CLL cells

The PI3K delta inhibitor idelalisib could turn chronic lymphocytic leukemia (CLL) into a highly treatable disease, according to the lead investigator of a phase 3 trial.

Results of the trial showed that adding idelalisib to treatment with rituximab can improve response and survival rates in patients with relapsed CLL.

In fact, the study was stopped early because idelalisib had a significant impact on progression-free survival.

“This study, and others we have conducted on idelalisib, demonstrates that we may no longer need to use chemotherapy in CLL,” said lead investigator Richard R. Furman, MD, of Weill Cornell Medical College in New York.

“Even if this cancer remains incurable, it now can be treated as if it was a chronic disease—with a pill, in the same way that high blood pressure is treated.”

Dr Furman and his colleagues reported the results of this study in The New England Journal of Medicine.

The trial was funded by Gilead, the makers of idelalisib. Dr Furman has served as an advisor for this company.

The study included 220 CLL patients who could not receive chemotherapy. Nearly two-thirds of the patients had advanced-stage disease. The median time from CLL diagnosis was 9 years, and patients had received a median of 3 previous treatments.

Most of the patients were 65 or older (78%). Forty percent had at least moderate renal dysfunction, and 35% had poor bone marrow function.

Half of the patients were randomized to receive idelalisib plus rituximab and the other half to rituximab plus placebo.

“It is remarkable how quickly idelalisib worked in this heavily treated group of patients, many of whom were resistant to chemotherapy,” Dr Furman said. “We saw responses within a week.”

Patients in the idelalisib arm had a much higher overall response rate than patients in the placebo arm—81% and 13%, respectively (P<0.001). But all responses were partial responses.

At 24 weeks, the rate of progression-free survival was 93% in the idelalisib arm and 46% in the placebo arm (P<0.001). The median progression-free survival was 5.5 months in the placebo arm and not reached in the idelalisib arm (P<0.001).

And at 12 months, the overall survival rate was 92% in the idelalisib arm and 80% in the placebo arm (P=0.02).

The difference in outcomes between the treatment groups prompted an independent data-monitoring committee to halt the study early, in October 2013, so that all participants could receive idelalisib.

Most adverse events (AEs), in either treatment group, were grade 2 or lower. The most common AEs in the idelalisib arm were pyrexia, fatigue, nausea, chills, and diarrhea. In the placebo arm, the most common AEs were infusion-related reactions, fatigue, cough, nausea, and dyspnea.

There were more serious AEs in the idelalisib arm than in the placebo arm—40% and 35%, respectively. The most frequent serious AEs were pneumonia, pyrexia, and febrile neutropenia (in both treatment arms).

Despite these events, the researchers considered idelalisib to be well-tolerated in this patient population.

“Having a treatment like idelalisib, which is highly effective and well-tolerated, and thus can generate responses in patients that are unable to tolerate treatment and unlikely to respond, indicates the potential for idelalisib in all patients,” Dr Furman said.

CLL cells

The PI3K delta inhibitor idelalisib could turn chronic lymphocytic leukemia (CLL) into a highly treatable disease, according to the lead investigator of a phase 3 trial.

Results of the trial showed that adding idelalisib to treatment with rituximab can improve response and survival rates in patients with relapsed CLL.

In fact, the study was stopped early because idelalisib had a significant impact on progression-free survival.

“This study, and others we have conducted on idelalisib, demonstrates that we may no longer need to use chemotherapy in CLL,” said lead investigator Richard R. Furman, MD, of Weill Cornell Medical College in New York.

“Even if this cancer remains incurable, it now can be treated as if it was a chronic disease—with a pill, in the same way that high blood pressure is treated.”

Dr Furman and his colleagues reported the results of this study in The New England Journal of Medicine.

The trial was funded by Gilead, the makers of idelalisib. Dr Furman has served as an advisor for this company.

The study included 220 CLL patients who could not receive chemotherapy. Nearly two-thirds of the patients had advanced-stage disease. The median time from CLL diagnosis was 9 years, and patients had received a median of 3 previous treatments.

Most of the patients were 65 or older (78%). Forty percent had at least moderate renal dysfunction, and 35% had poor bone marrow function.

Half of the patients were randomized to receive idelalisib plus rituximab and the other half to rituximab plus placebo.

“It is remarkable how quickly idelalisib worked in this heavily treated group of patients, many of whom were resistant to chemotherapy,” Dr Furman said. “We saw responses within a week.”

Patients in the idelalisib arm had a much higher overall response rate than patients in the placebo arm—81% and 13%, respectively (P<0.001). But all responses were partial responses.

At 24 weeks, the rate of progression-free survival was 93% in the idelalisib arm and 46% in the placebo arm (P<0.001). The median progression-free survival was 5.5 months in the placebo arm and not reached in the idelalisib arm (P<0.001).

And at 12 months, the overall survival rate was 92% in the idelalisib arm and 80% in the placebo arm (P=0.02).

The difference in outcomes between the treatment groups prompted an independent data-monitoring committee to halt the study early, in October 2013, so that all participants could receive idelalisib.

Most adverse events (AEs), in either treatment group, were grade 2 or lower. The most common AEs in the idelalisib arm were pyrexia, fatigue, nausea, chills, and diarrhea. In the placebo arm, the most common AEs were infusion-related reactions, fatigue, cough, nausea, and dyspnea.

There were more serious AEs in the idelalisib arm than in the placebo arm—40% and 35%, respectively. The most frequent serious AEs were pneumonia, pyrexia, and febrile neutropenia (in both treatment arms).

Despite these events, the researchers considered idelalisib to be well-tolerated in this patient population.

“Having a treatment like idelalisib, which is highly effective and well-tolerated, and thus can generate responses in patients that are unable to tolerate treatment and unlikely to respond, indicates the potential for idelalisib in all patients,” Dr Furman said.

CLL cells

The PI3K delta inhibitor idelalisib could turn chronic lymphocytic leukemia (CLL) into a highly treatable disease, according to the lead investigator of a phase 3 trial.

Results of the trial showed that adding idelalisib to treatment with rituximab can improve response and survival rates in patients with relapsed CLL.

In fact, the study was stopped early because idelalisib had a significant impact on progression-free survival.

“This study, and others we have conducted on idelalisib, demonstrates that we may no longer need to use chemotherapy in CLL,” said lead investigator Richard R. Furman, MD, of Weill Cornell Medical College in New York.

“Even if this cancer remains incurable, it now can be treated as if it was a chronic disease—with a pill, in the same way that high blood pressure is treated.”

Dr Furman and his colleagues reported the results of this study in The New England Journal of Medicine.

The trial was funded by Gilead, the makers of idelalisib. Dr Furman has served as an advisor for this company.

The study included 220 CLL patients who could not receive chemotherapy. Nearly two-thirds of the patients had advanced-stage disease. The median time from CLL diagnosis was 9 years, and patients had received a median of 3 previous treatments.

Most of the patients were 65 or older (78%). Forty percent had at least moderate renal dysfunction, and 35% had poor bone marrow function.

Half of the patients were randomized to receive idelalisib plus rituximab and the other half to rituximab plus placebo.

“It is remarkable how quickly idelalisib worked in this heavily treated group of patients, many of whom were resistant to chemotherapy,” Dr Furman said. “We saw responses within a week.”

Patients in the idelalisib arm had a much higher overall response rate than patients in the placebo arm—81% and 13%, respectively (P<0.001). But all responses were partial responses.

At 24 weeks, the rate of progression-free survival was 93% in the idelalisib arm and 46% in the placebo arm (P<0.001). The median progression-free survival was 5.5 months in the placebo arm and not reached in the idelalisib arm (P<0.001).

And at 12 months, the overall survival rate was 92% in the idelalisib arm and 80% in the placebo arm (P=0.02).

The difference in outcomes between the treatment groups prompted an independent data-monitoring committee to halt the study early, in October 2013, so that all participants could receive idelalisib.

Most adverse events (AEs), in either treatment group, were grade 2 or lower. The most common AEs in the idelalisib arm were pyrexia, fatigue, nausea, chills, and diarrhea. In the placebo arm, the most common AEs were infusion-related reactions, fatigue, cough, nausea, and dyspnea.

There were more serious AEs in the idelalisib arm than in the placebo arm—40% and 35%, respectively. The most frequent serious AEs were pneumonia, pyrexia, and febrile neutropenia (in both treatment arms).

Despite these events, the researchers considered idelalisib to be well-tolerated in this patient population.

“Having a treatment like idelalisib, which is highly effective and well-tolerated, and thus can generate responses in patients that are unable to tolerate treatment and unlikely to respond, indicates the potential for idelalisib in all patients,” Dr Furman said.

Preparing medication for a trial

Credit: Esther Dyson

New research suggests that drugs are often rejected by the US Food and Drug Administration (FDA), not because they are unsafe or ineffective, but because there is not enough evidence to determine the drugs’ safety and efficacy.

Investigators reviewed about 300 drug applications and discovered a number of reasons why drugs were denied approval on the first try.

The FDA cited issues with dosing, trial populations, study endpoints, and inconsistencies in data as reasons for denial.

Leonard V. Sacks, MBBCh, of the FDA in Silver Springs, Maryland, and his colleagues conducted this research and reported the results in JAMA.

The team reviewed marketing applications for all new molecular entities (NMEs; active ingredients never before marketed in the US) first submitted to the FDA between 2000 and 2012.

They used FDA correspondence and reviews to determine the scientific and regulatory reasons approvals were delayed or denied.

Of the 302 NME applications, 222 (73.5%) ultimately achieved marketing approval.

Half of all NMEs (151) were rejected on the first try, but 71 (47.0%) of these were approved following resubmission. The median time to approval was 435 days after the first action letter (range, 47-2374 days).

Drugs were denied approval for a number of reasons, including:

• Uncertainty about the optimal dose to maximize efficacy and minimize safety risks (15.9%)
• Inconsistent results for multiple predefined study endpoints (13.2%)
• Trial endpoints were unsatisfactory (13.2%)
• Inconsistencies in efficacy for portions of the study population (11.3%)
• The populations studied did not reflect the populations likely to use the drug (7.3%).

The investigators also found that the frequency of safety deficiencies was similar among never-approved drugs and drugs with delayed approval. However, efficacy deficiencies were significantly more frequent among the never-approved drugs than among those with delayed approvals.

There were 48 drugs with initial efficacy concerns, and only 31.3% of these were eventually approved, compared to 61.5% of the 39 drugs with safety concerns alone.

There were 20 drugs (13.2%) that, despite showing superiority to placebo, were considered to have inadequate efficacy compared with the standard of care.

The investigators said that, taken together, these findings suggest there is room for improvement in new drug applications. But if drug sponsors increase communication with the FDA, particularly with regard to study design, they could reduce delays in drug approval.

Preparing medication for a trial

Credit: Esther Dyson

New research suggests that drugs are often rejected by the US Food and Drug Administration (FDA), not because they are unsafe or ineffective, but because there is not enough evidence to determine the drugs’ safety and efficacy.

Investigators reviewed about 300 drug applications and discovered a number of reasons why drugs were denied approval on the first try.

The FDA cited issues with dosing, trial populations, study endpoints, and inconsistencies in data as reasons for denial.

Leonard V. Sacks, MBBCh, of the FDA in Silver Springs, Maryland, and his colleagues conducted this research and reported the results in JAMA.

The team reviewed marketing applications for all new molecular entities (NMEs; active ingredients never before marketed in the US) first submitted to the FDA between 2000 and 2012.

They used FDA correspondence and reviews to determine the scientific and regulatory reasons approvals were delayed or denied.

Of the 302 NME applications, 222 (73.5%) ultimately achieved marketing approval.

Half of all NMEs (151) were rejected on the first try, but 71 (47.0%) of these were approved following resubmission. The median time to approval was 435 days after the first action letter (range, 47-2374 days).

Drugs were denied approval for a number of reasons, including:

• Uncertainty about the optimal dose to maximize efficacy and minimize safety risks (15.9%)
• Inconsistent results for multiple predefined study endpoints (13.2%)
• Trial endpoints were unsatisfactory (13.2%)
• Inconsistencies in efficacy for portions of the study population (11.3%)
• The populations studied did not reflect the populations likely to use the drug (7.3%).

The investigators also found that the frequency of safety deficiencies was similar among never-approved drugs and drugs with delayed approval. However, efficacy deficiencies were significantly more frequent among the never-approved drugs than among those with delayed approvals.

There were 48 drugs with initial efficacy concerns, and only 31.3% of these were eventually approved, compared to 61.5% of the 39 drugs with safety concerns alone.

There were 20 drugs (13.2%) that, despite showing superiority to placebo, were considered to have inadequate efficacy compared with the standard of care.

The investigators said that, taken together, these findings suggest there is room for improvement in new drug applications. But if drug sponsors increase communication with the FDA, particularly with regard to study design, they could reduce delays in drug approval.

Preparing medication for a trial

Credit: Esther Dyson

New research suggests that drugs are often rejected by the US Food and Drug Administration (FDA), not because they are unsafe or ineffective, but because there is not enough evidence to determine the drugs’ safety and efficacy.

Investigators reviewed about 300 drug applications and discovered a number of reasons why drugs were denied approval on the first try.

The FDA cited issues with dosing, trial populations, study endpoints, and inconsistencies in data as reasons for denial.

Leonard V. Sacks, MBBCh, of the FDA in Silver Springs, Maryland, and his colleagues conducted this research and reported the results in JAMA.

The team reviewed marketing applications for all new molecular entities (NMEs; active ingredients never before marketed in the US) first submitted to the FDA between 2000 and 2012.

They used FDA correspondence and reviews to determine the scientific and regulatory reasons approvals were delayed or denied.

Of the 302 NME applications, 222 (73.5%) ultimately achieved marketing approval.

Half of all NMEs (151) were rejected on the first try, but 71 (47.0%) of these were approved following resubmission. The median time to approval was 435 days after the first action letter (range, 47-2374 days).

Drugs were denied approval for a number of reasons, including:

• Uncertainty about the optimal dose to maximize efficacy and minimize safety risks (15.9%)
• Inconsistent results for multiple predefined study endpoints (13.2%)
• Trial endpoints were unsatisfactory (13.2%)
• Inconsistencies in efficacy for portions of the study population (11.3%)
• The populations studied did not reflect the populations likely to use the drug (7.3%).

The investigators also found that the frequency of safety deficiencies was similar among never-approved drugs and drugs with delayed approval. However, efficacy deficiencies were significantly more frequent among the never-approved drugs than among those with delayed approvals.

There were 48 drugs with initial efficacy concerns, and only 31.3% of these were eventually approved, compared to 61.5% of the 39 drugs with safety concerns alone.

There were 20 drugs (13.2%) that, despite showing superiority to placebo, were considered to have inadequate efficacy compared with the standard of care.

The investigators said that, taken together, these findings suggest there is room for improvement in new drug applications. But if drug sponsors increase communication with the FDA, particularly with regard to study design, they could reduce delays in drug approval.

Hospitalists needn't worry much about federal data released this month that shows healthcare employment figures dropping for the first time in a decade. A recent report from the Bureau of Labor Statistics reflects the loss of 6,000 jobs in healthcare last December, and employment gains falling to 17,000 per month on average in 2013 compared with 27,000 per month in 2012.

"The overall decline in healthcare spending and employment will have a small effect on hospitalist growth," says Anupam Jena, MD, PhD, assistant professor of healthcare policy and medicine at Harvard Medical School, and an internist at Massachusetts General Hospital, both in Boston. "It certainly is true that the demand for hospital care has decreased over the last two decades and will continue to decrease as hospitals and providers become more incentivized to keep patients out of the hospital. But this effect is offset by the fact that hospitalists continue to account for larger and larger shares of all inpatient care in the U.S."

Dr. Jena says the fact that healthcare companies lost 6,000 positions last December—the first monthly loss since July 2003, according to CNN—isn't surprising, as it comes on the heels of a report from the Centers for Medicare and Medicaid Services that the rate of increases in healthcare spending has slowed over the past four years as well.

Dr. Jena says that, while healthcare reform under the Affordable Care Act may "trim the fat" by reducing the amount of lower-value health services and the number of providers that perform them, HM is still a budding field. As long as the specialty continues to demonstrate value via cost savings and reduced length of stay, that scenario isn’t likely to change, he adds.

"Although healthcare reforms will probably reduce hospitalizations, I expect the demand for hospitalists to continue to grow," Dr. Jena says. "There are still 30% of hospitalizations in the U.S. that are not covered by hospitalists, which means there is room to grow."

Visit our website for more information on healthcare economics.

Hospitalists needn't worry much about federal data released this month that shows healthcare employment figures dropping for the first time in a decade. A recent report from the Bureau of Labor Statistics reflects the loss of 6,000 jobs in healthcare last December, and employment gains falling to 17,000 per month on average in 2013 compared with 27,000 per month in 2012.

"The overall decline in healthcare spending and employment will have a small effect on hospitalist growth," says Anupam Jena, MD, PhD, assistant professor of healthcare policy and medicine at Harvard Medical School, and an internist at Massachusetts General Hospital, both in Boston. "It certainly is true that the demand for hospital care has decreased over the last two decades and will continue to decrease as hospitals and providers become more incentivized to keep patients out of the hospital. But this effect is offset by the fact that hospitalists continue to account for larger and larger shares of all inpatient care in the U.S."

Dr. Jena says the fact that healthcare companies lost 6,000 positions last December—the first monthly loss since July 2003, according to CNN—isn't surprising, as it comes on the heels of a report from the Centers for Medicare and Medicaid Services that the rate of increases in healthcare spending has slowed over the past four years as well.

Dr. Jena says that, while healthcare reform under the Affordable Care Act may "trim the fat" by reducing the amount of lower-value health services and the number of providers that perform them, HM is still a budding field. As long as the specialty continues to demonstrate value via cost savings and reduced length of stay, that scenario isn’t likely to change, he adds.

"Although healthcare reforms will probably reduce hospitalizations, I expect the demand for hospitalists to continue to grow," Dr. Jena says. "There are still 30% of hospitalizations in the U.S. that are not covered by hospitalists, which means there is room to grow."

Visit our website for more information on healthcare economics.

Hospitalists needn't worry much about federal data released this month that shows healthcare employment figures dropping for the first time in a decade. A recent report from the Bureau of Labor Statistics reflects the loss of 6,000 jobs in healthcare last December, and employment gains falling to 17,000 per month on average in 2013 compared with 27,000 per month in 2012.

"The overall decline in healthcare spending and employment will have a small effect on hospitalist growth," says Anupam Jena, MD, PhD, assistant professor of healthcare policy and medicine at Harvard Medical School, and an internist at Massachusetts General Hospital, both in Boston. "It certainly is true that the demand for hospital care has decreased over the last two decades and will continue to decrease as hospitals and providers become more incentivized to keep patients out of the hospital. But this effect is offset by the fact that hospitalists continue to account for larger and larger shares of all inpatient care in the U.S."

Dr. Jena says the fact that healthcare companies lost 6,000 positions last December—the first monthly loss since July 2003, according to CNN—isn't surprising, as it comes on the heels of a report from the Centers for Medicare and Medicaid Services that the rate of increases in healthcare spending has slowed over the past four years as well.

Dr. Jena says that, while healthcare reform under the Affordable Care Act may "trim the fat" by reducing the amount of lower-value health services and the number of providers that perform them, HM is still a budding field. As long as the specialty continues to demonstrate value via cost savings and reduced length of stay, that scenario isn’t likely to change, he adds.

"Although healthcare reforms will probably reduce hospitalizations, I expect the demand for hospitalists to continue to grow," Dr. Jena says. "There are still 30% of hospitalizations in the U.S. that are not covered by hospitalists, which means there is room to grow."

Visit our website for more information on healthcare economics.

Clinical question: In patients with peptic ulcer bleeding, are oral PPIs of equal benefit to intravenous PPIs?

Background: PPI therapy has been shown in several studies to reduce re-bleeding risk in patients when used adjunctively for peptic ulcer bleeding. In spite of this data, there is still uncertainty about the optimal dose and route of administration.

Study design: Meta-analysis of prospective, randomized control trials.

Setting: OVID database search in June 2012.

Synopsis: A literature search identified six prospective randomized control trials. Overall, 615 patients were included across the six trials. No significant difference in risk of re-bleeding was discovered between the two groups (8.6% oral vs. 9.3% IV, RR: 0.92, 95% CI: 0.56–1.5). Length of hospital stay was statistically significantly lower for oral PPIs (-0.74 day, 95% CI: -1.10 to -0.39 day).

Because these findings are based on a meta-analysis of studies with notable flaws—including lack of blinding—it is difficult to draw any definitive conclusions from this data. Hospitalists should use care before changing their practice patterns, given the risk of bias and need for further study.

Bottom line: Oral PPIs may reduce hospital length of stay without an increased risk of re-bleeding; however, further study with a well-powered, double-blind, randomized control trial is necessary.

Citation: Tsoi KK, Hirai HW, Sung JJ. Meta-analysis: Comparison of oral vs. intravenous proton pump inhibitors in patients with peptic ulcer bleeding. Aliment Pharmacol Ther. 2013;38(7):721-728.

Visit our website for more information on the use of proton pump inhibitors.

Clinical question: In patients with peptic ulcer bleeding, are oral PPIs of equal benefit to intravenous PPIs?

Background: PPI therapy has been shown in several studies to reduce re-bleeding risk in patients when used adjunctively for peptic ulcer bleeding. In spite of this data, there is still uncertainty about the optimal dose and route of administration.

Study design: Meta-analysis of prospective, randomized control trials.

Setting: OVID database search in June 2012.

Synopsis: A literature search identified six prospective randomized control trials. Overall, 615 patients were included across the six trials. No significant difference in risk of re-bleeding was discovered between the two groups (8.6% oral vs. 9.3% IV, RR: 0.92, 95% CI: 0.56–1.5). Length of hospital stay was statistically significantly lower for oral PPIs (-0.74 day, 95% CI: -1.10 to -0.39 day).

Because these findings are based on a meta-analysis of studies with notable flaws—including lack of blinding—it is difficult to draw any definitive conclusions from this data. Hospitalists should use care before changing their practice patterns, given the risk of bias and need for further study.

Bottom line: Oral PPIs may reduce hospital length of stay without an increased risk of re-bleeding; however, further study with a well-powered, double-blind, randomized control trial is necessary.

Citation: Tsoi KK, Hirai HW, Sung JJ. Meta-analysis: Comparison of oral vs. intravenous proton pump inhibitors in patients with peptic ulcer bleeding. Aliment Pharmacol Ther. 2013;38(7):721-728.

Visit our website for more information on the use of proton pump inhibitors.

Clinical question: In patients with peptic ulcer bleeding, are oral PPIs of equal benefit to intravenous PPIs?

Background: PPI therapy has been shown in several studies to reduce re-bleeding risk in patients when used adjunctively for peptic ulcer bleeding. In spite of this data, there is still uncertainty about the optimal dose and route of administration.

Study design: Meta-analysis of prospective, randomized control trials.

Setting: OVID database search in June 2012.

Synopsis: A literature search identified six prospective randomized control trials. Overall, 615 patients were included across the six trials. No significant difference in risk of re-bleeding was discovered between the two groups (8.6% oral vs. 9.3% IV, RR: 0.92, 95% CI: 0.56–1.5). Length of hospital stay was statistically significantly lower for oral PPIs (-0.74 day, 95% CI: -1.10 to -0.39 day).

Because these findings are based on a meta-analysis of studies with notable flaws—including lack of blinding—it is difficult to draw any definitive conclusions from this data. Hospitalists should use care before changing their practice patterns, given the risk of bias and need for further study.

Bottom line: Oral PPIs may reduce hospital length of stay without an increased risk of re-bleeding; however, further study with a well-powered, double-blind, randomized control trial is necessary.

Citation: Tsoi KK, Hirai HW, Sung JJ. Meta-analysis: Comparison of oral vs. intravenous proton pump inhibitors in patients with peptic ulcer bleeding. Aliment Pharmacol Ther. 2013;38(7):721-728.

Visit our website for more information on the use of proton pump inhibitors.

Tell me a story. Is there anyone who hasn’t uttered those four words? As humans we are hard wired to both tell and listen to stories. Indeed, professional storyteller Bill Harley, in a 2012 TEDx talk entitled, "Stories Out Loud," said that storytelling is "at the very center of what it means to be human."

This is why storytelling is a powerful marketing tool for you and your practice. In a noisy social media world, stories allow your voice to be heard.

Here are some reasons why you should be using storytelling to market your practice:

• A story is experiential – it shares an experience or observation.

• Stories help us make sense of our lives.

• They help you connect with your patients, build trust, and market your brand.

• They can capture your patients’ attention.

• They can inspire and appeal to emotions.

• Stories are easier to remember than facts and statistics.

• They feel authentic and help show the real you and real patients.

• Stories can be educational by putting difficult concepts into meaningful context.

• They can be an effective call to action for patients.

How powerful is storytelling? Do an Internet search of "patient stories," and the results will feature some of the country’s top hospitals such as the Mayo Clinic, Memorial Sloan-Kettering Cancer Center, and St. Jude's Children's Research Hospital. Take some time visiting these sites. Watch a few videos and ask yourself what makes them effective.

When it comes to marketing your practice, you can tell stories in person to patients, on video, in blog posts, or even in images on sites like Pinterest. Although videos can be done by a professional videographer using ambient lighting and music, they don’t have to be. You might decide to videotape a procedure with your video camera or upload patient stories using your iPhone.

Before using a story, remember to respect patients’ privacy and to get their consent appropriately if they are identifiable in a story. Make sure your story is short, relevant, and compelling and leaves the consumer with a better understanding of the issue.

Do you use stories in your practice? Do you have tips for physicians on how to use stories effectively in their practice? Please share them.

Dr. Benabio is a practicing dermatologist and physician director of health care transformation at Kaiser Permanente in San Diego. Connect with him on Twitter @Dermdoc or drop him a line at [email protected].

Tell me a story. Is there anyone who hasn’t uttered those four words? As humans we are hard wired to both tell and listen to stories. Indeed, professional storyteller Bill Harley, in a 2012 TEDx talk entitled, "Stories Out Loud," said that storytelling is "at the very center of what it means to be human."

This is why storytelling is a powerful marketing tool for you and your practice. In a noisy social media world, stories allow your voice to be heard.

Here are some reasons why you should be using storytelling to market your practice:

• A story is experiential – it shares an experience or observation.

• Stories help us make sense of our lives.

• They help you connect with your patients, build trust, and market your brand.

• They can capture your patients’ attention.

• They can inspire and appeal to emotions.

• Stories are easier to remember than facts and statistics.

• They feel authentic and help show the real you and real patients.

• Stories can be educational by putting difficult concepts into meaningful context.

• They can be an effective call to action for patients.

How powerful is storytelling? Do an Internet search of "patient stories," and the results will feature some of the country’s top hospitals such as the Mayo Clinic, Memorial Sloan-Kettering Cancer Center, and St. Jude's Children's Research Hospital. Take some time visiting these sites. Watch a few videos and ask yourself what makes them effective.

When it comes to marketing your practice, you can tell stories in person to patients, on video, in blog posts, or even in images on sites like Pinterest. Although videos can be done by a professional videographer using ambient lighting and music, they don’t have to be. You might decide to videotape a procedure with your video camera or upload patient stories using your iPhone.

Before using a story, remember to respect patients’ privacy and to get their consent appropriately if they are identifiable in a story. Make sure your story is short, relevant, and compelling and leaves the consumer with a better understanding of the issue.

Do you use stories in your practice? Do you have tips for physicians on how to use stories effectively in their practice? Please share them.

Dr. Benabio is a practicing dermatologist and physician director of health care transformation at Kaiser Permanente in San Diego. Connect with him on Twitter @Dermdoc or drop him a line at [email protected].

Tell me a story. Is there anyone who hasn’t uttered those four words? As humans we are hard wired to both tell and listen to stories. Indeed, professional storyteller Bill Harley, in a 2012 TEDx talk entitled, "Stories Out Loud," said that storytelling is "at the very center of what it means to be human."

This is why storytelling is a powerful marketing tool for you and your practice. In a noisy social media world, stories allow your voice to be heard.

Here are some reasons why you should be using storytelling to market your practice:

• A story is experiential – it shares an experience or observation.

• Stories help us make sense of our lives.

• They help you connect with your patients, build trust, and market your brand.

• They can capture your patients’ attention.

• They can inspire and appeal to emotions.

• Stories are easier to remember than facts and statistics.

• They feel authentic and help show the real you and real patients.

• Stories can be educational by putting difficult concepts into meaningful context.

• They can be an effective call to action for patients.

How powerful is storytelling? Do an Internet search of "patient stories," and the results will feature some of the country’s top hospitals such as the Mayo Clinic, Memorial Sloan-Kettering Cancer Center, and St. Jude's Children's Research Hospital. Take some time visiting these sites. Watch a few videos and ask yourself what makes them effective.

When it comes to marketing your practice, you can tell stories in person to patients, on video, in blog posts, or even in images on sites like Pinterest. Although videos can be done by a professional videographer using ambient lighting and music, they don’t have to be. You might decide to videotape a procedure with your video camera or upload patient stories using your iPhone.

Before using a story, remember to respect patients’ privacy and to get their consent appropriately if they are identifiable in a story. Make sure your story is short, relevant, and compelling and leaves the consumer with a better understanding of the issue.

Do you use stories in your practice? Do you have tips for physicians on how to use stories effectively in their practice? Please share them.

Dr. Benabio is a practicing dermatologist and physician director of health care transformation at Kaiser Permanente in San Diego. Connect with him on Twitter @Dermdoc or drop him a line at [email protected].

CHAMPIONSGATE, FLA. – Injections of botulinum neurotoxin type A on the nose, cheeks, and chin can significantly improve the appearance of some rosacea patients, in part by reducing overactivity of the sebaceous gland, according to Dr. Erin Gilbert of SUNY Downstate Medical Center, New York.

"I have had remarkably consistent results" using neuromodulators to treat patients with papulopustular and erythematotelangiectatic rosacea, Dr. Gilbert said in a presentation at the Orlando Dermatology Aesthetic and Clinical Conference.

Current therapies for rosacea include topical antibiotics, azelaic acid, metronidazole, sodium sulfacetamide, and the recently approved brimonidine, Dr. Gilbert said. Subantimicrobially dosed doxycycline remains the first and only oral therapy currently approved by the Food and Drug Administration, she noted.

Botulinum toxin represents a cutting-edge treatment option for rosacea that capitalizes on the skin’s biochemistry: Specific neuropeptide genes are up- or downregulated in rosacea patients, explained Dr. Gilbert, who also holds a Ph.D. in neural and behavioral sciences.

In addition, the expression of non-neuronal transient receptor potential (TRPV2, 3, and 4) ion channels is differentially upregulated in phymatous, erythematotelangiectatic, and papulopustular rosacea subtypes, she said.

When botulinum toxin type A is injected in the nose, cheeks, and chin of rosacea patients, the sebaceous gland activity and vasodilatory responses decrease. This translates to clinical findings, including reduced flushing and oil production, decreased inflammatory lesion counts, and reduced pore size, said Dr. Gilbert.

"The question is, what’s the mechanism?" she said. The answer: "Rosacea is likely improving when nerves stop talking to blood vessels and to the immune system."

For what it is worth, histology on patients with papulopustular and erythematotelangiectatic rosacea shows significant fibrosis, she noted.

Additional research is needed, but Dr. Steven H. Dayan of the University of Illinois, Chicago, and his colleagues published data on a short series of 13 patients in the Journal of Drugs in Dermatology. Their data showed substantial reduction of flushing, redness, and inflammation within a week of treatment, with effects lasting up to 3 months. No adverse events were reported (J. Drugs Dermatol. 2012;11:e76-e79).

To treat rosacea patients with botulinum toxin type A, "you have to map out the treatment area," Dr. Gilbert said. She uses 0.5-2 units in intradermal blebs spaced 1 cm apart.

She has observed improvements at 7-14 days after a single treatment, with a maximum effect evident in 2-8 weeks, but with effects persisting for an average of 4-6 months and sometimes as long as 7 months.

Her additional treatment pearls include reconstituting each of the three FDA-approved neurotoxins with 1 cc of saline, and using small syringes. She generally injects 7-10 units per cheek. "Don’t forget to treat the nose," she said.

Botulinum toxin type A (onabotulinumtoxinA) is not approved by the FDA to treat rosacea, but a randomized, double-blind, placebo-controlled pilot study comparing incobotulinumtoxinA to placebo for the treatment of rosacea is underway, conducted by Dr. Dayan and sponsored by Merz Pharmaceuticals.

Dr. Gilbert has served as a consultant for Merz Aesthetics, Allergan, and Medicis Aesthetics, and as a consultant and speaker for Johnson & Johnston and Glytone.

[email protected]

On Twitter @hsplete

CHAMPIONSGATE, FLA. – Injections of botulinum neurotoxin type A on the nose, cheeks, and chin can significantly improve the appearance of some rosacea patients, in part by reducing overactivity of the sebaceous gland, according to Dr. Erin Gilbert of SUNY Downstate Medical Center, New York.

"I have had remarkably consistent results" using neuromodulators to treat patients with papulopustular and erythematotelangiectatic rosacea, Dr. Gilbert said in a presentation at the Orlando Dermatology Aesthetic and Clinical Conference.

Current therapies for rosacea include topical antibiotics, azelaic acid, metronidazole, sodium sulfacetamide, and the recently approved brimonidine, Dr. Gilbert said. Subantimicrobially dosed doxycycline remains the first and only oral therapy currently approved by the Food and Drug Administration, she noted.

Botulinum toxin represents a cutting-edge treatment option for rosacea that capitalizes on the skin’s biochemistry: Specific neuropeptide genes are up- or downregulated in rosacea patients, explained Dr. Gilbert, who also holds a Ph.D. in neural and behavioral sciences.

In addition, the expression of non-neuronal transient receptor potential (TRPV2, 3, and 4) ion channels is differentially upregulated in phymatous, erythematotelangiectatic, and papulopustular rosacea subtypes, she said.

When botulinum toxin type A is injected in the nose, cheeks, and chin of rosacea patients, the sebaceous gland activity and vasodilatory responses decrease. This translates to clinical findings, including reduced flushing and oil production, decreased inflammatory lesion counts, and reduced pore size, said Dr. Gilbert.

"The question is, what’s the mechanism?" she said. The answer: "Rosacea is likely improving when nerves stop talking to blood vessels and to the immune system."

For what it is worth, histology on patients with papulopustular and erythematotelangiectatic rosacea shows significant fibrosis, she noted.

Additional research is needed, but Dr. Steven H. Dayan of the University of Illinois, Chicago, and his colleagues published data on a short series of 13 patients in the Journal of Drugs in Dermatology. Their data showed substantial reduction of flushing, redness, and inflammation within a week of treatment, with effects lasting up to 3 months. No adverse events were reported (J. Drugs Dermatol. 2012;11:e76-e79).

To treat rosacea patients with botulinum toxin type A, "you have to map out the treatment area," Dr. Gilbert said. She uses 0.5-2 units in intradermal blebs spaced 1 cm apart.

She has observed improvements at 7-14 days after a single treatment, with a maximum effect evident in 2-8 weeks, but with effects persisting for an average of 4-6 months and sometimes as long as 7 months.

Her additional treatment pearls include reconstituting each of the three FDA-approved neurotoxins with 1 cc of saline, and using small syringes. She generally injects 7-10 units per cheek. "Don’t forget to treat the nose," she said.

Botulinum toxin type A (onabotulinumtoxinA) is not approved by the FDA to treat rosacea, but a randomized, double-blind, placebo-controlled pilot study comparing incobotulinumtoxinA to placebo for the treatment of rosacea is underway, conducted by Dr. Dayan and sponsored by Merz Pharmaceuticals.

Dr. Gilbert has served as a consultant for Merz Aesthetics, Allergan, and Medicis Aesthetics, and as a consultant and speaker for Johnson & Johnston and Glytone.

[email protected]

On Twitter @hsplete

CHAMPIONSGATE, FLA. – Injections of botulinum neurotoxin type A on the nose, cheeks, and chin can significantly improve the appearance of some rosacea patients, in part by reducing overactivity of the sebaceous gland, according to Dr. Erin Gilbert of SUNY Downstate Medical Center, New York.

"I have had remarkably consistent results" using neuromodulators to treat patients with papulopustular and erythematotelangiectatic rosacea, Dr. Gilbert said in a presentation at the Orlando Dermatology Aesthetic and Clinical Conference.

Current therapies for rosacea include topical antibiotics, azelaic acid, metronidazole, sodium sulfacetamide, and the recently approved brimonidine, Dr. Gilbert said. Subantimicrobially dosed doxycycline remains the first and only oral therapy currently approved by the Food and Drug Administration, she noted.

Botulinum toxin represents a cutting-edge treatment option for rosacea that capitalizes on the skin’s biochemistry: Specific neuropeptide genes are up- or downregulated in rosacea patients, explained Dr. Gilbert, who also holds a Ph.D. in neural and behavioral sciences.

In addition, the expression of non-neuronal transient receptor potential (TRPV2, 3, and 4) ion channels is differentially upregulated in phymatous, erythematotelangiectatic, and papulopustular rosacea subtypes, she said.

When botulinum toxin type A is injected in the nose, cheeks, and chin of rosacea patients, the sebaceous gland activity and vasodilatory responses decrease. This translates to clinical findings, including reduced flushing and oil production, decreased inflammatory lesion counts, and reduced pore size, said Dr. Gilbert.

"The question is, what’s the mechanism?" she said. The answer: "Rosacea is likely improving when nerves stop talking to blood vessels and to the immune system."

For what it is worth, histology on patients with papulopustular and erythematotelangiectatic rosacea shows significant fibrosis, she noted.

Additional research is needed, but Dr. Steven H. Dayan of the University of Illinois, Chicago, and his colleagues published data on a short series of 13 patients in the Journal of Drugs in Dermatology. Their data showed substantial reduction of flushing, redness, and inflammation within a week of treatment, with effects lasting up to 3 months. No adverse events were reported (J. Drugs Dermatol. 2012;11:e76-e79).

To treat rosacea patients with botulinum toxin type A, "you have to map out the treatment area," Dr. Gilbert said. She uses 0.5-2 units in intradermal blebs spaced 1 cm apart.

She has observed improvements at 7-14 days after a single treatment, with a maximum effect evident in 2-8 weeks, but with effects persisting for an average of 4-6 months and sometimes as long as 7 months.

Her additional treatment pearls include reconstituting each of the three FDA-approved neurotoxins with 1 cc of saline, and using small syringes. She generally injects 7-10 units per cheek. "Don’t forget to treat the nose," she said.

Botulinum toxin type A (onabotulinumtoxinA) is not approved by the FDA to treat rosacea, but a randomized, double-blind, placebo-controlled pilot study comparing incobotulinumtoxinA to placebo for the treatment of rosacea is underway, conducted by Dr. Dayan and sponsored by Merz Pharmaceuticals.

Dr. Gilbert has served as a consultant for Merz Aesthetics, Allergan, and Medicis Aesthetics, and as a consultant and speaker for Johnson & Johnston and Glytone.

[email protected]

On Twitter @hsplete

Bag of saline solution

The US Food and Drug Administration (FDA) has acknowledged the current shortage of intravenous (IV) solutions, particularly 0.9% sodium chloride injection (ie, saline), which is used as a priming solution and to provide patients with the necessary fluids for hydration.

The agency said the shortage has been triggered by a range of factors. A few manufacturers have cited increased demand as the cause, and the FDA said this could be a result of flu season.

The agency is now working with 3 manufacturers of IV solutions, Baxter Healthcare Corp., B. Braun Medical Inc., and Hospira Inc., to help preserve the supply of these products.

However, the FDA noted that addressing the shortage will depend on the demand of these products and supplier production. Millions of these IV solutions are used each week by healthcare professionals.

Visit the FDA’s drug shortage webpage for updates.

Bag of saline solution

The US Food and Drug Administration (FDA) has acknowledged the current shortage of intravenous (IV) solutions, particularly 0.9% sodium chloride injection (ie, saline), which is used as a priming solution and to provide patients with the necessary fluids for hydration.

The agency said the shortage has been triggered by a range of factors. A few manufacturers have cited increased demand as the cause, and the FDA said this could be a result of flu season.

The agency is now working with 3 manufacturers of IV solutions, Baxter Healthcare Corp., B. Braun Medical Inc., and Hospira Inc., to help preserve the supply of these products.

However, the FDA noted that addressing the shortage will depend on the demand of these products and supplier production. Millions of these IV solutions are used each week by healthcare professionals.

Visit the FDA’s drug shortage webpage for updates.

Bag of saline solution

The US Food and Drug Administration (FDA) has acknowledged the current shortage of intravenous (IV) solutions, particularly 0.9% sodium chloride injection (ie, saline), which is used as a priming solution and to provide patients with the necessary fluids for hydration.

The agency said the shortage has been triggered by a range of factors. A few manufacturers have cited increased demand as the cause, and the FDA said this could be a result of flu season.

The agency is now working with 3 manufacturers of IV solutions, Baxter Healthcare Corp., B. Braun Medical Inc., and Hospira Inc., to help preserve the supply of these products.

However, the FDA noted that addressing the shortage will depend on the demand of these products and supplier production. Millions of these IV solutions are used each week by healthcare professionals.

Visit the FDA’s drug shortage webpage for updates.

Monoclonal antibodies

Credit: Linda Bartlett

The Japanese Ministry of Health, Labour and Welfare has approved brentuximab vedotin (Adcetris) for the treatment of patients with relapsed or refractory, CD30+ Hodgkin lymphoma (HL) or anaplastic large-cell lymphoma (ALCL).

The approval was based on a phase 1/2 trial in Japanese patients with relapsed or refractory, CD30+ HL or systemic ALCL, as well as data from two phase 2 trials—one of 102 HL patients and one of 58 patients with ALCL.

Brentuximab vedotin is an antibody-drug conjugate consisting of an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E.

The conjugate employs a linker system designed to be stable in the bloodstream but release monomethyl auristatin E upon internalization into CD30-expressing tumor cells.

Brentuximab vedotin was approved by the US Food and Drug Administration (FDA) in August 2011 and gained conditional approval from Health Canada in February 2013 for the following indications:

• To treat HL patients who had failed autologous stem cell transplant (auto-SCT) or were not eligible for auto-SCT and had failed at least 2 prior multi-agent chemotherapy regimens
• To treat patients with systemic ALCL after they failed at least 1 multi-agent chemotherapy regimen.

The drug received conditional marketing authorization by the European Commission in October 2012 to treat:

• Adult patients with relapsed or refractory, systemic ALCL
• Adults with relapsed or refractory, CD30-positive HL who had undergone auto-SCT or received 2 prior therapies when auto-SCT or multi-agent chemotherapy were not appropriate.

The FDA has granted brentuximab vedotin orphan designation to treat mycosis fungoides. And trials have suggested the drug is active in diffuse large B-cell lymphoma, as well as leukemias and multiple myeloma.

However, brentuximab vedotin also made the FDA watch list due to adverse events associated with the drug’s use. The FDA added a boxed warning to the drug’s label in January 2012, after 3 cases of progressive multifocal leukoencephalopathy were reported in patients receiving brentuximab vedotin.

Monoclonal antibodies

Credit: Linda Bartlett

The Japanese Ministry of Health, Labour and Welfare has approved brentuximab vedotin (Adcetris) for the treatment of patients with relapsed or refractory, CD30+ Hodgkin lymphoma (HL) or anaplastic large-cell lymphoma (ALCL).

The approval was based on a phase 1/2 trial in Japanese patients with relapsed or refractory, CD30+ HL or systemic ALCL, as well as data from two phase 2 trials—one of 102 HL patients and one of 58 patients with ALCL.

Brentuximab vedotin is an antibody-drug conjugate consisting of an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E.

The conjugate employs a linker system designed to be stable in the bloodstream but release monomethyl auristatin E upon internalization into CD30-expressing tumor cells.

Brentuximab vedotin was approved by the US Food and Drug Administration (FDA) in August 2011 and gained conditional approval from Health Canada in February 2013 for the following indications:

• To treat HL patients who had failed autologous stem cell transplant (auto-SCT) or were not eligible for auto-SCT and had failed at least 2 prior multi-agent chemotherapy regimens
• To treat patients with systemic ALCL after they failed at least 1 multi-agent chemotherapy regimen.

The drug received conditional marketing authorization by the European Commission in October 2012 to treat:

• Adult patients with relapsed or refractory, systemic ALCL
• Adults with relapsed or refractory, CD30-positive HL who had undergone auto-SCT or received 2 prior therapies when auto-SCT or multi-agent chemotherapy were not appropriate.

The FDA has granted brentuximab vedotin orphan designation to treat mycosis fungoides. And trials have suggested the drug is active in diffuse large B-cell lymphoma, as well as leukemias and multiple myeloma.

However, brentuximab vedotin also made the FDA watch list due to adverse events associated with the drug’s use. The FDA added a boxed warning to the drug’s label in January 2012, after 3 cases of progressive multifocal leukoencephalopathy were reported in patients receiving brentuximab vedotin.

Monoclonal antibodies

Credit: Linda Bartlett

The Japanese Ministry of Health, Labour and Welfare has approved brentuximab vedotin (Adcetris) for the treatment of patients with relapsed or refractory, CD30+ Hodgkin lymphoma (HL) or anaplastic large-cell lymphoma (ALCL).

The approval was based on a phase 1/2 trial in Japanese patients with relapsed or refractory, CD30+ HL or systemic ALCL, as well as data from two phase 2 trials—one of 102 HL patients and one of 58 patients with ALCL.

Brentuximab vedotin is an antibody-drug conjugate consisting of an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E.

The conjugate employs a linker system designed to be stable in the bloodstream but release monomethyl auristatin E upon internalization into CD30-expressing tumor cells.

Brentuximab vedotin was approved by the US Food and Drug Administration (FDA) in August 2011 and gained conditional approval from Health Canada in February 2013 for the following indications:

• To treat HL patients who had failed autologous stem cell transplant (auto-SCT) or were not eligible for auto-SCT and had failed at least 2 prior multi-agent chemotherapy regimens
• To treat patients with systemic ALCL after they failed at least 1 multi-agent chemotherapy regimen.

The drug received conditional marketing authorization by the European Commission in October 2012 to treat:

• Adult patients with relapsed or refractory, systemic ALCL
• Adults with relapsed or refractory, CD30-positive HL who had undergone auto-SCT or received 2 prior therapies when auto-SCT or multi-agent chemotherapy were not appropriate.

The FDA has granted brentuximab vedotin orphan designation to treat mycosis fungoides. And trials have suggested the drug is active in diffuse large B-cell lymphoma, as well as leukemias and multiple myeloma.

However, brentuximab vedotin also made the FDA watch list due to adverse events associated with the drug’s use. The FDA added a boxed warning to the drug’s label in January 2012, after 3 cases of progressive multifocal leukoencephalopathy were reported in patients receiving brentuximab vedotin.

Drug production

Credit: FDA

A new study suggests the US Food and Drug Administration (FDA) does not hold drug trials to the same set of standards.

The research revealed substantial differences in trials used to support drugs approved between 2005 and 2012.

Some drugs were approved based on results from multiple studies, while other approvals were based on data from a single trial.

Furthermore, trials varied greatly with regard to size, length of study period, type of comparator, and metrics of efficacy.

These results appear in the current issue of JAMA.

“Based on our analysis, some drugs are approved on the basis of large, high-quality clinical trials, while others are approved based on results of smaller trials,” said senior study author Joseph Ross, MD, of the Yale School of Medicine in New Haven, Connecticut.

“There was a lack of uniformity in the level of evidence the FDA used. We also found that only 40% of drug approvals involved a clinical trial that compared a new drug to existing treatment offerings. This is an important step for determining whether the new drug is a better option than existing, older drugs.”

Dr Ross and his colleagues evaluated the strength of clinical trial evidence supporting FDA approval decisions by characterizing key features of efficacy trials, such as size, duration, and endpoints.

The researchers used publicly available FDA documents to identify 188 drugs approved between 2005 and 2012 for 206 indications on the basis of 448 pivotal efficacy trials.

The team identified trials for 201 of the indications. Four drugs (including 1 used for 2 different indications) were approved without a pivotal efficacy trial.

So among the 201 indications, the median number of trials reviewed per indication was 2 (interquartile range [IQR], 1-2.5). Seventy-four indications (36.8%) were approved on the basis of a single trial, 77 (38.3%) on data from 2 trials, and 50 (24.9%) on data from 3 or more trials.

Most trials were randomized (89.3%) and double-blinded (79.5%). The median duration of a trial was 14.0 weeks (IQR, 6.0-26.0 weeks), and 113 trials (25.2%) lasted 6 months or longer.

The median number of total subjects enrolled in a trial was 446 (IQR, 205-678), and the median number of patients in the intervention arm of a study was 271 (IQR, 133-426).

More than half of trials (55.1%) used a placebo for comparison, 31.9% used an active comparator (such as another drug), and 12.9% had no comparator.

The primary endpoint was a surrogate outcome in 48.9% of trials, a clinical outcome for 29%, and a clinical scale for 22.1%.

These results suggest the quality of clinical trial evidence the FDA uses to make approval decisions varies widely across indications, the researchers said.

Study author Nicholas S. Downing, a student at the Yale School of Medicine, noted that survey data suggest patients expect drugs approved by the FDA to be both safe and effective.

“Based on our study of the data, we can’t be certain that this expectation is necessarily justified,” he said, “given the quantity and quality of the variability we saw in the drug approval process.”

Drug production

Credit: FDA

A new study suggests the US Food and Drug Administration (FDA) does not hold drug trials to the same set of standards.

The research revealed substantial differences in trials used to support drugs approved between 2005 and 2012.

Some drugs were approved based on results from multiple studies, while other approvals were based on data from a single trial.

Furthermore, trials varied greatly with regard to size, length of study period, type of comparator, and metrics of efficacy.

These results appear in the current issue of JAMA.

“Based on our analysis, some drugs are approved on the basis of large, high-quality clinical trials, while others are approved based on results of smaller trials,” said senior study author Joseph Ross, MD, of the Yale School of Medicine in New Haven, Connecticut.

“There was a lack of uniformity in the level of evidence the FDA used. We also found that only 40% of drug approvals involved a clinical trial that compared a new drug to existing treatment offerings. This is an important step for determining whether the new drug is a better option than existing, older drugs.”

Dr Ross and his colleagues evaluated the strength of clinical trial evidence supporting FDA approval decisions by characterizing key features of efficacy trials, such as size, duration, and endpoints.

The researchers used publicly available FDA documents to identify 188 drugs approved between 2005 and 2012 for 206 indications on the basis of 448 pivotal efficacy trials.

The team identified trials for 201 of the indications. Four drugs (including 1 used for 2 different indications) were approved without a pivotal efficacy trial.

So among the 201 indications, the median number of trials reviewed per indication was 2 (interquartile range [IQR], 1-2.5). Seventy-four indications (36.8%) were approved on the basis of a single trial, 77 (38.3%) on data from 2 trials, and 50 (24.9%) on data from 3 or more trials.

Most trials were randomized (89.3%) and double-blinded (79.5%). The median duration of a trial was 14.0 weeks (IQR, 6.0-26.0 weeks), and 113 trials (25.2%) lasted 6 months or longer.

The median number of total subjects enrolled in a trial was 446 (IQR, 205-678), and the median number of patients in the intervention arm of a study was 271 (IQR, 133-426).

More than half of trials (55.1%) used a placebo for comparison, 31.9% used an active comparator (such as another drug), and 12.9% had no comparator.

The primary endpoint was a surrogate outcome in 48.9% of trials, a clinical outcome for 29%, and a clinical scale for 22.1%.

These results suggest the quality of clinical trial evidence the FDA uses to make approval decisions varies widely across indications, the researchers said.

Study author Nicholas S. Downing, a student at the Yale School of Medicine, noted that survey data suggest patients expect drugs approved by the FDA to be both safe and effective.

“Based on our study of the data, we can’t be certain that this expectation is necessarily justified,” he said, “given the quantity and quality of the variability we saw in the drug approval process.”

Drug production

Credit: FDA

A new study suggests the US Food and Drug Administration (FDA) does not hold drug trials to the same set of standards.

The research revealed substantial differences in trials used to support drugs approved between 2005 and 2012.

Some drugs were approved based on results from multiple studies, while other approvals were based on data from a single trial.

Furthermore, trials varied greatly with regard to size, length of study period, type of comparator, and metrics of efficacy.

These results appear in the current issue of JAMA.

“Based on our analysis, some drugs are approved on the basis of large, high-quality clinical trials, while others are approved based on results of smaller trials,” said senior study author Joseph Ross, MD, of the Yale School of Medicine in New Haven, Connecticut.

“There was a lack of uniformity in the level of evidence the FDA used. We also found that only 40% of drug approvals involved a clinical trial that compared a new drug to existing treatment offerings. This is an important step for determining whether the new drug is a better option than existing, older drugs.”

Dr Ross and his colleagues evaluated the strength of clinical trial evidence supporting FDA approval decisions by characterizing key features of efficacy trials, such as size, duration, and endpoints.

The researchers used publicly available FDA documents to identify 188 drugs approved between 2005 and 2012 for 206 indications on the basis of 448 pivotal efficacy trials.

The team identified trials for 201 of the indications. Four drugs (including 1 used for 2 different indications) were approved without a pivotal efficacy trial.

So among the 201 indications, the median number of trials reviewed per indication was 2 (interquartile range [IQR], 1-2.5). Seventy-four indications (36.8%) were approved on the basis of a single trial, 77 (38.3%) on data from 2 trials, and 50 (24.9%) on data from 3 or more trials.

Most trials were randomized (89.3%) and double-blinded (79.5%). The median duration of a trial was 14.0 weeks (IQR, 6.0-26.0 weeks), and 113 trials (25.2%) lasted 6 months or longer.

The median number of total subjects enrolled in a trial was 446 (IQR, 205-678), and the median number of patients in the intervention arm of a study was 271 (IQR, 133-426).

More than half of trials (55.1%) used a placebo for comparison, 31.9% used an active comparator (such as another drug), and 12.9% had no comparator.

The primary endpoint was a surrogate outcome in 48.9% of trials, a clinical outcome for 29%, and a clinical scale for 22.1%.

These results suggest the quality of clinical trial evidence the FDA uses to make approval decisions varies widely across indications, the researchers said.

Study author Nicholas S. Downing, a student at the Yale School of Medicine, noted that survey data suggest patients expect drugs approved by the FDA to be both safe and effective.

“Based on our study of the data, we can’t be certain that this expectation is necessarily justified,” he said, “given the quantity and quality of the variability we saw in the drug approval process.”

By their very nature, antidotes and detoxification agents are needed in situations where the health and well-being of the mother are in jeopardy. In nearly all such cases, the mother’s condition will take priority over the safety of the embryo-fetus. Only two of the drugs (ethanol and penicillamine) are known to cause embryo or fetal harm but, for most of these drugs, the reported human pregnancy experience is very limited or absent. Nevertheless, pregnant women should be treated the same way as nonpregnant women.

Activated charcoal prevents absorption of substances from the gut and is no risk to the mother or her pregnancy. Similarly, ipecac syrup, which is used to induce vomiting, is safe in pregnancy.

Several agents are available for the reversal of opioid (natural or synthetic) overdose that is causing respiratory depression and/or marked sedation: naloxone, naltrexone, and nalmefene, a long-acting derivative of naltrexone (plasma half-life about 10 hours). Of the three agents, naloxone is the one for which there is the most human pregnancy experience. It has no intrinsic respiratory depressive activity or other narcotic effects of its own. All of these agents can be used in pregnancy for acute narcotic overdose.

Acetylcysteine is used to prevent or lessen hepatic injury following the ingestion of potentially hepatic toxic doses of acetaminophen. The antidote is not teratogenic or embryo toxic, and limited human pregnancy data have not shown fetal toxicity. After IV administration, acetylcysteine crosses the placenta in sufficient amounts to achieve protective serum levels in the fetus.

Potentially life-threatening digoxin overdose can be treated with IV digoxin immune Fab (ovine). The use of the agent has been reported in 44 pregnancies, but none of the cases involved digitalis overdose (all women had severe preeclampsia). No fetal harm secondary to the drug was observed.

Flumazenil is indicated for the reversal of benzodiazepine overdose. The drug is not teratogenic or embryo-fetal toxic in animals at systemic exposures near those obtained in humans. Based on very limited data, it appears to cross the human placenta and to reverse the depressive effects of benzodiazepines on the fetus.

Fomepizole is used for the treatment of ethylene glycol or methanol ingestion. It inhibits alcohol dehydrogenase, an enzyme that catalyzes the oxidation of the two chemicals to their toxic metabolites. The drug was not teratogenic in mice, but only one case of human pregnancy exposure has been reported, and the pregnancy outcome was unknown. Ethanol also has been used for poisonings with these two chemicals. Although the fetal effects of this short-term (24-48 hours) use have not been studied, neurotoxicity is a potential complication.

Glucarpidase is indicated for the treatment of toxic plasma methotrexate levels. It converts methotrexate to inactive metabolites. There are no reports of its use in human or animal pregnancies. Human reports are unlikely because methotrexate is contraindicated in pregnancy.

There are six agents available to treat heavy metal (arsenic, gold, iron, lead, and mercury) intoxication: deferasirox (iron), deferoxamine (iron), dimercaprol (arsenic, gold, lead, and mercury), edetate calcium disodium (lead), penicillamine (copper and mercury), and succimer (lead).

Deferasirox is indicated for chronic iron overload due to blood transfusions. Three reports have described its use in the first half of pregnancy without embryo or fetal harm. Deferoxamine is used for the treatment of both acute and chronic iron overload. Although the drug causes toxicity in two animal species, the human pregnancy experience is substantial, and no embryo or fetal adverse effects attributable to the agent have been reported. Dimercaprol (British anti-Lewisite; BAL) is used for the treatment of arsenic, gold, and acute mercury poisoning (not effective for chronic mercury poisoning). It is also combined with edetate calcium disodium for lead poisoning. High doses are embryotoxic and teratogenic in mice. The published human pregnancy experience is limited and all involved exposures after the first trimester. High levels of arsenic or lead were found in the newborns in two cases.

Edetate calcium disodium forms stable chelates with a number of metals, but it is primarily used for lead overdose, either alone or in combination with dimercaprol. There are only a few reports of its use in human pregnancy, all occurring late in gestation. A potential complication of therapy is maternal hypotension that could jeopardize placental perfusion. The agent also chelates zinc, resulting in zinc deficiency. This mechanism was thought to be involved in the teratogenic effects seen in animals.

Penicillamine has been used in mercury poisoning (one report), in addition to its indication as a chelating agent for copper in the treatment of Wilson’s disease. Exposure in the first trimester is related to a risk of connective tissue anomalies, primarily cutis laxa. Succimer (dimercaptosuccinic acid; DMSA) has been used for lead, arsenic, mercury, and cadmium poisoning. It also chelates zinc quite effectively. The agent is toxic and/or teratogenic in mice and rats, but some of the effects may have been secondary to zinc deficiency. Because of the complete absence of human pregnancy experience, antidotes other than succimer probably are preferable.

Lanthanum carbonate and sevelamer are indicated to reduce serum phosphate levels in patients with end-stage renal disease. The drugs bind dietary phosphate from food during digestion in the gut. There are no reports of their use in human pregnancy. The systemic bioavailability is minimal, and the drugs should have no effect on the embryo or fetus. However, they may prevent intestinal vitamin absorption, especially of fat-soluble vitamins.

The cholinergic agent physostigmine is capable of reversing the central nervous system effects of anticholinergics, such as scopolamine and tricyclic antidepressants. The reported human pregnancy experience is limited to the third trimester.

Methylene blue has been used for cyanide poisoning. In humans, it is teratogenic and fetal toxic when given by intra-amniotic injection, but its oral use as an antidote in pregnancy has not been reported. The cyanide antidote package contains amyl nitrite, sodium nitrite, and sodium thiosulfate. The effects of these agents on human pregnancy also are unknown, as are the effects of high-dose hydroxocobalamin, an analogue of vitamin B₁₂ also used in cyanide poisoning.

Pralidoxime (2-PAM) reactivates cholinesterase that has been inactivated by organophosphate pesticides and chemicals with anticholinesterase activity, thereby relieving the paralysis of the muscles of respiration. The drug is available in an autoinjector that can be used rapidly in cases of exposure to nerve agents possessing anticholinesterase activity (organophosphate poisoning). Animal reproduction tests have not been conducted with pralidoxime, and the human pregnancy experience is limited to a few cases of insecticide poisoning (second and third trimesters). Healthy infants were later delivered in these cases.

Four antivenins are commercially available for acute envenomation: black widow spider antivenin, Centruroides (scorpion) immune F(ab\')₂ (equine), crotalidae polyvalent immune Fab (ovine) (North American rattlesnake), and North American coral snake antivenin (equine). In addition, botulism antitoxin heptavalent (equine) is used for food poisoning caused by the neurotoxic bacterium Clostridium botulinum. Animal reproduction studies have not been conducted with these products, and human reports are limited or absent.

Sapropterin, a cofactor for the enzyme phenylalanine hydroxylase, reduces blood phenylalanine levels in patients with phenylketonuria. The drug is given daily if diet alone does not control maternal phenylalanine levels. Use of the drug in human pregnancy has not been reported.

A number of other agents can be classified as antidotes, in addition to their primary indications, because they can reverse the toxic effects of other agents. These antidotes include atropine (severe bradycardia, poisonings with organophosphates and carbamates), calcium chloride or gluconate (severe hypocalcemia, calcium-channel-blocker overdose, exposure to hydrofluoric acid), glucagon (hypoglycemia), folinic acid (methotrexate overdose), protamine (heparin overdose), pyridoxine (isoniazid-induced seizures; adjunct in ethylene glycol poisoning), and vitamin K (phytonadione) (warfarin overdose). The pregnancy data are extensive for many of these agents and are not suggestive of significant embryo or fetal risk.

Mr. Briggs is a pharmacist clinical specialist at the outpatient clinics of Memorial Care Center for Women at Miller Children’s Hospital in Long Beach, Calif.; clinical professor of pharmacy at the University of California, San Francisco; and adjunct professor of pharmacy at the University of Southern California, Los Angeles, and Washington State University, Spokane. He also is coauthor of "Drugs in Pregnancy and Lactation," and coeditor of "Diseases, Complications, and Drug Therapy in Obstetrics." He had no relevant financial disclosures. Contact him at [email protected].

By their very nature, antidotes and detoxification agents are needed in situations where the health and well-being of the mother are in jeopardy. In nearly all such cases, the mother’s condition will take priority over the safety of the embryo-fetus. Only two of the drugs (ethanol and penicillamine) are known to cause embryo or fetal harm but, for most of these drugs, the reported human pregnancy experience is very limited or absent. Nevertheless, pregnant women should be treated the same way as nonpregnant women.

Activated charcoal prevents absorption of substances from the gut and is no risk to the mother or her pregnancy. Similarly, ipecac syrup, which is used to induce vomiting, is safe in pregnancy.

Several agents are available for the reversal of opioid (natural or synthetic) overdose that is causing respiratory depression and/or marked sedation: naloxone, naltrexone, and nalmefene, a long-acting derivative of naltrexone (plasma half-life about 10 hours). Of the three agents, naloxone is the one for which there is the most human pregnancy experience. It has no intrinsic respiratory depressive activity or other narcotic effects of its own. All of these agents can be used in pregnancy for acute narcotic overdose.

Acetylcysteine is used to prevent or lessen hepatic injury following the ingestion of potentially hepatic toxic doses of acetaminophen. The antidote is not teratogenic or embryo toxic, and limited human pregnancy data have not shown fetal toxicity. After IV administration, acetylcysteine crosses the placenta in sufficient amounts to achieve protective serum levels in the fetus.

Potentially life-threatening digoxin overdose can be treated with IV digoxin immune Fab (ovine). The use of the agent has been reported in 44 pregnancies, but none of the cases involved digitalis overdose (all women had severe preeclampsia). No fetal harm secondary to the drug was observed.

Flumazenil is indicated for the reversal of benzodiazepine overdose. The drug is not teratogenic or embryo-fetal toxic in animals at systemic exposures near those obtained in humans. Based on very limited data, it appears to cross the human placenta and to reverse the depressive effects of benzodiazepines on the fetus.

Fomepizole is used for the treatment of ethylene glycol or methanol ingestion. It inhibits alcohol dehydrogenase, an enzyme that catalyzes the oxidation of the two chemicals to their toxic metabolites. The drug was not teratogenic in mice, but only one case of human pregnancy exposure has been reported, and the pregnancy outcome was unknown. Ethanol also has been used for poisonings with these two chemicals. Although the fetal effects of this short-term (24-48 hours) use have not been studied, neurotoxicity is a potential complication.

Glucarpidase is indicated for the treatment of toxic plasma methotrexate levels. It converts methotrexate to inactive metabolites. There are no reports of its use in human or animal pregnancies. Human reports are unlikely because methotrexate is contraindicated in pregnancy.

There are six agents available to treat heavy metal (arsenic, gold, iron, lead, and mercury) intoxication: deferasirox (iron), deferoxamine (iron), dimercaprol (arsenic, gold, lead, and mercury), edetate calcium disodium (lead), penicillamine (copper and mercury), and succimer (lead).

Deferasirox is indicated for chronic iron overload due to blood transfusions. Three reports have described its use in the first half of pregnancy without embryo or fetal harm. Deferoxamine is used for the treatment of both acute and chronic iron overload. Although the drug causes toxicity in two animal species, the human pregnancy experience is substantial, and no embryo or fetal adverse effects attributable to the agent have been reported. Dimercaprol (British anti-Lewisite; BAL) is used for the treatment of arsenic, gold, and acute mercury poisoning (not effective for chronic mercury poisoning). It is also combined with edetate calcium disodium for lead poisoning. High doses are embryotoxic and teratogenic in mice. The published human pregnancy experience is limited and all involved exposures after the first trimester. High levels of arsenic or lead were found in the newborns in two cases.

Edetate calcium disodium forms stable chelates with a number of metals, but it is primarily used for lead overdose, either alone or in combination with dimercaprol. There are only a few reports of its use in human pregnancy, all occurring late in gestation. A potential complication of therapy is maternal hypotension that could jeopardize placental perfusion. The agent also chelates zinc, resulting in zinc deficiency. This mechanism was thought to be involved in the teratogenic effects seen in animals.

Penicillamine has been used in mercury poisoning (one report), in addition to its indication as a chelating agent for copper in the treatment of Wilson’s disease. Exposure in the first trimester is related to a risk of connective tissue anomalies, primarily cutis laxa. Succimer (dimercaptosuccinic acid; DMSA) has been used for lead, arsenic, mercury, and cadmium poisoning. It also chelates zinc quite effectively. The agent is toxic and/or teratogenic in mice and rats, but some of the effects may have been secondary to zinc deficiency. Because of the complete absence of human pregnancy experience, antidotes other than succimer probably are preferable.

Lanthanum carbonate and sevelamer are indicated to reduce serum phosphate levels in patients with end-stage renal disease. The drugs bind dietary phosphate from food during digestion in the gut. There are no reports of their use in human pregnancy. The systemic bioavailability is minimal, and the drugs should have no effect on the embryo or fetus. However, they may prevent intestinal vitamin absorption, especially of fat-soluble vitamins.

The cholinergic agent physostigmine is capable of reversing the central nervous system effects of anticholinergics, such as scopolamine and tricyclic antidepressants. The reported human pregnancy experience is limited to the third trimester.

Methylene blue has been used for cyanide poisoning. In humans, it is teratogenic and fetal toxic when given by intra-amniotic injection, but its oral use as an antidote in pregnancy has not been reported. The cyanide antidote package contains amyl nitrite, sodium nitrite, and sodium thiosulfate. The effects of these agents on human pregnancy also are unknown, as are the effects of high-dose hydroxocobalamin, an analogue of vitamin B₁₂ also used in cyanide poisoning.

Pralidoxime (2-PAM) reactivates cholinesterase that has been inactivated by organophosphate pesticides and chemicals with anticholinesterase activity, thereby relieving the paralysis of the muscles of respiration. The drug is available in an autoinjector that can be used rapidly in cases of exposure to nerve agents possessing anticholinesterase activity (organophosphate poisoning). Animal reproduction tests have not been conducted with pralidoxime, and the human pregnancy experience is limited to a few cases of insecticide poisoning (second and third trimesters). Healthy infants were later delivered in these cases.

Four antivenins are commercially available for acute envenomation: black widow spider antivenin, Centruroides (scorpion) immune F(ab\')₂ (equine), crotalidae polyvalent immune Fab (ovine) (North American rattlesnake), and North American coral snake antivenin (equine). In addition, botulism antitoxin heptavalent (equine) is used for food poisoning caused by the neurotoxic bacterium Clostridium botulinum. Animal reproduction studies have not been conducted with these products, and human reports are limited or absent.

Sapropterin, a cofactor for the enzyme phenylalanine hydroxylase, reduces blood phenylalanine levels in patients with phenylketonuria. The drug is given daily if diet alone does not control maternal phenylalanine levels. Use of the drug in human pregnancy has not been reported.

A number of other agents can be classified as antidotes, in addition to their primary indications, because they can reverse the toxic effects of other agents. These antidotes include atropine (severe bradycardia, poisonings with organophosphates and carbamates), calcium chloride or gluconate (severe hypocalcemia, calcium-channel-blocker overdose, exposure to hydrofluoric acid), glucagon (hypoglycemia), folinic acid (methotrexate overdose), protamine (heparin overdose), pyridoxine (isoniazid-induced seizures; adjunct in ethylene glycol poisoning), and vitamin K (phytonadione) (warfarin overdose). The pregnancy data are extensive for many of these agents and are not suggestive of significant embryo or fetal risk.

Mr. Briggs is a pharmacist clinical specialist at the outpatient clinics of Memorial Care Center for Women at Miller Children’s Hospital in Long Beach, Calif.; clinical professor of pharmacy at the University of California, San Francisco; and adjunct professor of pharmacy at the University of Southern California, Los Angeles, and Washington State University, Spokane. He also is coauthor of "Drugs in Pregnancy and Lactation," and coeditor of "Diseases, Complications, and Drug Therapy in Obstetrics." He had no relevant financial disclosures. Contact him at [email protected].

By their very nature, antidotes and detoxification agents are needed in situations where the health and well-being of the mother are in jeopardy. In nearly all such cases, the mother’s condition will take priority over the safety of the embryo-fetus. Only two of the drugs (ethanol and penicillamine) are known to cause embryo or fetal harm but, for most of these drugs, the reported human pregnancy experience is very limited or absent. Nevertheless, pregnant women should be treated the same way as nonpregnant women.

Activated charcoal prevents absorption of substances from the gut and is no risk to the mother or her pregnancy. Similarly, ipecac syrup, which is used to induce vomiting, is safe in pregnancy.

Several agents are available for the reversal of opioid (natural or synthetic) overdose that is causing respiratory depression and/or marked sedation: naloxone, naltrexone, and nalmefene, a long-acting derivative of naltrexone (plasma half-life about 10 hours). Of the three agents, naloxone is the one for which there is the most human pregnancy experience. It has no intrinsic respiratory depressive activity or other narcotic effects of its own. All of these agents can be used in pregnancy for acute narcotic overdose.

Acetylcysteine is used to prevent or lessen hepatic injury following the ingestion of potentially hepatic toxic doses of acetaminophen. The antidote is not teratogenic or embryo toxic, and limited human pregnancy data have not shown fetal toxicity. After IV administration, acetylcysteine crosses the placenta in sufficient amounts to achieve protective serum levels in the fetus.

Potentially life-threatening digoxin overdose can be treated with IV digoxin immune Fab (ovine). The use of the agent has been reported in 44 pregnancies, but none of the cases involved digitalis overdose (all women had severe preeclampsia). No fetal harm secondary to the drug was observed.

Flumazenil is indicated for the reversal of benzodiazepine overdose. The drug is not teratogenic or embryo-fetal toxic in animals at systemic exposures near those obtained in humans. Based on very limited data, it appears to cross the human placenta and to reverse the depressive effects of benzodiazepines on the fetus.

Fomepizole is used for the treatment of ethylene glycol or methanol ingestion. It inhibits alcohol dehydrogenase, an enzyme that catalyzes the oxidation of the two chemicals to their toxic metabolites. The drug was not teratogenic in mice, but only one case of human pregnancy exposure has been reported, and the pregnancy outcome was unknown. Ethanol also has been used for poisonings with these two chemicals. Although the fetal effects of this short-term (24-48 hours) use have not been studied, neurotoxicity is a potential complication.

Glucarpidase is indicated for the treatment of toxic plasma methotrexate levels. It converts methotrexate to inactive metabolites. There are no reports of its use in human or animal pregnancies. Human reports are unlikely because methotrexate is contraindicated in pregnancy.

There are six agents available to treat heavy metal (arsenic, gold, iron, lead, and mercury) intoxication: deferasirox (iron), deferoxamine (iron), dimercaprol (arsenic, gold, lead, and mercury), edetate calcium disodium (lead), penicillamine (copper and mercury), and succimer (lead).

Deferasirox is indicated for chronic iron overload due to blood transfusions. Three reports have described its use in the first half of pregnancy without embryo or fetal harm. Deferoxamine is used for the treatment of both acute and chronic iron overload. Although the drug causes toxicity in two animal species, the human pregnancy experience is substantial, and no embryo or fetal adverse effects attributable to the agent have been reported. Dimercaprol (British anti-Lewisite; BAL) is used for the treatment of arsenic, gold, and acute mercury poisoning (not effective for chronic mercury poisoning). It is also combined with edetate calcium disodium for lead poisoning. High doses are embryotoxic and teratogenic in mice. The published human pregnancy experience is limited and all involved exposures after the first trimester. High levels of arsenic or lead were found in the newborns in two cases.

Edetate calcium disodium forms stable chelates with a number of metals, but it is primarily used for lead overdose, either alone or in combination with dimercaprol. There are only a few reports of its use in human pregnancy, all occurring late in gestation. A potential complication of therapy is maternal hypotension that could jeopardize placental perfusion. The agent also chelates zinc, resulting in zinc deficiency. This mechanism was thought to be involved in the teratogenic effects seen in animals.

Penicillamine has been used in mercury poisoning (one report), in addition to its indication as a chelating agent for copper in the treatment of Wilson’s disease. Exposure in the first trimester is related to a risk of connective tissue anomalies, primarily cutis laxa. Succimer (dimercaptosuccinic acid; DMSA) has been used for lead, arsenic, mercury, and cadmium poisoning. It also chelates zinc quite effectively. The agent is toxic and/or teratogenic in mice and rats, but some of the effects may have been secondary to zinc deficiency. Because of the complete absence of human pregnancy experience, antidotes other than succimer probably are preferable.

Lanthanum carbonate and sevelamer are indicated to reduce serum phosphate levels in patients with end-stage renal disease. The drugs bind dietary phosphate from food during digestion in the gut. There are no reports of their use in human pregnancy. The systemic bioavailability is minimal, and the drugs should have no effect on the embryo or fetus. However, they may prevent intestinal vitamin absorption, especially of fat-soluble vitamins.

The cholinergic agent physostigmine is capable of reversing the central nervous system effects of anticholinergics, such as scopolamine and tricyclic antidepressants. The reported human pregnancy experience is limited to the third trimester.

Methylene blue has been used for cyanide poisoning. In humans, it is teratogenic and fetal toxic when given by intra-amniotic injection, but its oral use as an antidote in pregnancy has not been reported. The cyanide antidote package contains amyl nitrite, sodium nitrite, and sodium thiosulfate. The effects of these agents on human pregnancy also are unknown, as are the effects of high-dose hydroxocobalamin, an analogue of vitamin B₁₂ also used in cyanide poisoning.

Pralidoxime (2-PAM) reactivates cholinesterase that has been inactivated by organophosphate pesticides and chemicals with anticholinesterase activity, thereby relieving the paralysis of the muscles of respiration. The drug is available in an autoinjector that can be used rapidly in cases of exposure to nerve agents possessing anticholinesterase activity (organophosphate poisoning). Animal reproduction tests have not been conducted with pralidoxime, and the human pregnancy experience is limited to a few cases of insecticide poisoning (second and third trimesters). Healthy infants were later delivered in these cases.

Four antivenins are commercially available for acute envenomation: black widow spider antivenin, Centruroides (scorpion) immune F(ab\')₂ (equine), crotalidae polyvalent immune Fab (ovine) (North American rattlesnake), and North American coral snake antivenin (equine). In addition, botulism antitoxin heptavalent (equine) is used for food poisoning caused by the neurotoxic bacterium Clostridium botulinum. Animal reproduction studies have not been conducted with these products, and human reports are limited or absent.

Sapropterin, a cofactor for the enzyme phenylalanine hydroxylase, reduces blood phenylalanine levels in patients with phenylketonuria. The drug is given daily if diet alone does not control maternal phenylalanine levels. Use of the drug in human pregnancy has not been reported.

A number of other agents can be classified as antidotes, in addition to their primary indications, because they can reverse the toxic effects of other agents. These antidotes include atropine (severe bradycardia, poisonings with organophosphates and carbamates), calcium chloride or gluconate (severe hypocalcemia, calcium-channel-blocker overdose, exposure to hydrofluoric acid), glucagon (hypoglycemia), folinic acid (methotrexate overdose), protamine (heparin overdose), pyridoxine (isoniazid-induced seizures; adjunct in ethylene glycol poisoning), and vitamin K (phytonadione) (warfarin overdose). The pregnancy data are extensive for many of these agents and are not suggestive of significant embryo or fetal risk.

Mr. Briggs is a pharmacist clinical specialist at the outpatient clinics of Memorial Care Center for Women at Miller Children’s Hospital in Long Beach, Calif.; clinical professor of pharmacy at the University of California, San Francisco; and adjunct professor of pharmacy at the University of Southern California, Los Angeles, and Washington State University, Spokane. He also is coauthor of "Drugs in Pregnancy and Lactation," and coeditor of "Diseases, Complications, and Drug Therapy in Obstetrics." He had no relevant financial disclosures. Contact him at [email protected].