Health Policy

Antibiotics are one of the most frequently prescribed medications in both inpatient and outpatient settings.^1,2 More than 266 million courses of antibiotics are prescribed annually in the outpatient setting; 49.9% of hospitalized patients were prescribed ≥ 1 antibiotic during their hospitalization.^1,2 Among all classes of antibiotics, penicillins are prescribed due to their clinical efficacy, cost-effectiveness, and general safety for all ages. Unfortunately, penicillins also are the most common drug allergy listed in medical records. Patients with this allergy are consistently treated with broad-spectrum antibiotics, have more antibiotic resistant infections, incur higher health care costs, and experience more adverse effects (AEs).^3,4

Drug allergies are distinguished by different immune mechanisms, including IgE-mediated reaction, T-lymphocyte-mediated mild skin reactions, and severe cutaneous adverse reactions (SCAR), or other systemic immune syndromes, such as hemolytic anemia, nephritis, and rash with eosinophilia.³ Although drug allergies should be a concern, compelling evidence shows that > 90% of patients labeled with a penicillin allergy are not allergic to penicillins (and associated β-lactams).^3,4 Although this evidence is growing, clinicians still hesitate to prescribe penicillin, and patients are similarly anxious to take them. This article reviews the health care consequences of penicillin allergy and the application of this information to military medicine and readiness.

Penicillin Allergy Prevalence

Since their approval for public use in 1945, penicillins have been one of the most often prescribed antibiotics due to their clinical efficacy for many types of infections.³ However, 8 to 10% of the US population and up to 15% of hospitalized patients have a documented penicillin allergy, which limits the ability to use these effective antibiotics.^3,4 Once a patient is labeled with a penicillin allergy, many clinicians avoid prescribing all β-lactam antibiotics to patients. Clinicians also avoid prescribing cephalosporins due to the concern for potential cross-reactivity (at a rate of about 2%, which is lower than previously reported).³ These reported allergies are often not clear and range from patients avoiding penicillins because their parents exhibited allergies, they had a symptom that was not likely allergic (ie, nausea, headache, itching with no rash), being told by their parents that they had a rash as a child, or experiencing severe anaphylaxis or other systemic reaction.^3,4 Despite the high rates of documented penicillin allergy, studies now show that most patients do not have a serious allergy; < 1% of the population has a true immune-mediated penicillin allergy.^3,4

Broad-Spectrum Antibiotic Risks

Even though penicillin allergies are often not confirmed, many patients are treated with alternative antibiotics. Unfortunately, most alternative antibiotics are not as effective or as safe as penicillin.^3,4 Twenty percent of hospitalized patients will experience an AE related to their antibiotic; 19.3% of emergency department visits for adverse drug reactions (ADRs) are from antibiotics.^5,6 Sulfonamides, clindamycin, and quinolones were the antibiotics most commonly associated with AEs.⁶

In a large database study over a 3-year period, > 400,000 hospitalizations were analyzed in patients matched for admission type, with and without a penicillin allergy in their medical record.⁷ Those with a documented penicillin allergy had longer hospitalizations; were treated with broad-spectrum antibiotics; and had increased rates of Clostridium difficile (C difficile), methicillin-resistant Staphylococcus aureus (MRSA), and vancomycin-resistant Enterococcus (VRE).^7,8 In addition to being first-line treatment for many common infections, penicillins often are used for dental, perinatal, and perioperative prophylaxis.^1,3 Nearly 25 million antibiotics are prescribed annually by dentists.¹ If a patient has a penicillin allergy listed in their medical record, they will inevitably receive a second- or third-line treatment that is less effective and has higher risks. Common alternative antibiotics include clindamycin, fluoroquinolones, macrolides, and vancomycin.^3,7,8

Clindamycin and fluoroquinolones are associated with C difficile infections.^9,10 Fluoroquinolones come with a boxed warning for known serious ADRs, including tendon rupture, peripheral neuropathy, central nervous system effects, and are known for causing cardiac reactions such as QT prolongation, life-threatening arrhythmias, and cardiovascular death.^11,12 Fluoroquinolones are associated with an increased risk for VRE and MRSA, in more than any other antibiotic classes.^3,7,12,13

Macrolides, such as azithromycin and clarithromycin, are another common class of antibiotics used as an alternative for penicillins. Both are used frequently for upper respiratory infections. Known ADRs to macrolides include gastrointestinal adverse effects (AEs) (ie, nausea, vomiting, diarrhea, and abdominal pain), liver toxicity (ie, abnormal liver function tests, hepatitis, and liver failure), and cardiac risks (ie, QT prolongation and sudden death). When compared with amoxicillin, there was an increased risk for cardiovascular mortality in those patients receiving macrolides.^14,15

Vancomycin is known for its potential to cause “red man syndrome,” an infusion-related reaction causing redness and itching as well as nephrotoxic and hematologic effects requiring close monitoring.³ Vancomycin is less effective than methicillin in clearing MRSA or other sensitive pathogens; however, vancomycin is used in patients with a penicillin allergy label.^16-18 Intrapartum antibiotic use of vancomycin for group B streptococcus infection was associated with clinically significant morbidity and ADRs.^19,20 Perioperatively, patients with penicillin allergies developed more surgical site infections due to the use of second-line antibiotics, such as vancomycin or others.²¹

Cost of Penicillin Allergies

Penicillin allergy plays an important role in rising health care costs. In 2017, health care spending reached 17.9% of the gross domestic product.²² Macy and Contreras demonstrated the significantly higher costs associated with having a reported (and unverified) penicillin allergy in a matched cohort study. Inferred for the extra hospital use, the penicillin allergy group cost the health care system $64,626,630 more than for the group who did not have a penicillin allergy label.⁷ A subsequent study by Macy and Contreras of both inpatient and outpatient settings showed a potential savings of $2,000 per patient per year in health care expenses with the testing and delabeling of penicillin allergies.²³ Use of newer and broad-spectrum antibiotics also are more costly and contribute to higher health care costs.²⁴

When these potential savings are applied to the military insurance population of 9.4 million beneficiaries (TRICARE, including active duty, their dependents, and all retirees participating in the program), the results showed that this could impart a savings of nearly $1.7 billion annually, using the model by Macy and Contreras.^23,25,26

Previously with colleagues, I reviewed penicillin’s role in military history, compiled data from relevant studies from military penicillin allergy rates and delabeling efforts, and calculated the potential economic impact of penicillin allergies along with the benefits of testing.²⁶ Calculations were estimated using the TRICARE beneficiary population (9.4 million) × the estimated prevalence (10%) to get an estimate of 940,000 TRICARE patients with penicillin allergy in their medical record.²⁵ If 90% of those patients were delabeled, this would equal 846,000 TRICARE patients. When multiplied by the potential savings of $2,000 per patient per year, the estimated savings would be $1,692,000,000 annually.^23,26

Current literature provides compelling evidence that all health care plans should use penicillin allergy testing and delabeling programs.^3,23,26 As most patients with a history of penicillin allergy in their medical records do not have a verified allergy, delabeling those who do not have a true allergy will have individual, public health, and cost benefits.^3,7,23,26

Antibiotic Stewardship

Antibiotic stewardship programs are now mandated to combat antibiotic resistance.^3,27 This program is supported by major medical organizations, including the Centers for Disease Control and Prevention, Society for Healthcare Epidemiology of America, Infectious Disease Society of America, and the American Academy of Allergy Asthma and Immunology.³ Given the role of broad-spectrum antibiotics in antibiotic resistance, penicillin allergy testing and delabeling is an important component of these programs.³

In the US, > 2 million people acquire antibiotic resistant infections annually; 23,000 people die of these infections.²⁷ More than 250,000 illnesses and 14,000 deaths annually are due to C difficile.²⁷ There are many factors contributing to the increase in antibiotic resistance; however, one established and consistent factor is the use of broad-spectrum antibiotics. Further, broad-spectrum antibiotics are often used when first-line agents, such as penicillins, cannot be used due to a reported “allergy.” In addition, there are fewer novel antibiotics being developed, and as they are introduced, pathogens develop resistance to these new agents.²⁷

Military Relevance

Infectious diseases have always accompanied military activity.^28-30 Despite preventive programs such as vaccinations, hygiene measures, and prophylactic antibiotics, military personnel are at increased risk for infections due to the military’s mobile nature and crowded living situations.^28-30 This situation has operational relevance from basic training, deployments, and combat operations to peacetime activities.

Military recruits are treated routinely with penicillin G benzathine as standard prophylaxis against streptococcal infections.^26,30 A recent study by the Marine Corps Recruiting Depot in San Diego, California showed that in a cohort of 402 young healthy male recruits, only 5 (1.5%) had a positive reaction to penicillin testing and challenge over a 21-month period.³¹ The delabeled other 397 (98.5%) marine recruits were able to receive benzathine penicillin prophylaxis successfully.³¹ Recruits with a penicillin allergy who had a positive test or were not tested received azithromycin (or erythromycin at some recruit training locations).^26,31 Military members may need to operate in remote or austere locations; the ability to use penicillins is important for readiness.

Evaluation and Management of Reported Penicillin Allergy

Verifying penicillin allergies is an important first step in optimizing medical care and decreasing resistance and ADRs.^3,4,32,33 Although allergists can provide specialized evaluation, due to the high prevalence of penicillin allergy in the US, all health care team members, including clinicians and pharmacists, should be educated about penicillin allergies and be able to implement evaluations in both inpatient and outpatient settings. Reactions to any of the penicillins should be considered, including the natural penicillins (penicillin V, etc), antistaphylococcal penicillins (dicloxacillin), aminopenicillins (amoxicillin and ampicillin), and extended-spectrum penicillins (piperacillin).³ A thorough history, including the prior reaction (age, type of reaction) and subsequent tolerance are helpful in stratifying patients.^3,26

Patient Risk Levels

Based on the clinical history, patients would fall into 4 categories from low risk, medium risk, high risk, to do not test/use.^3,32,33 Low-risk patients are those who report mild or nonallergic symptoms (ie, gastrointestinal symptoms, headache, yeast infection, etc), remote cutaneous reactions (> 10 years), or in those with a family history of penicillin allergy.^3,32,33 Low-risk patients often can be safely tested with an oral challenge. Although there are different approaches to the oral challenge, a single amoxicillin dose of 250 mg followed by 1 hour of direct monitoring is usually sufficient.^3,32,33

Medium-risk patients have a more recent (< 1 year) history of pruritic rashes, urticaria, and/or angioedema without a history of severe or systemic reactions. These patients benefit from negative skin testing prior to an oral challenge, which can be performed by trained clinicians or pharmacists or an allergist. However, due to limited availability of skin testing and the potential for false positive testing with skin tests, a single dose or graded challenge would be a reasonable approach as well.^3,32,33

High-risk patients are those with severe symptoms (anaphylaxis), a history of reactions to other β-lactam antibiotics, and/or recurrent reactions to antibiotics. These patients benefit from a formal evaluation by an allergist and skin testing prior to challenge.^3,32,33 Testing and/or challenge should not be performed in patients who report a history of severe cutaneous reactions (blistering rash, such as Stevens Johnson syndrome), hemolytic anemia, serum sickness, drug fever, and other organ dysfunction.^3,4,31,32

Conclusions

Penicillin allergies are an important barrier to effective antibiotic treatments and are associated with worse outcomes and higher economic costs.^3,7,23,26,34 Therefore, in addition to vaccinations, infection control measures, and public health education, penicillin allergy verification and delabeling programs should be a proactive component of military medical readiness and all antibiotic stewardship initiatives in all health care settings.²⁹ Given the many issues and negative impact of having a penicillin allergy label, penicillin delabeling will allow service members to be treated with the necessary antibiotics with fewer adverse complications, and return them to health and readiness for operational duties. In the current standardization of the Defense Health Agency, implementing this program across all services would have significant clinical, public health, and cost benefits for patients, the health care team, taxpayers, and the community at large.

Many patients report an allergy to penicillin, but only a small portion have a current true immune-mediated allergy. Given the clinical, public health, and economic costs associated with a penicillin allergy label, evaluation and clearance of penicillin allergies is a simple method that would improve clinical outcomes, decrease AEs to high-risk alternative broad-spectrum antibiotics, and prevent the spread of antibiotic resistance. In the military, penicillin delabeling improves readiness with optimal antibiotic options and avoidance of unnecessary risks of using alternative antibiotics, expediting return to full duty for military personnel.

Antibiotics are one of the most frequently prescribed medications in both inpatient and outpatient settings.^1,2 More than 266 million courses of antibiotics are prescribed annually in the outpatient setting; 49.9% of hospitalized patients were prescribed ≥ 1 antibiotic during their hospitalization.^1,2 Among all classes of antibiotics, penicillins are prescribed due to their clinical efficacy, cost-effectiveness, and general safety for all ages. Unfortunately, penicillins also are the most common drug allergy listed in medical records. Patients with this allergy are consistently treated with broad-spectrum antibiotics, have more antibiotic resistant infections, incur higher health care costs, and experience more adverse effects (AEs).^3,4

Drug allergies are distinguished by different immune mechanisms, including IgE-mediated reaction, T-lymphocyte-mediated mild skin reactions, and severe cutaneous adverse reactions (SCAR), or other systemic immune syndromes, such as hemolytic anemia, nephritis, and rash with eosinophilia.³ Although drug allergies should be a concern, compelling evidence shows that > 90% of patients labeled with a penicillin allergy are not allergic to penicillins (and associated β-lactams).^3,4 Although this evidence is growing, clinicians still hesitate to prescribe penicillin, and patients are similarly anxious to take them. This article reviews the health care consequences of penicillin allergy and the application of this information to military medicine and readiness.

Penicillin Allergy Prevalence

Since their approval for public use in 1945, penicillins have been one of the most often prescribed antibiotics due to their clinical efficacy for many types of infections.³ However, 8 to 10% of the US population and up to 15% of hospitalized patients have a documented penicillin allergy, which limits the ability to use these effective antibiotics.^3,4 Once a patient is labeled with a penicillin allergy, many clinicians avoid prescribing all β-lactam antibiotics to patients. Clinicians also avoid prescribing cephalosporins due to the concern for potential cross-reactivity (at a rate of about 2%, which is lower than previously reported).³ These reported allergies are often not clear and range from patients avoiding penicillins because their parents exhibited allergies, they had a symptom that was not likely allergic (ie, nausea, headache, itching with no rash), being told by their parents that they had a rash as a child, or experiencing severe anaphylaxis or other systemic reaction.^3,4 Despite the high rates of documented penicillin allergy, studies now show that most patients do not have a serious allergy; < 1% of the population has a true immune-mediated penicillin allergy.^3,4

Broad-Spectrum Antibiotic Risks

Even though penicillin allergies are often not confirmed, many patients are treated with alternative antibiotics. Unfortunately, most alternative antibiotics are not as effective or as safe as penicillin.^3,4 Twenty percent of hospitalized patients will experience an AE related to their antibiotic; 19.3% of emergency department visits for adverse drug reactions (ADRs) are from antibiotics.^5,6 Sulfonamides, clindamycin, and quinolones were the antibiotics most commonly associated with AEs.⁶

In a large database study over a 3-year period, > 400,000 hospitalizations were analyzed in patients matched for admission type, with and without a penicillin allergy in their medical record.⁷ Those with a documented penicillin allergy had longer hospitalizations; were treated with broad-spectrum antibiotics; and had increased rates of Clostridium difficile (C difficile), methicillin-resistant Staphylococcus aureus (MRSA), and vancomycin-resistant Enterococcus (VRE).^7,8 In addition to being first-line treatment for many common infections, penicillins often are used for dental, perinatal, and perioperative prophylaxis.^1,3 Nearly 25 million antibiotics are prescribed annually by dentists.¹ If a patient has a penicillin allergy listed in their medical record, they will inevitably receive a second- or third-line treatment that is less effective and has higher risks. Common alternative antibiotics include clindamycin, fluoroquinolones, macrolides, and vancomycin.^3,7,8

Clindamycin and fluoroquinolones are associated with C difficile infections.^9,10 Fluoroquinolones come with a boxed warning for known serious ADRs, including tendon rupture, peripheral neuropathy, central nervous system effects, and are known for causing cardiac reactions such as QT prolongation, life-threatening arrhythmias, and cardiovascular death.^11,12 Fluoroquinolones are associated with an increased risk for VRE and MRSA, in more than any other antibiotic classes.^3,7,12,13

Macrolides, such as azithromycin and clarithromycin, are another common class of antibiotics used as an alternative for penicillins. Both are used frequently for upper respiratory infections. Known ADRs to macrolides include gastrointestinal adverse effects (AEs) (ie, nausea, vomiting, diarrhea, and abdominal pain), liver toxicity (ie, abnormal liver function tests, hepatitis, and liver failure), and cardiac risks (ie, QT prolongation and sudden death). When compared with amoxicillin, there was an increased risk for cardiovascular mortality in those patients receiving macrolides.^14,15

Vancomycin is known for its potential to cause “red man syndrome,” an infusion-related reaction causing redness and itching as well as nephrotoxic and hematologic effects requiring close monitoring.³ Vancomycin is less effective than methicillin in clearing MRSA or other sensitive pathogens; however, vancomycin is used in patients with a penicillin allergy label.^16-18 Intrapartum antibiotic use of vancomycin for group B streptococcus infection was associated with clinically significant morbidity and ADRs.^19,20 Perioperatively, patients with penicillin allergies developed more surgical site infections due to the use of second-line antibiotics, such as vancomycin or others.²¹

Cost of Penicillin Allergies

Penicillin allergy plays an important role in rising health care costs. In 2017, health care spending reached 17.9% of the gross domestic product.²² Macy and Contreras demonstrated the significantly higher costs associated with having a reported (and unverified) penicillin allergy in a matched cohort study. Inferred for the extra hospital use, the penicillin allergy group cost the health care system $64,626,630 more than for the group who did not have a penicillin allergy label.⁷ A subsequent study by Macy and Contreras of both inpatient and outpatient settings showed a potential savings of $2,000 per patient per year in health care expenses with the testing and delabeling of penicillin allergies.²³ Use of newer and broad-spectrum antibiotics also are more costly and contribute to higher health care costs.²⁴

When these potential savings are applied to the military insurance population of 9.4 million beneficiaries (TRICARE, including active duty, their dependents, and all retirees participating in the program), the results showed that this could impart a savings of nearly $1.7 billion annually, using the model by Macy and Contreras.^23,25,26

Previously with colleagues, I reviewed penicillin’s role in military history, compiled data from relevant studies from military penicillin allergy rates and delabeling efforts, and calculated the potential economic impact of penicillin allergies along with the benefits of testing.²⁶ Calculations were estimated using the TRICARE beneficiary population (9.4 million) × the estimated prevalence (10%) to get an estimate of 940,000 TRICARE patients with penicillin allergy in their medical record.²⁵ If 90% of those patients were delabeled, this would equal 846,000 TRICARE patients. When multiplied by the potential savings of $2,000 per patient per year, the estimated savings would be $1,692,000,000 annually.^23,26

Current literature provides compelling evidence that all health care plans should use penicillin allergy testing and delabeling programs.^3,23,26 As most patients with a history of penicillin allergy in their medical records do not have a verified allergy, delabeling those who do not have a true allergy will have individual, public health, and cost benefits.^3,7,23,26

Antibiotic Stewardship

Antibiotic stewardship programs are now mandated to combat antibiotic resistance.^3,27 This program is supported by major medical organizations, including the Centers for Disease Control and Prevention, Society for Healthcare Epidemiology of America, Infectious Disease Society of America, and the American Academy of Allergy Asthma and Immunology.³ Given the role of broad-spectrum antibiotics in antibiotic resistance, penicillin allergy testing and delabeling is an important component of these programs.³

In the US, > 2 million people acquire antibiotic resistant infections annually; 23,000 people die of these infections.²⁷ More than 250,000 illnesses and 14,000 deaths annually are due to C difficile.²⁷ There are many factors contributing to the increase in antibiotic resistance; however, one established and consistent factor is the use of broad-spectrum antibiotics. Further, broad-spectrum antibiotics are often used when first-line agents, such as penicillins, cannot be used due to a reported “allergy.” In addition, there are fewer novel antibiotics being developed, and as they are introduced, pathogens develop resistance to these new agents.²⁷

Military Relevance

Infectious diseases have always accompanied military activity.^28-30 Despite preventive programs such as vaccinations, hygiene measures, and prophylactic antibiotics, military personnel are at increased risk for infections due to the military’s mobile nature and crowded living situations.^28-30 This situation has operational relevance from basic training, deployments, and combat operations to peacetime activities.

Military recruits are treated routinely with penicillin G benzathine as standard prophylaxis against streptococcal infections.^26,30 A recent study by the Marine Corps Recruiting Depot in San Diego, California showed that in a cohort of 402 young healthy male recruits, only 5 (1.5%) had a positive reaction to penicillin testing and challenge over a 21-month period.³¹ The delabeled other 397 (98.5%) marine recruits were able to receive benzathine penicillin prophylaxis successfully.³¹ Recruits with a penicillin allergy who had a positive test or were not tested received azithromycin (or erythromycin at some recruit training locations).^26,31 Military members may need to operate in remote or austere locations; the ability to use penicillins is important for readiness.

Evaluation and Management of Reported Penicillin Allergy

Verifying penicillin allergies is an important first step in optimizing medical care and decreasing resistance and ADRs.^3,4,32,33 Although allergists can provide specialized evaluation, due to the high prevalence of penicillin allergy in the US, all health care team members, including clinicians and pharmacists, should be educated about penicillin allergies and be able to implement evaluations in both inpatient and outpatient settings. Reactions to any of the penicillins should be considered, including the natural penicillins (penicillin V, etc), antistaphylococcal penicillins (dicloxacillin), aminopenicillins (amoxicillin and ampicillin), and extended-spectrum penicillins (piperacillin).³ A thorough history, including the prior reaction (age, type of reaction) and subsequent tolerance are helpful in stratifying patients.^3,26

Patient Risk Levels

Based on the clinical history, patients would fall into 4 categories from low risk, medium risk, high risk, to do not test/use.^3,32,33 Low-risk patients are those who report mild or nonallergic symptoms (ie, gastrointestinal symptoms, headache, yeast infection, etc), remote cutaneous reactions (> 10 years), or in those with a family history of penicillin allergy.^3,32,33 Low-risk patients often can be safely tested with an oral challenge. Although there are different approaches to the oral challenge, a single amoxicillin dose of 250 mg followed by 1 hour of direct monitoring is usually sufficient.^3,32,33

Medium-risk patients have a more recent (< 1 year) history of pruritic rashes, urticaria, and/or angioedema without a history of severe or systemic reactions. These patients benefit from negative skin testing prior to an oral challenge, which can be performed by trained clinicians or pharmacists or an allergist. However, due to limited availability of skin testing and the potential for false positive testing with skin tests, a single dose or graded challenge would be a reasonable approach as well.^3,32,33

High-risk patients are those with severe symptoms (anaphylaxis), a history of reactions to other β-lactam antibiotics, and/or recurrent reactions to antibiotics. These patients benefit from a formal evaluation by an allergist and skin testing prior to challenge.^3,32,33 Testing and/or challenge should not be performed in patients who report a history of severe cutaneous reactions (blistering rash, such as Stevens Johnson syndrome), hemolytic anemia, serum sickness, drug fever, and other organ dysfunction.^3,4,31,32

Conclusions

Penicillin allergies are an important barrier to effective antibiotic treatments and are associated with worse outcomes and higher economic costs.^3,7,23,26,34 Therefore, in addition to vaccinations, infection control measures, and public health education, penicillin allergy verification and delabeling programs should be a proactive component of military medical readiness and all antibiotic stewardship initiatives in all health care settings.²⁹ Given the many issues and negative impact of having a penicillin allergy label, penicillin delabeling will allow service members to be treated with the necessary antibiotics with fewer adverse complications, and return them to health and readiness for operational duties. In the current standardization of the Defense Health Agency, implementing this program across all services would have significant clinical, public health, and cost benefits for patients, the health care team, taxpayers, and the community at large.

Many patients report an allergy to penicillin, but only a small portion have a current true immune-mediated allergy. Given the clinical, public health, and economic costs associated with a penicillin allergy label, evaluation and clearance of penicillin allergies is a simple method that would improve clinical outcomes, decrease AEs to high-risk alternative broad-spectrum antibiotics, and prevent the spread of antibiotic resistance. In the military, penicillin delabeling improves readiness with optimal antibiotic options and avoidance of unnecessary risks of using alternative antibiotics, expediting return to full duty for military personnel.

Antibiotics are one of the most frequently prescribed medications in both inpatient and outpatient settings.^1,2 More than 266 million courses of antibiotics are prescribed annually in the outpatient setting; 49.9% of hospitalized patients were prescribed ≥ 1 antibiotic during their hospitalization.^1,2 Among all classes of antibiotics, penicillins are prescribed due to their clinical efficacy, cost-effectiveness, and general safety for all ages. Unfortunately, penicillins also are the most common drug allergy listed in medical records. Patients with this allergy are consistently treated with broad-spectrum antibiotics, have more antibiotic resistant infections, incur higher health care costs, and experience more adverse effects (AEs).^3,4

Drug allergies are distinguished by different immune mechanisms, including IgE-mediated reaction, T-lymphocyte-mediated mild skin reactions, and severe cutaneous adverse reactions (SCAR), or other systemic immune syndromes, such as hemolytic anemia, nephritis, and rash with eosinophilia.³ Although drug allergies should be a concern, compelling evidence shows that > 90% of patients labeled with a penicillin allergy are not allergic to penicillins (and associated β-lactams).^3,4 Although this evidence is growing, clinicians still hesitate to prescribe penicillin, and patients are similarly anxious to take them. This article reviews the health care consequences of penicillin allergy and the application of this information to military medicine and readiness.

Penicillin Allergy Prevalence

Since their approval for public use in 1945, penicillins have been one of the most often prescribed antibiotics due to their clinical efficacy for many types of infections.³ However, 8 to 10% of the US population and up to 15% of hospitalized patients have a documented penicillin allergy, which limits the ability to use these effective antibiotics.^3,4 Once a patient is labeled with a penicillin allergy, many clinicians avoid prescribing all β-lactam antibiotics to patients. Clinicians also avoid prescribing cephalosporins due to the concern for potential cross-reactivity (at a rate of about 2%, which is lower than previously reported).³ These reported allergies are often not clear and range from patients avoiding penicillins because their parents exhibited allergies, they had a symptom that was not likely allergic (ie, nausea, headache, itching with no rash), being told by their parents that they had a rash as a child, or experiencing severe anaphylaxis or other systemic reaction.^3,4 Despite the high rates of documented penicillin allergy, studies now show that most patients do not have a serious allergy; < 1% of the population has a true immune-mediated penicillin allergy.^3,4

Broad-Spectrum Antibiotic Risks

Even though penicillin allergies are often not confirmed, many patients are treated with alternative antibiotics. Unfortunately, most alternative antibiotics are not as effective or as safe as penicillin.^3,4 Twenty percent of hospitalized patients will experience an AE related to their antibiotic; 19.3% of emergency department visits for adverse drug reactions (ADRs) are from antibiotics.^5,6 Sulfonamides, clindamycin, and quinolones were the antibiotics most commonly associated with AEs.⁶

In a large database study over a 3-year period, > 400,000 hospitalizations were analyzed in patients matched for admission type, with and without a penicillin allergy in their medical record.⁷ Those with a documented penicillin allergy had longer hospitalizations; were treated with broad-spectrum antibiotics; and had increased rates of Clostridium difficile (C difficile), methicillin-resistant Staphylococcus aureus (MRSA), and vancomycin-resistant Enterococcus (VRE).^7,8 In addition to being first-line treatment for many common infections, penicillins often are used for dental, perinatal, and perioperative prophylaxis.^1,3 Nearly 25 million antibiotics are prescribed annually by dentists.¹ If a patient has a penicillin allergy listed in their medical record, they will inevitably receive a second- or third-line treatment that is less effective and has higher risks. Common alternative antibiotics include clindamycin, fluoroquinolones, macrolides, and vancomycin.^3,7,8

Clindamycin and fluoroquinolones are associated with C difficile infections.^9,10 Fluoroquinolones come with a boxed warning for known serious ADRs, including tendon rupture, peripheral neuropathy, central nervous system effects, and are known for causing cardiac reactions such as QT prolongation, life-threatening arrhythmias, and cardiovascular death.^11,12 Fluoroquinolones are associated with an increased risk for VRE and MRSA, in more than any other antibiotic classes.^3,7,12,13

Macrolides, such as azithromycin and clarithromycin, are another common class of antibiotics used as an alternative for penicillins. Both are used frequently for upper respiratory infections. Known ADRs to macrolides include gastrointestinal adverse effects (AEs) (ie, nausea, vomiting, diarrhea, and abdominal pain), liver toxicity (ie, abnormal liver function tests, hepatitis, and liver failure), and cardiac risks (ie, QT prolongation and sudden death). When compared with amoxicillin, there was an increased risk for cardiovascular mortality in those patients receiving macrolides.^14,15

Vancomycin is known for its potential to cause “red man syndrome,” an infusion-related reaction causing redness and itching as well as nephrotoxic and hematologic effects requiring close monitoring.³ Vancomycin is less effective than methicillin in clearing MRSA or other sensitive pathogens; however, vancomycin is used in patients with a penicillin allergy label.^16-18 Intrapartum antibiotic use of vancomycin for group B streptococcus infection was associated with clinically significant morbidity and ADRs.^19,20 Perioperatively, patients with penicillin allergies developed more surgical site infections due to the use of second-line antibiotics, such as vancomycin or others.²¹

Cost of Penicillin Allergies

Penicillin allergy plays an important role in rising health care costs. In 2017, health care spending reached 17.9% of the gross domestic product.²² Macy and Contreras demonstrated the significantly higher costs associated with having a reported (and unverified) penicillin allergy in a matched cohort study. Inferred for the extra hospital use, the penicillin allergy group cost the health care system $64,626,630 more than for the group who did not have a penicillin allergy label.⁷ A subsequent study by Macy and Contreras of both inpatient and outpatient settings showed a potential savings of $2,000 per patient per year in health care expenses with the testing and delabeling of penicillin allergies.²³ Use of newer and broad-spectrum antibiotics also are more costly and contribute to higher health care costs.²⁴

When these potential savings are applied to the military insurance population of 9.4 million beneficiaries (TRICARE, including active duty, their dependents, and all retirees participating in the program), the results showed that this could impart a savings of nearly $1.7 billion annually, using the model by Macy and Contreras.^23,25,26

Previously with colleagues, I reviewed penicillin’s role in military history, compiled data from relevant studies from military penicillin allergy rates and delabeling efforts, and calculated the potential economic impact of penicillin allergies along with the benefits of testing.²⁶ Calculations were estimated using the TRICARE beneficiary population (9.4 million) × the estimated prevalence (10%) to get an estimate of 940,000 TRICARE patients with penicillin allergy in their medical record.²⁵ If 90% of those patients were delabeled, this would equal 846,000 TRICARE patients. When multiplied by the potential savings of $2,000 per patient per year, the estimated savings would be $1,692,000,000 annually.^23,26

Current literature provides compelling evidence that all health care plans should use penicillin allergy testing and delabeling programs.^3,23,26 As most patients with a history of penicillin allergy in their medical records do not have a verified allergy, delabeling those who do not have a true allergy will have individual, public health, and cost benefits.^3,7,23,26

Antibiotic Stewardship

Antibiotic stewardship programs are now mandated to combat antibiotic resistance.^3,27 This program is supported by major medical organizations, including the Centers for Disease Control and Prevention, Society for Healthcare Epidemiology of America, Infectious Disease Society of America, and the American Academy of Allergy Asthma and Immunology.³ Given the role of broad-spectrum antibiotics in antibiotic resistance, penicillin allergy testing and delabeling is an important component of these programs.³

In the US, > 2 million people acquire antibiotic resistant infections annually; 23,000 people die of these infections.²⁷ More than 250,000 illnesses and 14,000 deaths annually are due to C difficile.²⁷ There are many factors contributing to the increase in antibiotic resistance; however, one established and consistent factor is the use of broad-spectrum antibiotics. Further, broad-spectrum antibiotics are often used when first-line agents, such as penicillins, cannot be used due to a reported “allergy.” In addition, there are fewer novel antibiotics being developed, and as they are introduced, pathogens develop resistance to these new agents.²⁷

Military Relevance

Infectious diseases have always accompanied military activity.^28-30 Despite preventive programs such as vaccinations, hygiene measures, and prophylactic antibiotics, military personnel are at increased risk for infections due to the military’s mobile nature and crowded living situations.^28-30 This situation has operational relevance from basic training, deployments, and combat operations to peacetime activities.

Military recruits are treated routinely with penicillin G benzathine as standard prophylaxis against streptococcal infections.^26,30 A recent study by the Marine Corps Recruiting Depot in San Diego, California showed that in a cohort of 402 young healthy male recruits, only 5 (1.5%) had a positive reaction to penicillin testing and challenge over a 21-month period.³¹ The delabeled other 397 (98.5%) marine recruits were able to receive benzathine penicillin prophylaxis successfully.³¹ Recruits with a penicillin allergy who had a positive test or were not tested received azithromycin (or erythromycin at some recruit training locations).^26,31 Military members may need to operate in remote or austere locations; the ability to use penicillins is important for readiness.

Evaluation and Management of Reported Penicillin Allergy

Verifying penicillin allergies is an important first step in optimizing medical care and decreasing resistance and ADRs.^3,4,32,33 Although allergists can provide specialized evaluation, due to the high prevalence of penicillin allergy in the US, all health care team members, including clinicians and pharmacists, should be educated about penicillin allergies and be able to implement evaluations in both inpatient and outpatient settings. Reactions to any of the penicillins should be considered, including the natural penicillins (penicillin V, etc), antistaphylococcal penicillins (dicloxacillin), aminopenicillins (amoxicillin and ampicillin), and extended-spectrum penicillins (piperacillin).³ A thorough history, including the prior reaction (age, type of reaction) and subsequent tolerance are helpful in stratifying patients.^3,26

Patient Risk Levels

Based on the clinical history, patients would fall into 4 categories from low risk, medium risk, high risk, to do not test/use.^3,32,33 Low-risk patients are those who report mild or nonallergic symptoms (ie, gastrointestinal symptoms, headache, yeast infection, etc), remote cutaneous reactions (> 10 years), or in those with a family history of penicillin allergy.^3,32,33 Low-risk patients often can be safely tested with an oral challenge. Although there are different approaches to the oral challenge, a single amoxicillin dose of 250 mg followed by 1 hour of direct monitoring is usually sufficient.^3,32,33

Medium-risk patients have a more recent (< 1 year) history of pruritic rashes, urticaria, and/or angioedema without a history of severe or systemic reactions. These patients benefit from negative skin testing prior to an oral challenge, which can be performed by trained clinicians or pharmacists or an allergist. However, due to limited availability of skin testing and the potential for false positive testing with skin tests, a single dose or graded challenge would be a reasonable approach as well.^3,32,33

High-risk patients are those with severe symptoms (anaphylaxis), a history of reactions to other β-lactam antibiotics, and/or recurrent reactions to antibiotics. These patients benefit from a formal evaluation by an allergist and skin testing prior to challenge.^3,32,33 Testing and/or challenge should not be performed in patients who report a history of severe cutaneous reactions (blistering rash, such as Stevens Johnson syndrome), hemolytic anemia, serum sickness, drug fever, and other organ dysfunction.^3,4,31,32

Conclusions

Penicillin allergies are an important barrier to effective antibiotic treatments and are associated with worse outcomes and higher economic costs.^3,7,23,26,34 Therefore, in addition to vaccinations, infection control measures, and public health education, penicillin allergy verification and delabeling programs should be a proactive component of military medical readiness and all antibiotic stewardship initiatives in all health care settings.²⁹ Given the many issues and negative impact of having a penicillin allergy label, penicillin delabeling will allow service members to be treated with the necessary antibiotics with fewer adverse complications, and return them to health and readiness for operational duties. In the current standardization of the Defense Health Agency, implementing this program across all services would have significant clinical, public health, and cost benefits for patients, the health care team, taxpayers, and the community at large.

Many patients report an allergy to penicillin, but only a small portion have a current true immune-mediated allergy. Given the clinical, public health, and economic costs associated with a penicillin allergy label, evaluation and clearance of penicillin allergies is a simple method that would improve clinical outcomes, decrease AEs to high-risk alternative broad-spectrum antibiotics, and prevent the spread of antibiotic resistance. In the military, penicillin delabeling improves readiness with optimal antibiotic options and avoidance of unnecessary risks of using alternative antibiotics, expediting return to full duty for military personnel.

The Centers for Disease Control and Prevention acknowledged Oct. 5 in updated guidance that COVID-19 can sometimes be spread through the air, especially in enclosed spaces with poor ventilation, when people are more than 6 feet apart.

The information reiterates, however, that “COVID-19 is thought to spread mainly through close contact from person to person, including between people who are physically near each other (within about 6 feet). People who are infected but do not show symptoms can also spread the virus to others.”

In a statement to the media, the CDC said, “Today’s update acknowledges the existence of some published reports showing limited, uncommon circumstances where people with COVID-19 infected others who were more than 6 feet away or shortly after the COVID-19–positive person left an area. In these instances, transmission occurred in poorly ventilated and enclosed spaces that often involved activities that caused heavier breathing, like singing or exercise. Such environments and activities may contribute to the buildup of virus-carrying particles.”

“This is HUGE and been long delayed. But glad it’s now CDC official,” tweeted Eric Feigl-Ding, MD, an epidemiologist and health economist at Harvard University, Boston on Oct. 5.

The CDC announcement follows an abrupt flip-flop on information last month surrounding the aerosol spread of the virus.
 

Information deleted from website last month

On September 18, the CDC had added to its existing guidance that the virus is spread “through respiratory droplets or small particles, such as those in aerosols, produced when an infected person coughs, sneezes, sings, talks, or breathes. These particles can be inhaled into the nose, mouth, airways, and lungs and cause infection.”

The CDC then deleted that guidance on Sept. 21, saying it was a draft update released in error.

A key element of the now-deleted guidance said, “this is thought to be the main way the virus spreads.”

The information updated today reverses the now-deleted guidance and says aerosol transmission is not the main way the virus spreads.

It states that people who are within 6 feet of a person with COVID-19 or have direct contact with that person have the greatest risk of infection.

The CDC reiterated in the statement to the media today, “People can protect themselves from the virus that causes COVID-19 by staying at least 6 feet away from others, wearing a mask that covers their nose and mouth, washing their hands frequently, cleaning touched surfaces often, and staying home when sick.”

Among the journals that have published evidence on aerosol spread is Clinical Infectious Diseases, which, on July 6, published the paper, “It Is Time to Address Airborne Transmission of Coronavirus Disease 2019,” which was supported by 239 scientists.

The authors wrote, “there is significant potential for inhalation exposure to viruses in microscopic respiratory droplets (microdroplets) at short to medium distances (up to several meters, or room scale).”

Aerosols and airborne transmission “are the only way to explain super-spreader events we are seeing,” said Kimberly Prather, PhD, an atmospheric chemist at the University of California at San Diego, in an interview Oct. 5 with the Washington Post.

Dr. Prather added that, once aerosolization is acknowledged, this becomes a “fixable” problem through proper ventilation.

“Wear masks at all times indoors when others are present,” Dr. Prather said. But when inside, she said, there’s no such thing as a completely safe social distance.

This article first appeared on Medscape.com.

The Centers for Disease Control and Prevention acknowledged Oct. 5 in updated guidance that COVID-19 can sometimes be spread through the air, especially in enclosed spaces with poor ventilation, when people are more than 6 feet apart.

The information reiterates, however, that “COVID-19 is thought to spread mainly through close contact from person to person, including between people who are physically near each other (within about 6 feet). People who are infected but do not show symptoms can also spread the virus to others.”

In a statement to the media, the CDC said, “Today’s update acknowledges the existence of some published reports showing limited, uncommon circumstances where people with COVID-19 infected others who were more than 6 feet away or shortly after the COVID-19–positive person left an area. In these instances, transmission occurred in poorly ventilated and enclosed spaces that often involved activities that caused heavier breathing, like singing or exercise. Such environments and activities may contribute to the buildup of virus-carrying particles.”

“This is HUGE and been long delayed. But glad it’s now CDC official,” tweeted Eric Feigl-Ding, MD, an epidemiologist and health economist at Harvard University, Boston on Oct. 5.

The CDC announcement follows an abrupt flip-flop on information last month surrounding the aerosol spread of the virus.
 

Information deleted from website last month

On September 18, the CDC had added to its existing guidance that the virus is spread “through respiratory droplets or small particles, such as those in aerosols, produced when an infected person coughs, sneezes, sings, talks, or breathes. These particles can be inhaled into the nose, mouth, airways, and lungs and cause infection.”

The CDC then deleted that guidance on Sept. 21, saying it was a draft update released in error.

A key element of the now-deleted guidance said, “this is thought to be the main way the virus spreads.”

The information updated today reverses the now-deleted guidance and says aerosol transmission is not the main way the virus spreads.

It states that people who are within 6 feet of a person with COVID-19 or have direct contact with that person have the greatest risk of infection.

The CDC reiterated in the statement to the media today, “People can protect themselves from the virus that causes COVID-19 by staying at least 6 feet away from others, wearing a mask that covers their nose and mouth, washing their hands frequently, cleaning touched surfaces often, and staying home when sick.”

Among the journals that have published evidence on aerosol spread is Clinical Infectious Diseases, which, on July 6, published the paper, “It Is Time to Address Airborne Transmission of Coronavirus Disease 2019,” which was supported by 239 scientists.

The authors wrote, “there is significant potential for inhalation exposure to viruses in microscopic respiratory droplets (microdroplets) at short to medium distances (up to several meters, or room scale).”

Aerosols and airborne transmission “are the only way to explain super-spreader events we are seeing,” said Kimberly Prather, PhD, an atmospheric chemist at the University of California at San Diego, in an interview Oct. 5 with the Washington Post.

Dr. Prather added that, once aerosolization is acknowledged, this becomes a “fixable” problem through proper ventilation.

“Wear masks at all times indoors when others are present,” Dr. Prather said. But when inside, she said, there’s no such thing as a completely safe social distance.

This article first appeared on Medscape.com.

The Centers for Disease Control and Prevention acknowledged Oct. 5 in updated guidance that COVID-19 can sometimes be spread through the air, especially in enclosed spaces with poor ventilation, when people are more than 6 feet apart.

The information reiterates, however, that “COVID-19 is thought to spread mainly through close contact from person to person, including between people who are physically near each other (within about 6 feet). People who are infected but do not show symptoms can also spread the virus to others.”

In a statement to the media, the CDC said, “Today’s update acknowledges the existence of some published reports showing limited, uncommon circumstances where people with COVID-19 infected others who were more than 6 feet away or shortly after the COVID-19–positive person left an area. In these instances, transmission occurred in poorly ventilated and enclosed spaces that often involved activities that caused heavier breathing, like singing or exercise. Such environments and activities may contribute to the buildup of virus-carrying particles.”

“This is HUGE and been long delayed. But glad it’s now CDC official,” tweeted Eric Feigl-Ding, MD, an epidemiologist and health economist at Harvard University, Boston on Oct. 5.

The CDC announcement follows an abrupt flip-flop on information last month surrounding the aerosol spread of the virus.
 

Information deleted from website last month

On September 18, the CDC had added to its existing guidance that the virus is spread “through respiratory droplets or small particles, such as those in aerosols, produced when an infected person coughs, sneezes, sings, talks, or breathes. These particles can be inhaled into the nose, mouth, airways, and lungs and cause infection.”

The CDC then deleted that guidance on Sept. 21, saying it was a draft update released in error.

A key element of the now-deleted guidance said, “this is thought to be the main way the virus spreads.”

The information updated today reverses the now-deleted guidance and says aerosol transmission is not the main way the virus spreads.

It states that people who are within 6 feet of a person with COVID-19 or have direct contact with that person have the greatest risk of infection.

The CDC reiterated in the statement to the media today, “People can protect themselves from the virus that causes COVID-19 by staying at least 6 feet away from others, wearing a mask that covers their nose and mouth, washing their hands frequently, cleaning touched surfaces often, and staying home when sick.”

Among the journals that have published evidence on aerosol spread is Clinical Infectious Diseases, which, on July 6, published the paper, “It Is Time to Address Airborne Transmission of Coronavirus Disease 2019,” which was supported by 239 scientists.

The authors wrote, “there is significant potential for inhalation exposure to viruses in microscopic respiratory droplets (microdroplets) at short to medium distances (up to several meters, or room scale).”

Aerosols and airborne transmission “are the only way to explain super-spreader events we are seeing,” said Kimberly Prather, PhD, an atmospheric chemist at the University of California at San Diego, in an interview Oct. 5 with the Washington Post.

Dr. Prather added that, once aerosolization is acknowledged, this becomes a “fixable” problem through proper ventilation.

“Wear masks at all times indoors when others are present,” Dr. Prather said. But when inside, she said, there’s no such thing as a completely safe social distance.

This article first appeared on Medscape.com.

President Donald Trump’s COVID-19 diagnosis is raising fresh questions about the White House’s strategy for testing and containing the virus for a president whose cavalier attitude about the coronavirus has persisted since it landed on American shores.

The president has said others are tested before getting close to him, appearing to hold it as an iron shield of safety. He has largely eschewed mask-wearing and social distancing in meetings, travel and public events, while holding rallies for thousands of often maskless supporters.

The Trump administration has increasingly pinned its coronavirus testing strategy for the nation on antigen tests, which do not need a traditional lab for processing and quickly return results to patients. But the results are less accurate than those of the slower PCR tests. 

An early antigen test used by the White House was woefully inaccurate. But the new antigen test the White House is using has not been independently evaluated for accuracy and reliability. Moreover, this is the kit the Trump administration is pushing out to thousands of nursing homes to test residents and staff.

Testing “isn’t a ‘get out of jail free card,’” said Dr. Alan Wells, medical director of clinical labs at the University of Pittsburgh Medical Center and creator of its test for the novel coronavirus. In general, antigen tests can miss up to half the cases that are detected by polymerase chain reaction tests, depending on the population of patients tested, he said.

The White House said the president’s diagnosis was confirmed with a PCR test but declined to say which test delivered his initial result. The White House has been using a new antigen test from Abbott Laboratories to screen its staff for COVID-19, according to two administration officials. 

The test, known as BinaxNOW, received an emergency use authorization from the Food and Drug Administration in August. It produces results in 15 minutes. Yet little is independently known about how effective it is. According to the company, the test is 97% accurate in detecting positives and 98.5% accurate in identifying those without disease. Abbott’s stated performance of its antigen test was based on examining people within 7 days of COVID symptoms appearing.

The president and first lady have both had symptoms, according to White House chief of staff Mark Meadows and the first lady’s Twitter account. The president was admitted to Walter Reed National Military Medical Center on Friday evening “out of an abundance of caution,” White House press secretary Kayleigh McEnany said in a statement.

Vice President Mike Pence is also tested daily for the virus and tested negative, spokesperson Devin O’Malley said Friday, but he did not respond to a follow-up question about which test was used.

Trump heavily promoted another Abbott rapid testing device, the ID NOW, earlier this year. But that test relies on different technology than the newer Abbott antigen test.

“I have not seen any independent evaluation of the Binax assay in the literature or in the blogs,” Wells said. “It is an unknown.”

The Department of Health and Human Services announced in August that it had signed a $760 million contract with Abbott for 150 million BinaxNOW antigen tests, which are now being distributed to nursing homes and historically black colleges and universities, as well as to governors to help inform decisions about opening and closing schools. The Big Ten football conference has also pinned playing hopes on the deployment of antigen tests following Trump’s political pressure.

However, even senior federal officials concede that a test alone isn’t likely to stop the spread of a virus that has sickened more than 7 million Americans.

“Testing does not substitute for avoiding crowded indoor spaces, washing hands, or wearing a mask when you can’t physically distance; further, a negative test today does not mean that you won’t be positive tomorrow,” Adm. Brett Giroir, the senior HHS official helming the administration’s testing effort, said in a statement at the time.

Trump could be part of a “super-spreading event,” said Dr. Michael Osterholm, director of the Center for Infectious Disease Research and Policy at the University of Minnesota.

Given the timing of Trump’s positive test — which he announced on Twitter early Friday – his infection “likely happened 5 or more days ago,” Osterholm said. “If so, then he was widely infectious as early as Tuesday,” the day of the first presidential debate in Cleveland.

At least seven people who attended a Rose Garden announcement last Saturday, when Trump announced his nomination of Judge Amy Coney Barrett to the Supreme Court, have since tested positive for the coronavirus. They include Trump’s former adviser Kellyanne Conway, Republican Sens. Mike Lee and Thom Tillis, and the president of the University of Notre Dame, the Rev. John Jenkins.

“Having that many infected people there all at one time, we’re still going to see transmission coming off that event for a couple days,” Osterholm said.

Osterholm notes that about 20% of infected people lead to 80% of COVID-19 cases, because “super spreaders” can infect so many people at once.

He notes that participants and audience members at Tuesday’s debate were separated by at least 6 feet. But 6 feet isn’t always enough to prevent infection, he said.

While many COVID-19 infections appear to be spread by respiratory droplets, which usually fall to the ground within 6 feet, people who are singing or speaking loudly can project virus much further. Evidence also suggests that the novel coronavirus can spread through aerosols, floating in the air like a speck of dust.

“I wonder how much virus was floating in that room that night,” Osterholm said.

Other experts say it’s too soon to say whether Trump was infected in a super-spreader event. “The president and his wife have had many exposures to many people in enclosed venues without protection,” so they could have been infected at any number of places, said Dr. William Schaffner, an infectious disease specialist at the Vanderbilt University School of Medicine. 

Although Democratic presidential candidate and former Vice President Joe Biden tested negative for the virus with a PCR test Friday, experts note that false-negative results are common in the first few days after infection. Test results over the next several days will yield more useful information.

It can take more than a week for the virus to reproduce enough to be detected, Wells said: “You are probably not detectable for 3, 5, 7, even 10 days after you’re exposed.”

In Minnesota, where Trump held an outdoor campaign rally in Duluth with hundreds of attendees Wednesday, health officials warned that a 14-day quarantine is necessary, regardless of test results.

“Anyone who was a direct contact of President Trump or known COVID-19 cases needs to quarantine and should get tested,” the Minnesota Department of Health said.

Ongoing lapses in test result reporting could hamper efforts to track and isolate sick people. As of Sept. 10, 21 states and the District of Columbia were not reporting all antigen test results, according to a KHN investigation, a lapse in reporting that officials say leaves them blind to disease spread. Since then, public health departments in Arizona, North Carolina and South Dakota all have announced plans to add antigen testing to their case reporting.

Requests for comment to the D.C. Department of Health were referred to Mayor Muriel Bowser’s office, which did not respond. District health officials told KHN in early September that the White House does not report antigen test results to them – a potential violation of federal law under the CARES Act, which says any institution performing tests to diagnose COVID-19 must report all results to local or state public health departments.

Dr. Amesh Adalja, a senior scholar at the Johns Hopkins University Center for Health Security, said it’s not surprising that Trump tested positive, given that so many of his close associates – including his national security adviser and Secret Service officers – have also been infected by the virus.

“When you look at the number of social contacts and travel schedules, it’s not surprising,” Adalja said.

Kaiser Health News is a nonprofit news service covering health issues. It is an editorially independent program of KFF (Kaiser Family Foundation), which is not affiliated with Kaiser Permanente.

President Donald Trump’s COVID-19 diagnosis is raising fresh questions about the White House’s strategy for testing and containing the virus for a president whose cavalier attitude about the coronavirus has persisted since it landed on American shores.

The president has said others are tested before getting close to him, appearing to hold it as an iron shield of safety. He has largely eschewed mask-wearing and social distancing in meetings, travel and public events, while holding rallies for thousands of often maskless supporters.

The Trump administration has increasingly pinned its coronavirus testing strategy for the nation on antigen tests, which do not need a traditional lab for processing and quickly return results to patients. But the results are less accurate than those of the slower PCR tests. 

An early antigen test used by the White House was woefully inaccurate. But the new antigen test the White House is using has not been independently evaluated for accuracy and reliability. Moreover, this is the kit the Trump administration is pushing out to thousands of nursing homes to test residents and staff.

Testing “isn’t a ‘get out of jail free card,’” said Dr. Alan Wells, medical director of clinical labs at the University of Pittsburgh Medical Center and creator of its test for the novel coronavirus. In general, antigen tests can miss up to half the cases that are detected by polymerase chain reaction tests, depending on the population of patients tested, he said.

The White House said the president’s diagnosis was confirmed with a PCR test but declined to say which test delivered his initial result. The White House has been using a new antigen test from Abbott Laboratories to screen its staff for COVID-19, according to two administration officials. 

The test, known as BinaxNOW, received an emergency use authorization from the Food and Drug Administration in August. It produces results in 15 minutes. Yet little is independently known about how effective it is. According to the company, the test is 97% accurate in detecting positives and 98.5% accurate in identifying those without disease. Abbott’s stated performance of its antigen test was based on examining people within 7 days of COVID symptoms appearing.

The president and first lady have both had symptoms, according to White House chief of staff Mark Meadows and the first lady’s Twitter account. The president was admitted to Walter Reed National Military Medical Center on Friday evening “out of an abundance of caution,” White House press secretary Kayleigh McEnany said in a statement.

Vice President Mike Pence is also tested daily for the virus and tested negative, spokesperson Devin O’Malley said Friday, but he did not respond to a follow-up question about which test was used.

Trump heavily promoted another Abbott rapid testing device, the ID NOW, earlier this year. But that test relies on different technology than the newer Abbott antigen test.

“I have not seen any independent evaluation of the Binax assay in the literature or in the blogs,” Wells said. “It is an unknown.”

The Department of Health and Human Services announced in August that it had signed a $760 million contract with Abbott for 150 million BinaxNOW antigen tests, which are now being distributed to nursing homes and historically black colleges and universities, as well as to governors to help inform decisions about opening and closing schools. The Big Ten football conference has also pinned playing hopes on the deployment of antigen tests following Trump’s political pressure.

However, even senior federal officials concede that a test alone isn’t likely to stop the spread of a virus that has sickened more than 7 million Americans.

“Testing does not substitute for avoiding crowded indoor spaces, washing hands, or wearing a mask when you can’t physically distance; further, a negative test today does not mean that you won’t be positive tomorrow,” Adm. Brett Giroir, the senior HHS official helming the administration’s testing effort, said in a statement at the time.

Trump could be part of a “super-spreading event,” said Dr. Michael Osterholm, director of the Center for Infectious Disease Research and Policy at the University of Minnesota.

Given the timing of Trump’s positive test — which he announced on Twitter early Friday – his infection “likely happened 5 or more days ago,” Osterholm said. “If so, then he was widely infectious as early as Tuesday,” the day of the first presidential debate in Cleveland.

At least seven people who attended a Rose Garden announcement last Saturday, when Trump announced his nomination of Judge Amy Coney Barrett to the Supreme Court, have since tested positive for the coronavirus. They include Trump’s former adviser Kellyanne Conway, Republican Sens. Mike Lee and Thom Tillis, and the president of the University of Notre Dame, the Rev. John Jenkins.

“Having that many infected people there all at one time, we’re still going to see transmission coming off that event for a couple days,” Osterholm said.

Osterholm notes that about 20% of infected people lead to 80% of COVID-19 cases, because “super spreaders” can infect so many people at once.

He notes that participants and audience members at Tuesday’s debate were separated by at least 6 feet. But 6 feet isn’t always enough to prevent infection, he said.

While many COVID-19 infections appear to be spread by respiratory droplets, which usually fall to the ground within 6 feet, people who are singing or speaking loudly can project virus much further. Evidence also suggests that the novel coronavirus can spread through aerosols, floating in the air like a speck of dust.

“I wonder how much virus was floating in that room that night,” Osterholm said.

Other experts say it’s too soon to say whether Trump was infected in a super-spreader event. “The president and his wife have had many exposures to many people in enclosed venues without protection,” so they could have been infected at any number of places, said Dr. William Schaffner, an infectious disease specialist at the Vanderbilt University School of Medicine. 

Although Democratic presidential candidate and former Vice President Joe Biden tested negative for the virus with a PCR test Friday, experts note that false-negative results are common in the first few days after infection. Test results over the next several days will yield more useful information.

It can take more than a week for the virus to reproduce enough to be detected, Wells said: “You are probably not detectable for 3, 5, 7, even 10 days after you’re exposed.”

In Minnesota, where Trump held an outdoor campaign rally in Duluth with hundreds of attendees Wednesday, health officials warned that a 14-day quarantine is necessary, regardless of test results.

“Anyone who was a direct contact of President Trump or known COVID-19 cases needs to quarantine and should get tested,” the Minnesota Department of Health said.

Ongoing lapses in test result reporting could hamper efforts to track and isolate sick people. As of Sept. 10, 21 states and the District of Columbia were not reporting all antigen test results, according to a KHN investigation, a lapse in reporting that officials say leaves them blind to disease spread. Since then, public health departments in Arizona, North Carolina and South Dakota all have announced plans to add antigen testing to their case reporting.

Requests for comment to the D.C. Department of Health were referred to Mayor Muriel Bowser’s office, which did not respond. District health officials told KHN in early September that the White House does not report antigen test results to them – a potential violation of federal law under the CARES Act, which says any institution performing tests to diagnose COVID-19 must report all results to local or state public health departments.

Dr. Amesh Adalja, a senior scholar at the Johns Hopkins University Center for Health Security, said it’s not surprising that Trump tested positive, given that so many of his close associates – including his national security adviser and Secret Service officers – have also been infected by the virus.

“When you look at the number of social contacts and travel schedules, it’s not surprising,” Adalja said.

Kaiser Health News is a nonprofit news service covering health issues. It is an editorially independent program of KFF (Kaiser Family Foundation), which is not affiliated with Kaiser Permanente.

President Donald Trump’s COVID-19 diagnosis is raising fresh questions about the White House’s strategy for testing and containing the virus for a president whose cavalier attitude about the coronavirus has persisted since it landed on American shores.

The president has said others are tested before getting close to him, appearing to hold it as an iron shield of safety. He has largely eschewed mask-wearing and social distancing in meetings, travel and public events, while holding rallies for thousands of often maskless supporters.

The Trump administration has increasingly pinned its coronavirus testing strategy for the nation on antigen tests, which do not need a traditional lab for processing and quickly return results to patients. But the results are less accurate than those of the slower PCR tests. 

An early antigen test used by the White House was woefully inaccurate. But the new antigen test the White House is using has not been independently evaluated for accuracy and reliability. Moreover, this is the kit the Trump administration is pushing out to thousands of nursing homes to test residents and staff.

Testing “isn’t a ‘get out of jail free card,’” said Dr. Alan Wells, medical director of clinical labs at the University of Pittsburgh Medical Center and creator of its test for the novel coronavirus. In general, antigen tests can miss up to half the cases that are detected by polymerase chain reaction tests, depending on the population of patients tested, he said.

The White House said the president’s diagnosis was confirmed with a PCR test but declined to say which test delivered his initial result. The White House has been using a new antigen test from Abbott Laboratories to screen its staff for COVID-19, according to two administration officials. 

The test, known as BinaxNOW, received an emergency use authorization from the Food and Drug Administration in August. It produces results in 15 minutes. Yet little is independently known about how effective it is. According to the company, the test is 97% accurate in detecting positives and 98.5% accurate in identifying those without disease. Abbott’s stated performance of its antigen test was based on examining people within 7 days of COVID symptoms appearing.

The president and first lady have both had symptoms, according to White House chief of staff Mark Meadows and the first lady’s Twitter account. The president was admitted to Walter Reed National Military Medical Center on Friday evening “out of an abundance of caution,” White House press secretary Kayleigh McEnany said in a statement.

Vice President Mike Pence is also tested daily for the virus and tested negative, spokesperson Devin O’Malley said Friday, but he did not respond to a follow-up question about which test was used.

Trump heavily promoted another Abbott rapid testing device, the ID NOW, earlier this year. But that test relies on different technology than the newer Abbott antigen test.

“I have not seen any independent evaluation of the Binax assay in the literature or in the blogs,” Wells said. “It is an unknown.”

The Department of Health and Human Services announced in August that it had signed a $760 million contract with Abbott for 150 million BinaxNOW antigen tests, which are now being distributed to nursing homes and historically black colleges and universities, as well as to governors to help inform decisions about opening and closing schools. The Big Ten football conference has also pinned playing hopes on the deployment of antigen tests following Trump’s political pressure.

However, even senior federal officials concede that a test alone isn’t likely to stop the spread of a virus that has sickened more than 7 million Americans.

“Testing does not substitute for avoiding crowded indoor spaces, washing hands, or wearing a mask when you can’t physically distance; further, a negative test today does not mean that you won’t be positive tomorrow,” Adm. Brett Giroir, the senior HHS official helming the administration’s testing effort, said in a statement at the time.

Trump could be part of a “super-spreading event,” said Dr. Michael Osterholm, director of the Center for Infectious Disease Research and Policy at the University of Minnesota.

Given the timing of Trump’s positive test — which he announced on Twitter early Friday – his infection “likely happened 5 or more days ago,” Osterholm said. “If so, then he was widely infectious as early as Tuesday,” the day of the first presidential debate in Cleveland.

At least seven people who attended a Rose Garden announcement last Saturday, when Trump announced his nomination of Judge Amy Coney Barrett to the Supreme Court, have since tested positive for the coronavirus. They include Trump’s former adviser Kellyanne Conway, Republican Sens. Mike Lee and Thom Tillis, and the president of the University of Notre Dame, the Rev. John Jenkins.

“Having that many infected people there all at one time, we’re still going to see transmission coming off that event for a couple days,” Osterholm said.

Osterholm notes that about 20% of infected people lead to 80% of COVID-19 cases, because “super spreaders” can infect so many people at once.

He notes that participants and audience members at Tuesday’s debate were separated by at least 6 feet. But 6 feet isn’t always enough to prevent infection, he said.

While many COVID-19 infections appear to be spread by respiratory droplets, which usually fall to the ground within 6 feet, people who are singing or speaking loudly can project virus much further. Evidence also suggests that the novel coronavirus can spread through aerosols, floating in the air like a speck of dust.

“I wonder how much virus was floating in that room that night,” Osterholm said.

Other experts say it’s too soon to say whether Trump was infected in a super-spreader event. “The president and his wife have had many exposures to many people in enclosed venues without protection,” so they could have been infected at any number of places, said Dr. William Schaffner, an infectious disease specialist at the Vanderbilt University School of Medicine. 

Although Democratic presidential candidate and former Vice President Joe Biden tested negative for the virus with a PCR test Friday, experts note that false-negative results are common in the first few days after infection. Test results over the next several days will yield more useful information.

It can take more than a week for the virus to reproduce enough to be detected, Wells said: “You are probably not detectable for 3, 5, 7, even 10 days after you’re exposed.”

In Minnesota, where Trump held an outdoor campaign rally in Duluth with hundreds of attendees Wednesday, health officials warned that a 14-day quarantine is necessary, regardless of test results.

“Anyone who was a direct contact of President Trump or known COVID-19 cases needs to quarantine and should get tested,” the Minnesota Department of Health said.

Ongoing lapses in test result reporting could hamper efforts to track and isolate sick people. As of Sept. 10, 21 states and the District of Columbia were not reporting all antigen test results, according to a KHN investigation, a lapse in reporting that officials say leaves them blind to disease spread. Since then, public health departments in Arizona, North Carolina and South Dakota all have announced plans to add antigen testing to their case reporting.

Requests for comment to the D.C. Department of Health were referred to Mayor Muriel Bowser’s office, which did not respond. District health officials told KHN in early September that the White House does not report antigen test results to them – a potential violation of federal law under the CARES Act, which says any institution performing tests to diagnose COVID-19 must report all results to local or state public health departments.

Dr. Amesh Adalja, a senior scholar at the Johns Hopkins University Center for Health Security, said it’s not surprising that Trump tested positive, given that so many of his close associates – including his national security adviser and Secret Service officers – have also been infected by the virus.

“When you look at the number of social contacts and travel schedules, it’s not surprising,” Adalja said.

Kaiser Health News is a nonprofit news service covering health issues. It is an editorially independent program of KFF (Kaiser Family Foundation), which is not affiliated with Kaiser Permanente.

U.S. regulators eventually could safely approve vaccines for COVID-19 if the process is kept free of political pressure regarding time lines, study protocols, and safety standards, expert witnesses told a House panel investigating the process on Wednesday.

The career staff of the Food and Drug Administration can be counted on to appropriately weigh whether a vaccine should be cleared for use in preventing COVID-19, witnesses, including Paul A. Offit, MD, of Children’s Hospital of Philadelphia, told the House Energy and Commerce Committee’s oversight and investigations panel.

FDA staffers would object to attempts by the Trump administration to rush a vaccine to the public without proper vetting, as would veteran federal researchers, including National Institutes of Health Director Francis S. Collins, MD, PhD, and Anthony S. Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, Offit said.

“If COVID-19 vaccines are released before they’re ready to be released, you will hear from these people, and you will also hear from people like Dr. Francis Collins and Tony Fauci, both of whom are trusted by the American public, as well as many other academicians and researchers who wouldn’t stand for this,” he said.

“The public is already nervous about these vaccines,” said Offit, who serves on key FDA and Centers for Disease Control and Prevention committees overseeing vaccine policy. “If trusted health officials stand up and decry a premature release, the celebration by the administration will be short-lived.”

Overly optimistic estimates about a potential approval can only serve to erode the public’s trust in these crucial vaccines, said another witness, Ashish K. Jha, MD, MPH, the dean of Brown University’s School of Public Health, in Providence, Rhode Island.

“All political leaders need to stop talking about things like time lines,” Jha told the lawmakers.

President Donald Trump has several times suggested that a COVID vaccine might be approved ahead of the November 3 election, where he faces a significant challenge from his Democratic rival, former Vice President Joe Biden.

In a Tuesday night debate with Biden, Trump again raised the idea of a quick approval. “Now we’re weeks away from a vaccine,” Trump said during the debate.

Trump’s estimates, though, are not in line with those offered by most firms involved with making vaccines. The most optimistic projections have come from Pfizer Inc. The drugmaker’s chief executive, Albert Bourla, has spoken about his company possibly having data to present to the FDA as early as late October about the safety and effectiveness of a vaccine.

In a September 8 interview with the Today show, Bourla said there was a 60% chance his company would meet that goal. In response to a question, he made it clear his comments applied to a potential Pfizer application, not an approval or release of a vaccine by that time.

In response to concerns about political pressures, the FDA in June issued guidance outlining what its staff would require for approval of a COVID-19 vaccine.
 

Pushback on politics

Another witness at the Wednesday hearing, Mark McClellan, MD, PhD, a former FDA commissioner (2002 – 2004), pushed back on objections to a potential release of further guidance from the agency.

“Some recent statements from the White House have implied that FDA’s plan to release additional written guidance on its expectations for emergency use authorization of a vaccine is unnecessarily raising the bar on regulatory standards for authorization,” said McClellan in his testimony for the House panel. “That is not the case.”

Instead, further FDA guidance would be a welcome form of feedback for the firms trying to develop COVID-19 vaccines, according to McClellan, who also serves on the board of directors for Johnson & Johnson. Johnson & Johnson is among the firms that have advanced a COVID-19 vaccine candidate to phase 3 testing. In his role as a director, he serves on the board’s regulatory compliance committee.

Along with politics, recent stumbles at FDA with emergency use authorizations (EUAs) of treatments for COVID-19 have eroded the public’s confidence in the agency, Jha told the House panel. The FDA approved hydroxychloroquine, a medicine promoted by Trump for use in COVID, under an EUA in March and then revoked this clearance in June.

Jha said the FDA’s most serious misstep was its handling of convalescent plasma, which was approved through an EUA on August 23 “in a highly advertised and widely televised announcement including the president.

“The announcement solidified in the public conversation the impression that, increasingly with this administration, politics are taking over trusted, nonpartisan scientific institutions,” he said in his testimony.

Approving a COVID-19 vaccine on the limited evidence through an EUA would mark a serious departure from FDA policy, according to Jha.

“While we sometimes accept a certain level of potential harm in experimental treatments for those who are severely ill, vaccines are given to healthy people and therefore need to have a substantially higher measure of safety and effectiveness,” he explained.

Jha said the FDA has only once before used this EUA approach for a vaccine. That was for a vaccine against inhaled anthrax and was mostly distributed to high-risk soldiers and civilians in war zones.

COVID-19, in contrast, is an infection that has changed lives around the world. The virus has contributed to more than 1 million deaths, including more than 200,000 in the United States, according to the World Health Organization.

Scientists are hoping vaccines will help curb this infection, although much of the future success of vaccines depends on how widely they are used, witnesses told the House panel.
 

Debate on approaches for vaccine effectiveness

In his testimony, Jha also noted concerns about COVID-19 vaccine trials. He included a reference to a Sept. 22 opinion article titled, “These Coronavirus Trials Don›t Answer the One Question We Need to Know,” which was written by Peter Doshi, PhD, of the University of Maryland School of Pharmacy, in Baltimore, and Eric Topol, MD, a professor of molecular medicine at Scripps Research in La Jolla, Calif. Topol is also editor in chief of Medscape.

Topol and Doshi questioned why the firms Moderna, Pfizer, and AstraZeneca structured their competing trials such that “a vaccine could meet the companies’ benchmark for success if it lowered the risk of mild Covid-19, but was never shown to reduce moderate or severe forms of the disease, or the risk of hospitalization, admissions to the intensive care unit or death.”

“To say a vaccine works should mean that most people no longer run the risk of getting seriously sick,” Topol and Doshi wrote. “That’s not what these trials will determine.”

There was disagreement about this point at the hearing. U.S. Representative Morgan Griffith (R-Va.) read the section of the Doshi-Topol article quoted above and asked one witness, Offit, to weigh in.

“Do you agree with those concerns? And either way, tell me why,” Griffith asked.

“I don’t agree,” Offit responded.

“I think it’s actually much harder to prevent asymptomatic infection or mildly symptomatic infection,” he said. “If you can prevent that, you are much more likely to prevent moderate to severe disease. So I think they have it backwards.”

But other researchers also question the approaches used with the current crop of COVID-19 vaccines.

“With the current protocols, it is conceivable that a vaccine might be considered effective – and eventually approved – based primarily on its ability to prevent mild cases alone,” wrote William Haseltine, PhD, president of the nonprofit ACCESS Health International, in a September 22 opinion article in the Washington Post titled: “Beware of COVID-19 Vaccine Trials Designed to Succeed From the Start.”
In an interview with Medscape Medical News on Wednesday, Haseltine said he maintains these concerns about the tests. Earlier in his career, he was a leader in HIV research through his lab at Harvard University in Cambridge, Massachusetts, and he subsequently led a biotech company, Human Genome Sciences.

He fears consumers will not get what they might expect from the vaccines being tested.

“What people care about is if this is going to keep them out of the hospital and will it keep them alive. And that’s not even part of this protocol,” Haseltine said.

This article first appeared on Medscape.com.

U.S. regulators eventually could safely approve vaccines for COVID-19 if the process is kept free of political pressure regarding time lines, study protocols, and safety standards, expert witnesses told a House panel investigating the process on Wednesday.

The career staff of the Food and Drug Administration can be counted on to appropriately weigh whether a vaccine should be cleared for use in preventing COVID-19, witnesses, including Paul A. Offit, MD, of Children’s Hospital of Philadelphia, told the House Energy and Commerce Committee’s oversight and investigations panel.

FDA staffers would object to attempts by the Trump administration to rush a vaccine to the public without proper vetting, as would veteran federal researchers, including National Institutes of Health Director Francis S. Collins, MD, PhD, and Anthony S. Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, Offit said.

“If COVID-19 vaccines are released before they’re ready to be released, you will hear from these people, and you will also hear from people like Dr. Francis Collins and Tony Fauci, both of whom are trusted by the American public, as well as many other academicians and researchers who wouldn’t stand for this,” he said.

“The public is already nervous about these vaccines,” said Offit, who serves on key FDA and Centers for Disease Control and Prevention committees overseeing vaccine policy. “If trusted health officials stand up and decry a premature release, the celebration by the administration will be short-lived.”

Overly optimistic estimates about a potential approval can only serve to erode the public’s trust in these crucial vaccines, said another witness, Ashish K. Jha, MD, MPH, the dean of Brown University’s School of Public Health, in Providence, Rhode Island.

“All political leaders need to stop talking about things like time lines,” Jha told the lawmakers.

President Donald Trump has several times suggested that a COVID vaccine might be approved ahead of the November 3 election, where he faces a significant challenge from his Democratic rival, former Vice President Joe Biden.

In a Tuesday night debate with Biden, Trump again raised the idea of a quick approval. “Now we’re weeks away from a vaccine,” Trump said during the debate.

Trump’s estimates, though, are not in line with those offered by most firms involved with making vaccines. The most optimistic projections have come from Pfizer Inc. The drugmaker’s chief executive, Albert Bourla, has spoken about his company possibly having data to present to the FDA as early as late October about the safety and effectiveness of a vaccine.

In a September 8 interview with the Today show, Bourla said there was a 60% chance his company would meet that goal. In response to a question, he made it clear his comments applied to a potential Pfizer application, not an approval or release of a vaccine by that time.

In response to concerns about political pressures, the FDA in June issued guidance outlining what its staff would require for approval of a COVID-19 vaccine.
 

Pushback on politics

Another witness at the Wednesday hearing, Mark McClellan, MD, PhD, a former FDA commissioner (2002 – 2004), pushed back on objections to a potential release of further guidance from the agency.

“Some recent statements from the White House have implied that FDA’s plan to release additional written guidance on its expectations for emergency use authorization of a vaccine is unnecessarily raising the bar on regulatory standards for authorization,” said McClellan in his testimony for the House panel. “That is not the case.”

Instead, further FDA guidance would be a welcome form of feedback for the firms trying to develop COVID-19 vaccines, according to McClellan, who also serves on the board of directors for Johnson & Johnson. Johnson & Johnson is among the firms that have advanced a COVID-19 vaccine candidate to phase 3 testing. In his role as a director, he serves on the board’s regulatory compliance committee.

Along with politics, recent stumbles at FDA with emergency use authorizations (EUAs) of treatments for COVID-19 have eroded the public’s confidence in the agency, Jha told the House panel. The FDA approved hydroxychloroquine, a medicine promoted by Trump for use in COVID, under an EUA in March and then revoked this clearance in June.

Jha said the FDA’s most serious misstep was its handling of convalescent plasma, which was approved through an EUA on August 23 “in a highly advertised and widely televised announcement including the president.

“The announcement solidified in the public conversation the impression that, increasingly with this administration, politics are taking over trusted, nonpartisan scientific institutions,” he said in his testimony.

Approving a COVID-19 vaccine on the limited evidence through an EUA would mark a serious departure from FDA policy, according to Jha.

“While we sometimes accept a certain level of potential harm in experimental treatments for those who are severely ill, vaccines are given to healthy people and therefore need to have a substantially higher measure of safety and effectiveness,” he explained.

Jha said the FDA has only once before used this EUA approach for a vaccine. That was for a vaccine against inhaled anthrax and was mostly distributed to high-risk soldiers and civilians in war zones.

COVID-19, in contrast, is an infection that has changed lives around the world. The virus has contributed to more than 1 million deaths, including more than 200,000 in the United States, according to the World Health Organization.

Scientists are hoping vaccines will help curb this infection, although much of the future success of vaccines depends on how widely they are used, witnesses told the House panel.
 

Debate on approaches for vaccine effectiveness

In his testimony, Jha also noted concerns about COVID-19 vaccine trials. He included a reference to a Sept. 22 opinion article titled, “These Coronavirus Trials Don›t Answer the One Question We Need to Know,” which was written by Peter Doshi, PhD, of the University of Maryland School of Pharmacy, in Baltimore, and Eric Topol, MD, a professor of molecular medicine at Scripps Research in La Jolla, Calif. Topol is also editor in chief of Medscape.

Topol and Doshi questioned why the firms Moderna, Pfizer, and AstraZeneca structured their competing trials such that “a vaccine could meet the companies’ benchmark for success if it lowered the risk of mild Covid-19, but was never shown to reduce moderate or severe forms of the disease, or the risk of hospitalization, admissions to the intensive care unit or death.”

“To say a vaccine works should mean that most people no longer run the risk of getting seriously sick,” Topol and Doshi wrote. “That’s not what these trials will determine.”

There was disagreement about this point at the hearing. U.S. Representative Morgan Griffith (R-Va.) read the section of the Doshi-Topol article quoted above and asked one witness, Offit, to weigh in.

“Do you agree with those concerns? And either way, tell me why,” Griffith asked.

“I don’t agree,” Offit responded.

“I think it’s actually much harder to prevent asymptomatic infection or mildly symptomatic infection,” he said. “If you can prevent that, you are much more likely to prevent moderate to severe disease. So I think they have it backwards.”

But other researchers also question the approaches used with the current crop of COVID-19 vaccines.

“With the current protocols, it is conceivable that a vaccine might be considered effective – and eventually approved – based primarily on its ability to prevent mild cases alone,” wrote William Haseltine, PhD, president of the nonprofit ACCESS Health International, in a September 22 opinion article in the Washington Post titled: “Beware of COVID-19 Vaccine Trials Designed to Succeed From the Start.”
In an interview with Medscape Medical News on Wednesday, Haseltine said he maintains these concerns about the tests. Earlier in his career, he was a leader in HIV research through his lab at Harvard University in Cambridge, Massachusetts, and he subsequently led a biotech company, Human Genome Sciences.

He fears consumers will not get what they might expect from the vaccines being tested.

“What people care about is if this is going to keep them out of the hospital and will it keep them alive. And that’s not even part of this protocol,” Haseltine said.

This article first appeared on Medscape.com.

U.S. regulators eventually could safely approve vaccines for COVID-19 if the process is kept free of political pressure regarding time lines, study protocols, and safety standards, expert witnesses told a House panel investigating the process on Wednesday.

The career staff of the Food and Drug Administration can be counted on to appropriately weigh whether a vaccine should be cleared for use in preventing COVID-19, witnesses, including Paul A. Offit, MD, of Children’s Hospital of Philadelphia, told the House Energy and Commerce Committee’s oversight and investigations panel.

FDA staffers would object to attempts by the Trump administration to rush a vaccine to the public without proper vetting, as would veteran federal researchers, including National Institutes of Health Director Francis S. Collins, MD, PhD, and Anthony S. Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, Offit said.

“If COVID-19 vaccines are released before they’re ready to be released, you will hear from these people, and you will also hear from people like Dr. Francis Collins and Tony Fauci, both of whom are trusted by the American public, as well as many other academicians and researchers who wouldn’t stand for this,” he said.

“The public is already nervous about these vaccines,” said Offit, who serves on key FDA and Centers for Disease Control and Prevention committees overseeing vaccine policy. “If trusted health officials stand up and decry a premature release, the celebration by the administration will be short-lived.”

Overly optimistic estimates about a potential approval can only serve to erode the public’s trust in these crucial vaccines, said another witness, Ashish K. Jha, MD, MPH, the dean of Brown University’s School of Public Health, in Providence, Rhode Island.

“All political leaders need to stop talking about things like time lines,” Jha told the lawmakers.

President Donald Trump has several times suggested that a COVID vaccine might be approved ahead of the November 3 election, where he faces a significant challenge from his Democratic rival, former Vice President Joe Biden.

In a Tuesday night debate with Biden, Trump again raised the idea of a quick approval. “Now we’re weeks away from a vaccine,” Trump said during the debate.

Trump’s estimates, though, are not in line with those offered by most firms involved with making vaccines. The most optimistic projections have come from Pfizer Inc. The drugmaker’s chief executive, Albert Bourla, has spoken about his company possibly having data to present to the FDA as early as late October about the safety and effectiveness of a vaccine.

In a September 8 interview with the Today show, Bourla said there was a 60% chance his company would meet that goal. In response to a question, he made it clear his comments applied to a potential Pfizer application, not an approval or release of a vaccine by that time.

In response to concerns about political pressures, the FDA in June issued guidance outlining what its staff would require for approval of a COVID-19 vaccine.
 

Pushback on politics

Another witness at the Wednesday hearing, Mark McClellan, MD, PhD, a former FDA commissioner (2002 – 2004), pushed back on objections to a potential release of further guidance from the agency.

“Some recent statements from the White House have implied that FDA’s plan to release additional written guidance on its expectations for emergency use authorization of a vaccine is unnecessarily raising the bar on regulatory standards for authorization,” said McClellan in his testimony for the House panel. “That is not the case.”

Instead, further FDA guidance would be a welcome form of feedback for the firms trying to develop COVID-19 vaccines, according to McClellan, who also serves on the board of directors for Johnson & Johnson. Johnson & Johnson is among the firms that have advanced a COVID-19 vaccine candidate to phase 3 testing. In his role as a director, he serves on the board’s regulatory compliance committee.

Along with politics, recent stumbles at FDA with emergency use authorizations (EUAs) of treatments for COVID-19 have eroded the public’s confidence in the agency, Jha told the House panel. The FDA approved hydroxychloroquine, a medicine promoted by Trump for use in COVID, under an EUA in March and then revoked this clearance in June.

Jha said the FDA’s most serious misstep was its handling of convalescent plasma, which was approved through an EUA on August 23 “in a highly advertised and widely televised announcement including the president.

“The announcement solidified in the public conversation the impression that, increasingly with this administration, politics are taking over trusted, nonpartisan scientific institutions,” he said in his testimony.

Approving a COVID-19 vaccine on the limited evidence through an EUA would mark a serious departure from FDA policy, according to Jha.

“While we sometimes accept a certain level of potential harm in experimental treatments for those who are severely ill, vaccines are given to healthy people and therefore need to have a substantially higher measure of safety and effectiveness,” he explained.

Jha said the FDA has only once before used this EUA approach for a vaccine. That was for a vaccine against inhaled anthrax and was mostly distributed to high-risk soldiers and civilians in war zones.

COVID-19, in contrast, is an infection that has changed lives around the world. The virus has contributed to more than 1 million deaths, including more than 200,000 in the United States, according to the World Health Organization.

Scientists are hoping vaccines will help curb this infection, although much of the future success of vaccines depends on how widely they are used, witnesses told the House panel.
 

Debate on approaches for vaccine effectiveness

In his testimony, Jha also noted concerns about COVID-19 vaccine trials. He included a reference to a Sept. 22 opinion article titled, “These Coronavirus Trials Don›t Answer the One Question We Need to Know,” which was written by Peter Doshi, PhD, of the University of Maryland School of Pharmacy, in Baltimore, and Eric Topol, MD, a professor of molecular medicine at Scripps Research in La Jolla, Calif. Topol is also editor in chief of Medscape.

Topol and Doshi questioned why the firms Moderna, Pfizer, and AstraZeneca structured their competing trials such that “a vaccine could meet the companies’ benchmark for success if it lowered the risk of mild Covid-19, but was never shown to reduce moderate or severe forms of the disease, or the risk of hospitalization, admissions to the intensive care unit or death.”

“To say a vaccine works should mean that most people no longer run the risk of getting seriously sick,” Topol and Doshi wrote. “That’s not what these trials will determine.”

There was disagreement about this point at the hearing. U.S. Representative Morgan Griffith (R-Va.) read the section of the Doshi-Topol article quoted above and asked one witness, Offit, to weigh in.

“Do you agree with those concerns? And either way, tell me why,” Griffith asked.

“I don’t agree,” Offit responded.

“I think it’s actually much harder to prevent asymptomatic infection or mildly symptomatic infection,” he said. “If you can prevent that, you are much more likely to prevent moderate to severe disease. So I think they have it backwards.”

But other researchers also question the approaches used with the current crop of COVID-19 vaccines.

“With the current protocols, it is conceivable that a vaccine might be considered effective – and eventually approved – based primarily on its ability to prevent mild cases alone,” wrote William Haseltine, PhD, president of the nonprofit ACCESS Health International, in a September 22 opinion article in the Washington Post titled: “Beware of COVID-19 Vaccine Trials Designed to Succeed From the Start.”
In an interview with Medscape Medical News on Wednesday, Haseltine said he maintains these concerns about the tests. Earlier in his career, he was a leader in HIV research through his lab at Harvard University in Cambridge, Massachusetts, and he subsequently led a biotech company, Human Genome Sciences.

He fears consumers will not get what they might expect from the vaccines being tested.

“What people care about is if this is going to keep them out of the hospital and will it keep them alive. And that’s not even part of this protocol,” Haseltine said.

This article first appeared on Medscape.com.

Clozapine is an atypical antipsychotic that the US Food and Drug Administration (FDA) approved for use in schizophrenia and suicidality associated with schizophrenia or schizoaffective disorder. Clozapine has been shown to be superior to other antipsychotic treatment for treatment resistant schizophrenia (TRS), which is defined as failure of 2 adequate trials of antipsychotic therapy.¹ Up to 30% of patients with schizophrenia are classified as treatment resistant.²

Clozapine is considered the drug of choice for patients with TRS in both the US Department of Veterans Affairs (VA) policies and other evidence-based guidelines and remains the only antipsychotic with FDA approval for TRS.^2-5 Patients treated with clozapine have fewer psychiatric hospitalizations, fewer suicide attempts, lower rates of nonadherence, and less antipsychotic polypharmacy compared with patients who are treated with other antipsychotic therapy.^6,7 A 2016 study by Gören and colleagues found that in addition to the clinical benefits, there is the potential for cost savings of $22,000 for each veteran switched to and treated with clozapine for 1 year even when accounting for the cost of monitoring and potential adverse event management.⁸ This translates to a total savings of > $80 million if current utilization were doubled and half of those patients continued treatment for 1 year within the Veterans Health Administration (VHA). However, despite evidence supporting use, < 10% of Medicaid-eligible patients and only 4% of patients with schizophrenia in the VHA are prescribed clozapine.^8,9

Clozapine is underutilized for a variety of reasons, including intensive monitoring requirements, potential for severe adverse drug reactions, and concern for patient adherence.⁸ Common adverse effects (AEs) can range from mild to severe and include weight gain, constipation, sedation, orthostatic hypotension, and excessive salivation. Clozapine also carries a boxed warning for agranulocytosis, seizures, myocarditis, other cardiovascular and respiratory AEs (including orthostatic hypotension), and increased mortality in elderly patients with dementia.

Severe agranulocytosis occurs in between 0.05% and 0.86% of patients, which led the FDA to implement a Risk Evaluation and Mitigation Strategy (REMS) program for clozapine prescribing in 2015. Prior to the REMS program, each of the 6 clozapine manufacturers were required to maintain a registry to monitor for agranulocytosis. Per the REMS program requirements, health care providers (HCPs), dispensing pharmacies, and patients must be enrolled in the program and provide an updated absolute neutrophil count (ANC) prior to prescribing or dispensing clozapine. This is potentially time consuming, particularly during the first 6 months of treatment when the ANC must be monitored weekly and prescriptions are restricted to a 7-day supply. With recent changes to the REMS program, pharmacists are no longer permitted to enroll patients in the REMS system. This adds to the administrative burden on HCPs and may decrease further the likelihood of prescribing clozapine due to lack of time for these tasks. Within the VHA, a separate entity, the VA National Clozapine Coordinating Center (NCCC), reduces the administrative burden on HCPs by monitoring laboratory values, controlling dispensing, and communicating data electronically to the FDA REMS program.¹⁰

Despite the various administrative and clinical barriers and facilitators to prescribing that exist, previous studies have found that certain organizational characteristics also may influence clozapine prescribing rates. Gören and colleagues found that utilization at VHA facilities ranged from < 5% to about 20% of patients with schizophrenia. In this study, facilities with higher utilization of clozapine were more likely to have integrated nonphysician psychiatric providers in clinics and to have clear organizational structure and processes for the treatment of severe mental illness, while facilities with lower utilization rates were less likely to have a point person for clozapine management.¹¹

Although many national efforts have been made to increase clozapine use in recent years, no study has examined HCP perception of barriers and facilitators of clozapine use in the VHA. The objective of this study is to identify barriers and facilitators of clozapine use within the VHA as perceived by HCPs so that these may be addressed to increase appropriate utilization of clozapine in veterans with TRS.

Methods

This study was conducted as a national survey of mental health providers within the VHA who had a scope of practice that allowed clozapine prescribing. Any HCP in a solely administrative role was excluded. The survey tool was reviewed by clinical pharmacy specialists at the Lexington VA Health Care System for content and ease of administration. Following appropriate institutional review board approval, the survey was submitted to the organizational assessment subcommittee and the 5 national VA unions for approval per VA policy. The survey tool was built and administered through REDCap (Nashville, Tennessee) software. An electronic link was sent out to the national VA psychiatric pharmacist and national psychiatry chief listservs for dissemination to the psychiatric providers at each facility with weekly reminders sent out during the 4-week study period to maximize participation. The 29-item survey was developed to assess demographic information, HCP characteristics, perceived barriers and facilitators of clozapine use, and general clozapine knowledge. Knowledge-based questions included appropriate indications, starting dose, baseline ANC requirement, ANC monitoring requirements, and possible AEs.

Primary outcomes assessed were perceived barriers to clozapine prescribing, opinions of potential interventions to facilitate clozapine prescribing, knowledge regarding clozapine, and the impact of medication management clinics on clozapine prescribing. For the purposes of this study, a clozapine clinic was defined as an interdisciplinary team dedicated to clozapine prescribing and monitoring.

Secondary outcomes included a comparison of clozapine prescribing rates among different subgroups of HCPs. Subgroups included HCP discipline, geographic region, presence of academic affiliation, level of comfort or familiarity with clozapine, and percentage of time spent in direct patient care. The regional Veterans Integrated Service Networks (VISN) were used to evaluate the effect of geographic region on prescribing practices.

Results of the survey were analyzed using descriptive statistics. The Mann-Whitney U test was utilized to compare ordinal data from questions that were scored on a Likert scale, and nominal data was compared utilizing the χ² test. For all objectives, an α of < .05 was considered significant.

Results

Ninety-eight HCPs from 17 VISNs responded during the 4-week survey period. One participant was excluded due to a solely administrative role. HCP characteristics and demographics are described in Table 1. The majority of respondents practice in an outpatient mental health setting either at the main VA campus or at a community-based outpatient clinic (CBOC).

Primary Outcomes

Perceived Barriers to Prescribing

The majority of survey respondents rated all factors listed as at least somewhat of a barrier to prescribing. Table 2 describes the perception of these various factors as barriers to clozapine prescribing. Along with prespecified variables, a free text box was available to participants to identify other perceived barriers not listed. Among other concerns listed in this text box were patient buy-in (11.3%), process/coordination of prescribing (8.2%), time restrictions (7.2%), prescriber restrictions (7.2%), access (3.1%), credentialing problems (2.1%), and lack of clear education materials (1%).

Perceived Facilitators to Prescribing

When asked to consider the potential for increased prescribing with various interventions, most participants reported that all identified facilitators would be at least somewhat likely to increase their clozapine utilization. Table 3 describes the perception of these various factors as facilitators to clozapine prescribing. Other identified facilitators included nursing or pharmacy support for follow-ups (4.1%), advanced practice registered nurse credentialing for VHA prescribing (3.1%), utilization of national REMS program without the NCCC (3.1%), outside pharmacy use during titration phase (2.1%), prespecified coverage for HCPs while on leave (1%), and increased access to specialty consults for AEs (1%).

Clozapine Knowledge Assessment

Overall, the average score on the clozapine knowledge assessment portion of the survey was 85.6%. The most commonly missed questions concerned the minimum ANC required to initiate clozapine and the appropriate starting dose for clozapine (Table 4). No significant difference was seen in clozapine utilization based on the clozapine knowledge assessment score when HCPs who scored≤ 60% were compared with those who scored ≥ 80% (P = .29).

Clozapine Clinic

No statistically significant difference was found (P = .35) when rates of prescribing between facilities with or without a dedicated clozapine clinic were compared (Table 5). Additionally, the involvement of a pharmacist in clozapine management clinics did not lead to a statistically significant difference in utilization rates (P = .45).

Secondary Outcomes

Self-rated level of comfort with clozapine prescribing was significantly associated with rates of clozapine prescribing (P < .01). HCPs who rated themselves as somewhat or very comfortable were significantly more likely to prescribe clozapine (Table 6). Providers who rated themselves as very familiar with clozapine monitoring requirements (Table 7) were significantly more likely to prescribe clozapine (P < .01). This significance remained when comparing HCPs who rated themselves as very familiar to those who ranked themselves as somewhat familiar (P = .01). There was no statistically significant difference in clozapine prescribing based on academic medical center affiliation, time spent in direct patient care, or geographic location.

Discussion

This survey targeted VHA HCPs who were licensed to prescribe clozapine to identify barriers and facilitators of use, along with HCP characteristics that may impact clozapine utilization. The findings of this study indicate that even though HCPs may perceive many legitimate barriers to clozapine prescribing, such as the frequent laboratory monitoring requirements, some factors may increase their willingness to prescribe clozapine. Many of these facilitators involve addressing logistical concerns and the administrative burden that accompanies clozapine use. These findings echo previous studies done within and outside the VHA.^8,9

While some identified barriers would require national policy changes to address, others could be addressed at VHA facilities. It may be prudent for each VA facility to identify a HCP who is familiar with clozapine to serve as a subject matter expert. This would be beneficial to those HCPs who feel their patients may benefit from clozapine, but who lack experience in prescribing, or for those with concerns about appropriateness of a specific patient. Additionally, this point of contact could be a valuable resource for concerns regarding administrative issues that may arise with the laboratory reporting system. In some facilities, it may be beneficial to set aside dedicated prescriber time in a clinic designed for clozapine management. Many HCPs in this survey identified the establishment of a clozapine clinic as an intervention that would increase their likelihood of prescribing clozapine. This type of clinic may alleviate some of the concerns regarding appointment availability for weekly or bimonthly appointments early in therapy by having additional staff and time dedicated to accommodating the need for frequent visits.

The majority of respondents to this survey were concerned about the logistics of clozapine monitoring and prescribing; however, this is largely dictated by FDA and VHA policies and regulations. Per national guidance, patients within the VHA should only receive prescriptions for clozapine from their local VA facility pharmacy. It takes many veterans ≥ 1 hour to travel to the closest VA hospital or CBOC. This is especially true for facilities with largely rural catchments. These patients often lack many resources that may be present in more urban areas, such as reliable public transportation. This creates challenges for both weekly laboratory monitoring and dispensing of weekly clozapine prescriptions early in therapy. The option to get clozapine from a local non-VA pharmacy and complete laboratory monitoring at a non-VA laboratory facility could make a clozapine trial more feasible for these veterans. Another consideration is increasing the availability of VA-funded transportation for these patients to assist them in getting to their appointments. Serious mental illness case workers or mental health intensive case management services also may prove useful in arranging for transportation for laboratory monitoring.

Providers with higher self-rated comfort and familiarity with monitoring requirements had a significantly increased likelihood of clozapine utilization. Lack of experience was commonly identified as a barrier to prescribing. Subsequently, the majority of respondents felt that educational sessions would increase their likelihood to prescribe clozapine. This could be addressed at both a facility and national level. As discussed above, a subject matter expert at each facility could provide some of this education and guidance for prescribers who have little or no experience with clozapine. Additionally, national educational presentations and academic detailing campaigns may be an efficient way to provide standardized education across the VHA. Dissemination of required education via the VA Talent Management System is another potential route that would ensure all providers received adequate training regarding the specific challenges of prescribing clozapine within the VA.

Strengths and Limitations

The strengths of this study lie in directly assessing HCP perceptions of barriers and facilitators. It is ultimately up to each individual HCP to decide to use clozapine. Addressing the concerns of these HCPs will be advantageous in efforts to increase clozapine utilization. Additionally, to the authors’ knowledge this is the first study to assess provider characteristics and knowledge of clozapine in relation to utilization rates.

The method of distribution was a major limitation of this study. This survey was distributed via national e-mail listservs; however, no listserv exists within the VA that targets all psychiatric providers. This study relied on the psychiatry chiefs and psychiatric pharmacists within each facility to further disseminate the survey, which could have led to lower response rates than what may be gathered via more direct contact methods. In addition, targeting psychiatric section chiefs and pharmacists may have introduced response bias. Another limitation to this study was the small number of responses. It is possible that this study was not adequately powered to detect significant differences in clozapine prescribing based on HCP characteristics or clozapine clinic availability. Further studies investigating the impact of provider characteristics on clozapine utilization are warranted.

Conclusion

Even though clozapine is an effective medication for TRS, providers underutilize it for a variety of reasons. Commonly identified barriers to prescribing in this study included frequent monitoring requirements, logistics of prescribing (including the REMS program and transportation for laboratory monitoring), pharmacotherapy preferences, and concern about the potential AEs. Facilitators identified in this study included implementation of clozapine clinics, having a specified contact point within the facility to assist with administrative responsibility, educational sessions, and the ability to utilize outside laboratories.

While some of these barriers and facilitators cannot be fully addressed without national policy change, individual facilities should make every effort to identify institution-specific concerns and address these. Clozapine clinic implementation and educational sessions appear to be reasonable considerations. This study did not identify any HCP characteristics that significantly impacted the likelihood of prescribing clozapine aside from self-rated comfort and familiarity with clozapine. However, further studies are needed to fully assess the impact of provider characteristics on clozapine utilization.

Clozapine is an atypical antipsychotic that the US Food and Drug Administration (FDA) approved for use in schizophrenia and suicidality associated with schizophrenia or schizoaffective disorder. Clozapine has been shown to be superior to other antipsychotic treatment for treatment resistant schizophrenia (TRS), which is defined as failure of 2 adequate trials of antipsychotic therapy.¹ Up to 30% of patients with schizophrenia are classified as treatment resistant.²

Clozapine is considered the drug of choice for patients with TRS in both the US Department of Veterans Affairs (VA) policies and other evidence-based guidelines and remains the only antipsychotic with FDA approval for TRS.^2-5 Patients treated with clozapine have fewer psychiatric hospitalizations, fewer suicide attempts, lower rates of nonadherence, and less antipsychotic polypharmacy compared with patients who are treated with other antipsychotic therapy.^6,7 A 2016 study by Gören and colleagues found that in addition to the clinical benefits, there is the potential for cost savings of $22,000 for each veteran switched to and treated with clozapine for 1 year even when accounting for the cost of monitoring and potential adverse event management.⁸ This translates to a total savings of > $80 million if current utilization were doubled and half of those patients continued treatment for 1 year within the Veterans Health Administration (VHA). However, despite evidence supporting use, < 10% of Medicaid-eligible patients and only 4% of patients with schizophrenia in the VHA are prescribed clozapine.^8,9

Clozapine is underutilized for a variety of reasons, including intensive monitoring requirements, potential for severe adverse drug reactions, and concern for patient adherence.⁸ Common adverse effects (AEs) can range from mild to severe and include weight gain, constipation, sedation, orthostatic hypotension, and excessive salivation. Clozapine also carries a boxed warning for agranulocytosis, seizures, myocarditis, other cardiovascular and respiratory AEs (including orthostatic hypotension), and increased mortality in elderly patients with dementia.

Severe agranulocytosis occurs in between 0.05% and 0.86% of patients, which led the FDA to implement a Risk Evaluation and Mitigation Strategy (REMS) program for clozapine prescribing in 2015. Prior to the REMS program, each of the 6 clozapine manufacturers were required to maintain a registry to monitor for agranulocytosis. Per the REMS program requirements, health care providers (HCPs), dispensing pharmacies, and patients must be enrolled in the program and provide an updated absolute neutrophil count (ANC) prior to prescribing or dispensing clozapine. This is potentially time consuming, particularly during the first 6 months of treatment when the ANC must be monitored weekly and prescriptions are restricted to a 7-day supply. With recent changes to the REMS program, pharmacists are no longer permitted to enroll patients in the REMS system. This adds to the administrative burden on HCPs and may decrease further the likelihood of prescribing clozapine due to lack of time for these tasks. Within the VHA, a separate entity, the VA National Clozapine Coordinating Center (NCCC), reduces the administrative burden on HCPs by monitoring laboratory values, controlling dispensing, and communicating data electronically to the FDA REMS program.¹⁰

Despite the various administrative and clinical barriers and facilitators to prescribing that exist, previous studies have found that certain organizational characteristics also may influence clozapine prescribing rates. Gören and colleagues found that utilization at VHA facilities ranged from < 5% to about 20% of patients with schizophrenia. In this study, facilities with higher utilization of clozapine were more likely to have integrated nonphysician psychiatric providers in clinics and to have clear organizational structure and processes for the treatment of severe mental illness, while facilities with lower utilization rates were less likely to have a point person for clozapine management.¹¹

Although many national efforts have been made to increase clozapine use in recent years, no study has examined HCP perception of barriers and facilitators of clozapine use in the VHA. The objective of this study is to identify barriers and facilitators of clozapine use within the VHA as perceived by HCPs so that these may be addressed to increase appropriate utilization of clozapine in veterans with TRS.

Methods

This study was conducted as a national survey of mental health providers within the VHA who had a scope of practice that allowed clozapine prescribing. Any HCP in a solely administrative role was excluded. The survey tool was reviewed by clinical pharmacy specialists at the Lexington VA Health Care System for content and ease of administration. Following appropriate institutional review board approval, the survey was submitted to the organizational assessment subcommittee and the 5 national VA unions for approval per VA policy. The survey tool was built and administered through REDCap (Nashville, Tennessee) software. An electronic link was sent out to the national VA psychiatric pharmacist and national psychiatry chief listservs for dissemination to the psychiatric providers at each facility with weekly reminders sent out during the 4-week study period to maximize participation. The 29-item survey was developed to assess demographic information, HCP characteristics, perceived barriers and facilitators of clozapine use, and general clozapine knowledge. Knowledge-based questions included appropriate indications, starting dose, baseline ANC requirement, ANC monitoring requirements, and possible AEs.

Primary outcomes assessed were perceived barriers to clozapine prescribing, opinions of potential interventions to facilitate clozapine prescribing, knowledge regarding clozapine, and the impact of medication management clinics on clozapine prescribing. For the purposes of this study, a clozapine clinic was defined as an interdisciplinary team dedicated to clozapine prescribing and monitoring.

Secondary outcomes included a comparison of clozapine prescribing rates among different subgroups of HCPs. Subgroups included HCP discipline, geographic region, presence of academic affiliation, level of comfort or familiarity with clozapine, and percentage of time spent in direct patient care. The regional Veterans Integrated Service Networks (VISN) were used to evaluate the effect of geographic region on prescribing practices.

Results of the survey were analyzed using descriptive statistics. The Mann-Whitney U test was utilized to compare ordinal data from questions that were scored on a Likert scale, and nominal data was compared utilizing the χ² test. For all objectives, an α of < .05 was considered significant.

Results

Ninety-eight HCPs from 17 VISNs responded during the 4-week survey period. One participant was excluded due to a solely administrative role. HCP characteristics and demographics are described in Table 1. The majority of respondents practice in an outpatient mental health setting either at the main VA campus or at a community-based outpatient clinic (CBOC).

Primary Outcomes

Perceived Barriers to Prescribing

The majority of survey respondents rated all factors listed as at least somewhat of a barrier to prescribing. Table 2 describes the perception of these various factors as barriers to clozapine prescribing. Along with prespecified variables, a free text box was available to participants to identify other perceived barriers not listed. Among other concerns listed in this text box were patient buy-in (11.3%), process/coordination of prescribing (8.2%), time restrictions (7.2%), prescriber restrictions (7.2%), access (3.1%), credentialing problems (2.1%), and lack of clear education materials (1%).

Perceived Facilitators to Prescribing

When asked to consider the potential for increased prescribing with various interventions, most participants reported that all identified facilitators would be at least somewhat likely to increase their clozapine utilization. Table 3 describes the perception of these various factors as facilitators to clozapine prescribing. Other identified facilitators included nursing or pharmacy support for follow-ups (4.1%), advanced practice registered nurse credentialing for VHA prescribing (3.1%), utilization of national REMS program without the NCCC (3.1%), outside pharmacy use during titration phase (2.1%), prespecified coverage for HCPs while on leave (1%), and increased access to specialty consults for AEs (1%).

Clozapine Knowledge Assessment

Overall, the average score on the clozapine knowledge assessment portion of the survey was 85.6%. The most commonly missed questions concerned the minimum ANC required to initiate clozapine and the appropriate starting dose for clozapine (Table 4). No significant difference was seen in clozapine utilization based on the clozapine knowledge assessment score when HCPs who scored≤ 60% were compared with those who scored ≥ 80% (P = .29).

Clozapine Clinic

No statistically significant difference was found (P = .35) when rates of prescribing between facilities with or without a dedicated clozapine clinic were compared (Table 5). Additionally, the involvement of a pharmacist in clozapine management clinics did not lead to a statistically significant difference in utilization rates (P = .45).

Secondary Outcomes

Self-rated level of comfort with clozapine prescribing was significantly associated with rates of clozapine prescribing (P < .01). HCPs who rated themselves as somewhat or very comfortable were significantly more likely to prescribe clozapine (Table 6). Providers who rated themselves as very familiar with clozapine monitoring requirements (Table 7) were significantly more likely to prescribe clozapine (P < .01). This significance remained when comparing HCPs who rated themselves as very familiar to those who ranked themselves as somewhat familiar (P = .01). There was no statistically significant difference in clozapine prescribing based on academic medical center affiliation, time spent in direct patient care, or geographic location.

Discussion

This survey targeted VHA HCPs who were licensed to prescribe clozapine to identify barriers and facilitators of use, along with HCP characteristics that may impact clozapine utilization. The findings of this study indicate that even though HCPs may perceive many legitimate barriers to clozapine prescribing, such as the frequent laboratory monitoring requirements, some factors may increase their willingness to prescribe clozapine. Many of these facilitators involve addressing logistical concerns and the administrative burden that accompanies clozapine use. These findings echo previous studies done within and outside the VHA.^8,9

While some identified barriers would require national policy changes to address, others could be addressed at VHA facilities. It may be prudent for each VA facility to identify a HCP who is familiar with clozapine to serve as a subject matter expert. This would be beneficial to those HCPs who feel their patients may benefit from clozapine, but who lack experience in prescribing, or for those with concerns about appropriateness of a specific patient. Additionally, this point of contact could be a valuable resource for concerns regarding administrative issues that may arise with the laboratory reporting system. In some facilities, it may be beneficial to set aside dedicated prescriber time in a clinic designed for clozapine management. Many HCPs in this survey identified the establishment of a clozapine clinic as an intervention that would increase their likelihood of prescribing clozapine. This type of clinic may alleviate some of the concerns regarding appointment availability for weekly or bimonthly appointments early in therapy by having additional staff and time dedicated to accommodating the need for frequent visits.

The majority of respondents to this survey were concerned about the logistics of clozapine monitoring and prescribing; however, this is largely dictated by FDA and VHA policies and regulations. Per national guidance, patients within the VHA should only receive prescriptions for clozapine from their local VA facility pharmacy. It takes many veterans ≥ 1 hour to travel to the closest VA hospital or CBOC. This is especially true for facilities with largely rural catchments. These patients often lack many resources that may be present in more urban areas, such as reliable public transportation. This creates challenges for both weekly laboratory monitoring and dispensing of weekly clozapine prescriptions early in therapy. The option to get clozapine from a local non-VA pharmacy and complete laboratory monitoring at a non-VA laboratory facility could make a clozapine trial more feasible for these veterans. Another consideration is increasing the availability of VA-funded transportation for these patients to assist them in getting to their appointments. Serious mental illness case workers or mental health intensive case management services also may prove useful in arranging for transportation for laboratory monitoring.

Providers with higher self-rated comfort and familiarity with monitoring requirements had a significantly increased likelihood of clozapine utilization. Lack of experience was commonly identified as a barrier to prescribing. Subsequently, the majority of respondents felt that educational sessions would increase their likelihood to prescribe clozapine. This could be addressed at both a facility and national level. As discussed above, a subject matter expert at each facility could provide some of this education and guidance for prescribers who have little or no experience with clozapine. Additionally, national educational presentations and academic detailing campaigns may be an efficient way to provide standardized education across the VHA. Dissemination of required education via the VA Talent Management System is another potential route that would ensure all providers received adequate training regarding the specific challenges of prescribing clozapine within the VA.

Strengths and Limitations

The strengths of this study lie in directly assessing HCP perceptions of barriers and facilitators. It is ultimately up to each individual HCP to decide to use clozapine. Addressing the concerns of these HCPs will be advantageous in efforts to increase clozapine utilization. Additionally, to the authors’ knowledge this is the first study to assess provider characteristics and knowledge of clozapine in relation to utilization rates.

The method of distribution was a major limitation of this study. This survey was distributed via national e-mail listservs; however, no listserv exists within the VA that targets all psychiatric providers. This study relied on the psychiatry chiefs and psychiatric pharmacists within each facility to further disseminate the survey, which could have led to lower response rates than what may be gathered via more direct contact methods. In addition, targeting psychiatric section chiefs and pharmacists may have introduced response bias. Another limitation to this study was the small number of responses. It is possible that this study was not adequately powered to detect significant differences in clozapine prescribing based on HCP characteristics or clozapine clinic availability. Further studies investigating the impact of provider characteristics on clozapine utilization are warranted.

Conclusion

Even though clozapine is an effective medication for TRS, providers underutilize it for a variety of reasons. Commonly identified barriers to prescribing in this study included frequent monitoring requirements, logistics of prescribing (including the REMS program and transportation for laboratory monitoring), pharmacotherapy preferences, and concern about the potential AEs. Facilitators identified in this study included implementation of clozapine clinics, having a specified contact point within the facility to assist with administrative responsibility, educational sessions, and the ability to utilize outside laboratories.

While some of these barriers and facilitators cannot be fully addressed without national policy change, individual facilities should make every effort to identify institution-specific concerns and address these. Clozapine clinic implementation and educational sessions appear to be reasonable considerations. This study did not identify any HCP characteristics that significantly impacted the likelihood of prescribing clozapine aside from self-rated comfort and familiarity with clozapine. However, further studies are needed to fully assess the impact of provider characteristics on clozapine utilization.

Clozapine is an atypical antipsychotic that the US Food and Drug Administration (FDA) approved for use in schizophrenia and suicidality associated with schizophrenia or schizoaffective disorder. Clozapine has been shown to be superior to other antipsychotic treatment for treatment resistant schizophrenia (TRS), which is defined as failure of 2 adequate trials of antipsychotic therapy.¹ Up to 30% of patients with schizophrenia are classified as treatment resistant.²

Clozapine is considered the drug of choice for patients with TRS in both the US Department of Veterans Affairs (VA) policies and other evidence-based guidelines and remains the only antipsychotic with FDA approval for TRS.^2-5 Patients treated with clozapine have fewer psychiatric hospitalizations, fewer suicide attempts, lower rates of nonadherence, and less antipsychotic polypharmacy compared with patients who are treated with other antipsychotic therapy.^6,7 A 2016 study by Gören and colleagues found that in addition to the clinical benefits, there is the potential for cost savings of $22,000 for each veteran switched to and treated with clozapine for 1 year even when accounting for the cost of monitoring and potential adverse event management.⁸ This translates to a total savings of > $80 million if current utilization were doubled and half of those patients continued treatment for 1 year within the Veterans Health Administration (VHA). However, despite evidence supporting use, < 10% of Medicaid-eligible patients and only 4% of patients with schizophrenia in the VHA are prescribed clozapine.^8,9

Clozapine is underutilized for a variety of reasons, including intensive monitoring requirements, potential for severe adverse drug reactions, and concern for patient adherence.⁸ Common adverse effects (AEs) can range from mild to severe and include weight gain, constipation, sedation, orthostatic hypotension, and excessive salivation. Clozapine also carries a boxed warning for agranulocytosis, seizures, myocarditis, other cardiovascular and respiratory AEs (including orthostatic hypotension), and increased mortality in elderly patients with dementia.

Severe agranulocytosis occurs in between 0.05% and 0.86% of patients, which led the FDA to implement a Risk Evaluation and Mitigation Strategy (REMS) program for clozapine prescribing in 2015. Prior to the REMS program, each of the 6 clozapine manufacturers were required to maintain a registry to monitor for agranulocytosis. Per the REMS program requirements, health care providers (HCPs), dispensing pharmacies, and patients must be enrolled in the program and provide an updated absolute neutrophil count (ANC) prior to prescribing or dispensing clozapine. This is potentially time consuming, particularly during the first 6 months of treatment when the ANC must be monitored weekly and prescriptions are restricted to a 7-day supply. With recent changes to the REMS program, pharmacists are no longer permitted to enroll patients in the REMS system. This adds to the administrative burden on HCPs and may decrease further the likelihood of prescribing clozapine due to lack of time for these tasks. Within the VHA, a separate entity, the VA National Clozapine Coordinating Center (NCCC), reduces the administrative burden on HCPs by monitoring laboratory values, controlling dispensing, and communicating data electronically to the FDA REMS program.¹⁰

Despite the various administrative and clinical barriers and facilitators to prescribing that exist, previous studies have found that certain organizational characteristics also may influence clozapine prescribing rates. Gören and colleagues found that utilization at VHA facilities ranged from < 5% to about 20% of patients with schizophrenia. In this study, facilities with higher utilization of clozapine were more likely to have integrated nonphysician psychiatric providers in clinics and to have clear organizational structure and processes for the treatment of severe mental illness, while facilities with lower utilization rates were less likely to have a point person for clozapine management.¹¹

Although many national efforts have been made to increase clozapine use in recent years, no study has examined HCP perception of barriers and facilitators of clozapine use in the VHA. The objective of this study is to identify barriers and facilitators of clozapine use within the VHA as perceived by HCPs so that these may be addressed to increase appropriate utilization of clozapine in veterans with TRS.

Methods

This study was conducted as a national survey of mental health providers within the VHA who had a scope of practice that allowed clozapine prescribing. Any HCP in a solely administrative role was excluded. The survey tool was reviewed by clinical pharmacy specialists at the Lexington VA Health Care System for content and ease of administration. Following appropriate institutional review board approval, the survey was submitted to the organizational assessment subcommittee and the 5 national VA unions for approval per VA policy. The survey tool was built and administered through REDCap (Nashville, Tennessee) software. An electronic link was sent out to the national VA psychiatric pharmacist and national psychiatry chief listservs for dissemination to the psychiatric providers at each facility with weekly reminders sent out during the 4-week study period to maximize participation. The 29-item survey was developed to assess demographic information, HCP characteristics, perceived barriers and facilitators of clozapine use, and general clozapine knowledge. Knowledge-based questions included appropriate indications, starting dose, baseline ANC requirement, ANC monitoring requirements, and possible AEs.

Primary outcomes assessed were perceived barriers to clozapine prescribing, opinions of potential interventions to facilitate clozapine prescribing, knowledge regarding clozapine, and the impact of medication management clinics on clozapine prescribing. For the purposes of this study, a clozapine clinic was defined as an interdisciplinary team dedicated to clozapine prescribing and monitoring.

Secondary outcomes included a comparison of clozapine prescribing rates among different subgroups of HCPs. Subgroups included HCP discipline, geographic region, presence of academic affiliation, level of comfort or familiarity with clozapine, and percentage of time spent in direct patient care. The regional Veterans Integrated Service Networks (VISN) were used to evaluate the effect of geographic region on prescribing practices.

Results of the survey were analyzed using descriptive statistics. The Mann-Whitney U test was utilized to compare ordinal data from questions that were scored on a Likert scale, and nominal data was compared utilizing the χ² test. For all objectives, an α of < .05 was considered significant.

Results

Ninety-eight HCPs from 17 VISNs responded during the 4-week survey period. One participant was excluded due to a solely administrative role. HCP characteristics and demographics are described in Table 1. The majority of respondents practice in an outpatient mental health setting either at the main VA campus or at a community-based outpatient clinic (CBOC).

Primary Outcomes

Perceived Barriers to Prescribing

The majority of survey respondents rated all factors listed as at least somewhat of a barrier to prescribing. Table 2 describes the perception of these various factors as barriers to clozapine prescribing. Along with prespecified variables, a free text box was available to participants to identify other perceived barriers not listed. Among other concerns listed in this text box were patient buy-in (11.3%), process/coordination of prescribing (8.2%), time restrictions (7.2%), prescriber restrictions (7.2%), access (3.1%), credentialing problems (2.1%), and lack of clear education materials (1%).

Perceived Facilitators to Prescribing

When asked to consider the potential for increased prescribing with various interventions, most participants reported that all identified facilitators would be at least somewhat likely to increase their clozapine utilization. Table 3 describes the perception of these various factors as facilitators to clozapine prescribing. Other identified facilitators included nursing or pharmacy support for follow-ups (4.1%), advanced practice registered nurse credentialing for VHA prescribing (3.1%), utilization of national REMS program without the NCCC (3.1%), outside pharmacy use during titration phase (2.1%), prespecified coverage for HCPs while on leave (1%), and increased access to specialty consults for AEs (1%).

Clozapine Knowledge Assessment

Overall, the average score on the clozapine knowledge assessment portion of the survey was 85.6%. The most commonly missed questions concerned the minimum ANC required to initiate clozapine and the appropriate starting dose for clozapine (Table 4). No significant difference was seen in clozapine utilization based on the clozapine knowledge assessment score when HCPs who scored≤ 60% were compared with those who scored ≥ 80% (P = .29).

Clozapine Clinic

No statistically significant difference was found (P = .35) when rates of prescribing between facilities with or without a dedicated clozapine clinic were compared (Table 5). Additionally, the involvement of a pharmacist in clozapine management clinics did not lead to a statistically significant difference in utilization rates (P = .45).

Secondary Outcomes

Self-rated level of comfort with clozapine prescribing was significantly associated with rates of clozapine prescribing (P < .01). HCPs who rated themselves as somewhat or very comfortable were significantly more likely to prescribe clozapine (Table 6). Providers who rated themselves as very familiar with clozapine monitoring requirements (Table 7) were significantly more likely to prescribe clozapine (P < .01). This significance remained when comparing HCPs who rated themselves as very familiar to those who ranked themselves as somewhat familiar (P = .01). There was no statistically significant difference in clozapine prescribing based on academic medical center affiliation, time spent in direct patient care, or geographic location.

Discussion

This survey targeted VHA HCPs who were licensed to prescribe clozapine to identify barriers and facilitators of use, along with HCP characteristics that may impact clozapine utilization. The findings of this study indicate that even though HCPs may perceive many legitimate barriers to clozapine prescribing, such as the frequent laboratory monitoring requirements, some factors may increase their willingness to prescribe clozapine. Many of these facilitators involve addressing logistical concerns and the administrative burden that accompanies clozapine use. These findings echo previous studies done within and outside the VHA.^8,9

While some identified barriers would require national policy changes to address, others could be addressed at VHA facilities. It may be prudent for each VA facility to identify a HCP who is familiar with clozapine to serve as a subject matter expert. This would be beneficial to those HCPs who feel their patients may benefit from clozapine, but who lack experience in prescribing, or for those with concerns about appropriateness of a specific patient. Additionally, this point of contact could be a valuable resource for concerns regarding administrative issues that may arise with the laboratory reporting system. In some facilities, it may be beneficial to set aside dedicated prescriber time in a clinic designed for clozapine management. Many HCPs in this survey identified the establishment of a clozapine clinic as an intervention that would increase their likelihood of prescribing clozapine. This type of clinic may alleviate some of the concerns regarding appointment availability for weekly or bimonthly appointments early in therapy by having additional staff and time dedicated to accommodating the need for frequent visits.

The majority of respondents to this survey were concerned about the logistics of clozapine monitoring and prescribing; however, this is largely dictated by FDA and VHA policies and regulations. Per national guidance, patients within the VHA should only receive prescriptions for clozapine from their local VA facility pharmacy. It takes many veterans ≥ 1 hour to travel to the closest VA hospital or CBOC. This is especially true for facilities with largely rural catchments. These patients often lack many resources that may be present in more urban areas, such as reliable public transportation. This creates challenges for both weekly laboratory monitoring and dispensing of weekly clozapine prescriptions early in therapy. The option to get clozapine from a local non-VA pharmacy and complete laboratory monitoring at a non-VA laboratory facility could make a clozapine trial more feasible for these veterans. Another consideration is increasing the availability of VA-funded transportation for these patients to assist them in getting to their appointments. Serious mental illness case workers or mental health intensive case management services also may prove useful in arranging for transportation for laboratory monitoring.

Providers with higher self-rated comfort and familiarity with monitoring requirements had a significantly increased likelihood of clozapine utilization. Lack of experience was commonly identified as a barrier to prescribing. Subsequently, the majority of respondents felt that educational sessions would increase their likelihood to prescribe clozapine. This could be addressed at both a facility and national level. As discussed above, a subject matter expert at each facility could provide some of this education and guidance for prescribers who have little or no experience with clozapine. Additionally, national educational presentations and academic detailing campaigns may be an efficient way to provide standardized education across the VHA. Dissemination of required education via the VA Talent Management System is another potential route that would ensure all providers received adequate training regarding the specific challenges of prescribing clozapine within the VA.

Strengths and Limitations

The strengths of this study lie in directly assessing HCP perceptions of barriers and facilitators. It is ultimately up to each individual HCP to decide to use clozapine. Addressing the concerns of these HCPs will be advantageous in efforts to increase clozapine utilization. Additionally, to the authors’ knowledge this is the first study to assess provider characteristics and knowledge of clozapine in relation to utilization rates.

The method of distribution was a major limitation of this study. This survey was distributed via national e-mail listservs; however, no listserv exists within the VA that targets all psychiatric providers. This study relied on the psychiatry chiefs and psychiatric pharmacists within each facility to further disseminate the survey, which could have led to lower response rates than what may be gathered via more direct contact methods. In addition, targeting psychiatric section chiefs and pharmacists may have introduced response bias. Another limitation to this study was the small number of responses. It is possible that this study was not adequately powered to detect significant differences in clozapine prescribing based on HCP characteristics or clozapine clinic availability. Further studies investigating the impact of provider characteristics on clozapine utilization are warranted.

Conclusion

Even though clozapine is an effective medication for TRS, providers underutilize it for a variety of reasons. Commonly identified barriers to prescribing in this study included frequent monitoring requirements, logistics of prescribing (including the REMS program and transportation for laboratory monitoring), pharmacotherapy preferences, and concern about the potential AEs. Facilitators identified in this study included implementation of clozapine clinics, having a specified contact point within the facility to assist with administrative responsibility, educational sessions, and the ability to utilize outside laboratories.

While some of these barriers and facilitators cannot be fully addressed without national policy change, individual facilities should make every effort to identify institution-specific concerns and address these. Clozapine clinic implementation and educational sessions appear to be reasonable considerations. This study did not identify any HCP characteristics that significantly impacted the likelihood of prescribing clozapine aside from self-rated comfort and familiarity with clozapine. However, further studies are needed to fully assess the impact of provider characteristics on clozapine utilization.

Despite the ongoing epidemic of misuse, overuse, and diversion of opioids, the Food and Drug Administration has set a low bar for approval of these medications over the past 20 years, new research suggests.

Results of a cross-sectional study reveal that between 1997 and 2018, the majority of approvals of opioids for the treatment of chronic pain were based on pivotal trials that lacked critical safety and efficacy data.

The study results also show that the FDA did not require manufacturers to collect safety data on tolerance, withdrawal, overdose, misuse, and diversion in any rigorous fashion.

In addition, during the study period, 17 of the 39 new drug applications (NDAs) (only one was an innovator product, known as a new molecular entity) for chronic pain were approved with an “enriched enrollment randomized withdrawal” (EERW) trial design. Such a design, in this case, allowed manufacturers to exclude 32%-43% of the initially enrolled patients from the double-blind treatment phase.

“The question for regulators, policy makers, and others is: How did we get to a point where these approvals took place based on trials that were by design unlikely to yield some of the most important information about safety and efficacy that patients and clinicians would care about?” study investigator G. Caleb Alexander, MD, Johns Hopkins University, Baltimore, said in an interview.

The study was published online Sept. 29 in the Annals of Internal Medicine.
 

‘Cooking the books’

Little is known about the evidence required by the FDA for new approvals of opioid analgesics.

To characterize the quality of safety and efficacy data in NDAs for opioid analgesics approved by the FDA between 1997 and 2018, the investigators conducted the cross-sectional analysis using data from ClinicalTrials.gov, FDA reviews, and peer-reviewed publications regarding phase 3 pivotal trials.

The investigators examined the key characteristics of each NDA, including the number, size, and duration of pivotal trials, trial control groups, use of EERW, and systematically measured safety outcomes.

Results showed that most of the 48 NDAs evaluated were for new dosage forms (52.1%) or new formulations (18.8%). Only one (2.1%) was for a new molecular entity.

Of 39 NDAs approved for the treatment of chronic pain, only 21 products were supported by at least one pivotal trial. The mean duration of these 28 trials was 84 days, and they enrolled a median of 299 patients.

Results showed that, for 17 of the 39 opioids approved for chronic pain, pivotal trials had an EERW design. For the latest period – 2012-2018 – trials of all eight of the approved opioids used the EERW method.

This EERW design allows the manufacturer to assess efficacy “among a subset of patients most likely to respond and least likely to have adverse effects, reducing generalizability to real-world settings,” the investigators noted.

They called on the FDA to stop relying on this type of trial to assess opioid efficacy.

In an August 2020 article, Andrew Kolodny, MD, pointed out the pitfalls of the EERW approach. In such a study, all participants are made physiologically dependent on the opioid in a 4- to 6-week open-label phase. Only those who tolerate the drug and find it helpful are included in the randomized study. Dr. Kolodny is codirector of opioid policy research at Brandeis University, Waltham, Mass.

“Critics of EERW have correctly described this methodology as ‘cooking the books,’ ” Dr. Kolodny writes.

He noted that the agency’s decision to rely on EERW trials for opioids was “based on discussions at private meetings between FDA officials and pharmaceutical company executives hosted by an organization called Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials.” The 2013 meetings were reported in an article published in the Washington Post.

Little sign of change

Among NDAs for chronic pain, the investigators found that eight (20.5%) included pooled safety reviews that reported systematic assessment of diversion. Seven (17.9%) reported systematic measurement of nonmedical use, and 15 (38.5%) assessed incident tolerance.

The study revealed that eight of nine products that were approved for acute pain were supported by at least one pivotal trial. The median duration of these 19 trials was 1 day, and they enrolled a median of 329 patients.

The investigators noted that the findings “underscore the evidence gaps that have limited clinicians’ and patients’ understanding and appreciation of the inherent risks of prescription opioid analgesics.”

Dr. Alexander, who has been an FDA advisory committee chairman and currently serves as a consultant to plaintiffs who are suing opioid manufacturers in federal multidistrict litigation, said the study “is a story about missed opportunities to improve the safety and to improve the regulatory review of these products.”

Coinvestigator Peter Lurie, MD, who was an official at the FDA from 2009 to 2017, said that “there’s not a lot of signs that things are changing” at the agency.

The study shows that the FDA has “accepted what the companies have been presenting,” said Dr. Lurie, who is president of the Center for Science in the Public Interest.

The FDA “absolutely has the authority” to require manufacturers to undertake more rigorous trials, but agency culture keeps it from making such demands, especially if doing so means a new applicant might have to conduct trials that weren’t previously required, Dr. Lurie said in an interview.

“FDA is pretty rigorous about trying to establish a level playing field. That’s a virtuous thing, but it becomes problematic when that prevents change,” said Dr. Lurie.

The most recent FDA guidance to manufacturers, issued in 2019, does not provide advice on criteria for endpoints, study duration, or which populations are most likely to benefit from opioid treatment. The agency also does not require drug manufacturers to formally collect data on safety, tolerance, overdose symptoms, or constipation.

The guidance does suggest that the agency would likely take into account public health considerations when evaluating opioids, such as the risk to the overall population for overdose and diversion.
 

‘Overwhelming evidence’

Dr. Kolodny said that, as far as he is aware, “this is the first scientific publication in a peer-reviewed journal demonstrating clearly the problems with FDA’s opioid approval process.”

The article offers “overwhelming evidence that they are improperly approving the most dangerous medications – medications that killed more people than any other medication on the market,” added Dr. Kolodny, who is also president of Physicians for Responsible Opioid Prescribing.

Asked to respond to the study findings, FDA spokesperson Charles Kohler said the agency “does not comment on specific studies but evaluates them as part of the body of evidence to further our understanding about a particular issue and assist in our mission to protect public health.”

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

Despite the ongoing epidemic of misuse, overuse, and diversion of opioids, the Food and Drug Administration has set a low bar for approval of these medications over the past 20 years, new research suggests.

Results of a cross-sectional study reveal that between 1997 and 2018, the majority of approvals of opioids for the treatment of chronic pain were based on pivotal trials that lacked critical safety and efficacy data.

The study results also show that the FDA did not require manufacturers to collect safety data on tolerance, withdrawal, overdose, misuse, and diversion in any rigorous fashion.

In addition, during the study period, 17 of the 39 new drug applications (NDAs) (only one was an innovator product, known as a new molecular entity) for chronic pain were approved with an “enriched enrollment randomized withdrawal” (EERW) trial design. Such a design, in this case, allowed manufacturers to exclude 32%-43% of the initially enrolled patients from the double-blind treatment phase.

“The question for regulators, policy makers, and others is: How did we get to a point where these approvals took place based on trials that were by design unlikely to yield some of the most important information about safety and efficacy that patients and clinicians would care about?” study investigator G. Caleb Alexander, MD, Johns Hopkins University, Baltimore, said in an interview.

The study was published online Sept. 29 in the Annals of Internal Medicine.
 

‘Cooking the books’

Little is known about the evidence required by the FDA for new approvals of opioid analgesics.

To characterize the quality of safety and efficacy data in NDAs for opioid analgesics approved by the FDA between 1997 and 2018, the investigators conducted the cross-sectional analysis using data from ClinicalTrials.gov, FDA reviews, and peer-reviewed publications regarding phase 3 pivotal trials.

The investigators examined the key characteristics of each NDA, including the number, size, and duration of pivotal trials, trial control groups, use of EERW, and systematically measured safety outcomes.

Results showed that most of the 48 NDAs evaluated were for new dosage forms (52.1%) or new formulations (18.8%). Only one (2.1%) was for a new molecular entity.

Of 39 NDAs approved for the treatment of chronic pain, only 21 products were supported by at least one pivotal trial. The mean duration of these 28 trials was 84 days, and they enrolled a median of 299 patients.

Results showed that, for 17 of the 39 opioids approved for chronic pain, pivotal trials had an EERW design. For the latest period – 2012-2018 – trials of all eight of the approved opioids used the EERW method.

This EERW design allows the manufacturer to assess efficacy “among a subset of patients most likely to respond and least likely to have adverse effects, reducing generalizability to real-world settings,” the investigators noted.

They called on the FDA to stop relying on this type of trial to assess opioid efficacy.

In an August 2020 article, Andrew Kolodny, MD, pointed out the pitfalls of the EERW approach. In such a study, all participants are made physiologically dependent on the opioid in a 4- to 6-week open-label phase. Only those who tolerate the drug and find it helpful are included in the randomized study. Dr. Kolodny is codirector of opioid policy research at Brandeis University, Waltham, Mass.

“Critics of EERW have correctly described this methodology as ‘cooking the books,’ ” Dr. Kolodny writes.

He noted that the agency’s decision to rely on EERW trials for opioids was “based on discussions at private meetings between FDA officials and pharmaceutical company executives hosted by an organization called Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials.” The 2013 meetings were reported in an article published in the Washington Post.

Little sign of change

Among NDAs for chronic pain, the investigators found that eight (20.5%) included pooled safety reviews that reported systematic assessment of diversion. Seven (17.9%) reported systematic measurement of nonmedical use, and 15 (38.5%) assessed incident tolerance.

The study revealed that eight of nine products that were approved for acute pain were supported by at least one pivotal trial. The median duration of these 19 trials was 1 day, and they enrolled a median of 329 patients.

The investigators noted that the findings “underscore the evidence gaps that have limited clinicians’ and patients’ understanding and appreciation of the inherent risks of prescription opioid analgesics.”

Dr. Alexander, who has been an FDA advisory committee chairman and currently serves as a consultant to plaintiffs who are suing opioid manufacturers in federal multidistrict litigation, said the study “is a story about missed opportunities to improve the safety and to improve the regulatory review of these products.”

Coinvestigator Peter Lurie, MD, who was an official at the FDA from 2009 to 2017, said that “there’s not a lot of signs that things are changing” at the agency.

The study shows that the FDA has “accepted what the companies have been presenting,” said Dr. Lurie, who is president of the Center for Science in the Public Interest.

The FDA “absolutely has the authority” to require manufacturers to undertake more rigorous trials, but agency culture keeps it from making such demands, especially if doing so means a new applicant might have to conduct trials that weren’t previously required, Dr. Lurie said in an interview.

“FDA is pretty rigorous about trying to establish a level playing field. That’s a virtuous thing, but it becomes problematic when that prevents change,” said Dr. Lurie.

The most recent FDA guidance to manufacturers, issued in 2019, does not provide advice on criteria for endpoints, study duration, or which populations are most likely to benefit from opioid treatment. The agency also does not require drug manufacturers to formally collect data on safety, tolerance, overdose symptoms, or constipation.

The guidance does suggest that the agency would likely take into account public health considerations when evaluating opioids, such as the risk to the overall population for overdose and diversion.
 

‘Overwhelming evidence’

Dr. Kolodny said that, as far as he is aware, “this is the first scientific publication in a peer-reviewed journal demonstrating clearly the problems with FDA’s opioid approval process.”

The article offers “overwhelming evidence that they are improperly approving the most dangerous medications – medications that killed more people than any other medication on the market,” added Dr. Kolodny, who is also president of Physicians for Responsible Opioid Prescribing.

Asked to respond to the study findings, FDA spokesperson Charles Kohler said the agency “does not comment on specific studies but evaluates them as part of the body of evidence to further our understanding about a particular issue and assist in our mission to protect public health.”

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

Despite the ongoing epidemic of misuse, overuse, and diversion of opioids, the Food and Drug Administration has set a low bar for approval of these medications over the past 20 years, new research suggests.

Results of a cross-sectional study reveal that between 1997 and 2018, the majority of approvals of opioids for the treatment of chronic pain were based on pivotal trials that lacked critical safety and efficacy data.

The study results also show that the FDA did not require manufacturers to collect safety data on tolerance, withdrawal, overdose, misuse, and diversion in any rigorous fashion.

In addition, during the study period, 17 of the 39 new drug applications (NDAs) (only one was an innovator product, known as a new molecular entity) for chronic pain were approved with an “enriched enrollment randomized withdrawal” (EERW) trial design. Such a design, in this case, allowed manufacturers to exclude 32%-43% of the initially enrolled patients from the double-blind treatment phase.

“The question for regulators, policy makers, and others is: How did we get to a point where these approvals took place based on trials that were by design unlikely to yield some of the most important information about safety and efficacy that patients and clinicians would care about?” study investigator G. Caleb Alexander, MD, Johns Hopkins University, Baltimore, said in an interview.

The study was published online Sept. 29 in the Annals of Internal Medicine.
 

‘Cooking the books’

Little is known about the evidence required by the FDA for new approvals of opioid analgesics.

To characterize the quality of safety and efficacy data in NDAs for opioid analgesics approved by the FDA between 1997 and 2018, the investigators conducted the cross-sectional analysis using data from ClinicalTrials.gov, FDA reviews, and peer-reviewed publications regarding phase 3 pivotal trials.

The investigators examined the key characteristics of each NDA, including the number, size, and duration of pivotal trials, trial control groups, use of EERW, and systematically measured safety outcomes.

Results showed that most of the 48 NDAs evaluated were for new dosage forms (52.1%) or new formulations (18.8%). Only one (2.1%) was for a new molecular entity.

Of 39 NDAs approved for the treatment of chronic pain, only 21 products were supported by at least one pivotal trial. The mean duration of these 28 trials was 84 days, and they enrolled a median of 299 patients.

Results showed that, for 17 of the 39 opioids approved for chronic pain, pivotal trials had an EERW design. For the latest period – 2012-2018 – trials of all eight of the approved opioids used the EERW method.

This EERW design allows the manufacturer to assess efficacy “among a subset of patients most likely to respond and least likely to have adverse effects, reducing generalizability to real-world settings,” the investigators noted.

They called on the FDA to stop relying on this type of trial to assess opioid efficacy.

In an August 2020 article, Andrew Kolodny, MD, pointed out the pitfalls of the EERW approach. In such a study, all participants are made physiologically dependent on the opioid in a 4- to 6-week open-label phase. Only those who tolerate the drug and find it helpful are included in the randomized study. Dr. Kolodny is codirector of opioid policy research at Brandeis University, Waltham, Mass.

“Critics of EERW have correctly described this methodology as ‘cooking the books,’ ” Dr. Kolodny writes.

He noted that the agency’s decision to rely on EERW trials for opioids was “based on discussions at private meetings between FDA officials and pharmaceutical company executives hosted by an organization called Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials.” The 2013 meetings were reported in an article published in the Washington Post.

Little sign of change

Among NDAs for chronic pain, the investigators found that eight (20.5%) included pooled safety reviews that reported systematic assessment of diversion. Seven (17.9%) reported systematic measurement of nonmedical use, and 15 (38.5%) assessed incident tolerance.

The study revealed that eight of nine products that were approved for acute pain were supported by at least one pivotal trial. The median duration of these 19 trials was 1 day, and they enrolled a median of 329 patients.

The investigators noted that the findings “underscore the evidence gaps that have limited clinicians’ and patients’ understanding and appreciation of the inherent risks of prescription opioid analgesics.”

Dr. Alexander, who has been an FDA advisory committee chairman and currently serves as a consultant to plaintiffs who are suing opioid manufacturers in federal multidistrict litigation, said the study “is a story about missed opportunities to improve the safety and to improve the regulatory review of these products.”

Coinvestigator Peter Lurie, MD, who was an official at the FDA from 2009 to 2017, said that “there’s not a lot of signs that things are changing” at the agency.

The study shows that the FDA has “accepted what the companies have been presenting,” said Dr. Lurie, who is president of the Center for Science in the Public Interest.

The FDA “absolutely has the authority” to require manufacturers to undertake more rigorous trials, but agency culture keeps it from making such demands, especially if doing so means a new applicant might have to conduct trials that weren’t previously required, Dr. Lurie said in an interview.

“FDA is pretty rigorous about trying to establish a level playing field. That’s a virtuous thing, but it becomes problematic when that prevents change,” said Dr. Lurie.

The most recent FDA guidance to manufacturers, issued in 2019, does not provide advice on criteria for endpoints, study duration, or which populations are most likely to benefit from opioid treatment. The agency also does not require drug manufacturers to formally collect data on safety, tolerance, overdose symptoms, or constipation.

The guidance does suggest that the agency would likely take into account public health considerations when evaluating opioids, such as the risk to the overall population for overdose and diversion.
 

‘Overwhelming evidence’

Dr. Kolodny said that, as far as he is aware, “this is the first scientific publication in a peer-reviewed journal demonstrating clearly the problems with FDA’s opioid approval process.”

The article offers “overwhelming evidence that they are improperly approving the most dangerous medications – medications that killed more people than any other medication on the market,” added Dr. Kolodny, who is also president of Physicians for Responsible Opioid Prescribing.

Asked to respond to the study findings, FDA spokesperson Charles Kohler said the agency “does not comment on specific studies but evaluates them as part of the body of evidence to further our understanding about a particular issue and assist in our mission to protect public health.”

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

Spending on medications is expected to grow from $344 billion in 2018 to $420 billion in 2023, largely driven by the introduction of new branded drugs.¹ These costs place substantial financial burden on patients, with nearly 30% of patients not taking their prescriptions as directed because of costs. Although many new medications have transformed how we care for patients, others may not offer meaningful benefit over existing less-costly alternatives that are supported by declining effect sizes of conventional placebo-controlled trials.² Most medications are approved based on placebo-controlled trial data that does not include an arm comparing the new drug to standard of care, leaving clinicians and patients unable to make meaningful comparisons when deciding on the most appropriate or cost-effective treatment. We consider ways in which clinicians, patients, payers, and regulators could compel more meaningful trials from industry.

Although we often look to the US Food and Drug Administration (FDA) to ensure rigorous and appropriate testing of new medications, the primary mission of the FDA is to ensure efficacy and safety. As a result, pharmaceutical companies seeking approval in the United States have little incentive to go beyond providing the minimal level of evidence required: placebo-controlled randomized trials. Although these trials provide important data on whether a treatment works and its associated risks, they do not provide data on comparative effectiveness. When relevant inexpensive medications are already on the market for the same indication, these placebo-controlled trials provide inadequate evidence to guide clinical decision-making. This issue is particularly relevant in dermatology given how easily topical medications can be combined or reformulated to pursue additional market exclusivity. The addition of an active comparator arm represents an important opportunity to improve the value of these studies.

In the pivotal trials of clindamycin phosphate 1.2%–benzoyl peroxide 2.5% gel for the treatment of acne, the experimental group was not only compared to vehicle but also the active comparator arms of clindamycin alone and benzoyl peroxide alone. The mean percentage change in total lesions was 47.9% with clindamycin phosphate 1.2%–benzoyl peroxide 2.5% gel, 41.6% with the active comparator arm of benzoyl peroxide alone, 40.4% with the active comparator arm of clindamycin alone, and 26.2% for vehicle.³ With these data in mind, clinicians and patients can decide whether the additional benefit of this new product over benzoyl peroxide alone is worth the increased cost.

In contrast, the trials of dapsone gel 7.5% for the treatment of acne did not include an active comparator. The mean percentage change in total lesions was 48.9% for dapsone gel and 43.2% for vehicle.⁴ Given these data, it is possible that dapsone gel may be no more effective, or possibly less effective, than alternatives such as benzoyl peroxide or other topical antibiotics. Nevertheless, dapsone annual sales were more than $200 million in 2016,⁵ suggesting that effectively marketed new products can achieve high sales even without convincing evidence of their value compared to standard of care. Although dapsone may be a useful treatment, we cannot effectively make patient-centered clinical decisions given the lack of an active comparator trial design.

This issue is not limited to acne. Phase 3 trials of halobetasol propionate foam 0.05% for psoriasis and crisaborole for atopic dermatitis also did not include an active comparator arm.^6,7 Given that topical steroids—and calcineurin inhibitors for atopic dermatitis—are mainstays of treatment for each condition, it is difficult to determine whether these new treatments offer meaningful advantages over existing options and how to incorporate them into our management strategies.

Unfortunately, expensive new medications that are adopted without convincing evidence of their benefit above standard of care can put patients at risk for financial toxicity, either directly through higher out-of-pocket costs or indirectly through higher premiums. Given the impact of rising medication costs on clinicians, patients, and payers, we propose several approaches these stakeholders could adopt to encourage the use of active comparator trial designs.

Clinicians and patients can encourage these trials by remaining skeptical of new treatments that were only compared to vehicle or placebo. Because new medications often are more expensive, clinicians and patients could avoid using these treatments without evidence of either increased efficacy or improved safety and tolerability. In addition, health care institutions should consider reducing pharmaceutical representatives’ access to clinicians to encourage treatment decisions based on the published literature and comparative effectiveness data rather than marketing.

Payers, such as Medicare, also could play a role by requiring active comparator trials for coverage of new medications, particularly when there are already other effective treatments available or other medications in the same class. Payers also could give preferred coverage tier or step therapy status to medications that demonstrate value over existing options.

Although regulatory approaches to increase use of active comparator designs may be more politically challenging to introduce, these options would be more administratively robust. The FDA or a novel regulatory body could require that new treatments demonstrate value in addition to safety and efficacy. This approach would be similar to the role of The National Institute for Health and Care Excellence in the United Kingdom or the recommendations of the European Medicines Agency. Such a group also could provide independent adjudication to ensure appropriate selection of a relevant active comparator. Another approach would be to give extended market exclusivity to medications that are approved based on trials including an additional active comparator arm, an approach used by the European Medicines Agency.

Any approach that encourages increased use of active comparator trials is not without potential downsides. It will be important to avoid unintended consequences of reduced research for rare diseases with smaller markets that may not be able to support the increased cost of these trials. As a result, it would be reasonable to forgo active comparator designs for mediations indicated for rare and orphan diseases or for medications with novel mechanisms of action.

Another argument against including an active comparator arm is that it may stifle innovation by driving up the cost of conducting trials; however, if a product is so marginally innovative that it cannot demonstrate superior safety or efficacy to an existing product, such a new treatment may not be worth the increased cost. In addition, patients provide a notable contribution by participating in these trials, and it is important to ensure that their efforts result in the highest-quality data possible. Furthermore, given the adverse physical and psychosocial impact of a wide variety of dermatologic diseases, the inclusion of an active comparator arm reduces the likelihood that patients will receive placebo, which will make these trials more ethical when effective treatments are available.⁸ By raising the bar, we can encourage pharmaceutical companies to pursue novel approaches that are more likely to have a revolutionary impact rather than minor modifications or formulations that offer little to no benefit at substantially increased cost.

Although some recent clinical trials in dermatology have included active comparators, many new medications continue to be introduced without any evidence of how they compare to existing standards of care. Until clinicians, patients, payers, and regulators demand that pharmaceutical companies conduct the necessary trials to not only demonstrate whether a treatment is effective and safe but also how it provides value, there will be continued introduction of marginal innovations rather than revolutionary treatments that improve patients’ lives. The next time a new medication is approved, as clinicians, patients, and payers, we must ask ourselves, is this treatment worth it?

Spending on medications is expected to grow from $344 billion in 2018 to $420 billion in 2023, largely driven by the introduction of new branded drugs.¹ These costs place substantial financial burden on patients, with nearly 30% of patients not taking their prescriptions as directed because of costs. Although many new medications have transformed how we care for patients, others may not offer meaningful benefit over existing less-costly alternatives that are supported by declining effect sizes of conventional placebo-controlled trials.² Most medications are approved based on placebo-controlled trial data that does not include an arm comparing the new drug to standard of care, leaving clinicians and patients unable to make meaningful comparisons when deciding on the most appropriate or cost-effective treatment. We consider ways in which clinicians, patients, payers, and regulators could compel more meaningful trials from industry.

Although we often look to the US Food and Drug Administration (FDA) to ensure rigorous and appropriate testing of new medications, the primary mission of the FDA is to ensure efficacy and safety. As a result, pharmaceutical companies seeking approval in the United States have little incentive to go beyond providing the minimal level of evidence required: placebo-controlled randomized trials. Although these trials provide important data on whether a treatment works and its associated risks, they do not provide data on comparative effectiveness. When relevant inexpensive medications are already on the market for the same indication, these placebo-controlled trials provide inadequate evidence to guide clinical decision-making. This issue is particularly relevant in dermatology given how easily topical medications can be combined or reformulated to pursue additional market exclusivity. The addition of an active comparator arm represents an important opportunity to improve the value of these studies.

In the pivotal trials of clindamycin phosphate 1.2%–benzoyl peroxide 2.5% gel for the treatment of acne, the experimental group was not only compared to vehicle but also the active comparator arms of clindamycin alone and benzoyl peroxide alone. The mean percentage change in total lesions was 47.9% with clindamycin phosphate 1.2%–benzoyl peroxide 2.5% gel, 41.6% with the active comparator arm of benzoyl peroxide alone, 40.4% with the active comparator arm of clindamycin alone, and 26.2% for vehicle.³ With these data in mind, clinicians and patients can decide whether the additional benefit of this new product over benzoyl peroxide alone is worth the increased cost.

In contrast, the trials of dapsone gel 7.5% for the treatment of acne did not include an active comparator. The mean percentage change in total lesions was 48.9% for dapsone gel and 43.2% for vehicle.⁴ Given these data, it is possible that dapsone gel may be no more effective, or possibly less effective, than alternatives such as benzoyl peroxide or other topical antibiotics. Nevertheless, dapsone annual sales were more than $200 million in 2016,⁵ suggesting that effectively marketed new products can achieve high sales even without convincing evidence of their value compared to standard of care. Although dapsone may be a useful treatment, we cannot effectively make patient-centered clinical decisions given the lack of an active comparator trial design.

This issue is not limited to acne. Phase 3 trials of halobetasol propionate foam 0.05% for psoriasis and crisaborole for atopic dermatitis also did not include an active comparator arm.^6,7 Given that topical steroids—and calcineurin inhibitors for atopic dermatitis—are mainstays of treatment for each condition, it is difficult to determine whether these new treatments offer meaningful advantages over existing options and how to incorporate them into our management strategies.

Unfortunately, expensive new medications that are adopted without convincing evidence of their benefit above standard of care can put patients at risk for financial toxicity, either directly through higher out-of-pocket costs or indirectly through higher premiums. Given the impact of rising medication costs on clinicians, patients, and payers, we propose several approaches these stakeholders could adopt to encourage the use of active comparator trial designs.

Clinicians and patients can encourage these trials by remaining skeptical of new treatments that were only compared to vehicle or placebo. Because new medications often are more expensive, clinicians and patients could avoid using these treatments without evidence of either increased efficacy or improved safety and tolerability. In addition, health care institutions should consider reducing pharmaceutical representatives’ access to clinicians to encourage treatment decisions based on the published literature and comparative effectiveness data rather than marketing.

Payers, such as Medicare, also could play a role by requiring active comparator trials for coverage of new medications, particularly when there are already other effective treatments available or other medications in the same class. Payers also could give preferred coverage tier or step therapy status to medications that demonstrate value over existing options.

Although regulatory approaches to increase use of active comparator designs may be more politically challenging to introduce, these options would be more administratively robust. The FDA or a novel regulatory body could require that new treatments demonstrate value in addition to safety and efficacy. This approach would be similar to the role of The National Institute for Health and Care Excellence in the United Kingdom or the recommendations of the European Medicines Agency. Such a group also could provide independent adjudication to ensure appropriate selection of a relevant active comparator. Another approach would be to give extended market exclusivity to medications that are approved based on trials including an additional active comparator arm, an approach used by the European Medicines Agency.

Any approach that encourages increased use of active comparator trials is not without potential downsides. It will be important to avoid unintended consequences of reduced research for rare diseases with smaller markets that may not be able to support the increased cost of these trials. As a result, it would be reasonable to forgo active comparator designs for mediations indicated for rare and orphan diseases or for medications with novel mechanisms of action.

Another argument against including an active comparator arm is that it may stifle innovation by driving up the cost of conducting trials; however, if a product is so marginally innovative that it cannot demonstrate superior safety or efficacy to an existing product, such a new treatment may not be worth the increased cost. In addition, patients provide a notable contribution by participating in these trials, and it is important to ensure that their efforts result in the highest-quality data possible. Furthermore, given the adverse physical and psychosocial impact of a wide variety of dermatologic diseases, the inclusion of an active comparator arm reduces the likelihood that patients will receive placebo, which will make these trials more ethical when effective treatments are available.⁸ By raising the bar, we can encourage pharmaceutical companies to pursue novel approaches that are more likely to have a revolutionary impact rather than minor modifications or formulations that offer little to no benefit at substantially increased cost.

Although some recent clinical trials in dermatology have included active comparators, many new medications continue to be introduced without any evidence of how they compare to existing standards of care. Until clinicians, patients, payers, and regulators demand that pharmaceutical companies conduct the necessary trials to not only demonstrate whether a treatment is effective and safe but also how it provides value, there will be continued introduction of marginal innovations rather than revolutionary treatments that improve patients’ lives. The next time a new medication is approved, as clinicians, patients, and payers, we must ask ourselves, is this treatment worth it?

Spending on medications is expected to grow from $344 billion in 2018 to $420 billion in 2023, largely driven by the introduction of new branded drugs.¹ These costs place substantial financial burden on patients, with nearly 30% of patients not taking their prescriptions as directed because of costs. Although many new medications have transformed how we care for patients, others may not offer meaningful benefit over existing less-costly alternatives that are supported by declining effect sizes of conventional placebo-controlled trials.² Most medications are approved based on placebo-controlled trial data that does not include an arm comparing the new drug to standard of care, leaving clinicians and patients unable to make meaningful comparisons when deciding on the most appropriate or cost-effective treatment. We consider ways in which clinicians, patients, payers, and regulators could compel more meaningful trials from industry.

Although we often look to the US Food and Drug Administration (FDA) to ensure rigorous and appropriate testing of new medications, the primary mission of the FDA is to ensure efficacy and safety. As a result, pharmaceutical companies seeking approval in the United States have little incentive to go beyond providing the minimal level of evidence required: placebo-controlled randomized trials. Although these trials provide important data on whether a treatment works and its associated risks, they do not provide data on comparative effectiveness. When relevant inexpensive medications are already on the market for the same indication, these placebo-controlled trials provide inadequate evidence to guide clinical decision-making. This issue is particularly relevant in dermatology given how easily topical medications can be combined or reformulated to pursue additional market exclusivity. The addition of an active comparator arm represents an important opportunity to improve the value of these studies.

In the pivotal trials of clindamycin phosphate 1.2%–benzoyl peroxide 2.5% gel for the treatment of acne, the experimental group was not only compared to vehicle but also the active comparator arms of clindamycin alone and benzoyl peroxide alone. The mean percentage change in total lesions was 47.9% with clindamycin phosphate 1.2%–benzoyl peroxide 2.5% gel, 41.6% with the active comparator arm of benzoyl peroxide alone, 40.4% with the active comparator arm of clindamycin alone, and 26.2% for vehicle.³ With these data in mind, clinicians and patients can decide whether the additional benefit of this new product over benzoyl peroxide alone is worth the increased cost.

In contrast, the trials of dapsone gel 7.5% for the treatment of acne did not include an active comparator. The mean percentage change in total lesions was 48.9% for dapsone gel and 43.2% for vehicle.⁴ Given these data, it is possible that dapsone gel may be no more effective, or possibly less effective, than alternatives such as benzoyl peroxide or other topical antibiotics. Nevertheless, dapsone annual sales were more than $200 million in 2016,⁵ suggesting that effectively marketed new products can achieve high sales even without convincing evidence of their value compared to standard of care. Although dapsone may be a useful treatment, we cannot effectively make patient-centered clinical decisions given the lack of an active comparator trial design.

This issue is not limited to acne. Phase 3 trials of halobetasol propionate foam 0.05% for psoriasis and crisaborole for atopic dermatitis also did not include an active comparator arm.^6,7 Given that topical steroids—and calcineurin inhibitors for atopic dermatitis—are mainstays of treatment for each condition, it is difficult to determine whether these new treatments offer meaningful advantages over existing options and how to incorporate them into our management strategies.

Unfortunately, expensive new medications that are adopted without convincing evidence of their benefit above standard of care can put patients at risk for financial toxicity, either directly through higher out-of-pocket costs or indirectly through higher premiums. Given the impact of rising medication costs on clinicians, patients, and payers, we propose several approaches these stakeholders could adopt to encourage the use of active comparator trial designs.

Clinicians and patients can encourage these trials by remaining skeptical of new treatments that were only compared to vehicle or placebo. Because new medications often are more expensive, clinicians and patients could avoid using these treatments without evidence of either increased efficacy or improved safety and tolerability. In addition, health care institutions should consider reducing pharmaceutical representatives’ access to clinicians to encourage treatment decisions based on the published literature and comparative effectiveness data rather than marketing.

Payers, such as Medicare, also could play a role by requiring active comparator trials for coverage of new medications, particularly when there are already other effective treatments available or other medications in the same class. Payers also could give preferred coverage tier or step therapy status to medications that demonstrate value over existing options.

Although regulatory approaches to increase use of active comparator designs may be more politically challenging to introduce, these options would be more administratively robust. The FDA or a novel regulatory body could require that new treatments demonstrate value in addition to safety and efficacy. This approach would be similar to the role of The National Institute for Health and Care Excellence in the United Kingdom or the recommendations of the European Medicines Agency. Such a group also could provide independent adjudication to ensure appropriate selection of a relevant active comparator. Another approach would be to give extended market exclusivity to medications that are approved based on trials including an additional active comparator arm, an approach used by the European Medicines Agency.

Any approach that encourages increased use of active comparator trials is not without potential downsides. It will be important to avoid unintended consequences of reduced research for rare diseases with smaller markets that may not be able to support the increased cost of these trials. As a result, it would be reasonable to forgo active comparator designs for mediations indicated for rare and orphan diseases or for medications with novel mechanisms of action.

Another argument against including an active comparator arm is that it may stifle innovation by driving up the cost of conducting trials; however, if a product is so marginally innovative that it cannot demonstrate superior safety or efficacy to an existing product, such a new treatment may not be worth the increased cost. In addition, patients provide a notable contribution by participating in these trials, and it is important to ensure that their efforts result in the highest-quality data possible. Furthermore, given the adverse physical and psychosocial impact of a wide variety of dermatologic diseases, the inclusion of an active comparator arm reduces the likelihood that patients will receive placebo, which will make these trials more ethical when effective treatments are available.⁸ By raising the bar, we can encourage pharmaceutical companies to pursue novel approaches that are more likely to have a revolutionary impact rather than minor modifications or formulations that offer little to no benefit at substantially increased cost.

Although some recent clinical trials in dermatology have included active comparators, many new medications continue to be introduced without any evidence of how they compare to existing standards of care. Until clinicians, patients, payers, and regulators demand that pharmaceutical companies conduct the necessary trials to not only demonstrate whether a treatment is effective and safe but also how it provides value, there will be continued introduction of marginal innovations rather than revolutionary treatments that improve patients’ lives. The next time a new medication is approved, as clinicians, patients, and payers, we must ask ourselves, is this treatment worth it?

America has been struggling to understand its racial dynamics since the arrival of enslaved Africans more than 400 years ago. Today, with much of the world more polarized than ever, and certainly in our United States, there is a need for something to shift us from our fear and survival paranoid schizoid (us-vs.-them) position to an integrated form if we are to come out of this unusual democratic and societal unrest whole.

Courtesy Random House

Yet, we’ve never had the lexicon to adequately describe the sociopolitical dynamics rooted in race and racism and their power to shape the thinking of all who originate in this country and all who enter its self-made borders whether forcefully or voluntarily. Enter Isabel Wilkerson, a Pulitzer Prize–winning, former New York Times Chicago bureau chief, and author of “The Warmth of Other Suns: The Epic Story of America’s Great Migration” (New York: Random House, 2010) with her second book, “Caste: The Origins of Our Discontents” (New York: Random House, 2020).

Ms. Wilkerson quickly gets to work in an engaging storytelling style of weaving past to present with ideas she supports with letters from the past, historians’ impressions, research studies, and data. Her observations and research are bookended by the lead up to the 2016 presidential election and its aftermath on the one end, and the impending 2020 presidential election on the other. In her view, the reemergence of violence that has accelerated in the 21st century and the renewed commitment to promote white supremacy can be understood if we expand our view of race and racism to consider the enduring power of caste. For, in Ms. Wilkerson’s view, the fear of the 2042 U.S. census (which is predicted to reflect for the first time a non-White majority) is a driving force behind the dominant caste’s determination to maintain the status quo power dynamics in the United States.

In an effort to explain American’s racial hierarchy, Ms. Wilkerson explains the need for a new lexicon “that may sound like a foreign language,” but this is intentional on her part. She writes:

“To recalibrate how we see ourselves, I use language that may be more commonly associated with people in other cultures, to suggest a new way of understanding our hierarchy: Dominant caste, ruling majority, favored caste, or upper caste, instead of, or in addition to, white. Middle castes instead of, or in addition to, Asian or Latino. Subordinate caste, lowest caste, bottom caste, disfavored caste, historically stigmatized instead of African-American. Original, conquered, or indigenous peoples instead of, or in addition to, Native American. Marginalized people in addition to, or instead of, women of any race, or minorities of any kind.”

Early in the book Ms. Wilkerson anchors her argument in Rev. Dr. Martin Luther King Jr.’s sojourn to India. Rather than focus on the known history of Dr. King’s admiration of Mohandas Gandhi, Ms. Wilkerson directs our attention to Dr. King’s discovery of his connection to Dalits, those who had been considered “untouchables” until Bhimrao Ramji Ambedkar, the Indian economist, jurist, social reformer, and Dalit leader, fiercely and successfully advocated for a rebranding of his caste of origin; instead of “untouchables” they would be considered Dalits or “broken people.” Dr. King did not meet Mr. Ambedkar, who died 3 years before this journey, but Ms. Wilkerson writes that Dr. King acknowledged the kinship, “And he said unto himself, Yes, I am an untouchable, and every Negro in the United States is an untouchable.” The Dalits and Dr. King recognized in each other their shared positions as subordinates in a global caste system.

In answering the question about the difference between racism and casteism, Ms. Wilkerson writes:

“Because caste and race are interwoven in America, it can be hard to separate the two. ... Casteism is the investment in keeping the hierarchy as it is in order to maintain your own ranking, advantage, privilege, or to elevate yourself above others or to keep others beneath you.”

Reading “Caste: The Origins of Our Discontents” is akin to the experience of gaining relief after struggling for years with a chronic malady that has a fluctuating course: Under the surface is low-grade pain that is compartmentalized and often met with denial or gaslighting when symptoms and systems are reported to members of the dominant caste. Yet, when there are acute flare-ups and increasingly frequent deadly encounters, the defenses of denial are painfully revealed; structures are broken and sometimes burned down. This has been the clinical course of racism, particularly in the United States. In that vein, an early reaction while reading “Caste” might be comparable to hearing an interpretation that educates, clarifies, resonates, and lands perfectly on the right diagnosis at the right moment.
 

Approach proves clarifying

In conceptualizing the malady as one of caste, Ms. Wilkerson achieves several things simultaneously – she names the malady, thus providing a lexicon, describes its symptoms, and most importantly, in our opinion, shares some of the compelling data from her field studies. By focusing on India, Nazi Germany, and the United States, she describes how easily one system influences another in the global effort to maintain power among the privileged.

This is not a new way of conceptualizing racial hierarchy; however, what is truly persuasive is Ms. Wilkerson’s ability to weave her rigorous research, sociopolitical analysis, and cogent psychological insights and interpretations to explain the 400-year trajectory of racialized caste in the United States. She achieves this exigent task with beautiful prose that motivates the reader to return time and time again to learn gut-wrenching painful historical details. She summarizes truths that have been unearthed (again) about Germany, India, and, in particular, the United States during her research and travels around the world. In doing so, she provides vivid examples of racism layered on caste. Consider the following:

“The Nazis were impressed by the American custom of lynching its subordinate caste of African-Americans, having become aware of the ritual torture and mutilations that typically accompanied them. Hitler especially marveled at the American ‘knack for maintaining an air of robust innocence in the wake of mass death.’ ” Ms. Wilkerson informs us that Hitler sent emissaries to study America’s Jim Crow system and then imported some features to orchestrate the Holocaust in Nazi Germany.

Her most vivid example of internalized casteism is the experience of a Dalit scholar who still experiences anxiety and a corresponding sense of inadequacy in the presence of someone who is considered to be from a higher caste.

A painful account of interpersonal racism is captured as Ms. Wilkerson recounts her experience after a routine business flight from Chicago to Detroit. She details her difficulty leaving a rental car parking lot because she had become so disoriented after being profiled and accosted by Drug Enforcement Administration agents who had intercepted her in the airport terminal and followed her onto the airport shuttle bus as she attempted to reach her destination. She provides a description of “getting turned around in a parking lot that I had been to dozens of times, going in circles, not able to get out, not registering the signs to the exit, not seeing how to get to Interstate 94, when I knew full well how to get to I-94 after all the times I’d driven it. ... This was the thievery of caste, stealing the time and psychic resources of the marginalized, draining energy in an already uphill competition. They were not, like me, frozen and disoriented, trying to make sense of a public violation that seemed all the more menacing now that I could see it in full. The quiet mundanity of that terror has never left me, the scars outliving the cut.”

This account is consistent with the dissociative, disorienting dynamics of race-based trauma. Her experience is not uncommon and helps to explain the activism of those in the subordinate caste who have attained some measure of wealth, power, and influence, and are motivated to expend their resources (energy, time, fame, and/or wealth) to raise awareness about social and political injustices by calling out structural racism in medicine, protesting police use of force by taking a knee, boycotting sporting events, and even demanding that football stadiums be used as polling sites. At the end of the day, all of us who have “made it” know that when we leave our homes, our relegation to the subordinate caste determines how we are perceived and what landmines we must navigate to make it through the day and that determine whether we will make it home.

This tour de force work of art has the potential to be a game changer in the way that we think about racial polarization in the United States. It is hoped that this new language opens up a space that allows each of us to explore this hegemony while identifying our placement and actions we take to maintain it, for each of us undeniably has a position in this caste system.

Having this new lexicon summons to mind the reactions of patients who gain immediate relief from having their illnesses named. In the case of the U.S. malady that has gripped us all, Ms. Wilkerson reiterates the importance of naming the condition. She writes:

“Because, to truly understand America, we must open our eyes to the hidden work of a caste system that has gone unnamed but prevails among us to our collective detriment, to see that we have more in common with each other and with cultures that we might otherwise dismiss, and to summon the courage to consider that therein may lie the answers.”

The naming allows both doctor and patient to have greater insight, understanding its origins and course, as well as having hope that there is a remedy. Naming facilitates the space for a shift in thinking and implementation of treatment protocols, such as Nazi Germany’s “zero tolerance policy” of swastikas in comparison to the ongoing U.S. controversy about the display of Confederate symbols. At this point in history, we welcome a diagnosis that has the potential to shift us from these poles of dominant and subordinate, black and white, good and bad, toward integration and wholeness of the individual psyche and collective global community. This is similar to what Melanie Klein calls the depressive position. Ms. Wilkerson suggests, in relinquishing these polar splits, we increase our capacity to shift to a space where our psychic integration occurs and our inextricable interdependence and responsibility for one another are honored.
 

Dr. Dunlap is a psychiatrist and psychoanalyst, and clinical professor of psychiatry and behavioral sciences at George Washington University. She is interested in the management of “difference” – race, gender, ethnicity, and intersectionality – in dyadic relationships and group dynamics; and the impact of racism on interpersonal relationships in institutional structures. Dr. Dunlap practices in Washington and has no disclosures. Dr. Dennis is a clinical psychologist and psychoanalyst. Her interests are in gender and ethnic diversity, health equity, and supervision and training. Dr. Dennis practices in Washington and has no disclosures.

America has been struggling to understand its racial dynamics since the arrival of enslaved Africans more than 400 years ago. Today, with much of the world more polarized than ever, and certainly in our United States, there is a need for something to shift us from our fear and survival paranoid schizoid (us-vs.-them) position to an integrated form if we are to come out of this unusual democratic and societal unrest whole.

Courtesy Random House

Yet, we’ve never had the lexicon to adequately describe the sociopolitical dynamics rooted in race and racism and their power to shape the thinking of all who originate in this country and all who enter its self-made borders whether forcefully or voluntarily. Enter Isabel Wilkerson, a Pulitzer Prize–winning, former New York Times Chicago bureau chief, and author of “The Warmth of Other Suns: The Epic Story of America’s Great Migration” (New York: Random House, 2010) with her second book, “Caste: The Origins of Our Discontents” (New York: Random House, 2020).

Ms. Wilkerson quickly gets to work in an engaging storytelling style of weaving past to present with ideas she supports with letters from the past, historians’ impressions, research studies, and data. Her observations and research are bookended by the lead up to the 2016 presidential election and its aftermath on the one end, and the impending 2020 presidential election on the other. In her view, the reemergence of violence that has accelerated in the 21st century and the renewed commitment to promote white supremacy can be understood if we expand our view of race and racism to consider the enduring power of caste. For, in Ms. Wilkerson’s view, the fear of the 2042 U.S. census (which is predicted to reflect for the first time a non-White majority) is a driving force behind the dominant caste’s determination to maintain the status quo power dynamics in the United States.

In an effort to explain American’s racial hierarchy, Ms. Wilkerson explains the need for a new lexicon “that may sound like a foreign language,” but this is intentional on her part. She writes:

“To recalibrate how we see ourselves, I use language that may be more commonly associated with people in other cultures, to suggest a new way of understanding our hierarchy: Dominant caste, ruling majority, favored caste, or upper caste, instead of, or in addition to, white. Middle castes instead of, or in addition to, Asian or Latino. Subordinate caste, lowest caste, bottom caste, disfavored caste, historically stigmatized instead of African-American. Original, conquered, or indigenous peoples instead of, or in addition to, Native American. Marginalized people in addition to, or instead of, women of any race, or minorities of any kind.”

Early in the book Ms. Wilkerson anchors her argument in Rev. Dr. Martin Luther King Jr.’s sojourn to India. Rather than focus on the known history of Dr. King’s admiration of Mohandas Gandhi, Ms. Wilkerson directs our attention to Dr. King’s discovery of his connection to Dalits, those who had been considered “untouchables” until Bhimrao Ramji Ambedkar, the Indian economist, jurist, social reformer, and Dalit leader, fiercely and successfully advocated for a rebranding of his caste of origin; instead of “untouchables” they would be considered Dalits or “broken people.” Dr. King did not meet Mr. Ambedkar, who died 3 years before this journey, but Ms. Wilkerson writes that Dr. King acknowledged the kinship, “And he said unto himself, Yes, I am an untouchable, and every Negro in the United States is an untouchable.” The Dalits and Dr. King recognized in each other their shared positions as subordinates in a global caste system.

In answering the question about the difference between racism and casteism, Ms. Wilkerson writes:

“Because caste and race are interwoven in America, it can be hard to separate the two. ... Casteism is the investment in keeping the hierarchy as it is in order to maintain your own ranking, advantage, privilege, or to elevate yourself above others or to keep others beneath you.”

Reading “Caste: The Origins of Our Discontents” is akin to the experience of gaining relief after struggling for years with a chronic malady that has a fluctuating course: Under the surface is low-grade pain that is compartmentalized and often met with denial or gaslighting when symptoms and systems are reported to members of the dominant caste. Yet, when there are acute flare-ups and increasingly frequent deadly encounters, the defenses of denial are painfully revealed; structures are broken and sometimes burned down. This has been the clinical course of racism, particularly in the United States. In that vein, an early reaction while reading “Caste” might be comparable to hearing an interpretation that educates, clarifies, resonates, and lands perfectly on the right diagnosis at the right moment.
 

Approach proves clarifying

In conceptualizing the malady as one of caste, Ms. Wilkerson achieves several things simultaneously – she names the malady, thus providing a lexicon, describes its symptoms, and most importantly, in our opinion, shares some of the compelling data from her field studies. By focusing on India, Nazi Germany, and the United States, she describes how easily one system influences another in the global effort to maintain power among the privileged.

This is not a new way of conceptualizing racial hierarchy; however, what is truly persuasive is Ms. Wilkerson’s ability to weave her rigorous research, sociopolitical analysis, and cogent psychological insights and interpretations to explain the 400-year trajectory of racialized caste in the United States. She achieves this exigent task with beautiful prose that motivates the reader to return time and time again to learn gut-wrenching painful historical details. She summarizes truths that have been unearthed (again) about Germany, India, and, in particular, the United States during her research and travels around the world. In doing so, she provides vivid examples of racism layered on caste. Consider the following:

“The Nazis were impressed by the American custom of lynching its subordinate caste of African-Americans, having become aware of the ritual torture and mutilations that typically accompanied them. Hitler especially marveled at the American ‘knack for maintaining an air of robust innocence in the wake of mass death.’ ” Ms. Wilkerson informs us that Hitler sent emissaries to study America’s Jim Crow system and then imported some features to orchestrate the Holocaust in Nazi Germany.

Her most vivid example of internalized casteism is the experience of a Dalit scholar who still experiences anxiety and a corresponding sense of inadequacy in the presence of someone who is considered to be from a higher caste.

A painful account of interpersonal racism is captured as Ms. Wilkerson recounts her experience after a routine business flight from Chicago to Detroit. She details her difficulty leaving a rental car parking lot because she had become so disoriented after being profiled and accosted by Drug Enforcement Administration agents who had intercepted her in the airport terminal and followed her onto the airport shuttle bus as she attempted to reach her destination. She provides a description of “getting turned around in a parking lot that I had been to dozens of times, going in circles, not able to get out, not registering the signs to the exit, not seeing how to get to Interstate 94, when I knew full well how to get to I-94 after all the times I’d driven it. ... This was the thievery of caste, stealing the time and psychic resources of the marginalized, draining energy in an already uphill competition. They were not, like me, frozen and disoriented, trying to make sense of a public violation that seemed all the more menacing now that I could see it in full. The quiet mundanity of that terror has never left me, the scars outliving the cut.”

This account is consistent with the dissociative, disorienting dynamics of race-based trauma. Her experience is not uncommon and helps to explain the activism of those in the subordinate caste who have attained some measure of wealth, power, and influence, and are motivated to expend their resources (energy, time, fame, and/or wealth) to raise awareness about social and political injustices by calling out structural racism in medicine, protesting police use of force by taking a knee, boycotting sporting events, and even demanding that football stadiums be used as polling sites. At the end of the day, all of us who have “made it” know that when we leave our homes, our relegation to the subordinate caste determines how we are perceived and what landmines we must navigate to make it through the day and that determine whether we will make it home.

This tour de force work of art has the potential to be a game changer in the way that we think about racial polarization in the United States. It is hoped that this new language opens up a space that allows each of us to explore this hegemony while identifying our placement and actions we take to maintain it, for each of us undeniably has a position in this caste system.

Having this new lexicon summons to mind the reactions of patients who gain immediate relief from having their illnesses named. In the case of the U.S. malady that has gripped us all, Ms. Wilkerson reiterates the importance of naming the condition. She writes:

“Because, to truly understand America, we must open our eyes to the hidden work of a caste system that has gone unnamed but prevails among us to our collective detriment, to see that we have more in common with each other and with cultures that we might otherwise dismiss, and to summon the courage to consider that therein may lie the answers.”

The naming allows both doctor and patient to have greater insight, understanding its origins and course, as well as having hope that there is a remedy. Naming facilitates the space for a shift in thinking and implementation of treatment protocols, such as Nazi Germany’s “zero tolerance policy” of swastikas in comparison to the ongoing U.S. controversy about the display of Confederate symbols. At this point in history, we welcome a diagnosis that has the potential to shift us from these poles of dominant and subordinate, black and white, good and bad, toward integration and wholeness of the individual psyche and collective global community. This is similar to what Melanie Klein calls the depressive position. Ms. Wilkerson suggests, in relinquishing these polar splits, we increase our capacity to shift to a space where our psychic integration occurs and our inextricable interdependence and responsibility for one another are honored.
 

Dr. Dunlap is a psychiatrist and psychoanalyst, and clinical professor of psychiatry and behavioral sciences at George Washington University. She is interested in the management of “difference” – race, gender, ethnicity, and intersectionality – in dyadic relationships and group dynamics; and the impact of racism on interpersonal relationships in institutional structures. Dr. Dunlap practices in Washington and has no disclosures. Dr. Dennis is a clinical psychologist and psychoanalyst. Her interests are in gender and ethnic diversity, health equity, and supervision and training. Dr. Dennis practices in Washington and has no disclosures.

America has been struggling to understand its racial dynamics since the arrival of enslaved Africans more than 400 years ago. Today, with much of the world more polarized than ever, and certainly in our United States, there is a need for something to shift us from our fear and survival paranoid schizoid (us-vs.-them) position to an integrated form if we are to come out of this unusual democratic and societal unrest whole.

Courtesy Random House

Yet, we’ve never had the lexicon to adequately describe the sociopolitical dynamics rooted in race and racism and their power to shape the thinking of all who originate in this country and all who enter its self-made borders whether forcefully or voluntarily. Enter Isabel Wilkerson, a Pulitzer Prize–winning, former New York Times Chicago bureau chief, and author of “The Warmth of Other Suns: The Epic Story of America’s Great Migration” (New York: Random House, 2010) with her second book, “Caste: The Origins of Our Discontents” (New York: Random House, 2020).

Ms. Wilkerson quickly gets to work in an engaging storytelling style of weaving past to present with ideas she supports with letters from the past, historians’ impressions, research studies, and data. Her observations and research are bookended by the lead up to the 2016 presidential election and its aftermath on the one end, and the impending 2020 presidential election on the other. In her view, the reemergence of violence that has accelerated in the 21st century and the renewed commitment to promote white supremacy can be understood if we expand our view of race and racism to consider the enduring power of caste. For, in Ms. Wilkerson’s view, the fear of the 2042 U.S. census (which is predicted to reflect for the first time a non-White majority) is a driving force behind the dominant caste’s determination to maintain the status quo power dynamics in the United States.

In an effort to explain American’s racial hierarchy, Ms. Wilkerson explains the need for a new lexicon “that may sound like a foreign language,” but this is intentional on her part. She writes:

“To recalibrate how we see ourselves, I use language that may be more commonly associated with people in other cultures, to suggest a new way of understanding our hierarchy: Dominant caste, ruling majority, favored caste, or upper caste, instead of, or in addition to, white. Middle castes instead of, or in addition to, Asian or Latino. Subordinate caste, lowest caste, bottom caste, disfavored caste, historically stigmatized instead of African-American. Original, conquered, or indigenous peoples instead of, or in addition to, Native American. Marginalized people in addition to, or instead of, women of any race, or minorities of any kind.”

Early in the book Ms. Wilkerson anchors her argument in Rev. Dr. Martin Luther King Jr.’s sojourn to India. Rather than focus on the known history of Dr. King’s admiration of Mohandas Gandhi, Ms. Wilkerson directs our attention to Dr. King’s discovery of his connection to Dalits, those who had been considered “untouchables” until Bhimrao Ramji Ambedkar, the Indian economist, jurist, social reformer, and Dalit leader, fiercely and successfully advocated for a rebranding of his caste of origin; instead of “untouchables” they would be considered Dalits or “broken people.” Dr. King did not meet Mr. Ambedkar, who died 3 years before this journey, but Ms. Wilkerson writes that Dr. King acknowledged the kinship, “And he said unto himself, Yes, I am an untouchable, and every Negro in the United States is an untouchable.” The Dalits and Dr. King recognized in each other their shared positions as subordinates in a global caste system.

In answering the question about the difference between racism and casteism, Ms. Wilkerson writes:

“Because caste and race are interwoven in America, it can be hard to separate the two. ... Casteism is the investment in keeping the hierarchy as it is in order to maintain your own ranking, advantage, privilege, or to elevate yourself above others or to keep others beneath you.”

Reading “Caste: The Origins of Our Discontents” is akin to the experience of gaining relief after struggling for years with a chronic malady that has a fluctuating course: Under the surface is low-grade pain that is compartmentalized and often met with denial or gaslighting when symptoms and systems are reported to members of the dominant caste. Yet, when there are acute flare-ups and increasingly frequent deadly encounters, the defenses of denial are painfully revealed; structures are broken and sometimes burned down. This has been the clinical course of racism, particularly in the United States. In that vein, an early reaction while reading “Caste” might be comparable to hearing an interpretation that educates, clarifies, resonates, and lands perfectly on the right diagnosis at the right moment.
 

Approach proves clarifying

In conceptualizing the malady as one of caste, Ms. Wilkerson achieves several things simultaneously – she names the malady, thus providing a lexicon, describes its symptoms, and most importantly, in our opinion, shares some of the compelling data from her field studies. By focusing on India, Nazi Germany, and the United States, she describes how easily one system influences another in the global effort to maintain power among the privileged.

This is not a new way of conceptualizing racial hierarchy; however, what is truly persuasive is Ms. Wilkerson’s ability to weave her rigorous research, sociopolitical analysis, and cogent psychological insights and interpretations to explain the 400-year trajectory of racialized caste in the United States. She achieves this exigent task with beautiful prose that motivates the reader to return time and time again to learn gut-wrenching painful historical details. She summarizes truths that have been unearthed (again) about Germany, India, and, in particular, the United States during her research and travels around the world. In doing so, she provides vivid examples of racism layered on caste. Consider the following:

“The Nazis were impressed by the American custom of lynching its subordinate caste of African-Americans, having become aware of the ritual torture and mutilations that typically accompanied them. Hitler especially marveled at the American ‘knack for maintaining an air of robust innocence in the wake of mass death.’ ” Ms. Wilkerson informs us that Hitler sent emissaries to study America’s Jim Crow system and then imported some features to orchestrate the Holocaust in Nazi Germany.

Her most vivid example of internalized casteism is the experience of a Dalit scholar who still experiences anxiety and a corresponding sense of inadequacy in the presence of someone who is considered to be from a higher caste.

A painful account of interpersonal racism is captured as Ms. Wilkerson recounts her experience after a routine business flight from Chicago to Detroit. She details her difficulty leaving a rental car parking lot because she had become so disoriented after being profiled and accosted by Drug Enforcement Administration agents who had intercepted her in the airport terminal and followed her onto the airport shuttle bus as she attempted to reach her destination. She provides a description of “getting turned around in a parking lot that I had been to dozens of times, going in circles, not able to get out, not registering the signs to the exit, not seeing how to get to Interstate 94, when I knew full well how to get to I-94 after all the times I’d driven it. ... This was the thievery of caste, stealing the time and psychic resources of the marginalized, draining energy in an already uphill competition. They were not, like me, frozen and disoriented, trying to make sense of a public violation that seemed all the more menacing now that I could see it in full. The quiet mundanity of that terror has never left me, the scars outliving the cut.”

This account is consistent with the dissociative, disorienting dynamics of race-based trauma. Her experience is not uncommon and helps to explain the activism of those in the subordinate caste who have attained some measure of wealth, power, and influence, and are motivated to expend their resources (energy, time, fame, and/or wealth) to raise awareness about social and political injustices by calling out structural racism in medicine, protesting police use of force by taking a knee, boycotting sporting events, and even demanding that football stadiums be used as polling sites. At the end of the day, all of us who have “made it” know that when we leave our homes, our relegation to the subordinate caste determines how we are perceived and what landmines we must navigate to make it through the day and that determine whether we will make it home.

This tour de force work of art has the potential to be a game changer in the way that we think about racial polarization in the United States. It is hoped that this new language opens up a space that allows each of us to explore this hegemony while identifying our placement and actions we take to maintain it, for each of us undeniably has a position in this caste system.

Having this new lexicon summons to mind the reactions of patients who gain immediate relief from having their illnesses named. In the case of the U.S. malady that has gripped us all, Ms. Wilkerson reiterates the importance of naming the condition. She writes:

“Because, to truly understand America, we must open our eyes to the hidden work of a caste system that has gone unnamed but prevails among us to our collective detriment, to see that we have more in common with each other and with cultures that we might otherwise dismiss, and to summon the courage to consider that therein may lie the answers.”

The naming allows both doctor and patient to have greater insight, understanding its origins and course, as well as having hope that there is a remedy. Naming facilitates the space for a shift in thinking and implementation of treatment protocols, such as Nazi Germany’s “zero tolerance policy” of swastikas in comparison to the ongoing U.S. controversy about the display of Confederate symbols. At this point in history, we welcome a diagnosis that has the potential to shift us from these poles of dominant and subordinate, black and white, good and bad, toward integration and wholeness of the individual psyche and collective global community. This is similar to what Melanie Klein calls the depressive position. Ms. Wilkerson suggests, in relinquishing these polar splits, we increase our capacity to shift to a space where our psychic integration occurs and our inextricable interdependence and responsibility for one another are honored.
 

Dr. Dunlap is a psychiatrist and psychoanalyst, and clinical professor of psychiatry and behavioral sciences at George Washington University. She is interested in the management of “difference” – race, gender, ethnicity, and intersectionality – in dyadic relationships and group dynamics; and the impact of racism on interpersonal relationships in institutional structures. Dr. Dunlap practices in Washington and has no disclosures. Dr. Dennis is a clinical psychologist and psychoanalyst. Her interests are in gender and ethnic diversity, health equity, and supervision and training. Dr. Dennis practices in Washington and has no disclosures.

States have begun preparing to distribute a COVID-19 vaccine if one is approved, a CDC official said today.

The CDC released guidance for states on Sept. 16 titled COVID-19 Vaccination Program Interim Playbook for Jurisdiction Operations. The document discusses vaccine ordering, storage, and handling and says that states should submit their plans for vaccine distribution to the agency by Oct. 16.

“Every jurisdiction is heavily involved right now in their plan development,” CDC official Janell Routh, MD, told the Advisory Committee on Immunization Practices during its Sept. 22 meeting. “It was really impressive to me that, even though the playbook only went out last week, states and jurisdictions have been thinking about this for quite some time.”

However, one committee member suggested that setting a deadline before more safety, efficacy, and storage information is known may be premature.

“I cannot imagine that we will actually know the final storage requirements for this vaccine by Oct. 16, which makes me a little concerned about finalizing state plans,” said Helen “Keipp” Talbot, MD, MPH, associate professor of medicine at Vanderbilt University Medical Center in Nashville, Tenn. “We also don’t know the best populations yet when it comes to efficacy and safety.”

Dr. Routh said the CDC is asking states to plan on the basis of assumptions. “We know those plans will constantly be improving, changing, as we learn more information,” Dr. Routh said. States agreed to return a plan 30 days after the playbook was released, which is how the Oct. 16 deadline was established, she said.

States are encouraged to think broadly. Plans may include contingencies for a product that requires ultracold storage or for distributing more than one vaccine product, Dr. Routh said.

“One goal is to be ready on the first day that we can actually distribute vaccine,” Nancy Messonnier, MD, director of the National Center for Immunization and Respiratory Diseases, said during the meeting. “Our colleagues in Operation Warp Speed say that they expect there will be vaccine as early as November, and therefore we need to be ready so there is no delay in distributing that vaccine. And that phase, that early phase, is really close upon us.”

Many states have already developed plans, and the CDC is providing technical assistance as needed to monitor the plans regularly, Dr. Routh said.
 

Key issues identified

From holding pilot meetings with five jurisdictions, officials learned that public confidence in the vaccine is among states’ greatest concerns, Dr. Routh said. In addition, distribution is resource intensive, and social distancing adds logistical complexity.

Specific guidance on whom to vaccinate in the early stages will smooth the process, officials suggested during the pilot meetings. For the first several weeks, vaccine doses may be limited to priority populations, such as health care workers.

“This interim playbook is a living document,” Dr. Routh emphasized. “We definitely plan to update the content regularly as we learn more information about what vaccines and when they will be released.”

During the early stages of COVID-19 vaccination, officials plan to implement an enhanced monitoring program in which vaccine recipients would complete surveys about adverse events, in addition to the traditional vaccine safety monitoring programs that already exist, officials said.
 

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

States have begun preparing to distribute a COVID-19 vaccine if one is approved, a CDC official said today.

The CDC released guidance for states on Sept. 16 titled COVID-19 Vaccination Program Interim Playbook for Jurisdiction Operations. The document discusses vaccine ordering, storage, and handling and says that states should submit their plans for vaccine distribution to the agency by Oct. 16.

“Every jurisdiction is heavily involved right now in their plan development,” CDC official Janell Routh, MD, told the Advisory Committee on Immunization Practices during its Sept. 22 meeting. “It was really impressive to me that, even though the playbook only went out last week, states and jurisdictions have been thinking about this for quite some time.”

However, one committee member suggested that setting a deadline before more safety, efficacy, and storage information is known may be premature.

“I cannot imagine that we will actually know the final storage requirements for this vaccine by Oct. 16, which makes me a little concerned about finalizing state plans,” said Helen “Keipp” Talbot, MD, MPH, associate professor of medicine at Vanderbilt University Medical Center in Nashville, Tenn. “We also don’t know the best populations yet when it comes to efficacy and safety.”

Dr. Routh said the CDC is asking states to plan on the basis of assumptions. “We know those plans will constantly be improving, changing, as we learn more information,” Dr. Routh said. States agreed to return a plan 30 days after the playbook was released, which is how the Oct. 16 deadline was established, she said.

States are encouraged to think broadly. Plans may include contingencies for a product that requires ultracold storage or for distributing more than one vaccine product, Dr. Routh said.

“One goal is to be ready on the first day that we can actually distribute vaccine,” Nancy Messonnier, MD, director of the National Center for Immunization and Respiratory Diseases, said during the meeting. “Our colleagues in Operation Warp Speed say that they expect there will be vaccine as early as November, and therefore we need to be ready so there is no delay in distributing that vaccine. And that phase, that early phase, is really close upon us.”

Many states have already developed plans, and the CDC is providing technical assistance as needed to monitor the plans regularly, Dr. Routh said.
 

Key issues identified

From holding pilot meetings with five jurisdictions, officials learned that public confidence in the vaccine is among states’ greatest concerns, Dr. Routh said. In addition, distribution is resource intensive, and social distancing adds logistical complexity.

Specific guidance on whom to vaccinate in the early stages will smooth the process, officials suggested during the pilot meetings. For the first several weeks, vaccine doses may be limited to priority populations, such as health care workers.

“This interim playbook is a living document,” Dr. Routh emphasized. “We definitely plan to update the content regularly as we learn more information about what vaccines and when they will be released.”

During the early stages of COVID-19 vaccination, officials plan to implement an enhanced monitoring program in which vaccine recipients would complete surveys about adverse events, in addition to the traditional vaccine safety monitoring programs that already exist, officials said.
 

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

States have begun preparing to distribute a COVID-19 vaccine if one is approved, a CDC official said today.

The CDC released guidance for states on Sept. 16 titled COVID-19 Vaccination Program Interim Playbook for Jurisdiction Operations. The document discusses vaccine ordering, storage, and handling and says that states should submit their plans for vaccine distribution to the agency by Oct. 16.

“Every jurisdiction is heavily involved right now in their plan development,” CDC official Janell Routh, MD, told the Advisory Committee on Immunization Practices during its Sept. 22 meeting. “It was really impressive to me that, even though the playbook only went out last week, states and jurisdictions have been thinking about this for quite some time.”

However, one committee member suggested that setting a deadline before more safety, efficacy, and storage information is known may be premature.

“I cannot imagine that we will actually know the final storage requirements for this vaccine by Oct. 16, which makes me a little concerned about finalizing state plans,” said Helen “Keipp” Talbot, MD, MPH, associate professor of medicine at Vanderbilt University Medical Center in Nashville, Tenn. “We also don’t know the best populations yet when it comes to efficacy and safety.”

Dr. Routh said the CDC is asking states to plan on the basis of assumptions. “We know those plans will constantly be improving, changing, as we learn more information,” Dr. Routh said. States agreed to return a plan 30 days after the playbook was released, which is how the Oct. 16 deadline was established, she said.

States are encouraged to think broadly. Plans may include contingencies for a product that requires ultracold storage or for distributing more than one vaccine product, Dr. Routh said.

“One goal is to be ready on the first day that we can actually distribute vaccine,” Nancy Messonnier, MD, director of the National Center for Immunization and Respiratory Diseases, said during the meeting. “Our colleagues in Operation Warp Speed say that they expect there will be vaccine as early as November, and therefore we need to be ready so there is no delay in distributing that vaccine. And that phase, that early phase, is really close upon us.”

Many states have already developed plans, and the CDC is providing technical assistance as needed to monitor the plans regularly, Dr. Routh said.
 

Key issues identified

From holding pilot meetings with five jurisdictions, officials learned that public confidence in the vaccine is among states’ greatest concerns, Dr. Routh said. In addition, distribution is resource intensive, and social distancing adds logistical complexity.

Specific guidance on whom to vaccinate in the early stages will smooth the process, officials suggested during the pilot meetings. For the first several weeks, vaccine doses may be limited to priority populations, such as health care workers.

“This interim playbook is a living document,” Dr. Routh emphasized. “We definitely plan to update the content regularly as we learn more information about what vaccines and when they will be released.”

During the early stages of COVID-19 vaccination, officials plan to implement an enhanced monitoring program in which vaccine recipients would complete surveys about adverse events, in addition to the traditional vaccine safety monitoring programs that already exist, officials said.
 

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

On March 3 of this year, Bryant Cameron Webb, MD, JD, won two-thirds of the vote in Virginia’s Democratic primary race. In November, he’ll compete against Republican Bob Good to represent the state’s 5th Congressional District. If he succeeds, he will become the first Black physician ever elected to a seat in Congress.

Courtesy Dr. Bryant Cameron Webb

The political and social unrest across the United States in recent months has resulted in millions of people becoming more proactive: from sports arenas to the halls of Congress, the rally cry of Black Lives Matter has echoed like never before after the killing of George Floyd and Breonna Taylor at the hands of law enforcement. Dr. Webb, a practicing internist and professor at the University of Virginia, Charlottesville, is among many physicians joining the cause. If elected, he hopes to bring a unique perspective to Washington and advocate for racial equity to help combat systemic racist policies that result in health disparities.

“For me as a professor at UVA in both public health sciences and in medicine, I have a lot to bring to this moment,” he commented, “real expertise on issues that are critical to the nation. Beyond my passion for health and wellness, I have a passion for justice.”

Dr. Webb also believes that serving in Congress is a way to help his patients. “I balance the work of direct patient care and patient advocacy in different spaces,” said the Spotsylvania County native. “Working in Congress is patient advocacy to me. It’s where I can be at my highest use to the people I take care of. It is different from direct patient care. I think this [unique] background that I have is needed in Congress.”

Dr. Webb has never held an elected office before, and he’s looking to get elected in a district that voted for President Trump in the past election. He knows challenges lie ahead.
 

A calling

The field of medicine called for Dr. Webb at an early age. He credits his family doctor, a Black man, for inspiring him. “With six kids in our family, we saw the doctor frequently. Dr. Yarboro was a young Black man just a few years out of residency. My mom had supreme confidence in him, and he made us feel at ease. So I wanted to be a doctor ever since I was 5 or 6 years old.”

Dr. Webb earned a bachelor’s degree from the University of Virginia in 2005. He entered medical school at Wake Forest University, Winston-Salem, N.C., the following year. Following his third year of medical training, he heeded another calling: He took time off to attend law school. He enrolled in Loyola University of Chicago School of Law and earned his juris doctorate in 2012.

The move may seem an unexpected turn. But Dr. Webb feels his law degree enhances his work. “I think that it’s because I’m so steeped in the legal resources that folks need to navigate. I think I am able to provide better care. ... It’s a complement and helpful to me professionally, whether it’s fighting with an insurance company or with a prescription drug company.”

After law school, Dr. Webb finished his medical training at Wake Forest and moved north, where he completed an internal medicine residency at New York–Presbyterian Hospital. Then came yet another twist in Dr. Webb’s unconventional career path: in 2016, he was selected by President Obama as a White House fellow. He spent the next 2 years in Washington, where he worked on Mr. Obama’s My Brother’s Keeper Task Force, an initiative that addresses opportunity gaps faced by boys and young men of color.

Adeze Enekwechi, MD, president of Impaq and associate professor at the George Washington University, Washington, worked with Dr. Webb at the White House. “This is the place where he will have the most impact. We’ve been talking and writing about health equity ever since our time [there]. Not everybody can speak that language. Being an African American male physician and an attorney can really help drive change by being the right person at the table.”
 

Why here? Why now?

Dr. Webb sees patients 2-3 days a week on alternating weeks and knows well the concerns of people who struggle with health. Now he’s ready to have those conversations on a larger platform. “As a Black physician, it’s about bringing that healer mindset to these problems. It’s not about just going there to brow beat people or add to that divisive nature in Congress. You acknowledge that the problems exist, and then bridge,” he said, hoping that bridging party divides can be a catalyst for healing.

Carla Boutin-Foster, MD, associate dean, office of diversity education and research at the State University of New York, Brooklyn, has mentored Dr. Webb since 2013. With his credentials, confidence, and persistence, she believes, he will be a great representative of the medical community in D.C. “You need someone who respects the Constitution. When policy needs to be developed, you need a healer, someone who understands the science of vaccines. This is something Cam has been groomed for. It’s something he has been living and practicing for years.”

The killing of George Floyd and the uprising that ensued has opened the dialogue about racial inequality in America. Health care is not immune to racial bias, and the effects are palatable. One survey conducted by the Larry A. Green Center, in collaboration with the Primary Care Collaborative and 3rd Conversation, found that more than 40% of clinicians say Mr. Floyd’s demise has become a topic of concern among patients of all demographics.

When it comes to racism, Dr. Webb understands that he plays a critical role in moving America forward. “We have so many voices that are powerful and important in the highest level of legislation. We have to use those voices to root out the injustices in our society, like in the Breonna Taylor case. We have to do so because that is how you achieve the American dream,” he said.

The social determinants of health – or “ZIP-code risk” – has been proven to influence health outcomes, yet few physicians screen for them during patient visits. For Dr. Webb, discussing things like housing security and interpersonal violence are critical to providing care.

One of Dr. Webb’s biggest supporters is his wife of 11 years, Leigh Ann Webb, MD, MBA, an emergency medicine physician and assistant professor of emergency medicine at UVA. “He is an effective leader and a consensus builder,” she said of her husband, with whom she has two children. “There has always been something very unique and special about him and the way he engages the world. We need more thoughtful, intelligent people like him to help our country move forward.”

In addition to being the director of health policy and equity at UVA this fall, Dr. Webb plans to teach a course at UVA centered around the social determinants of health called Place Matters. “The focus is on understanding how education and housing and food insecurity all come together to cause illness,” he said. “Health doesn’t happen in hospitals and clinics. It happens in the community.”

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

On March 3 of this year, Bryant Cameron Webb, MD, JD, won two-thirds of the vote in Virginia’s Democratic primary race. In November, he’ll compete against Republican Bob Good to represent the state’s 5th Congressional District. If he succeeds, he will become the first Black physician ever elected to a seat in Congress.

Courtesy Dr. Bryant Cameron Webb

The political and social unrest across the United States in recent months has resulted in millions of people becoming more proactive: from sports arenas to the halls of Congress, the rally cry of Black Lives Matter has echoed like never before after the killing of George Floyd and Breonna Taylor at the hands of law enforcement. Dr. Webb, a practicing internist and professor at the University of Virginia, Charlottesville, is among many physicians joining the cause. If elected, he hopes to bring a unique perspective to Washington and advocate for racial equity to help combat systemic racist policies that result in health disparities.

“For me as a professor at UVA in both public health sciences and in medicine, I have a lot to bring to this moment,” he commented, “real expertise on issues that are critical to the nation. Beyond my passion for health and wellness, I have a passion for justice.”

Dr. Webb also believes that serving in Congress is a way to help his patients. “I balance the work of direct patient care and patient advocacy in different spaces,” said the Spotsylvania County native. “Working in Congress is patient advocacy to me. It’s where I can be at my highest use to the people I take care of. It is different from direct patient care. I think this [unique] background that I have is needed in Congress.”

Dr. Webb has never held an elected office before, and he’s looking to get elected in a district that voted for President Trump in the past election. He knows challenges lie ahead.
 

A calling

The field of medicine called for Dr. Webb at an early age. He credits his family doctor, a Black man, for inspiring him. “With six kids in our family, we saw the doctor frequently. Dr. Yarboro was a young Black man just a few years out of residency. My mom had supreme confidence in him, and he made us feel at ease. So I wanted to be a doctor ever since I was 5 or 6 years old.”

Dr. Webb earned a bachelor’s degree from the University of Virginia in 2005. He entered medical school at Wake Forest University, Winston-Salem, N.C., the following year. Following his third year of medical training, he heeded another calling: He took time off to attend law school. He enrolled in Loyola University of Chicago School of Law and earned his juris doctorate in 2012.

The move may seem an unexpected turn. But Dr. Webb feels his law degree enhances his work. “I think that it’s because I’m so steeped in the legal resources that folks need to navigate. I think I am able to provide better care. ... It’s a complement and helpful to me professionally, whether it’s fighting with an insurance company or with a prescription drug company.”

After law school, Dr. Webb finished his medical training at Wake Forest and moved north, where he completed an internal medicine residency at New York–Presbyterian Hospital. Then came yet another twist in Dr. Webb’s unconventional career path: in 2016, he was selected by President Obama as a White House fellow. He spent the next 2 years in Washington, where he worked on Mr. Obama’s My Brother’s Keeper Task Force, an initiative that addresses opportunity gaps faced by boys and young men of color.

Adeze Enekwechi, MD, president of Impaq and associate professor at the George Washington University, Washington, worked with Dr. Webb at the White House. “This is the place where he will have the most impact. We’ve been talking and writing about health equity ever since our time [there]. Not everybody can speak that language. Being an African American male physician and an attorney can really help drive change by being the right person at the table.”
 

Why here? Why now?

Dr. Webb sees patients 2-3 days a week on alternating weeks and knows well the concerns of people who struggle with health. Now he’s ready to have those conversations on a larger platform. “As a Black physician, it’s about bringing that healer mindset to these problems. It’s not about just going there to brow beat people or add to that divisive nature in Congress. You acknowledge that the problems exist, and then bridge,” he said, hoping that bridging party divides can be a catalyst for healing.

Carla Boutin-Foster, MD, associate dean, office of diversity education and research at the State University of New York, Brooklyn, has mentored Dr. Webb since 2013. With his credentials, confidence, and persistence, she believes, he will be a great representative of the medical community in D.C. “You need someone who respects the Constitution. When policy needs to be developed, you need a healer, someone who understands the science of vaccines. This is something Cam has been groomed for. It’s something he has been living and practicing for years.”

The killing of George Floyd and the uprising that ensued has opened the dialogue about racial inequality in America. Health care is not immune to racial bias, and the effects are palatable. One survey conducted by the Larry A. Green Center, in collaboration with the Primary Care Collaborative and 3rd Conversation, found that more than 40% of clinicians say Mr. Floyd’s demise has become a topic of concern among patients of all demographics.

When it comes to racism, Dr. Webb understands that he plays a critical role in moving America forward. “We have so many voices that are powerful and important in the highest level of legislation. We have to use those voices to root out the injustices in our society, like in the Breonna Taylor case. We have to do so because that is how you achieve the American dream,” he said.

The social determinants of health – or “ZIP-code risk” – has been proven to influence health outcomes, yet few physicians screen for them during patient visits. For Dr. Webb, discussing things like housing security and interpersonal violence are critical to providing care.

One of Dr. Webb’s biggest supporters is his wife of 11 years, Leigh Ann Webb, MD, MBA, an emergency medicine physician and assistant professor of emergency medicine at UVA. “He is an effective leader and a consensus builder,” she said of her husband, with whom she has two children. “There has always been something very unique and special about him and the way he engages the world. We need more thoughtful, intelligent people like him to help our country move forward.”

In addition to being the director of health policy and equity at UVA this fall, Dr. Webb plans to teach a course at UVA centered around the social determinants of health called Place Matters. “The focus is on understanding how education and housing and food insecurity all come together to cause illness,” he said. “Health doesn’t happen in hospitals and clinics. It happens in the community.”

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

On March 3 of this year, Bryant Cameron Webb, MD, JD, won two-thirds of the vote in Virginia’s Democratic primary race. In November, he’ll compete against Republican Bob Good to represent the state’s 5th Congressional District. If he succeeds, he will become the first Black physician ever elected to a seat in Congress.

Courtesy Dr. Bryant Cameron Webb

The political and social unrest across the United States in recent months has resulted in millions of people becoming more proactive: from sports arenas to the halls of Congress, the rally cry of Black Lives Matter has echoed like never before after the killing of George Floyd and Breonna Taylor at the hands of law enforcement. Dr. Webb, a practicing internist and professor at the University of Virginia, Charlottesville, is among many physicians joining the cause. If elected, he hopes to bring a unique perspective to Washington and advocate for racial equity to help combat systemic racist policies that result in health disparities.

“For me as a professor at UVA in both public health sciences and in medicine, I have a lot to bring to this moment,” he commented, “real expertise on issues that are critical to the nation. Beyond my passion for health and wellness, I have a passion for justice.”

Dr. Webb also believes that serving in Congress is a way to help his patients. “I balance the work of direct patient care and patient advocacy in different spaces,” said the Spotsylvania County native. “Working in Congress is patient advocacy to me. It’s where I can be at my highest use to the people I take care of. It is different from direct patient care. I think this [unique] background that I have is needed in Congress.”

Dr. Webb has never held an elected office before, and he’s looking to get elected in a district that voted for President Trump in the past election. He knows challenges lie ahead.
 

A calling

The field of medicine called for Dr. Webb at an early age. He credits his family doctor, a Black man, for inspiring him. “With six kids in our family, we saw the doctor frequently. Dr. Yarboro was a young Black man just a few years out of residency. My mom had supreme confidence in him, and he made us feel at ease. So I wanted to be a doctor ever since I was 5 or 6 years old.”

Dr. Webb earned a bachelor’s degree from the University of Virginia in 2005. He entered medical school at Wake Forest University, Winston-Salem, N.C., the following year. Following his third year of medical training, he heeded another calling: He took time off to attend law school. He enrolled in Loyola University of Chicago School of Law and earned his juris doctorate in 2012.

The move may seem an unexpected turn. But Dr. Webb feels his law degree enhances his work. “I think that it’s because I’m so steeped in the legal resources that folks need to navigate. I think I am able to provide better care. ... It’s a complement and helpful to me professionally, whether it’s fighting with an insurance company or with a prescription drug company.”

After law school, Dr. Webb finished his medical training at Wake Forest and moved north, where he completed an internal medicine residency at New York–Presbyterian Hospital. Then came yet another twist in Dr. Webb’s unconventional career path: in 2016, he was selected by President Obama as a White House fellow. He spent the next 2 years in Washington, where he worked on Mr. Obama’s My Brother’s Keeper Task Force, an initiative that addresses opportunity gaps faced by boys and young men of color.

Adeze Enekwechi, MD, president of Impaq and associate professor at the George Washington University, Washington, worked with Dr. Webb at the White House. “This is the place where he will have the most impact. We’ve been talking and writing about health equity ever since our time [there]. Not everybody can speak that language. Being an African American male physician and an attorney can really help drive change by being the right person at the table.”
 

Why here? Why now?

Dr. Webb sees patients 2-3 days a week on alternating weeks and knows well the concerns of people who struggle with health. Now he’s ready to have those conversations on a larger platform. “As a Black physician, it’s about bringing that healer mindset to these problems. It’s not about just going there to brow beat people or add to that divisive nature in Congress. You acknowledge that the problems exist, and then bridge,” he said, hoping that bridging party divides can be a catalyst for healing.

Carla Boutin-Foster, MD, associate dean, office of diversity education and research at the State University of New York, Brooklyn, has mentored Dr. Webb since 2013. With his credentials, confidence, and persistence, she believes, he will be a great representative of the medical community in D.C. “You need someone who respects the Constitution. When policy needs to be developed, you need a healer, someone who understands the science of vaccines. This is something Cam has been groomed for. It’s something he has been living and practicing for years.”

The killing of George Floyd and the uprising that ensued has opened the dialogue about racial inequality in America. Health care is not immune to racial bias, and the effects are palatable. One survey conducted by the Larry A. Green Center, in collaboration with the Primary Care Collaborative and 3rd Conversation, found that more than 40% of clinicians say Mr. Floyd’s demise has become a topic of concern among patients of all demographics.

When it comes to racism, Dr. Webb understands that he plays a critical role in moving America forward. “We have so many voices that are powerful and important in the highest level of legislation. We have to use those voices to root out the injustices in our society, like in the Breonna Taylor case. We have to do so because that is how you achieve the American dream,” he said.

The social determinants of health – or “ZIP-code risk” – has been proven to influence health outcomes, yet few physicians screen for them during patient visits. For Dr. Webb, discussing things like housing security and interpersonal violence are critical to providing care.

One of Dr. Webb’s biggest supporters is his wife of 11 years, Leigh Ann Webb, MD, MBA, an emergency medicine physician and assistant professor of emergency medicine at UVA. “He is an effective leader and a consensus builder,” she said of her husband, with whom she has two children. “There has always been something very unique and special about him and the way he engages the world. We need more thoughtful, intelligent people like him to help our country move forward.”

In addition to being the director of health policy and equity at UVA this fall, Dr. Webb plans to teach a course at UVA centered around the social determinants of health called Place Matters. “The focus is on understanding how education and housing and food insecurity all come together to cause illness,” he said. “Health doesn’t happen in hospitals and clinics. It happens in the community.”

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