For the treatment of acute gout, corticosteroids may be as effective as nonsteroidal anti-inflammatory drugs but with fewer side effects, based on findings from a meta-analysis of six randomized, controlled trials.

“There is insufficient information to determine the comparative efficacy of corticosteroids and NSAID[s] to treat acute gout, while corticosteroids appear to have a more favorable safety profile for selected [adverse events],” Christy A. Billy, MD, of the University of Sydney and her coauthors wrote in their report published online in the Journal of Rheumatology (J Rheumatol. 2017 Aug. doi: 10.3899/jrheum.170137).

Two previous systematic reviews also suggested that corticosteroids may be therapeutically equivalent to but safer than NSAIDs, but both were based on a very small number of available studies and suffered from statistical between-trial heterogeneity.

The meta-analysis of six trials included a total of 817 patients. The trials had a mean follow-up of 15 days. Two trials were in hospitalized patients, two involved patients in the emergency department, one included outpatients, and one did not disclose the location of clinical presentation. Mean age of participants ranged from 44 years to 65.9 years, and the proportion of men ranged from 70% to 100%.

With respect to pain scores, the researchers found no significant difference between corticosteroid and NSAIDs within 7 days of treatment based on moderate-quality evidence from two randomized, controlled trials (RCTs) involving 534 patients (standardized mean difference = –0.09; 95% confidence interval, –0.26 to 0.08). There was also no difference between the two on pain after 7 or more days based on low-quality evidence from two RCTs of 506 patients (SMD = 0.32; 95% CI, –0.27 to 0.92). There was no evidence of statistical heterogeneity in the short-term trials, but there was evidence of significant heterogeneity in trials measuring treatment effects for 7 days or longer (P = .01; I^{2 [heterogeneity]} = 85%).

Two RCTs of 173 patients gave low-quality evidence to show no difference between corticosteroids and NSAIDs in the rate of treatment response in the short term (relative risk, 1.07; 95% CI, 0.80-1.44; moderate heterogeneity, P = .15, I² = 53%). One long-term study of the rate of treatment response provided similar results. There were also no between-group differences in joint swelling, erythema, tenderness, or activity limitations.

The investigators discovered that patients who took corticosteroids had a lower risk of indigestion in three RCTs with 526 patients (RR, 0.50; 95% CI, 0.27-0.92), nausea in three RCTs of 566 patients (RR, 0.25; 95% CI, 0.11-0.54), and vomiting in two RCTs totaling 506 patients (RR, 0.11; 95% CI, 0.02-0.56).

Patients taking corticosteroids had a higher risk of rash in two RCTs of 506 patients (RR, 4.62; 95% CI, 1.34-15.97). There was statistically significant heterogeneity in summary effects of treatment for total adverse events across all six studies (P = .04; I² = 56%).

This meta-analysis was limited by the small number of clinical trials available for inclusion, which prevented the estimate of a number of outcomes and subgroup analyses. There was also a high risk of bias in many of the studies. Only half of the studies confirmed the diagnosis of gout by the presence of monosodium urate crystals within joint spaces. No studies reported on the effects of treatment on kidney function or injury.

The authors disclosed no source of funding or financial relationships.

[email protected]

For the treatment of acute gout, corticosteroids may be as effective as nonsteroidal anti-inflammatory drugs but with fewer side effects, based on findings from a meta-analysis of six randomized, controlled trials.

“There is insufficient information to determine the comparative efficacy of corticosteroids and NSAID[s] to treat acute gout, while corticosteroids appear to have a more favorable safety profile for selected [adverse events],” Christy A. Billy, MD, of the University of Sydney and her coauthors wrote in their report published online in the Journal of Rheumatology (J Rheumatol. 2017 Aug. doi: 10.3899/jrheum.170137).

Two previous systematic reviews also suggested that corticosteroids may be therapeutically equivalent to but safer than NSAIDs, but both were based on a very small number of available studies and suffered from statistical between-trial heterogeneity.

The meta-analysis of six trials included a total of 817 patients. The trials had a mean follow-up of 15 days. Two trials were in hospitalized patients, two involved patients in the emergency department, one included outpatients, and one did not disclose the location of clinical presentation. Mean age of participants ranged from 44 years to 65.9 years, and the proportion of men ranged from 70% to 100%.

With respect to pain scores, the researchers found no significant difference between corticosteroid and NSAIDs within 7 days of treatment based on moderate-quality evidence from two randomized, controlled trials (RCTs) involving 534 patients (standardized mean difference = –0.09; 95% confidence interval, –0.26 to 0.08). There was also no difference between the two on pain after 7 or more days based on low-quality evidence from two RCTs of 506 patients (SMD = 0.32; 95% CI, –0.27 to 0.92). There was no evidence of statistical heterogeneity in the short-term trials, but there was evidence of significant heterogeneity in trials measuring treatment effects for 7 days or longer (P = .01; I^{2 [heterogeneity]} = 85%).

Two RCTs of 173 patients gave low-quality evidence to show no difference between corticosteroids and NSAIDs in the rate of treatment response in the short term (relative risk, 1.07; 95% CI, 0.80-1.44; moderate heterogeneity, P = .15, I² = 53%). One long-term study of the rate of treatment response provided similar results. There were also no between-group differences in joint swelling, erythema, tenderness, or activity limitations.

The investigators discovered that patients who took corticosteroids had a lower risk of indigestion in three RCTs with 526 patients (RR, 0.50; 95% CI, 0.27-0.92), nausea in three RCTs of 566 patients (RR, 0.25; 95% CI, 0.11-0.54), and vomiting in two RCTs totaling 506 patients (RR, 0.11; 95% CI, 0.02-0.56).

Patients taking corticosteroids had a higher risk of rash in two RCTs of 506 patients (RR, 4.62; 95% CI, 1.34-15.97). There was statistically significant heterogeneity in summary effects of treatment for total adverse events across all six studies (P = .04; I² = 56%).

This meta-analysis was limited by the small number of clinical trials available for inclusion, which prevented the estimate of a number of outcomes and subgroup analyses. There was also a high risk of bias in many of the studies. Only half of the studies confirmed the diagnosis of gout by the presence of monosodium urate crystals within joint spaces. No studies reported on the effects of treatment on kidney function or injury.

The authors disclosed no source of funding or financial relationships.

[email protected]

For the treatment of acute gout, corticosteroids may be as effective as nonsteroidal anti-inflammatory drugs but with fewer side effects, based on findings from a meta-analysis of six randomized, controlled trials.

“There is insufficient information to determine the comparative efficacy of corticosteroids and NSAID[s] to treat acute gout, while corticosteroids appear to have a more favorable safety profile for selected [adverse events],” Christy A. Billy, MD, of the University of Sydney and her coauthors wrote in their report published online in the Journal of Rheumatology (J Rheumatol. 2017 Aug. doi: 10.3899/jrheum.170137).

Two previous systematic reviews also suggested that corticosteroids may be therapeutically equivalent to but safer than NSAIDs, but both were based on a very small number of available studies and suffered from statistical between-trial heterogeneity.

The meta-analysis of six trials included a total of 817 patients. The trials had a mean follow-up of 15 days. Two trials were in hospitalized patients, two involved patients in the emergency department, one included outpatients, and one did not disclose the location of clinical presentation. Mean age of participants ranged from 44 years to 65.9 years, and the proportion of men ranged from 70% to 100%.

With respect to pain scores, the researchers found no significant difference between corticosteroid and NSAIDs within 7 days of treatment based on moderate-quality evidence from two randomized, controlled trials (RCTs) involving 534 patients (standardized mean difference = –0.09; 95% confidence interval, –0.26 to 0.08). There was also no difference between the two on pain after 7 or more days based on low-quality evidence from two RCTs of 506 patients (SMD = 0.32; 95% CI, –0.27 to 0.92). There was no evidence of statistical heterogeneity in the short-term trials, but there was evidence of significant heterogeneity in trials measuring treatment effects for 7 days or longer (P = .01; I^{2 [heterogeneity]} = 85%).

Two RCTs of 173 patients gave low-quality evidence to show no difference between corticosteroids and NSAIDs in the rate of treatment response in the short term (relative risk, 1.07; 95% CI, 0.80-1.44; moderate heterogeneity, P = .15, I² = 53%). One long-term study of the rate of treatment response provided similar results. There were also no between-group differences in joint swelling, erythema, tenderness, or activity limitations.

The investigators discovered that patients who took corticosteroids had a lower risk of indigestion in three RCTs with 526 patients (RR, 0.50; 95% CI, 0.27-0.92), nausea in three RCTs of 566 patients (RR, 0.25; 95% CI, 0.11-0.54), and vomiting in two RCTs totaling 506 patients (RR, 0.11; 95% CI, 0.02-0.56).

Patients taking corticosteroids had a higher risk of rash in two RCTs of 506 patients (RR, 4.62; 95% CI, 1.34-15.97). There was statistically significant heterogeneity in summary effects of treatment for total adverse events across all six studies (P = .04; I² = 56%).

This meta-analysis was limited by the small number of clinical trials available for inclusion, which prevented the estimate of a number of outcomes and subgroup analyses. There was also a high risk of bias in many of the studies. Only half of the studies confirmed the diagnosis of gout by the presence of monosodium urate crystals within joint spaces. No studies reported on the effects of treatment on kidney function or injury.

The authors disclosed no source of funding or financial relationships.

[email protected]

LONDON – Women veterans with either depression or post-traumatic stress disorder face a doubling in their risk of dementia – and having both increases the risk even more, Dr. Kristine Yaffe reported at the Alzheimer’s Association International Conference.*

The risk ratios for incident dementia that Dr. Yaffe of the University of California, San Francisco, and her colleagues calculated from their analysis of a cohort of 149,000 older female veterans in the national Veterans Health Administration (VHA) database remained unchanged even when they adjusted for age, education, medical comorbidities, and other confounders.

Correction, 8/7/17: An earlier version of this article misstated Dr. Kristine Yaffe's degree.

[email protected]

On Twitter @alz_gal

LONDON – Women veterans with either depression or post-traumatic stress disorder face a doubling in their risk of dementia – and having both increases the risk even more, Dr. Kristine Yaffe reported at the Alzheimer’s Association International Conference.*

The risk ratios for incident dementia that Dr. Yaffe of the University of California, San Francisco, and her colleagues calculated from their analysis of a cohort of 149,000 older female veterans in the national Veterans Health Administration (VHA) database remained unchanged even when they adjusted for age, education, medical comorbidities, and other confounders.

Correction, 8/7/17: An earlier version of this article misstated Dr. Kristine Yaffe's degree.

[email protected]

On Twitter @alz_gal

LONDON – Women veterans with either depression or post-traumatic stress disorder face a doubling in their risk of dementia – and having both increases the risk even more, Dr. Kristine Yaffe reported at the Alzheimer’s Association International Conference.*

The risk ratios for incident dementia that Dr. Yaffe of the University of California, San Francisco, and her colleagues calculated from their analysis of a cohort of 149,000 older female veterans in the national Veterans Health Administration (VHA) database remained unchanged even when they adjusted for age, education, medical comorbidities, and other confounders.

Correction, 8/7/17: An earlier version of this article misstated Dr. Kristine Yaffe's degree.

[email protected]

On Twitter @alz_gal

Amid all the turbulence over the future of the Affordable Care Act, one facet continues unchanged: President Trump’s administration is penalizing more than half the nation’s hospitals for having too many patients return within a month.

Medicare is punishing 2,573 hospitals, just two dozen short of what it did last year under President Obama, according to federal records released Aug. 2. Starting in October, the federal government will cut those hospitals’ payments by as much as 3% for a year.

Medicare docked all but 174 of those hospitals last year as well. The $564 million the government projects to save also is roughly the same as it was last year under Obama.

High rates of readmissions have been a safety concern for decades, with one in five Medicare patients historically ending up back in the hospital within 30 days. In 2011, 3.3 million adults returned to the hospital, running up medical costs estimated at $41 billion, according to the Agency for Healthcare Research and Quality.

The penalties, which begin their sixth year in October, have coincided with a nationwide decrease in hospital repeat patients. Between 2007 and 2015, the frequency of readmissions for conditions targeted by Medicare dropped from 21.5% to 17.8%, with the majority of the decrease occurring shortly after the ACA passed in 2010, according to a study conducted by Obama administration health policy experts and published in 2016 in the New England Journal of Medicine.

Some hospitals began giving impoverished patients free medications that they prescribed for their recovery, while others sent nurses to check up on patients seen as most likely to relapse in their homes. Readmissions dropped more quickly at hospitals potentially subject to the penalty than at other hospitals, another study found.

“The sum of the evidence really suggests that this program is helping people,” said Susannah Bernheim, MD, the director of quality measurement at the Yale/Yale-New Haven Hospital Center for Outcomes Research and Evaluation.

But the pace of these reductions has been leveling off in the past few years, indicating that the penalties’ ability to induce improvements may be waning.

“Presumably, hospitals made substantial changes during the implementation period but could not sustain such a high rate of reductions in the long term,” the New England Journal article said.

An analysis by Dr. Bernheim’s group found no decrease in the overall rate of readmissions between 2012 and 2015, although small drops in the medical conditions targeted by the penalties continued.

“We have indeed reached the limits of what changes in how we deliver care will allow us to do,” said Nancy Foster, vice president for quality at the American Hospital Association. “We can’t prevent every readmission. It could be that there is further room for improvement, but we just don’t know what the technique is to make that happen.”

The Hospital Readmissions Reduction Program was designed to use the purchasing power of Medicare to reward hospitals for higher quality. Those penalties, along with other ones aimed at improving hospital care, have been spared the partisan rancor over the law, and they would have continued under the GOP repeal proposals that stalled in Congress. But they have also been largely ignored.

Ashish Jha, MD, a professor at the Harvard T.H. Chan School of Public Health, Boston, said the fight over abolishing the ACA has drowned out talk about how to make the health care system more effective.

“We’ve spent the last 6 months fighting about how we’re going to pay for health insurance, which is one part of the ACA,” he said. “There’s been almost no discussion of the underlying health care delivery system changes that the ACA ushered in, and that is more important in the long run to be discussing because that’s what’s going to determine the underlying costs and outcomes of the health system.”

The readmission penalties are intended to neutralize an unintended incentive in the way Medicare pays hospitals that had profited from return patients. Medicare pays hospitals a lump sum for a patient’s stay based on the nature of the admission and other factors. Since hospitals generally are not paid extra if patients remain longer, they seek to discharge patients as soon as is medically feasible. If the patient ends up back in the hospital, it becomes a financial benefit as the hospital is paid for that second stay, filling a bed that would not have generated income if the patient had remained there continuously.

Because of the way the readmission penalty program was designed, it is not surprising that the new results are so similar to last year’s. As before, Medicare determined the penalties based on readmissions of the same six types of patients: those admitted for heart attacks, heart failure, pneumonia, chronic lung disease, hip or knee replacements, or coronary artery bypass graft surgery. Hospitals were judged on patients discharged between July 2013 and June 2016. Because the government looks at a 3-year period, 2 of those years were also examined in determining last year’s penalties.

This year, the average penalty will be 0.73% of each payment Medicare makes for a patient between Oct. 1 and Sept. 30, 2018, according to a Kaiser Health News analysis. That too was practically the same as last year. Forty-eight hospitals received the maximum punishment of a 3% reduction. Medicare did not release hospital-specific estimates for how much lost money these penalties would translate to.

More than 1,500 hospitals treating veterans, children, and psychiatric patients were exempted from penalties this year as required by law. Critical access hospitals, which Medicare also pays differently, also were excluded. So were Maryland hospitals because Congress has given that state extra leeway in how it distributes Medicare money.

Of the 3,241 hospitals whose readmissions were evaluated, Medicare penalized four out of five, the KHN analysis found. That is because the program’s methods are not very forgiving: A hospital can be penalized even if it has higher than expected readmission rates for only one of the six conditions that are targeted. Every nonexcluded hospital in Delaware and West Virginia will have their reimbursements reduced. Ninety percent or more will be punished in Arizona, Connecticut, Florida, Kentucky, Massachusetts, Minnesota, New Jersey, New York, and Virginia. Sixty percent or fewer will be penalized in Colorado, Kansas, Idaho, Montana, Oregon, South Dakota, and Utah.

Since the readmission program’s structure is set by law, the administration cannot make major changes unilaterally, even if it wanted to.

Congress last year instructed Medicare to make one future alteration in response to complaints from safety-net hospitals and major academic medical centers.

They have objected that their patients tended to be lower income than other hospitals and were more likely to return to the hospital, sometimes because they didn’t have a primary care doctor and other times because they could not afford the right medication or diet. Those hospitals argued that this was a disadvantage for them since Medicare bases its readmission targets on industry-wide trends and that it hurt them financially, depriving them of resources they could use to help those same patients.

Dr. Bernheim noted that, despite those complaints, safety-net hospitals have shown some of the greatest drops in readmission rates. In October 2018, Medicare will begin basing the penalties on how hospitals compared with their peer groups with similar numbers of poor patients. Akin Demehin, director of policy at the hospital association, said, “We expect the adjustment will provide some relief for safety-net hospitals.”

Medicare is planning to release two other rounds of recurring quality incentives for hospitals later this year. One gives out bonuses and penalties based on a mix of measures, with Medicare redistributing $1.9 billion based on how hospitals perform and improve. The other, the Hospital-Acquired Condition Reduction Program, cuts payments to roughly 750 hospitals with the highest rates of infections and other patient injuries by 1%.
 

Kaiser Health News is a national health policy news service that is part of the nonpartisan Henry J. Kaiser Family Foundation. KHN’s coverage related to aging & improving care of older adults is supported by The John A. Hartford Foundation.

Amid all the turbulence over the future of the Affordable Care Act, one facet continues unchanged: President Trump’s administration is penalizing more than half the nation’s hospitals for having too many patients return within a month.

Medicare is punishing 2,573 hospitals, just two dozen short of what it did last year under President Obama, according to federal records released Aug. 2. Starting in October, the federal government will cut those hospitals’ payments by as much as 3% for a year.

Medicare docked all but 174 of those hospitals last year as well. The $564 million the government projects to save also is roughly the same as it was last year under Obama.

High rates of readmissions have been a safety concern for decades, with one in five Medicare patients historically ending up back in the hospital within 30 days. In 2011, 3.3 million adults returned to the hospital, running up medical costs estimated at $41 billion, according to the Agency for Healthcare Research and Quality.

The penalties, which begin their sixth year in October, have coincided with a nationwide decrease in hospital repeat patients. Between 2007 and 2015, the frequency of readmissions for conditions targeted by Medicare dropped from 21.5% to 17.8%, with the majority of the decrease occurring shortly after the ACA passed in 2010, according to a study conducted by Obama administration health policy experts and published in 2016 in the New England Journal of Medicine.

Some hospitals began giving impoverished patients free medications that they prescribed for their recovery, while others sent nurses to check up on patients seen as most likely to relapse in their homes. Readmissions dropped more quickly at hospitals potentially subject to the penalty than at other hospitals, another study found.

“The sum of the evidence really suggests that this program is helping people,” said Susannah Bernheim, MD, the director of quality measurement at the Yale/Yale-New Haven Hospital Center for Outcomes Research and Evaluation.

But the pace of these reductions has been leveling off in the past few years, indicating that the penalties’ ability to induce improvements may be waning.

“Presumably, hospitals made substantial changes during the implementation period but could not sustain such a high rate of reductions in the long term,” the New England Journal article said.

An analysis by Dr. Bernheim’s group found no decrease in the overall rate of readmissions between 2012 and 2015, although small drops in the medical conditions targeted by the penalties continued.

“We have indeed reached the limits of what changes in how we deliver care will allow us to do,” said Nancy Foster, vice president for quality at the American Hospital Association. “We can’t prevent every readmission. It could be that there is further room for improvement, but we just don’t know what the technique is to make that happen.”

The Hospital Readmissions Reduction Program was designed to use the purchasing power of Medicare to reward hospitals for higher quality. Those penalties, along with other ones aimed at improving hospital care, have been spared the partisan rancor over the law, and they would have continued under the GOP repeal proposals that stalled in Congress. But they have also been largely ignored.

Ashish Jha, MD, a professor at the Harvard T.H. Chan School of Public Health, Boston, said the fight over abolishing the ACA has drowned out talk about how to make the health care system more effective.

“We’ve spent the last 6 months fighting about how we’re going to pay for health insurance, which is one part of the ACA,” he said. “There’s been almost no discussion of the underlying health care delivery system changes that the ACA ushered in, and that is more important in the long run to be discussing because that’s what’s going to determine the underlying costs and outcomes of the health system.”

The readmission penalties are intended to neutralize an unintended incentive in the way Medicare pays hospitals that had profited from return patients. Medicare pays hospitals a lump sum for a patient’s stay based on the nature of the admission and other factors. Since hospitals generally are not paid extra if patients remain longer, they seek to discharge patients as soon as is medically feasible. If the patient ends up back in the hospital, it becomes a financial benefit as the hospital is paid for that second stay, filling a bed that would not have generated income if the patient had remained there continuously.

Because of the way the readmission penalty program was designed, it is not surprising that the new results are so similar to last year’s. As before, Medicare determined the penalties based on readmissions of the same six types of patients: those admitted for heart attacks, heart failure, pneumonia, chronic lung disease, hip or knee replacements, or coronary artery bypass graft surgery. Hospitals were judged on patients discharged between July 2013 and June 2016. Because the government looks at a 3-year period, 2 of those years were also examined in determining last year’s penalties.

This year, the average penalty will be 0.73% of each payment Medicare makes for a patient between Oct. 1 and Sept. 30, 2018, according to a Kaiser Health News analysis. That too was practically the same as last year. Forty-eight hospitals received the maximum punishment of a 3% reduction. Medicare did not release hospital-specific estimates for how much lost money these penalties would translate to.

More than 1,500 hospitals treating veterans, children, and psychiatric patients were exempted from penalties this year as required by law. Critical access hospitals, which Medicare also pays differently, also were excluded. So were Maryland hospitals because Congress has given that state extra leeway in how it distributes Medicare money.

Of the 3,241 hospitals whose readmissions were evaluated, Medicare penalized four out of five, the KHN analysis found. That is because the program’s methods are not very forgiving: A hospital can be penalized even if it has higher than expected readmission rates for only one of the six conditions that are targeted. Every nonexcluded hospital in Delaware and West Virginia will have their reimbursements reduced. Ninety percent or more will be punished in Arizona, Connecticut, Florida, Kentucky, Massachusetts, Minnesota, New Jersey, New York, and Virginia. Sixty percent or fewer will be penalized in Colorado, Kansas, Idaho, Montana, Oregon, South Dakota, and Utah.

Since the readmission program’s structure is set by law, the administration cannot make major changes unilaterally, even if it wanted to.

Congress last year instructed Medicare to make one future alteration in response to complaints from safety-net hospitals and major academic medical centers.

They have objected that their patients tended to be lower income than other hospitals and were more likely to return to the hospital, sometimes because they didn’t have a primary care doctor and other times because they could not afford the right medication or diet. Those hospitals argued that this was a disadvantage for them since Medicare bases its readmission targets on industry-wide trends and that it hurt them financially, depriving them of resources they could use to help those same patients.

Dr. Bernheim noted that, despite those complaints, safety-net hospitals have shown some of the greatest drops in readmission rates. In October 2018, Medicare will begin basing the penalties on how hospitals compared with their peer groups with similar numbers of poor patients. Akin Demehin, director of policy at the hospital association, said, “We expect the adjustment will provide some relief for safety-net hospitals.”

Medicare is planning to release two other rounds of recurring quality incentives for hospitals later this year. One gives out bonuses and penalties based on a mix of measures, with Medicare redistributing $1.9 billion based on how hospitals perform and improve. The other, the Hospital-Acquired Condition Reduction Program, cuts payments to roughly 750 hospitals with the highest rates of infections and other patient injuries by 1%.
 

Kaiser Health News is a national health policy news service that is part of the nonpartisan Henry J. Kaiser Family Foundation. KHN’s coverage related to aging & improving care of older adults is supported by The John A. Hartford Foundation.

Amid all the turbulence over the future of the Affordable Care Act, one facet continues unchanged: President Trump’s administration is penalizing more than half the nation’s hospitals for having too many patients return within a month.

Medicare is punishing 2,573 hospitals, just two dozen short of what it did last year under President Obama, according to federal records released Aug. 2. Starting in October, the federal government will cut those hospitals’ payments by as much as 3% for a year.

Medicare docked all but 174 of those hospitals last year as well. The $564 million the government projects to save also is roughly the same as it was last year under Obama.

High rates of readmissions have been a safety concern for decades, with one in five Medicare patients historically ending up back in the hospital within 30 days. In 2011, 3.3 million adults returned to the hospital, running up medical costs estimated at $41 billion, according to the Agency for Healthcare Research and Quality.

The penalties, which begin their sixth year in October, have coincided with a nationwide decrease in hospital repeat patients. Between 2007 and 2015, the frequency of readmissions for conditions targeted by Medicare dropped from 21.5% to 17.8%, with the majority of the decrease occurring shortly after the ACA passed in 2010, according to a study conducted by Obama administration health policy experts and published in 2016 in the New England Journal of Medicine.

Some hospitals began giving impoverished patients free medications that they prescribed for their recovery, while others sent nurses to check up on patients seen as most likely to relapse in their homes. Readmissions dropped more quickly at hospitals potentially subject to the penalty than at other hospitals, another study found.

“The sum of the evidence really suggests that this program is helping people,” said Susannah Bernheim, MD, the director of quality measurement at the Yale/Yale-New Haven Hospital Center for Outcomes Research and Evaluation.

But the pace of these reductions has been leveling off in the past few years, indicating that the penalties’ ability to induce improvements may be waning.

“Presumably, hospitals made substantial changes during the implementation period but could not sustain such a high rate of reductions in the long term,” the New England Journal article said.

An analysis by Dr. Bernheim’s group found no decrease in the overall rate of readmissions between 2012 and 2015, although small drops in the medical conditions targeted by the penalties continued.

“We have indeed reached the limits of what changes in how we deliver care will allow us to do,” said Nancy Foster, vice president for quality at the American Hospital Association. “We can’t prevent every readmission. It could be that there is further room for improvement, but we just don’t know what the technique is to make that happen.”

The Hospital Readmissions Reduction Program was designed to use the purchasing power of Medicare to reward hospitals for higher quality. Those penalties, along with other ones aimed at improving hospital care, have been spared the partisan rancor over the law, and they would have continued under the GOP repeal proposals that stalled in Congress. But they have also been largely ignored.

Ashish Jha, MD, a professor at the Harvard T.H. Chan School of Public Health, Boston, said the fight over abolishing the ACA has drowned out talk about how to make the health care system more effective.

“We’ve spent the last 6 months fighting about how we’re going to pay for health insurance, which is one part of the ACA,” he said. “There’s been almost no discussion of the underlying health care delivery system changes that the ACA ushered in, and that is more important in the long run to be discussing because that’s what’s going to determine the underlying costs and outcomes of the health system.”

The readmission penalties are intended to neutralize an unintended incentive in the way Medicare pays hospitals that had profited from return patients. Medicare pays hospitals a lump sum for a patient’s stay based on the nature of the admission and other factors. Since hospitals generally are not paid extra if patients remain longer, they seek to discharge patients as soon as is medically feasible. If the patient ends up back in the hospital, it becomes a financial benefit as the hospital is paid for that second stay, filling a bed that would not have generated income if the patient had remained there continuously.

Because of the way the readmission penalty program was designed, it is not surprising that the new results are so similar to last year’s. As before, Medicare determined the penalties based on readmissions of the same six types of patients: those admitted for heart attacks, heart failure, pneumonia, chronic lung disease, hip or knee replacements, or coronary artery bypass graft surgery. Hospitals were judged on patients discharged between July 2013 and June 2016. Because the government looks at a 3-year period, 2 of those years were also examined in determining last year’s penalties.

This year, the average penalty will be 0.73% of each payment Medicare makes for a patient between Oct. 1 and Sept. 30, 2018, according to a Kaiser Health News analysis. That too was practically the same as last year. Forty-eight hospitals received the maximum punishment of a 3% reduction. Medicare did not release hospital-specific estimates for how much lost money these penalties would translate to.

More than 1,500 hospitals treating veterans, children, and psychiatric patients were exempted from penalties this year as required by law. Critical access hospitals, which Medicare also pays differently, also were excluded. So were Maryland hospitals because Congress has given that state extra leeway in how it distributes Medicare money.

Of the 3,241 hospitals whose readmissions were evaluated, Medicare penalized four out of five, the KHN analysis found. That is because the program’s methods are not very forgiving: A hospital can be penalized even if it has higher than expected readmission rates for only one of the six conditions that are targeted. Every nonexcluded hospital in Delaware and West Virginia will have their reimbursements reduced. Ninety percent or more will be punished in Arizona, Connecticut, Florida, Kentucky, Massachusetts, Minnesota, New Jersey, New York, and Virginia. Sixty percent or fewer will be penalized in Colorado, Kansas, Idaho, Montana, Oregon, South Dakota, and Utah.

Since the readmission program’s structure is set by law, the administration cannot make major changes unilaterally, even if it wanted to.

Congress last year instructed Medicare to make one future alteration in response to complaints from safety-net hospitals and major academic medical centers.

They have objected that their patients tended to be lower income than other hospitals and were more likely to return to the hospital, sometimes because they didn’t have a primary care doctor and other times because they could not afford the right medication or diet. Those hospitals argued that this was a disadvantage for them since Medicare bases its readmission targets on industry-wide trends and that it hurt them financially, depriving them of resources they could use to help those same patients.

Dr. Bernheim noted that, despite those complaints, safety-net hospitals have shown some of the greatest drops in readmission rates. In October 2018, Medicare will begin basing the penalties on how hospitals compared with their peer groups with similar numbers of poor patients. Akin Demehin, director of policy at the hospital association, said, “We expect the adjustment will provide some relief for safety-net hospitals.”

Medicare is planning to release two other rounds of recurring quality incentives for hospitals later this year. One gives out bonuses and penalties based on a mix of measures, with Medicare redistributing $1.9 billion based on how hospitals perform and improve. The other, the Hospital-Acquired Condition Reduction Program, cuts payments to roughly 750 hospitals with the highest rates of infections and other patient injuries by 1%.
 

Kaiser Health News is a national health policy news service that is part of the nonpartisan Henry J. Kaiser Family Foundation. KHN’s coverage related to aging & improving care of older adults is supported by The John A. Hartford Foundation.

Dapivirine vaginal ring and oral pre-exposure prophylaxis (PrEP) are effective HIV prevention measures in adolescent girls, according to two studies presented at the International AIDS Society Conference on HIV Pathogenesis and Treatment in Paris.

These solutions could be critical in lowering the rate of HIV and AIDS in girls between the ages of 15 and 25 years, a population that has proven to be particularly vulnerable to HIV infection, researchers say.

grandeduc/Thinkstock

[email protected]

On Twitter @eaztweets

Dapivirine vaginal ring and oral pre-exposure prophylaxis (PrEP) are effective HIV prevention measures in adolescent girls, according to two studies presented at the International AIDS Society Conference on HIV Pathogenesis and Treatment in Paris.

These solutions could be critical in lowering the rate of HIV and AIDS in girls between the ages of 15 and 25 years, a population that has proven to be particularly vulnerable to HIV infection, researchers say.

grandeduc/Thinkstock

[email protected]

On Twitter @eaztweets

Dapivirine vaginal ring and oral pre-exposure prophylaxis (PrEP) are effective HIV prevention measures in adolescent girls, according to two studies presented at the International AIDS Society Conference on HIV Pathogenesis and Treatment in Paris.

These solutions could be critical in lowering the rate of HIV and AIDS in girls between the ages of 15 and 25 years, a population that has proven to be particularly vulnerable to HIV infection, researchers say.

grandeduc/Thinkstock

[email protected]

On Twitter @eaztweets

The first pangenotypic treatment for the hepatitis C virus, which also shaves 4 weeks off current regimens, has just been approved by the Food and Drug Administration.

Manufactured by AbbVie, glecaprevir/pibrentasvir (Mavyret) combines a nonstructural protein 3/4A protease inhibitor with a next-generation NS5A protein inhibitor for a once-daily, ribavirin-free treatment for adults with any of the major genotypes of chronic hepatitis C virus (HCV) infection.

“This approval provides a shorter treatment duration for many patients, and also a treatment option for certain patients with genotype 1 infection, the most common HCV genotype in the United States, who were not successfully treated with other direct-acting antiviral treatments in the past,” Edward Cox, MD, director of the office of antimicrobial products in the FDA’s Center for Drug Evaluation and Research, Silver Spring, Md., said in a statement.

[email protected]

On Twitter @whitneymcknight

The first pangenotypic treatment for the hepatitis C virus, which also shaves 4 weeks off current regimens, has just been approved by the Food and Drug Administration.

Manufactured by AbbVie, glecaprevir/pibrentasvir (Mavyret) combines a nonstructural protein 3/4A protease inhibitor with a next-generation NS5A protein inhibitor for a once-daily, ribavirin-free treatment for adults with any of the major genotypes of chronic hepatitis C virus (HCV) infection.

“This approval provides a shorter treatment duration for many patients, and also a treatment option for certain patients with genotype 1 infection, the most common HCV genotype in the United States, who were not successfully treated with other direct-acting antiviral treatments in the past,” Edward Cox, MD, director of the office of antimicrobial products in the FDA’s Center for Drug Evaluation and Research, Silver Spring, Md., said in a statement.

[email protected]

On Twitter @whitneymcknight

The first pangenotypic treatment for the hepatitis C virus, which also shaves 4 weeks off current regimens, has just been approved by the Food and Drug Administration.

Manufactured by AbbVie, glecaprevir/pibrentasvir (Mavyret) combines a nonstructural protein 3/4A protease inhibitor with a next-generation NS5A protein inhibitor for a once-daily, ribavirin-free treatment for adults with any of the major genotypes of chronic hepatitis C virus (HCV) infection.

“This approval provides a shorter treatment duration for many patients, and also a treatment option for certain patients with genotype 1 infection, the most common HCV genotype in the United States, who were not successfully treated with other direct-acting antiviral treatments in the past,” Edward Cox, MD, director of the office of antimicrobial products in the FDA’s Center for Drug Evaluation and Research, Silver Spring, Md., said in a statement.

[email protected]

On Twitter @whitneymcknight

More than many other pregnancy complications, diabetes exemplifies the impact of social determinants of health.

The medical management of diabetes during pregnancy involves major lifestyle changes. Diabetes care is largely a patient-driven social experience involving complex and demanding self-care behaviors and tasks.

The pregnant woman with diabetes is placed on a diet that is often novel to her and may be in conflict with the eating patterns of her family. She is advised to exercise, read nutrition labels, and purchase and cook healthy food. She often has to pick up prescriptions, check finger sticks and log results, accurately draw up insulin, and manage strict schedules.

Management requires a tremendous amount of daily engagement during a period of time that, in and of itself, is cognitively demanding.

Outcomes, in turn, are impacted by social context and social factors – by the patient’s economic stability and the safety and characteristics of her neighborhood, for instance, as well as her work schedule, her social support, and her level of health literacy. Each of these factors can influence behaviors and decision making, and ultimately glycemic control and perinatal outcomes.

The social determinants of diabetes-related health are so individualized and impactful that they must be realized and addressed throughout our care, from the way in which we communicate at the initial prenatal checkup to the support we offer for self-management.

Barriers to diabetes self-care

While the incidence of type 2 diabetes is increasing among all social, ethnic, and racial groups, its prevalence among nonpregnant U.S. adults is greatest among racial/ethnic minorities, as well as in individuals with a low-income status. Women who enter pregnancy with preexisting diabetes are more likely to be racial/ethnic minorities.

What we can do

Much of what we can do in our practices to identify and address social determinants and alleviate barriers to effective diabetes management is about finding the “sweet spot” – about being able to convey the right information in the right amount, with the right timing and the right delivery.

While we can’t improve a woman’s neighborhood or resolve food instability, I believe that we can still work to improve outcomes for women who experience these problems. Here are some key strategies for optimal support of our patients:

Inquire about social factors

Identify hurdles by asking questions such as: Where do you live? Is it safe to walk in your neighborhood? If not, where’s your closest mall? What kind of job do you have, and does your employer allow breaks to take care of your health? How are things going at home? Who is at home to help you? Are you having any trouble affording food? How can we help you learn to adapt your personal or cultural food preferences to healthier options?

Look for small actions to take. I often write letters to my patients’ employers requesting that they be given short, frequent breaks to accommodate their care regimens. I also work to ensure that diet recommendations and medication/insulin regimens are customized for patients with irregular meal and sleep schedules, such as those working night shifts.

Employ a social worker if possible, especially if your practice cares for large numbers of underserved women.

Serve as a resource center, and engage your team in doing so. Be prepared to refer women for social services support, food banks, intimate partner violence support services, and other local resources.

Take a low-health-literacy approach

Health literacy is the ability to obtain and utilize health information. It has been widely investigated outside of pregnancy (and to some extent during pregnancy), and has been found to be at the root of many disparities in health care and health outcomes. Numeracy, a type of health literacy, is the ability to understand numbers, perform basic calculations, and use simple math skills in a way that helps one’s health.

The barriers created by inadequate health literacy are distinct from language barriers. I’ve had patients who can read the labels on their insulin vials but cannot distinguish the short-acting from the long-acting formulation, or who can read the words on a nutrition label but don’t know how to interpret the amount of carbohydrates and determine if a food fits the diet plan.

Moreover, while health literacy is correlated with cognitive ability, it still is a distinct skill set. Studies have shown that patients educated in a traditional sense – college-educated professionals, for instance – will not necessarily understand health-related words and instructions.

Research similarly suggests that a low-health-literacy approach that uses focused, simple, and straightforward messages benefits everyone. This type of approach involves the following:
 

Simple language

Teach-back techniques (“tell me you what your understanding is of what I just told you”)

Diagrams, handouts, and brochures written at a sixth-grade level.

Teaching that is limited to five to eight key messages per session, and reinforcement of these messages over time.

Promote self-efficacy

Self-efficacy is the confidence in one’s ability to perform certain health behaviors. It involves motivation as well as knowledge of the disease, the rationale for treatment, and the specific behaviors that are required for effective self-care.

Help patients understand “why it matters” – that diabetes raises the risk of macrosomia, shoulder dystocia, hypertension, long-term diabetes, and other adverse maternal and neonatal outcomes. Explain basic physiologic concepts and provide background information. This builds self-efficacy.

Do not issue recommendations for exercising and eating well without asking: How can I help you do this? What do you need to be able to eat healthy? Do you need an appointment with a nutritionist? Do you need to see a social worker?

Inquire about and help patients identify supportive family members or other “champions.” Look for ways to incorporate these support people into the patient’s care. At a minimum, encourage the patient to ask her support person to eat healthy with her and/or to understand her daily tasks so that this individual can offer reminders and be a source of support when she feels exhausted or overwhelmed.

If possible, facilitate some type of “diabetes buddy” program to offer peer support and help patients stay engaged in their care, or use group education sessions.

Piggyback on your patients’ own motivating factors. Research has shown that women are extraordinarily motivated to stop smoking during pregnancy because of the health of the fetus. This should extend as well to the difficult lifestyle changes required for diabetes self-care.

View pregnancy as a “golden opportunity” to promote healthy life changes that endure because of the often-extraordinary levels of motivation that women feel or can be encouraged to feel.

Facilitate access

The ability to attend frequent appointments and to juggle the logistics of transportation, child care, and time off work (all part of the burden of disease management) is a social determinant of health. It’s something we should ask about, and it is often something we can positively impact by modifying our practice hours and/or using telehealth or mobile health techniques.

Dr. Yee is an assistant professor in the division of maternal-fetal medicine at Northwestern University, Chicago. She reported having no relevant financial disclosures.

More than many other pregnancy complications, diabetes exemplifies the impact of social determinants of health.

The medical management of diabetes during pregnancy involves major lifestyle changes. Diabetes care is largely a patient-driven social experience involving complex and demanding self-care behaviors and tasks.

The pregnant woman with diabetes is placed on a diet that is often novel to her and may be in conflict with the eating patterns of her family. She is advised to exercise, read nutrition labels, and purchase and cook healthy food. She often has to pick up prescriptions, check finger sticks and log results, accurately draw up insulin, and manage strict schedules.

Management requires a tremendous amount of daily engagement during a period of time that, in and of itself, is cognitively demanding.

Outcomes, in turn, are impacted by social context and social factors – by the patient’s economic stability and the safety and characteristics of her neighborhood, for instance, as well as her work schedule, her social support, and her level of health literacy. Each of these factors can influence behaviors and decision making, and ultimately glycemic control and perinatal outcomes.

The social determinants of diabetes-related health are so individualized and impactful that they must be realized and addressed throughout our care, from the way in which we communicate at the initial prenatal checkup to the support we offer for self-management.

Barriers to diabetes self-care

While the incidence of type 2 diabetes is increasing among all social, ethnic, and racial groups, its prevalence among nonpregnant U.S. adults is greatest among racial/ethnic minorities, as well as in individuals with a low-income status. Women who enter pregnancy with preexisting diabetes are more likely to be racial/ethnic minorities.

What we can do

Much of what we can do in our practices to identify and address social determinants and alleviate barriers to effective diabetes management is about finding the “sweet spot” – about being able to convey the right information in the right amount, with the right timing and the right delivery.

While we can’t improve a woman’s neighborhood or resolve food instability, I believe that we can still work to improve outcomes for women who experience these problems. Here are some key strategies for optimal support of our patients:

Inquire about social factors

Identify hurdles by asking questions such as: Where do you live? Is it safe to walk in your neighborhood? If not, where’s your closest mall? What kind of job do you have, and does your employer allow breaks to take care of your health? How are things going at home? Who is at home to help you? Are you having any trouble affording food? How can we help you learn to adapt your personal or cultural food preferences to healthier options?

Look for small actions to take. I often write letters to my patients’ employers requesting that they be given short, frequent breaks to accommodate their care regimens. I also work to ensure that diet recommendations and medication/insulin regimens are customized for patients with irregular meal and sleep schedules, such as those working night shifts.

Employ a social worker if possible, especially if your practice cares for large numbers of underserved women.

Serve as a resource center, and engage your team in doing so. Be prepared to refer women for social services support, food banks, intimate partner violence support services, and other local resources.

Take a low-health-literacy approach

Health literacy is the ability to obtain and utilize health information. It has been widely investigated outside of pregnancy (and to some extent during pregnancy), and has been found to be at the root of many disparities in health care and health outcomes. Numeracy, a type of health literacy, is the ability to understand numbers, perform basic calculations, and use simple math skills in a way that helps one’s health.

The barriers created by inadequate health literacy are distinct from language barriers. I’ve had patients who can read the labels on their insulin vials but cannot distinguish the short-acting from the long-acting formulation, or who can read the words on a nutrition label but don’t know how to interpret the amount of carbohydrates and determine if a food fits the diet plan.

Moreover, while health literacy is correlated with cognitive ability, it still is a distinct skill set. Studies have shown that patients educated in a traditional sense – college-educated professionals, for instance – will not necessarily understand health-related words and instructions.

Research similarly suggests that a low-health-literacy approach that uses focused, simple, and straightforward messages benefits everyone. This type of approach involves the following:
 

Simple language

Teach-back techniques (“tell me you what your understanding is of what I just told you”)

Diagrams, handouts, and brochures written at a sixth-grade level.

Teaching that is limited to five to eight key messages per session, and reinforcement of these messages over time.

Promote self-efficacy

Self-efficacy is the confidence in one’s ability to perform certain health behaviors. It involves motivation as well as knowledge of the disease, the rationale for treatment, and the specific behaviors that are required for effective self-care.

Help patients understand “why it matters” – that diabetes raises the risk of macrosomia, shoulder dystocia, hypertension, long-term diabetes, and other adverse maternal and neonatal outcomes. Explain basic physiologic concepts and provide background information. This builds self-efficacy.

Do not issue recommendations for exercising and eating well without asking: How can I help you do this? What do you need to be able to eat healthy? Do you need an appointment with a nutritionist? Do you need to see a social worker?

Inquire about and help patients identify supportive family members or other “champions.” Look for ways to incorporate these support people into the patient’s care. At a minimum, encourage the patient to ask her support person to eat healthy with her and/or to understand her daily tasks so that this individual can offer reminders and be a source of support when she feels exhausted or overwhelmed.

If possible, facilitate some type of “diabetes buddy” program to offer peer support and help patients stay engaged in their care, or use group education sessions.

Piggyback on your patients’ own motivating factors. Research has shown that women are extraordinarily motivated to stop smoking during pregnancy because of the health of the fetus. This should extend as well to the difficult lifestyle changes required for diabetes self-care.

View pregnancy as a “golden opportunity” to promote healthy life changes that endure because of the often-extraordinary levels of motivation that women feel or can be encouraged to feel.

Facilitate access

The ability to attend frequent appointments and to juggle the logistics of transportation, child care, and time off work (all part of the burden of disease management) is a social determinant of health. It’s something we should ask about, and it is often something we can positively impact by modifying our practice hours and/or using telehealth or mobile health techniques.

Dr. Yee is an assistant professor in the division of maternal-fetal medicine at Northwestern University, Chicago. She reported having no relevant financial disclosures.

More than many other pregnancy complications, diabetes exemplifies the impact of social determinants of health.

The medical management of diabetes during pregnancy involves major lifestyle changes. Diabetes care is largely a patient-driven social experience involving complex and demanding self-care behaviors and tasks.

The pregnant woman with diabetes is placed on a diet that is often novel to her and may be in conflict with the eating patterns of her family. She is advised to exercise, read nutrition labels, and purchase and cook healthy food. She often has to pick up prescriptions, check finger sticks and log results, accurately draw up insulin, and manage strict schedules.

Management requires a tremendous amount of daily engagement during a period of time that, in and of itself, is cognitively demanding.

Outcomes, in turn, are impacted by social context and social factors – by the patient’s economic stability and the safety and characteristics of her neighborhood, for instance, as well as her work schedule, her social support, and her level of health literacy. Each of these factors can influence behaviors and decision making, and ultimately glycemic control and perinatal outcomes.

The social determinants of diabetes-related health are so individualized and impactful that they must be realized and addressed throughout our care, from the way in which we communicate at the initial prenatal checkup to the support we offer for self-management.

Barriers to diabetes self-care

While the incidence of type 2 diabetes is increasing among all social, ethnic, and racial groups, its prevalence among nonpregnant U.S. adults is greatest among racial/ethnic minorities, as well as in individuals with a low-income status. Women who enter pregnancy with preexisting diabetes are more likely to be racial/ethnic minorities.

What we can do

Much of what we can do in our practices to identify and address social determinants and alleviate barriers to effective diabetes management is about finding the “sweet spot” – about being able to convey the right information in the right amount, with the right timing and the right delivery.

While we can’t improve a woman’s neighborhood or resolve food instability, I believe that we can still work to improve outcomes for women who experience these problems. Here are some key strategies for optimal support of our patients:

Inquire about social factors

Identify hurdles by asking questions such as: Where do you live? Is it safe to walk in your neighborhood? If not, where’s your closest mall? What kind of job do you have, and does your employer allow breaks to take care of your health? How are things going at home? Who is at home to help you? Are you having any trouble affording food? How can we help you learn to adapt your personal or cultural food preferences to healthier options?

Look for small actions to take. I often write letters to my patients’ employers requesting that they be given short, frequent breaks to accommodate their care regimens. I also work to ensure that diet recommendations and medication/insulin regimens are customized for patients with irregular meal and sleep schedules, such as those working night shifts.

Employ a social worker if possible, especially if your practice cares for large numbers of underserved women.

Serve as a resource center, and engage your team in doing so. Be prepared to refer women for social services support, food banks, intimate partner violence support services, and other local resources.

Take a low-health-literacy approach

Health literacy is the ability to obtain and utilize health information. It has been widely investigated outside of pregnancy (and to some extent during pregnancy), and has been found to be at the root of many disparities in health care and health outcomes. Numeracy, a type of health literacy, is the ability to understand numbers, perform basic calculations, and use simple math skills in a way that helps one’s health.

The barriers created by inadequate health literacy are distinct from language barriers. I’ve had patients who can read the labels on their insulin vials but cannot distinguish the short-acting from the long-acting formulation, or who can read the words on a nutrition label but don’t know how to interpret the amount of carbohydrates and determine if a food fits the diet plan.

Moreover, while health literacy is correlated with cognitive ability, it still is a distinct skill set. Studies have shown that patients educated in a traditional sense – college-educated professionals, for instance – will not necessarily understand health-related words and instructions.

Research similarly suggests that a low-health-literacy approach that uses focused, simple, and straightforward messages benefits everyone. This type of approach involves the following:
 

Simple language

Teach-back techniques (“tell me you what your understanding is of what I just told you”)

Diagrams, handouts, and brochures written at a sixth-grade level.

Teaching that is limited to five to eight key messages per session, and reinforcement of these messages over time.

Promote self-efficacy

Self-efficacy is the confidence in one’s ability to perform certain health behaviors. It involves motivation as well as knowledge of the disease, the rationale for treatment, and the specific behaviors that are required for effective self-care.

Help patients understand “why it matters” – that diabetes raises the risk of macrosomia, shoulder dystocia, hypertension, long-term diabetes, and other adverse maternal and neonatal outcomes. Explain basic physiologic concepts and provide background information. This builds self-efficacy.

Do not issue recommendations for exercising and eating well without asking: How can I help you do this? What do you need to be able to eat healthy? Do you need an appointment with a nutritionist? Do you need to see a social worker?

Inquire about and help patients identify supportive family members or other “champions.” Look for ways to incorporate these support people into the patient’s care. At a minimum, encourage the patient to ask her support person to eat healthy with her and/or to understand her daily tasks so that this individual can offer reminders and be a source of support when she feels exhausted or overwhelmed.

If possible, facilitate some type of “diabetes buddy” program to offer peer support and help patients stay engaged in their care, or use group education sessions.

Piggyback on your patients’ own motivating factors. Research has shown that women are extraordinarily motivated to stop smoking during pregnancy because of the health of the fetus. This should extend as well to the difficult lifestyle changes required for diabetes self-care.

View pregnancy as a “golden opportunity” to promote healthy life changes that endure because of the often-extraordinary levels of motivation that women feel or can be encouraged to feel.

Facilitate access

The ability to attend frequent appointments and to juggle the logistics of transportation, child care, and time off work (all part of the burden of disease management) is a social determinant of health. It’s something we should ask about, and it is often something we can positively impact by modifying our practice hours and/or using telehealth or mobile health techniques.

Dr. Yee is an assistant professor in the division of maternal-fetal medicine at Northwestern University, Chicago. She reported having no relevant financial disclosures.

With the rise of obesity and diabetes, especially type 2 diabetes, in the general population, the likelihood of encountering a patient with diabetes in pregnancy also continues to increase. Women with diabetes who are pregnant require specialized medical guidance, additional monitoring, and a health care team well versed in the possible complications that can arise during pregnancy, delivery, and after birth.

Even with strict glycemic control, women with diabetes in pregnancy are much more likely to experience complications, such as preeclampsia, babies with major congenital defects, large-for-gestational-age fetuses, and children with a higher propensity for chronic diseases later in life, compared with women without diabetes.

Dr. Reece, who specializes in maternal-fetal medicine, is vice president for medical affairs at the University of Maryland, Baltimore, as well as the John Z. and Akiko K. Bowers Distinguished Professor and dean of the school of medicine. Dr. Reece said he had no relevant financial disclosures. He is the medical editor of this column. Contact him at [email protected].

With the rise of obesity and diabetes, especially type 2 diabetes, in the general population, the likelihood of encountering a patient with diabetes in pregnancy also continues to increase. Women with diabetes who are pregnant require specialized medical guidance, additional monitoring, and a health care team well versed in the possible complications that can arise during pregnancy, delivery, and after birth.

Even with strict glycemic control, women with diabetes in pregnancy are much more likely to experience complications, such as preeclampsia, babies with major congenital defects, large-for-gestational-age fetuses, and children with a higher propensity for chronic diseases later in life, compared with women without diabetes.

Dr. Reece, who specializes in maternal-fetal medicine, is vice president for medical affairs at the University of Maryland, Baltimore, as well as the John Z. and Akiko K. Bowers Distinguished Professor and dean of the school of medicine. Dr. Reece said he had no relevant financial disclosures. He is the medical editor of this column. Contact him at [email protected].

With the rise of obesity and diabetes, especially type 2 diabetes, in the general population, the likelihood of encountering a patient with diabetes in pregnancy also continues to increase. Women with diabetes who are pregnant require specialized medical guidance, additional monitoring, and a health care team well versed in the possible complications that can arise during pregnancy, delivery, and after birth.

Even with strict glycemic control, women with diabetes in pregnancy are much more likely to experience complications, such as preeclampsia, babies with major congenital defects, large-for-gestational-age fetuses, and children with a higher propensity for chronic diseases later in life, compared with women without diabetes.

Dr. Reece, who specializes in maternal-fetal medicine, is vice president for medical affairs at the University of Maryland, Baltimore, as well as the John Z. and Akiko K. Bowers Distinguished Professor and dean of the school of medicine. Dr. Reece said he had no relevant financial disclosures. He is the medical editor of this column. Contact him at [email protected].

The three most potent human teratogens, with the possible inclusion of some of the first antineoplastics, are isotretinoin, alcohol, and hyperglycemia.

As with all teratogens, the toxicity is dose related. For example, the risk of embryo-fetal harm from hyperglycemia increases markedly when the HbA_1c is greater than 8%. Moreover, diabetes accounts for more than 90% of the harm caused by chronic diseases. Consequently, control of glucose levels in pregnancy is critical.

Alpha-glucosidase inhibitors

The two agents is this subclass are acarbose (Precose) and miglitol (Glyset). The human pregnancy data with acarbose are limited, and no human pregnancy data have been found for miglitol. The animal data for both drugs suggest low risk.

Biguanides

There are substantial human pregnancy data for metformin in both type 2 and gestational diabetes. When combined with insulin, it is effective in significantly lowering the amount of insulin required to control hyperglycemia. It also may be effective when used alone. The risk of embryo-fetal harm with this drug appears to be very low or nonexistent. The animal data suggest low risk.

Dipeptidyl peptidase-4 inhibitors

There are four drugs in this subclass: alogliptin (Nesina), linagliptin (Tradjenta), saxagliptin (Onglyza), and sitagliptin (Januvia). No reports of the use of the first three drugs in human pregnancy have been found. However, the Merck Pregnancy Registries (2006-2009) described the outcomes of eight women who were exposed to sitagliptin or sitagliptin/metformin in the first trimester. The outcomes of these pregnancies were five healthy newborns, two spontaneous abortions, and one fetal death at 34 weeks’ gestation. In that case, the mother took sitagliptin and metformin separately during the first 5 weeks of gestation. The animal data for all four drugs suggest low risk.

Meglitinides

Nateglinide (Starlix) and repaglinide (Prandin) are the agents in this subclass. There is no human pregnancy data for nateglinide, but there is limited data (eight pregnancies) for repaglinide. No birth defects or other toxicity was noted in these cases. The animal data suggest low risk.

Sulfonylureas

Six drugs are included in this subclass: chlorpropamide, glimepiride (Amaryl), glipizide (Glucotrol), glyburide, tolazamide (Tolinase), and tolbutamide. These agents were among the first oral antidiabetic agents. As a result, they have the most human pregnancy data. Although birth defects were observed in newborns of mothers who had used one of these drugs, the defects were thought to be the result of uncontrolled diabetes. The animal data suggest low risk.

SGLT2 inhibitors

There are three drugs in this sodium-glucose cotransporter-2 inhibitor subclass: canagliflozin (Invokana), dapagliflozin (Farxiga), and empagliflozin (Jardiance). No reports describing the use of these drugs in human pregnancy have been located. The animal data suggest low risk.

Thiazolidinediones

Pioglitazone (Actos) and rosiglitazone (Avandia) form this subclass. There are limited human pregnancy data for both drugs. The animal data suggest moderate risk for embryo-fetal toxicity but not for structural defects.

Lactation

All of the above drugs will probably be excreted into breast milk, but the amounts are typically unknown. When they have been measured, the amounts were usually low. However, there is still a risk for hypoglycemia in a nursing infant. Combination products containing two antidiabetic agents are best avoided. The safest course is to use insulin, but, if this is not an option, then the lowest effective dose should be used. In addition, the infant’s blood glucose levels should be routinely monitored.

Mr. Briggs is a clinical professor of pharmacy at the University of California, San Francisco, and an adjunct professor of pharmacy at the University of Southern California, Los Angeles, as well as at Washington State University, Spokane. He coauthored “Drugs in Pregnancy and Lactation” and coedited “Diseases, Complications, and Drug Therapy in Obstetrics.” He reported having no relevant financial disclosures.

The three most potent human teratogens, with the possible inclusion of some of the first antineoplastics, are isotretinoin, alcohol, and hyperglycemia.

As with all teratogens, the toxicity is dose related. For example, the risk of embryo-fetal harm from hyperglycemia increases markedly when the HbA_1c is greater than 8%. Moreover, diabetes accounts for more than 90% of the harm caused by chronic diseases. Consequently, control of glucose levels in pregnancy is critical.

Alpha-glucosidase inhibitors

The two agents is this subclass are acarbose (Precose) and miglitol (Glyset). The human pregnancy data with acarbose are limited, and no human pregnancy data have been found for miglitol. The animal data for both drugs suggest low risk.

Biguanides

There are substantial human pregnancy data for metformin in both type 2 and gestational diabetes. When combined with insulin, it is effective in significantly lowering the amount of insulin required to control hyperglycemia. It also may be effective when used alone. The risk of embryo-fetal harm with this drug appears to be very low or nonexistent. The animal data suggest low risk.

Dipeptidyl peptidase-4 inhibitors

There are four drugs in this subclass: alogliptin (Nesina), linagliptin (Tradjenta), saxagliptin (Onglyza), and sitagliptin (Januvia). No reports of the use of the first three drugs in human pregnancy have been found. However, the Merck Pregnancy Registries (2006-2009) described the outcomes of eight women who were exposed to sitagliptin or sitagliptin/metformin in the first trimester. The outcomes of these pregnancies were five healthy newborns, two spontaneous abortions, and one fetal death at 34 weeks’ gestation. In that case, the mother took sitagliptin and metformin separately during the first 5 weeks of gestation. The animal data for all four drugs suggest low risk.

Meglitinides

Nateglinide (Starlix) and repaglinide (Prandin) are the agents in this subclass. There is no human pregnancy data for nateglinide, but there is limited data (eight pregnancies) for repaglinide. No birth defects or other toxicity was noted in these cases. The animal data suggest low risk.

Sulfonylureas

Six drugs are included in this subclass: chlorpropamide, glimepiride (Amaryl), glipizide (Glucotrol), glyburide, tolazamide (Tolinase), and tolbutamide. These agents were among the first oral antidiabetic agents. As a result, they have the most human pregnancy data. Although birth defects were observed in newborns of mothers who had used one of these drugs, the defects were thought to be the result of uncontrolled diabetes. The animal data suggest low risk.

SGLT2 inhibitors

There are three drugs in this sodium-glucose cotransporter-2 inhibitor subclass: canagliflozin (Invokana), dapagliflozin (Farxiga), and empagliflozin (Jardiance). No reports describing the use of these drugs in human pregnancy have been located. The animal data suggest low risk.

Thiazolidinediones

Pioglitazone (Actos) and rosiglitazone (Avandia) form this subclass. There are limited human pregnancy data for both drugs. The animal data suggest moderate risk for embryo-fetal toxicity but not for structural defects.

Lactation

All of the above drugs will probably be excreted into breast milk, but the amounts are typically unknown. When they have been measured, the amounts were usually low. However, there is still a risk for hypoglycemia in a nursing infant. Combination products containing two antidiabetic agents are best avoided. The safest course is to use insulin, but, if this is not an option, then the lowest effective dose should be used. In addition, the infant’s blood glucose levels should be routinely monitored.

Mr. Briggs is a clinical professor of pharmacy at the University of California, San Francisco, and an adjunct professor of pharmacy at the University of Southern California, Los Angeles, as well as at Washington State University, Spokane. He coauthored “Drugs in Pregnancy and Lactation” and coedited “Diseases, Complications, and Drug Therapy in Obstetrics.” He reported having no relevant financial disclosures.

The three most potent human teratogens, with the possible inclusion of some of the first antineoplastics, are isotretinoin, alcohol, and hyperglycemia.

As with all teratogens, the toxicity is dose related. For example, the risk of embryo-fetal harm from hyperglycemia increases markedly when the HbA_1c is greater than 8%. Moreover, diabetes accounts for more than 90% of the harm caused by chronic diseases. Consequently, control of glucose levels in pregnancy is critical.

Alpha-glucosidase inhibitors

The two agents is this subclass are acarbose (Precose) and miglitol (Glyset). The human pregnancy data with acarbose are limited, and no human pregnancy data have been found for miglitol. The animal data for both drugs suggest low risk.

Biguanides

There are substantial human pregnancy data for metformin in both type 2 and gestational diabetes. When combined with insulin, it is effective in significantly lowering the amount of insulin required to control hyperglycemia. It also may be effective when used alone. The risk of embryo-fetal harm with this drug appears to be very low or nonexistent. The animal data suggest low risk.

Dipeptidyl peptidase-4 inhibitors

There are four drugs in this subclass: alogliptin (Nesina), linagliptin (Tradjenta), saxagliptin (Onglyza), and sitagliptin (Januvia). No reports of the use of the first three drugs in human pregnancy have been found. However, the Merck Pregnancy Registries (2006-2009) described the outcomes of eight women who were exposed to sitagliptin or sitagliptin/metformin in the first trimester. The outcomes of these pregnancies were five healthy newborns, two spontaneous abortions, and one fetal death at 34 weeks’ gestation. In that case, the mother took sitagliptin and metformin separately during the first 5 weeks of gestation. The animal data for all four drugs suggest low risk.

Meglitinides

Nateglinide (Starlix) and repaglinide (Prandin) are the agents in this subclass. There is no human pregnancy data for nateglinide, but there is limited data (eight pregnancies) for repaglinide. No birth defects or other toxicity was noted in these cases. The animal data suggest low risk.

Sulfonylureas

Six drugs are included in this subclass: chlorpropamide, glimepiride (Amaryl), glipizide (Glucotrol), glyburide, tolazamide (Tolinase), and tolbutamide. These agents were among the first oral antidiabetic agents. As a result, they have the most human pregnancy data. Although birth defects were observed in newborns of mothers who had used one of these drugs, the defects were thought to be the result of uncontrolled diabetes. The animal data suggest low risk.

SGLT2 inhibitors

There are three drugs in this sodium-glucose cotransporter-2 inhibitor subclass: canagliflozin (Invokana), dapagliflozin (Farxiga), and empagliflozin (Jardiance). No reports describing the use of these drugs in human pregnancy have been located. The animal data suggest low risk.

Thiazolidinediones

Pioglitazone (Actos) and rosiglitazone (Avandia) form this subclass. There are limited human pregnancy data for both drugs. The animal data suggest moderate risk for embryo-fetal toxicity but not for structural defects.

Lactation

All of the above drugs will probably be excreted into breast milk, but the amounts are typically unknown. When they have been measured, the amounts were usually low. However, there is still a risk for hypoglycemia in a nursing infant. Combination products containing two antidiabetic agents are best avoided. The safest course is to use insulin, but, if this is not an option, then the lowest effective dose should be used. In addition, the infant’s blood glucose levels should be routinely monitored.

Mr. Briggs is a clinical professor of pharmacy at the University of California, San Francisco, and an adjunct professor of pharmacy at the University of Southern California, Los Angeles, as well as at Washington State University, Spokane. He coauthored “Drugs in Pregnancy and Lactation” and coedited “Diseases, Complications, and Drug Therapy in Obstetrics.” He reported having no relevant financial disclosures.

Human papillomavirus (HPV) is the most common sexually transmitted infection. Exposure is widespread and most individuals clear the infection without symptoms or development of disease. However, a subset of individuals experience persistent infection, a state which can lead to carcinogenesis of lower genital tract malignancies, particularly cervical cancer.¹

jarun011/Thinkstock

Vaccine coverage

Persistent infection with high-risk (oncogenic) HPV is well known to be the cause of cervical cancer. There are two HPV vaccines manufactured for the purposes of cervical cancer, anal cancer, and genital wart prevention (Cervarix and Gardasil). The Cervarix vaccine covers high-risk HPV subtypes 16 and 18 and the Gardasil vaccine prevents both low-risk HPV subtypes 6 and 11, which can cause genital warts, and high-risk HPV subtypes 16, 18, 31, 33, 45, 52 and 58, which cause cervical dysplasia and cancer.

High-risk HPV is also associated with head and neck, vulvar, vaginal, and penile cancers, though the vaccines are not approved by the Food and Drug Administration for prevention of these diseases.²

Vaccination indications

Alex Raths/thinkstockphotos

Since vaccination prevents multiple subtypes of HPV, an individual who has already been exposed will still benefit from protection from other subtypes of HPV through vaccination. HPV vaccination is not approved during pregnancy but can be initiated in the postpartum period when women are engaged in their health care and receiving other vaccinations, such as varicella or the MMR vaccine.

Recommended schedule

Until October 2016, the vaccination schedule was based on a three-dose series (0, 2, and 6 months). Currently, the CDC recommends that children aged under 15 years at the time of first dose may opt for a two-dose series (0 and 6-12 months). For those aged 15-26 years, the three-dose schedule remains the recommended course.

The benefits of two-dose schedule are convenience, cost, and increased likelihood of completion. Data presented at the 2017 Society of Gynecologic Oncology Annual Meeting on Women’s Cancer showed that rates of cervical dysplasia were equivalent for women who completed a two-dose schedule versus a three-dose schedule.⁴

Efficacy

A recent meta-analysis of clinical trials of the HPV vaccines describe efficacy of 95%-97% in prevention of CIN 1-3.⁵ While its greatest efficacy is in its ability to prevent primary HPV infection, there still is some benefit for individuals who already were exposed to HPV prior to vaccination. As stated previously, women with a history of prior HPV vaccination have lower rates of recurrence of cervical dysplasia after treatment. Additionally, recent research has shown that women who received HPV vaccinations after a LEEP procedure for CIN 2 or 3 experience significantly lower recurrence rates, compared with women who did not receive vaccinations after LEEP (2.5% vs. 8.5%).⁶ This raises the possibility of a therapeutic role for HPV vaccination in women infected with HPV. Prospective studies are currently evaluating this question.

Myths

The most common side effects of the HPV vaccine are pain, redness, or swelling at the injection site. Other known side effects include fever, headache or malaise, nausea, syncope, or muscle/joint pain – similar to other vaccinations. Anaphylaxis is a rare complication.

Some parents and pediatricians report concerns that vaccination could lead to earlier sexual activity. Multiple studies have shown that girls who receive HPV vaccination are no more likely to become pregnant or get a sexually transmitted infection (proxies for intercourse) than are girls who were not vaccinated.^7,8

Maximizing vaccination rates

HPV vaccination rates in the United States lag significantly behind rates in countries with national vaccine programs, such as Australia and Denmark.⁹ Early data from Australia already have shown a decrease in genital warts and CIN 2+ incidence within the 10 years of starting its school-based vaccine program, with approximately 73% of 12- to 15-year-olds having completed the vaccine series.² In contrast, just 40% and 22% of 13- to 17-year-old girls and boys in the United States, respectively, had completed the vaccine series in 2014, according to the CDC.¹⁰

Vaccination gaps between girls and boys are narrowing, and more teens will be able to complete the series with the new two-dose recommendation for those younger than 15 years. However, our current rates of vaccination are significantly lower for HPV than for other routinely recommended adolescent vaccines (such as Tdap and meningococcal) and more must be done to encourage vaccination.

Studies have shown that parents are more likely to vaccinate their children if providers recommend the vaccine.¹¹ As women’s health care providers, we do not always see children during the time period that is ideal for vaccination. However, we take care of many women who are presenting for routine gynecologic care, pregnancy, or with abnormal Pap smear screenings. These are ideal opportunities to educate and offer HPV vaccination to women in the approved age groups, as well as to encourage parents to vaccinate their children.

As with other vaccines, the recommendation should be clear and focused on the cancer prevention benefit. Using methods in which the recommendation is “announced” in a brief statement assuming parents/patients are ready to vaccinate versus open-ended conversations, has been studied as a potentially successful method to increase uptake of HPV vaccination.¹² Additionally, documentation of HPV vaccination status should be built into electronic medical record templates to prompt clinicians to ask and offer HPV vaccination at visits, including postpartum visits.

Dr. Rahangdale is an associate professor of ob.gyn. at the University of North Carolina, Chapel Hill, and is director of the North Carolina Women’s Hospital Cervical Dysplasia Clinic. Dr. Rossi is an assistant professor in the division of gynecologic oncology at UNC-Chapel Hill. They reported having no relevant financial disclosures.

References

1. Am J Epidemiol. 2008 Jul 15;168(2):123-37.

2. Int J Cancer. 2012 Nov 1;131(9):1969-82.

3. BMJ. 2012 Mar 27;344:e1401. doi: 10.1136/bmj.e1401.

4. Gynecol Oncol. 2017 Jun. doi. org/10.1016/j.ygyno.2017.03.031.

5. Int J Prev Med. 2017 Jun 1;8:44. doi: 10.4103/ijpvm.IJPVM_413_16.

6. Gynecol Oncol. 2013 Aug;130(2):264-8.

7. Pediatrics. 2012 Nov;130(5):798-805.

8. JAMA Intern Med. 2015 Apr;175(4):617-23.

9. Clin Pediatr (Phila). 2016 Sep;55(10):904-14.

10. MMWR Morb Mortal Wkly Rep. 2015 Jul 31;64(29):784-92.

11. Vaccine. 2016 Feb 24;34(9):1187-92.

12. Pediatrics. 2017 Jan;139(1). pii:e20161764. doi: 10.1542/peds.2016-1764.


 

Human papillomavirus (HPV) is the most common sexually transmitted infection. Exposure is widespread and most individuals clear the infection without symptoms or development of disease. However, a subset of individuals experience persistent infection, a state which can lead to carcinogenesis of lower genital tract malignancies, particularly cervical cancer.¹

jarun011/Thinkstock

Vaccine coverage

Persistent infection with high-risk (oncogenic) HPV is well known to be the cause of cervical cancer. There are two HPV vaccines manufactured for the purposes of cervical cancer, anal cancer, and genital wart prevention (Cervarix and Gardasil). The Cervarix vaccine covers high-risk HPV subtypes 16 and 18 and the Gardasil vaccine prevents both low-risk HPV subtypes 6 and 11, which can cause genital warts, and high-risk HPV subtypes 16, 18, 31, 33, 45, 52 and 58, which cause cervical dysplasia and cancer.

High-risk HPV is also associated with head and neck, vulvar, vaginal, and penile cancers, though the vaccines are not approved by the Food and Drug Administration for prevention of these diseases.²

Vaccination indications

Alex Raths/thinkstockphotos

Since vaccination prevents multiple subtypes of HPV, an individual who has already been exposed will still benefit from protection from other subtypes of HPV through vaccination. HPV vaccination is not approved during pregnancy but can be initiated in the postpartum period when women are engaged in their health care and receiving other vaccinations, such as varicella or the MMR vaccine.

Recommended schedule

Until October 2016, the vaccination schedule was based on a three-dose series (0, 2, and 6 months). Currently, the CDC recommends that children aged under 15 years at the time of first dose may opt for a two-dose series (0 and 6-12 months). For those aged 15-26 years, the three-dose schedule remains the recommended course.

The benefits of two-dose schedule are convenience, cost, and increased likelihood of completion. Data presented at the 2017 Society of Gynecologic Oncology Annual Meeting on Women’s Cancer showed that rates of cervical dysplasia were equivalent for women who completed a two-dose schedule versus a three-dose schedule.⁴

Efficacy

A recent meta-analysis of clinical trials of the HPV vaccines describe efficacy of 95%-97% in prevention of CIN 1-3.⁵ While its greatest efficacy is in its ability to prevent primary HPV infection, there still is some benefit for individuals who already were exposed to HPV prior to vaccination. As stated previously, women with a history of prior HPV vaccination have lower rates of recurrence of cervical dysplasia after treatment. Additionally, recent research has shown that women who received HPV vaccinations after a LEEP procedure for CIN 2 or 3 experience significantly lower recurrence rates, compared with women who did not receive vaccinations after LEEP (2.5% vs. 8.5%).⁶ This raises the possibility of a therapeutic role for HPV vaccination in women infected with HPV. Prospective studies are currently evaluating this question.

Myths

The most common side effects of the HPV vaccine are pain, redness, or swelling at the injection site. Other known side effects include fever, headache or malaise, nausea, syncope, or muscle/joint pain – similar to other vaccinations. Anaphylaxis is a rare complication.

Some parents and pediatricians report concerns that vaccination could lead to earlier sexual activity. Multiple studies have shown that girls who receive HPV vaccination are no more likely to become pregnant or get a sexually transmitted infection (proxies for intercourse) than are girls who were not vaccinated.^7,8

Maximizing vaccination rates

HPV vaccination rates in the United States lag significantly behind rates in countries with national vaccine programs, such as Australia and Denmark.⁹ Early data from Australia already have shown a decrease in genital warts and CIN 2+ incidence within the 10 years of starting its school-based vaccine program, with approximately 73% of 12- to 15-year-olds having completed the vaccine series.² In contrast, just 40% and 22% of 13- to 17-year-old girls and boys in the United States, respectively, had completed the vaccine series in 2014, according to the CDC.¹⁰

Vaccination gaps between girls and boys are narrowing, and more teens will be able to complete the series with the new two-dose recommendation for those younger than 15 years. However, our current rates of vaccination are significantly lower for HPV than for other routinely recommended adolescent vaccines (such as Tdap and meningococcal) and more must be done to encourage vaccination.

Studies have shown that parents are more likely to vaccinate their children if providers recommend the vaccine.¹¹ As women’s health care providers, we do not always see children during the time period that is ideal for vaccination. However, we take care of many women who are presenting for routine gynecologic care, pregnancy, or with abnormal Pap smear screenings. These are ideal opportunities to educate and offer HPV vaccination to women in the approved age groups, as well as to encourage parents to vaccinate their children.

As with other vaccines, the recommendation should be clear and focused on the cancer prevention benefit. Using methods in which the recommendation is “announced” in a brief statement assuming parents/patients are ready to vaccinate versus open-ended conversations, has been studied as a potentially successful method to increase uptake of HPV vaccination.¹² Additionally, documentation of HPV vaccination status should be built into electronic medical record templates to prompt clinicians to ask and offer HPV vaccination at visits, including postpartum visits.

Dr. Rahangdale is an associate professor of ob.gyn. at the University of North Carolina, Chapel Hill, and is director of the North Carolina Women’s Hospital Cervical Dysplasia Clinic. Dr. Rossi is an assistant professor in the division of gynecologic oncology at UNC-Chapel Hill. They reported having no relevant financial disclosures.

References

1. Am J Epidemiol. 2008 Jul 15;168(2):123-37.

2. Int J Cancer. 2012 Nov 1;131(9):1969-82.

3. BMJ. 2012 Mar 27;344:e1401. doi: 10.1136/bmj.e1401.

4. Gynecol Oncol. 2017 Jun. doi. org/10.1016/j.ygyno.2017.03.031.

5. Int J Prev Med. 2017 Jun 1;8:44. doi: 10.4103/ijpvm.IJPVM_413_16.

6. Gynecol Oncol. 2013 Aug;130(2):264-8.

7. Pediatrics. 2012 Nov;130(5):798-805.

8. JAMA Intern Med. 2015 Apr;175(4):617-23.

9. Clin Pediatr (Phila). 2016 Sep;55(10):904-14.

10. MMWR Morb Mortal Wkly Rep. 2015 Jul 31;64(29):784-92.

11. Vaccine. 2016 Feb 24;34(9):1187-92.

12. Pediatrics. 2017 Jan;139(1). pii:e20161764. doi: 10.1542/peds.2016-1764.


 

Human papillomavirus (HPV) is the most common sexually transmitted infection. Exposure is widespread and most individuals clear the infection without symptoms or development of disease. However, a subset of individuals experience persistent infection, a state which can lead to carcinogenesis of lower genital tract malignancies, particularly cervical cancer.¹

jarun011/Thinkstock

Vaccine coverage

Persistent infection with high-risk (oncogenic) HPV is well known to be the cause of cervical cancer. There are two HPV vaccines manufactured for the purposes of cervical cancer, anal cancer, and genital wart prevention (Cervarix and Gardasil). The Cervarix vaccine covers high-risk HPV subtypes 16 and 18 and the Gardasil vaccine prevents both low-risk HPV subtypes 6 and 11, which can cause genital warts, and high-risk HPV subtypes 16, 18, 31, 33, 45, 52 and 58, which cause cervical dysplasia and cancer.

High-risk HPV is also associated with head and neck, vulvar, vaginal, and penile cancers, though the vaccines are not approved by the Food and Drug Administration for prevention of these diseases.²

Vaccination indications

Alex Raths/thinkstockphotos

Since vaccination prevents multiple subtypes of HPV, an individual who has already been exposed will still benefit from protection from other subtypes of HPV through vaccination. HPV vaccination is not approved during pregnancy but can be initiated in the postpartum period when women are engaged in their health care and receiving other vaccinations, such as varicella or the MMR vaccine.

Recommended schedule

Until October 2016, the vaccination schedule was based on a three-dose series (0, 2, and 6 months). Currently, the CDC recommends that children aged under 15 years at the time of first dose may opt for a two-dose series (0 and 6-12 months). For those aged 15-26 years, the three-dose schedule remains the recommended course.

The benefits of two-dose schedule are convenience, cost, and increased likelihood of completion. Data presented at the 2017 Society of Gynecologic Oncology Annual Meeting on Women’s Cancer showed that rates of cervical dysplasia were equivalent for women who completed a two-dose schedule versus a three-dose schedule.⁴

Efficacy

A recent meta-analysis of clinical trials of the HPV vaccines describe efficacy of 95%-97% in prevention of CIN 1-3.⁵ While its greatest efficacy is in its ability to prevent primary HPV infection, there still is some benefit for individuals who already were exposed to HPV prior to vaccination. As stated previously, women with a history of prior HPV vaccination have lower rates of recurrence of cervical dysplasia after treatment. Additionally, recent research has shown that women who received HPV vaccinations after a LEEP procedure for CIN 2 or 3 experience significantly lower recurrence rates, compared with women who did not receive vaccinations after LEEP (2.5% vs. 8.5%).⁶ This raises the possibility of a therapeutic role for HPV vaccination in women infected with HPV. Prospective studies are currently evaluating this question.

Myths

The most common side effects of the HPV vaccine are pain, redness, or swelling at the injection site. Other known side effects include fever, headache or malaise, nausea, syncope, or muscle/joint pain – similar to other vaccinations. Anaphylaxis is a rare complication.

Some parents and pediatricians report concerns that vaccination could lead to earlier sexual activity. Multiple studies have shown that girls who receive HPV vaccination are no more likely to become pregnant or get a sexually transmitted infection (proxies for intercourse) than are girls who were not vaccinated.^7,8

Maximizing vaccination rates

HPV vaccination rates in the United States lag significantly behind rates in countries with national vaccine programs, such as Australia and Denmark.⁹ Early data from Australia already have shown a decrease in genital warts and CIN 2+ incidence within the 10 years of starting its school-based vaccine program, with approximately 73% of 12- to 15-year-olds having completed the vaccine series.² In contrast, just 40% and 22% of 13- to 17-year-old girls and boys in the United States, respectively, had completed the vaccine series in 2014, according to the CDC.¹⁰

Vaccination gaps between girls and boys are narrowing, and more teens will be able to complete the series with the new two-dose recommendation for those younger than 15 years. However, our current rates of vaccination are significantly lower for HPV than for other routinely recommended adolescent vaccines (such as Tdap and meningococcal) and more must be done to encourage vaccination.

Studies have shown that parents are more likely to vaccinate their children if providers recommend the vaccine.¹¹ As women’s health care providers, we do not always see children during the time period that is ideal for vaccination. However, we take care of many women who are presenting for routine gynecologic care, pregnancy, or with abnormal Pap smear screenings. These are ideal opportunities to educate and offer HPV vaccination to women in the approved age groups, as well as to encourage parents to vaccinate their children.

As with other vaccines, the recommendation should be clear and focused on the cancer prevention benefit. Using methods in which the recommendation is “announced” in a brief statement assuming parents/patients are ready to vaccinate versus open-ended conversations, has been studied as a potentially successful method to increase uptake of HPV vaccination.¹² Additionally, documentation of HPV vaccination status should be built into electronic medical record templates to prompt clinicians to ask and offer HPV vaccination at visits, including postpartum visits.

Dr. Rahangdale is an associate professor of ob.gyn. at the University of North Carolina, Chapel Hill, and is director of the North Carolina Women’s Hospital Cervical Dysplasia Clinic. Dr. Rossi is an assistant professor in the division of gynecologic oncology at UNC-Chapel Hill. They reported having no relevant financial disclosures.

References

1. Am J Epidemiol. 2008 Jul 15;168(2):123-37.

2. Int J Cancer. 2012 Nov 1;131(9):1969-82.

3. BMJ. 2012 Mar 27;344:e1401. doi: 10.1136/bmj.e1401.

4. Gynecol Oncol. 2017 Jun. doi. org/10.1016/j.ygyno.2017.03.031.

5. Int J Prev Med. 2017 Jun 1;8:44. doi: 10.4103/ijpvm.IJPVM_413_16.

6. Gynecol Oncol. 2013 Aug;130(2):264-8.

7. Pediatrics. 2012 Nov;130(5):798-805.

8. JAMA Intern Med. 2015 Apr;175(4):617-23.

9. Clin Pediatr (Phila). 2016 Sep;55(10):904-14.

10. MMWR Morb Mortal Wkly Rep. 2015 Jul 31;64(29):784-92.

11. Vaccine. 2016 Feb 24;34(9):1187-92.

12. Pediatrics. 2017 Jan;139(1). pii:e20161764. doi: 10.1542/peds.2016-1764.


 

The Ebola epidemic of 2014-2016 challenged many federal agencies to find creative ways to help address the vexing problems created by the spread of the disease. There were many factors complicating the response, including the recovery from civil wars in Liberia and Sierra Leone that decimated the physical infrastructure as well as education and other vital services.

The response from the U.S. and the global community took many forms: Not only was there a need for the typical medical care support, but also for basic public health systems to track the spread of disease, provide clean water, and dispose of infectious waste. Because no known preventive vaccines or therapeutics existed for those infected, the recognition of a research component to the response became abundantly clear as the epidemic continued. As a result, the National Institutes of Health (NIH) and the USPHS Commissioned Corps (Corps) serendipitously found themselves allied in a mutually beneficial relationship in the establishment of an Ebola clinical research program in West Africa.

This article describes the events that led to the NIH and Corps participation in the Ebola response, the roles filled by the Corps in supporting the NIH, and the lessons observed from that collaboration. Also presented are considerations regarding preparation of a clinical research response to future outbreaks.

NIH Clinical Research first Response

The 2014-2016 Ebola epidemic in West Africa demonstrated the need for federal agencies to reassess their capacity to respond to global threats to protect the health security of the U.S.¹ The outbreak also challenged the U.S. government to mobilize unique resources that matched the need of this international (and domestic) response.

In 2014, President Barack Obama announced that the U.S. would launch a government response to the Ebola effort. Although a comprehensive research and development program already was in place to establish Ebola virus disease (EVD) countermeasures, no FDA-approved diagnostics, therapeutics, or preventive vaccines were readily available. Fortunately, FDA regulations regarding emergency use authorizations allowed for the use of several EVD diagnostics during this outbreak.² However, the development of drugs and vaccines specific to Ebola had yet to make their way to phase 1 safety studies.

Two vaccine products went into phase 1 studies in the U.S. within months of the declaration of the emergency.^3,4 Additionally, the NIH had organized a collaborative effort between the U.S. government and academic community to identify a research strategy for the evaluation of therapeutics.⁵ Regardless of the state of countermeasures and research proposals, the initial need was for disease control measures and care for Ebola patients. The CDC took the lead in working within the international community to establish an incident management system that could help the impacted countries enact mechanisms to bring the epidemic under control.⁶

As the epidemic progressed, leaders in the Corps and the NIH responded on pathways that eventually would intersect. One of the unfortunate outcomes of the early efforts of improperly protected health care providers was the unintentional transmission of Ebola.⁷ The Corps identified the need to provide high-level care to the health care worker community as one incentive to motivate health care workers to volunteer for hazardous duty inside Ebola treatment units (ETUs).^8,9 Engulfed in the epidemic response, the U.S. government through the National Security Council and secretary of the Department of Health and Human Services (DHHS) evoked its statutory authority to deploy the Corps (42 U.S. Code 204a).

In the first week of October 2014, the Corps sent an advanced echelon team to assess the situation, partner with key host country and international stakeholders, and begin establishment of the U.S. government’s first ever ETU. With logistics, security, and resource support from the DoD and response coordination from the U.S. Agency for International Development, the Corps then deployed the first of four 70-person team rotations to staff the Monrovia Medical Unit (MMU), an ETU specifically dedicated to the treatment of Ebola-infected health care workers. At the time, it was the only ETU specifically dedicated to health care workers in all of Africa. The MMU operated until May 2015 and provided direct patient care for health care workers with Ebola, malaria, and other illnesses.^8,10

In August 2014, representatives from the CDC met with Liberia’s Minister of Health and Social Welfare Walter T. Gwenigale, MD, to discuss the range of available options that could facilitate a better understanding of the prevention and treatment of the disease. This meeting resulted in a letter dated August 22, 2014, from Dr. Gwenigale to then DHHS Sylvia Burwell, requesting a research response. Secretary Burwell responded on October 2, 2014, describing the immediate dispatch of the deputy director for clinical research of the National Institute of Allergy and Infectious Diseases (NIAID) to Liberia to engage in initial discussions with the Liberian minister and other key Liberians involved in the response.

Representatives from the CDC and the commander of the Corps’ Ebola response (and acting deputy surgeon general) were included in those initial meetings, which led to a recognized need for a robust clinical research program of the highest ethical and scientific standards consistent with the expressed requirements of Liberia.¹¹ A second and third trip to Liberia with larger U.S. teams resulted in an agreement signed on November 19, 2014 for the scientific investigation of strategies that tested interventions for treatment, control, and prevention of Ebola.¹²

The agreement led to the establishment of the Partnership for Research on Ebola Virus in Liberia (PREVAIL) to identify research priorities in a collaborative manner between Liberian and American scientists. The first protocol, a vaccine study, was launched in early February 2015.¹² This monumental task involved the support of hundreds of Liberians and dozens of NIH staff who volunteered for rotations to Liberia. Of the 108 volunteers from within the NIH, 18 were PHS officers. 
Shortly after launching the vaccine study, the next priority was initiating the treatment study. This study was delayed primarily due to ZMapp (Mapp Biopharmaceatical, San Diego,CA) production limitations. ZMapp, a monoclonal antibody cocktail, was the first Ebola therapeutic product to be evaluated in a randomized trial.^5,13

During the planning for the study, NIAID staff in Liberia met with Corps staff of the MMU to discuss the logistics associated with implementation of the ZMapp protocol at the MMU. During that meeting, the NIAID deputy director for clinical research expressed interest in obtaining Corps support from outside the NIH to sustain the research effort in West Africa. More specifically, additional pharmacy and laboratory staff were needed to augment NIH research operations. At the time, the MMU commander had recently transitioned from service as the acting surgeon general and was in a unique position to recommend additional Corps resources that could help in the research response.

The February 2015 discussion resulted in the establishment of an NIH/PHS research partnership that continues to exist. This new opportunity was not a significant stretch for the PHS as there was great interest from the Corps for responding to the Ebola crisis. The enthusiasm was consistent with the overall ethos of the Corps, which as a service was composed of highly qualified active-duty, deployable, uniformed, public health professionals who respond to public health crises at home and abroad. To date, 19 Corps officers from outside the NIH have deployed in support of the NIH Ebola clinical research program. An additional 18 Corps officers assigned within the NIH also volunteered for duty in West Africa. Of the 37 Corps officers supporting the NIH clinical research program, 7 served on more than 1 rotation.

Program Expansion

The Ebola clinical research program expanded over time from the initial PREVAIL vaccine study to include studies of therapeutic agents, natural history in Ebola survivors, and an additional vaccine study. The PHS officers have been integral in conducting these studies. The initial study implemented in Liberia, known as PREVAIL I, involved the evaluation of 2 vaccine strategies vs placebo.^12,14 In addition to the NIH-based Corps officers supporting the study, the Readiness and Deployment Operations Group (RedDOG) initiated deployments for an additional 2 pharmacy and 7 laboratory officers to support this study. During the deployment, the pharmacists were asked to extend their reach to Sierra Leone and later to Guinea to help establish PREVAIL II, an evaluation of ZMapp in the treatment of Ebola.¹³ A total of 9 Corps pharmacists, 2 nurses, and 3 physicians deployed to Sierra Leone or Guinea to assist in the PREVAIL II study.

As the epidemic came to an end in Liberia in May 2015, the need for a long-term assessment of Ebola survivors was recognized, resulting in PREVAIL III.¹⁵ Noteworthy in the survivor study was an ophthalmic substudy led by a Corps officer assigned to the National Eye Institute.^16,17 The survivor study also identified that the persistence of the Ebola virus was longer than previously known and that sexual transmission via semen from infected males remained a potential mode of transmission.¹⁸ To address the lingering viral load, a study of an antiviral drug was initiated in Liberia in the summer of 2016, PREVAIL IV.¹⁹

Four Corps pharmacists helped train Liberian pharmacists to establish and sustain this randomized, double-blind, placebo-controlled study. Most recently, Corps pharmacists were deployed to support the initiation of the Partnership for Research on Ebola Vaccines (PREVAC), a collaborative partnership with researchers from Liberia, Guinea, and Sierra Leone with cosponsors from the NIH, Institut national de la santé et de la recherche médicale (Inserm) in France, and the London School of Hygiene and Tropical Medicine in the United Kingdom.²⁰

Deployment Procedures

As previously mentioned, 108 staff (civil service, assigned PHS, and contractors) from within the NIH volunteered for deployment to assist in the clinical research Ebola response. The typical rotation for those volunteers was limited to 3 weeks to minimize the disruption of their normal work assignments. Volunteers were organized into small teams within the Division of Clinical Research were composed of the right mix of physicians, nurses, medical technologists, and pharmacists. The team ensured that staff obtained official government passports, scheduled airline reservations, and received an orientation to the deployment setting as well as to the research studies (Table). Additionally, the team coordinated the voucher submission process for reimbursement of expenses on return from the country. An additional team member was stationed in Liberia to coordinate the housing and transportation arrangements with a local hotel near the U.S. Embassy.

Within a week of the February 2015 initial meeting in Liberia to establish the NIH/PHS collaboration, the NIH deployment team met by phone with the Corps’ RedDOG to discuss initial requirements (eg, number of officers needed, disciplines, time lines, and documentation needed for deployment). These initial discussions resulted in the establishment of more formal processes that evolved over time as the 2 organizations gained experience. Based on the identification of the numbers and types of officers needed, RedDOG used procedures similar to the process for staffing the MMU. A communication went out to the Corps seeking interested officers.

Deployment slots were filled based on the personal availability of the officer and coordination with their immediate supervisor and agency. Officers needed to meet medical clearance requirements and provide current health care provider licensure information. Additional training requirements needed to be completed (eg, U.S. State Department training and good clinical practice [GCP] if not already current). Corps officers also took part in the NIH orientation program for deploying personnel to familiarize them to the situation on the ground in West Africa and the specific clinical research protocols that they would encounter. Given that most of the Corps officers were coming from outside the NIH, the onboarding activities required significant attention to detail as procedures for arranging travel (eg, passport, visa, and airline reservations) and processes for reimbursement of travel/per diem pay differed from more traditional deployments directed through the Corps headquarters.

Commissioned Corps Roles in the Research Response

Whereas the establishment of the research program in Liberia was based primarily on relationships forged over a 2-month period by the NIAID deputy director for clinical research and staff, the extension of the research program into Sierra Leone (March 2015) and Guinea (June 2015) was on a substantially shorter time line. As a result, Corps officers were thrust into roles that immediately employed their leadership and diplomacy skills.

In Sierra Leone and Guinea, the NIAID deputy director for clinical research established initial relationships within the countries. However, Corps officers found themselves in regular interactions with regulators in the Ministry of Health to ensure that applications were complete and import permits for incoming shipments were cleared. Additionally, the research collaboration in Sierra Leone was coordinated through an investigator assigned to a military hospital converted into an ETU. The Corps officers were well suited to maintain and build on that relationship in expanding the protocol to other ETUs throughout Sierra Leone. A site established by the CDC within the Sierra Leone Ministry of Health coordinated ZMapp storage. The Corps officers formed working relationships with the CDC team to establish and improve cold-chain logistics and transportation of the ZMapp to the various ETUs around the country. Corps officers were integral in working with the in-country contract hiring agency. Activities included establishing criteria for clinical research positions, providing input on the interview of respective candidates, and training staff as the team formed. In Sierra Leone, local staff members were hired to work at specific facilities as research coordinators working with the health care delivery teams.

The U.S. team consisted of a physician, nurse research coordinator, and a pharmacist travelling to the sites with a logistics/operations staff member remaining in Freetown.

Fortunately, a Corps nurse on the team had been part of the initial MMU deployment and was trained to work in a special care unit at the NIH for patients with highly contagious infections. This practical experience was essential in the establishment of procedures in a hazardous environment for the administration of the IV ZMapp, monitoring of adverse effects (AEs), provision of medications to mitigate infusion-related reactions, and documentation of those AEs.

The U.S. research team regularly departed Freetown early in the morning 7 days a week with the various supplies needed as they visited up to 4 ETU sites to prepare the ZMapp at the site, await information on any AEs, and collect case report forms (Figures 1 and 2). The ETUs were spread out over a 90-mile radius and could be described as austere platforms for health care delivery.

An additional challenge was dealing with the multinational organizations that staffed the various ETUs. Relief organizations from Italy, the United Kingdom, China, as well as the Sierra Leone military provided the staffing for the 4 ETUs. Regardless of who operated the ETU, the concept of randomization to ZMapp or standard of care required significant tact and diplomacy in communicating the scientific necessity in order to appropriately answer the research question. As Davey and colleagues pointed out, the randomized, controlled trial established the appropriate ethical framework to determine whether the research intervention was associated with harmful effects as there had not been a phase 1 safety study with the drug.¹³

As the summer approached in Sierra Leone, the team worked through challenges in the IV administration of ZMapp as the protein structure of the monoclonal antibody had not previously been subjected to West African environmental extremes. A balance between speed of administration to prevent protein aggregation in the heat as opposed to the risk of infusion reactions from a foreign protein required the team to communicate frequently with, the manufacturer of ZMapp, to establish realistic infusion rate tables. Additionally, as the various deployment teams rotated in and out, procedures for establishing continuity of research operations were enacted and improved on with each rotation. Good documentation practices to adequately collect all required study information (eg, recording AEs, deviations, and signatures on various forms) proved critical to continuity of research operations.

In Guinea, not only was there the new wrinkle of working within a country where the primary language was French, but also a French cosponsor, Inserm. The NIAID clinical director capitalized on the research infrastructure established for a recently completed Inserm study of favipiravir in the treatment of Ebola to extend the ZMapp study to Guinea. Fortunately, many of the Inserm staff were bilingual and readily responded to the NIH training on the requirements of the ZMapp protocol. However, procedures for cold-chain storage and transportation needed to be established. In Guinea, the PHS officers were key in establishing access and temperature monitoring procedures for a secure room inside the U.S. embassy. The issues associated with cold-chain procedures in the infrastructure-limited environments of West Africa are substantial and warrant consideration of a stand-alone paper. Corps officers also took part in weekly country-focused team meetings with embassy staff to describe progress with the ZMapp study.

As the epidemic waned and NIH transitioned to the survivor and viral persistence studies, the operational tempo changed to allow Corps officers to take part in more definitive capacity building efforts. An initial PHS volunteer from the FDA accepted a position within NIAID as a clinical research oversight manager for pharmacy operations. This individual deployed on numerous occasions to the 3 affected West African countries to further establish cold-chain processes for pharmaceuticals and biologics. He also worked with a multidisciplinary team to renovate a clinical research facility in a rural setting in Guinea. In Liberia, he coordinated an effort with other Corps officers to provide educational seminars on clinical research principles and drug-specific topics with the University of Liberia School of Pharmacy.

Challenges

In each instance, the partnership experience was not without a few problems. The match of skills between the officers who wanted to help and those needed for the research program did not always coincide. While the Corps has more than 1,200 pharmacy officers on active duty, only a fraction of those have experience conducting FDA-regulated clinical research.

Communication problems and time pressures were also constant companions to both the Corps and the NIH. The Corps was going through the largest international deployment in its history to staff multiple missions (including the primary MMU mission in Liberia). The addition of the NIH partnership, while consistent with the MMU staffing mission, provided even more work for a very limited resource. Communicating to the many Corps officers who wanted to volunteer and keeping deployment time lines on track were a challenge. Complicating the matter was the addition of stray e-mails from well-intentioned NIH and Corps staff who communicated directly with colleagues to encourage participation, not fully understanding the policies and protocol governing the deployment process.

Time was always an issue as the rotation schedules were relatively short and the number of activities to make an officer deployment ready were numerous. Obtaining official passports and visas was a challenge as that activity required coordination with the U.S. Department of State. Airline schedules changed with little or no notice, complicating deployments and returns. As the NIH added additional research studies for which support was required, time lines for studies to start became difficult to predict with certainty due to factors outside the control of the NIH. Recently, additional security training requirements for government workers traveling abroad were instituted, further complicating the process of deploying an officer.

The Corps officers taking part in this research response (which was not consistent with customary deployments from Corps headquarters) necessarily were volunteers from full-time assignments within DHHS, and as such, required the permission of their supervisory chain to volunteer. Regardless of this limitation, there was widespread support for these additional and specific research deployments. Although the use of short-term rotations was not ideal, in the end, the rotation plans worked, and the NIH was able to fulfill its research mission with the support of the Corps.

Lessons Learned/Preparing for the Future

Many lessons have been learned and continue to be learned throughout this research response and NIH/Corps partnership. Effective and frequent communication between the organization requesting Corps officers and the Corps headquarters is crucial. In the initial deployments, officers were deployed from the FDA with the assumption that they would be familiar with FDA-regulated clinical research. This was not always the case. The NIH and Corps headquarters later collaborated to develop a survey to send to Corps officers that was used to identify specific skill sets needed by officers who would be deploying to conduct clinical research. NIH personnel prescreened survey responses to identify and prioritize officers for deployment consideration by the deployment authority. This process resulted in the selection of officers who generally needed less training and guidance.

Effective training in clinical research principles for deployed officers and other staff needs to be developed and made available to all deploying individuals. All clinical research staff are required to have training on GCP, but most GCP training programs focus primarily on the ethical principles of research as outlined by the Declaration of Helsinki, Nuremberg Code, and other documents. Few GCP training programs present adequate information on the hands-on conduct of clinical research, especially research regulated by the FDA and other government bodies and therefore subject to certain strict requirements. Examples of crucial but often overlooked topics are source document retention, good documentation practices, cold-chain principles, and other issues related to the creation and retention of adequate trial records.²¹

The handoff between returning and deploying officers is crucial. Due to various issues with changing time lines, flights, and administrative processes, it is imperative to plan adequate overlap between returning and deploying officers. Delays in obtaining passports or visas, flight cancellations, and other unforeseen issues may unexpectedly shorten any planned overlap periods. A full workweek is desirable for overlap so that the new officer may experience tasks that occur throughout the week, be introduced to the various team members, and have help if unexpected events occur. A regular staff member should check periodically that proper procedures are being followed, as some information may be missed during each handoff, and consecutive unchecked handoffs could result in large deviations of important procedures. Onboarding and offboarding checklists should be developed and updated regularly to guide the handoff process.

On a larger scale, the respective agencies and other stakeholders involved in planning clinical research for public health emergencies need to be included in regular tabletop training exercises to better understand how to coordinate a response when needed. Additionally, although many of the Corps officers who took part in this deployment served as mentors for others preparing for deployment, establishing a formal roster of experienced officers to support specific roles of this type of response would help serve as a resource center for future deployments. Finally, coordination between any operating division (or agency) and the Corps should be through the established Corps command infrastructure to eliminate miscommunication and complicating deployment processes.²²

Conclusion

The increasing connectedness of this world, as demonstrated by the Ebola epidemic, requires that the HHS engage globally to provide international leadership and technical expertise in science, policy, and programs and work in concert with interagency partners.²³ The missions of the PHS and NIH intersected in a synergistic manner in the research response to the Ebola epidemic of 2014-2016. The PHS Corps mission includes to “protect, promote, and advance the health and safety of the Nation...through rapid and effective response…and advancement of public health science.”²⁴ The Corps mission directly supported the NIH mission to seek fundamental knowledge about the nature and behavior of living systems and the application of that knowledge to enhance health, lengthen life, and reduce illness and disability.²⁵

The scope and scale of DHHS’s response to the Ebola epidemic was unprecedented. The NIH research program, although successful and an important component, was but a small part in bringing the Ebola crisis to an end. The CDC (including the many Corps officers assigned to that agency) worked successfully with the international community and the host countries to bring the disease under control. The Biological Advanced Research and Development Authority provided expert project management, making vaccines and therapeutics available for research.

The DoD was a partner in the development of countermeasures and phase 1 clinical research programs as well as establishing laboratory facilities in Liberia. The Department of State facilitated the many interactions required for the mobilization of resources into West Africa. The collective efforts of the U.S. government contributed immensely to the protection of U.S. borders and to the successful resolution of the Ebola outbreak of 2014-2016.

The Ebola epidemic of 2014-2016 challenged many federal agencies to find creative ways to help address the vexing problems created by the spread of the disease. There were many factors complicating the response, including the recovery from civil wars in Liberia and Sierra Leone that decimated the physical infrastructure as well as education and other vital services.

The response from the U.S. and the global community took many forms: Not only was there a need for the typical medical care support, but also for basic public health systems to track the spread of disease, provide clean water, and dispose of infectious waste. Because no known preventive vaccines or therapeutics existed for those infected, the recognition of a research component to the response became abundantly clear as the epidemic continued. As a result, the National Institutes of Health (NIH) and the USPHS Commissioned Corps (Corps) serendipitously found themselves allied in a mutually beneficial relationship in the establishment of an Ebola clinical research program in West Africa.

This article describes the events that led to the NIH and Corps participation in the Ebola response, the roles filled by the Corps in supporting the NIH, and the lessons observed from that collaboration. Also presented are considerations regarding preparation of a clinical research response to future outbreaks.

NIH Clinical Research first Response

The 2014-2016 Ebola epidemic in West Africa demonstrated the need for federal agencies to reassess their capacity to respond to global threats to protect the health security of the U.S.¹ The outbreak also challenged the U.S. government to mobilize unique resources that matched the need of this international (and domestic) response.

In 2014, President Barack Obama announced that the U.S. would launch a government response to the Ebola effort. Although a comprehensive research and development program already was in place to establish Ebola virus disease (EVD) countermeasures, no FDA-approved diagnostics, therapeutics, or preventive vaccines were readily available. Fortunately, FDA regulations regarding emergency use authorizations allowed for the use of several EVD diagnostics during this outbreak.² However, the development of drugs and vaccines specific to Ebola had yet to make their way to phase 1 safety studies.

Two vaccine products went into phase 1 studies in the U.S. within months of the declaration of the emergency.^3,4 Additionally, the NIH had organized a collaborative effort between the U.S. government and academic community to identify a research strategy for the evaluation of therapeutics.⁵ Regardless of the state of countermeasures and research proposals, the initial need was for disease control measures and care for Ebola patients. The CDC took the lead in working within the international community to establish an incident management system that could help the impacted countries enact mechanisms to bring the epidemic under control.⁶

As the epidemic progressed, leaders in the Corps and the NIH responded on pathways that eventually would intersect. One of the unfortunate outcomes of the early efforts of improperly protected health care providers was the unintentional transmission of Ebola.⁷ The Corps identified the need to provide high-level care to the health care worker community as one incentive to motivate health care workers to volunteer for hazardous duty inside Ebola treatment units (ETUs).^8,9 Engulfed in the epidemic response, the U.S. government through the National Security Council and secretary of the Department of Health and Human Services (DHHS) evoked its statutory authority to deploy the Corps (42 U.S. Code 204a).

In the first week of October 2014, the Corps sent an advanced echelon team to assess the situation, partner with key host country and international stakeholders, and begin establishment of the U.S. government’s first ever ETU. With logistics, security, and resource support from the DoD and response coordination from the U.S. Agency for International Development, the Corps then deployed the first of four 70-person team rotations to staff the Monrovia Medical Unit (MMU), an ETU specifically dedicated to the treatment of Ebola-infected health care workers. At the time, it was the only ETU specifically dedicated to health care workers in all of Africa. The MMU operated until May 2015 and provided direct patient care for health care workers with Ebola, malaria, and other illnesses.^8,10

In August 2014, representatives from the CDC met with Liberia’s Minister of Health and Social Welfare Walter T. Gwenigale, MD, to discuss the range of available options that could facilitate a better understanding of the prevention and treatment of the disease. This meeting resulted in a letter dated August 22, 2014, from Dr. Gwenigale to then DHHS Sylvia Burwell, requesting a research response. Secretary Burwell responded on October 2, 2014, describing the immediate dispatch of the deputy director for clinical research of the National Institute of Allergy and Infectious Diseases (NIAID) to Liberia to engage in initial discussions with the Liberian minister and other key Liberians involved in the response.

Representatives from the CDC and the commander of the Corps’ Ebola response (and acting deputy surgeon general) were included in those initial meetings, which led to a recognized need for a robust clinical research program of the highest ethical and scientific standards consistent with the expressed requirements of Liberia.¹¹ A second and third trip to Liberia with larger U.S. teams resulted in an agreement signed on November 19, 2014 for the scientific investigation of strategies that tested interventions for treatment, control, and prevention of Ebola.¹²

The agreement led to the establishment of the Partnership for Research on Ebola Virus in Liberia (PREVAIL) to identify research priorities in a collaborative manner between Liberian and American scientists. The first protocol, a vaccine study, was launched in early February 2015.¹² This monumental task involved the support of hundreds of Liberians and dozens of NIH staff who volunteered for rotations to Liberia. Of the 108 volunteers from within the NIH, 18 were PHS officers. 
Shortly after launching the vaccine study, the next priority was initiating the treatment study. This study was delayed primarily due to ZMapp (Mapp Biopharmaceatical, San Diego,CA) production limitations. ZMapp, a monoclonal antibody cocktail, was the first Ebola therapeutic product to be evaluated in a randomized trial.^5,13

During the planning for the study, NIAID staff in Liberia met with Corps staff of the MMU to discuss the logistics associated with implementation of the ZMapp protocol at the MMU. During that meeting, the NIAID deputy director for clinical research expressed interest in obtaining Corps support from outside the NIH to sustain the research effort in West Africa. More specifically, additional pharmacy and laboratory staff were needed to augment NIH research operations. At the time, the MMU commander had recently transitioned from service as the acting surgeon general and was in a unique position to recommend additional Corps resources that could help in the research response.

The February 2015 discussion resulted in the establishment of an NIH/PHS research partnership that continues to exist. This new opportunity was not a significant stretch for the PHS as there was great interest from the Corps for responding to the Ebola crisis. The enthusiasm was consistent with the overall ethos of the Corps, which as a service was composed of highly qualified active-duty, deployable, uniformed, public health professionals who respond to public health crises at home and abroad. To date, 19 Corps officers from outside the NIH have deployed in support of the NIH Ebola clinical research program. An additional 18 Corps officers assigned within the NIH also volunteered for duty in West Africa. Of the 37 Corps officers supporting the NIH clinical research program, 7 served on more than 1 rotation.

Program Expansion

The Ebola clinical research program expanded over time from the initial PREVAIL vaccine study to include studies of therapeutic agents, natural history in Ebola survivors, and an additional vaccine study. The PHS officers have been integral in conducting these studies. The initial study implemented in Liberia, known as PREVAIL I, involved the evaluation of 2 vaccine strategies vs placebo.^12,14 In addition to the NIH-based Corps officers supporting the study, the Readiness and Deployment Operations Group (RedDOG) initiated deployments for an additional 2 pharmacy and 7 laboratory officers to support this study. During the deployment, the pharmacists were asked to extend their reach to Sierra Leone and later to Guinea to help establish PREVAIL II, an evaluation of ZMapp in the treatment of Ebola.¹³ A total of 9 Corps pharmacists, 2 nurses, and 3 physicians deployed to Sierra Leone or Guinea to assist in the PREVAIL II study.

As the epidemic came to an end in Liberia in May 2015, the need for a long-term assessment of Ebola survivors was recognized, resulting in PREVAIL III.¹⁵ Noteworthy in the survivor study was an ophthalmic substudy led by a Corps officer assigned to the National Eye Institute.^16,17 The survivor study also identified that the persistence of the Ebola virus was longer than previously known and that sexual transmission via semen from infected males remained a potential mode of transmission.¹⁸ To address the lingering viral load, a study of an antiviral drug was initiated in Liberia in the summer of 2016, PREVAIL IV.¹⁹

Four Corps pharmacists helped train Liberian pharmacists to establish and sustain this randomized, double-blind, placebo-controlled study. Most recently, Corps pharmacists were deployed to support the initiation of the Partnership for Research on Ebola Vaccines (PREVAC), a collaborative partnership with researchers from Liberia, Guinea, and Sierra Leone with cosponsors from the NIH, Institut national de la santé et de la recherche médicale (Inserm) in France, and the London School of Hygiene and Tropical Medicine in the United Kingdom.²⁰

Deployment Procedures

As previously mentioned, 108 staff (civil service, assigned PHS, and contractors) from within the NIH volunteered for deployment to assist in the clinical research Ebola response. The typical rotation for those volunteers was limited to 3 weeks to minimize the disruption of their normal work assignments. Volunteers were organized into small teams within the Division of Clinical Research were composed of the right mix of physicians, nurses, medical technologists, and pharmacists. The team ensured that staff obtained official government passports, scheduled airline reservations, and received an orientation to the deployment setting as well as to the research studies (Table). Additionally, the team coordinated the voucher submission process for reimbursement of expenses on return from the country. An additional team member was stationed in Liberia to coordinate the housing and transportation arrangements with a local hotel near the U.S. Embassy.

Within a week of the February 2015 initial meeting in Liberia to establish the NIH/PHS collaboration, the NIH deployment team met by phone with the Corps’ RedDOG to discuss initial requirements (eg, number of officers needed, disciplines, time lines, and documentation needed for deployment). These initial discussions resulted in the establishment of more formal processes that evolved over time as the 2 organizations gained experience. Based on the identification of the numbers and types of officers needed, RedDOG used procedures similar to the process for staffing the MMU. A communication went out to the Corps seeking interested officers.

Deployment slots were filled based on the personal availability of the officer and coordination with their immediate supervisor and agency. Officers needed to meet medical clearance requirements and provide current health care provider licensure information. Additional training requirements needed to be completed (eg, U.S. State Department training and good clinical practice [GCP] if not already current). Corps officers also took part in the NIH orientation program for deploying personnel to familiarize them to the situation on the ground in West Africa and the specific clinical research protocols that they would encounter. Given that most of the Corps officers were coming from outside the NIH, the onboarding activities required significant attention to detail as procedures for arranging travel (eg, passport, visa, and airline reservations) and processes for reimbursement of travel/per diem pay differed from more traditional deployments directed through the Corps headquarters.

Commissioned Corps Roles in the Research Response

Whereas the establishment of the research program in Liberia was based primarily on relationships forged over a 2-month period by the NIAID deputy director for clinical research and staff, the extension of the research program into Sierra Leone (March 2015) and Guinea (June 2015) was on a substantially shorter time line. As a result, Corps officers were thrust into roles that immediately employed their leadership and diplomacy skills.

In Sierra Leone and Guinea, the NIAID deputy director for clinical research established initial relationships within the countries. However, Corps officers found themselves in regular interactions with regulators in the Ministry of Health to ensure that applications were complete and import permits for incoming shipments were cleared. Additionally, the research collaboration in Sierra Leone was coordinated through an investigator assigned to a military hospital converted into an ETU. The Corps officers were well suited to maintain and build on that relationship in expanding the protocol to other ETUs throughout Sierra Leone. A site established by the CDC within the Sierra Leone Ministry of Health coordinated ZMapp storage. The Corps officers formed working relationships with the CDC team to establish and improve cold-chain logistics and transportation of the ZMapp to the various ETUs around the country. Corps officers were integral in working with the in-country contract hiring agency. Activities included establishing criteria for clinical research positions, providing input on the interview of respective candidates, and training staff as the team formed. In Sierra Leone, local staff members were hired to work at specific facilities as research coordinators working with the health care delivery teams.

The U.S. team consisted of a physician, nurse research coordinator, and a pharmacist travelling to the sites with a logistics/operations staff member remaining in Freetown.

Fortunately, a Corps nurse on the team had been part of the initial MMU deployment and was trained to work in a special care unit at the NIH for patients with highly contagious infections. This practical experience was essential in the establishment of procedures in a hazardous environment for the administration of the IV ZMapp, monitoring of adverse effects (AEs), provision of medications to mitigate infusion-related reactions, and documentation of those AEs.

The U.S. research team regularly departed Freetown early in the morning 7 days a week with the various supplies needed as they visited up to 4 ETU sites to prepare the ZMapp at the site, await information on any AEs, and collect case report forms (Figures 1 and 2). The ETUs were spread out over a 90-mile radius and could be described as austere platforms for health care delivery.

An additional challenge was dealing with the multinational organizations that staffed the various ETUs. Relief organizations from Italy, the United Kingdom, China, as well as the Sierra Leone military provided the staffing for the 4 ETUs. Regardless of who operated the ETU, the concept of randomization to ZMapp or standard of care required significant tact and diplomacy in communicating the scientific necessity in order to appropriately answer the research question. As Davey and colleagues pointed out, the randomized, controlled trial established the appropriate ethical framework to determine whether the research intervention was associated with harmful effects as there had not been a phase 1 safety study with the drug.¹³

As the summer approached in Sierra Leone, the team worked through challenges in the IV administration of ZMapp as the protein structure of the monoclonal antibody had not previously been subjected to West African environmental extremes. A balance between speed of administration to prevent protein aggregation in the heat as opposed to the risk of infusion reactions from a foreign protein required the team to communicate frequently with, the manufacturer of ZMapp, to establish realistic infusion rate tables. Additionally, as the various deployment teams rotated in and out, procedures for establishing continuity of research operations were enacted and improved on with each rotation. Good documentation practices to adequately collect all required study information (eg, recording AEs, deviations, and signatures on various forms) proved critical to continuity of research operations.

In Guinea, not only was there the new wrinkle of working within a country where the primary language was French, but also a French cosponsor, Inserm. The NIAID clinical director capitalized on the research infrastructure established for a recently completed Inserm study of favipiravir in the treatment of Ebola to extend the ZMapp study to Guinea. Fortunately, many of the Inserm staff were bilingual and readily responded to the NIH training on the requirements of the ZMapp protocol. However, procedures for cold-chain storage and transportation needed to be established. In Guinea, the PHS officers were key in establishing access and temperature monitoring procedures for a secure room inside the U.S. embassy. The issues associated with cold-chain procedures in the infrastructure-limited environments of West Africa are substantial and warrant consideration of a stand-alone paper. Corps officers also took part in weekly country-focused team meetings with embassy staff to describe progress with the ZMapp study.

As the epidemic waned and NIH transitioned to the survivor and viral persistence studies, the operational tempo changed to allow Corps officers to take part in more definitive capacity building efforts. An initial PHS volunteer from the FDA accepted a position within NIAID as a clinical research oversight manager for pharmacy operations. This individual deployed on numerous occasions to the 3 affected West African countries to further establish cold-chain processes for pharmaceuticals and biologics. He also worked with a multidisciplinary team to renovate a clinical research facility in a rural setting in Guinea. In Liberia, he coordinated an effort with other Corps officers to provide educational seminars on clinical research principles and drug-specific topics with the University of Liberia School of Pharmacy.

Challenges

In each instance, the partnership experience was not without a few problems. The match of skills between the officers who wanted to help and those needed for the research program did not always coincide. While the Corps has more than 1,200 pharmacy officers on active duty, only a fraction of those have experience conducting FDA-regulated clinical research.

Communication problems and time pressures were also constant companions to both the Corps and the NIH. The Corps was going through the largest international deployment in its history to staff multiple missions (including the primary MMU mission in Liberia). The addition of the NIH partnership, while consistent with the MMU staffing mission, provided even more work for a very limited resource. Communicating to the many Corps officers who wanted to volunteer and keeping deployment time lines on track were a challenge. Complicating the matter was the addition of stray e-mails from well-intentioned NIH and Corps staff who communicated directly with colleagues to encourage participation, not fully understanding the policies and protocol governing the deployment process.

Time was always an issue as the rotation schedules were relatively short and the number of activities to make an officer deployment ready were numerous. Obtaining official passports and visas was a challenge as that activity required coordination with the U.S. Department of State. Airline schedules changed with little or no notice, complicating deployments and returns. As the NIH added additional research studies for which support was required, time lines for studies to start became difficult to predict with certainty due to factors outside the control of the NIH. Recently, additional security training requirements for government workers traveling abroad were instituted, further complicating the process of deploying an officer.

The Corps officers taking part in this research response (which was not consistent with customary deployments from Corps headquarters) necessarily were volunteers from full-time assignments within DHHS, and as such, required the permission of their supervisory chain to volunteer. Regardless of this limitation, there was widespread support for these additional and specific research deployments. Although the use of short-term rotations was not ideal, in the end, the rotation plans worked, and the NIH was able to fulfill its research mission with the support of the Corps.

Lessons Learned/Preparing for the Future

Many lessons have been learned and continue to be learned throughout this research response and NIH/Corps partnership. Effective and frequent communication between the organization requesting Corps officers and the Corps headquarters is crucial. In the initial deployments, officers were deployed from the FDA with the assumption that they would be familiar with FDA-regulated clinical research. This was not always the case. The NIH and Corps headquarters later collaborated to develop a survey to send to Corps officers that was used to identify specific skill sets needed by officers who would be deploying to conduct clinical research. NIH personnel prescreened survey responses to identify and prioritize officers for deployment consideration by the deployment authority. This process resulted in the selection of officers who generally needed less training and guidance.

Effective training in clinical research principles for deployed officers and other staff needs to be developed and made available to all deploying individuals. All clinical research staff are required to have training on GCP, but most GCP training programs focus primarily on the ethical principles of research as outlined by the Declaration of Helsinki, Nuremberg Code, and other documents. Few GCP training programs present adequate information on the hands-on conduct of clinical research, especially research regulated by the FDA and other government bodies and therefore subject to certain strict requirements. Examples of crucial but often overlooked topics are source document retention, good documentation practices, cold-chain principles, and other issues related to the creation and retention of adequate trial records.²¹

The handoff between returning and deploying officers is crucial. Due to various issues with changing time lines, flights, and administrative processes, it is imperative to plan adequate overlap between returning and deploying officers. Delays in obtaining passports or visas, flight cancellations, and other unforeseen issues may unexpectedly shorten any planned overlap periods. A full workweek is desirable for overlap so that the new officer may experience tasks that occur throughout the week, be introduced to the various team members, and have help if unexpected events occur. A regular staff member should check periodically that proper procedures are being followed, as some information may be missed during each handoff, and consecutive unchecked handoffs could result in large deviations of important procedures. Onboarding and offboarding checklists should be developed and updated regularly to guide the handoff process.

On a larger scale, the respective agencies and other stakeholders involved in planning clinical research for public health emergencies need to be included in regular tabletop training exercises to better understand how to coordinate a response when needed. Additionally, although many of the Corps officers who took part in this deployment served as mentors for others preparing for deployment, establishing a formal roster of experienced officers to support specific roles of this type of response would help serve as a resource center for future deployments. Finally, coordination between any operating division (or agency) and the Corps should be through the established Corps command infrastructure to eliminate miscommunication and complicating deployment processes.²²

Conclusion

The increasing connectedness of this world, as demonstrated by the Ebola epidemic, requires that the HHS engage globally to provide international leadership and technical expertise in science, policy, and programs and work in concert with interagency partners.²³ The missions of the PHS and NIH intersected in a synergistic manner in the research response to the Ebola epidemic of 2014-2016. The PHS Corps mission includes to “protect, promote, and advance the health and safety of the Nation...through rapid and effective response…and advancement of public health science.”²⁴ The Corps mission directly supported the NIH mission to seek fundamental knowledge about the nature and behavior of living systems and the application of that knowledge to enhance health, lengthen life, and reduce illness and disability.²⁵

The scope and scale of DHHS’s response to the Ebola epidemic was unprecedented. The NIH research program, although successful and an important component, was but a small part in bringing the Ebola crisis to an end. The CDC (including the many Corps officers assigned to that agency) worked successfully with the international community and the host countries to bring the disease under control. The Biological Advanced Research and Development Authority provided expert project management, making vaccines and therapeutics available for research.

The DoD was a partner in the development of countermeasures and phase 1 clinical research programs as well as establishing laboratory facilities in Liberia. The Department of State facilitated the many interactions required for the mobilization of resources into West Africa. The collective efforts of the U.S. government contributed immensely to the protection of U.S. borders and to the successful resolution of the Ebola outbreak of 2014-2016.

The Ebola epidemic of 2014-2016 challenged many federal agencies to find creative ways to help address the vexing problems created by the spread of the disease. There were many factors complicating the response, including the recovery from civil wars in Liberia and Sierra Leone that decimated the physical infrastructure as well as education and other vital services.

The response from the U.S. and the global community took many forms: Not only was there a need for the typical medical care support, but also for basic public health systems to track the spread of disease, provide clean water, and dispose of infectious waste. Because no known preventive vaccines or therapeutics existed for those infected, the recognition of a research component to the response became abundantly clear as the epidemic continued. As a result, the National Institutes of Health (NIH) and the USPHS Commissioned Corps (Corps) serendipitously found themselves allied in a mutually beneficial relationship in the establishment of an Ebola clinical research program in West Africa.

This article describes the events that led to the NIH and Corps participation in the Ebola response, the roles filled by the Corps in supporting the NIH, and the lessons observed from that collaboration. Also presented are considerations regarding preparation of a clinical research response to future outbreaks.

NIH Clinical Research first Response

The 2014-2016 Ebola epidemic in West Africa demonstrated the need for federal agencies to reassess their capacity to respond to global threats to protect the health security of the U.S.¹ The outbreak also challenged the U.S. government to mobilize unique resources that matched the need of this international (and domestic) response.

In 2014, President Barack Obama announced that the U.S. would launch a government response to the Ebola effort. Although a comprehensive research and development program already was in place to establish Ebola virus disease (EVD) countermeasures, no FDA-approved diagnostics, therapeutics, or preventive vaccines were readily available. Fortunately, FDA regulations regarding emergency use authorizations allowed for the use of several EVD diagnostics during this outbreak.² However, the development of drugs and vaccines specific to Ebola had yet to make their way to phase 1 safety studies.

Two vaccine products went into phase 1 studies in the U.S. within months of the declaration of the emergency.^3,4 Additionally, the NIH had organized a collaborative effort between the U.S. government and academic community to identify a research strategy for the evaluation of therapeutics.⁵ Regardless of the state of countermeasures and research proposals, the initial need was for disease control measures and care for Ebola patients. The CDC took the lead in working within the international community to establish an incident management system that could help the impacted countries enact mechanisms to bring the epidemic under control.⁶

As the epidemic progressed, leaders in the Corps and the NIH responded on pathways that eventually would intersect. One of the unfortunate outcomes of the early efforts of improperly protected health care providers was the unintentional transmission of Ebola.⁷ The Corps identified the need to provide high-level care to the health care worker community as one incentive to motivate health care workers to volunteer for hazardous duty inside Ebola treatment units (ETUs).^8,9 Engulfed in the epidemic response, the U.S. government through the National Security Council and secretary of the Department of Health and Human Services (DHHS) evoked its statutory authority to deploy the Corps (42 U.S. Code 204a).

In the first week of October 2014, the Corps sent an advanced echelon team to assess the situation, partner with key host country and international stakeholders, and begin establishment of the U.S. government’s first ever ETU. With logistics, security, and resource support from the DoD and response coordination from the U.S. Agency for International Development, the Corps then deployed the first of four 70-person team rotations to staff the Monrovia Medical Unit (MMU), an ETU specifically dedicated to the treatment of Ebola-infected health care workers. At the time, it was the only ETU specifically dedicated to health care workers in all of Africa. The MMU operated until May 2015 and provided direct patient care for health care workers with Ebola, malaria, and other illnesses.^8,10

In August 2014, representatives from the CDC met with Liberia’s Minister of Health and Social Welfare Walter T. Gwenigale, MD, to discuss the range of available options that could facilitate a better understanding of the prevention and treatment of the disease. This meeting resulted in a letter dated August 22, 2014, from Dr. Gwenigale to then DHHS Sylvia Burwell, requesting a research response. Secretary Burwell responded on October 2, 2014, describing the immediate dispatch of the deputy director for clinical research of the National Institute of Allergy and Infectious Diseases (NIAID) to Liberia to engage in initial discussions with the Liberian minister and other key Liberians involved in the response.

Representatives from the CDC and the commander of the Corps’ Ebola response (and acting deputy surgeon general) were included in those initial meetings, which led to a recognized need for a robust clinical research program of the highest ethical and scientific standards consistent with the expressed requirements of Liberia.¹¹ A second and third trip to Liberia with larger U.S. teams resulted in an agreement signed on November 19, 2014 for the scientific investigation of strategies that tested interventions for treatment, control, and prevention of Ebola.¹²

The agreement led to the establishment of the Partnership for Research on Ebola Virus in Liberia (PREVAIL) to identify research priorities in a collaborative manner between Liberian and American scientists. The first protocol, a vaccine study, was launched in early February 2015.¹² This monumental task involved the support of hundreds of Liberians and dozens of NIH staff who volunteered for rotations to Liberia. Of the 108 volunteers from within the NIH, 18 were PHS officers. 
Shortly after launching the vaccine study, the next priority was initiating the treatment study. This study was delayed primarily due to ZMapp (Mapp Biopharmaceatical, San Diego,CA) production limitations. ZMapp, a monoclonal antibody cocktail, was the first Ebola therapeutic product to be evaluated in a randomized trial.^5,13

During the planning for the study, NIAID staff in Liberia met with Corps staff of the MMU to discuss the logistics associated with implementation of the ZMapp protocol at the MMU. During that meeting, the NIAID deputy director for clinical research expressed interest in obtaining Corps support from outside the NIH to sustain the research effort in West Africa. More specifically, additional pharmacy and laboratory staff were needed to augment NIH research operations. At the time, the MMU commander had recently transitioned from service as the acting surgeon general and was in a unique position to recommend additional Corps resources that could help in the research response.

The February 2015 discussion resulted in the establishment of an NIH/PHS research partnership that continues to exist. This new opportunity was not a significant stretch for the PHS as there was great interest from the Corps for responding to the Ebola crisis. The enthusiasm was consistent with the overall ethos of the Corps, which as a service was composed of highly qualified active-duty, deployable, uniformed, public health professionals who respond to public health crises at home and abroad. To date, 19 Corps officers from outside the NIH have deployed in support of the NIH Ebola clinical research program. An additional 18 Corps officers assigned within the NIH also volunteered for duty in West Africa. Of the 37 Corps officers supporting the NIH clinical research program, 7 served on more than 1 rotation.

Program Expansion

The Ebola clinical research program expanded over time from the initial PREVAIL vaccine study to include studies of therapeutic agents, natural history in Ebola survivors, and an additional vaccine study. The PHS officers have been integral in conducting these studies. The initial study implemented in Liberia, known as PREVAIL I, involved the evaluation of 2 vaccine strategies vs placebo.^12,14 In addition to the NIH-based Corps officers supporting the study, the Readiness and Deployment Operations Group (RedDOG) initiated deployments for an additional 2 pharmacy and 7 laboratory officers to support this study. During the deployment, the pharmacists were asked to extend their reach to Sierra Leone and later to Guinea to help establish PREVAIL II, an evaluation of ZMapp in the treatment of Ebola.¹³ A total of 9 Corps pharmacists, 2 nurses, and 3 physicians deployed to Sierra Leone or Guinea to assist in the PREVAIL II study.

As the epidemic came to an end in Liberia in May 2015, the need for a long-term assessment of Ebola survivors was recognized, resulting in PREVAIL III.¹⁵ Noteworthy in the survivor study was an ophthalmic substudy led by a Corps officer assigned to the National Eye Institute.^16,17 The survivor study also identified that the persistence of the Ebola virus was longer than previously known and that sexual transmission via semen from infected males remained a potential mode of transmission.¹⁸ To address the lingering viral load, a study of an antiviral drug was initiated in Liberia in the summer of 2016, PREVAIL IV.¹⁹

Four Corps pharmacists helped train Liberian pharmacists to establish and sustain this randomized, double-blind, placebo-controlled study. Most recently, Corps pharmacists were deployed to support the initiation of the Partnership for Research on Ebola Vaccines (PREVAC), a collaborative partnership with researchers from Liberia, Guinea, and Sierra Leone with cosponsors from the NIH, Institut national de la santé et de la recherche médicale (Inserm) in France, and the London School of Hygiene and Tropical Medicine in the United Kingdom.²⁰

Deployment Procedures

As previously mentioned, 108 staff (civil service, assigned PHS, and contractors) from within the NIH volunteered for deployment to assist in the clinical research Ebola response. The typical rotation for those volunteers was limited to 3 weeks to minimize the disruption of their normal work assignments. Volunteers were organized into small teams within the Division of Clinical Research were composed of the right mix of physicians, nurses, medical technologists, and pharmacists. The team ensured that staff obtained official government passports, scheduled airline reservations, and received an orientation to the deployment setting as well as to the research studies (Table). Additionally, the team coordinated the voucher submission process for reimbursement of expenses on return from the country. An additional team member was stationed in Liberia to coordinate the housing and transportation arrangements with a local hotel near the U.S. Embassy.

Within a week of the February 2015 initial meeting in Liberia to establish the NIH/PHS collaboration, the NIH deployment team met by phone with the Corps’ RedDOG to discuss initial requirements (eg, number of officers needed, disciplines, time lines, and documentation needed for deployment). These initial discussions resulted in the establishment of more formal processes that evolved over time as the 2 organizations gained experience. Based on the identification of the numbers and types of officers needed, RedDOG used procedures similar to the process for staffing the MMU. A communication went out to the Corps seeking interested officers.

Deployment slots were filled based on the personal availability of the officer and coordination with their immediate supervisor and agency. Officers needed to meet medical clearance requirements and provide current health care provider licensure information. Additional training requirements needed to be completed (eg, U.S. State Department training and good clinical practice [GCP] if not already current). Corps officers also took part in the NIH orientation program for deploying personnel to familiarize them to the situation on the ground in West Africa and the specific clinical research protocols that they would encounter. Given that most of the Corps officers were coming from outside the NIH, the onboarding activities required significant attention to detail as procedures for arranging travel (eg, passport, visa, and airline reservations) and processes for reimbursement of travel/per diem pay differed from more traditional deployments directed through the Corps headquarters.

Commissioned Corps Roles in the Research Response

Whereas the establishment of the research program in Liberia was based primarily on relationships forged over a 2-month period by the NIAID deputy director for clinical research and staff, the extension of the research program into Sierra Leone (March 2015) and Guinea (June 2015) was on a substantially shorter time line. As a result, Corps officers were thrust into roles that immediately employed their leadership and diplomacy skills.

In Sierra Leone and Guinea, the NIAID deputy director for clinical research established initial relationships within the countries. However, Corps officers found themselves in regular interactions with regulators in the Ministry of Health to ensure that applications were complete and import permits for incoming shipments were cleared. Additionally, the research collaboration in Sierra Leone was coordinated through an investigator assigned to a military hospital converted into an ETU. The Corps officers were well suited to maintain and build on that relationship in expanding the protocol to other ETUs throughout Sierra Leone. A site established by the CDC within the Sierra Leone Ministry of Health coordinated ZMapp storage. The Corps officers formed working relationships with the CDC team to establish and improve cold-chain logistics and transportation of the ZMapp to the various ETUs around the country. Corps officers were integral in working with the in-country contract hiring agency. Activities included establishing criteria for clinical research positions, providing input on the interview of respective candidates, and training staff as the team formed. In Sierra Leone, local staff members were hired to work at specific facilities as research coordinators working with the health care delivery teams.

The U.S. team consisted of a physician, nurse research coordinator, and a pharmacist travelling to the sites with a logistics/operations staff member remaining in Freetown.

Fortunately, a Corps nurse on the team had been part of the initial MMU deployment and was trained to work in a special care unit at the NIH for patients with highly contagious infections. This practical experience was essential in the establishment of procedures in a hazardous environment for the administration of the IV ZMapp, monitoring of adverse effects (AEs), provision of medications to mitigate infusion-related reactions, and documentation of those AEs.

The U.S. research team regularly departed Freetown early in the morning 7 days a week with the various supplies needed as they visited up to 4 ETU sites to prepare the ZMapp at the site, await information on any AEs, and collect case report forms (Figures 1 and 2). The ETUs were spread out over a 90-mile radius and could be described as austere platforms for health care delivery.

An additional challenge was dealing with the multinational organizations that staffed the various ETUs. Relief organizations from Italy, the United Kingdom, China, as well as the Sierra Leone military provided the staffing for the 4 ETUs. Regardless of who operated the ETU, the concept of randomization to ZMapp or standard of care required significant tact and diplomacy in communicating the scientific necessity in order to appropriately answer the research question. As Davey and colleagues pointed out, the randomized, controlled trial established the appropriate ethical framework to determine whether the research intervention was associated with harmful effects as there had not been a phase 1 safety study with the drug.¹³

As the summer approached in Sierra Leone, the team worked through challenges in the IV administration of ZMapp as the protein structure of the monoclonal antibody had not previously been subjected to West African environmental extremes. A balance between speed of administration to prevent protein aggregation in the heat as opposed to the risk of infusion reactions from a foreign protein required the team to communicate frequently with, the manufacturer of ZMapp, to establish realistic infusion rate tables. Additionally, as the various deployment teams rotated in and out, procedures for establishing continuity of research operations were enacted and improved on with each rotation. Good documentation practices to adequately collect all required study information (eg, recording AEs, deviations, and signatures on various forms) proved critical to continuity of research operations.

In Guinea, not only was there the new wrinkle of working within a country where the primary language was French, but also a French cosponsor, Inserm. The NIAID clinical director capitalized on the research infrastructure established for a recently completed Inserm study of favipiravir in the treatment of Ebola to extend the ZMapp study to Guinea. Fortunately, many of the Inserm staff were bilingual and readily responded to the NIH training on the requirements of the ZMapp protocol. However, procedures for cold-chain storage and transportation needed to be established. In Guinea, the PHS officers were key in establishing access and temperature monitoring procedures for a secure room inside the U.S. embassy. The issues associated with cold-chain procedures in the infrastructure-limited environments of West Africa are substantial and warrant consideration of a stand-alone paper. Corps officers also took part in weekly country-focused team meetings with embassy staff to describe progress with the ZMapp study.

As the epidemic waned and NIH transitioned to the survivor and viral persistence studies, the operational tempo changed to allow Corps officers to take part in more definitive capacity building efforts. An initial PHS volunteer from the FDA accepted a position within NIAID as a clinical research oversight manager for pharmacy operations. This individual deployed on numerous occasions to the 3 affected West African countries to further establish cold-chain processes for pharmaceuticals and biologics. He also worked with a multidisciplinary team to renovate a clinical research facility in a rural setting in Guinea. In Liberia, he coordinated an effort with other Corps officers to provide educational seminars on clinical research principles and drug-specific topics with the University of Liberia School of Pharmacy.

Challenges

In each instance, the partnership experience was not without a few problems. The match of skills between the officers who wanted to help and those needed for the research program did not always coincide. While the Corps has more than 1,200 pharmacy officers on active duty, only a fraction of those have experience conducting FDA-regulated clinical research.

Communication problems and time pressures were also constant companions to both the Corps and the NIH. The Corps was going through the largest international deployment in its history to staff multiple missions (including the primary MMU mission in Liberia). The addition of the NIH partnership, while consistent with the MMU staffing mission, provided even more work for a very limited resource. Communicating to the many Corps officers who wanted to volunteer and keeping deployment time lines on track were a challenge. Complicating the matter was the addition of stray e-mails from well-intentioned NIH and Corps staff who communicated directly with colleagues to encourage participation, not fully understanding the policies and protocol governing the deployment process.

Time was always an issue as the rotation schedules were relatively short and the number of activities to make an officer deployment ready were numerous. Obtaining official passports and visas was a challenge as that activity required coordination with the U.S. Department of State. Airline schedules changed with little or no notice, complicating deployments and returns. As the NIH added additional research studies for which support was required, time lines for studies to start became difficult to predict with certainty due to factors outside the control of the NIH. Recently, additional security training requirements for government workers traveling abroad were instituted, further complicating the process of deploying an officer.

The Corps officers taking part in this research response (which was not consistent with customary deployments from Corps headquarters) necessarily were volunteers from full-time assignments within DHHS, and as such, required the permission of their supervisory chain to volunteer. Regardless of this limitation, there was widespread support for these additional and specific research deployments. Although the use of short-term rotations was not ideal, in the end, the rotation plans worked, and the NIH was able to fulfill its research mission with the support of the Corps.

Lessons Learned/Preparing for the Future

Many lessons have been learned and continue to be learned throughout this research response and NIH/Corps partnership. Effective and frequent communication between the organization requesting Corps officers and the Corps headquarters is crucial. In the initial deployments, officers were deployed from the FDA with the assumption that they would be familiar with FDA-regulated clinical research. This was not always the case. The NIH and Corps headquarters later collaborated to develop a survey to send to Corps officers that was used to identify specific skill sets needed by officers who would be deploying to conduct clinical research. NIH personnel prescreened survey responses to identify and prioritize officers for deployment consideration by the deployment authority. This process resulted in the selection of officers who generally needed less training and guidance.

Effective training in clinical research principles for deployed officers and other staff needs to be developed and made available to all deploying individuals. All clinical research staff are required to have training on GCP, but most GCP training programs focus primarily on the ethical principles of research as outlined by the Declaration of Helsinki, Nuremberg Code, and other documents. Few GCP training programs present adequate information on the hands-on conduct of clinical research, especially research regulated by the FDA and other government bodies and therefore subject to certain strict requirements. Examples of crucial but often overlooked topics are source document retention, good documentation practices, cold-chain principles, and other issues related to the creation and retention of adequate trial records.²¹

The handoff between returning and deploying officers is crucial. Due to various issues with changing time lines, flights, and administrative processes, it is imperative to plan adequate overlap between returning and deploying officers. Delays in obtaining passports or visas, flight cancellations, and other unforeseen issues may unexpectedly shorten any planned overlap periods. A full workweek is desirable for overlap so that the new officer may experience tasks that occur throughout the week, be introduced to the various team members, and have help if unexpected events occur. A regular staff member should check periodically that proper procedures are being followed, as some information may be missed during each handoff, and consecutive unchecked handoffs could result in large deviations of important procedures. Onboarding and offboarding checklists should be developed and updated regularly to guide the handoff process.

On a larger scale, the respective agencies and other stakeholders involved in planning clinical research for public health emergencies need to be included in regular tabletop training exercises to better understand how to coordinate a response when needed. Additionally, although many of the Corps officers who took part in this deployment served as mentors for others preparing for deployment, establishing a formal roster of experienced officers to support specific roles of this type of response would help serve as a resource center for future deployments. Finally, coordination between any operating division (or agency) and the Corps should be through the established Corps command infrastructure to eliminate miscommunication and complicating deployment processes.²²

Conclusion

The increasing connectedness of this world, as demonstrated by the Ebola epidemic, requires that the HHS engage globally to provide international leadership and technical expertise in science, policy, and programs and work in concert with interagency partners.²³ The missions of the PHS and NIH intersected in a synergistic manner in the research response to the Ebola epidemic of 2014-2016. The PHS Corps mission includes to “protect, promote, and advance the health and safety of the Nation...through rapid and effective response…and advancement of public health science.”²⁴ The Corps mission directly supported the NIH mission to seek fundamental knowledge about the nature and behavior of living systems and the application of that knowledge to enhance health, lengthen life, and reduce illness and disability.²⁵

The scope and scale of DHHS’s response to the Ebola epidemic was unprecedented. The NIH research program, although successful and an important component, was but a small part in bringing the Ebola crisis to an end. The CDC (including the many Corps officers assigned to that agency) worked successfully with the international community and the host countries to bring the disease under control. The Biological Advanced Research and Development Authority provided expert project management, making vaccines and therapeutics available for research.

The DoD was a partner in the development of countermeasures and phase 1 clinical research programs as well as establishing laboratory facilities in Liberia. The Department of State facilitated the many interactions required for the mobilization of resources into West Africa. The collective efforts of the U.S. government contributed immensely to the protection of U.S. borders and to the successful resolution of the Ebola outbreak of 2014-2016.