not traditionally continue it specifically past the first 6 months, was that it can cause myopathies or cytopenias, so we still have to counsel patients regarding these risks and monitor that,” she said.

Additionally, colchicine can have drug interactions with statins or calcium channel blockers that can change colchicine levels. “I think the dose here is so low, the 0.5 mg, that it’s probably still safe, but again, it’s something that we have to take a look at in the patient’s whole picture and the rest of their burden of their meds in order to make a decision with them,” Dr. Bartels said.

Possibilities in dermatology

The LoDoCo2 trial one of two major randomized trials that supported approval of colchicine 0.5 mg, reported that treated patients had a 60% lower rate of gout than the placebo group (1.4% vs. 3.4%). Joel Gelfand, MD, MSCE, the James J. Leyden professor of dermatology and epidemiology at the University of Pennsylvania, Philadelphia, pointed to this in evaluating the dermatologic implications of the drug’s approval. “This may be of particular interest as people with psoriasis have an increased risk of gout,” he said in emailed comments.

University of Pennsylvania

Colchicine’s mechanism of action to reduce inflammation parallels that of tumor necrosis factor (TNF) inhibitors used for dermatologic indications, namely by inhibiting leukocyte adhesion to disrupt the downregulation of TNF receptors, Dr. Gelfand said.

“Interestingly, observational data suggests biologics that target TNF such as adalimumab, etanercept, etc., are associated with a reduction in CV events, and in placebo-controlled trials we conducted in psoriasis patients, it reduced key inflammatory mediators of cardiovascular disease, including IL [interleukin]-6,” he said. “Randomized clinical trials to evaluate the ability of TNF inhibitors, which are now available as biosimilars, to prevent cardiovascular events in high-risk patients, should be conducted, and more work is needed to identify which additional immune-targeted treatments may lower CV risk with an acceptable safety profile.”

Colchicine currently has few indications for rare conditions in dermatology, Dr. Gelfand said, including Sweets syndrome, subcorneal pustular dermatosis, and cutaneous vasculitis. “There are some reports to suggest it may help psoriatic disease, but current data are limited and insufficient to recommend its use for psoriasis and/or psoriatic arthritis,” he said.

The approval of colchicine 0.5 mg for ASCVD could be meaningful for people with psoriasis who are also being treated for CV risk factors, Dr. Gelfand said. “Additional considerations such as signs of residual inflammation (elevated hsCRP) and CV imaging findings may be used to further guide shared decision-making for optimal use,” he said.

Another consideration he noted: “This is also a novel 0.5-mg formulation, and thus cost may be an issue.”
 

Would side effects bar use in gastroenterology?

Colchicine 0.5 mg may not move the needle much for expanding treatment of ASCVD in patients with inflammatory bowel disease (IBD) and potentially other gastrointestinal conditions, Edward Loftus Jr., MD, the Maxine and Jack Zarrow Family professor of gastroenterology specifically for IBD at the Mayo Clinic in Rochester, Minn., told MDEdge in emailed comments. “Given the GI side effect profile [of colchicine], I am not sure I would go there,” he said.

Mayo Clinic

“Hopefully, the prescribers of this low-dose formulation are aware of the gastrointestinal side effects, such as diarrhea and nausea, and educate patients about these side effects so that a proper risk-benefit discussion can ensue,” he said.

Dr. Bartels reporting a previous financial relationship with Pfizer. Dr. Gelfand said he has financial relationships with AbbVie, Amgen, Bristol-Myers Squibb, Boehringer Ingelheim, Celldex, GlaxoSmithKline, Twill, Lilly, Leo, Moonlake, Janssen Biologics, Novartis, Pfizer, UCB, Neuroderm, and Veolia North America. Dr. Loftus disclosed relationships with AbbVie, Alvotech, Amgen, Arena, Avalo, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene/Receptos, Celltrion Healthcare, Eli Lilly, Fresenius Kabi, Genentech, Gilead, GlaxoSmithKline, Gossamer Bio, Iterative Health, Janssen, KSL Diagnostics, Morphic, Ono, Pfizer, Sun, Surrozen, Takeda, Theravance, and UCB.
 

Guidelines recommend chemoradiation (CRT) before surgery for patients with clinical stage II-III rectal cancer in order to lower the risk of locoregional recurrence, but there is a growing concern among oncologists that the approach leads to overtreatment.

However, the issue has been how best to identify patients who would do well with less intensive treatment.

A German team reported a promising approach to this issue, describing the use of preoperative MRI to assess the mesorectal fascia (MRF) for the presence of a tumor. The paper was published in the Journal of Clinical Oncology.

The thinking is that with uninvolved MRF, the tumor is removed by total mesorectal excision (TME) alone, while patients with involved MRF need neoadjuvant chemoradiation therapy to shrink the tumor before resection.

The team put the idea to the test in 884 patients with cT2-4 rectal cancer.

There were 530 patients (60%) with clear MRFs, and they proceeded directly to total mesorectal excision. The 5-year locoregional recurrence rate was just 2.9% in this group.

In comparison, almost 6% of the 354 patients who received neoadjuvant CRT in this study had a locoregional recurrence within 5 years of TME.

Neoadjuvant chemoradiation offers “no advantage over optimized surgery” for such patients “if a 5-year [locoregional recurrence] rate of approximately 5% is acceptable,” said investigators, led by Reinhard Ruppert, MD, of the department of general and visceral surgery, endocrine surgery, and coloproctology at the Municipal Hospital of Munich-Neuperlach.

If so, neoadjuvant chemoradiation “and its adverse effects can be avoided in 60% of the total population and in 45% of patients with clinical stage II and III cancer” as found in the study, they said.

“The risk of undertreatment because of the omission of” neoadjuvant chemoradiation is low, they commented. Of the 10 patients who had a negative MRF but turned out to have positive resection margins at surgery, only one had a recurrence, the team noted.

Overall, the study suggests that neoadjuvant chemoradiation therapy can be restricted to patients at high risk of locoregional recurrence. “These findings may be used for guiding clinical surgical practice and the administration of neoadjuvant radiotherapy or neoadjuvant chemoradiotherapy,” the investigators said.
 

Concern about reproducibility

Approached for comment, Alan Venook, MD, a gastrointestinal oncologist at the University of California, San Francisco, said, “This is another paper that pretty much confirms the assumption that we overtreat many patients with rectal cancer.”

These “data support the principle that many, if not most, patients with localized rectal cancer do not require trimodality therapy (chemotherapy, radiation, surgery) to achieve cure. That said, it remains a real challenge to figure out which of the modalities can or should be omitted in the average patient,” Dr. Venook told this news organization.

Overall, the German results “are excellent” but it’s unknown if the results can be replicated in community settings, given the expertise needed to discern MRF involvement on MRI and the fact that not every patient gets TME, the gold-standard surgery used in the trial, he said.

Venook said that at his university, given the rapidly evolving literature on de-escalating treatment, every rectal cancer case is discussed at a multidisciplinary tumor board to decide the best course of action.
 

Study details

Patients in the trial were treated at 14 centers in Germany from 2007 to 2016; nodal involvement was allowed, but subjects had no distant metastases. The call on whether or not they had MRF involvement was based on the distance between the MRF on preoperative MRI and their tumor, suspicious lymph nodes, and tumor deposits.

Patients with a distance greater than 1 mm were considered low risk for recurrence and underwent upfront total mesorectal excision. Those with a distance of 1 mm or fewer as well as patients with cT4 tumors and cT3 tumors in the lower rectal third – a location that makes it difficult to assess the MRF involvement – received up to 50.4 Gy radiation plus fluorouracil before surgery.

The 5-year rate of distant metastases was 15.9% in the upfront surgery group versus 30.5% in the nCRT arm; 11% of the upfront surgery group died of rectal cancer during follow-up versus 21.8% of the nCRT arm.

The work was funded by Johannes Gutenberg University Mainz. Dr. Ruppert and Dr. Venook report no relevant financial relationships. Three investigators reported honoraria and/or travel expenses from Intuitive Surgical, AbbVie, Johnson & Johnson, and other companies.

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

Guidelines recommend chemoradiation (CRT) before surgery for patients with clinical stage II-III rectal cancer in order to lower the risk of locoregional recurrence, but there is a growing concern among oncologists that the approach leads to overtreatment.

However, the issue has been how best to identify patients who would do well with less intensive treatment.

A German team reported a promising approach to this issue, describing the use of preoperative MRI to assess the mesorectal fascia (MRF) for the presence of a tumor. The paper was published in the Journal of Clinical Oncology.

The thinking is that with uninvolved MRF, the tumor is removed by total mesorectal excision (TME) alone, while patients with involved MRF need neoadjuvant chemoradiation therapy to shrink the tumor before resection.

The team put the idea to the test in 884 patients with cT2-4 rectal cancer.

There were 530 patients (60%) with clear MRFs, and they proceeded directly to total mesorectal excision. The 5-year locoregional recurrence rate was just 2.9% in this group.

In comparison, almost 6% of the 354 patients who received neoadjuvant CRT in this study had a locoregional recurrence within 5 years of TME.

Neoadjuvant chemoradiation offers “no advantage over optimized surgery” for such patients “if a 5-year [locoregional recurrence] rate of approximately 5% is acceptable,” said investigators, led by Reinhard Ruppert, MD, of the department of general and visceral surgery, endocrine surgery, and coloproctology at the Municipal Hospital of Munich-Neuperlach.

If so, neoadjuvant chemoradiation “and its adverse effects can be avoided in 60% of the total population and in 45% of patients with clinical stage II and III cancer” as found in the study, they said.

“The risk of undertreatment because of the omission of” neoadjuvant chemoradiation is low, they commented. Of the 10 patients who had a negative MRF but turned out to have positive resection margins at surgery, only one had a recurrence, the team noted.

Overall, the study suggests that neoadjuvant chemoradiation therapy can be restricted to patients at high risk of locoregional recurrence. “These findings may be used for guiding clinical surgical practice and the administration of neoadjuvant radiotherapy or neoadjuvant chemoradiotherapy,” the investigators said.
 

Concern about reproducibility

Approached for comment, Alan Venook, MD, a gastrointestinal oncologist at the University of California, San Francisco, said, “This is another paper that pretty much confirms the assumption that we overtreat many patients with rectal cancer.”

These “data support the principle that many, if not most, patients with localized rectal cancer do not require trimodality therapy (chemotherapy, radiation, surgery) to achieve cure. That said, it remains a real challenge to figure out which of the modalities can or should be omitted in the average patient,” Dr. Venook told this news organization.

Overall, the German results “are excellent” but it’s unknown if the results can be replicated in community settings, given the expertise needed to discern MRF involvement on MRI and the fact that not every patient gets TME, the gold-standard surgery used in the trial, he said.

Venook said that at his university, given the rapidly evolving literature on de-escalating treatment, every rectal cancer case is discussed at a multidisciplinary tumor board to decide the best course of action.
 

Study details

Patients in the trial were treated at 14 centers in Germany from 2007 to 2016; nodal involvement was allowed, but subjects had no distant metastases. The call on whether or not they had MRF involvement was based on the distance between the MRF on preoperative MRI and their tumor, suspicious lymph nodes, and tumor deposits.

Patients with a distance greater than 1 mm were considered low risk for recurrence and underwent upfront total mesorectal excision. Those with a distance of 1 mm or fewer as well as patients with cT4 tumors and cT3 tumors in the lower rectal third – a location that makes it difficult to assess the MRF involvement – received up to 50.4 Gy radiation plus fluorouracil before surgery.

The 5-year rate of distant metastases was 15.9% in the upfront surgery group versus 30.5% in the nCRT arm; 11% of the upfront surgery group died of rectal cancer during follow-up versus 21.8% of the nCRT arm.

The work was funded by Johannes Gutenberg University Mainz. Dr. Ruppert and Dr. Venook report no relevant financial relationships. Three investigators reported honoraria and/or travel expenses from Intuitive Surgical, AbbVie, Johnson & Johnson, and other companies.

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

Guidelines recommend chemoradiation (CRT) before surgery for patients with clinical stage II-III rectal cancer in order to lower the risk of locoregional recurrence, but there is a growing concern among oncologists that the approach leads to overtreatment.

However, the issue has been how best to identify patients who would do well with less intensive treatment.

A German team reported a promising approach to this issue, describing the use of preoperative MRI to assess the mesorectal fascia (MRF) for the presence of a tumor. The paper was published in the Journal of Clinical Oncology.

The thinking is that with uninvolved MRF, the tumor is removed by total mesorectal excision (TME) alone, while patients with involved MRF need neoadjuvant chemoradiation therapy to shrink the tumor before resection.

The team put the idea to the test in 884 patients with cT2-4 rectal cancer.

There were 530 patients (60%) with clear MRFs, and they proceeded directly to total mesorectal excision. The 5-year locoregional recurrence rate was just 2.9% in this group.

In comparison, almost 6% of the 354 patients who received neoadjuvant CRT in this study had a locoregional recurrence within 5 years of TME.

Neoadjuvant chemoradiation offers “no advantage over optimized surgery” for such patients “if a 5-year [locoregional recurrence] rate of approximately 5% is acceptable,” said investigators, led by Reinhard Ruppert, MD, of the department of general and visceral surgery, endocrine surgery, and coloproctology at the Municipal Hospital of Munich-Neuperlach.

If so, neoadjuvant chemoradiation “and its adverse effects can be avoided in 60% of the total population and in 45% of patients with clinical stage II and III cancer” as found in the study, they said.

“The risk of undertreatment because of the omission of” neoadjuvant chemoradiation is low, they commented. Of the 10 patients who had a negative MRF but turned out to have positive resection margins at surgery, only one had a recurrence, the team noted.

Overall, the study suggests that neoadjuvant chemoradiation therapy can be restricted to patients at high risk of locoregional recurrence. “These findings may be used for guiding clinical surgical practice and the administration of neoadjuvant radiotherapy or neoadjuvant chemoradiotherapy,” the investigators said.
 

Concern about reproducibility

Approached for comment, Alan Venook, MD, a gastrointestinal oncologist at the University of California, San Francisco, said, “This is another paper that pretty much confirms the assumption that we overtreat many patients with rectal cancer.”

These “data support the principle that many, if not most, patients with localized rectal cancer do not require trimodality therapy (chemotherapy, radiation, surgery) to achieve cure. That said, it remains a real challenge to figure out which of the modalities can or should be omitted in the average patient,” Dr. Venook told this news organization.

Overall, the German results “are excellent” but it’s unknown if the results can be replicated in community settings, given the expertise needed to discern MRF involvement on MRI and the fact that not every patient gets TME, the gold-standard surgery used in the trial, he said.

Venook said that at his university, given the rapidly evolving literature on de-escalating treatment, every rectal cancer case is discussed at a multidisciplinary tumor board to decide the best course of action.
 

Study details

Patients in the trial were treated at 14 centers in Germany from 2007 to 2016; nodal involvement was allowed, but subjects had no distant metastases. The call on whether or not they had MRF involvement was based on the distance between the MRF on preoperative MRI and their tumor, suspicious lymph nodes, and tumor deposits.

Patients with a distance greater than 1 mm were considered low risk for recurrence and underwent upfront total mesorectal excision. Those with a distance of 1 mm or fewer as well as patients with cT4 tumors and cT3 tumors in the lower rectal third – a location that makes it difficult to assess the MRF involvement – received up to 50.4 Gy radiation plus fluorouracil before surgery.

The 5-year rate of distant metastases was 15.9% in the upfront surgery group versus 30.5% in the nCRT arm; 11% of the upfront surgery group died of rectal cancer during follow-up versus 21.8% of the nCRT arm.

The work was funded by Johannes Gutenberg University Mainz. Dr. Ruppert and Dr. Venook report no relevant financial relationships. Three investigators reported honoraria and/or travel expenses from Intuitive Surgical, AbbVie, Johnson & Johnson, and other companies.

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

It was one of those dog days of August where the humidity is palpable and the pressure is so hot and thick you can almost feel the ions in the air. At the time (2022), I was a White House fellow and senior adviser in the West Wing Office of Public Engagement and in the Office of the Vice President.

I was leaving the White House around 7:00 p.m. through the front gate on Lafayette Square. I had a dinner reservation with a friend, so I was in a rush. It was super overcast. Lo and behold, three steps after I closed the gate behind me, it started pouring. Rain came down so hard I had to take shelter.

There’s a stone building in front of the White House with archways, so I took cover underneath one of them, hoping that in a couple of minutes the rain would pass. Behind the archways are these thick, black, iron gates.

Just as I was about to make a run for it, I heard: BOOM!

It was like a bomb had gone off. In one moment, I saw the lightning bolt, heard the thunder, and felt the heat. It was all one rush of sensation. I couldn’t remember having been that scared in a long time.

I thought, “I definitely have to get out of here. In a couple of minutes there might be another strike, and I’m sitting next to iron gates!” I saw a little bit of a window in the downpour, so I started booking it. I knew there was a sheltered Secret Service area around the corner where they park their cars. A much safer place to be.

I was sprinting on the sidewalk and spotted a bunch of Secret Service agents on their bikes riding in the opposite direction, back toward the park. I knew they wouldn’t be out on bikes in this mess without a reason. As they reached me, one agent said, “Clear the sidewalk! We’re coming through with a bunch of equipment.”

I yelled, “What’s going on?”

“Four people were just struck by lightning,” he said as he zoomed past.

I thought: “Sh*t. I have to go back.”

It was like two different parts of my brain were active at the exact same time. My subcortical brain at the level of the amygdala was like: “You just ran from there, idiot. Why are you running back?” And another part of my brain was like: “This is who you are.”

The lightning had struck one of the largest trees in the park. Four bodies splayed out in one direction from the tree. They’d been taking shelter underneath it when they were hit and were blown off to one side. By the time I got there, two Secret Service agents were on the scene doing CPR. Some bystanders had started to run over.

I did a quick round of pulse checks to see everyone’s status, and all four were apneic and pulseless. I told the two Secret Service agents to keep doing compressions on the first person. Two bystanders also began compressions on another person, an older man.

More Secret Service agents arrived, and I said, “We need to do compressions on this other person right now.” One of the agents took a moment to question who I could be and why I was there. I said, “I’m a doctor. I know I’m not dressed like one, but I’m a physician.”

I told some agents to go find an AED, because these people needed to be shocked.

After they left, I was effectively trying to triage which of these four people would get the AED first. Initially, I spent more of my time on the young man, and we began to get some response from him. I then spent some time with the young woman.

It turned out there were AEDs in the pouches on the Secret Service bikes, but they were very small, dinky AEDs. We tried to apply the pads, but it was downpouring so much that the adhesive wouldn’t stick. I told one of the agents we needed a towel.

Through all this I was concerned we were going to be struck again. I mean, the metal statue of Lafayette was right there! They say lighting doesn’t strike in the same place twice, but who knows if that’s really true?

The towel arrived, and we were able to get the chests of the younger people dry enough for the AED pads. We applied two shocks first to the woman, then the young man. We got his pulse back quickly. The woman’s came back as well, but it felt much weaker.

EMS arrived shortly thereafter. We got all four patients on the transport, and they were transferred to the hospital.

The whole experience had taken 14 minutes.

At the time, I felt confident that the young man was going to survive. We’re taught that lightning bolt strikes are survivable if you can shock someone quickly. He also got pretty good CPR. But the next day I was watching the news and learned that he had passed away. So, of course I was thinking the worst about the others as well.

But a week and a half later, I learned that the young woman had been discharged from the ICU. She was the only one who made it. Her name is Amber, and we got connected through a reporter. About 2 weeks later, I invited her to the White House. I took her to the Oval Office. I met her mom and dad and husband, and we had dinner. We’ve been in touch ever since.

I remember the first time we talked on the phone, Amber said something along the lines of, “This sucks. Obviously, I was not planning for any of this to happen. But I also think there’s something good that could come from this.”

I was so surprised and happy to hear her say that. I had something similar happen to me when I was a teenager – caught in the wrong place at the wrong time. I tried to intervene in a gang fight in my neighborhood. I thought a kid was going to get killed, so I jumped in, imagining I could save the day. I didn’t. They broke a bunch of my bones and I was in the hospital for a bit.

I remember thinking then that my life was over. But after some time, I found a new perspective, which was: Maybe that life is over. But maybe this could be the beginning of a new one. And maybe those things that I’ve been afraid of doing, the dreams that I have, maybe now I’m actually free to go after them.

I told Amber, if there are things that you have been waiting to do, this could be the time. She wants to be an international human rights activist, and she is kicking butt in a graduate school program to begin on that pathway. It’s been really cool to watch her chase this dream with way more vigor than she had before.

I think we bonded because we’ve gone through – obviously not the same thing, but a similar moment of being confronted with your own mortality. Realizing that life can just shatter. And so, while we’re here, we might as well go for it with all the force of a person who knows this could all disappear in an instant.

It was an extremely humbling moment. It reaffirmed that my life is not about me. I have to use the time that I’ve got on behalf of other people as much as I can. What is my life about if not being useful?

Dr. Martin is an emergency medicine physician and faculty member at the MGH Center for Social Justice and Health Equity at Harvard Medical School, Boston.

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

It was one of those dog days of August where the humidity is palpable and the pressure is so hot and thick you can almost feel the ions in the air. At the time (2022), I was a White House fellow and senior adviser in the West Wing Office of Public Engagement and in the Office of the Vice President.

I was leaving the White House around 7:00 p.m. through the front gate on Lafayette Square. I had a dinner reservation with a friend, so I was in a rush. It was super overcast. Lo and behold, three steps after I closed the gate behind me, it started pouring. Rain came down so hard I had to take shelter.

There’s a stone building in front of the White House with archways, so I took cover underneath one of them, hoping that in a couple of minutes the rain would pass. Behind the archways are these thick, black, iron gates.

Just as I was about to make a run for it, I heard: BOOM!

It was like a bomb had gone off. In one moment, I saw the lightning bolt, heard the thunder, and felt the heat. It was all one rush of sensation. I couldn’t remember having been that scared in a long time.

I thought, “I definitely have to get out of here. In a couple of minutes there might be another strike, and I’m sitting next to iron gates!” I saw a little bit of a window in the downpour, so I started booking it. I knew there was a sheltered Secret Service area around the corner where they park their cars. A much safer place to be.

I was sprinting on the sidewalk and spotted a bunch of Secret Service agents on their bikes riding in the opposite direction, back toward the park. I knew they wouldn’t be out on bikes in this mess without a reason. As they reached me, one agent said, “Clear the sidewalk! We’re coming through with a bunch of equipment.”

I yelled, “What’s going on?”

“Four people were just struck by lightning,” he said as he zoomed past.

I thought: “Sh*t. I have to go back.”

It was like two different parts of my brain were active at the exact same time. My subcortical brain at the level of the amygdala was like: “You just ran from there, idiot. Why are you running back?” And another part of my brain was like: “This is who you are.”

The lightning had struck one of the largest trees in the park. Four bodies splayed out in one direction from the tree. They’d been taking shelter underneath it when they were hit and were blown off to one side. By the time I got there, two Secret Service agents were on the scene doing CPR. Some bystanders had started to run over.

I did a quick round of pulse checks to see everyone’s status, and all four were apneic and pulseless. I told the two Secret Service agents to keep doing compressions on the first person. Two bystanders also began compressions on another person, an older man.

More Secret Service agents arrived, and I said, “We need to do compressions on this other person right now.” One of the agents took a moment to question who I could be and why I was there. I said, “I’m a doctor. I know I’m not dressed like one, but I’m a physician.”

I told some agents to go find an AED, because these people needed to be shocked.

After they left, I was effectively trying to triage which of these four people would get the AED first. Initially, I spent more of my time on the young man, and we began to get some response from him. I then spent some time with the young woman.

It turned out there were AEDs in the pouches on the Secret Service bikes, but they were very small, dinky AEDs. We tried to apply the pads, but it was downpouring so much that the adhesive wouldn’t stick. I told one of the agents we needed a towel.

Through all this I was concerned we were going to be struck again. I mean, the metal statue of Lafayette was right there! They say lighting doesn’t strike in the same place twice, but who knows if that’s really true?

The towel arrived, and we were able to get the chests of the younger people dry enough for the AED pads. We applied two shocks first to the woman, then the young man. We got his pulse back quickly. The woman’s came back as well, but it felt much weaker.

EMS arrived shortly thereafter. We got all four patients on the transport, and they were transferred to the hospital.

The whole experience had taken 14 minutes.

At the time, I felt confident that the young man was going to survive. We’re taught that lightning bolt strikes are survivable if you can shock someone quickly. He also got pretty good CPR. But the next day I was watching the news and learned that he had passed away. So, of course I was thinking the worst about the others as well.

But a week and a half later, I learned that the young woman had been discharged from the ICU. She was the only one who made it. Her name is Amber, and we got connected through a reporter. About 2 weeks later, I invited her to the White House. I took her to the Oval Office. I met her mom and dad and husband, and we had dinner. We’ve been in touch ever since.

I remember the first time we talked on the phone, Amber said something along the lines of, “This sucks. Obviously, I was not planning for any of this to happen. But I also think there’s something good that could come from this.”

I was so surprised and happy to hear her say that. I had something similar happen to me when I was a teenager – caught in the wrong place at the wrong time. I tried to intervene in a gang fight in my neighborhood. I thought a kid was going to get killed, so I jumped in, imagining I could save the day. I didn’t. They broke a bunch of my bones and I was in the hospital for a bit.

I remember thinking then that my life was over. But after some time, I found a new perspective, which was: Maybe that life is over. But maybe this could be the beginning of a new one. And maybe those things that I’ve been afraid of doing, the dreams that I have, maybe now I’m actually free to go after them.

I told Amber, if there are things that you have been waiting to do, this could be the time. She wants to be an international human rights activist, and she is kicking butt in a graduate school program to begin on that pathway. It’s been really cool to watch her chase this dream with way more vigor than she had before.

I think we bonded because we’ve gone through – obviously not the same thing, but a similar moment of being confronted with your own mortality. Realizing that life can just shatter. And so, while we’re here, we might as well go for it with all the force of a person who knows this could all disappear in an instant.

It was an extremely humbling moment. It reaffirmed that my life is not about me. I have to use the time that I’ve got on behalf of other people as much as I can. What is my life about if not being useful?

Dr. Martin is an emergency medicine physician and faculty member at the MGH Center for Social Justice and Health Equity at Harvard Medical School, Boston.

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

It was one of those dog days of August where the humidity is palpable and the pressure is so hot and thick you can almost feel the ions in the air. At the time (2022), I was a White House fellow and senior adviser in the West Wing Office of Public Engagement and in the Office of the Vice President.

I was leaving the White House around 7:00 p.m. through the front gate on Lafayette Square. I had a dinner reservation with a friend, so I was in a rush. It was super overcast. Lo and behold, three steps after I closed the gate behind me, it started pouring. Rain came down so hard I had to take shelter.

There’s a stone building in front of the White House with archways, so I took cover underneath one of them, hoping that in a couple of minutes the rain would pass. Behind the archways are these thick, black, iron gates.

Just as I was about to make a run for it, I heard: BOOM!

It was like a bomb had gone off. In one moment, I saw the lightning bolt, heard the thunder, and felt the heat. It was all one rush of sensation. I couldn’t remember having been that scared in a long time.

I thought, “I definitely have to get out of here. In a couple of minutes there might be another strike, and I’m sitting next to iron gates!” I saw a little bit of a window in the downpour, so I started booking it. I knew there was a sheltered Secret Service area around the corner where they park their cars. A much safer place to be.

I was sprinting on the sidewalk and spotted a bunch of Secret Service agents on their bikes riding in the opposite direction, back toward the park. I knew they wouldn’t be out on bikes in this mess without a reason. As they reached me, one agent said, “Clear the sidewalk! We’re coming through with a bunch of equipment.”

I yelled, “What’s going on?”

“Four people were just struck by lightning,” he said as he zoomed past.

I thought: “Sh*t. I have to go back.”

It was like two different parts of my brain were active at the exact same time. My subcortical brain at the level of the amygdala was like: “You just ran from there, idiot. Why are you running back?” And another part of my brain was like: “This is who you are.”

The lightning had struck one of the largest trees in the park. Four bodies splayed out in one direction from the tree. They’d been taking shelter underneath it when they were hit and were blown off to one side. By the time I got there, two Secret Service agents were on the scene doing CPR. Some bystanders had started to run over.

I did a quick round of pulse checks to see everyone’s status, and all four were apneic and pulseless. I told the two Secret Service agents to keep doing compressions on the first person. Two bystanders also began compressions on another person, an older man.

More Secret Service agents arrived, and I said, “We need to do compressions on this other person right now.” One of the agents took a moment to question who I could be and why I was there. I said, “I’m a doctor. I know I’m not dressed like one, but I’m a physician.”

I told some agents to go find an AED, because these people needed to be shocked.

After they left, I was effectively trying to triage which of these four people would get the AED first. Initially, I spent more of my time on the young man, and we began to get some response from him. I then spent some time with the young woman.

It turned out there were AEDs in the pouches on the Secret Service bikes, but they were very small, dinky AEDs. We tried to apply the pads, but it was downpouring so much that the adhesive wouldn’t stick. I told one of the agents we needed a towel.

Through all this I was concerned we were going to be struck again. I mean, the metal statue of Lafayette was right there! They say lighting doesn’t strike in the same place twice, but who knows if that’s really true?

The towel arrived, and we were able to get the chests of the younger people dry enough for the AED pads. We applied two shocks first to the woman, then the young man. We got his pulse back quickly. The woman’s came back as well, but it felt much weaker.

EMS arrived shortly thereafter. We got all four patients on the transport, and they were transferred to the hospital.

The whole experience had taken 14 minutes.

At the time, I felt confident that the young man was going to survive. We’re taught that lightning bolt strikes are survivable if you can shock someone quickly. He also got pretty good CPR. But the next day I was watching the news and learned that he had passed away. So, of course I was thinking the worst about the others as well.

But a week and a half later, I learned that the young woman had been discharged from the ICU. She was the only one who made it. Her name is Amber, and we got connected through a reporter. About 2 weeks later, I invited her to the White House. I took her to the Oval Office. I met her mom and dad and husband, and we had dinner. We’ve been in touch ever since.

I remember the first time we talked on the phone, Amber said something along the lines of, “This sucks. Obviously, I was not planning for any of this to happen. But I also think there’s something good that could come from this.”

I was so surprised and happy to hear her say that. I had something similar happen to me when I was a teenager – caught in the wrong place at the wrong time. I tried to intervene in a gang fight in my neighborhood. I thought a kid was going to get killed, so I jumped in, imagining I could save the day. I didn’t. They broke a bunch of my bones and I was in the hospital for a bit.

I remember thinking then that my life was over. But after some time, I found a new perspective, which was: Maybe that life is over. But maybe this could be the beginning of a new one. And maybe those things that I’ve been afraid of doing, the dreams that I have, maybe now I’m actually free to go after them.

I told Amber, if there are things that you have been waiting to do, this could be the time. She wants to be an international human rights activist, and she is kicking butt in a graduate school program to begin on that pathway. It’s been really cool to watch her chase this dream with way more vigor than she had before.

I think we bonded because we’ve gone through – obviously not the same thing, but a similar moment of being confronted with your own mortality. Realizing that life can just shatter. And so, while we’re here, we might as well go for it with all the force of a person who knows this could all disappear in an instant.

It was an extremely humbling moment. It reaffirmed that my life is not about me. I have to use the time that I’ve got on behalf of other people as much as I can. What is my life about if not being useful?

Dr. Martin is an emergency medicine physician and faculty member at the MGH Center for Social Justice and Health Equity at Harvard Medical School, Boston.

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

In women who have locally advanced breast cancer (LABC), staging defines the extent of the disease and guides therapy.

Researchers have found in the first large, randomized, controlled study on the subject that ¹⁸ F-labeled fluorodeoxyglucose positron emission tomography–computed tomography (PET-CT) finds more distant metastases and allows more accurate staging than usual staging, which is determined by a bone scan and computed tomography (CT) of the thorax/abdomen and pelvis.

Findings of the study, led by Ian S. Dayes, MD, MSc, with the department of oncology at McMaster University in Hamilton, Ont., were published online in the Journal of Clinical Oncology.
 

Scans indicate less aggressive treatment strategy

The authors of the new study wrote that women with LABC, who are at high risk of metastatic disease, have large tumors that “can involve the chest wall or skin, clinically fixed axillary lymph nodes, or infraclavicular, supraclavicular, or internal mammary lymphadenopathy.”

If staging does not detect metastases, treatment is centered on combined modality therapy with curative intent (neoadjuvant chemotherapy and surgery, followed by regional radiation). If metastases are found, the treatment goal changes to controlling the disease.

In this study, twice as many women saw their stage increase from stage IIB or III to stage IV when PET-CT was used instead of conventional staging, guiding their treatment toward less aggressive care to control, rather than attempt to cure, the disease.

The women included in this study had histological evidence of invasive ductal carcinoma of the breast and TNM stage III or IIb (T3N0, but not T2N1).
 

Methods and results

Between December 2016 and April 2022, consenting patients from six regional cancer centers in Ontario were randomly assigned to one of two groups: 184 patients were randomly assigned to whole-body PET-CT and 185 patients to conventional staging.

Overall, the authors wrote, 43 (23%) of PET-CT patients “were upstaged” to stage IV compared with 21 (11%) of the conventionally staged patients (relative risk, 2.4; 95% confidence interval [CI], 1.4-4.2, P = .002).

There were 33 patients in a subset with inflammatory breast cancer and, among them, 4 of 16 (25%) PET-CT patients were upstaged to stage IV compared with 4 of 17 (24%) conventionally staged patients.

In the patients who did not have inflammatory breast cancer, 39 of 168 (23%) PET-CT patients were upstaged compared with 17 (10%) of 168 in the conventionally staged group.

Journal of Clinical Oncology (JCO) Senior Deputy Editor Kathy D. Miller, MD, said that, “PET/CT staging identifies distant disease in more patients and changes goals of therapy. Further research is needed to determine the impact on patient outcome.”
 

Findings have already changed practice

Senior author, Mark Levine, MD, MSc, also with McMaster, said in an interview that the results of this study have already changed practice in Canada, and he expects the United States to follow suit.

Dr. Levine said the study is important “in terms of helping plan therapy and being very open and honest with patients as to their prognosis.”

The findings constitute level 1 evidence in favor of PET-CT. Already, in Canada, “because of the results of the study, people with stage III breast cancer can get a PET scan,” he said.

Dr. Levine said he expects this evidence also to clarify “wishy-washy” National Comprehensive Cancer Network guidelines on using PET scans for LABC in the United States when the guidelines are next updated.

“That will make it easier for payers in the United States,” he added.

Cost effectiveness, Dr. Levine said, is complicated, because on one hand PET scans are quite costly. But its use would lead to more women getting less aggressive and expensive therapy and surgery.

Dr. Levine noted that his team will be analyzing cost-effectiveness over the next year.
 

New questions with more in stage IV

In an editorial, Lajos Pusztai, MD, DPhil, scientific codirector of the breast center at Yale University in New Haven, Conn., noted that, “all good studies raise new questions” and this one is no exception.

He pointed out that the number of women with stage IV metastatic breast cancer (MBC) has been increasing over the past 2 decades because of more sensitive staging methods. At the same time the number of women with recurrent metastatic disease is decreasing, because adjuvant therapies have improved.
 

Findings highlight need for stage IV treatment studies

Dr. Pusztai noted that the patients who have de novo oligometastatic stage IV disease “are a unique subset among patients with MBC,” and the best treatment [for them] has not been established in randomized, controlled trials.

“Almost all randomized trials that targeted oligometastatic patients accrued mostly recurrent metastatic cancers; many included various cancer types, and none have tested the value of systemic multidrug regimens administered with curative intent,” he wrote.

If the health care systems adopt PET-CT for routine staging of locally advanced breast cancer, that will increase the diagnosis of de novo oligometastatic stage IV breast cancer, Dr. Pusztai said. That “underlines the importance of conducting studies for this unique subset of patients to establish level 1 evidence-based treatment strategies.”

Dr. Dayes has received honoraria from Verity Pharmaceuticals. One coauthor is employed by Point Biopharma. Other coauthors reported ties with AbbVie, Agendia, Genomic Health, InMode and Lutronic. Dr. Pusztai’s institution has received research funding from Merck, Genentech, Seagen, AstraZeneca, Bristol Myers Squibb, and Pfizer. He has received honoraria and travel expenses and has served in a consulting role for several pharmaceutical companies. Full disclosures are available on Open Payments.

In women who have locally advanced breast cancer (LABC), staging defines the extent of the disease and guides therapy.

Researchers have found in the first large, randomized, controlled study on the subject that ¹⁸ F-labeled fluorodeoxyglucose positron emission tomography–computed tomography (PET-CT) finds more distant metastases and allows more accurate staging than usual staging, which is determined by a bone scan and computed tomography (CT) of the thorax/abdomen and pelvis.

Findings of the study, led by Ian S. Dayes, MD, MSc, with the department of oncology at McMaster University in Hamilton, Ont., were published online in the Journal of Clinical Oncology.
 

Scans indicate less aggressive treatment strategy

The authors of the new study wrote that women with LABC, who are at high risk of metastatic disease, have large tumors that “can involve the chest wall or skin, clinically fixed axillary lymph nodes, or infraclavicular, supraclavicular, or internal mammary lymphadenopathy.”

If staging does not detect metastases, treatment is centered on combined modality therapy with curative intent (neoadjuvant chemotherapy and surgery, followed by regional radiation). If metastases are found, the treatment goal changes to controlling the disease.

In this study, twice as many women saw their stage increase from stage IIB or III to stage IV when PET-CT was used instead of conventional staging, guiding their treatment toward less aggressive care to control, rather than attempt to cure, the disease.

The women included in this study had histological evidence of invasive ductal carcinoma of the breast and TNM stage III or IIb (T3N0, but not T2N1).
 

Methods and results

Between December 2016 and April 2022, consenting patients from six regional cancer centers in Ontario were randomly assigned to one of two groups: 184 patients were randomly assigned to whole-body PET-CT and 185 patients to conventional staging.

Overall, the authors wrote, 43 (23%) of PET-CT patients “were upstaged” to stage IV compared with 21 (11%) of the conventionally staged patients (relative risk, 2.4; 95% confidence interval [CI], 1.4-4.2, P = .002).

There were 33 patients in a subset with inflammatory breast cancer and, among them, 4 of 16 (25%) PET-CT patients were upstaged to stage IV compared with 4 of 17 (24%) conventionally staged patients.

In the patients who did not have inflammatory breast cancer, 39 of 168 (23%) PET-CT patients were upstaged compared with 17 (10%) of 168 in the conventionally staged group.

Journal of Clinical Oncology (JCO) Senior Deputy Editor Kathy D. Miller, MD, said that, “PET/CT staging identifies distant disease in more patients and changes goals of therapy. Further research is needed to determine the impact on patient outcome.”
 

Findings have already changed practice

Senior author, Mark Levine, MD, MSc, also with McMaster, said in an interview that the results of this study have already changed practice in Canada, and he expects the United States to follow suit.

Dr. Levine said the study is important “in terms of helping plan therapy and being very open and honest with patients as to their prognosis.”

The findings constitute level 1 evidence in favor of PET-CT. Already, in Canada, “because of the results of the study, people with stage III breast cancer can get a PET scan,” he said.

Dr. Levine said he expects this evidence also to clarify “wishy-washy” National Comprehensive Cancer Network guidelines on using PET scans for LABC in the United States when the guidelines are next updated.

“That will make it easier for payers in the United States,” he added.

Cost effectiveness, Dr. Levine said, is complicated, because on one hand PET scans are quite costly. But its use would lead to more women getting less aggressive and expensive therapy and surgery.

Dr. Levine noted that his team will be analyzing cost-effectiveness over the next year.
 

New questions with more in stage IV

In an editorial, Lajos Pusztai, MD, DPhil, scientific codirector of the breast center at Yale University in New Haven, Conn., noted that, “all good studies raise new questions” and this one is no exception.

He pointed out that the number of women with stage IV metastatic breast cancer (MBC) has been increasing over the past 2 decades because of more sensitive staging methods. At the same time the number of women with recurrent metastatic disease is decreasing, because adjuvant therapies have improved.
 

Findings highlight need for stage IV treatment studies

Dr. Pusztai noted that the patients who have de novo oligometastatic stage IV disease “are a unique subset among patients with MBC,” and the best treatment [for them] has not been established in randomized, controlled trials.

“Almost all randomized trials that targeted oligometastatic patients accrued mostly recurrent metastatic cancers; many included various cancer types, and none have tested the value of systemic multidrug regimens administered with curative intent,” he wrote.

If the health care systems adopt PET-CT for routine staging of locally advanced breast cancer, that will increase the diagnosis of de novo oligometastatic stage IV breast cancer, Dr. Pusztai said. That “underlines the importance of conducting studies for this unique subset of patients to establish level 1 evidence-based treatment strategies.”

Dr. Dayes has received honoraria from Verity Pharmaceuticals. One coauthor is employed by Point Biopharma. Other coauthors reported ties with AbbVie, Agendia, Genomic Health, InMode and Lutronic. Dr. Pusztai’s institution has received research funding from Merck, Genentech, Seagen, AstraZeneca, Bristol Myers Squibb, and Pfizer. He has received honoraria and travel expenses and has served in a consulting role for several pharmaceutical companies. Full disclosures are available on Open Payments.

In women who have locally advanced breast cancer (LABC), staging defines the extent of the disease and guides therapy.

Researchers have found in the first large, randomized, controlled study on the subject that ¹⁸ F-labeled fluorodeoxyglucose positron emission tomography–computed tomography (PET-CT) finds more distant metastases and allows more accurate staging than usual staging, which is determined by a bone scan and computed tomography (CT) of the thorax/abdomen and pelvis.

Findings of the study, led by Ian S. Dayes, MD, MSc, with the department of oncology at McMaster University in Hamilton, Ont., were published online in the Journal of Clinical Oncology.
 

Scans indicate less aggressive treatment strategy

The authors of the new study wrote that women with LABC, who are at high risk of metastatic disease, have large tumors that “can involve the chest wall or skin, clinically fixed axillary lymph nodes, or infraclavicular, supraclavicular, or internal mammary lymphadenopathy.”

If staging does not detect metastases, treatment is centered on combined modality therapy with curative intent (neoadjuvant chemotherapy and surgery, followed by regional radiation). If metastases are found, the treatment goal changes to controlling the disease.

In this study, twice as many women saw their stage increase from stage IIB or III to stage IV when PET-CT was used instead of conventional staging, guiding their treatment toward less aggressive care to control, rather than attempt to cure, the disease.

The women included in this study had histological evidence of invasive ductal carcinoma of the breast and TNM stage III or IIb (T3N0, but not T2N1).
 

Methods and results

Between December 2016 and April 2022, consenting patients from six regional cancer centers in Ontario were randomly assigned to one of two groups: 184 patients were randomly assigned to whole-body PET-CT and 185 patients to conventional staging.

Overall, the authors wrote, 43 (23%) of PET-CT patients “were upstaged” to stage IV compared with 21 (11%) of the conventionally staged patients (relative risk, 2.4; 95% confidence interval [CI], 1.4-4.2, P = .002).

There were 33 patients in a subset with inflammatory breast cancer and, among them, 4 of 16 (25%) PET-CT patients were upstaged to stage IV compared with 4 of 17 (24%) conventionally staged patients.

In the patients who did not have inflammatory breast cancer, 39 of 168 (23%) PET-CT patients were upstaged compared with 17 (10%) of 168 in the conventionally staged group.

Journal of Clinical Oncology (JCO) Senior Deputy Editor Kathy D. Miller, MD, said that, “PET/CT staging identifies distant disease in more patients and changes goals of therapy. Further research is needed to determine the impact on patient outcome.”
 

Findings have already changed practice

Senior author, Mark Levine, MD, MSc, also with McMaster, said in an interview that the results of this study have already changed practice in Canada, and he expects the United States to follow suit.

Dr. Levine said the study is important “in terms of helping plan therapy and being very open and honest with patients as to their prognosis.”

The findings constitute level 1 evidence in favor of PET-CT. Already, in Canada, “because of the results of the study, people with stage III breast cancer can get a PET scan,” he said.

Dr. Levine said he expects this evidence also to clarify “wishy-washy” National Comprehensive Cancer Network guidelines on using PET scans for LABC in the United States when the guidelines are next updated.

“That will make it easier for payers in the United States,” he added.

Cost effectiveness, Dr. Levine said, is complicated, because on one hand PET scans are quite costly. But its use would lead to more women getting less aggressive and expensive therapy and surgery.

Dr. Levine noted that his team will be analyzing cost-effectiveness over the next year.
 

New questions with more in stage IV

In an editorial, Lajos Pusztai, MD, DPhil, scientific codirector of the breast center at Yale University in New Haven, Conn., noted that, “all good studies raise new questions” and this one is no exception.

He pointed out that the number of women with stage IV metastatic breast cancer (MBC) has been increasing over the past 2 decades because of more sensitive staging methods. At the same time the number of women with recurrent metastatic disease is decreasing, because adjuvant therapies have improved.
 

Findings highlight need for stage IV treatment studies

Dr. Pusztai noted that the patients who have de novo oligometastatic stage IV disease “are a unique subset among patients with MBC,” and the best treatment [for them] has not been established in randomized, controlled trials.

“Almost all randomized trials that targeted oligometastatic patients accrued mostly recurrent metastatic cancers; many included various cancer types, and none have tested the value of systemic multidrug regimens administered with curative intent,” he wrote.

If the health care systems adopt PET-CT for routine staging of locally advanced breast cancer, that will increase the diagnosis of de novo oligometastatic stage IV breast cancer, Dr. Pusztai said. That “underlines the importance of conducting studies for this unique subset of patients to establish level 1 evidence-based treatment strategies.”

Dr. Dayes has received honoraria from Verity Pharmaceuticals. One coauthor is employed by Point Biopharma. Other coauthors reported ties with AbbVie, Agendia, Genomic Health, InMode and Lutronic. Dr. Pusztai’s institution has received research funding from Merck, Genentech, Seagen, AstraZeneca, Bristol Myers Squibb, and Pfizer. He has received honoraria and travel expenses and has served in a consulting role for several pharmaceutical companies. Full disclosures are available on Open Payments.

More than 15 years in the making, the revised AAP Clinical Practice Guideline Revision: Management of Hyperbilirubinemia in the Newborn Infant 35 or More Weeks of Gestation was released in 2022. A key driving force for this revision was the expanded evidence base regarding monitoring and treatment of newborns 35 or more weeks’ gestation to prevent bilirubin encephalopathy and kernicterus.

Here, we summarize the highlights of the new guidelines and point out practical ways to incorporate these guidelines into daily practice.
 

What has changed?

If you are familiar with the previous guidelines (2004 or the 2009 update) for the management of newborn jaundice, you’ll note that the treatment graphs for phototherapy and exchange transfusion have been updated with new, slightly higher thresholds.

Bilirubin thresholds for starting phototherapy are about 2 mg/dL higher overall than indicated in previous iterations of the guidelines.

This change reflects new evidence that infants don’t typically develop bilirubin neurotoxicity until the total serum bilirubin (TSB) reaches levels well above the previous exchange transfusion threshold, justifying a narrow increase in the bilirubin level for starting phototherapy. Also, phototherapy treatment thresholds are now risk-adjusted, with separate curves for each gestational age from 35 weeks to > 38 weeks.

To find the applicable phototherapy threshold, use the infant’s gestational age (rounding down) and determine whether the infant has even a single neurotoxicity risk factor other than prematurity. Neurotoxicity risk factors include a low albumin level, isoimmune hemolytic disease, glucose-6-phosphate dehydrogenase (G6PD) deficiency, or other hemolytic conditions; sepsis; or any significant clinical instability in the previous 24 hours.

For example, a 38^4/7 weeks’ gestation newborn has a TSB of 12 mg/dL at 48 hours of age but no neurotoxicity risk factors. Using the graph Phototherapy Thresholds: No Hyperbilirubinemia Neurotoxicity Risk Factors, should the infant be placed under phototherapy at this time? (Answer: No. The threshold for starting phototherapy on this infant is approximately 16 mg/dL.)

When hyperbilirubinemia becomes a medical emergency

A new term, “escalation of care,” has been adopted to describe actions to take when the newborn’s TSB climbs to within 2 mg/dL of the exchange transfusion threshold – a medical emergency. Instructions on how to ensure intensive phototherapy, and when to initiate an urgent exchange transfusion, are given, including the critical need to maintain intensive phototherapy continuously during infant transport and admission to another facility.

Transcutaneous vs. serum bilirubin

Either a serum TSB or a transcutaneous bilirubin (TcB) should be measured in all infants between 24 and 48 hours after birth or before discharge if that occurs earlier. TcB measurements are valid and reliable when used as a screening test to identify infants who require a TSB measurement. Although the two tests are generally correlated, they are not identical, and treatment decisions should be based on TSB levels. A TSB should be obtained if the TcB exceeds or is within 3 mg/dL of the phototherapy treatment threshold, or if the TcB is ≥ 15 mg/dL.

Following up: When to check another bilirubin level

Prior to these new guidelines, the question of when to get the next bilirubin level was based on Vinod Bhutani, MD’s risk nomogram, which classified newborn bilirubin levels within high-, intermediate-, or low-risk zones for needing phototherapy. A bilirubin level in the high-risk zone indicated the need for earlier follow-up. These risk zones have been replaced with a more specific table that provides recommended postdischarge follow-up based on how close the newborn’s bilirubin level is to the hour-specific threshold for treatment. The closer the latest TSB or TcB level is to the newborn’s risk-based phototherapy threshold, the sooner the follow-up to check another bilirubin level will need to be.

Most infants discharged before 72 hours of age will need follow-up within 2 days. Newborns with TSB levels nearing the level for phototherapy (within 2 mg/dL or less) should remain in the hospital.
 

Five tips for using the new guidelines

Bilitool.org, a popular and useful app, has already been updated to reflect the changes in the new guidelines, making it easy to apply the new thresholds and create a follow-up plan for each patient.

The guidelines provide recommendations for when to check rebound bilirubin levels after stopping phototherapy (hint: babies with neurotoxic risk factors). A TcB device should not be used while the infant is being treated with phototherapy. However, a TcB can be measured once the baby has been off phototherapy for at least 24 hours.

If you have at least two bilirubin measurements, you can calculate the “rate of rise” in bilirubin level. A rapid rate of rise, which serves as a clinical indicator of hemolysis, is defined as ≥ 0.3 mg/dL per hour in the first 24 hours or ≥ 0.2 mg/dL per hour after the first 24 hours of life. This is especially helpful when hemolysis is suspected even if the newborn’s direct antibody test (DAT) is negative. In this scenario, the infant is considered to have a neurotoxic risk factor.

When you initiate phototherapy, be aware of the infant’s bilirubin level threshold for stopping phototherapy (2 mg/dL below the starting phototherapy threshold), as well as the threshold for escalation of care (2 mg/dL below the exchange transfusion threshold).

Because the thresholds for starting phototherapy and initiating exchange transfusion are slightly higher and specific to gestational age, clinicians can more confidently use less phototherapy.
 

Other guideline highlights

The neurotoxic risk factors and corresponding thresholds are important. If the newborn has one or more neurotoxic risk factors other than prematurity, the neurotoxic risk threshold graph should be used when assessing the need for treatment. Neurotoxic risk thresholds should also be used for newborns whose bilirubin levels continue rising on phototherapy.

The guidelines emphasize that G6PD is one of the most important causes of hazardous hyperbilirubinemia leading to kernicterus in the United States and worldwide. Overall, 13% of African American males and about 4% of African American females have G6PD deficiency.

Finally, the guidelines remind clinicians that an important way to reduce the chances that phototherapy will be needed is to encourage early and frequent feeding (8-12 times in 24 hours).

The AAP Clinical Practice Guideline Revision: Management of Hyperbilirubinemia in the Newborn Infant 35 or More Weeks of Gestation contains a great deal more information, but these basic principles should allow practitioners to begin to incorporate these guidelines into daily practice.

Dr. Amaya is associate professor, department of pediatrics, Medical University of South Carolina, Charleston, and medical director, level 1 nursery, department of pediatrics, MUSC general academic pediatrics. She disclosed ties with Medical University of South Carolina. Dr. Balog is clinical associate professor of pediatrics, Medical University of South Carolina, Charleston. She has no relevant financial relationships. Dr. Basco is professor, department of pediatrics, Medical University of South Carolina, Charleston; director, division of general pediatrics, department of pediatrics, MUSC Children’s Hospital. He has disclosed no relevant financial relationships.

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

More than 15 years in the making, the revised AAP Clinical Practice Guideline Revision: Management of Hyperbilirubinemia in the Newborn Infant 35 or More Weeks of Gestation was released in 2022. A key driving force for this revision was the expanded evidence base regarding monitoring and treatment of newborns 35 or more weeks’ gestation to prevent bilirubin encephalopathy and kernicterus.

Here, we summarize the highlights of the new guidelines and point out practical ways to incorporate these guidelines into daily practice.
 

What has changed?

If you are familiar with the previous guidelines (2004 or the 2009 update) for the management of newborn jaundice, you’ll note that the treatment graphs for phototherapy and exchange transfusion have been updated with new, slightly higher thresholds.

Bilirubin thresholds for starting phototherapy are about 2 mg/dL higher overall than indicated in previous iterations of the guidelines.

This change reflects new evidence that infants don’t typically develop bilirubin neurotoxicity until the total serum bilirubin (TSB) reaches levels well above the previous exchange transfusion threshold, justifying a narrow increase in the bilirubin level for starting phototherapy. Also, phototherapy treatment thresholds are now risk-adjusted, with separate curves for each gestational age from 35 weeks to > 38 weeks.

To find the applicable phototherapy threshold, use the infant’s gestational age (rounding down) and determine whether the infant has even a single neurotoxicity risk factor other than prematurity. Neurotoxicity risk factors include a low albumin level, isoimmune hemolytic disease, glucose-6-phosphate dehydrogenase (G6PD) deficiency, or other hemolytic conditions; sepsis; or any significant clinical instability in the previous 24 hours.

For example, a 38^4/7 weeks’ gestation newborn has a TSB of 12 mg/dL at 48 hours of age but no neurotoxicity risk factors. Using the graph Phototherapy Thresholds: No Hyperbilirubinemia Neurotoxicity Risk Factors, should the infant be placed under phototherapy at this time? (Answer: No. The threshold for starting phototherapy on this infant is approximately 16 mg/dL.)

When hyperbilirubinemia becomes a medical emergency

A new term, “escalation of care,” has been adopted to describe actions to take when the newborn’s TSB climbs to within 2 mg/dL of the exchange transfusion threshold – a medical emergency. Instructions on how to ensure intensive phototherapy, and when to initiate an urgent exchange transfusion, are given, including the critical need to maintain intensive phototherapy continuously during infant transport and admission to another facility.

Transcutaneous vs. serum bilirubin

Either a serum TSB or a transcutaneous bilirubin (TcB) should be measured in all infants between 24 and 48 hours after birth or before discharge if that occurs earlier. TcB measurements are valid and reliable when used as a screening test to identify infants who require a TSB measurement. Although the two tests are generally correlated, they are not identical, and treatment decisions should be based on TSB levels. A TSB should be obtained if the TcB exceeds or is within 3 mg/dL of the phototherapy treatment threshold, or if the TcB is ≥ 15 mg/dL.

Following up: When to check another bilirubin level

Prior to these new guidelines, the question of when to get the next bilirubin level was based on Vinod Bhutani, MD’s risk nomogram, which classified newborn bilirubin levels within high-, intermediate-, or low-risk zones for needing phototherapy. A bilirubin level in the high-risk zone indicated the need for earlier follow-up. These risk zones have been replaced with a more specific table that provides recommended postdischarge follow-up based on how close the newborn’s bilirubin level is to the hour-specific threshold for treatment. The closer the latest TSB or TcB level is to the newborn’s risk-based phototherapy threshold, the sooner the follow-up to check another bilirubin level will need to be.

Most infants discharged before 72 hours of age will need follow-up within 2 days. Newborns with TSB levels nearing the level for phototherapy (within 2 mg/dL or less) should remain in the hospital.
 

Five tips for using the new guidelines

Bilitool.org, a popular and useful app, has already been updated to reflect the changes in the new guidelines, making it easy to apply the new thresholds and create a follow-up plan for each patient.

The guidelines provide recommendations for when to check rebound bilirubin levels after stopping phototherapy (hint: babies with neurotoxic risk factors). A TcB device should not be used while the infant is being treated with phototherapy. However, a TcB can be measured once the baby has been off phototherapy for at least 24 hours.

If you have at least two bilirubin measurements, you can calculate the “rate of rise” in bilirubin level. A rapid rate of rise, which serves as a clinical indicator of hemolysis, is defined as ≥ 0.3 mg/dL per hour in the first 24 hours or ≥ 0.2 mg/dL per hour after the first 24 hours of life. This is especially helpful when hemolysis is suspected even if the newborn’s direct antibody test (DAT) is negative. In this scenario, the infant is considered to have a neurotoxic risk factor.

When you initiate phototherapy, be aware of the infant’s bilirubin level threshold for stopping phototherapy (2 mg/dL below the starting phototherapy threshold), as well as the threshold for escalation of care (2 mg/dL below the exchange transfusion threshold).

Because the thresholds for starting phototherapy and initiating exchange transfusion are slightly higher and specific to gestational age, clinicians can more confidently use less phototherapy.
 

Other guideline highlights

The neurotoxic risk factors and corresponding thresholds are important. If the newborn has one or more neurotoxic risk factors other than prematurity, the neurotoxic risk threshold graph should be used when assessing the need for treatment. Neurotoxic risk thresholds should also be used for newborns whose bilirubin levels continue rising on phototherapy.

The guidelines emphasize that G6PD is one of the most important causes of hazardous hyperbilirubinemia leading to kernicterus in the United States and worldwide. Overall, 13% of African American males and about 4% of African American females have G6PD deficiency.

Finally, the guidelines remind clinicians that an important way to reduce the chances that phototherapy will be needed is to encourage early and frequent feeding (8-12 times in 24 hours).

The AAP Clinical Practice Guideline Revision: Management of Hyperbilirubinemia in the Newborn Infant 35 or More Weeks of Gestation contains a great deal more information, but these basic principles should allow practitioners to begin to incorporate these guidelines into daily practice.

Dr. Amaya is associate professor, department of pediatrics, Medical University of South Carolina, Charleston, and medical director, level 1 nursery, department of pediatrics, MUSC general academic pediatrics. She disclosed ties with Medical University of South Carolina. Dr. Balog is clinical associate professor of pediatrics, Medical University of South Carolina, Charleston. She has no relevant financial relationships. Dr. Basco is professor, department of pediatrics, Medical University of South Carolina, Charleston; director, division of general pediatrics, department of pediatrics, MUSC Children’s Hospital. He has disclosed no relevant financial relationships.

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

More than 15 years in the making, the revised AAP Clinical Practice Guideline Revision: Management of Hyperbilirubinemia in the Newborn Infant 35 or More Weeks of Gestation was released in 2022. A key driving force for this revision was the expanded evidence base regarding monitoring and treatment of newborns 35 or more weeks’ gestation to prevent bilirubin encephalopathy and kernicterus.

Here, we summarize the highlights of the new guidelines and point out practical ways to incorporate these guidelines into daily practice.
 

What has changed?

If you are familiar with the previous guidelines (2004 or the 2009 update) for the management of newborn jaundice, you’ll note that the treatment graphs for phototherapy and exchange transfusion have been updated with new, slightly higher thresholds.

Bilirubin thresholds for starting phototherapy are about 2 mg/dL higher overall than indicated in previous iterations of the guidelines.

This change reflects new evidence that infants don’t typically develop bilirubin neurotoxicity until the total serum bilirubin (TSB) reaches levels well above the previous exchange transfusion threshold, justifying a narrow increase in the bilirubin level for starting phototherapy. Also, phototherapy treatment thresholds are now risk-adjusted, with separate curves for each gestational age from 35 weeks to > 38 weeks.

To find the applicable phototherapy threshold, use the infant’s gestational age (rounding down) and determine whether the infant has even a single neurotoxicity risk factor other than prematurity. Neurotoxicity risk factors include a low albumin level, isoimmune hemolytic disease, glucose-6-phosphate dehydrogenase (G6PD) deficiency, or other hemolytic conditions; sepsis; or any significant clinical instability in the previous 24 hours.

For example, a 38^4/7 weeks’ gestation newborn has a TSB of 12 mg/dL at 48 hours of age but no neurotoxicity risk factors. Using the graph Phototherapy Thresholds: No Hyperbilirubinemia Neurotoxicity Risk Factors, should the infant be placed under phototherapy at this time? (Answer: No. The threshold for starting phototherapy on this infant is approximately 16 mg/dL.)

When hyperbilirubinemia becomes a medical emergency

A new term, “escalation of care,” has been adopted to describe actions to take when the newborn’s TSB climbs to within 2 mg/dL of the exchange transfusion threshold – a medical emergency. Instructions on how to ensure intensive phototherapy, and when to initiate an urgent exchange transfusion, are given, including the critical need to maintain intensive phototherapy continuously during infant transport and admission to another facility.

Transcutaneous vs. serum bilirubin

Either a serum TSB or a transcutaneous bilirubin (TcB) should be measured in all infants between 24 and 48 hours after birth or before discharge if that occurs earlier. TcB measurements are valid and reliable when used as a screening test to identify infants who require a TSB measurement. Although the two tests are generally correlated, they are not identical, and treatment decisions should be based on TSB levels. A TSB should be obtained if the TcB exceeds or is within 3 mg/dL of the phototherapy treatment threshold, or if the TcB is ≥ 15 mg/dL.

Following up: When to check another bilirubin level

Prior to these new guidelines, the question of when to get the next bilirubin level was based on Vinod Bhutani, MD’s risk nomogram, which classified newborn bilirubin levels within high-, intermediate-, or low-risk zones for needing phototherapy. A bilirubin level in the high-risk zone indicated the need for earlier follow-up. These risk zones have been replaced with a more specific table that provides recommended postdischarge follow-up based on how close the newborn’s bilirubin level is to the hour-specific threshold for treatment. The closer the latest TSB or TcB level is to the newborn’s risk-based phototherapy threshold, the sooner the follow-up to check another bilirubin level will need to be.

Most infants discharged before 72 hours of age will need follow-up within 2 days. Newborns with TSB levels nearing the level for phototherapy (within 2 mg/dL or less) should remain in the hospital.
 

Five tips for using the new guidelines

Bilitool.org, a popular and useful app, has already been updated to reflect the changes in the new guidelines, making it easy to apply the new thresholds and create a follow-up plan for each patient.

The guidelines provide recommendations for when to check rebound bilirubin levels after stopping phototherapy (hint: babies with neurotoxic risk factors). A TcB device should not be used while the infant is being treated with phototherapy. However, a TcB can be measured once the baby has been off phototherapy for at least 24 hours.

If you have at least two bilirubin measurements, you can calculate the “rate of rise” in bilirubin level. A rapid rate of rise, which serves as a clinical indicator of hemolysis, is defined as ≥ 0.3 mg/dL per hour in the first 24 hours or ≥ 0.2 mg/dL per hour after the first 24 hours of life. This is especially helpful when hemolysis is suspected even if the newborn’s direct antibody test (DAT) is negative. In this scenario, the infant is considered to have a neurotoxic risk factor.

When you initiate phototherapy, be aware of the infant’s bilirubin level threshold for stopping phototherapy (2 mg/dL below the starting phototherapy threshold), as well as the threshold for escalation of care (2 mg/dL below the exchange transfusion threshold).

Because the thresholds for starting phototherapy and initiating exchange transfusion are slightly higher and specific to gestational age, clinicians can more confidently use less phototherapy.
 

Other guideline highlights

The neurotoxic risk factors and corresponding thresholds are important. If the newborn has one or more neurotoxic risk factors other than prematurity, the neurotoxic risk threshold graph should be used when assessing the need for treatment. Neurotoxic risk thresholds should also be used for newborns whose bilirubin levels continue rising on phototherapy.

The guidelines emphasize that G6PD is one of the most important causes of hazardous hyperbilirubinemia leading to kernicterus in the United States and worldwide. Overall, 13% of African American males and about 4% of African American females have G6PD deficiency.

Finally, the guidelines remind clinicians that an important way to reduce the chances that phototherapy will be needed is to encourage early and frequent feeding (8-12 times in 24 hours).

The AAP Clinical Practice Guideline Revision: Management of Hyperbilirubinemia in the Newborn Infant 35 or More Weeks of Gestation contains a great deal more information, but these basic principles should allow practitioners to begin to incorporate these guidelines into daily practice.

Dr. Amaya is associate professor, department of pediatrics, Medical University of South Carolina, Charleston, and medical director, level 1 nursery, department of pediatrics, MUSC general academic pediatrics. She disclosed ties with Medical University of South Carolina. Dr. Balog is clinical associate professor of pediatrics, Medical University of South Carolina, Charleston. She has no relevant financial relationships. Dr. Basco is professor, department of pediatrics, Medical University of South Carolina, Charleston; director, division of general pediatrics, department of pediatrics, MUSC Children’s Hospital. He has disclosed no relevant financial relationships.

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

AUSTIN – Treatment of migraines with rimegepant is associated with a reduction of butalbital dose and prescriptions, according to a real-world analysis. Butalbital is the only commonly prescribed short-acting barbiturate in the United States, according to Noah Rosen, MD, who presented the study at the annual meeting of the American Headache Society.

Despite its effectiveness, the drug carries a risk of abuse as well as neurologic side effects, and has also been linked to an increase in medication overuse headache, which in turn can affect quality of life and lead to more disability and health care costs. “Although acute treatment recommendations supported by AHS discourage the use of barbiturates for the acute treatment of migraine, butalbital and associated medications are still widely prescribed, so effective, low-risk novel abortive and preventive therapies that have potential barbiturate-sparing characteristics do have the potential to help people with migraine,” said Dr. Rosen during his presentation. He is the program director of neurology at Hofstra Northwell Health, Hempstead, N.Y.

His group previously showed an association between rimegepant initiation and a reduction in opioid use in another real-world analysis.

The present study retrospectively analyzed data from 34,486 patients drawn from the U.S.-based Longitudinal Access and Adjudication Data (LAAD) produced by IQVIA, which is an anonymized integrated commercial medical and prescription claims database. The period studied was between November 2015 and November 2022. The median age was 47 and 89% were female. Eligibility criteria included the presence of at least 6 months of baseline data before exposure to rimegepant and at least 6 months of follow-up, at least two rimegepant refills, and at least one butalbital prescription during the baseline period.

During the baseline period, the mean number of milligrams of butalbital dispensed was 1,012, and this dropped to 742 during follow-up (–26.7%). The mean number of butalbital prescription fills dropped from 0.47 to 0.32 (–32.0%). About half of patients (49.4%) had no butalbital refills after starting rimegepant. The researchers also examined triptan use and found no difference. “We saw that it actually made no significant difference with the deflection from baseline or discontinuation if they had been given a triptan or not. This seemed to concur with my own experiences with triptan use and not affecting barbiturate dosing,” said Dr. Rosen.
 

‘Good news’

The results are good news, according to Jason Sico, MD, who comoderated the session. “I remember being a PGY-2 neurology resident and hearing a lecture from Stew Tepper [now professor of medicine at Geisel School of Medicine at Dartmouth, Hanover, N.H.] that fiorinal and fioricet were the F words of headache medicine, so it’s really great to see a modality that could lower barbiturate use,” said Dr. Sico, who is an associate professor of neurology and internal medicine at Yale University, New Haven, Conn.

Dr. Rosen responded: “I don’t mean to malign a single chemical, because fioricet has provided many people treatment over time, but with the introduction of newer options, we would hope to see a trend toward that use.”

A listener on the virtual platform asked whether the decline in barbiturate use could be due to education by the provider on the dangers of barbiturate use when rimegepant was prescribed. “This is one of those big limitations of claims data analysis is we can speculate what the influence or the cause is, because this type of data analysis does not show causation. There are many different things that could influence the discontinuation. Education is a huge one, although you would hope that if somebody is prescribed butalbital on a regular basis, that there’s some physician contact or education that’s part of that as well. But it’s possible it plays a role,” said Dr. Rosen.
 

Any strategy to reduce butalbital use in migraine is important

Alan Rapoport, MD, who attended the session, was also asked to comment on the study. “Butalbital-containing medications can help headache pain but have not been approved by the FDA for a migraine indication. They can also decrease anxiety in the migraine patient, but if used frequently, they cause dependency. When used too often, butalbital-containing medications are major causes of medication overuse headache. They’re often used with other acute care medications such as triptans and over-the-counter products, and combinations of these drugs can be even more of a problem because one only needs to use any of these medicines in combination for 10 days a month or more, for at least 3 months, for a doctor to diagnose a patient with medication overuse headache. So any attempt and success to reduce the frequency of taking butalbital-containing medication is important. That can be done by counseling the patient to take fewer tablets per month, but this often does not work. This study shows a good success rate in reducing the use of these medications by treating the patient with rimegepant 75 mg ODT given once every other day. This dose has been approved by the FDA for prevention in migraine, but has not previously been shown as a treatment for overuse of butalbital or medication. Previous studies have shown that rimegepant reduced migraine days per month and the use of acute care medications monthly. It this study, rimegepant decreases the number of butalbital-containing medications taken,” said Dr. Rapoport, who is a clinical professor of neurology at the University of California, Los Angeles, and editor in chief of Neurology Reviews.

Dr. Rosen has financial ties to Allergan/Abbvie, Amgen, BioHaven, Eli Lilly, Lundbeck, Novartis, Supernus, and Teva. Dr. Sico did not disclose any conflicts of interest. Dr. Rapoport advises AbbVie, Biohaven, Cala Health, Dr. Reddy’s, Pfizer, Satsuma, Teva Pharmaceutical Industries, and Theranica. He is on the speakers bureaus of AbbVie, Dr. Reddy’s, Impel, Pfizer, and Teva Pharmaceutical Industries. He is editor in chief of Neurology Reviews and on the editorial board of CNS Drugs.

AUSTIN – Treatment of migraines with rimegepant is associated with a reduction of butalbital dose and prescriptions, according to a real-world analysis. Butalbital is the only commonly prescribed short-acting barbiturate in the United States, according to Noah Rosen, MD, who presented the study at the annual meeting of the American Headache Society.

Despite its effectiveness, the drug carries a risk of abuse as well as neurologic side effects, and has also been linked to an increase in medication overuse headache, which in turn can affect quality of life and lead to more disability and health care costs. “Although acute treatment recommendations supported by AHS discourage the use of barbiturates for the acute treatment of migraine, butalbital and associated medications are still widely prescribed, so effective, low-risk novel abortive and preventive therapies that have potential barbiturate-sparing characteristics do have the potential to help people with migraine,” said Dr. Rosen during his presentation. He is the program director of neurology at Hofstra Northwell Health, Hempstead, N.Y.

His group previously showed an association between rimegepant initiation and a reduction in opioid use in another real-world analysis.

The present study retrospectively analyzed data from 34,486 patients drawn from the U.S.-based Longitudinal Access and Adjudication Data (LAAD) produced by IQVIA, which is an anonymized integrated commercial medical and prescription claims database. The period studied was between November 2015 and November 2022. The median age was 47 and 89% were female. Eligibility criteria included the presence of at least 6 months of baseline data before exposure to rimegepant and at least 6 months of follow-up, at least two rimegepant refills, and at least one butalbital prescription during the baseline period.

During the baseline period, the mean number of milligrams of butalbital dispensed was 1,012, and this dropped to 742 during follow-up (–26.7%). The mean number of butalbital prescription fills dropped from 0.47 to 0.32 (–32.0%). About half of patients (49.4%) had no butalbital refills after starting rimegepant. The researchers also examined triptan use and found no difference. “We saw that it actually made no significant difference with the deflection from baseline or discontinuation if they had been given a triptan or not. This seemed to concur with my own experiences with triptan use and not affecting barbiturate dosing,” said Dr. Rosen.
 

‘Good news’

The results are good news, according to Jason Sico, MD, who comoderated the session. “I remember being a PGY-2 neurology resident and hearing a lecture from Stew Tepper [now professor of medicine at Geisel School of Medicine at Dartmouth, Hanover, N.H.] that fiorinal and fioricet were the F words of headache medicine, so it’s really great to see a modality that could lower barbiturate use,” said Dr. Sico, who is an associate professor of neurology and internal medicine at Yale University, New Haven, Conn.

Dr. Rosen responded: “I don’t mean to malign a single chemical, because fioricet has provided many people treatment over time, but with the introduction of newer options, we would hope to see a trend toward that use.”

A listener on the virtual platform asked whether the decline in barbiturate use could be due to education by the provider on the dangers of barbiturate use when rimegepant was prescribed. “This is one of those big limitations of claims data analysis is we can speculate what the influence or the cause is, because this type of data analysis does not show causation. There are many different things that could influence the discontinuation. Education is a huge one, although you would hope that if somebody is prescribed butalbital on a regular basis, that there’s some physician contact or education that’s part of that as well. But it’s possible it plays a role,” said Dr. Rosen.
 

Any strategy to reduce butalbital use in migraine is important

Alan Rapoport, MD, who attended the session, was also asked to comment on the study. “Butalbital-containing medications can help headache pain but have not been approved by the FDA for a migraine indication. They can also decrease anxiety in the migraine patient, but if used frequently, they cause dependency. When used too often, butalbital-containing medications are major causes of medication overuse headache. They’re often used with other acute care medications such as triptans and over-the-counter products, and combinations of these drugs can be even more of a problem because one only needs to use any of these medicines in combination for 10 days a month or more, for at least 3 months, for a doctor to diagnose a patient with medication overuse headache. So any attempt and success to reduce the frequency of taking butalbital-containing medication is important. That can be done by counseling the patient to take fewer tablets per month, but this often does not work. This study shows a good success rate in reducing the use of these medications by treating the patient with rimegepant 75 mg ODT given once every other day. This dose has been approved by the FDA for prevention in migraine, but has not previously been shown as a treatment for overuse of butalbital or medication. Previous studies have shown that rimegepant reduced migraine days per month and the use of acute care medications monthly. It this study, rimegepant decreases the number of butalbital-containing medications taken,” said Dr. Rapoport, who is a clinical professor of neurology at the University of California, Los Angeles, and editor in chief of Neurology Reviews.

Dr. Rosen has financial ties to Allergan/Abbvie, Amgen, BioHaven, Eli Lilly, Lundbeck, Novartis, Supernus, and Teva. Dr. Sico did not disclose any conflicts of interest. Dr. Rapoport advises AbbVie, Biohaven, Cala Health, Dr. Reddy’s, Pfizer, Satsuma, Teva Pharmaceutical Industries, and Theranica. He is on the speakers bureaus of AbbVie, Dr. Reddy’s, Impel, Pfizer, and Teva Pharmaceutical Industries. He is editor in chief of Neurology Reviews and on the editorial board of CNS Drugs.

AUSTIN – Treatment of migraines with rimegepant is associated with a reduction of butalbital dose and prescriptions, according to a real-world analysis. Butalbital is the only commonly prescribed short-acting barbiturate in the United States, according to Noah Rosen, MD, who presented the study at the annual meeting of the American Headache Society.

Despite its effectiveness, the drug carries a risk of abuse as well as neurologic side effects, and has also been linked to an increase in medication overuse headache, which in turn can affect quality of life and lead to more disability and health care costs. “Although acute treatment recommendations supported by AHS discourage the use of barbiturates for the acute treatment of migraine, butalbital and associated medications are still widely prescribed, so effective, low-risk novel abortive and preventive therapies that have potential barbiturate-sparing characteristics do have the potential to help people with migraine,” said Dr. Rosen during his presentation. He is the program director of neurology at Hofstra Northwell Health, Hempstead, N.Y.

His group previously showed an association between rimegepant initiation and a reduction in opioid use in another real-world analysis.

The present study retrospectively analyzed data from 34,486 patients drawn from the U.S.-based Longitudinal Access and Adjudication Data (LAAD) produced by IQVIA, which is an anonymized integrated commercial medical and prescription claims database. The period studied was between November 2015 and November 2022. The median age was 47 and 89% were female. Eligibility criteria included the presence of at least 6 months of baseline data before exposure to rimegepant and at least 6 months of follow-up, at least two rimegepant refills, and at least one butalbital prescription during the baseline period.

During the baseline period, the mean number of milligrams of butalbital dispensed was 1,012, and this dropped to 742 during follow-up (–26.7%). The mean number of butalbital prescription fills dropped from 0.47 to 0.32 (–32.0%). About half of patients (49.4%) had no butalbital refills after starting rimegepant. The researchers also examined triptan use and found no difference. “We saw that it actually made no significant difference with the deflection from baseline or discontinuation if they had been given a triptan or not. This seemed to concur with my own experiences with triptan use and not affecting barbiturate dosing,” said Dr. Rosen.
 

‘Good news’

The results are good news, according to Jason Sico, MD, who comoderated the session. “I remember being a PGY-2 neurology resident and hearing a lecture from Stew Tepper [now professor of medicine at Geisel School of Medicine at Dartmouth, Hanover, N.H.] that fiorinal and fioricet were the F words of headache medicine, so it’s really great to see a modality that could lower barbiturate use,” said Dr. Sico, who is an associate professor of neurology and internal medicine at Yale University, New Haven, Conn.

Dr. Rosen responded: “I don’t mean to malign a single chemical, because fioricet has provided many people treatment over time, but with the introduction of newer options, we would hope to see a trend toward that use.”

A listener on the virtual platform asked whether the decline in barbiturate use could be due to education by the provider on the dangers of barbiturate use when rimegepant was prescribed. “This is one of those big limitations of claims data analysis is we can speculate what the influence or the cause is, because this type of data analysis does not show causation. There are many different things that could influence the discontinuation. Education is a huge one, although you would hope that if somebody is prescribed butalbital on a regular basis, that there’s some physician contact or education that’s part of that as well. But it’s possible it plays a role,” said Dr. Rosen.
 

Any strategy to reduce butalbital use in migraine is important

Alan Rapoport, MD, who attended the session, was also asked to comment on the study. “Butalbital-containing medications can help headache pain but have not been approved by the FDA for a migraine indication. They can also decrease anxiety in the migraine patient, but if used frequently, they cause dependency. When used too often, butalbital-containing medications are major causes of medication overuse headache. They’re often used with other acute care medications such as triptans and over-the-counter products, and combinations of these drugs can be even more of a problem because one only needs to use any of these medicines in combination for 10 days a month or more, for at least 3 months, for a doctor to diagnose a patient with medication overuse headache. So any attempt and success to reduce the frequency of taking butalbital-containing medication is important. That can be done by counseling the patient to take fewer tablets per month, but this often does not work. This study shows a good success rate in reducing the use of these medications by treating the patient with rimegepant 75 mg ODT given once every other day. This dose has been approved by the FDA for prevention in migraine, but has not previously been shown as a treatment for overuse of butalbital or medication. Previous studies have shown that rimegepant reduced migraine days per month and the use of acute care medications monthly. It this study, rimegepant decreases the number of butalbital-containing medications taken,” said Dr. Rapoport, who is a clinical professor of neurology at the University of California, Los Angeles, and editor in chief of Neurology Reviews.

Dr. Rosen has financial ties to Allergan/Abbvie, Amgen, BioHaven, Eli Lilly, Lundbeck, Novartis, Supernus, and Teva. Dr. Sico did not disclose any conflicts of interest. Dr. Rapoport advises AbbVie, Biohaven, Cala Health, Dr. Reddy’s, Pfizer, Satsuma, Teva Pharmaceutical Industries, and Theranica. He is on the speakers bureaus of AbbVie, Dr. Reddy’s, Impel, Pfizer, and Teva Pharmaceutical Industries. He is editor in chief of Neurology Reviews and on the editorial board of CNS Drugs.

The word “regulations” gets a mixed response. Some see regulations as necessary to protect public safety, while others argue that they block innovation, success, and profits.

This is common in all industries, and certainly pharmaceuticals. On any given day there are stories on industry news sites about disputes between companies and regulatory agencies.

I’d agree that some regulation is needed. The history of pharmacy has had both remarkable successes – and failures.

Let’s look at migraines, since that’s in my field. The calcitonin gene-related peptide (CGRP) drugs have been a remarkable breakthrough, certainly the biggest one since the triptans in 1992. There are currently seven on the market for both prevention and abortive use. They’re effective and (to date) pretty safe.

But it wasn’t always that way. Look back just 14 years ago to 2009, when the first promising CGRP agent (MK-3207) had its development halted because of hepatic abnormalities. It’s cousin telcagepant (MK-0974) came to a similar end 2 years later.

Without regulations in place (and the potential for lawsuits) these might have made it to market, bringing migraine relief to some and potentially serious liver damage to others. So Merck made the right decision to axe them. Researchers learned from the experience, went back to the drawing board, and developed the current generation of far-safer drugs.

This came into sharp focus in another industry recently, when the eyes of the world were on the north Atlantic. A small tourist submarine imploded and killed five people. During the inevitable media coverage it came out that the submarine hadn’t been certified for safety by any of the agencies that handle such things, falling into a gray area in international waters where inspections aren’t required.

This isn’t to say it wasn’t safe – it had made several dives before – but obviously not safe enough. While I didn’t know the late Stockton Rush (the owner/designer) it sounds like he viewed regulations as stifling innovation, and in one interview said “at some point, safety is just pure waste.” He ignored warnings from several sides about the submersible’s ability to handle deep ocean pressure and the inevitable wear and tear repeated dives will have on the hull.

I understand there’s a margin of luck, too. Bad things can happen to any of us – or any company. Some things can’t be clearly foreseen. Some drugs don’t start to show problems until they’re on the market and reach a certain number of prescriptions.

But there’s a reason we have regulations. Pretty much every government has, going back to the Roman Empire, covering numerous things. In a perfect world we wouldn’t need them.

But people are far from perfect. And the consequences can be terrible.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

The word “regulations” gets a mixed response. Some see regulations as necessary to protect public safety, while others argue that they block innovation, success, and profits.

This is common in all industries, and certainly pharmaceuticals. On any given day there are stories on industry news sites about disputes between companies and regulatory agencies.

I’d agree that some regulation is needed. The history of pharmacy has had both remarkable successes – and failures.

Let’s look at migraines, since that’s in my field. The calcitonin gene-related peptide (CGRP) drugs have been a remarkable breakthrough, certainly the biggest one since the triptans in 1992. There are currently seven on the market for both prevention and abortive use. They’re effective and (to date) pretty safe.

But it wasn’t always that way. Look back just 14 years ago to 2009, when the first promising CGRP agent (MK-3207) had its development halted because of hepatic abnormalities. It’s cousin telcagepant (MK-0974) came to a similar end 2 years later.

Without regulations in place (and the potential for lawsuits) these might have made it to market, bringing migraine relief to some and potentially serious liver damage to others. So Merck made the right decision to axe them. Researchers learned from the experience, went back to the drawing board, and developed the current generation of far-safer drugs.

This came into sharp focus in another industry recently, when the eyes of the world were on the north Atlantic. A small tourist submarine imploded and killed five people. During the inevitable media coverage it came out that the submarine hadn’t been certified for safety by any of the agencies that handle such things, falling into a gray area in international waters where inspections aren’t required.

This isn’t to say it wasn’t safe – it had made several dives before – but obviously not safe enough. While I didn’t know the late Stockton Rush (the owner/designer) it sounds like he viewed regulations as stifling innovation, and in one interview said “at some point, safety is just pure waste.” He ignored warnings from several sides about the submersible’s ability to handle deep ocean pressure and the inevitable wear and tear repeated dives will have on the hull.

I understand there’s a margin of luck, too. Bad things can happen to any of us – or any company. Some things can’t be clearly foreseen. Some drugs don’t start to show problems until they’re on the market and reach a certain number of prescriptions.

But there’s a reason we have regulations. Pretty much every government has, going back to the Roman Empire, covering numerous things. In a perfect world we wouldn’t need them.

But people are far from perfect. And the consequences can be terrible.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

The word “regulations” gets a mixed response. Some see regulations as necessary to protect public safety, while others argue that they block innovation, success, and profits.

This is common in all industries, and certainly pharmaceuticals. On any given day there are stories on industry news sites about disputes between companies and regulatory agencies.

I’d agree that some regulation is needed. The history of pharmacy has had both remarkable successes – and failures.

Let’s look at migraines, since that’s in my field. The calcitonin gene-related peptide (CGRP) drugs have been a remarkable breakthrough, certainly the biggest one since the triptans in 1992. There are currently seven on the market for both prevention and abortive use. They’re effective and (to date) pretty safe.

But it wasn’t always that way. Look back just 14 years ago to 2009, when the first promising CGRP agent (MK-3207) had its development halted because of hepatic abnormalities. It’s cousin telcagepant (MK-0974) came to a similar end 2 years later.

Without regulations in place (and the potential for lawsuits) these might have made it to market, bringing migraine relief to some and potentially serious liver damage to others. So Merck made the right decision to axe them. Researchers learned from the experience, went back to the drawing board, and developed the current generation of far-safer drugs.

This came into sharp focus in another industry recently, when the eyes of the world were on the north Atlantic. A small tourist submarine imploded and killed five people. During the inevitable media coverage it came out that the submarine hadn’t been certified for safety by any of the agencies that handle such things, falling into a gray area in international waters where inspections aren’t required.

This isn’t to say it wasn’t safe – it had made several dives before – but obviously not safe enough. While I didn’t know the late Stockton Rush (the owner/designer) it sounds like he viewed regulations as stifling innovation, and in one interview said “at some point, safety is just pure waste.” He ignored warnings from several sides about the submersible’s ability to handle deep ocean pressure and the inevitable wear and tear repeated dives will have on the hull.

I understand there’s a margin of luck, too. Bad things can happen to any of us – or any company. Some things can’t be clearly foreseen. Some drugs don’t start to show problems until they’re on the market and reach a certain number of prescriptions.

But there’s a reason we have regulations. Pretty much every government has, going back to the Roman Empire, covering numerous things. In a perfect world we wouldn’t need them.

But people are far from perfect. And the consequences can be terrible.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

A Risk Evaluation and Mitigation Strategy (REMS) is a drug safety program the FDA can require for certain medications with serious safety concerns to help ensure the benefits of the medication outweigh its risks (Box¹). The FDA may require medication guides, patient package inserts, communication plans for health care professionals, and/or certain packaging and safe disposal technologies for medications that pose a serious risk of abuse or overdose. The FDA may also require elements to assure safe use and/or an implementation system be included in the REMS. Pharmaceutical manufacturers then develop a proposed REMS for FDA review.² If the FDA approves the proposed REMS, the manufacturer is responsible for implementing the REMS requirements.

Box

The REMS program for clozapine³ has been the subject of much discussion in the psychiatric community. The adverse impact of the 2015 update to the clozapine REMS program was emphasized at meetings of both the American Psychiatric Association and the College of Psychiatric and Neurologic Pharmacists. A white paper published by the National Association of State Mental Health Program Directors shortly after the 2015 update concluded, “clozapine is underused due to a variety of barriers related to the drug and its properties, the health care system, regulatory requirements, and reimbursement issues.”⁴ After an update to the clozapine REMS program in 2021, the FDA temporarily suspended enforcement of certain requirements due to concerns from health care professionals about patient access to the medication because of problems with implementing the clozapine REMS program.^5,6 In November 2022, the FDA issued a second announcement of enforcement discretion related to additional requirements of the REMS program.⁵ The FDA had previously announced a decision to not take action regarding adherence to REMS requirements for certain laboratory tests in March 2020, during the COVID-19 pandemic.⁷

REMS programs for other psychiatric medications may also present challenges. The REMS programs for esketamine⁸ and olanzapine for extended-release (ER) injectable suspension⁹ include certain risks that require postadministration monitoring. Some facilities have had to dedicate additional space and clinician time to ensure REMS requirements are met.

To further understand health care professionals’ perspectives regarding the value and burden of these REMS programs, a collaborative effort of the University of Maryland (College Park and Baltimore campuses) Center of Excellence in Regulatory Science and Innovation with the FDA was undertaken. The REMS for clozapine, olanzapine for ER injectable suspension, and esketamine were examined to develop recommendations for improving patient access while ensuring safe medication use and limiting the impact on health care professionals.

Assessing the REMS programs

Focus groups were held with health care professionals nominated by professional organizations to gather their perspectives on the REMS requirements. There was 1 focus group for each of the 3 medications. A facilitator’s guide was developed that contained the details of how to conduct the focus group along with the medication-specific questions. The questions were based on the REMS requirements as of May 2021 and assessed the impact of the REMS on patient safety, patient access, and health care professional workload; effects from the COVID-19 pandemic; and suggestions to improve the REMS programs. The University of Maryland Institutional Review Board reviewed the materials and processes and made the determination of exempt.

Health care professionals were eligible to participate in a focus group if they had ≥1 year of experience working with patients who use the specific medication and ≥6 months of experience within the past year working with the REMS program for that medication. Participants were excluded if they were employed by a pharmaceutical manufacturer or the FDA. The focus groups were conducted virtually using an online conferencing service during summer 2021 and were scheduled for 90 minutes. Prior to the focus group, participants received information from the “Goals” and “Summary” tabs of the FDA REMS website¹⁰ for the specific medication along with patient/caregiver guides, which were available for clozapine and olanzapine for ER injectable suspension. For each focus group, there was a target sample size of 6 to 9 participants. However, there were only 4 participants in the olanzapine for ER injectable suspension focus group, which we believed was due to lower national utilization of this medication. Individuals were only able to participate in 1 focus group, so the unique participant count for all 3 focus groups totaled 17 (Table 1).

Themes extracted from qualitative analysis of the focus group responses were the value of the REMS programs; registration/enrollment processes and REMS websites; monitoring requirements; care transitions; and COVID considerations (Table 2). While the REMS programs were perceived to increase practitioner and patient awareness of potential harms, discussions centered on the relative cost-to-benefit of the required reporting and other REMS requirements. There were challenges with the registration/enrollment processes and REMS websites that also affected patient care during transitions to different health care settings or clinicians. Patient access was affected by disparities in care related to monitoring requirements and clinician availability.

Continue to: COVID impacted all REMS...

COVID impacted all REMS programs. Physical distancing was an issue for medications that required extensive postadministration monitoring (ie, esketamine and olanzapine for ER injectable suspension). Access to laboratory services was an issue for clozapine.

Medication-specific themes are listed in Table 3 and relate to terms and descriptions in the REMS or additional regulatory requirements from the Drug Enforcement Agency (DEA). Suggestions for improvement to the REMS are presented in Table 4.

Recommendations for improving REMS

A group consisting of health care professionals, policy experts, and mental health advocates reviewed the information provided by the focus groups and developed the following recommendations.

Overarching recommendations

Each REMS should include a section providing justification for its existence, including a risk analysis of the data regarding the risk the REMS is designed to mitigate. This analysis should be repeated on a regular basis as scientific evidence regarding the risk and its epidemiology evolves. This additional section should also explain how the program requirements of the REMS as implemented (or planned) will achieve the aims of the REMS and weigh the potential benefits of the REMS requirements as implemented (or planned) by the manufacturer vs the potential risks of the REMS requirements as implemented (or planned) by the manufacturer.

Each REMS should have specific quantifiable outcomes. For example, it should specify a reduction in occurrence of the rate of the concerned risk by a specified amount.

Continue to: Ensure adequate...

Ensure adequate stakeholder input during the REMS development and real-world testing in multiple environments before implementing the REMS to identify unanticipated consequences that might impact patient access, patient safety, and health care professional burden. Implementation testing should explore issues such as purchasing and procurement, billing and reimbursement, and relevant factors such as other federal regulations or requirements (eg, the DEA or Medicare).

Ensure harmonization of the REMS forms and processes (eg, initiation and monitoring) for different medications where possible. A prescriber, pharmacist, or system should not face additional barriers to participate in a REMS based on REMS-specific intricacies (ie, prescription systems, data submission systems, or ordering systems). This streamlining will likely decrease clinical inertia to initiate care with the REMS medication, decrease health care professional burden, and improve compliance with REMS requirements.

REMS should anticipate the need for care transitions and employ provisions to ensure seamless care. Considerations should be given to transitions that occur due to:

• Different care settings (eg, inpatient, outpatient, or long-term care)
• Different geographies (eg, patient moves)
• Changes in clinicians, including leaves or absences
• Changes in facilities (eg, pharmacies).

REMS should mirror normal health care professional workflow, including how monitoring data are collected and how and with which frequency pharmacies fill prescriptions.Enhanced information technology to support REMS programs is needed. For example, REMS should be integrated with major electronic patient health record and pharmacy systems to reduce the effort required for clinicians to supply data and automate REMS processes.

For medications that are subject to other agencies and their regulations (eg, the CDC, Centers for Medicare & Medicaid Services, or the DEA), REMS should be required to meet all standards of all agencies with a single system that accommodates normal health care professional workflow.

Continue to: REMS should have a...

REMS should have a standard disclaimer that allows the health care professional to waive certain provisions of the REMS in cases when the specific provisions of the REMS pose a greater risk to the patient than the risk posed by waiving the requirement.

Assure the actions implemented by the industry to meet the requirements for each REMS program are based on peer-reviewed evidence and provide a reasonable expectation to achieve the anticipated benefit.

Ensure that manufacturers make all accumulated REMS data available in a de­identified manner for use by qualified scientific researchers. Additionally, each REMS should have a plan for data access upon initiation and termination of the REMS.

Each REMS should collect data on the performance of the centers and/or personnel who operate the REMS and submit this data for review by qualified outside reviewers. Parameters to assess could include:

• timeliness of response
• timeliness of problem resolution
• data availability and its helpfulness to patient care
• adequacy of resources.

Recommendations for clozapine REMS

These comments relate to the clozapine REMS program prior to the July 2021 announcement that FDA had approved a modification.

Provide a clear definition for “benign ethnic neutropenia.”

Ensure the REMS includes patient-specific adjustments to allow flexibility for monitoring. During COVID, the FDA allowed clinicians to “use their best medical judgment in weighing the benefits and risks of continuing treatment in the absence of laboratory testing.”⁷ This guidance, which allowed flexibility to absolute neutrophil count (ANC) monitoring, was perceived as positive and safe. Before the changes in the REMS requirements, patients with benign ethnic neutropenia were restricted from accessing their medication or encountered harm from additional pharmacotherapy to mitigate ANC levels.

Continue to: Recommendations for olanzapine for ER injectable suspension REMS

 

 

Recommendations for olanzapine for ER injectable suspension REMS

Provide clear explicit instructions on what is required to have “ready access to emergency services.”

Ensure the REMS include patient-specific adjustments to allow flexibility for postadministration monitoring (eg, sedation or blood pressure). Specific patient groups may have differential access to certain types of facilities, transportation, or other resources. For example, consider the administration of olanzapine for ER injectable suspension by a mobile treatment team with an adequate protocol (eg, via videoconferencing or phone calls).

Ensure actions with peer-reviewed evidence demonstrating efficacy/effectiveness are included in the REMS. How was the 3-hour cut-point determined? Has it been reevaluated?

Ensure the REMS requirements allow for seamless care during transitions, particularly when clinicians are on vacation.

Continue to: Recommendations for esketamine REMS

 

 

Recommendations for esketamine REMS

Ensure the REMS includes patient-specific adjustments to allow flexibility for post­administration monitoring. Specific patient groups may have differential access to certain types of facilities, transportation, or other resources. For example, consider the administration of esketamine by a mobile treatment team with an adequate protocol (eg, via videoconferencing or phone calls).

Ensure actions with peer-reviewed evidence demonstrating efficacy/effectiveness of requirements are included in the REMS. How was the 2-hour cut-point determined? Has it been reevaluated?

Ensure that the REMS meet all standards of the DEA, with a single system that accommodates normal health care professional workflow.

A summary of the findings

Overall, the REMS programs for these 3 medications were positively perceived for raising awareness of safe medication use for clinicians and patients. Monitoring patients for safety concerns is important and REMS requirements provide accountability.

Continue to: The use of a single shared...

The use of a single shared REMS system for documenting requirements for clozapine (compared to separate systems for each manufacturer) was a positive move forward in implementation. The focus group welcomed the increased awareness of benign ethnic neutropenia as a result of this condition being incorporated in the revised monitoring requirements of the clozapine REMS.

Focus group participants raised the issue of the real-world efficiency of the REMS programs (reduced access and increased clinician workload) vs the benefits (patient safety). They noted that excessive workload could lead to clinicians becoming unwilling to use a medication that requires a REMS. Clinician workload may be further compromised when REMS logistics disrupt the normal workflow and transitions of care between clinicians or settings. This latter aspect is of particular concern for clozapine.

The complexities of the registration and reporting system for olanzapine for ER injectable suspension and the lack of clarity about monitoring were noted to have discouraged the opening of treatment sites. This scarcity of sites may make clinicians hesitant to use this medication, and instead opt for alternative treatments in patients who may be appropriate candidates.

There has also been limited growth of esketamine treatment sites, especially in comparison to ketamine treatment sites.^11-14 Esketamine is FDA-approved for treatment-resistant depression in adults and for depressive symptoms in adults with major depressive disorder with acute suicidal ideation or behavior. Ketamine is not FDA-approved for treating depression but is being used off-label to treat this disorder.¹⁵ The FDA determined that ketamine does not require a REMS to ensure the benefits outweigh the risks for its approved indications as an anesthetic agent, anesthesia-inducing agent, or supplement to anesthesia. Since ketamine has no REMS requirements, there may be a lower burden for its use. Thus, clinicians are treating patients for depression with this medication without needing to comply with a REMS.¹⁶

Technology plays a role in workload burden, and integrating health care processes within current workflow systems, such as using electronic patient health records and pharmacy systems, is recommended. The FDA has been exploring technologies to facilitate the completion of REMS requirements, including mandatory education within the prescribers’ and pharmacists’ workflow.¹⁷ This is a complex task that requires multiple stakeholders with differing perspectives and incentives to align.

Continue to: The data collected for the REMS...

The data collected for the REMS program belongs to the medication’s manufacturer. Current regulations do not require manufacturers to make this data available to qualified scientific researchers. A regulatory mandate to establish data sharing methods would improve transparency and enhance efforts to better understand the outcomes of the REMS programs.

A few caveats

Both the overarching and medication-specific recommendations were based on a small number of participants’ discussions related to clozapine, olanzapine for ER injectable suspension, and esketamine. These recommendations do not include other medications with REMS that are used to treat psychiatric disorders, such as loxapine, buprenorphine ER, and buprenorphine transmucosal products. Larger-scale qualitative and quantitative research is needed to better understand health care professionals’ perspectives. Lastly, some of the recommendations outlined in this article are beyond the current purview or authority of the FDA and may require legislative or regulatory action to implement.

Bottom Line

Risk Evaluation and Mitigation Strategy (REMS) programs are designed to help reduce the occurrence and/or severity of serious risks or to inform decision-making. However, REMS requirements may adversely impact patient access to certain REMS medications and clinician burden. Health care professionals can provide informed recommendations for improving the REMS programs for clozapine, olanzapine for extended-release injectable suspension, and esketamine.

Related Resources

• FDA. Frequently asked questions (FAQs) about REMS. www.fda.gov/drugs/risk-evaluation-and-mitigation-strategies-rems/frequently-asked-questions-faqs-about-rems

Drug Brand Names

Buprenorphine extended-release • Sublocade
Buprenorphine transmucosal • Subutex, Suboxone
Clozapine • Clozaril
Esketamine • Spravato
Ketamine • Ketalar
Lithium • Eskalith, Lithobid
Loxapine • Adasuve
Olanzapine extended-release injectable suspension • Zyprexa Relprevv

A Risk Evaluation and Mitigation Strategy (REMS) is a drug safety program the FDA can require for certain medications with serious safety concerns to help ensure the benefits of the medication outweigh its risks (Box¹). The FDA may require medication guides, patient package inserts, communication plans for health care professionals, and/or certain packaging and safe disposal technologies for medications that pose a serious risk of abuse or overdose. The FDA may also require elements to assure safe use and/or an implementation system be included in the REMS. Pharmaceutical manufacturers then develop a proposed REMS for FDA review.² If the FDA approves the proposed REMS, the manufacturer is responsible for implementing the REMS requirements.

Box

The REMS program for clozapine³ has been the subject of much discussion in the psychiatric community. The adverse impact of the 2015 update to the clozapine REMS program was emphasized at meetings of both the American Psychiatric Association and the College of Psychiatric and Neurologic Pharmacists. A white paper published by the National Association of State Mental Health Program Directors shortly after the 2015 update concluded, “clozapine is underused due to a variety of barriers related to the drug and its properties, the health care system, regulatory requirements, and reimbursement issues.”⁴ After an update to the clozapine REMS program in 2021, the FDA temporarily suspended enforcement of certain requirements due to concerns from health care professionals about patient access to the medication because of problems with implementing the clozapine REMS program.^5,6 In November 2022, the FDA issued a second announcement of enforcement discretion related to additional requirements of the REMS program.⁵ The FDA had previously announced a decision to not take action regarding adherence to REMS requirements for certain laboratory tests in March 2020, during the COVID-19 pandemic.⁷

REMS programs for other psychiatric medications may also present challenges. The REMS programs for esketamine⁸ and olanzapine for extended-release (ER) injectable suspension⁹ include certain risks that require postadministration monitoring. Some facilities have had to dedicate additional space and clinician time to ensure REMS requirements are met.

To further understand health care professionals’ perspectives regarding the value and burden of these REMS programs, a collaborative effort of the University of Maryland (College Park and Baltimore campuses) Center of Excellence in Regulatory Science and Innovation with the FDA was undertaken. The REMS for clozapine, olanzapine for ER injectable suspension, and esketamine were examined to develop recommendations for improving patient access while ensuring safe medication use and limiting the impact on health care professionals.

Assessing the REMS programs

Focus groups were held with health care professionals nominated by professional organizations to gather their perspectives on the REMS requirements. There was 1 focus group for each of the 3 medications. A facilitator’s guide was developed that contained the details of how to conduct the focus group along with the medication-specific questions. The questions were based on the REMS requirements as of May 2021 and assessed the impact of the REMS on patient safety, patient access, and health care professional workload; effects from the COVID-19 pandemic; and suggestions to improve the REMS programs. The University of Maryland Institutional Review Board reviewed the materials and processes and made the determination of exempt.

Health care professionals were eligible to participate in a focus group if they had ≥1 year of experience working with patients who use the specific medication and ≥6 months of experience within the past year working with the REMS program for that medication. Participants were excluded if they were employed by a pharmaceutical manufacturer or the FDA. The focus groups were conducted virtually using an online conferencing service during summer 2021 and were scheduled for 90 minutes. Prior to the focus group, participants received information from the “Goals” and “Summary” tabs of the FDA REMS website¹⁰ for the specific medication along with patient/caregiver guides, which were available for clozapine and olanzapine for ER injectable suspension. For each focus group, there was a target sample size of 6 to 9 participants. However, there were only 4 participants in the olanzapine for ER injectable suspension focus group, which we believed was due to lower national utilization of this medication. Individuals were only able to participate in 1 focus group, so the unique participant count for all 3 focus groups totaled 17 (Table 1).

Themes extracted from qualitative analysis of the focus group responses were the value of the REMS programs; registration/enrollment processes and REMS websites; monitoring requirements; care transitions; and COVID considerations (Table 2). While the REMS programs were perceived to increase practitioner and patient awareness of potential harms, discussions centered on the relative cost-to-benefit of the required reporting and other REMS requirements. There were challenges with the registration/enrollment processes and REMS websites that also affected patient care during transitions to different health care settings or clinicians. Patient access was affected by disparities in care related to monitoring requirements and clinician availability.

Continue to: COVID impacted all REMS...

COVID impacted all REMS programs. Physical distancing was an issue for medications that required extensive postadministration monitoring (ie, esketamine and olanzapine for ER injectable suspension). Access to laboratory services was an issue for clozapine.

Medication-specific themes are listed in Table 3 and relate to terms and descriptions in the REMS or additional regulatory requirements from the Drug Enforcement Agency (DEA). Suggestions for improvement to the REMS are presented in Table 4.

Recommendations for improving REMS

A group consisting of health care professionals, policy experts, and mental health advocates reviewed the information provided by the focus groups and developed the following recommendations.

Overarching recommendations

Each REMS should include a section providing justification for its existence, including a risk analysis of the data regarding the risk the REMS is designed to mitigate. This analysis should be repeated on a regular basis as scientific evidence regarding the risk and its epidemiology evolves. This additional section should also explain how the program requirements of the REMS as implemented (or planned) will achieve the aims of the REMS and weigh the potential benefits of the REMS requirements as implemented (or planned) by the manufacturer vs the potential risks of the REMS requirements as implemented (or planned) by the manufacturer.

Each REMS should have specific quantifiable outcomes. For example, it should specify a reduction in occurrence of the rate of the concerned risk by a specified amount.

Continue to: Ensure adequate...

Ensure adequate stakeholder input during the REMS development and real-world testing in multiple environments before implementing the REMS to identify unanticipated consequences that might impact patient access, patient safety, and health care professional burden. Implementation testing should explore issues such as purchasing and procurement, billing and reimbursement, and relevant factors such as other federal regulations or requirements (eg, the DEA or Medicare).

Ensure harmonization of the REMS forms and processes (eg, initiation and monitoring) for different medications where possible. A prescriber, pharmacist, or system should not face additional barriers to participate in a REMS based on REMS-specific intricacies (ie, prescription systems, data submission systems, or ordering systems). This streamlining will likely decrease clinical inertia to initiate care with the REMS medication, decrease health care professional burden, and improve compliance with REMS requirements.

REMS should anticipate the need for care transitions and employ provisions to ensure seamless care. Considerations should be given to transitions that occur due to:

• Different care settings (eg, inpatient, outpatient, or long-term care)
• Different geographies (eg, patient moves)
• Changes in clinicians, including leaves or absences
• Changes in facilities (eg, pharmacies).

REMS should mirror normal health care professional workflow, including how monitoring data are collected and how and with which frequency pharmacies fill prescriptions.Enhanced information technology to support REMS programs is needed. For example, REMS should be integrated with major electronic patient health record and pharmacy systems to reduce the effort required for clinicians to supply data and automate REMS processes.

For medications that are subject to other agencies and their regulations (eg, the CDC, Centers for Medicare & Medicaid Services, or the DEA), REMS should be required to meet all standards of all agencies with a single system that accommodates normal health care professional workflow.

Continue to: REMS should have a...

REMS should have a standard disclaimer that allows the health care professional to waive certain provisions of the REMS in cases when the specific provisions of the REMS pose a greater risk to the patient than the risk posed by waiving the requirement.

Assure the actions implemented by the industry to meet the requirements for each REMS program are based on peer-reviewed evidence and provide a reasonable expectation to achieve the anticipated benefit.

Ensure that manufacturers make all accumulated REMS data available in a de­identified manner for use by qualified scientific researchers. Additionally, each REMS should have a plan for data access upon initiation and termination of the REMS.

Each REMS should collect data on the performance of the centers and/or personnel who operate the REMS and submit this data for review by qualified outside reviewers. Parameters to assess could include:

• timeliness of response
• timeliness of problem resolution
• data availability and its helpfulness to patient care
• adequacy of resources.

Recommendations for clozapine REMS

These comments relate to the clozapine REMS program prior to the July 2021 announcement that FDA had approved a modification.

Provide a clear definition for “benign ethnic neutropenia.”

Ensure the REMS includes patient-specific adjustments to allow flexibility for monitoring. During COVID, the FDA allowed clinicians to “use their best medical judgment in weighing the benefits and risks of continuing treatment in the absence of laboratory testing.”⁷ This guidance, which allowed flexibility to absolute neutrophil count (ANC) monitoring, was perceived as positive and safe. Before the changes in the REMS requirements, patients with benign ethnic neutropenia were restricted from accessing their medication or encountered harm from additional pharmacotherapy to mitigate ANC levels.

Continue to: Recommendations for olanzapine for ER injectable suspension REMS

 

 

Recommendations for olanzapine for ER injectable suspension REMS

Provide clear explicit instructions on what is required to have “ready access to emergency services.”

Ensure the REMS include patient-specific adjustments to allow flexibility for postadministration monitoring (eg, sedation or blood pressure). Specific patient groups may have differential access to certain types of facilities, transportation, or other resources. For example, consider the administration of olanzapine for ER injectable suspension by a mobile treatment team with an adequate protocol (eg, via videoconferencing or phone calls).

Ensure actions with peer-reviewed evidence demonstrating efficacy/effectiveness are included in the REMS. How was the 3-hour cut-point determined? Has it been reevaluated?

Ensure the REMS requirements allow for seamless care during transitions, particularly when clinicians are on vacation.

Continue to: Recommendations for esketamine REMS

 

 

Recommendations for esketamine REMS

Ensure the REMS includes patient-specific adjustments to allow flexibility for post­administration monitoring. Specific patient groups may have differential access to certain types of facilities, transportation, or other resources. For example, consider the administration of esketamine by a mobile treatment team with an adequate protocol (eg, via videoconferencing or phone calls).

Ensure actions with peer-reviewed evidence demonstrating efficacy/effectiveness of requirements are included in the REMS. How was the 2-hour cut-point determined? Has it been reevaluated?

Ensure that the REMS meet all standards of the DEA, with a single system that accommodates normal health care professional workflow.

A summary of the findings

Overall, the REMS programs for these 3 medications were positively perceived for raising awareness of safe medication use for clinicians and patients. Monitoring patients for safety concerns is important and REMS requirements provide accountability.

Continue to: The use of a single shared...

The use of a single shared REMS system for documenting requirements for clozapine (compared to separate systems for each manufacturer) was a positive move forward in implementation. The focus group welcomed the increased awareness of benign ethnic neutropenia as a result of this condition being incorporated in the revised monitoring requirements of the clozapine REMS.

Focus group participants raised the issue of the real-world efficiency of the REMS programs (reduced access and increased clinician workload) vs the benefits (patient safety). They noted that excessive workload could lead to clinicians becoming unwilling to use a medication that requires a REMS. Clinician workload may be further compromised when REMS logistics disrupt the normal workflow and transitions of care between clinicians or settings. This latter aspect is of particular concern for clozapine.

The complexities of the registration and reporting system for olanzapine for ER injectable suspension and the lack of clarity about monitoring were noted to have discouraged the opening of treatment sites. This scarcity of sites may make clinicians hesitant to use this medication, and instead opt for alternative treatments in patients who may be appropriate candidates.

There has also been limited growth of esketamine treatment sites, especially in comparison to ketamine treatment sites.^11-14 Esketamine is FDA-approved for treatment-resistant depression in adults and for depressive symptoms in adults with major depressive disorder with acute suicidal ideation or behavior. Ketamine is not FDA-approved for treating depression but is being used off-label to treat this disorder.¹⁵ The FDA determined that ketamine does not require a REMS to ensure the benefits outweigh the risks for its approved indications as an anesthetic agent, anesthesia-inducing agent, or supplement to anesthesia. Since ketamine has no REMS requirements, there may be a lower burden for its use. Thus, clinicians are treating patients for depression with this medication without needing to comply with a REMS.¹⁶

Technology plays a role in workload burden, and integrating health care processes within current workflow systems, such as using electronic patient health records and pharmacy systems, is recommended. The FDA has been exploring technologies to facilitate the completion of REMS requirements, including mandatory education within the prescribers’ and pharmacists’ workflow.¹⁷ This is a complex task that requires multiple stakeholders with differing perspectives and incentives to align.

Continue to: The data collected for the REMS...

The data collected for the REMS program belongs to the medication’s manufacturer. Current regulations do not require manufacturers to make this data available to qualified scientific researchers. A regulatory mandate to establish data sharing methods would improve transparency and enhance efforts to better understand the outcomes of the REMS programs.

A few caveats

Both the overarching and medication-specific recommendations were based on a small number of participants’ discussions related to clozapine, olanzapine for ER injectable suspension, and esketamine. These recommendations do not include other medications with REMS that are used to treat psychiatric disorders, such as loxapine, buprenorphine ER, and buprenorphine transmucosal products. Larger-scale qualitative and quantitative research is needed to better understand health care professionals’ perspectives. Lastly, some of the recommendations outlined in this article are beyond the current purview or authority of the FDA and may require legislative or regulatory action to implement.

Bottom Line

Risk Evaluation and Mitigation Strategy (REMS) programs are designed to help reduce the occurrence and/or severity of serious risks or to inform decision-making. However, REMS requirements may adversely impact patient access to certain REMS medications and clinician burden. Health care professionals can provide informed recommendations for improving the REMS programs for clozapine, olanzapine for extended-release injectable suspension, and esketamine.

Related Resources

• FDA. Frequently asked questions (FAQs) about REMS. www.fda.gov/drugs/risk-evaluation-and-mitigation-strategies-rems/frequently-asked-questions-faqs-about-rems

Drug Brand Names

Buprenorphine extended-release • Sublocade
Buprenorphine transmucosal • Subutex, Suboxone
Clozapine • Clozaril
Esketamine • Spravato
Ketamine • Ketalar
Lithium • Eskalith, Lithobid
Loxapine • Adasuve
Olanzapine extended-release injectable suspension • Zyprexa Relprevv

A Risk Evaluation and Mitigation Strategy (REMS) is a drug safety program the FDA can require for certain medications with serious safety concerns to help ensure the benefits of the medication outweigh its risks (Box¹). The FDA may require medication guides, patient package inserts, communication plans for health care professionals, and/or certain packaging and safe disposal technologies for medications that pose a serious risk of abuse or overdose. The FDA may also require elements to assure safe use and/or an implementation system be included in the REMS. Pharmaceutical manufacturers then develop a proposed REMS for FDA review.² If the FDA approves the proposed REMS, the manufacturer is responsible for implementing the REMS requirements.

Box

The REMS program for clozapine³ has been the subject of much discussion in the psychiatric community. The adverse impact of the 2015 update to the clozapine REMS program was emphasized at meetings of both the American Psychiatric Association and the College of Psychiatric and Neurologic Pharmacists. A white paper published by the National Association of State Mental Health Program Directors shortly after the 2015 update concluded, “clozapine is underused due to a variety of barriers related to the drug and its properties, the health care system, regulatory requirements, and reimbursement issues.”⁴ After an update to the clozapine REMS program in 2021, the FDA temporarily suspended enforcement of certain requirements due to concerns from health care professionals about patient access to the medication because of problems with implementing the clozapine REMS program.^5,6 In November 2022, the FDA issued a second announcement of enforcement discretion related to additional requirements of the REMS program.⁵ The FDA had previously announced a decision to not take action regarding adherence to REMS requirements for certain laboratory tests in March 2020, during the COVID-19 pandemic.⁷

REMS programs for other psychiatric medications may also present challenges. The REMS programs for esketamine⁸ and olanzapine for extended-release (ER) injectable suspension⁹ include certain risks that require postadministration monitoring. Some facilities have had to dedicate additional space and clinician time to ensure REMS requirements are met.

To further understand health care professionals’ perspectives regarding the value and burden of these REMS programs, a collaborative effort of the University of Maryland (College Park and Baltimore campuses) Center of Excellence in Regulatory Science and Innovation with the FDA was undertaken. The REMS for clozapine, olanzapine for ER injectable suspension, and esketamine were examined to develop recommendations for improving patient access while ensuring safe medication use and limiting the impact on health care professionals.

Assessing the REMS programs

Focus groups were held with health care professionals nominated by professional organizations to gather their perspectives on the REMS requirements. There was 1 focus group for each of the 3 medications. A facilitator’s guide was developed that contained the details of how to conduct the focus group along with the medication-specific questions. The questions were based on the REMS requirements as of May 2021 and assessed the impact of the REMS on patient safety, patient access, and health care professional workload; effects from the COVID-19 pandemic; and suggestions to improve the REMS programs. The University of Maryland Institutional Review Board reviewed the materials and processes and made the determination of exempt.

Health care professionals were eligible to participate in a focus group if they had ≥1 year of experience working with patients who use the specific medication and ≥6 months of experience within the past year working with the REMS program for that medication. Participants were excluded if they were employed by a pharmaceutical manufacturer or the FDA. The focus groups were conducted virtually using an online conferencing service during summer 2021 and were scheduled for 90 minutes. Prior to the focus group, participants received information from the “Goals” and “Summary” tabs of the FDA REMS website¹⁰ for the specific medication along with patient/caregiver guides, which were available for clozapine and olanzapine for ER injectable suspension. For each focus group, there was a target sample size of 6 to 9 participants. However, there were only 4 participants in the olanzapine for ER injectable suspension focus group, which we believed was due to lower national utilization of this medication. Individuals were only able to participate in 1 focus group, so the unique participant count for all 3 focus groups totaled 17 (Table 1).

Themes extracted from qualitative analysis of the focus group responses were the value of the REMS programs; registration/enrollment processes and REMS websites; monitoring requirements; care transitions; and COVID considerations (Table 2). While the REMS programs were perceived to increase practitioner and patient awareness of potential harms, discussions centered on the relative cost-to-benefit of the required reporting and other REMS requirements. There were challenges with the registration/enrollment processes and REMS websites that also affected patient care during transitions to different health care settings or clinicians. Patient access was affected by disparities in care related to monitoring requirements and clinician availability.

Continue to: COVID impacted all REMS...

COVID impacted all REMS programs. Physical distancing was an issue for medications that required extensive postadministration monitoring (ie, esketamine and olanzapine for ER injectable suspension). Access to laboratory services was an issue for clozapine.

Medication-specific themes are listed in Table 3 and relate to terms and descriptions in the REMS or additional regulatory requirements from the Drug Enforcement Agency (DEA). Suggestions for improvement to the REMS are presented in Table 4.

Recommendations for improving REMS

A group consisting of health care professionals, policy experts, and mental health advocates reviewed the information provided by the focus groups and developed the following recommendations.

Overarching recommendations

Each REMS should include a section providing justification for its existence, including a risk analysis of the data regarding the risk the REMS is designed to mitigate. This analysis should be repeated on a regular basis as scientific evidence regarding the risk and its epidemiology evolves. This additional section should also explain how the program requirements of the REMS as implemented (or planned) will achieve the aims of the REMS and weigh the potential benefits of the REMS requirements as implemented (or planned) by the manufacturer vs the potential risks of the REMS requirements as implemented (or planned) by the manufacturer.

Each REMS should have specific quantifiable outcomes. For example, it should specify a reduction in occurrence of the rate of the concerned risk by a specified amount.

Continue to: Ensure adequate...

Ensure adequate stakeholder input during the REMS development and real-world testing in multiple environments before implementing the REMS to identify unanticipated consequences that might impact patient access, patient safety, and health care professional burden. Implementation testing should explore issues such as purchasing and procurement, billing and reimbursement, and relevant factors such as other federal regulations or requirements (eg, the DEA or Medicare).

Ensure harmonization of the REMS forms and processes (eg, initiation and monitoring) for different medications where possible. A prescriber, pharmacist, or system should not face additional barriers to participate in a REMS based on REMS-specific intricacies (ie, prescription systems, data submission systems, or ordering systems). This streamlining will likely decrease clinical inertia to initiate care with the REMS medication, decrease health care professional burden, and improve compliance with REMS requirements.

REMS should anticipate the need for care transitions and employ provisions to ensure seamless care. Considerations should be given to transitions that occur due to:

• Different care settings (eg, inpatient, outpatient, or long-term care)
• Different geographies (eg, patient moves)
• Changes in clinicians, including leaves or absences
• Changes in facilities (eg, pharmacies).

REMS should mirror normal health care professional workflow, including how monitoring data are collected and how and with which frequency pharmacies fill prescriptions.Enhanced information technology to support REMS programs is needed. For example, REMS should be integrated with major electronic patient health record and pharmacy systems to reduce the effort required for clinicians to supply data and automate REMS processes.

For medications that are subject to other agencies and their regulations (eg, the CDC, Centers for Medicare & Medicaid Services, or the DEA), REMS should be required to meet all standards of all agencies with a single system that accommodates normal health care professional workflow.

Continue to: REMS should have a...

REMS should have a standard disclaimer that allows the health care professional to waive certain provisions of the REMS in cases when the specific provisions of the REMS pose a greater risk to the patient than the risk posed by waiving the requirement.

Assure the actions implemented by the industry to meet the requirements for each REMS program are based on peer-reviewed evidence and provide a reasonable expectation to achieve the anticipated benefit.

Ensure that manufacturers make all accumulated REMS data available in a de­identified manner for use by qualified scientific researchers. Additionally, each REMS should have a plan for data access upon initiation and termination of the REMS.

Each REMS should collect data on the performance of the centers and/or personnel who operate the REMS and submit this data for review by qualified outside reviewers. Parameters to assess could include:

• timeliness of response
• timeliness of problem resolution
• data availability and its helpfulness to patient care
• adequacy of resources.

Recommendations for clozapine REMS

These comments relate to the clozapine REMS program prior to the July 2021 announcement that FDA had approved a modification.

Provide a clear definition for “benign ethnic neutropenia.”

Ensure the REMS includes patient-specific adjustments to allow flexibility for monitoring. During COVID, the FDA allowed clinicians to “use their best medical judgment in weighing the benefits and risks of continuing treatment in the absence of laboratory testing.”⁷ This guidance, which allowed flexibility to absolute neutrophil count (ANC) monitoring, was perceived as positive and safe. Before the changes in the REMS requirements, patients with benign ethnic neutropenia were restricted from accessing their medication or encountered harm from additional pharmacotherapy to mitigate ANC levels.

Continue to: Recommendations for olanzapine for ER injectable suspension REMS

 

 

Recommendations for olanzapine for ER injectable suspension REMS

Provide clear explicit instructions on what is required to have “ready access to emergency services.”

Ensure the REMS include patient-specific adjustments to allow flexibility for postadministration monitoring (eg, sedation or blood pressure). Specific patient groups may have differential access to certain types of facilities, transportation, or other resources. For example, consider the administration of olanzapine for ER injectable suspension by a mobile treatment team with an adequate protocol (eg, via videoconferencing or phone calls).

Ensure actions with peer-reviewed evidence demonstrating efficacy/effectiveness are included in the REMS. How was the 3-hour cut-point determined? Has it been reevaluated?

Ensure the REMS requirements allow for seamless care during transitions, particularly when clinicians are on vacation.

Continue to: Recommendations for esketamine REMS

 

 

Recommendations for esketamine REMS

Ensure the REMS includes patient-specific adjustments to allow flexibility for post­administration monitoring. Specific patient groups may have differential access to certain types of facilities, transportation, or other resources. For example, consider the administration of esketamine by a mobile treatment team with an adequate protocol (eg, via videoconferencing or phone calls).

Ensure actions with peer-reviewed evidence demonstrating efficacy/effectiveness of requirements are included in the REMS. How was the 2-hour cut-point determined? Has it been reevaluated?

Ensure that the REMS meet all standards of the DEA, with a single system that accommodates normal health care professional workflow.

A summary of the findings

Overall, the REMS programs for these 3 medications were positively perceived for raising awareness of safe medication use for clinicians and patients. Monitoring patients for safety concerns is important and REMS requirements provide accountability.

Continue to: The use of a single shared...

The use of a single shared REMS system for documenting requirements for clozapine (compared to separate systems for each manufacturer) was a positive move forward in implementation. The focus group welcomed the increased awareness of benign ethnic neutropenia as a result of this condition being incorporated in the revised monitoring requirements of the clozapine REMS.

Focus group participants raised the issue of the real-world efficiency of the REMS programs (reduced access and increased clinician workload) vs the benefits (patient safety). They noted that excessive workload could lead to clinicians becoming unwilling to use a medication that requires a REMS. Clinician workload may be further compromised when REMS logistics disrupt the normal workflow and transitions of care between clinicians or settings. This latter aspect is of particular concern for clozapine.

The complexities of the registration and reporting system for olanzapine for ER injectable suspension and the lack of clarity about monitoring were noted to have discouraged the opening of treatment sites. This scarcity of sites may make clinicians hesitant to use this medication, and instead opt for alternative treatments in patients who may be appropriate candidates.

There has also been limited growth of esketamine treatment sites, especially in comparison to ketamine treatment sites.^11-14 Esketamine is FDA-approved for treatment-resistant depression in adults and for depressive symptoms in adults with major depressive disorder with acute suicidal ideation or behavior. Ketamine is not FDA-approved for treating depression but is being used off-label to treat this disorder.¹⁵ The FDA determined that ketamine does not require a REMS to ensure the benefits outweigh the risks for its approved indications as an anesthetic agent, anesthesia-inducing agent, or supplement to anesthesia. Since ketamine has no REMS requirements, there may be a lower burden for its use. Thus, clinicians are treating patients for depression with this medication without needing to comply with a REMS.¹⁶

Technology plays a role in workload burden, and integrating health care processes within current workflow systems, such as using electronic patient health records and pharmacy systems, is recommended. The FDA has been exploring technologies to facilitate the completion of REMS requirements, including mandatory education within the prescribers’ and pharmacists’ workflow.¹⁷ This is a complex task that requires multiple stakeholders with differing perspectives and incentives to align.

Continue to: The data collected for the REMS...

The data collected for the REMS program belongs to the medication’s manufacturer. Current regulations do not require manufacturers to make this data available to qualified scientific researchers. A regulatory mandate to establish data sharing methods would improve transparency and enhance efforts to better understand the outcomes of the REMS programs.

A few caveats

Both the overarching and medication-specific recommendations were based on a small number of participants’ discussions related to clozapine, olanzapine for ER injectable suspension, and esketamine. These recommendations do not include other medications with REMS that are used to treat psychiatric disorders, such as loxapine, buprenorphine ER, and buprenorphine transmucosal products. Larger-scale qualitative and quantitative research is needed to better understand health care professionals’ perspectives. Lastly, some of the recommendations outlined in this article are beyond the current purview or authority of the FDA and may require legislative or regulatory action to implement.

Bottom Line

Risk Evaluation and Mitigation Strategy (REMS) programs are designed to help reduce the occurrence and/or severity of serious risks or to inform decision-making. However, REMS requirements may adversely impact patient access to certain REMS medications and clinician burden. Health care professionals can provide informed recommendations for improving the REMS programs for clozapine, olanzapine for extended-release injectable suspension, and esketamine.

Related Resources

• FDA. Frequently asked questions (FAQs) about REMS. www.fda.gov/drugs/risk-evaluation-and-mitigation-strategies-rems/frequently-asked-questions-faqs-about-rems

Drug Brand Names

Buprenorphine extended-release • Sublocade
Buprenorphine transmucosal • Subutex, Suboxone
Clozapine • Clozaril
Esketamine • Spravato
Ketamine • Ketalar
Lithium • Eskalith, Lithobid
Loxapine • Adasuve
Olanzapine extended-release injectable suspension • Zyprexa Relprevv