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LGBTQ+ Youth Consult Questions remain over use of sex hormone therapy
“They Paused Puberty but Is There a Cost?”
“Bone Health: Puberty Blockers Not Fully Reversible.”
Headlines such as these from major national news outlets have begun to cast doubt on one of the medications used in treating gender-diverse adolescents and young adults. GnRH agonists, such as leuprorelin and triptorelin, were first approved by the Food and Drug Administration in the 1980s and have been used since then for a variety of medical indications. In the decades since, these medications have been successfully used with a generally favorable side effect profile.
GnRH agonists and puberty
In the treatment of precocious puberty, GnRH agonists are often started prior to the age of 7, depending on the age at which the affected patient begins showing signs of central puberty. These include breast development, scrotal enlargement, and so on. GnRH agonists typically are continued until age 10-12, depending on the patient and an informed discussion with the patient’s parents about optimal outcomes.1 Therefore, it is not uncommon to see these medications used for anywhere from 1 to 4 years, depending on the age at which precocious puberty started.
GnRH agonists are used in two populations of transgender individuals. The first group is those youths who have just started their natal, or biological, puberty. The medication is not started until the patient has biochemical or physical exam evidence that puberty has started. The medication is then continued until hormones are started. This is usually 2-3 years on average, depending on the age at which the medication was started. This is essentially comparable with cisgender youths who have taken these medications for precocious puberty. The second population of individuals who use GnRH agonists is transgender women who are also on estrogen therapy. In these women, the GnRH agonist is used for androgen (testosterone) suppression.
Concerns over bone health
One of the main concerns recently expressed about long-term use of GnRH agonists is their effect on bone density. Adolescence is a critical time for bone mineral density (BMD) accrual and this is driven by sex hormones. When GnRH agonists are used to delay puberty in transgender adolescents, this then delays the maturation of the adult skeleton until the GnRH agonist is stopped (and natal puberty resumes) or cross-sex hormones are started. In a recent multicenter study2 looking at baseline BMD of transgender youth at the time of GnRH agonist initiation, 30% of those assigned male at birth and 13% of those assigned female at birth had low bone mineral density for age (defined as a BMD z score of <–2). For those with low BMD, their physical activity scores were significantly lower than those with normal BMD. Thus, these adolescents require close follow-up, just like their cisgender peers.
There are currently no long-term data on the risk of developing fractures or osteoporosis in those individuals who were treated with GnRH agonists and then went on to start cross-sex hormone therapy. Some studies suggest that there is a risk that BMD does not recover after being on cross-sex hormones,3 while another study suggested that transgender men recover their BMD after being on testosterone.4 It is still unclear in that study why transgender women did not recover their BMD or why they were low at baseline. Interestingly, a 2012 study5 from Brazil showed that there was no difference in BMD for cisgender girls who had been off their GnRH agonist therapy for at least 3 years, as compared with their age-matched controls who had never been on GnRH agonist therapy. These conflicting data highlight the importance of long-term follow-up, as well as the need to include age-matched, cisgender control subjects, to better understand if there is truly a difference in transgender individuals or if today’s adolescents, in general, have low BMD.
Lingering questions
In summary, the use of GnRH agonists in transgender adolescents remains controversial because of the potential long-term effects on bone mineral density. However, this risk must be balanced against the risks of allowing natal puberty to progress in certain transgender individuals with the development of undesired secondary sex characteristics. More longitudinal studies are needed to better understand the long-term risks of osteoporosis and fractures in those who have undergone GnRH agonist therapy as part of their gender-affirming medical care, as well as any clinical interventions that might help mitigate this risk.
Dr. Cooper is assistant professor of pediatrics at UT Southwestern, Dallas, and an adolescent medicine specialist at Children’s Medical Center Dallas.
References
1. Harrington J et al. Treatment of precocious puberty. UpToDate. www.uptodate.com/contents/treatment-of-precocious-puberty.
2. Lee JY et al. J Endocr Soc. 2020;4(9):bvaa065. doi: 10.1210/jendso/bvaa065.
3. Klink D et al. J Clin Endocrinol Metab. 2015;100(2):E270-5. doi: 10.1210/jc.2014-2439.
4. Schagen SEE et al. J Clin Endocrinol Metab. 2020;105(12):e4252-e4263. doi: 10.1210/clinem/dgaa604.
5. Alessandri SB et al. Clinics (Sao Paulo). 2012;67(6):591-6. doi: 10.6061/clinics/2012(06)08.
“They Paused Puberty but Is There a Cost?”
“Bone Health: Puberty Blockers Not Fully Reversible.”
Headlines such as these from major national news outlets have begun to cast doubt on one of the medications used in treating gender-diverse adolescents and young adults. GnRH agonists, such as leuprorelin and triptorelin, were first approved by the Food and Drug Administration in the 1980s and have been used since then for a variety of medical indications. In the decades since, these medications have been successfully used with a generally favorable side effect profile.
GnRH agonists and puberty
In the treatment of precocious puberty, GnRH agonists are often started prior to the age of 7, depending on the age at which the affected patient begins showing signs of central puberty. These include breast development, scrotal enlargement, and so on. GnRH agonists typically are continued until age 10-12, depending on the patient and an informed discussion with the patient’s parents about optimal outcomes.1 Therefore, it is not uncommon to see these medications used for anywhere from 1 to 4 years, depending on the age at which precocious puberty started.
GnRH agonists are used in two populations of transgender individuals. The first group is those youths who have just started their natal, or biological, puberty. The medication is not started until the patient has biochemical or physical exam evidence that puberty has started. The medication is then continued until hormones are started. This is usually 2-3 years on average, depending on the age at which the medication was started. This is essentially comparable with cisgender youths who have taken these medications for precocious puberty. The second population of individuals who use GnRH agonists is transgender women who are also on estrogen therapy. In these women, the GnRH agonist is used for androgen (testosterone) suppression.
Concerns over bone health
One of the main concerns recently expressed about long-term use of GnRH agonists is their effect on bone density. Adolescence is a critical time for bone mineral density (BMD) accrual and this is driven by sex hormones. When GnRH agonists are used to delay puberty in transgender adolescents, this then delays the maturation of the adult skeleton until the GnRH agonist is stopped (and natal puberty resumes) or cross-sex hormones are started. In a recent multicenter study2 looking at baseline BMD of transgender youth at the time of GnRH agonist initiation, 30% of those assigned male at birth and 13% of those assigned female at birth had low bone mineral density for age (defined as a BMD z score of <–2). For those with low BMD, their physical activity scores were significantly lower than those with normal BMD. Thus, these adolescents require close follow-up, just like their cisgender peers.
There are currently no long-term data on the risk of developing fractures or osteoporosis in those individuals who were treated with GnRH agonists and then went on to start cross-sex hormone therapy. Some studies suggest that there is a risk that BMD does not recover after being on cross-sex hormones,3 while another study suggested that transgender men recover their BMD after being on testosterone.4 It is still unclear in that study why transgender women did not recover their BMD or why they were low at baseline. Interestingly, a 2012 study5 from Brazil showed that there was no difference in BMD for cisgender girls who had been off their GnRH agonist therapy for at least 3 years, as compared with their age-matched controls who had never been on GnRH agonist therapy. These conflicting data highlight the importance of long-term follow-up, as well as the need to include age-matched, cisgender control subjects, to better understand if there is truly a difference in transgender individuals or if today’s adolescents, in general, have low BMD.
Lingering questions
In summary, the use of GnRH agonists in transgender adolescents remains controversial because of the potential long-term effects on bone mineral density. However, this risk must be balanced against the risks of allowing natal puberty to progress in certain transgender individuals with the development of undesired secondary sex characteristics. More longitudinal studies are needed to better understand the long-term risks of osteoporosis and fractures in those who have undergone GnRH agonist therapy as part of their gender-affirming medical care, as well as any clinical interventions that might help mitigate this risk.
Dr. Cooper is assistant professor of pediatrics at UT Southwestern, Dallas, and an adolescent medicine specialist at Children’s Medical Center Dallas.
References
1. Harrington J et al. Treatment of precocious puberty. UpToDate. www.uptodate.com/contents/treatment-of-precocious-puberty.
2. Lee JY et al. J Endocr Soc. 2020;4(9):bvaa065. doi: 10.1210/jendso/bvaa065.
3. Klink D et al. J Clin Endocrinol Metab. 2015;100(2):E270-5. doi: 10.1210/jc.2014-2439.
4. Schagen SEE et al. J Clin Endocrinol Metab. 2020;105(12):e4252-e4263. doi: 10.1210/clinem/dgaa604.
5. Alessandri SB et al. Clinics (Sao Paulo). 2012;67(6):591-6. doi: 10.6061/clinics/2012(06)08.
“They Paused Puberty but Is There a Cost?”
“Bone Health: Puberty Blockers Not Fully Reversible.”
Headlines such as these from major national news outlets have begun to cast doubt on one of the medications used in treating gender-diverse adolescents and young adults. GnRH agonists, such as leuprorelin and triptorelin, were first approved by the Food and Drug Administration in the 1980s and have been used since then for a variety of medical indications. In the decades since, these medications have been successfully used with a generally favorable side effect profile.
GnRH agonists and puberty
In the treatment of precocious puberty, GnRH agonists are often started prior to the age of 7, depending on the age at which the affected patient begins showing signs of central puberty. These include breast development, scrotal enlargement, and so on. GnRH agonists typically are continued until age 10-12, depending on the patient and an informed discussion with the patient’s parents about optimal outcomes.1 Therefore, it is not uncommon to see these medications used for anywhere from 1 to 4 years, depending on the age at which precocious puberty started.
GnRH agonists are used in two populations of transgender individuals. The first group is those youths who have just started their natal, or biological, puberty. The medication is not started until the patient has biochemical or physical exam evidence that puberty has started. The medication is then continued until hormones are started. This is usually 2-3 years on average, depending on the age at which the medication was started. This is essentially comparable with cisgender youths who have taken these medications for precocious puberty. The second population of individuals who use GnRH agonists is transgender women who are also on estrogen therapy. In these women, the GnRH agonist is used for androgen (testosterone) suppression.
Concerns over bone health
One of the main concerns recently expressed about long-term use of GnRH agonists is their effect on bone density. Adolescence is a critical time for bone mineral density (BMD) accrual and this is driven by sex hormones. When GnRH agonists are used to delay puberty in transgender adolescents, this then delays the maturation of the adult skeleton until the GnRH agonist is stopped (and natal puberty resumes) or cross-sex hormones are started. In a recent multicenter study2 looking at baseline BMD of transgender youth at the time of GnRH agonist initiation, 30% of those assigned male at birth and 13% of those assigned female at birth had low bone mineral density for age (defined as a BMD z score of <–2). For those with low BMD, their physical activity scores were significantly lower than those with normal BMD. Thus, these adolescents require close follow-up, just like their cisgender peers.
There are currently no long-term data on the risk of developing fractures or osteoporosis in those individuals who were treated with GnRH agonists and then went on to start cross-sex hormone therapy. Some studies suggest that there is a risk that BMD does not recover after being on cross-sex hormones,3 while another study suggested that transgender men recover their BMD after being on testosterone.4 It is still unclear in that study why transgender women did not recover their BMD or why they were low at baseline. Interestingly, a 2012 study5 from Brazil showed that there was no difference in BMD for cisgender girls who had been off their GnRH agonist therapy for at least 3 years, as compared with their age-matched controls who had never been on GnRH agonist therapy. These conflicting data highlight the importance of long-term follow-up, as well as the need to include age-matched, cisgender control subjects, to better understand if there is truly a difference in transgender individuals or if today’s adolescents, in general, have low BMD.
Lingering questions
In summary, the use of GnRH agonists in transgender adolescents remains controversial because of the potential long-term effects on bone mineral density. However, this risk must be balanced against the risks of allowing natal puberty to progress in certain transgender individuals with the development of undesired secondary sex characteristics. More longitudinal studies are needed to better understand the long-term risks of osteoporosis and fractures in those who have undergone GnRH agonist therapy as part of their gender-affirming medical care, as well as any clinical interventions that might help mitigate this risk.
Dr. Cooper is assistant professor of pediatrics at UT Southwestern, Dallas, and an adolescent medicine specialist at Children’s Medical Center Dallas.
References
1. Harrington J et al. Treatment of precocious puberty. UpToDate. www.uptodate.com/contents/treatment-of-precocious-puberty.
2. Lee JY et al. J Endocr Soc. 2020;4(9):bvaa065. doi: 10.1210/jendso/bvaa065.
3. Klink D et al. J Clin Endocrinol Metab. 2015;100(2):E270-5. doi: 10.1210/jc.2014-2439.
4. Schagen SEE et al. J Clin Endocrinol Metab. 2020;105(12):e4252-e4263. doi: 10.1210/clinem/dgaa604.
5. Alessandri SB et al. Clinics (Sao Paulo). 2012;67(6):591-6. doi: 10.6061/clinics/2012(06)08.
Time to rebuild
A few months ago, after several months of considerable foot dragging, I wrote that I have accepted the American Academy of Pediatrics’ proclamation that we should begin to treat obesity as a disease.
While it may feel like we are just throwing in the towel, it sounds better if we admit that we may have reached the threshold beyond which total focus on prevention is not going to work.
I continue to be troubled by the lingering fear that, in declaring that obesity is a disease, we will suspend our current efforts at preventing the condition. Granted, most of these efforts at prevention have been woefully ineffective. However, I still believe that, much like ADHD, the rise in obesity in this country is a reflection of some serious flaws in our society. On the other hand, as an inveterate optimist I have not given up on the belief that we will find some yet-to-be-discovered changes in our societal fabric that will eventually turn the ship around.
With this somewhat contradictory combination of resignation and optimism in mind, I continue to seek out studies that hold some promise for prevention while we begin tinkering with the let’s-treat-it-like-a-disease approach.
I recently discovered a story about one such study from the Center for Economic and Social Research at the University of Southern California. Using data collected about adolescent dependents of military personnel, the researchers found that “exposure to a more advantageous built environment for more than 2 years was associated with lower probabilities of obesity.” Because more than half of these teenagers were living in housing that had been assigned by the military, the researchers could more easily control for a variety of factors some related to self-selection.
Interestingly, the data did not support associations between the adolescents’ diet, physical activity, or socioeconomic environments. The investigators noted that “more advantageous built environments were associated with lower consumption of unhealthy foods.” However, the study lacked the granularity to determine what segments of the built environment were most associated with the effect they were observing.
Like me, you may not be familiar with the term “built environment.” Turns out it is just exactly what we might expect – anything about the environment that is the result of human action – buildings, roadways, dams, neighborhoods – and what they do and don’t contain. For example, is the adolescent living in an environment that encourages walking or one that is overly motor vehicle–centric? Does his or her neighborhood have easily reachable grocery stores that offer a range of healthy foods or does the teenager live in a nutritional desert populated only by convenience stores? Is there ample space for outdoor physical activity?
The authors’ observation that the adolescents who benefited from living in advantageous environments had a lower consumption of unhealthy foods might suggest that access to a healthy diet might be a significant factor. For me, the take-home message is that in our search for preventive strategies we have barely scratched the surface. The observation that the associations these researchers were making was over a relatively short time span of 2 years should give us hope that if we think more broadly and creatively we may be to find solutions on a grand scale.
Over the last century we have built an environment that is clearly obesogenic. This paper offers a starting point from which we can learn which components of that environment are the most potent contributors to the obesity epidemic. Once we have that information the question remains: Can we find the political will to tear down and rebuilt?
Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].
A few months ago, after several months of considerable foot dragging, I wrote that I have accepted the American Academy of Pediatrics’ proclamation that we should begin to treat obesity as a disease.
While it may feel like we are just throwing in the towel, it sounds better if we admit that we may have reached the threshold beyond which total focus on prevention is not going to work.
I continue to be troubled by the lingering fear that, in declaring that obesity is a disease, we will suspend our current efforts at preventing the condition. Granted, most of these efforts at prevention have been woefully ineffective. However, I still believe that, much like ADHD, the rise in obesity in this country is a reflection of some serious flaws in our society. On the other hand, as an inveterate optimist I have not given up on the belief that we will find some yet-to-be-discovered changes in our societal fabric that will eventually turn the ship around.
With this somewhat contradictory combination of resignation and optimism in mind, I continue to seek out studies that hold some promise for prevention while we begin tinkering with the let’s-treat-it-like-a-disease approach.
I recently discovered a story about one such study from the Center for Economic and Social Research at the University of Southern California. Using data collected about adolescent dependents of military personnel, the researchers found that “exposure to a more advantageous built environment for more than 2 years was associated with lower probabilities of obesity.” Because more than half of these teenagers were living in housing that had been assigned by the military, the researchers could more easily control for a variety of factors some related to self-selection.
Interestingly, the data did not support associations between the adolescents’ diet, physical activity, or socioeconomic environments. The investigators noted that “more advantageous built environments were associated with lower consumption of unhealthy foods.” However, the study lacked the granularity to determine what segments of the built environment were most associated with the effect they were observing.
Like me, you may not be familiar with the term “built environment.” Turns out it is just exactly what we might expect – anything about the environment that is the result of human action – buildings, roadways, dams, neighborhoods – and what they do and don’t contain. For example, is the adolescent living in an environment that encourages walking or one that is overly motor vehicle–centric? Does his or her neighborhood have easily reachable grocery stores that offer a range of healthy foods or does the teenager live in a nutritional desert populated only by convenience stores? Is there ample space for outdoor physical activity?
The authors’ observation that the adolescents who benefited from living in advantageous environments had a lower consumption of unhealthy foods might suggest that access to a healthy diet might be a significant factor. For me, the take-home message is that in our search for preventive strategies we have barely scratched the surface. The observation that the associations these researchers were making was over a relatively short time span of 2 years should give us hope that if we think more broadly and creatively we may be to find solutions on a grand scale.
Over the last century we have built an environment that is clearly obesogenic. This paper offers a starting point from which we can learn which components of that environment are the most potent contributors to the obesity epidemic. Once we have that information the question remains: Can we find the political will to tear down and rebuilt?
Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].
A few months ago, after several months of considerable foot dragging, I wrote that I have accepted the American Academy of Pediatrics’ proclamation that we should begin to treat obesity as a disease.
While it may feel like we are just throwing in the towel, it sounds better if we admit that we may have reached the threshold beyond which total focus on prevention is not going to work.
I continue to be troubled by the lingering fear that, in declaring that obesity is a disease, we will suspend our current efforts at preventing the condition. Granted, most of these efforts at prevention have been woefully ineffective. However, I still believe that, much like ADHD, the rise in obesity in this country is a reflection of some serious flaws in our society. On the other hand, as an inveterate optimist I have not given up on the belief that we will find some yet-to-be-discovered changes in our societal fabric that will eventually turn the ship around.
With this somewhat contradictory combination of resignation and optimism in mind, I continue to seek out studies that hold some promise for prevention while we begin tinkering with the let’s-treat-it-like-a-disease approach.
I recently discovered a story about one such study from the Center for Economic and Social Research at the University of Southern California. Using data collected about adolescent dependents of military personnel, the researchers found that “exposure to a more advantageous built environment for more than 2 years was associated with lower probabilities of obesity.” Because more than half of these teenagers were living in housing that had been assigned by the military, the researchers could more easily control for a variety of factors some related to self-selection.
Interestingly, the data did not support associations between the adolescents’ diet, physical activity, or socioeconomic environments. The investigators noted that “more advantageous built environments were associated with lower consumption of unhealthy foods.” However, the study lacked the granularity to determine what segments of the built environment were most associated with the effect they were observing.
Like me, you may not be familiar with the term “built environment.” Turns out it is just exactly what we might expect – anything about the environment that is the result of human action – buildings, roadways, dams, neighborhoods – and what they do and don’t contain. For example, is the adolescent living in an environment that encourages walking or one that is overly motor vehicle–centric? Does his or her neighborhood have easily reachable grocery stores that offer a range of healthy foods or does the teenager live in a nutritional desert populated only by convenience stores? Is there ample space for outdoor physical activity?
The authors’ observation that the adolescents who benefited from living in advantageous environments had a lower consumption of unhealthy foods might suggest that access to a healthy diet might be a significant factor. For me, the take-home message is that in our search for preventive strategies we have barely scratched the surface. The observation that the associations these researchers were making was over a relatively short time span of 2 years should give us hope that if we think more broadly and creatively we may be to find solutions on a grand scale.
Over the last century we have built an environment that is clearly obesogenic. This paper offers a starting point from which we can learn which components of that environment are the most potent contributors to the obesity epidemic. Once we have that information the question remains: Can we find the political will to tear down and rebuilt?
Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].
Is vaping a gateway to cigarettes for kids?
Vaping may not be a gateway to long-term cigarette use for adolescents, a new study published in JAMA Network Open suggests.
Many studies have found that youth who vape are more likely to take up cigarette smoking, but whether that new habit lasts for a month or a lifetime has been unclear.
The percentage of adolescents who move on to smoking after starting to vape remains low, and those who do start smoking are unlikely to continue doing so for a long time, the new research shows.
“If they simply experiment with smoking but do not continue, their risks of smoking-related adverse health outcomes are low,” said Ruoyan Sun, PhD, assistant professor with the department of health policy and organization at the University of Alabama at Birmingham and the study’s lead author. “But if they do become regular or established smokers, then the risks can be substantial.”
Dr. Sun and her colleagues analyzed data from several waves of the longitudinal Population Assessment of Tobacco and Health study. Participants included 8,671 children and adolescents aged 12-17 years. Among teens who had ever vaped, 6% began smoking cigarettes and continued to smoke in the subsequent 3 years, the researchers found (95% confidence interval, 4.5%-8.0%), compared with 1.1% among teens who never vaped (95% CI, 0.8%-1.3%).
“The real concern is whether vaping is inducing significant numbers of young people to become confirmed smokers,” said Dr. Sun. “The answer is that it does not.”
Previous studies using PATH data have suggested that adolescents who use e-cigarettes are up to 3.5 times more likely than nonusers to start smoking tobacco cigarettes and that they may continue to use both products.
But in the new study, despite the low overall number of cigarette smokers, those in the group who used e-cigarettes were 81% more likely to continue smoking tobacco cigarettes after 3 years, compared with those who did not use e-cigarettes, researchers found (95% CI, 1.03-3.18).
Rachel Boykan, MD, clinical professor of pediatrics and attending physician at Stony Brook (N.Y.) Children’s Hospital, said that despite the findings, the overall messaging to patients remains the same: Vaping is linked to smoking.
“There is still a risk of initiation smoking among e-cigarette users – that is the take-home message,” Dr. Boykan, who was not affiliated with the study, said. “No risk of smoking initiation is acceptable. And of course, as we are learning, there are significant health risks with e-cigarette use alone.”
Among the entire group of teens, approximately 4% of the adolescents began smoking cigarettes; only 2.5% continued to smoke in the subsequent 3 years, the researchers found.
“Based on our odds ratio result, e-cigarette users are more likely to report continued cigarette smoking,” said Dr. Sun. “However, the risk differences were not significant.”
The low numbers of teens who continued to smoke also suggests that adolescents are more likely to quit than become long-term smokers.
Nicotine dependence may adversely affect the ability of adolescents to learn, remember, and maintain attention. Early research has suggested that long-term e-cigarette smokers may be at increased risk of developing some of the same conditions as tobacco smokers, such as chronic lung disease.
Brian Jenssen, MD, a pediatrician at Children’s Hospital of Philadelphia and assistant professor in the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, said that the analysis is limited in part because it does not include changes in smoking and vaping trends since the pandemic started, “which seems to have increased the risk of smoking and vaping use.”
Data from the 2022 National Youth Tobacco survey found that although the rate of middle school and high school students who begin to use e-cigarettes has steadily decreased during the past two decades, those who vape report using the devices more frequently.
Subsequent use of cigarettes is also only one measure of risk from vapes.
“The goal isn’t just about cigarettes,” said Dr. Jenssen, who was not affiliated with the new study. “The goal is about helping children live tobacco- and nicotine-free lives, and there seems to be an increasing intensity of use, which is causing its own health risks.”
The current study findings do not change how clinicians should counsel their patients, and they should continue to advise teens to abstain from vaping, he added.
Dr. Sun said it’s common for youth to experiment with multiple tobacco products.
“Clinicians should continue to monitor youth tobacco-use behaviors but with their concern being focused on youthful patients who sustain smoking instead of just trying cigarettes,” she said.
Some of the study authors received support from the National Cancer Institute of the National Institutes of Health and the U.S. Food and Drug Administration’s Center for Tobacco Products.
A version of this article first appeared on Medscape.com.
Vaping may not be a gateway to long-term cigarette use for adolescents, a new study published in JAMA Network Open suggests.
Many studies have found that youth who vape are more likely to take up cigarette smoking, but whether that new habit lasts for a month or a lifetime has been unclear.
The percentage of adolescents who move on to smoking after starting to vape remains low, and those who do start smoking are unlikely to continue doing so for a long time, the new research shows.
“If they simply experiment with smoking but do not continue, their risks of smoking-related adverse health outcomes are low,” said Ruoyan Sun, PhD, assistant professor with the department of health policy and organization at the University of Alabama at Birmingham and the study’s lead author. “But if they do become regular or established smokers, then the risks can be substantial.”
Dr. Sun and her colleagues analyzed data from several waves of the longitudinal Population Assessment of Tobacco and Health study. Participants included 8,671 children and adolescents aged 12-17 years. Among teens who had ever vaped, 6% began smoking cigarettes and continued to smoke in the subsequent 3 years, the researchers found (95% confidence interval, 4.5%-8.0%), compared with 1.1% among teens who never vaped (95% CI, 0.8%-1.3%).
“The real concern is whether vaping is inducing significant numbers of young people to become confirmed smokers,” said Dr. Sun. “The answer is that it does not.”
Previous studies using PATH data have suggested that adolescents who use e-cigarettes are up to 3.5 times more likely than nonusers to start smoking tobacco cigarettes and that they may continue to use both products.
But in the new study, despite the low overall number of cigarette smokers, those in the group who used e-cigarettes were 81% more likely to continue smoking tobacco cigarettes after 3 years, compared with those who did not use e-cigarettes, researchers found (95% CI, 1.03-3.18).
Rachel Boykan, MD, clinical professor of pediatrics and attending physician at Stony Brook (N.Y.) Children’s Hospital, said that despite the findings, the overall messaging to patients remains the same: Vaping is linked to smoking.
“There is still a risk of initiation smoking among e-cigarette users – that is the take-home message,” Dr. Boykan, who was not affiliated with the study, said. “No risk of smoking initiation is acceptable. And of course, as we are learning, there are significant health risks with e-cigarette use alone.”
Among the entire group of teens, approximately 4% of the adolescents began smoking cigarettes; only 2.5% continued to smoke in the subsequent 3 years, the researchers found.
“Based on our odds ratio result, e-cigarette users are more likely to report continued cigarette smoking,” said Dr. Sun. “However, the risk differences were not significant.”
The low numbers of teens who continued to smoke also suggests that adolescents are more likely to quit than become long-term smokers.
Nicotine dependence may adversely affect the ability of adolescents to learn, remember, and maintain attention. Early research has suggested that long-term e-cigarette smokers may be at increased risk of developing some of the same conditions as tobacco smokers, such as chronic lung disease.
Brian Jenssen, MD, a pediatrician at Children’s Hospital of Philadelphia and assistant professor in the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, said that the analysis is limited in part because it does not include changes in smoking and vaping trends since the pandemic started, “which seems to have increased the risk of smoking and vaping use.”
Data from the 2022 National Youth Tobacco survey found that although the rate of middle school and high school students who begin to use e-cigarettes has steadily decreased during the past two decades, those who vape report using the devices more frequently.
Subsequent use of cigarettes is also only one measure of risk from vapes.
“The goal isn’t just about cigarettes,” said Dr. Jenssen, who was not affiliated with the new study. “The goal is about helping children live tobacco- and nicotine-free lives, and there seems to be an increasing intensity of use, which is causing its own health risks.”
The current study findings do not change how clinicians should counsel their patients, and they should continue to advise teens to abstain from vaping, he added.
Dr. Sun said it’s common for youth to experiment with multiple tobacco products.
“Clinicians should continue to monitor youth tobacco-use behaviors but with their concern being focused on youthful patients who sustain smoking instead of just trying cigarettes,” she said.
Some of the study authors received support from the National Cancer Institute of the National Institutes of Health and the U.S. Food and Drug Administration’s Center for Tobacco Products.
A version of this article first appeared on Medscape.com.
Vaping may not be a gateway to long-term cigarette use for adolescents, a new study published in JAMA Network Open suggests.
Many studies have found that youth who vape are more likely to take up cigarette smoking, but whether that new habit lasts for a month or a lifetime has been unclear.
The percentage of adolescents who move on to smoking after starting to vape remains low, and those who do start smoking are unlikely to continue doing so for a long time, the new research shows.
“If they simply experiment with smoking but do not continue, their risks of smoking-related adverse health outcomes are low,” said Ruoyan Sun, PhD, assistant professor with the department of health policy and organization at the University of Alabama at Birmingham and the study’s lead author. “But if they do become regular or established smokers, then the risks can be substantial.”
Dr. Sun and her colleagues analyzed data from several waves of the longitudinal Population Assessment of Tobacco and Health study. Participants included 8,671 children and adolescents aged 12-17 years. Among teens who had ever vaped, 6% began smoking cigarettes and continued to smoke in the subsequent 3 years, the researchers found (95% confidence interval, 4.5%-8.0%), compared with 1.1% among teens who never vaped (95% CI, 0.8%-1.3%).
“The real concern is whether vaping is inducing significant numbers of young people to become confirmed smokers,” said Dr. Sun. “The answer is that it does not.”
Previous studies using PATH data have suggested that adolescents who use e-cigarettes are up to 3.5 times more likely than nonusers to start smoking tobacco cigarettes and that they may continue to use both products.
But in the new study, despite the low overall number of cigarette smokers, those in the group who used e-cigarettes were 81% more likely to continue smoking tobacco cigarettes after 3 years, compared with those who did not use e-cigarettes, researchers found (95% CI, 1.03-3.18).
Rachel Boykan, MD, clinical professor of pediatrics and attending physician at Stony Brook (N.Y.) Children’s Hospital, said that despite the findings, the overall messaging to patients remains the same: Vaping is linked to smoking.
“There is still a risk of initiation smoking among e-cigarette users – that is the take-home message,” Dr. Boykan, who was not affiliated with the study, said. “No risk of smoking initiation is acceptable. And of course, as we are learning, there are significant health risks with e-cigarette use alone.”
Among the entire group of teens, approximately 4% of the adolescents began smoking cigarettes; only 2.5% continued to smoke in the subsequent 3 years, the researchers found.
“Based on our odds ratio result, e-cigarette users are more likely to report continued cigarette smoking,” said Dr. Sun. “However, the risk differences were not significant.”
The low numbers of teens who continued to smoke also suggests that adolescents are more likely to quit than become long-term smokers.
Nicotine dependence may adversely affect the ability of adolescents to learn, remember, and maintain attention. Early research has suggested that long-term e-cigarette smokers may be at increased risk of developing some of the same conditions as tobacco smokers, such as chronic lung disease.
Brian Jenssen, MD, a pediatrician at Children’s Hospital of Philadelphia and assistant professor in the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, said that the analysis is limited in part because it does not include changes in smoking and vaping trends since the pandemic started, “which seems to have increased the risk of smoking and vaping use.”
Data from the 2022 National Youth Tobacco survey found that although the rate of middle school and high school students who begin to use e-cigarettes has steadily decreased during the past two decades, those who vape report using the devices more frequently.
Subsequent use of cigarettes is also only one measure of risk from vapes.
“The goal isn’t just about cigarettes,” said Dr. Jenssen, who was not affiliated with the new study. “The goal is about helping children live tobacco- and nicotine-free lives, and there seems to be an increasing intensity of use, which is causing its own health risks.”
The current study findings do not change how clinicians should counsel their patients, and they should continue to advise teens to abstain from vaping, he added.
Dr. Sun said it’s common for youth to experiment with multiple tobacco products.
“Clinicians should continue to monitor youth tobacco-use behaviors but with their concern being focused on youthful patients who sustain smoking instead of just trying cigarettes,” she said.
Some of the study authors received support from the National Cancer Institute of the National Institutes of Health and the U.S. Food and Drug Administration’s Center for Tobacco Products.
A version of this article first appeared on Medscape.com.
Frustration over iPLEDGE evident at FDA meeting
During 2 days of after the chaotic rollout of the new REMS platform at the end of 2021.
On March 29, at the end of the FDA’s joint meeting of two advisory committees that addressed ways to improve the iPLEDGE program, most panelists voted to change the 19-day lockout period for patients who can become pregnant, and the requirement that every month, providers must document counseling of those who cannot get pregnant and are taking the drug for acne.
However, there was no consensus on whether there should be a lockout at all or for how long, and what an appropriate interval for counseling those who cannot get pregnant would be, if not monthly. Those voting on the questions repeatedly cited a lack of data to make well-informed decisions.
The meeting of the two panels, the FDA’s Drug Safety and Risk Management Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee, was held March 28-29, to discuss proposed changes to iPLEDGE requirements, to minimize the program’s burden on patients, prescribers, and pharmacies – while maintaining safe use of the highly teratogenic drug.
Lockout based on outdated reasoning
John S. Barbieri, MD, a dermatologist and epidemiologist, and director of the Advanced Acne Therapeutics Clinic at Brigham and Women’s Hospital in Boston, speaking as deputy chair of the American Academy of Dermatology Association (AADA) iPLEDGE work group, described the burden of getting the drug to patients. He was not on the panel, but spoke during the open public hearing.
“Compared to other acne medications, the time it takes to successfully go from prescribed (isotretinoin) to when the patient actually has it in their hands is 5- to 10-fold higher,” he said.
Among the barriers is the 19-day lockout period for people who can get pregnant and miss the 7-day window for picking up their prescriptions. They must then wait 19 days to get a pregnancy test to clear them for receiving the medication.
Gregory Wedin, PharmD, pharmacovigilance and risk management director of Upsher-Smith Laboratories, who spoke on behalf of the Isotretinoin Products Manufacturer Group (IPMG), which manages iPLEDGE, said, “The rationale for the 19-day wait is to ensure the next confirmatory pregnancy test is completed after the most fertile period of the menstrual cycle is passed.”
Many don’t have a monthly cycle
But Dr. Barbieri said that reasoning is outdated.
“The current program’s focus on the menstrual cycle is really an antiquated approach,” he said. “Many patients do not have a monthly cycle due to medical conditions like polycystic ovarian syndrome, or due to [certain kinds of] contraception.”
He added, “By removing this 19-day lockout and, really, the archaic timing around the menstrual cycle in general in this program, we can simplify the program, improve it, and better align it with the real-world biology of our patients.” He added that patients are often missing the 7-day window for picking up their prescriptions through no fault of their own. Speakers at the hearing also mentioned insurance hassles and ordering delays.
Communication with IPMG
Ilona Frieden, MD, professor of dermatology and pediatrics at the University of California, San Francisco, and outgoing chair of the AADA iPLEDGE work group, cited difficulty in working with IPMG on modifications as another barrier. She also spoke during the open public hearing.
“Despite many, many attempts to work with the IPMG, we are not aware of any organizational structure or key leaders to communicate with. Instead we have been given repeatedly a generic email address for trying to establish a working relationship and we believe this may explain the inaction of the IPMG since our proposals 4 years ago in 2019.”
Among those proposals, she said, were allowing telemedicine visits as part of the iPLEDGE REMS program and reducing counseling attestation to every 6 months instead of monthly for those who cannot become pregnant.
She pointed to the chaotic rollout of modifications to the iPLEDGE program on a new website at the end of 2021.
In 2021, she said, “despite 6 months of notification, no prescriber input was solicited before revamping the website. This lack of transparency and accountability has been a major hurdle in improving iPLEDGE.”
Dr. Barbieri called the rollout “a debacle” that could have been mitigated with communication with IPMG. “We warned about every issue that happened and talked about ways to mitigate it and were largely ignored,” he said.
“By including dermatologists and key stakeholders in these discussions, as we move forward with changes to improve this program, we can make sure that it’s patient-centered.”
IPMG did not address the specific complaints about the working relationship with the AADA workgroup at the meeting.
Monthly attestation for counseling patients who cannot get pregnant
Dr. Barbieri said the monthly requirement to counsel patients who cannot get pregnant and document that counseling unfairly burdens clinicians and patients. “We’re essentially asking patients to come in monthly just to tell them not to share their drugs [or] donate blood,” he said.
Ken Katz, MD, MSc, a dermatologist at Kaiser Permanente in San Francisco, was among the panel members voting not to continue the 19-day lockout.
“I think this places an unduly high burden physically and psychologically on our patients. It seems arbitrary,” he said. “Likely we will miss some pregnancies; we are missing some already. But the burden is not matched by the benefit.”
IPMG representative Dr. Wedin, said, “while we cannot support eliminating or extending the confirmation interval to a year, the [iPLEDGE] sponsors are agreeable [to] a 120-day confirmation interval.”
He said that while an extension to 120 days would reduce burden on prescribers, it comes with the risk in reducing oversight by a certified iPLEDGE prescriber and potentially increasing the risk for drug sharing.
“A patient may be more likely to share their drug with another person the further along with therapy they get as their condition improves,” Dr. Wedin said.
Home pregnancy testing
The advisory groups were also tasked with discussing whether home pregnancy tests, allowed during the COVID-19 public health emergency, should continue to be allowed. Most committee members and those in the public hearing who spoke on the issue agreed that home tests should continue in an effort to increase access and decrease burden.
During the pandemic, iPLEDGE rules have been relaxed from having a pregnancy test done only at a Clinical Laboratory Improvement Amendments–certified laboratory.
Lindsey Crist, PharmD, a risk management analyst at the FDA, who presented the FDA review committee’s analysis, said that the FDA’s review committee recommends ending the allowance of home tests, citing insufficient data on use and the discovery of instances of falsification of pregnancy tests.
“One study at an academic medical center reviewed the medical records of 89 patients who used home pregnancy tests while taking isotretinoin during the public health emergency. It found that 15.7% submitted falsified pregnancy test results,” Dr. Crist said.
Dr. Crist added, however, that the review committee recommends allowing the tests to be done in a provider’s office as an alternative.
Workaround to avoid falsification
Advisory committee member Brian P. Green, DO, associate professor of dermatology at Penn State University, Hershey, Pa., spoke in support of home pregnancy tests.
“What we have people do for telemedicine is take the stick, write their name, write the date on it, and send a picture of that the same day as their visit,” he said. “That way we have the pregnancy test the same day. Allowing this to continue to happen at home is important. Bringing people in is burdensome and costly.”
Emmy Graber, MD, a dermatologist who practices in Boston, and a director of the American Acne and Rosacea Society (AARS), relayed an example of the burden for a patient using isotretinoin who lives 1.5 hours away from the dermatology office. She is able to meet the requirements of iPLEDGE only through telehealth.
“Home pregnancy tests are highly sensitive, equal to the ones done in CLIA-certified labs, and highly accurate when interpreted by a dermatology provider,” said Dr. Graber, who spoke on behalf of the AARS during the open public hearing.
“Notably, CLIA [Clinical Laboratory Improvement Amendments] certification is not required by other REMS programs” for teratogenic drugs, she added.
Dr. Graber said it’s important to note that in the time the pandemic exceptions have been made for isotretinoin patients, “there has been no reported spike in pregnancy in the past three years.
“We do have some data to show that it is not imposing additional harms,” she said.
Suggestions for improvement
At the end of the hearing, advisory committee members were asked to propose improvements to the iPLEDGE REMS program.
Dr. Green advocated for the addition of an iPLEDGE mobile app.
“Most people go to their phones rather than their computers, particularly teenagers and younger people,” he noted.
Advisory committee member Megha M. Tollefson, MD, professor of dermatology and pediatric and adolescent medicine at Mayo Clinic in Rochester, Minn., echoed the need for an iPLEDGE app.
The young patients getting isotretinoin “don’t respond to email, they don’t necessarily go onto web pages. If we’re going to be as effective as possible, it’s going to have to be through an app-based system.”
Dr. Tollefson said she would like to see patient counseling standardized through the app. “I think there’s a lot of variability in what counseling is given when it’s left to the individual prescriber or practice,” she said.
Exceptions for long-acting contraceptives?
Advisory committee member Abbey B. Berenson, MD, PhD, professor of obstetrics and gynecology at University of Texas Medical Branch in Galveston, said that patients taking long-acting reversible contraceptives (LARCs) may need to be considered differently when deciding the intervals for attestation or whether to have a lockout period.
“LARC methods’ rate of failure is extremely low,” she said. “While it is true, as it has been pointed out, that all methods can fail, when they’re over 99% effective, I think that we can treat those methods differently than we treat methods such as birth control pills or abstinence that fail far more often. That is one way we could minimize burden on the providers and the patients.”
She also suggested using members of the health care team other than physicians to complete counseling, such as a nurse or pharmacist.
Prescriptions for emergency contraception
Advisory committee member Sascha Dublin, MD, PhD, senior scientific investigator for Kaiser Permanente Washington Health Research Institute in Seattle, said most patients taking the drug who can get pregnant should get a prescription for emergency contraception at the time of the first isotretinoin prescription.
“They don’t have to buy it, but to make it available at the very beginning sets the expectation that it would be good to have in your medicine cabinet, particularly if the [contraception] choice is abstinence or birth control pills.”
Dr. Dublin also called for better transparency surrounding the role of IPMG.
She said IPMG should be expected to collect data in a way that allows examination of health disparities, including by race and ethnicity and insurance status. Dr. Dublin added that she was concerned about the poor communication between dermatological societies and IPMG.
“The FDA should really require that IPMG hold periodic, regularly scheduled stakeholder forums,” she said. “There has to be a mechanism in place for IPMG to listen to those concerns in real time and respond.”
The advisory committees’ recommendations to the FDA are nonbinding, but the FDA generally follows the recommendations of advisory panels.
During 2 days of after the chaotic rollout of the new REMS platform at the end of 2021.
On March 29, at the end of the FDA’s joint meeting of two advisory committees that addressed ways to improve the iPLEDGE program, most panelists voted to change the 19-day lockout period for patients who can become pregnant, and the requirement that every month, providers must document counseling of those who cannot get pregnant and are taking the drug for acne.
However, there was no consensus on whether there should be a lockout at all or for how long, and what an appropriate interval for counseling those who cannot get pregnant would be, if not monthly. Those voting on the questions repeatedly cited a lack of data to make well-informed decisions.
The meeting of the two panels, the FDA’s Drug Safety and Risk Management Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee, was held March 28-29, to discuss proposed changes to iPLEDGE requirements, to minimize the program’s burden on patients, prescribers, and pharmacies – while maintaining safe use of the highly teratogenic drug.
Lockout based on outdated reasoning
John S. Barbieri, MD, a dermatologist and epidemiologist, and director of the Advanced Acne Therapeutics Clinic at Brigham and Women’s Hospital in Boston, speaking as deputy chair of the American Academy of Dermatology Association (AADA) iPLEDGE work group, described the burden of getting the drug to patients. He was not on the panel, but spoke during the open public hearing.
“Compared to other acne medications, the time it takes to successfully go from prescribed (isotretinoin) to when the patient actually has it in their hands is 5- to 10-fold higher,” he said.
Among the barriers is the 19-day lockout period for people who can get pregnant and miss the 7-day window for picking up their prescriptions. They must then wait 19 days to get a pregnancy test to clear them for receiving the medication.
Gregory Wedin, PharmD, pharmacovigilance and risk management director of Upsher-Smith Laboratories, who spoke on behalf of the Isotretinoin Products Manufacturer Group (IPMG), which manages iPLEDGE, said, “The rationale for the 19-day wait is to ensure the next confirmatory pregnancy test is completed after the most fertile period of the menstrual cycle is passed.”
Many don’t have a monthly cycle
But Dr. Barbieri said that reasoning is outdated.
“The current program’s focus on the menstrual cycle is really an antiquated approach,” he said. “Many patients do not have a monthly cycle due to medical conditions like polycystic ovarian syndrome, or due to [certain kinds of] contraception.”
He added, “By removing this 19-day lockout and, really, the archaic timing around the menstrual cycle in general in this program, we can simplify the program, improve it, and better align it with the real-world biology of our patients.” He added that patients are often missing the 7-day window for picking up their prescriptions through no fault of their own. Speakers at the hearing also mentioned insurance hassles and ordering delays.
Communication with IPMG
Ilona Frieden, MD, professor of dermatology and pediatrics at the University of California, San Francisco, and outgoing chair of the AADA iPLEDGE work group, cited difficulty in working with IPMG on modifications as another barrier. She also spoke during the open public hearing.
“Despite many, many attempts to work with the IPMG, we are not aware of any organizational structure or key leaders to communicate with. Instead we have been given repeatedly a generic email address for trying to establish a working relationship and we believe this may explain the inaction of the IPMG since our proposals 4 years ago in 2019.”
Among those proposals, she said, were allowing telemedicine visits as part of the iPLEDGE REMS program and reducing counseling attestation to every 6 months instead of monthly for those who cannot become pregnant.
She pointed to the chaotic rollout of modifications to the iPLEDGE program on a new website at the end of 2021.
In 2021, she said, “despite 6 months of notification, no prescriber input was solicited before revamping the website. This lack of transparency and accountability has been a major hurdle in improving iPLEDGE.”
Dr. Barbieri called the rollout “a debacle” that could have been mitigated with communication with IPMG. “We warned about every issue that happened and talked about ways to mitigate it and were largely ignored,” he said.
“By including dermatologists and key stakeholders in these discussions, as we move forward with changes to improve this program, we can make sure that it’s patient-centered.”
IPMG did not address the specific complaints about the working relationship with the AADA workgroup at the meeting.
Monthly attestation for counseling patients who cannot get pregnant
Dr. Barbieri said the monthly requirement to counsel patients who cannot get pregnant and document that counseling unfairly burdens clinicians and patients. “We’re essentially asking patients to come in monthly just to tell them not to share their drugs [or] donate blood,” he said.
Ken Katz, MD, MSc, a dermatologist at Kaiser Permanente in San Francisco, was among the panel members voting not to continue the 19-day lockout.
“I think this places an unduly high burden physically and psychologically on our patients. It seems arbitrary,” he said. “Likely we will miss some pregnancies; we are missing some already. But the burden is not matched by the benefit.”
IPMG representative Dr. Wedin, said, “while we cannot support eliminating or extending the confirmation interval to a year, the [iPLEDGE] sponsors are agreeable [to] a 120-day confirmation interval.”
He said that while an extension to 120 days would reduce burden on prescribers, it comes with the risk in reducing oversight by a certified iPLEDGE prescriber and potentially increasing the risk for drug sharing.
“A patient may be more likely to share their drug with another person the further along with therapy they get as their condition improves,” Dr. Wedin said.
Home pregnancy testing
The advisory groups were also tasked with discussing whether home pregnancy tests, allowed during the COVID-19 public health emergency, should continue to be allowed. Most committee members and those in the public hearing who spoke on the issue agreed that home tests should continue in an effort to increase access and decrease burden.
During the pandemic, iPLEDGE rules have been relaxed from having a pregnancy test done only at a Clinical Laboratory Improvement Amendments–certified laboratory.
Lindsey Crist, PharmD, a risk management analyst at the FDA, who presented the FDA review committee’s analysis, said that the FDA’s review committee recommends ending the allowance of home tests, citing insufficient data on use and the discovery of instances of falsification of pregnancy tests.
“One study at an academic medical center reviewed the medical records of 89 patients who used home pregnancy tests while taking isotretinoin during the public health emergency. It found that 15.7% submitted falsified pregnancy test results,” Dr. Crist said.
Dr. Crist added, however, that the review committee recommends allowing the tests to be done in a provider’s office as an alternative.
Workaround to avoid falsification
Advisory committee member Brian P. Green, DO, associate professor of dermatology at Penn State University, Hershey, Pa., spoke in support of home pregnancy tests.
“What we have people do for telemedicine is take the stick, write their name, write the date on it, and send a picture of that the same day as their visit,” he said. “That way we have the pregnancy test the same day. Allowing this to continue to happen at home is important. Bringing people in is burdensome and costly.”
Emmy Graber, MD, a dermatologist who practices in Boston, and a director of the American Acne and Rosacea Society (AARS), relayed an example of the burden for a patient using isotretinoin who lives 1.5 hours away from the dermatology office. She is able to meet the requirements of iPLEDGE only through telehealth.
“Home pregnancy tests are highly sensitive, equal to the ones done in CLIA-certified labs, and highly accurate when interpreted by a dermatology provider,” said Dr. Graber, who spoke on behalf of the AARS during the open public hearing.
“Notably, CLIA [Clinical Laboratory Improvement Amendments] certification is not required by other REMS programs” for teratogenic drugs, she added.
Dr. Graber said it’s important to note that in the time the pandemic exceptions have been made for isotretinoin patients, “there has been no reported spike in pregnancy in the past three years.
“We do have some data to show that it is not imposing additional harms,” she said.
Suggestions for improvement
At the end of the hearing, advisory committee members were asked to propose improvements to the iPLEDGE REMS program.
Dr. Green advocated for the addition of an iPLEDGE mobile app.
“Most people go to their phones rather than their computers, particularly teenagers and younger people,” he noted.
Advisory committee member Megha M. Tollefson, MD, professor of dermatology and pediatric and adolescent medicine at Mayo Clinic in Rochester, Minn., echoed the need for an iPLEDGE app.
The young patients getting isotretinoin “don’t respond to email, they don’t necessarily go onto web pages. If we’re going to be as effective as possible, it’s going to have to be through an app-based system.”
Dr. Tollefson said she would like to see patient counseling standardized through the app. “I think there’s a lot of variability in what counseling is given when it’s left to the individual prescriber or practice,” she said.
Exceptions for long-acting contraceptives?
Advisory committee member Abbey B. Berenson, MD, PhD, professor of obstetrics and gynecology at University of Texas Medical Branch in Galveston, said that patients taking long-acting reversible contraceptives (LARCs) may need to be considered differently when deciding the intervals for attestation or whether to have a lockout period.
“LARC methods’ rate of failure is extremely low,” she said. “While it is true, as it has been pointed out, that all methods can fail, when they’re over 99% effective, I think that we can treat those methods differently than we treat methods such as birth control pills or abstinence that fail far more often. That is one way we could minimize burden on the providers and the patients.”
She also suggested using members of the health care team other than physicians to complete counseling, such as a nurse or pharmacist.
Prescriptions for emergency contraception
Advisory committee member Sascha Dublin, MD, PhD, senior scientific investigator for Kaiser Permanente Washington Health Research Institute in Seattle, said most patients taking the drug who can get pregnant should get a prescription for emergency contraception at the time of the first isotretinoin prescription.
“They don’t have to buy it, but to make it available at the very beginning sets the expectation that it would be good to have in your medicine cabinet, particularly if the [contraception] choice is abstinence or birth control pills.”
Dr. Dublin also called for better transparency surrounding the role of IPMG.
She said IPMG should be expected to collect data in a way that allows examination of health disparities, including by race and ethnicity and insurance status. Dr. Dublin added that she was concerned about the poor communication between dermatological societies and IPMG.
“The FDA should really require that IPMG hold periodic, regularly scheduled stakeholder forums,” she said. “There has to be a mechanism in place for IPMG to listen to those concerns in real time and respond.”
The advisory committees’ recommendations to the FDA are nonbinding, but the FDA generally follows the recommendations of advisory panels.
During 2 days of after the chaotic rollout of the new REMS platform at the end of 2021.
On March 29, at the end of the FDA’s joint meeting of two advisory committees that addressed ways to improve the iPLEDGE program, most panelists voted to change the 19-day lockout period for patients who can become pregnant, and the requirement that every month, providers must document counseling of those who cannot get pregnant and are taking the drug for acne.
However, there was no consensus on whether there should be a lockout at all or for how long, and what an appropriate interval for counseling those who cannot get pregnant would be, if not monthly. Those voting on the questions repeatedly cited a lack of data to make well-informed decisions.
The meeting of the two panels, the FDA’s Drug Safety and Risk Management Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee, was held March 28-29, to discuss proposed changes to iPLEDGE requirements, to minimize the program’s burden on patients, prescribers, and pharmacies – while maintaining safe use of the highly teratogenic drug.
Lockout based on outdated reasoning
John S. Barbieri, MD, a dermatologist and epidemiologist, and director of the Advanced Acne Therapeutics Clinic at Brigham and Women’s Hospital in Boston, speaking as deputy chair of the American Academy of Dermatology Association (AADA) iPLEDGE work group, described the burden of getting the drug to patients. He was not on the panel, but spoke during the open public hearing.
“Compared to other acne medications, the time it takes to successfully go from prescribed (isotretinoin) to when the patient actually has it in their hands is 5- to 10-fold higher,” he said.
Among the barriers is the 19-day lockout period for people who can get pregnant and miss the 7-day window for picking up their prescriptions. They must then wait 19 days to get a pregnancy test to clear them for receiving the medication.
Gregory Wedin, PharmD, pharmacovigilance and risk management director of Upsher-Smith Laboratories, who spoke on behalf of the Isotretinoin Products Manufacturer Group (IPMG), which manages iPLEDGE, said, “The rationale for the 19-day wait is to ensure the next confirmatory pregnancy test is completed after the most fertile period of the menstrual cycle is passed.”
Many don’t have a monthly cycle
But Dr. Barbieri said that reasoning is outdated.
“The current program’s focus on the menstrual cycle is really an antiquated approach,” he said. “Many patients do not have a monthly cycle due to medical conditions like polycystic ovarian syndrome, or due to [certain kinds of] contraception.”
He added, “By removing this 19-day lockout and, really, the archaic timing around the menstrual cycle in general in this program, we can simplify the program, improve it, and better align it with the real-world biology of our patients.” He added that patients are often missing the 7-day window for picking up their prescriptions through no fault of their own. Speakers at the hearing also mentioned insurance hassles and ordering delays.
Communication with IPMG
Ilona Frieden, MD, professor of dermatology and pediatrics at the University of California, San Francisco, and outgoing chair of the AADA iPLEDGE work group, cited difficulty in working with IPMG on modifications as another barrier. She also spoke during the open public hearing.
“Despite many, many attempts to work with the IPMG, we are not aware of any organizational structure or key leaders to communicate with. Instead we have been given repeatedly a generic email address for trying to establish a working relationship and we believe this may explain the inaction of the IPMG since our proposals 4 years ago in 2019.”
Among those proposals, she said, were allowing telemedicine visits as part of the iPLEDGE REMS program and reducing counseling attestation to every 6 months instead of monthly for those who cannot become pregnant.
She pointed to the chaotic rollout of modifications to the iPLEDGE program on a new website at the end of 2021.
In 2021, she said, “despite 6 months of notification, no prescriber input was solicited before revamping the website. This lack of transparency and accountability has been a major hurdle in improving iPLEDGE.”
Dr. Barbieri called the rollout “a debacle” that could have been mitigated with communication with IPMG. “We warned about every issue that happened and talked about ways to mitigate it and were largely ignored,” he said.
“By including dermatologists and key stakeholders in these discussions, as we move forward with changes to improve this program, we can make sure that it’s patient-centered.”
IPMG did not address the specific complaints about the working relationship with the AADA workgroup at the meeting.
Monthly attestation for counseling patients who cannot get pregnant
Dr. Barbieri said the monthly requirement to counsel patients who cannot get pregnant and document that counseling unfairly burdens clinicians and patients. “We’re essentially asking patients to come in monthly just to tell them not to share their drugs [or] donate blood,” he said.
Ken Katz, MD, MSc, a dermatologist at Kaiser Permanente in San Francisco, was among the panel members voting not to continue the 19-day lockout.
“I think this places an unduly high burden physically and psychologically on our patients. It seems arbitrary,” he said. “Likely we will miss some pregnancies; we are missing some already. But the burden is not matched by the benefit.”
IPMG representative Dr. Wedin, said, “while we cannot support eliminating or extending the confirmation interval to a year, the [iPLEDGE] sponsors are agreeable [to] a 120-day confirmation interval.”
He said that while an extension to 120 days would reduce burden on prescribers, it comes with the risk in reducing oversight by a certified iPLEDGE prescriber and potentially increasing the risk for drug sharing.
“A patient may be more likely to share their drug with another person the further along with therapy they get as their condition improves,” Dr. Wedin said.
Home pregnancy testing
The advisory groups were also tasked with discussing whether home pregnancy tests, allowed during the COVID-19 public health emergency, should continue to be allowed. Most committee members and those in the public hearing who spoke on the issue agreed that home tests should continue in an effort to increase access and decrease burden.
During the pandemic, iPLEDGE rules have been relaxed from having a pregnancy test done only at a Clinical Laboratory Improvement Amendments–certified laboratory.
Lindsey Crist, PharmD, a risk management analyst at the FDA, who presented the FDA review committee’s analysis, said that the FDA’s review committee recommends ending the allowance of home tests, citing insufficient data on use and the discovery of instances of falsification of pregnancy tests.
“One study at an academic medical center reviewed the medical records of 89 patients who used home pregnancy tests while taking isotretinoin during the public health emergency. It found that 15.7% submitted falsified pregnancy test results,” Dr. Crist said.
Dr. Crist added, however, that the review committee recommends allowing the tests to be done in a provider’s office as an alternative.
Workaround to avoid falsification
Advisory committee member Brian P. Green, DO, associate professor of dermatology at Penn State University, Hershey, Pa., spoke in support of home pregnancy tests.
“What we have people do for telemedicine is take the stick, write their name, write the date on it, and send a picture of that the same day as their visit,” he said. “That way we have the pregnancy test the same day. Allowing this to continue to happen at home is important. Bringing people in is burdensome and costly.”
Emmy Graber, MD, a dermatologist who practices in Boston, and a director of the American Acne and Rosacea Society (AARS), relayed an example of the burden for a patient using isotretinoin who lives 1.5 hours away from the dermatology office. She is able to meet the requirements of iPLEDGE only through telehealth.
“Home pregnancy tests are highly sensitive, equal to the ones done in CLIA-certified labs, and highly accurate when interpreted by a dermatology provider,” said Dr. Graber, who spoke on behalf of the AARS during the open public hearing.
“Notably, CLIA [Clinical Laboratory Improvement Amendments] certification is not required by other REMS programs” for teratogenic drugs, she added.
Dr. Graber said it’s important to note that in the time the pandemic exceptions have been made for isotretinoin patients, “there has been no reported spike in pregnancy in the past three years.
“We do have some data to show that it is not imposing additional harms,” she said.
Suggestions for improvement
At the end of the hearing, advisory committee members were asked to propose improvements to the iPLEDGE REMS program.
Dr. Green advocated for the addition of an iPLEDGE mobile app.
“Most people go to their phones rather than their computers, particularly teenagers and younger people,” he noted.
Advisory committee member Megha M. Tollefson, MD, professor of dermatology and pediatric and adolescent medicine at Mayo Clinic in Rochester, Minn., echoed the need for an iPLEDGE app.
The young patients getting isotretinoin “don’t respond to email, they don’t necessarily go onto web pages. If we’re going to be as effective as possible, it’s going to have to be through an app-based system.”
Dr. Tollefson said she would like to see patient counseling standardized through the app. “I think there’s a lot of variability in what counseling is given when it’s left to the individual prescriber or practice,” she said.
Exceptions for long-acting contraceptives?
Advisory committee member Abbey B. Berenson, MD, PhD, professor of obstetrics and gynecology at University of Texas Medical Branch in Galveston, said that patients taking long-acting reversible contraceptives (LARCs) may need to be considered differently when deciding the intervals for attestation or whether to have a lockout period.
“LARC methods’ rate of failure is extremely low,” she said. “While it is true, as it has been pointed out, that all methods can fail, when they’re over 99% effective, I think that we can treat those methods differently than we treat methods such as birth control pills or abstinence that fail far more often. That is one way we could minimize burden on the providers and the patients.”
She also suggested using members of the health care team other than physicians to complete counseling, such as a nurse or pharmacist.
Prescriptions for emergency contraception
Advisory committee member Sascha Dublin, MD, PhD, senior scientific investigator for Kaiser Permanente Washington Health Research Institute in Seattle, said most patients taking the drug who can get pregnant should get a prescription for emergency contraception at the time of the first isotretinoin prescription.
“They don’t have to buy it, but to make it available at the very beginning sets the expectation that it would be good to have in your medicine cabinet, particularly if the [contraception] choice is abstinence or birth control pills.”
Dr. Dublin also called for better transparency surrounding the role of IPMG.
She said IPMG should be expected to collect data in a way that allows examination of health disparities, including by race and ethnicity and insurance status. Dr. Dublin added that she was concerned about the poor communication between dermatological societies and IPMG.
“The FDA should really require that IPMG hold periodic, regularly scheduled stakeholder forums,” she said. “There has to be a mechanism in place for IPMG to listen to those concerns in real time and respond.”
The advisory committees’ recommendations to the FDA are nonbinding, but the FDA generally follows the recommendations of advisory panels.
FDA panels vote to modify isotretinoin iPLEDGE REMS
At a joint meeting of a drug for severe, nodular acne that is highly teratogenic.
The first vote was on whether to continue the 19-day lockout period for patients who can become pregnant and do not pick up their first prescription of isotretinoin within the 7-day prescription window. Those patients currently have to wait 19 days to get their second pregnancy test and receive the medication.
Most (17) of the 22 voting members voted not to continue the 19-day period; 4 voted to keep it; and 1 abstained. But there was no consensus on when the second pregnancy test should occur if the 19-day lockout is changed.
Ken Katz, MD, MSc, a dermatologist at Kaiser Permanente in San Francisco, was among those voting not to continue the 19-day lockout.
“I think this places an unduly high burden physically and psychologically on our patients. It seems arbitrary,” he said. “Likely we will miss some pregnancies; we are missing some already. But the burden is not matched by the benefit.”
The second question concerned patients who cannot become pregnant, and it asked when REMS should require that the prescriber document counseling the patient in the iPLEDGE system. The current requirement is monthly.
Listed options and the number of votes for each were:
- Only with the first prescription as part of patient enrollment (10)
- Monthly (1)
- Every 120 days (6)
- Some other frequency (5)
For this question too, while the members largely agreed the current monthly requirement is too burdensome, there was little agreement on what the most appropriate interval should be.
Lack of data
On both questions, several advisory committee members cited a lack of data on which they could base their decision.
On the documentation question, Megha Tollefson, MD, professor of dermatology at the Mayo Clinic, Rochester, Minn., said she voted for the fourth option (some other frequency) with the thought of yearly attestation.
“As a part of this, providers have to provide monthly counseling,” Dr. Tollefson said. “This is just a documentation requirement in the iPLEDGE system. I think most prescribers do document their monthly counseling in their own medical records. I would say it would be okay not to redocument that in iPLEDGE.”
The two votes came at the end of the second day of a joint meeting of the FDA’s Drug Safety and Risk Management Advisory Committee and Dermatologic and Ophthalmic Drugs Advisory Committee in which experts addressed ways to improve the iPLEDGE REMS for isotretinoin. A transition to a new platform for the iPLEDGE program caused chaos after its rollout at the end of 2021, resulting in extensive delays and denial of prescriptions.
The committees sought to balance reducing burden with maintaining safety and preventing fetal exposures to isotretinoin.
They were also tasked with discussing other REMS requirements without taking a vote on each topic.
Among those topics was whether home pregnancy tests, allowed during the COVID-19 public health emergency, should continue to be allowed. Most who spoke to the issue agreed that home tests should continue in an effort to increase access and decrease burden. Members suggested safeguards against falsified results that have been documented, including assigning names and barcodes to the test results and uploading the verification to the iPLEDGE website.
The advisory committees also discussed recommendations to encourage more participation in the iPLEDGE Pregnancy Registry.
The advisory committees’ recommendations to the FDA are nonbinding, but the FDA generally follows the recommendations of advisory panels.
A version of this article first appeared on Medscape.com.
At a joint meeting of a drug for severe, nodular acne that is highly teratogenic.
The first vote was on whether to continue the 19-day lockout period for patients who can become pregnant and do not pick up their first prescription of isotretinoin within the 7-day prescription window. Those patients currently have to wait 19 days to get their second pregnancy test and receive the medication.
Most (17) of the 22 voting members voted not to continue the 19-day period; 4 voted to keep it; and 1 abstained. But there was no consensus on when the second pregnancy test should occur if the 19-day lockout is changed.
Ken Katz, MD, MSc, a dermatologist at Kaiser Permanente in San Francisco, was among those voting not to continue the 19-day lockout.
“I think this places an unduly high burden physically and psychologically on our patients. It seems arbitrary,” he said. “Likely we will miss some pregnancies; we are missing some already. But the burden is not matched by the benefit.”
The second question concerned patients who cannot become pregnant, and it asked when REMS should require that the prescriber document counseling the patient in the iPLEDGE system. The current requirement is monthly.
Listed options and the number of votes for each were:
- Only with the first prescription as part of patient enrollment (10)
- Monthly (1)
- Every 120 days (6)
- Some other frequency (5)
For this question too, while the members largely agreed the current monthly requirement is too burdensome, there was little agreement on what the most appropriate interval should be.
Lack of data
On both questions, several advisory committee members cited a lack of data on which they could base their decision.
On the documentation question, Megha Tollefson, MD, professor of dermatology at the Mayo Clinic, Rochester, Minn., said she voted for the fourth option (some other frequency) with the thought of yearly attestation.
“As a part of this, providers have to provide monthly counseling,” Dr. Tollefson said. “This is just a documentation requirement in the iPLEDGE system. I think most prescribers do document their monthly counseling in their own medical records. I would say it would be okay not to redocument that in iPLEDGE.”
The two votes came at the end of the second day of a joint meeting of the FDA’s Drug Safety and Risk Management Advisory Committee and Dermatologic and Ophthalmic Drugs Advisory Committee in which experts addressed ways to improve the iPLEDGE REMS for isotretinoin. A transition to a new platform for the iPLEDGE program caused chaos after its rollout at the end of 2021, resulting in extensive delays and denial of prescriptions.
The committees sought to balance reducing burden with maintaining safety and preventing fetal exposures to isotretinoin.
They were also tasked with discussing other REMS requirements without taking a vote on each topic.
Among those topics was whether home pregnancy tests, allowed during the COVID-19 public health emergency, should continue to be allowed. Most who spoke to the issue agreed that home tests should continue in an effort to increase access and decrease burden. Members suggested safeguards against falsified results that have been documented, including assigning names and barcodes to the test results and uploading the verification to the iPLEDGE website.
The advisory committees also discussed recommendations to encourage more participation in the iPLEDGE Pregnancy Registry.
The advisory committees’ recommendations to the FDA are nonbinding, but the FDA generally follows the recommendations of advisory panels.
A version of this article first appeared on Medscape.com.
At a joint meeting of a drug for severe, nodular acne that is highly teratogenic.
The first vote was on whether to continue the 19-day lockout period for patients who can become pregnant and do not pick up their first prescription of isotretinoin within the 7-day prescription window. Those patients currently have to wait 19 days to get their second pregnancy test and receive the medication.
Most (17) of the 22 voting members voted not to continue the 19-day period; 4 voted to keep it; and 1 abstained. But there was no consensus on when the second pregnancy test should occur if the 19-day lockout is changed.
Ken Katz, MD, MSc, a dermatologist at Kaiser Permanente in San Francisco, was among those voting not to continue the 19-day lockout.
“I think this places an unduly high burden physically and psychologically on our patients. It seems arbitrary,” he said. “Likely we will miss some pregnancies; we are missing some already. But the burden is not matched by the benefit.”
The second question concerned patients who cannot become pregnant, and it asked when REMS should require that the prescriber document counseling the patient in the iPLEDGE system. The current requirement is monthly.
Listed options and the number of votes for each were:
- Only with the first prescription as part of patient enrollment (10)
- Monthly (1)
- Every 120 days (6)
- Some other frequency (5)
For this question too, while the members largely agreed the current monthly requirement is too burdensome, there was little agreement on what the most appropriate interval should be.
Lack of data
On both questions, several advisory committee members cited a lack of data on which they could base their decision.
On the documentation question, Megha Tollefson, MD, professor of dermatology at the Mayo Clinic, Rochester, Minn., said she voted for the fourth option (some other frequency) with the thought of yearly attestation.
“As a part of this, providers have to provide monthly counseling,” Dr. Tollefson said. “This is just a documentation requirement in the iPLEDGE system. I think most prescribers do document their monthly counseling in their own medical records. I would say it would be okay not to redocument that in iPLEDGE.”
The two votes came at the end of the second day of a joint meeting of the FDA’s Drug Safety and Risk Management Advisory Committee and Dermatologic and Ophthalmic Drugs Advisory Committee in which experts addressed ways to improve the iPLEDGE REMS for isotretinoin. A transition to a new platform for the iPLEDGE program caused chaos after its rollout at the end of 2021, resulting in extensive delays and denial of prescriptions.
The committees sought to balance reducing burden with maintaining safety and preventing fetal exposures to isotretinoin.
They were also tasked with discussing other REMS requirements without taking a vote on each topic.
Among those topics was whether home pregnancy tests, allowed during the COVID-19 public health emergency, should continue to be allowed. Most who spoke to the issue agreed that home tests should continue in an effort to increase access and decrease burden. Members suggested safeguards against falsified results that have been documented, including assigning names and barcodes to the test results and uploading the verification to the iPLEDGE website.
The advisory committees also discussed recommendations to encourage more participation in the iPLEDGE Pregnancy Registry.
The advisory committees’ recommendations to the FDA are nonbinding, but the FDA generally follows the recommendations of advisory panels.
A version of this article first appeared on Medscape.com.
FDA Advisory panels consider easing isotretinoin requirements
for patients, pharmacies, and prescribers.
Isotretinoin, previously called Accutane, is marketed as Absorica, Absorica LD, Claravis, Amnesteem, Myorisan, and Zenatane.
In a joint meeting of the FDA’s Drug Safety and Risk Management Advisory Committee and Dermatologic and Ophthalmic Drugs Advisory Committee, experts addressed ways to improve the modified iPLEDGE Risk Evaluation and Mitigation Strategy (iPLEDGE REMS) for isotretinoin that caused chaos after its rollout at the end of 2021.
In January 2022, problems were multiplying with the program for clinicians, pharmacists, and patients, causing extensive delays and prescription denials. In response, the FDA said it would continue to meet with the Isotretinoin Products Manufacturers Group (IPMG) to resolve problems.
March 28 was the first day of a 2-day meeting addressing what can be done to reduce burden with the iPLEDGE REMS while maintaining safety and preventing fetal exposure to the drug.
Key areas of concern
The meeting focused on several key areas.
The 19-day lockout period
The lockout is a current restriction for patients who can become pregnant and do not pick up their first prescription of isotretinoin within the specified 7-day prescription window. Currently, those who miss the window must wait 19 days from the date of the first pregnancy test to take an additional pregnancy test to be eligible to receive the drug.
Lindsey Crist, PharmD, a risk management analyst for the FDA, who presented the FDA review committee’s analysis, acknowledged that the lockout period causes delays in treatment and adds frustration and costs.
She said it’s important to remember that the lockout applies only to the first prescription. “It’s intended as an additional layer of screening to detect pregnancy,” she said.
“At least 12 pregnancies have been identified during the 19-day lockout from March 2017–September of 2022,” she noted.
The FDA is looking to the advisory committee to provide recommendations on whether the lockout period should be changed.
Home testing
During the pandemic, iPLEDGE rules have been relaxed from having a pregnancy test done only at a Clinical Laboratory Improvement Amendments–certified laboratory and home pregnancy tests have been allowed. The question now is whether home tests should continue to be allowed.
Ms. Crist said that the FDA’s review committee recommends ending the allowance of home tests, citing insufficient data on use and the discovery of instances of falsification of pregnancy tests.
“One study at an academic medical center reviewed the medical records of 89 patients who used home pregnancy tests while taking isotretinoin during the public health emergency. It found that 15.7% submitted falsified pregnancy test results,” she said.
Ms. Crist added, however, that the review committee recommends allowing the tests to be done in a provider’s office as an alternative.
Documenting counseling patients who cannot get pregnant
Currently, this documentation must be done monthly, primarily to counsel patients against drug sharing or giving blood. Proposed changes include extending the intervals for attestation or eliminating it to reduce burden on clinicians.
IPMG representative Gregory Wedin, PharmD, pharmacovigilance and risk management director for Upsher-Smith Laboratories, said, “while we cannot support eliminating or extending the confirmation interval to a year, the [iPLEDGE] sponsors are agreeable [to] a 120-day confirmation interval.”
He said that while extending to 120 days would reduce burden on prescribers, it comes with risk in reducing oversight by a certified iPLEDGE prescriber and potentially increasing the risk for drug sharing.
“A patient may be more likely to share their drug with another person the further along with therapy they get as their condition improves,” Mr. Wedin said.
On March 29, the panel will hear more recommendations for and against modifications to iPLEDGE REMS and will vote on select modifications at the end of the meeting.
A version of this article first appeared on Medscape.com.
for patients, pharmacies, and prescribers.
Isotretinoin, previously called Accutane, is marketed as Absorica, Absorica LD, Claravis, Amnesteem, Myorisan, and Zenatane.
In a joint meeting of the FDA’s Drug Safety and Risk Management Advisory Committee and Dermatologic and Ophthalmic Drugs Advisory Committee, experts addressed ways to improve the modified iPLEDGE Risk Evaluation and Mitigation Strategy (iPLEDGE REMS) for isotretinoin that caused chaos after its rollout at the end of 2021.
In January 2022, problems were multiplying with the program for clinicians, pharmacists, and patients, causing extensive delays and prescription denials. In response, the FDA said it would continue to meet with the Isotretinoin Products Manufacturers Group (IPMG) to resolve problems.
March 28 was the first day of a 2-day meeting addressing what can be done to reduce burden with the iPLEDGE REMS while maintaining safety and preventing fetal exposure to the drug.
Key areas of concern
The meeting focused on several key areas.
The 19-day lockout period
The lockout is a current restriction for patients who can become pregnant and do not pick up their first prescription of isotretinoin within the specified 7-day prescription window. Currently, those who miss the window must wait 19 days from the date of the first pregnancy test to take an additional pregnancy test to be eligible to receive the drug.
Lindsey Crist, PharmD, a risk management analyst for the FDA, who presented the FDA review committee’s analysis, acknowledged that the lockout period causes delays in treatment and adds frustration and costs.
She said it’s important to remember that the lockout applies only to the first prescription. “It’s intended as an additional layer of screening to detect pregnancy,” she said.
“At least 12 pregnancies have been identified during the 19-day lockout from March 2017–September of 2022,” she noted.
The FDA is looking to the advisory committee to provide recommendations on whether the lockout period should be changed.
Home testing
During the pandemic, iPLEDGE rules have been relaxed from having a pregnancy test done only at a Clinical Laboratory Improvement Amendments–certified laboratory and home pregnancy tests have been allowed. The question now is whether home tests should continue to be allowed.
Ms. Crist said that the FDA’s review committee recommends ending the allowance of home tests, citing insufficient data on use and the discovery of instances of falsification of pregnancy tests.
“One study at an academic medical center reviewed the medical records of 89 patients who used home pregnancy tests while taking isotretinoin during the public health emergency. It found that 15.7% submitted falsified pregnancy test results,” she said.
Ms. Crist added, however, that the review committee recommends allowing the tests to be done in a provider’s office as an alternative.
Documenting counseling patients who cannot get pregnant
Currently, this documentation must be done monthly, primarily to counsel patients against drug sharing or giving blood. Proposed changes include extending the intervals for attestation or eliminating it to reduce burden on clinicians.
IPMG representative Gregory Wedin, PharmD, pharmacovigilance and risk management director for Upsher-Smith Laboratories, said, “while we cannot support eliminating or extending the confirmation interval to a year, the [iPLEDGE] sponsors are agreeable [to] a 120-day confirmation interval.”
He said that while extending to 120 days would reduce burden on prescribers, it comes with risk in reducing oversight by a certified iPLEDGE prescriber and potentially increasing the risk for drug sharing.
“A patient may be more likely to share their drug with another person the further along with therapy they get as their condition improves,” Mr. Wedin said.
On March 29, the panel will hear more recommendations for and against modifications to iPLEDGE REMS and will vote on select modifications at the end of the meeting.
A version of this article first appeared on Medscape.com.
for patients, pharmacies, and prescribers.
Isotretinoin, previously called Accutane, is marketed as Absorica, Absorica LD, Claravis, Amnesteem, Myorisan, and Zenatane.
In a joint meeting of the FDA’s Drug Safety and Risk Management Advisory Committee and Dermatologic and Ophthalmic Drugs Advisory Committee, experts addressed ways to improve the modified iPLEDGE Risk Evaluation and Mitigation Strategy (iPLEDGE REMS) for isotretinoin that caused chaos after its rollout at the end of 2021.
In January 2022, problems were multiplying with the program for clinicians, pharmacists, and patients, causing extensive delays and prescription denials. In response, the FDA said it would continue to meet with the Isotretinoin Products Manufacturers Group (IPMG) to resolve problems.
March 28 was the first day of a 2-day meeting addressing what can be done to reduce burden with the iPLEDGE REMS while maintaining safety and preventing fetal exposure to the drug.
Key areas of concern
The meeting focused on several key areas.
The 19-day lockout period
The lockout is a current restriction for patients who can become pregnant and do not pick up their first prescription of isotretinoin within the specified 7-day prescription window. Currently, those who miss the window must wait 19 days from the date of the first pregnancy test to take an additional pregnancy test to be eligible to receive the drug.
Lindsey Crist, PharmD, a risk management analyst for the FDA, who presented the FDA review committee’s analysis, acknowledged that the lockout period causes delays in treatment and adds frustration and costs.
She said it’s important to remember that the lockout applies only to the first prescription. “It’s intended as an additional layer of screening to detect pregnancy,” she said.
“At least 12 pregnancies have been identified during the 19-day lockout from March 2017–September of 2022,” she noted.
The FDA is looking to the advisory committee to provide recommendations on whether the lockout period should be changed.
Home testing
During the pandemic, iPLEDGE rules have been relaxed from having a pregnancy test done only at a Clinical Laboratory Improvement Amendments–certified laboratory and home pregnancy tests have been allowed. The question now is whether home tests should continue to be allowed.
Ms. Crist said that the FDA’s review committee recommends ending the allowance of home tests, citing insufficient data on use and the discovery of instances of falsification of pregnancy tests.
“One study at an academic medical center reviewed the medical records of 89 patients who used home pregnancy tests while taking isotretinoin during the public health emergency. It found that 15.7% submitted falsified pregnancy test results,” she said.
Ms. Crist added, however, that the review committee recommends allowing the tests to be done in a provider’s office as an alternative.
Documenting counseling patients who cannot get pregnant
Currently, this documentation must be done monthly, primarily to counsel patients against drug sharing or giving blood. Proposed changes include extending the intervals for attestation or eliminating it to reduce burden on clinicians.
IPMG representative Gregory Wedin, PharmD, pharmacovigilance and risk management director for Upsher-Smith Laboratories, said, “while we cannot support eliminating or extending the confirmation interval to a year, the [iPLEDGE] sponsors are agreeable [to] a 120-day confirmation interval.”
He said that while extending to 120 days would reduce burden on prescribers, it comes with risk in reducing oversight by a certified iPLEDGE prescriber and potentially increasing the risk for drug sharing.
“A patient may be more likely to share their drug with another person the further along with therapy they get as their condition improves,” Mr. Wedin said.
On March 29, the panel will hear more recommendations for and against modifications to iPLEDGE REMS and will vote on select modifications at the end of the meeting.
A version of this article first appeared on Medscape.com.
JAK inhibitor ivarmacitinib shows efficacy for atopic dermatitis in a pivotal trial
NEW ORLEANS – The presented as a late-breaker at the annual meeting of the American Academy of Dermatology.
Two doses were studied in the placebo-controlled trial and both demonstrated “a favorable benefit-to-risk profile in patients with moderate to severe AD,” reported Yan Zhao, MD, a clinician and researcher in the department of dermatology, Peking University People’s Hospital, Beijing.
In the study, called QUARTZ3, 336 patients aged 12 and older at 51 sites in China and Canada were randomized to 4 mg once-daily ivarmacitinib, 8 mg once-daily QD ivarmacitinib, or placebo. The mean age of the population was 32 years and approximately one-third were female.
The mean duration of AD for participants was 10 years. The mean baseline Eczema Area and Severity Index (EASI) score was near 30. On the Investigator Global Assessment (IGA) tool, approximately 40% had a score of 4, which is the highest score on the scale and indicates severe disease. The remaining patients had an IGA score of 3.
The co-primary endpoints were change in IGA and EASI scores at 16 weeks, and both improved rapidly, showing statistical significance relative to placebo by 4 weeks with no plateauing effect at the end of the 16-week trial. By week 16, the proportion of patients with an EASI score of 75, signifying a 75% improvement, was 66%, 54%, and 22% for the 8-mg dose of ivarmacitinib, 4-mg dose of ivarmacitinib, and placebo groups (P < .001 versus placebo for both doses of active therapy), respectively.
The pattern of the IGA response was similar. By week 16, the proportion of patients achieving an IGA score of 0 (clear) or 1 (almost clear) was 42%, 36%, and 9% for the 8-mg dose of ivarmacitinib, 4-mg dose of ivarmacitinib, and placebo groups, respectively. The advantage of either dose over placebo was highly significant (P < .001) at 8, 12, and 16 weeks.
For the WI-NRS (Worst Itch – Numeric Rating Scale), the advantage of the 8-mg dose relative to placebo was significant (P < .001) at the 1-week evaluation. By 2 weeks, the 4-mg dose had gained the same degree of statistical significance relative to placebo. After week 4, when the maximum proportion of patients with a WI-NRS score ≤ 4 was reached (50%, 35%, and 10% in the 8-mg, 4-mg, and placebo groups), and the relative advantage of active treatment persisted until the end of the 16-week study.
Two scales were used to evaluate change in quality of life. On the DLQI (Dermatology Life Quality Index) and POEM (Patient-Oriented Eczema Measure), improvements were again rapid and sustained. By week 4, improvement with the 8-mg dose was about fourfold greater (P < .001) than improvement with placebo for DLQI and about sixfold greater (P < .001) for POEM. For the 4-mg dose, the relative differences were approximately threefold and fourfold greater, and both were significant (P <.001).
There was no further gain in these quality-of-life scales from week 4 to week 16, but the advantages relative to placebo were generally sustained, Dr. Zhao reported.
Ivarmacitinib was safe and well-tolerated, according to Dr. Zhao. The proportion of patients with a treatment-emergent adverse event that led to drug discontinuation was numerically higher (5.4%) in the placebo group than in the 8-mg (3.6%) or 4-mg group (2.7%). Rates of infection in the three groups were similar, and there were no major adverse cardiovascular events (MACE) or thromboembolism observed in any group.
Ivarmacitinib, which has about a 10-fold greater selectivity for JAK1 than JAK2 and a more than 70-fold greater selectivity for JAK1 than JAK3, is being tested for rheumatoid arthritis, inflammatory bowel disease, and alopecia areata in addition to AD, Dr. Zhao said. She also reported that an application for new drug approval has been submitted in China. Efforts to pursue regulatory approval elsewhere are anticipated.
Currently, there are three JAK inhibitors licensed for the treatment of AD in the United States. Upadacitinib (Rinvoq) and abrocitinib (Cibinqo) are also once-daily oral JAK1-selective inhibitors. Regulatory approval for AD by the Food and Drug Administration was granted to both in early 2022 and both now have an indication for moderate to severe disease in patients ages 12 years and older.
In September 2021, the first U.S. approval of a drug in this class for AD was granted for a topical formulation of ruxolitinib (Opzelura), which has selectivity for both JAK1 and JAK2. The indication is for mild to moderate AD in patients aged 12 years and older.
In the phase 3 clinical trial that led to approval of abrocitinib for AD, the comparator groups included placebo and active treatment with 300 mg dupilumab administered subcutaneously every other week. The higher of two doses of abrocitinib (100 mg) was numerically superior to dupilumab in terms of EASI 75 response at week 12 and was statistically superior for relief of itch at week 2.
Relative to the first-generation JAK inhibitor tofacitinib (Xeljanz), both of the approved oral JAK inhibitors for AD, abrocitinib and upadacitinib, have greater JAK1-selectivity. However, selectivity for all JAK inhibitors is relative rather than absolute, according to a recent review article on oral JAK inhibitors for AD. Efficacy and safety are likely determined by relative inhibition of each of the four JAK enzymes (JAK1, JAK2, JAK3, and TYK2). Although JAK1 appears to be an important target for AD treatment, the clinical significance of the degree of selectivity among oral JAK inhibitors is not yet clear.
In an interview, the senior author of that review article, Emma Guttman-Yassky, MD, PhD, emphasized this point. She said there is no evidence and no basis on which to speculate that any one drug in this class is better than another for AD. Dr. Guttman-Yassky is a professor and system chair of dermatology and immunology at the Icahn School of Medicine at Mount Sinai, New York.
“The efficacy [of ivarmacitinib] seems, in general, to be in line with other JAK inhibitors,” said Dr. Guttman-Yassky, who attended the late-breaker session during which these data were presented. Although she acknowledged that rapid control of pruritus is important clinically, she said the speed of itch relief as reported in the phase 3 ivarmacitinib trial does not distinguish it from other oral drugs in the class.
Shawn Kwatra, MD, director of the Johns Hopkins Itch Center, Johns Hopkins University, Baltimore, agreed.
“The rapid effects on itch of ivarmacitinib are consistent with those observed by the already approved JAK1-selective inhibitors abrocitinib and upadacitinib,” he said in an interview.
This suggests that head-to-head trials will be needed to draw any conclusions about the relative efficacy and safety of existing and emerging oral JAK inhibitors for AD.
Dr. Zhao has reported a financial relationship with Reistone Biopharma, which is developing ivarmacitinib and provided funding for the trial. Dr. Guttman-Yassky has reported financial relationships with more than 20 pharmaceutical companies, including companies that make JAK inhibitors. Dr. Kwatra has reported financial relationships with AbbVie, Aslan, Arcutis Biotherapeutics, Castle Biosciences, Celldex, Galderma, Genzada, Incyte, Johnson & Johnson, Leo Pharma, Novartis, Pfizer, Regeneron, and Sanofi.
A version of this article first appeared on Medscape.com.
NEW ORLEANS – The presented as a late-breaker at the annual meeting of the American Academy of Dermatology.
Two doses were studied in the placebo-controlled trial and both demonstrated “a favorable benefit-to-risk profile in patients with moderate to severe AD,” reported Yan Zhao, MD, a clinician and researcher in the department of dermatology, Peking University People’s Hospital, Beijing.
In the study, called QUARTZ3, 336 patients aged 12 and older at 51 sites in China and Canada were randomized to 4 mg once-daily ivarmacitinib, 8 mg once-daily QD ivarmacitinib, or placebo. The mean age of the population was 32 years and approximately one-third were female.
The mean duration of AD for participants was 10 years. The mean baseline Eczema Area and Severity Index (EASI) score was near 30. On the Investigator Global Assessment (IGA) tool, approximately 40% had a score of 4, which is the highest score on the scale and indicates severe disease. The remaining patients had an IGA score of 3.
The co-primary endpoints were change in IGA and EASI scores at 16 weeks, and both improved rapidly, showing statistical significance relative to placebo by 4 weeks with no plateauing effect at the end of the 16-week trial. By week 16, the proportion of patients with an EASI score of 75, signifying a 75% improvement, was 66%, 54%, and 22% for the 8-mg dose of ivarmacitinib, 4-mg dose of ivarmacitinib, and placebo groups (P < .001 versus placebo for both doses of active therapy), respectively.
The pattern of the IGA response was similar. By week 16, the proportion of patients achieving an IGA score of 0 (clear) or 1 (almost clear) was 42%, 36%, and 9% for the 8-mg dose of ivarmacitinib, 4-mg dose of ivarmacitinib, and placebo groups, respectively. The advantage of either dose over placebo was highly significant (P < .001) at 8, 12, and 16 weeks.
For the WI-NRS (Worst Itch – Numeric Rating Scale), the advantage of the 8-mg dose relative to placebo was significant (P < .001) at the 1-week evaluation. By 2 weeks, the 4-mg dose had gained the same degree of statistical significance relative to placebo. After week 4, when the maximum proportion of patients with a WI-NRS score ≤ 4 was reached (50%, 35%, and 10% in the 8-mg, 4-mg, and placebo groups), and the relative advantage of active treatment persisted until the end of the 16-week study.
Two scales were used to evaluate change in quality of life. On the DLQI (Dermatology Life Quality Index) and POEM (Patient-Oriented Eczema Measure), improvements were again rapid and sustained. By week 4, improvement with the 8-mg dose was about fourfold greater (P < .001) than improvement with placebo for DLQI and about sixfold greater (P < .001) for POEM. For the 4-mg dose, the relative differences were approximately threefold and fourfold greater, and both were significant (P <.001).
There was no further gain in these quality-of-life scales from week 4 to week 16, but the advantages relative to placebo were generally sustained, Dr. Zhao reported.
Ivarmacitinib was safe and well-tolerated, according to Dr. Zhao. The proportion of patients with a treatment-emergent adverse event that led to drug discontinuation was numerically higher (5.4%) in the placebo group than in the 8-mg (3.6%) or 4-mg group (2.7%). Rates of infection in the three groups were similar, and there were no major adverse cardiovascular events (MACE) or thromboembolism observed in any group.
Ivarmacitinib, which has about a 10-fold greater selectivity for JAK1 than JAK2 and a more than 70-fold greater selectivity for JAK1 than JAK3, is being tested for rheumatoid arthritis, inflammatory bowel disease, and alopecia areata in addition to AD, Dr. Zhao said. She also reported that an application for new drug approval has been submitted in China. Efforts to pursue regulatory approval elsewhere are anticipated.
Currently, there are three JAK inhibitors licensed for the treatment of AD in the United States. Upadacitinib (Rinvoq) and abrocitinib (Cibinqo) are also once-daily oral JAK1-selective inhibitors. Regulatory approval for AD by the Food and Drug Administration was granted to both in early 2022 and both now have an indication for moderate to severe disease in patients ages 12 years and older.
In September 2021, the first U.S. approval of a drug in this class for AD was granted for a topical formulation of ruxolitinib (Opzelura), which has selectivity for both JAK1 and JAK2. The indication is for mild to moderate AD in patients aged 12 years and older.
In the phase 3 clinical trial that led to approval of abrocitinib for AD, the comparator groups included placebo and active treatment with 300 mg dupilumab administered subcutaneously every other week. The higher of two doses of abrocitinib (100 mg) was numerically superior to dupilumab in terms of EASI 75 response at week 12 and was statistically superior for relief of itch at week 2.
Relative to the first-generation JAK inhibitor tofacitinib (Xeljanz), both of the approved oral JAK inhibitors for AD, abrocitinib and upadacitinib, have greater JAK1-selectivity. However, selectivity for all JAK inhibitors is relative rather than absolute, according to a recent review article on oral JAK inhibitors for AD. Efficacy and safety are likely determined by relative inhibition of each of the four JAK enzymes (JAK1, JAK2, JAK3, and TYK2). Although JAK1 appears to be an important target for AD treatment, the clinical significance of the degree of selectivity among oral JAK inhibitors is not yet clear.
In an interview, the senior author of that review article, Emma Guttman-Yassky, MD, PhD, emphasized this point. She said there is no evidence and no basis on which to speculate that any one drug in this class is better than another for AD. Dr. Guttman-Yassky is a professor and system chair of dermatology and immunology at the Icahn School of Medicine at Mount Sinai, New York.
“The efficacy [of ivarmacitinib] seems, in general, to be in line with other JAK inhibitors,” said Dr. Guttman-Yassky, who attended the late-breaker session during which these data were presented. Although she acknowledged that rapid control of pruritus is important clinically, she said the speed of itch relief as reported in the phase 3 ivarmacitinib trial does not distinguish it from other oral drugs in the class.
Shawn Kwatra, MD, director of the Johns Hopkins Itch Center, Johns Hopkins University, Baltimore, agreed.
“The rapid effects on itch of ivarmacitinib are consistent with those observed by the already approved JAK1-selective inhibitors abrocitinib and upadacitinib,” he said in an interview.
This suggests that head-to-head trials will be needed to draw any conclusions about the relative efficacy and safety of existing and emerging oral JAK inhibitors for AD.
Dr. Zhao has reported a financial relationship with Reistone Biopharma, which is developing ivarmacitinib and provided funding for the trial. Dr. Guttman-Yassky has reported financial relationships with more than 20 pharmaceutical companies, including companies that make JAK inhibitors. Dr. Kwatra has reported financial relationships with AbbVie, Aslan, Arcutis Biotherapeutics, Castle Biosciences, Celldex, Galderma, Genzada, Incyte, Johnson & Johnson, Leo Pharma, Novartis, Pfizer, Regeneron, and Sanofi.
A version of this article first appeared on Medscape.com.
NEW ORLEANS – The presented as a late-breaker at the annual meeting of the American Academy of Dermatology.
Two doses were studied in the placebo-controlled trial and both demonstrated “a favorable benefit-to-risk profile in patients with moderate to severe AD,” reported Yan Zhao, MD, a clinician and researcher in the department of dermatology, Peking University People’s Hospital, Beijing.
In the study, called QUARTZ3, 336 patients aged 12 and older at 51 sites in China and Canada were randomized to 4 mg once-daily ivarmacitinib, 8 mg once-daily QD ivarmacitinib, or placebo. The mean age of the population was 32 years and approximately one-third were female.
The mean duration of AD for participants was 10 years. The mean baseline Eczema Area and Severity Index (EASI) score was near 30. On the Investigator Global Assessment (IGA) tool, approximately 40% had a score of 4, which is the highest score on the scale and indicates severe disease. The remaining patients had an IGA score of 3.
The co-primary endpoints were change in IGA and EASI scores at 16 weeks, and both improved rapidly, showing statistical significance relative to placebo by 4 weeks with no plateauing effect at the end of the 16-week trial. By week 16, the proportion of patients with an EASI score of 75, signifying a 75% improvement, was 66%, 54%, and 22% for the 8-mg dose of ivarmacitinib, 4-mg dose of ivarmacitinib, and placebo groups (P < .001 versus placebo for both doses of active therapy), respectively.
The pattern of the IGA response was similar. By week 16, the proportion of patients achieving an IGA score of 0 (clear) or 1 (almost clear) was 42%, 36%, and 9% for the 8-mg dose of ivarmacitinib, 4-mg dose of ivarmacitinib, and placebo groups, respectively. The advantage of either dose over placebo was highly significant (P < .001) at 8, 12, and 16 weeks.
For the WI-NRS (Worst Itch – Numeric Rating Scale), the advantage of the 8-mg dose relative to placebo was significant (P < .001) at the 1-week evaluation. By 2 weeks, the 4-mg dose had gained the same degree of statistical significance relative to placebo. After week 4, when the maximum proportion of patients with a WI-NRS score ≤ 4 was reached (50%, 35%, and 10% in the 8-mg, 4-mg, and placebo groups), and the relative advantage of active treatment persisted until the end of the 16-week study.
Two scales were used to evaluate change in quality of life. On the DLQI (Dermatology Life Quality Index) and POEM (Patient-Oriented Eczema Measure), improvements were again rapid and sustained. By week 4, improvement with the 8-mg dose was about fourfold greater (P < .001) than improvement with placebo for DLQI and about sixfold greater (P < .001) for POEM. For the 4-mg dose, the relative differences were approximately threefold and fourfold greater, and both were significant (P <.001).
There was no further gain in these quality-of-life scales from week 4 to week 16, but the advantages relative to placebo were generally sustained, Dr. Zhao reported.
Ivarmacitinib was safe and well-tolerated, according to Dr. Zhao. The proportion of patients with a treatment-emergent adverse event that led to drug discontinuation was numerically higher (5.4%) in the placebo group than in the 8-mg (3.6%) or 4-mg group (2.7%). Rates of infection in the three groups were similar, and there were no major adverse cardiovascular events (MACE) or thromboembolism observed in any group.
Ivarmacitinib, which has about a 10-fold greater selectivity for JAK1 than JAK2 and a more than 70-fold greater selectivity for JAK1 than JAK3, is being tested for rheumatoid arthritis, inflammatory bowel disease, and alopecia areata in addition to AD, Dr. Zhao said. She also reported that an application for new drug approval has been submitted in China. Efforts to pursue regulatory approval elsewhere are anticipated.
Currently, there are three JAK inhibitors licensed for the treatment of AD in the United States. Upadacitinib (Rinvoq) and abrocitinib (Cibinqo) are also once-daily oral JAK1-selective inhibitors. Regulatory approval for AD by the Food and Drug Administration was granted to both in early 2022 and both now have an indication for moderate to severe disease in patients ages 12 years and older.
In September 2021, the first U.S. approval of a drug in this class for AD was granted for a topical formulation of ruxolitinib (Opzelura), which has selectivity for both JAK1 and JAK2. The indication is for mild to moderate AD in patients aged 12 years and older.
In the phase 3 clinical trial that led to approval of abrocitinib for AD, the comparator groups included placebo and active treatment with 300 mg dupilumab administered subcutaneously every other week. The higher of two doses of abrocitinib (100 mg) was numerically superior to dupilumab in terms of EASI 75 response at week 12 and was statistically superior for relief of itch at week 2.
Relative to the first-generation JAK inhibitor tofacitinib (Xeljanz), both of the approved oral JAK inhibitors for AD, abrocitinib and upadacitinib, have greater JAK1-selectivity. However, selectivity for all JAK inhibitors is relative rather than absolute, according to a recent review article on oral JAK inhibitors for AD. Efficacy and safety are likely determined by relative inhibition of each of the four JAK enzymes (JAK1, JAK2, JAK3, and TYK2). Although JAK1 appears to be an important target for AD treatment, the clinical significance of the degree of selectivity among oral JAK inhibitors is not yet clear.
In an interview, the senior author of that review article, Emma Guttman-Yassky, MD, PhD, emphasized this point. She said there is no evidence and no basis on which to speculate that any one drug in this class is better than another for AD. Dr. Guttman-Yassky is a professor and system chair of dermatology and immunology at the Icahn School of Medicine at Mount Sinai, New York.
“The efficacy [of ivarmacitinib] seems, in general, to be in line with other JAK inhibitors,” said Dr. Guttman-Yassky, who attended the late-breaker session during which these data were presented. Although she acknowledged that rapid control of pruritus is important clinically, she said the speed of itch relief as reported in the phase 3 ivarmacitinib trial does not distinguish it from other oral drugs in the class.
Shawn Kwatra, MD, director of the Johns Hopkins Itch Center, Johns Hopkins University, Baltimore, agreed.
“The rapid effects on itch of ivarmacitinib are consistent with those observed by the already approved JAK1-selective inhibitors abrocitinib and upadacitinib,” he said in an interview.
This suggests that head-to-head trials will be needed to draw any conclusions about the relative efficacy and safety of existing and emerging oral JAK inhibitors for AD.
Dr. Zhao has reported a financial relationship with Reistone Biopharma, which is developing ivarmacitinib and provided funding for the trial. Dr. Guttman-Yassky has reported financial relationships with more than 20 pharmaceutical companies, including companies that make JAK inhibitors. Dr. Kwatra has reported financial relationships with AbbVie, Aslan, Arcutis Biotherapeutics, Castle Biosciences, Celldex, Galderma, Genzada, Incyte, Johnson & Johnson, Leo Pharma, Novartis, Pfizer, Regeneron, and Sanofi.
A version of this article first appeared on Medscape.com.
AT AAD 2023
Substance abuse disorders may share a common genetic signature
suggest new findings that researchers say could eventually lead to universal therapies to treat multiple and comorbid addictions.
“Genetics play a key role in determining health throughout our lives, but they are not destiny. Our hope with genomic studies is to further illuminate factors that may protect or predispose a person to substance use disorders – knowledge that can be used to expand preventative services and empower individuals to make informed decisions about drug use,” Nora Volkow, MD, director of the National Institute on Drug Abuse, said in news release.
“A better understanding of genetics also brings us one step closer to developing personalized interventions that are tailored to an individual’s unique biology, environment, and lived experience in order to provide the most benefits,” Dr. Volkow added.
The research was published online in Nature Mental Health.
Global research
Led by a team at the Washington University in St. Louis, the study included more than 150 collaborating investigators from around the world.
The risk of developing SUDs is influenced by a complex interplay between genetics and environmental factors. In a genomewide association study, the investigators looked for variations in the genome that were closely associated with SUDs in more than 1 million people of European ancestry and 92,630 people of African ancestry.
Among the European ancestry sample, they discovered 19 single-nucleotide polymorphisms that were significantly associated with general addiction risk and 47 genetic variants linked to specific SUDs – 9 for alcohol, 32 for tobacco, 5 for cannabis, and 1 for opioids.
The strongest gene signals consistent across the various SUDs mapped to areas in the genome involved in dopamine-signaling regulation, which reinforces the role of the dopamine system in addiction.
The genomic pattern also predicted higher risk of mental and physical illness, including psychiatric disorders, suicidal behavior, respiratory disease, heart disease, and chronic pain conditions. In children aged 9 or 10 years, presumably without any SUD, these genes correlated with parental substance use and externalizing behavior.
“Substance use disorders and mental disorders often co-occur, and we know that the most effective treatments help people address both issues at the same time. The shared genetic mechanisms between substance use and mental disorders revealed in this study underscore the importance of thinking about these disorders in tandem,” Joshua A. Gordon, MD, PhD, director of the National Institute of Mental Health, said in a news release.
Repurpose existing drugs for SUDs?
Separately, the genomic analysis of individuals of African ancestry showed only one genetic variation associated with general addiction risk and one substance-specific variation for risk of alcohol use disorder. The smaller sample size may be one reason for the more limited findings in this population.
“There is a tremendous need for treatments that target addiction generally, given patterns of the use of multiple substances, lifetime substance use, and severity seen in the clinic,” lead researcher Alexander Hatoum, PhD, at Washington University in St. Louis, said in a news release.
“Our study opens the door to identifying medications that may be leveraged to treat addiction broadly, which may be especially useful for treating more severe forms, including addiction to multiple substances,” Dr. Hatoum added.
As part of the study, the researchers compiled a list of approved and investigational pharmaceutical drugs that could potentially be repurposed to treat SUDs.
The list includes more than 100 drugs to investigate in future clinical trials, including those that can influence regulation of dopamine signaling.
This research was supported by NIDA, the National Institute on Alcohol Abuse and Alcoholism, NIMH, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Institute on Aging.
A version of this article first appeared on Medscape.com.
suggest new findings that researchers say could eventually lead to universal therapies to treat multiple and comorbid addictions.
“Genetics play a key role in determining health throughout our lives, but they are not destiny. Our hope with genomic studies is to further illuminate factors that may protect or predispose a person to substance use disorders – knowledge that can be used to expand preventative services and empower individuals to make informed decisions about drug use,” Nora Volkow, MD, director of the National Institute on Drug Abuse, said in news release.
“A better understanding of genetics also brings us one step closer to developing personalized interventions that are tailored to an individual’s unique biology, environment, and lived experience in order to provide the most benefits,” Dr. Volkow added.
The research was published online in Nature Mental Health.
Global research
Led by a team at the Washington University in St. Louis, the study included more than 150 collaborating investigators from around the world.
The risk of developing SUDs is influenced by a complex interplay between genetics and environmental factors. In a genomewide association study, the investigators looked for variations in the genome that were closely associated with SUDs in more than 1 million people of European ancestry and 92,630 people of African ancestry.
Among the European ancestry sample, they discovered 19 single-nucleotide polymorphisms that were significantly associated with general addiction risk and 47 genetic variants linked to specific SUDs – 9 for alcohol, 32 for tobacco, 5 for cannabis, and 1 for opioids.
The strongest gene signals consistent across the various SUDs mapped to areas in the genome involved in dopamine-signaling regulation, which reinforces the role of the dopamine system in addiction.
The genomic pattern also predicted higher risk of mental and physical illness, including psychiatric disorders, suicidal behavior, respiratory disease, heart disease, and chronic pain conditions. In children aged 9 or 10 years, presumably without any SUD, these genes correlated with parental substance use and externalizing behavior.
“Substance use disorders and mental disorders often co-occur, and we know that the most effective treatments help people address both issues at the same time. The shared genetic mechanisms between substance use and mental disorders revealed in this study underscore the importance of thinking about these disorders in tandem,” Joshua A. Gordon, MD, PhD, director of the National Institute of Mental Health, said in a news release.
Repurpose existing drugs for SUDs?
Separately, the genomic analysis of individuals of African ancestry showed only one genetic variation associated with general addiction risk and one substance-specific variation for risk of alcohol use disorder. The smaller sample size may be one reason for the more limited findings in this population.
“There is a tremendous need for treatments that target addiction generally, given patterns of the use of multiple substances, lifetime substance use, and severity seen in the clinic,” lead researcher Alexander Hatoum, PhD, at Washington University in St. Louis, said in a news release.
“Our study opens the door to identifying medications that may be leveraged to treat addiction broadly, which may be especially useful for treating more severe forms, including addiction to multiple substances,” Dr. Hatoum added.
As part of the study, the researchers compiled a list of approved and investigational pharmaceutical drugs that could potentially be repurposed to treat SUDs.
The list includes more than 100 drugs to investigate in future clinical trials, including those that can influence regulation of dopamine signaling.
This research was supported by NIDA, the National Institute on Alcohol Abuse and Alcoholism, NIMH, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Institute on Aging.
A version of this article first appeared on Medscape.com.
suggest new findings that researchers say could eventually lead to universal therapies to treat multiple and comorbid addictions.
“Genetics play a key role in determining health throughout our lives, but they are not destiny. Our hope with genomic studies is to further illuminate factors that may protect or predispose a person to substance use disorders – knowledge that can be used to expand preventative services and empower individuals to make informed decisions about drug use,” Nora Volkow, MD, director of the National Institute on Drug Abuse, said in news release.
“A better understanding of genetics also brings us one step closer to developing personalized interventions that are tailored to an individual’s unique biology, environment, and lived experience in order to provide the most benefits,” Dr. Volkow added.
The research was published online in Nature Mental Health.
Global research
Led by a team at the Washington University in St. Louis, the study included more than 150 collaborating investigators from around the world.
The risk of developing SUDs is influenced by a complex interplay between genetics and environmental factors. In a genomewide association study, the investigators looked for variations in the genome that were closely associated with SUDs in more than 1 million people of European ancestry and 92,630 people of African ancestry.
Among the European ancestry sample, they discovered 19 single-nucleotide polymorphisms that were significantly associated with general addiction risk and 47 genetic variants linked to specific SUDs – 9 for alcohol, 32 for tobacco, 5 for cannabis, and 1 for opioids.
The strongest gene signals consistent across the various SUDs mapped to areas in the genome involved in dopamine-signaling regulation, which reinforces the role of the dopamine system in addiction.
The genomic pattern also predicted higher risk of mental and physical illness, including psychiatric disorders, suicidal behavior, respiratory disease, heart disease, and chronic pain conditions. In children aged 9 or 10 years, presumably without any SUD, these genes correlated with parental substance use and externalizing behavior.
“Substance use disorders and mental disorders often co-occur, and we know that the most effective treatments help people address both issues at the same time. The shared genetic mechanisms between substance use and mental disorders revealed in this study underscore the importance of thinking about these disorders in tandem,” Joshua A. Gordon, MD, PhD, director of the National Institute of Mental Health, said in a news release.
Repurpose existing drugs for SUDs?
Separately, the genomic analysis of individuals of African ancestry showed only one genetic variation associated with general addiction risk and one substance-specific variation for risk of alcohol use disorder. The smaller sample size may be one reason for the more limited findings in this population.
“There is a tremendous need for treatments that target addiction generally, given patterns of the use of multiple substances, lifetime substance use, and severity seen in the clinic,” lead researcher Alexander Hatoum, PhD, at Washington University in St. Louis, said in a news release.
“Our study opens the door to identifying medications that may be leveraged to treat addiction broadly, which may be especially useful for treating more severe forms, including addiction to multiple substances,” Dr. Hatoum added.
As part of the study, the researchers compiled a list of approved and investigational pharmaceutical drugs that could potentially be repurposed to treat SUDs.
The list includes more than 100 drugs to investigate in future clinical trials, including those that can influence regulation of dopamine signaling.
This research was supported by NIDA, the National Institute on Alcohol Abuse and Alcoholism, NIMH, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Institute on Aging.
A version of this article first appeared on Medscape.com.
FROM NATURE MENTAL HEALTH
Screen time and teenagers: Principles for parents
The Centers for Disease Control and Prevention recently released results of the most recent Youth Risk Behavior Survey, their once-a-decade survey of youth mental health and risk-taking behaviors. The headlines aren’t good: Self-reported rates of anxiety, depression, suicidal thoughts, and suicide attempts in adolescents have increased substantially from 2011 to 2021. This echoes epidemiologic data showing increasing rates of anxiety and depression over the last decade in 12- to 24-year-olds, but not in older age cohorts.
This trend started well before COVID, coinciding with the explosive growth in use of smartphones, apps, and social media platforms. Facebook launched in 2004, the iPhone in 2007, Instagram in 2010, and TikTok in 2016. A 2018 Pew Research survey of 13- to 17-year-olds found that 97% of them used at least one social media platform and 45% described themselves as online “almost constantly.” Social media does have great potential benefits for adolescents.
We all experienced how it supported relationships during COVID. It can provide supportive networks for teenagers isolated by exclusion, illness, or disability. It can support exploration of esoteric interests, expression of identity, entertainment, and relaxation. But certain children, as was true before social media, seem vulnerable to the bullying, loneliness, isolation, and disengagement that social media may exacerbate.
Several studies have shown an association between high daily screen time and adolescent anxiety and depression. These findings have not been consistently duplicated, and those that were could not establish causality. There appears to be a strong link between certain illnesses (ADHD, depression, anorexia nervosa) and excessive screen use, which can in turn worsen symptoms. But it is hard to know which came first or how they are related.
Now, a very large long-term observational study has suggested that there may be critical windows in adolescence (11-13 years in girls and 14-16 in boys and again at 19 years for both) during which time excessive screen time can put that child’s developing mental health at risk. This is nuanced and interesting progress, but you don’t have to wait another decade to offer the families in your practice some common sense guidance when they are asking how to balance their children’s needs to be independent and socially connected (and the fact that smartphones and social media are pervasive) with the risks of overuse. Equipped with these guiding principles, parents can set individualized, flexible ground rules, and adjust them as their children grow into young adults.
First: Know your child
Parents are, of course, the experts on their own child – their talents, interests, challenges, vulnerabilities, and developmental progress. Children with poor impulse control (including those with ADHD) are going to have greater difficulty turning away from highly addictive activities on their devices. Children who are anxious and shy may be prone to avoiding the stress of real-life situations, preferring virtual ones. Children with a history of depression may be vulnerable to relapse if their sleep and exercise routines are disrupted by excessive use. And children with eating disorders are especially vulnerable to the superficial social comparisons and “likes” that Instagram offers. Children with these vulnerabilities will benefit if their parents are aware of and can talk about these vulnerabilities, ideally with their child. They should be prepared to work with their teens to develop strategies that can help them learn how to manage their social media usage. These might include stopping screen use after a certain hour, leaving devices outside of bedrooms at night, and setting up apps that monitor and alert them about excessive use. They might use resources such as the AAP’s Family Media Plan (Media and Children [aap.org]), but simply taking the time to have regular, open, honest conversations about what is known and unknown about the potential risks of social media use is very protective.
Second: Use adolescent development as your guide
For those children who do not have a known vulnerability to overuse, consider the following areas that are essential to healthy development in adolescence as guideposts to help parents in setting reasonable ground rules: building independence, cultivating healthy social relationships, learning about their identity, managing their strong emotions, and developing the skills of self-care. If screen time supports these developmental areas, then it’s probably healthy. If it interferes with them, then not. And remember, parents should routinely discuss these principles with their children as well.
Independence
Key questions. Does their use of a device enable them to function more independently – that is, to arrange for rides, manage their schedules, homework, shifts, and so forth – on their own? Could it be done with a “dumb” device (text/call only)?
Social relationships
One-way viewing (Instagram, Facebook) with superficial acquaintances may promote isolation, anxiety, and depression, does not facilitate deepened relationships, and may be using up time that they could be investing in genuine social connections. But if they are using their devices to stay connected to good friends who live far away or just have different schedules, they can promote genuine, satisfying, bilateral social connections.
Key questions. Are they engaged in two-way communication with their devices? Are they staying connected to friends with whom they have a genuine, substantial relationship?
Investigating and experimenting with interests (identity)
Teenagers are supposed to be learning in deep and nuanced ways about their own interests and abilities during these years. This requires a lot of time invested in exploration and experimentation and a considerable amount of failure. Any activity that consumes a lot of their time without deepening meaningful knowledge of their interests and abilities (that is, activity that is only an escape or distraction) will interfere with their discovering their authentic identity.
Key questions. Is their use of devices facilitating this genuine exploration (setting up internships, practicing programming, or exploring interests that must be virtual)? Or is their device use just consuming precious time they could be using to genuinely explore potential interests?
Managing anxiety or distress
Exploring their identity and building social connections will involve a lot of stress, failure, disappointment, and even heartbreak. Learning to manage these uncomfortable feelings is an important part of adolescence. Distraction with a diverting entertainment can be one of several strategies for managing stress and distress. But if it becomes the only strategy, it can keep teens from getting “back in the game” and experiencing the fun, success, meaning, and joy that are also a big part of this exploration.
Key questions. Do they turn to their devices first when sad or stressed? Are they also able to use other strategies, such as talking with friends/family, exercising, or engaging in a meaningful pursuit to help them manage stress? Do they feel better after a little time spent on their device, or as if they will only feel good if they can stay on the device?
Self-care
Getting adequate, restful sleep (8-10 hours/night), finding regular time for exercise, cultivating healthy eating habits, and discovering what healthy strategies help them to unwind or relax is critical to a teenager’s healthiest development, and to healthy adult life. Some screens may help with motivating and tracking exercise, but screens in the bedroom interfere with going to bed, and with falling and staying asleep. Most teenagers are very busy and managing a lot of (normal) stress; the senseless fun or relaxation that are part of video games or surfing the Web are quick, practical, and effective ways to unwind. Don’t discourage your teenager from enjoying them. Instead, focus on also helping them to find other healthy ways to relax: hot baths, exercise, time with pets, crafts, reading, and listening to music are just a few examples. As they are building their identity, they should also be discovering how they best slow down and calm down.
Key questions. How many hours of sleep do they usually get on a school night? Is their phone (or other screen) in their bedroom during sleep? How do they relax? Do they have several strategies that do not require screens? Do they exercise regularly (3-5 times weekly)? Do they complain that they do not have enough time for exercise?
Third: Be mindful of what you model
Many of these principles can apply to our own use of smartphones, computers, and so on. Remind parents that their teenager will ultimately consider and follow their example much more than their commands. They should be prepared to talk about how they are thinking about the risks and benefits of social media use, how they are developing rules and expectations, and why they decided on them. These conversations model thoughtful and flexible decision-making.
It is critical that parents acknowledge that there are wonderful benefits to technology, including senseless fun. Then, it is easier to discuss how escaping into screen use can be hard to resist, and why it is important to practice resisting some temptations. Parents should find ways to follow the same rules they set for their teenager, or making them “family rules.” It’s important for our teenagers to learn about how to set these limits, as eventually they will be setting their own!
Dr. Swick is physician in chief at Ohana Center for Child and Adolescent Behavioral Health, Community Hospital of the Monterey (Calif.) Peninsula. Dr. Jellinek is professor emeritus of psychiatry and pediatrics, Harvard Medical School, Boston. Email them at [email protected].
The Centers for Disease Control and Prevention recently released results of the most recent Youth Risk Behavior Survey, their once-a-decade survey of youth mental health and risk-taking behaviors. The headlines aren’t good: Self-reported rates of anxiety, depression, suicidal thoughts, and suicide attempts in adolescents have increased substantially from 2011 to 2021. This echoes epidemiologic data showing increasing rates of anxiety and depression over the last decade in 12- to 24-year-olds, but not in older age cohorts.
This trend started well before COVID, coinciding with the explosive growth in use of smartphones, apps, and social media platforms. Facebook launched in 2004, the iPhone in 2007, Instagram in 2010, and TikTok in 2016. A 2018 Pew Research survey of 13- to 17-year-olds found that 97% of them used at least one social media platform and 45% described themselves as online “almost constantly.” Social media does have great potential benefits for adolescents.
We all experienced how it supported relationships during COVID. It can provide supportive networks for teenagers isolated by exclusion, illness, or disability. It can support exploration of esoteric interests, expression of identity, entertainment, and relaxation. But certain children, as was true before social media, seem vulnerable to the bullying, loneliness, isolation, and disengagement that social media may exacerbate.
Several studies have shown an association between high daily screen time and adolescent anxiety and depression. These findings have not been consistently duplicated, and those that were could not establish causality. There appears to be a strong link between certain illnesses (ADHD, depression, anorexia nervosa) and excessive screen use, which can in turn worsen symptoms. But it is hard to know which came first or how they are related.
Now, a very large long-term observational study has suggested that there may be critical windows in adolescence (11-13 years in girls and 14-16 in boys and again at 19 years for both) during which time excessive screen time can put that child’s developing mental health at risk. This is nuanced and interesting progress, but you don’t have to wait another decade to offer the families in your practice some common sense guidance when they are asking how to balance their children’s needs to be independent and socially connected (and the fact that smartphones and social media are pervasive) with the risks of overuse. Equipped with these guiding principles, parents can set individualized, flexible ground rules, and adjust them as their children grow into young adults.
First: Know your child
Parents are, of course, the experts on their own child – their talents, interests, challenges, vulnerabilities, and developmental progress. Children with poor impulse control (including those with ADHD) are going to have greater difficulty turning away from highly addictive activities on their devices. Children who are anxious and shy may be prone to avoiding the stress of real-life situations, preferring virtual ones. Children with a history of depression may be vulnerable to relapse if their sleep and exercise routines are disrupted by excessive use. And children with eating disorders are especially vulnerable to the superficial social comparisons and “likes” that Instagram offers. Children with these vulnerabilities will benefit if their parents are aware of and can talk about these vulnerabilities, ideally with their child. They should be prepared to work with their teens to develop strategies that can help them learn how to manage their social media usage. These might include stopping screen use after a certain hour, leaving devices outside of bedrooms at night, and setting up apps that monitor and alert them about excessive use. They might use resources such as the AAP’s Family Media Plan (Media and Children [aap.org]), but simply taking the time to have regular, open, honest conversations about what is known and unknown about the potential risks of social media use is very protective.
Second: Use adolescent development as your guide
For those children who do not have a known vulnerability to overuse, consider the following areas that are essential to healthy development in adolescence as guideposts to help parents in setting reasonable ground rules: building independence, cultivating healthy social relationships, learning about their identity, managing their strong emotions, and developing the skills of self-care. If screen time supports these developmental areas, then it’s probably healthy. If it interferes with them, then not. And remember, parents should routinely discuss these principles with their children as well.
Independence
Key questions. Does their use of a device enable them to function more independently – that is, to arrange for rides, manage their schedules, homework, shifts, and so forth – on their own? Could it be done with a “dumb” device (text/call only)?
Social relationships
One-way viewing (Instagram, Facebook) with superficial acquaintances may promote isolation, anxiety, and depression, does not facilitate deepened relationships, and may be using up time that they could be investing in genuine social connections. But if they are using their devices to stay connected to good friends who live far away or just have different schedules, they can promote genuine, satisfying, bilateral social connections.
Key questions. Are they engaged in two-way communication with their devices? Are they staying connected to friends with whom they have a genuine, substantial relationship?
Investigating and experimenting with interests (identity)
Teenagers are supposed to be learning in deep and nuanced ways about their own interests and abilities during these years. This requires a lot of time invested in exploration and experimentation and a considerable amount of failure. Any activity that consumes a lot of their time without deepening meaningful knowledge of their interests and abilities (that is, activity that is only an escape or distraction) will interfere with their discovering their authentic identity.
Key questions. Is their use of devices facilitating this genuine exploration (setting up internships, practicing programming, or exploring interests that must be virtual)? Or is their device use just consuming precious time they could be using to genuinely explore potential interests?
Managing anxiety or distress
Exploring their identity and building social connections will involve a lot of stress, failure, disappointment, and even heartbreak. Learning to manage these uncomfortable feelings is an important part of adolescence. Distraction with a diverting entertainment can be one of several strategies for managing stress and distress. But if it becomes the only strategy, it can keep teens from getting “back in the game” and experiencing the fun, success, meaning, and joy that are also a big part of this exploration.
Key questions. Do they turn to their devices first when sad or stressed? Are they also able to use other strategies, such as talking with friends/family, exercising, or engaging in a meaningful pursuit to help them manage stress? Do they feel better after a little time spent on their device, or as if they will only feel good if they can stay on the device?
Self-care
Getting adequate, restful sleep (8-10 hours/night), finding regular time for exercise, cultivating healthy eating habits, and discovering what healthy strategies help them to unwind or relax is critical to a teenager’s healthiest development, and to healthy adult life. Some screens may help with motivating and tracking exercise, but screens in the bedroom interfere with going to bed, and with falling and staying asleep. Most teenagers are very busy and managing a lot of (normal) stress; the senseless fun or relaxation that are part of video games or surfing the Web are quick, practical, and effective ways to unwind. Don’t discourage your teenager from enjoying them. Instead, focus on also helping them to find other healthy ways to relax: hot baths, exercise, time with pets, crafts, reading, and listening to music are just a few examples. As they are building their identity, they should also be discovering how they best slow down and calm down.
Key questions. How many hours of sleep do they usually get on a school night? Is their phone (or other screen) in their bedroom during sleep? How do they relax? Do they have several strategies that do not require screens? Do they exercise regularly (3-5 times weekly)? Do they complain that they do not have enough time for exercise?
Third: Be mindful of what you model
Many of these principles can apply to our own use of smartphones, computers, and so on. Remind parents that their teenager will ultimately consider and follow their example much more than their commands. They should be prepared to talk about how they are thinking about the risks and benefits of social media use, how they are developing rules and expectations, and why they decided on them. These conversations model thoughtful and flexible decision-making.
It is critical that parents acknowledge that there are wonderful benefits to technology, including senseless fun. Then, it is easier to discuss how escaping into screen use can be hard to resist, and why it is important to practice resisting some temptations. Parents should find ways to follow the same rules they set for their teenager, or making them “family rules.” It’s important for our teenagers to learn about how to set these limits, as eventually they will be setting their own!
Dr. Swick is physician in chief at Ohana Center for Child and Adolescent Behavioral Health, Community Hospital of the Monterey (Calif.) Peninsula. Dr. Jellinek is professor emeritus of psychiatry and pediatrics, Harvard Medical School, Boston. Email them at [email protected].
The Centers for Disease Control and Prevention recently released results of the most recent Youth Risk Behavior Survey, their once-a-decade survey of youth mental health and risk-taking behaviors. The headlines aren’t good: Self-reported rates of anxiety, depression, suicidal thoughts, and suicide attempts in adolescents have increased substantially from 2011 to 2021. This echoes epidemiologic data showing increasing rates of anxiety and depression over the last decade in 12- to 24-year-olds, but not in older age cohorts.
This trend started well before COVID, coinciding with the explosive growth in use of smartphones, apps, and social media platforms. Facebook launched in 2004, the iPhone in 2007, Instagram in 2010, and TikTok in 2016. A 2018 Pew Research survey of 13- to 17-year-olds found that 97% of them used at least one social media platform and 45% described themselves as online “almost constantly.” Social media does have great potential benefits for adolescents.
We all experienced how it supported relationships during COVID. It can provide supportive networks for teenagers isolated by exclusion, illness, or disability. It can support exploration of esoteric interests, expression of identity, entertainment, and relaxation. But certain children, as was true before social media, seem vulnerable to the bullying, loneliness, isolation, and disengagement that social media may exacerbate.
Several studies have shown an association between high daily screen time and adolescent anxiety and depression. These findings have not been consistently duplicated, and those that were could not establish causality. There appears to be a strong link between certain illnesses (ADHD, depression, anorexia nervosa) and excessive screen use, which can in turn worsen symptoms. But it is hard to know which came first or how they are related.
Now, a very large long-term observational study has suggested that there may be critical windows in adolescence (11-13 years in girls and 14-16 in boys and again at 19 years for both) during which time excessive screen time can put that child’s developing mental health at risk. This is nuanced and interesting progress, but you don’t have to wait another decade to offer the families in your practice some common sense guidance when they are asking how to balance their children’s needs to be independent and socially connected (and the fact that smartphones and social media are pervasive) with the risks of overuse. Equipped with these guiding principles, parents can set individualized, flexible ground rules, and adjust them as their children grow into young adults.
First: Know your child
Parents are, of course, the experts on their own child – their talents, interests, challenges, vulnerabilities, and developmental progress. Children with poor impulse control (including those with ADHD) are going to have greater difficulty turning away from highly addictive activities on their devices. Children who are anxious and shy may be prone to avoiding the stress of real-life situations, preferring virtual ones. Children with a history of depression may be vulnerable to relapse if their sleep and exercise routines are disrupted by excessive use. And children with eating disorders are especially vulnerable to the superficial social comparisons and “likes” that Instagram offers. Children with these vulnerabilities will benefit if their parents are aware of and can talk about these vulnerabilities, ideally with their child. They should be prepared to work with their teens to develop strategies that can help them learn how to manage their social media usage. These might include stopping screen use after a certain hour, leaving devices outside of bedrooms at night, and setting up apps that monitor and alert them about excessive use. They might use resources such as the AAP’s Family Media Plan (Media and Children [aap.org]), but simply taking the time to have regular, open, honest conversations about what is known and unknown about the potential risks of social media use is very protective.
Second: Use adolescent development as your guide
For those children who do not have a known vulnerability to overuse, consider the following areas that are essential to healthy development in adolescence as guideposts to help parents in setting reasonable ground rules: building independence, cultivating healthy social relationships, learning about their identity, managing their strong emotions, and developing the skills of self-care. If screen time supports these developmental areas, then it’s probably healthy. If it interferes with them, then not. And remember, parents should routinely discuss these principles with their children as well.
Independence
Key questions. Does their use of a device enable them to function more independently – that is, to arrange for rides, manage their schedules, homework, shifts, and so forth – on their own? Could it be done with a “dumb” device (text/call only)?
Social relationships
One-way viewing (Instagram, Facebook) with superficial acquaintances may promote isolation, anxiety, and depression, does not facilitate deepened relationships, and may be using up time that they could be investing in genuine social connections. But if they are using their devices to stay connected to good friends who live far away or just have different schedules, they can promote genuine, satisfying, bilateral social connections.
Key questions. Are they engaged in two-way communication with their devices? Are they staying connected to friends with whom they have a genuine, substantial relationship?
Investigating and experimenting with interests (identity)
Teenagers are supposed to be learning in deep and nuanced ways about their own interests and abilities during these years. This requires a lot of time invested in exploration and experimentation and a considerable amount of failure. Any activity that consumes a lot of their time without deepening meaningful knowledge of their interests and abilities (that is, activity that is only an escape or distraction) will interfere with their discovering their authentic identity.
Key questions. Is their use of devices facilitating this genuine exploration (setting up internships, practicing programming, or exploring interests that must be virtual)? Or is their device use just consuming precious time they could be using to genuinely explore potential interests?
Managing anxiety or distress
Exploring their identity and building social connections will involve a lot of stress, failure, disappointment, and even heartbreak. Learning to manage these uncomfortable feelings is an important part of adolescence. Distraction with a diverting entertainment can be one of several strategies for managing stress and distress. But if it becomes the only strategy, it can keep teens from getting “back in the game” and experiencing the fun, success, meaning, and joy that are also a big part of this exploration.
Key questions. Do they turn to their devices first when sad or stressed? Are they also able to use other strategies, such as talking with friends/family, exercising, or engaging in a meaningful pursuit to help them manage stress? Do they feel better after a little time spent on their device, or as if they will only feel good if they can stay on the device?
Self-care
Getting adequate, restful sleep (8-10 hours/night), finding regular time for exercise, cultivating healthy eating habits, and discovering what healthy strategies help them to unwind or relax is critical to a teenager’s healthiest development, and to healthy adult life. Some screens may help with motivating and tracking exercise, but screens in the bedroom interfere with going to bed, and with falling and staying asleep. Most teenagers are very busy and managing a lot of (normal) stress; the senseless fun or relaxation that are part of video games or surfing the Web are quick, practical, and effective ways to unwind. Don’t discourage your teenager from enjoying them. Instead, focus on also helping them to find other healthy ways to relax: hot baths, exercise, time with pets, crafts, reading, and listening to music are just a few examples. As they are building their identity, they should also be discovering how they best slow down and calm down.
Key questions. How many hours of sleep do they usually get on a school night? Is their phone (or other screen) in their bedroom during sleep? How do they relax? Do they have several strategies that do not require screens? Do they exercise regularly (3-5 times weekly)? Do they complain that they do not have enough time for exercise?
Third: Be mindful of what you model
Many of these principles can apply to our own use of smartphones, computers, and so on. Remind parents that their teenager will ultimately consider and follow their example much more than their commands. They should be prepared to talk about how they are thinking about the risks and benefits of social media use, how they are developing rules and expectations, and why they decided on them. These conversations model thoughtful and flexible decision-making.
It is critical that parents acknowledge that there are wonderful benefits to technology, including senseless fun. Then, it is easier to discuss how escaping into screen use can be hard to resist, and why it is important to practice resisting some temptations. Parents should find ways to follow the same rules they set for their teenager, or making them “family rules.” It’s important for our teenagers to learn about how to set these limits, as eventually they will be setting their own!
Dr. Swick is physician in chief at Ohana Center for Child and Adolescent Behavioral Health, Community Hospital of the Monterey (Calif.) Peninsula. Dr. Jellinek is professor emeritus of psychiatry and pediatrics, Harvard Medical School, Boston. Email them at [email protected].
Study finds quality of topical steroid withdrawal videos on YouTube subpar
NEW ORLEANS –
“Video-sharing platforms such as YouTube are a great place for patients to connect and find community with others dealing with the same conditions,” senior author Adam Friedman, MD, professor and chair of dermatology at George Washington University, Washington, said in an interview in advance of the annual meeting of the American Academy of Dermatology, where the study was presented during an e-poster session. “There is no doubt tremendous value in viewing the shared experience; however, it is important that medical advice be evidence based and validated. Seeking said advice from a medical professional such as a board-certified dermatologist will no doubt increase the likelihood that said guidance is supported by the literature and most importantly, will do no harm.”
Noting a trend of increased user-created content on social media and Internet sites about topical steroid withdrawal in recent years, Dr. Friedman, first author Erika McCormick, a fourth-year medical student at George Washington University, and colleagues used the keywords “topical steroid withdrawal” on YouTube to search for and analyze the top 10 most viewed videos on the subject.
Two independent reviewers used the modified DISCERN (mDISCERN) tool and the Global Quality Scale (GQS) to assess reliability and quality/scientific accuracy of videos, respectively. Average scores were generated for each video and the researchers used one way ANOVA, unpaired t-tests, and linear regression to analyze the ratings. For mDISCERN criteria, a point is given per each of five criteria for a possible score between 0 and 5. Examples of criteria included “Are the aims clear and achieved?” and “Is the information presented both balanced and unbiased”? For GQS, a score from 1 to 5 is designated based on criteria ranging from “poor quality, poor flow, most information missing” to “excellent quality and flow, very useful for patients.”
The researchers found that the mean combined mDISCERN score of the 10 videos was a 2, which indicates poor reliability and shortcomings. Similarly, the combined mean GQS score was 2.5, which suggests poor to moderate quality of videos, missing discussion of important topics, and limited use to patients. The researchers found no correlation between mDISCERN or GQS scores and length of video, duration on YouTube, or number of views, subscribers, or likes.
“We were disheartened that patient testimonial videos had the poorest quality and reliability of the information sources,” Ms. McCormick said in an interview. “Videos that included medical research and information from dermatologists had significantly higher quality and reliability scores than the remainder of videos.” Accurate information online is essential to help patients recognize topical steroid withdrawal and seek medical care, she continued.
Conversely, wide viewership of unreliable information “may contribute to fear of topical corticosteroids and dissuade use in patients with primary skin diseases that may benefit from this common treatment,” Dr. Friedman said. “Dermatologists must be aware of the content patients are consuming online, should guide patients in appraising quality and reliability of online resources, and must provide valid sources of additional information for their patients.” One such resource he recommended is the National Eczema Association, which has created online content for patients about topical steroid withdrawal.
Doris Day, MD, a New York–based dermatologist who was asked to comment on the study, said that many patients rely on YouTube as a go-to resource, with videos that can be watched at times of their choosing. “Oftentimes, the person on the video is relatable and has some general knowledge but is lacking the information that would be relevant and important for the individual patient,” said Dr. Day, who was not involved with the study. “The downside of this is that the person who takes that advice may not use the prescription properly or for the correct amount of time, which can lead to either undertreating or, even worse, overtreatment, which can have permanent consequences.”
One possible solution is for more doctors to create videos for YouTube, she added, “but that doesn’t guarantee that those would be the ones patients would choose to watch.” Another solution “is to have YouTube add qualifiers indicating that the information being discussed is not medical,” she suggested. “Ideally, patients will get all the information they need while they are in the office and also have clear written instructions and even a video they can review at a later time, made by the office, to help them feel they are getting personalized care and the attention they need.”
Ms. McCormick’s research is funded by a grant from Galderma. Dr. Friedman and Dr. Day had no relevant disclosures to report.
NEW ORLEANS –
“Video-sharing platforms such as YouTube are a great place for patients to connect and find community with others dealing with the same conditions,” senior author Adam Friedman, MD, professor and chair of dermatology at George Washington University, Washington, said in an interview in advance of the annual meeting of the American Academy of Dermatology, where the study was presented during an e-poster session. “There is no doubt tremendous value in viewing the shared experience; however, it is important that medical advice be evidence based and validated. Seeking said advice from a medical professional such as a board-certified dermatologist will no doubt increase the likelihood that said guidance is supported by the literature and most importantly, will do no harm.”
Noting a trend of increased user-created content on social media and Internet sites about topical steroid withdrawal in recent years, Dr. Friedman, first author Erika McCormick, a fourth-year medical student at George Washington University, and colleagues used the keywords “topical steroid withdrawal” on YouTube to search for and analyze the top 10 most viewed videos on the subject.
Two independent reviewers used the modified DISCERN (mDISCERN) tool and the Global Quality Scale (GQS) to assess reliability and quality/scientific accuracy of videos, respectively. Average scores were generated for each video and the researchers used one way ANOVA, unpaired t-tests, and linear regression to analyze the ratings. For mDISCERN criteria, a point is given per each of five criteria for a possible score between 0 and 5. Examples of criteria included “Are the aims clear and achieved?” and “Is the information presented both balanced and unbiased”? For GQS, a score from 1 to 5 is designated based on criteria ranging from “poor quality, poor flow, most information missing” to “excellent quality and flow, very useful for patients.”
The researchers found that the mean combined mDISCERN score of the 10 videos was a 2, which indicates poor reliability and shortcomings. Similarly, the combined mean GQS score was 2.5, which suggests poor to moderate quality of videos, missing discussion of important topics, and limited use to patients. The researchers found no correlation between mDISCERN or GQS scores and length of video, duration on YouTube, or number of views, subscribers, or likes.
“We were disheartened that patient testimonial videos had the poorest quality and reliability of the information sources,” Ms. McCormick said in an interview. “Videos that included medical research and information from dermatologists had significantly higher quality and reliability scores than the remainder of videos.” Accurate information online is essential to help patients recognize topical steroid withdrawal and seek medical care, she continued.
Conversely, wide viewership of unreliable information “may contribute to fear of topical corticosteroids and dissuade use in patients with primary skin diseases that may benefit from this common treatment,” Dr. Friedman said. “Dermatologists must be aware of the content patients are consuming online, should guide patients in appraising quality and reliability of online resources, and must provide valid sources of additional information for their patients.” One such resource he recommended is the National Eczema Association, which has created online content for patients about topical steroid withdrawal.
Doris Day, MD, a New York–based dermatologist who was asked to comment on the study, said that many patients rely on YouTube as a go-to resource, with videos that can be watched at times of their choosing. “Oftentimes, the person on the video is relatable and has some general knowledge but is lacking the information that would be relevant and important for the individual patient,” said Dr. Day, who was not involved with the study. “The downside of this is that the person who takes that advice may not use the prescription properly or for the correct amount of time, which can lead to either undertreating or, even worse, overtreatment, which can have permanent consequences.”
One possible solution is for more doctors to create videos for YouTube, she added, “but that doesn’t guarantee that those would be the ones patients would choose to watch.” Another solution “is to have YouTube add qualifiers indicating that the information being discussed is not medical,” she suggested. “Ideally, patients will get all the information they need while they are in the office and also have clear written instructions and even a video they can review at a later time, made by the office, to help them feel they are getting personalized care and the attention they need.”
Ms. McCormick’s research is funded by a grant from Galderma. Dr. Friedman and Dr. Day had no relevant disclosures to report.
NEW ORLEANS –
“Video-sharing platforms such as YouTube are a great place for patients to connect and find community with others dealing with the same conditions,” senior author Adam Friedman, MD, professor and chair of dermatology at George Washington University, Washington, said in an interview in advance of the annual meeting of the American Academy of Dermatology, where the study was presented during an e-poster session. “There is no doubt tremendous value in viewing the shared experience; however, it is important that medical advice be evidence based and validated. Seeking said advice from a medical professional such as a board-certified dermatologist will no doubt increase the likelihood that said guidance is supported by the literature and most importantly, will do no harm.”
Noting a trend of increased user-created content on social media and Internet sites about topical steroid withdrawal in recent years, Dr. Friedman, first author Erika McCormick, a fourth-year medical student at George Washington University, and colleagues used the keywords “topical steroid withdrawal” on YouTube to search for and analyze the top 10 most viewed videos on the subject.
Two independent reviewers used the modified DISCERN (mDISCERN) tool and the Global Quality Scale (GQS) to assess reliability and quality/scientific accuracy of videos, respectively. Average scores were generated for each video and the researchers used one way ANOVA, unpaired t-tests, and linear regression to analyze the ratings. For mDISCERN criteria, a point is given per each of five criteria for a possible score between 0 and 5. Examples of criteria included “Are the aims clear and achieved?” and “Is the information presented both balanced and unbiased”? For GQS, a score from 1 to 5 is designated based on criteria ranging from “poor quality, poor flow, most information missing” to “excellent quality and flow, very useful for patients.”
The researchers found that the mean combined mDISCERN score of the 10 videos was a 2, which indicates poor reliability and shortcomings. Similarly, the combined mean GQS score was 2.5, which suggests poor to moderate quality of videos, missing discussion of important topics, and limited use to patients. The researchers found no correlation between mDISCERN or GQS scores and length of video, duration on YouTube, or number of views, subscribers, or likes.
“We were disheartened that patient testimonial videos had the poorest quality and reliability of the information sources,” Ms. McCormick said in an interview. “Videos that included medical research and information from dermatologists had significantly higher quality and reliability scores than the remainder of videos.” Accurate information online is essential to help patients recognize topical steroid withdrawal and seek medical care, she continued.
Conversely, wide viewership of unreliable information “may contribute to fear of topical corticosteroids and dissuade use in patients with primary skin diseases that may benefit from this common treatment,” Dr. Friedman said. “Dermatologists must be aware of the content patients are consuming online, should guide patients in appraising quality and reliability of online resources, and must provide valid sources of additional information for their patients.” One such resource he recommended is the National Eczema Association, which has created online content for patients about topical steroid withdrawal.
Doris Day, MD, a New York–based dermatologist who was asked to comment on the study, said that many patients rely on YouTube as a go-to resource, with videos that can be watched at times of their choosing. “Oftentimes, the person on the video is relatable and has some general knowledge but is lacking the information that would be relevant and important for the individual patient,” said Dr. Day, who was not involved with the study. “The downside of this is that the person who takes that advice may not use the prescription properly or for the correct amount of time, which can lead to either undertreating or, even worse, overtreatment, which can have permanent consequences.”
One possible solution is for more doctors to create videos for YouTube, she added, “but that doesn’t guarantee that those would be the ones patients would choose to watch.” Another solution “is to have YouTube add qualifiers indicating that the information being discussed is not medical,” she suggested. “Ideally, patients will get all the information they need while they are in the office and also have clear written instructions and even a video they can review at a later time, made by the office, to help them feel they are getting personalized care and the attention they need.”
Ms. McCormick’s research is funded by a grant from Galderma. Dr. Friedman and Dr. Day had no relevant disclosures to report.
AT AAD 2023