Despite the fact that prescription medications are commonly used by pregnant women, for most products and for new drugs in particular, there is typically little to no human safety information available to aid clinicians and patients in managing risk. As randomized clinical trials are usually not considered ethical to perform in pregnancy, observational epidemiologic studies are often the next best option to address human pregnancy exposure. An increasingly common approach to gathering human safety data is postmarketing pregnancy registries.

These pregnancy registries are initiated many times by agreement between the manufacturer and a regulatory agency as a postmarketing commitment or requirement following shortly after drug approval. Furthermore, because use of a new drug in pregnant women might be relatively rare, a pregnancy registry may be the only feasible method for gathering preliminary safety information as quickly as possible so that potential signals might be detected and clinical decision making can be better informed.

Pregnancy registries vary in design, but all involve collection of data on exposure to the drug of interest in pregnant women, and collection of outcome data for those pregnancies. The primary outcome of interest is typically major congenital anomalies; some registries also collect outcome data on fetal/infant growth, preterm delivery, pregnancy loss, specific neonatal outcomes, and postnatal longer term growth and development. The rates of these outcomes can be compared with general population reference rates, or rates occurring in a specific comparison group that might be more similar to the exposed women, for example, in terms of the underlying maternal condition being treated by the drug.

In addition to early information on a new drug, some of the major advantages of many pregnancy registry designs are the ability to collect information on the exposure and other pregnancy details before the mother knows what the outcome of her pregnancy will be; direct collection of exposure information from the mother herself, so that important factors such as drug and alcohol use, dose, and exact timing of exposure to the drug of interest; information on important other factors such as tobacco, alcohol, and multivitamin use.

The most challenging aspect of pregnancy registries is recruitment, for which registries largely depend on obstetric providers and other specialty physicians. Although low numbers of recruited pregnancies may be caused by limited use of a new drug, clearly most pregnancy registries enroll a very small fraction of all exposed pregnancies that are in existence. A second, related issue is that there may be bias in the self-selection of women who do find out about the registry and agree to participate, thus raising questions about the generalizability of the findings. A third issue is that many registries experience high rates of "lost to follow-up," in which outcome information is unobtainable from the health care provider or the pregnant woman – in some cases as high as 40%. There is also a concern about bias involved with the timing in gestation when a pregnancy enters a registry, such as the later in gestation a pregnancy is enrolled, the more likely that prenatal diagnosis, pregnancy loss, or other adverse outcomes have already occurred – thus making the enrollment essentially retrospective.

Another concern is that few registries have a concurrently enrolled group of unexposed women for purposes of comparison. Thus, their findings are commonly compared to external reference statistics which may not be the most appropriate. Finally, in some registries, the absence of information on individual dose and specific timing in gestation of exposure may preclude evaluating the biological plausibility of any registry findings. All of these issues can lead to long delays in accumulation of sufficient information to draw meaningful inferences, and potential concerns about interpretation of results.

How can awareness of pregnancy registries and more representative enrollment of exposed women be improved? A variety of methods are used to inform physicians and their patients about existing pregnancy registries for the purpose of encouraging referrals, including the Food and Drug Administration website, information in product labeling and on product websites, direct to provider or direct to consumer advertising, and in commonly used resources for clinicians such as this column and Reprotox, an information system developed by the Reproductive Toxicology Center. However, with the rapidly increasing number of registries, it is challenging for physicians to remain current on which medications are being monitored through a registry, what the criteria for enrollment are, and how a physician or patient can find out more. Pregnancy registry designs that are disease based – such as encompassing all medications used to treat a specific disease in pregnancy – help simplify the referral process by broadening the criteria for enrollment. Particularly for specialty physicians, this can ease the burden of identifying eligible women for enrollment.

How can enrollment be accomplished as early as possible in pregnancy (after exposure, but before the outcome is known), and how can more complete ascertainment of exposure and outcome be improved? An approach that some registries have used to address this is by "direct to consumer" campaigns. Registries such as the Organization of Teratology Information Specialists (OTIS) Autoimmune Diseases in Pregnancy Registry require that the pregnant woman herself enroll in the study, and therefore, the study is marketed directly to those women, although physician referral is encouraged. At least in this case, this has led to low rates of lost to follow-up (less than 5%), recruitment timing that is typically before the seventh or eighth week of gestation, and collection of specific information on dose and timing in gestation of exposure.

Multiple drug, disease-based, multiple sponsor registries such as the Antiretroviral Drugs in Pregnancy Registry, the North American Antiepileptic Drugs in Pregnancy Registry (patients call 888-233-2334), and the National Pregnancy Registry for Atypical Antipsychotics (866-961-2388) offer distinct advantages but are not always feasible for a specific product. A national pregnancy registry for all new drugs has been suggested as another solution to many of the challenges facing single product registries and to streamline referral and follow-up. In addition, including pregnant women in selected preapproval studies has several advantages. Finally, creative new technologies for earlier and more complete ascertainment and referral, such as use of electronic medical records, should be fully explored. The need for safety information on new drugs is urgent.

Dr. Chambers is professor of pediatrics and family and preventive medicine at the University of California, San Diego. She is director of the California Teratogen Information Service and Clinical Research Program. Dr. Chambers is a past president of the Organization of Teratology Information Specialists and past president of the Teratology Society. Dr. Cohen directs the perinatal psychiatry program at Massachusetts General Hospital, which provides information about pregnancy and mental health. Dr. Koren is professor of pediatrics, pharmacology, pharmacy, and medical genetics at the University of Toronto. He heads the Research Leadership for Better Pharmacotherapy During Pregnancy and Lactation at the Hospital for Sick Children, Toronto, where he is director of the Motherisk program. 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.; a clinical professor of pharmacy at the University of California, San Francisco; and an adjunct professor of pharmacy at the University of Southern California, Los Angeles, and Washington State University, Spokane. He also is coauthor of "Drugs in Pregnancy and Lactation." Dr. Cohen is the principal investigator on the National Pregnancy Registry for Atypical Antipsychotics, which is sponsored by multiple atypical antipsychotic manufacturers.

Dr. Chambers, Dr. Koren, and Mr. Briggs said they had no relevant financial disclosures.

Despite the fact that prescription medications are commonly used by pregnant women, for most products and for new drugs in particular, there is typically little to no human safety information available to aid clinicians and patients in managing risk. As randomized clinical trials are usually not considered ethical to perform in pregnancy, observational epidemiologic studies are often the next best option to address human pregnancy exposure. An increasingly common approach to gathering human safety data is postmarketing pregnancy registries.

These pregnancy registries are initiated many times by agreement between the manufacturer and a regulatory agency as a postmarketing commitment or requirement following shortly after drug approval. Furthermore, because use of a new drug in pregnant women might be relatively rare, a pregnancy registry may be the only feasible method for gathering preliminary safety information as quickly as possible so that potential signals might be detected and clinical decision making can be better informed.

Pregnancy registries vary in design, but all involve collection of data on exposure to the drug of interest in pregnant women, and collection of outcome data for those pregnancies. The primary outcome of interest is typically major congenital anomalies; some registries also collect outcome data on fetal/infant growth, preterm delivery, pregnancy loss, specific neonatal outcomes, and postnatal longer term growth and development. The rates of these outcomes can be compared with general population reference rates, or rates occurring in a specific comparison group that might be more similar to the exposed women, for example, in terms of the underlying maternal condition being treated by the drug.

In addition to early information on a new drug, some of the major advantages of many pregnancy registry designs are the ability to collect information on the exposure and other pregnancy details before the mother knows what the outcome of her pregnancy will be; direct collection of exposure information from the mother herself, so that important factors such as drug and alcohol use, dose, and exact timing of exposure to the drug of interest; information on important other factors such as tobacco, alcohol, and multivitamin use.

The most challenging aspect of pregnancy registries is recruitment, for which registries largely depend on obstetric providers and other specialty physicians. Although low numbers of recruited pregnancies may be caused by limited use of a new drug, clearly most pregnancy registries enroll a very small fraction of all exposed pregnancies that are in existence. A second, related issue is that there may be bias in the self-selection of women who do find out about the registry and agree to participate, thus raising questions about the generalizability of the findings. A third issue is that many registries experience high rates of "lost to follow-up," in which outcome information is unobtainable from the health care provider or the pregnant woman – in some cases as high as 40%. There is also a concern about bias involved with the timing in gestation when a pregnancy enters a registry, such as the later in gestation a pregnancy is enrolled, the more likely that prenatal diagnosis, pregnancy loss, or other adverse outcomes have already occurred – thus making the enrollment essentially retrospective.

Another concern is that few registries have a concurrently enrolled group of unexposed women for purposes of comparison. Thus, their findings are commonly compared to external reference statistics which may not be the most appropriate. Finally, in some registries, the absence of information on individual dose and specific timing in gestation of exposure may preclude evaluating the biological plausibility of any registry findings. All of these issues can lead to long delays in accumulation of sufficient information to draw meaningful inferences, and potential concerns about interpretation of results.

How can awareness of pregnancy registries and more representative enrollment of exposed women be improved? A variety of methods are used to inform physicians and their patients about existing pregnancy registries for the purpose of encouraging referrals, including the Food and Drug Administration website, information in product labeling and on product websites, direct to provider or direct to consumer advertising, and in commonly used resources for clinicians such as this column and Reprotox, an information system developed by the Reproductive Toxicology Center. However, with the rapidly increasing number of registries, it is challenging for physicians to remain current on which medications are being monitored through a registry, what the criteria for enrollment are, and how a physician or patient can find out more. Pregnancy registry designs that are disease based – such as encompassing all medications used to treat a specific disease in pregnancy – help simplify the referral process by broadening the criteria for enrollment. Particularly for specialty physicians, this can ease the burden of identifying eligible women for enrollment.

How can enrollment be accomplished as early as possible in pregnancy (after exposure, but before the outcome is known), and how can more complete ascertainment of exposure and outcome be improved? An approach that some registries have used to address this is by "direct to consumer" campaigns. Registries such as the Organization of Teratology Information Specialists (OTIS) Autoimmune Diseases in Pregnancy Registry require that the pregnant woman herself enroll in the study, and therefore, the study is marketed directly to those women, although physician referral is encouraged. At least in this case, this has led to low rates of lost to follow-up (less than 5%), recruitment timing that is typically before the seventh or eighth week of gestation, and collection of specific information on dose and timing in gestation of exposure.

Multiple drug, disease-based, multiple sponsor registries such as the Antiretroviral Drugs in Pregnancy Registry, the North American Antiepileptic Drugs in Pregnancy Registry (patients call 888-233-2334), and the National Pregnancy Registry for Atypical Antipsychotics (866-961-2388) offer distinct advantages but are not always feasible for a specific product. A national pregnancy registry for all new drugs has been suggested as another solution to many of the challenges facing single product registries and to streamline referral and follow-up. In addition, including pregnant women in selected preapproval studies has several advantages. Finally, creative new technologies for earlier and more complete ascertainment and referral, such as use of electronic medical records, should be fully explored. The need for safety information on new drugs is urgent.

Dr. Chambers is professor of pediatrics and family and preventive medicine at the University of California, San Diego. She is director of the California Teratogen Information Service and Clinical Research Program. Dr. Chambers is a past president of the Organization of Teratology Information Specialists and past president of the Teratology Society. Dr. Cohen directs the perinatal psychiatry program at Massachusetts General Hospital, which provides information about pregnancy and mental health. Dr. Koren is professor of pediatrics, pharmacology, pharmacy, and medical genetics at the University of Toronto. He heads the Research Leadership for Better Pharmacotherapy During Pregnancy and Lactation at the Hospital for Sick Children, Toronto, where he is director of the Motherisk program. 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.; a clinical professor of pharmacy at the University of California, San Francisco; and an adjunct professor of pharmacy at the University of Southern California, Los Angeles, and Washington State University, Spokane. He also is coauthor of "Drugs in Pregnancy and Lactation." Dr. Cohen is the principal investigator on the National Pregnancy Registry for Atypical Antipsychotics, which is sponsored by multiple atypical antipsychotic manufacturers.

Dr. Chambers, Dr. Koren, and Mr. Briggs said they had no relevant financial disclosures.

Despite the fact that prescription medications are commonly used by pregnant women, for most products and for new drugs in particular, there is typically little to no human safety information available to aid clinicians and patients in managing risk. As randomized clinical trials are usually not considered ethical to perform in pregnancy, observational epidemiologic studies are often the next best option to address human pregnancy exposure. An increasingly common approach to gathering human safety data is postmarketing pregnancy registries.

These pregnancy registries are initiated many times by agreement between the manufacturer and a regulatory agency as a postmarketing commitment or requirement following shortly after drug approval. Furthermore, because use of a new drug in pregnant women might be relatively rare, a pregnancy registry may be the only feasible method for gathering preliminary safety information as quickly as possible so that potential signals might be detected and clinical decision making can be better informed.

Pregnancy registries vary in design, but all involve collection of data on exposure to the drug of interest in pregnant women, and collection of outcome data for those pregnancies. The primary outcome of interest is typically major congenital anomalies; some registries also collect outcome data on fetal/infant growth, preterm delivery, pregnancy loss, specific neonatal outcomes, and postnatal longer term growth and development. The rates of these outcomes can be compared with general population reference rates, or rates occurring in a specific comparison group that might be more similar to the exposed women, for example, in terms of the underlying maternal condition being treated by the drug.

In addition to early information on a new drug, some of the major advantages of many pregnancy registry designs are the ability to collect information on the exposure and other pregnancy details before the mother knows what the outcome of her pregnancy will be; direct collection of exposure information from the mother herself, so that important factors such as drug and alcohol use, dose, and exact timing of exposure to the drug of interest; information on important other factors such as tobacco, alcohol, and multivitamin use.

The most challenging aspect of pregnancy registries is recruitment, for which registries largely depend on obstetric providers and other specialty physicians. Although low numbers of recruited pregnancies may be caused by limited use of a new drug, clearly most pregnancy registries enroll a very small fraction of all exposed pregnancies that are in existence. A second, related issue is that there may be bias in the self-selection of women who do find out about the registry and agree to participate, thus raising questions about the generalizability of the findings. A third issue is that many registries experience high rates of "lost to follow-up," in which outcome information is unobtainable from the health care provider or the pregnant woman – in some cases as high as 40%. There is also a concern about bias involved with the timing in gestation when a pregnancy enters a registry, such as the later in gestation a pregnancy is enrolled, the more likely that prenatal diagnosis, pregnancy loss, or other adverse outcomes have already occurred – thus making the enrollment essentially retrospective.

Another concern is that few registries have a concurrently enrolled group of unexposed women for purposes of comparison. Thus, their findings are commonly compared to external reference statistics which may not be the most appropriate. Finally, in some registries, the absence of information on individual dose and specific timing in gestation of exposure may preclude evaluating the biological plausibility of any registry findings. All of these issues can lead to long delays in accumulation of sufficient information to draw meaningful inferences, and potential concerns about interpretation of results.

How can awareness of pregnancy registries and more representative enrollment of exposed women be improved? A variety of methods are used to inform physicians and their patients about existing pregnancy registries for the purpose of encouraging referrals, including the Food and Drug Administration website, information in product labeling and on product websites, direct to provider or direct to consumer advertising, and in commonly used resources for clinicians such as this column and Reprotox, an information system developed by the Reproductive Toxicology Center. However, with the rapidly increasing number of registries, it is challenging for physicians to remain current on which medications are being monitored through a registry, what the criteria for enrollment are, and how a physician or patient can find out more. Pregnancy registry designs that are disease based – such as encompassing all medications used to treat a specific disease in pregnancy – help simplify the referral process by broadening the criteria for enrollment. Particularly for specialty physicians, this can ease the burden of identifying eligible women for enrollment.

How can enrollment be accomplished as early as possible in pregnancy (after exposure, but before the outcome is known), and how can more complete ascertainment of exposure and outcome be improved? An approach that some registries have used to address this is by "direct to consumer" campaigns. Registries such as the Organization of Teratology Information Specialists (OTIS) Autoimmune Diseases in Pregnancy Registry require that the pregnant woman herself enroll in the study, and therefore, the study is marketed directly to those women, although physician referral is encouraged. At least in this case, this has led to low rates of lost to follow-up (less than 5%), recruitment timing that is typically before the seventh or eighth week of gestation, and collection of specific information on dose and timing in gestation of exposure.

Multiple drug, disease-based, multiple sponsor registries such as the Antiretroviral Drugs in Pregnancy Registry, the North American Antiepileptic Drugs in Pregnancy Registry (patients call 888-233-2334), and the National Pregnancy Registry for Atypical Antipsychotics (866-961-2388) offer distinct advantages but are not always feasible for a specific product. A national pregnancy registry for all new drugs has been suggested as another solution to many of the challenges facing single product registries and to streamline referral and follow-up. In addition, including pregnant women in selected preapproval studies has several advantages. Finally, creative new technologies for earlier and more complete ascertainment and referral, such as use of electronic medical records, should be fully explored. The need for safety information on new drugs is urgent.

Dr. Chambers is professor of pediatrics and family and preventive medicine at the University of California, San Diego. She is director of the California Teratogen Information Service and Clinical Research Program. Dr. Chambers is a past president of the Organization of Teratology Information Specialists and past president of the Teratology Society. Dr. Cohen directs the perinatal psychiatry program at Massachusetts General Hospital, which provides information about pregnancy and mental health. Dr. Koren is professor of pediatrics, pharmacology, pharmacy, and medical genetics at the University of Toronto. He heads the Research Leadership for Better Pharmacotherapy During Pregnancy and Lactation at the Hospital for Sick Children, Toronto, where he is director of the Motherisk program. 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.; a clinical professor of pharmacy at the University of California, San Francisco; and an adjunct professor of pharmacy at the University of Southern California, Los Angeles, and Washington State University, Spokane. He also is coauthor of "Drugs in Pregnancy and Lactation." Dr. Cohen is the principal investigator on the National Pregnancy Registry for Atypical Antipsychotics, which is sponsored by multiple atypical antipsychotic manufacturers.

Dr. Chambers, Dr. Koren, and Mr. Briggs said they had no relevant financial disclosures.

Objectives: This phase III trial asks whether the addition of temozolomide (Temodar) to radiation therapy can improve progression-free survival and/or overall survival of patients with grade 2 glioma at the most recent pathological diagnosis.

Key entry or exclusion criteria: Patients with a previous pathological diagnosis of grade 3 or 4 are excluded, as are patients with prior radiotherapy, cytotoxic chemotherapy, radiosurgery, or investigational therapy for the brain tumor. Prior surgery is permitted.

Locations: 173 sites

Goal: 540 patients

Study sponsor: Eastern Cooperative Oncology Group in collaboration with the National Cancer Institute.

Link for more information: clinicaltrials.gov/ct2/show/study/NCT00978458

NIH clinical trials identifier: NCT00978458

Objectives: This phase III trial asks whether the addition of temozolomide (Temodar) to radiation therapy can improve progression-free survival and/or overall survival of patients with grade 2 glioma at the most recent pathological diagnosis.

Key entry or exclusion criteria: Patients with a previous pathological diagnosis of grade 3 or 4 are excluded, as are patients with prior radiotherapy, cytotoxic chemotherapy, radiosurgery, or investigational therapy for the brain tumor. Prior surgery is permitted.

Locations: 173 sites

Goal: 540 patients

Study sponsor: Eastern Cooperative Oncology Group in collaboration with the National Cancer Institute.

Link for more information: clinicaltrials.gov/ct2/show/study/NCT00978458

NIH clinical trials identifier: NCT00978458

Objectives: This phase III trial asks whether the addition of temozolomide (Temodar) to radiation therapy can improve progression-free survival and/or overall survival of patients with grade 2 glioma at the most recent pathological diagnosis.

Key entry or exclusion criteria: Patients with a previous pathological diagnosis of grade 3 or 4 are excluded, as are patients with prior radiotherapy, cytotoxic chemotherapy, radiosurgery, or investigational therapy for the brain tumor. Prior surgery is permitted.

Locations: 173 sites

Goal: 540 patients

Study sponsor: Eastern Cooperative Oncology Group in collaboration with the National Cancer Institute.

Link for more information: clinicaltrials.gov/ct2/show/study/NCT00978458

NIH clinical trials identifier: NCT00978458

Antiviral therapy may reduce the risk of hepatocellular carcinoma in patients with hepatitis C infections, Dr. Nina Kimer reported in the Oct. 22 issue of BMJ Open, published online.

Moreover, the effect seems to persist regardless of whether sustained virologic response is achieved.

Dr. Kimer, of Copenhagen University Hospital, Hvidovre, Denmark, and colleagues conducted a meta-analysis of trials looking at hepatitis C-related cirrhosis or fibrosis (BMJ Open 2012;2:e001313 [doi:10.1136/bmjopen-2012-001313]).

Courtesy US. Dept of Veterans Affairs

The primary analysis focused on randomized controlled trials, although prospective cohort studies with control groups were included in sensitivity analyses.

The authors searched the Cochrane Library, PubMed, EMBASE, and Web of Science databases, as well as reference lists from relevant papers, conference proceedings, and the World Health Organization Trial Search Portal.

Studies looking at HIV and chronic hepatitis B were excluded, for a total of eight randomized trials and five prospective cohort studies.

The duration of therapy (which included pegylated interferon in two trials, interferon plus ribavirin in one trial, and interferon monotherapy in the remaining trials) varied from 1 to 5 years. Follow-up ranged from 2 to 8.7 years.

Overall, the authors found that 81 of 1,156 patients who received antiviral therapy and 129 of 1,074 control patients who received no therapy developed hepatocellular carcinoma.

The relative risk for antiviral therapy, compared with no treatment, was 0.53 (95% confidence interval, 0.34-0.81).

"The corresponding number needed to treat to prevent one case of [hepatocellular carcinoma] was eight patients," added the researchers.

And while the effect of antivirals was more pronounced among patients with a virological response (RR 0.15; 95% CI, 0.05-0.45), there was nevertheless a clear reduction in risk for nonresponders to antivirals, with a relative risk of 0.57, compared with controls (95% CI 0.37-0.85).

"Although the intervention was more beneficial among sustained virological responders than nonresponders, there was a clear effect in both patient groups. ... Antiviral therapy may have beneficial effects on the risk of developing HCC that are unrelated to the virological response."

On the other hand, there was no reported effect of antiviral therapy on all-cause mortality, liver-related mortality, or liver-related morbidity in this population.

Dr. Kimer conceded several limitations to this analysis. "Only two of the included trials evaluated pegylated interferon, which is the current standard treatment for chronic hepatitis C."

Moreover, the duration of treatment in several included studies was "relatively long, which may increase the proportion of responders."

Finally, Dr. Kimer added that the researchers were unable to perform subgroup analysis to determine which treatment duration or dose is best.

"Based on the duration of follow-up and the lack of clear evidence concerning morbidity or mortality, we cannot exclude that interferon delays rather than prevents carcinogenesis," concluded the investigators.

Nevertheless, the "protection from HCC might be even better among patients in current antiviral therapy since the proportion of virological responders continues to increase with ongoing improvements in therapy," they wrote.

"Additional randomized trials with longer follow-up are still warranted to determine whether this is the case," they noted.

The authors disclosed having no outside funding and no competing interests related to this study.

Antiviral therapy may reduce the risk of hepatocellular carcinoma in patients with hepatitis C infections, Dr. Nina Kimer reported in the Oct. 22 issue of BMJ Open, published online.

Moreover, the effect seems to persist regardless of whether sustained virologic response is achieved.

Dr. Kimer, of Copenhagen University Hospital, Hvidovre, Denmark, and colleagues conducted a meta-analysis of trials looking at hepatitis C-related cirrhosis or fibrosis (BMJ Open 2012;2:e001313 [doi:10.1136/bmjopen-2012-001313]).

Courtesy US. Dept of Veterans Affairs

The primary analysis focused on randomized controlled trials, although prospective cohort studies with control groups were included in sensitivity analyses.

The authors searched the Cochrane Library, PubMed, EMBASE, and Web of Science databases, as well as reference lists from relevant papers, conference proceedings, and the World Health Organization Trial Search Portal.

Studies looking at HIV and chronic hepatitis B were excluded, for a total of eight randomized trials and five prospective cohort studies.

The duration of therapy (which included pegylated interferon in two trials, interferon plus ribavirin in one trial, and interferon monotherapy in the remaining trials) varied from 1 to 5 years. Follow-up ranged from 2 to 8.7 years.

Overall, the authors found that 81 of 1,156 patients who received antiviral therapy and 129 of 1,074 control patients who received no therapy developed hepatocellular carcinoma.

The relative risk for antiviral therapy, compared with no treatment, was 0.53 (95% confidence interval, 0.34-0.81).

"The corresponding number needed to treat to prevent one case of [hepatocellular carcinoma] was eight patients," added the researchers.

And while the effect of antivirals was more pronounced among patients with a virological response (RR 0.15; 95% CI, 0.05-0.45), there was nevertheless a clear reduction in risk for nonresponders to antivirals, with a relative risk of 0.57, compared with controls (95% CI 0.37-0.85).

"Although the intervention was more beneficial among sustained virological responders than nonresponders, there was a clear effect in both patient groups. ... Antiviral therapy may have beneficial effects on the risk of developing HCC that are unrelated to the virological response."

On the other hand, there was no reported effect of antiviral therapy on all-cause mortality, liver-related mortality, or liver-related morbidity in this population.

Dr. Kimer conceded several limitations to this analysis. "Only two of the included trials evaluated pegylated interferon, which is the current standard treatment for chronic hepatitis C."

Moreover, the duration of treatment in several included studies was "relatively long, which may increase the proportion of responders."

Finally, Dr. Kimer added that the researchers were unable to perform subgroup analysis to determine which treatment duration or dose is best.

"Based on the duration of follow-up and the lack of clear evidence concerning morbidity or mortality, we cannot exclude that interferon delays rather than prevents carcinogenesis," concluded the investigators.

Nevertheless, the "protection from HCC might be even better among patients in current antiviral therapy since the proportion of virological responders continues to increase with ongoing improvements in therapy," they wrote.

"Additional randomized trials with longer follow-up are still warranted to determine whether this is the case," they noted.

The authors disclosed having no outside funding and no competing interests related to this study.

Antiviral therapy may reduce the risk of hepatocellular carcinoma in patients with hepatitis C infections, Dr. Nina Kimer reported in the Oct. 22 issue of BMJ Open, published online.

Moreover, the effect seems to persist regardless of whether sustained virologic response is achieved.

Dr. Kimer, of Copenhagen University Hospital, Hvidovre, Denmark, and colleagues conducted a meta-analysis of trials looking at hepatitis C-related cirrhosis or fibrosis (BMJ Open 2012;2:e001313 [doi:10.1136/bmjopen-2012-001313]).

Courtesy US. Dept of Veterans Affairs

The primary analysis focused on randomized controlled trials, although prospective cohort studies with control groups were included in sensitivity analyses.

The authors searched the Cochrane Library, PubMed, EMBASE, and Web of Science databases, as well as reference lists from relevant papers, conference proceedings, and the World Health Organization Trial Search Portal.

Studies looking at HIV and chronic hepatitis B were excluded, for a total of eight randomized trials and five prospective cohort studies.

The duration of therapy (which included pegylated interferon in two trials, interferon plus ribavirin in one trial, and interferon monotherapy in the remaining trials) varied from 1 to 5 years. Follow-up ranged from 2 to 8.7 years.

Overall, the authors found that 81 of 1,156 patients who received antiviral therapy and 129 of 1,074 control patients who received no therapy developed hepatocellular carcinoma.

The relative risk for antiviral therapy, compared with no treatment, was 0.53 (95% confidence interval, 0.34-0.81).

"The corresponding number needed to treat to prevent one case of [hepatocellular carcinoma] was eight patients," added the researchers.

And while the effect of antivirals was more pronounced among patients with a virological response (RR 0.15; 95% CI, 0.05-0.45), there was nevertheless a clear reduction in risk for nonresponders to antivirals, with a relative risk of 0.57, compared with controls (95% CI 0.37-0.85).

"Although the intervention was more beneficial among sustained virological responders than nonresponders, there was a clear effect in both patient groups. ... Antiviral therapy may have beneficial effects on the risk of developing HCC that are unrelated to the virological response."

On the other hand, there was no reported effect of antiviral therapy on all-cause mortality, liver-related mortality, or liver-related morbidity in this population.

Dr. Kimer conceded several limitations to this analysis. "Only two of the included trials evaluated pegylated interferon, which is the current standard treatment for chronic hepatitis C."

Moreover, the duration of treatment in several included studies was "relatively long, which may increase the proportion of responders."

Finally, Dr. Kimer added that the researchers were unable to perform subgroup analysis to determine which treatment duration or dose is best.

"Based on the duration of follow-up and the lack of clear evidence concerning morbidity or mortality, we cannot exclude that interferon delays rather than prevents carcinogenesis," concluded the investigators.

Nevertheless, the "protection from HCC might be even better among patients in current antiviral therapy since the proportion of virological responders continues to increase with ongoing improvements in therapy," they wrote.

"Additional randomized trials with longer follow-up are still warranted to determine whether this is the case," they noted.

The authors disclosed having no outside funding and no competing interests related to this study.

NEW YORK—Hospitalists are poised to become key allies with hospital quality and safety officers nationwide, according to veteran hospitalist Jennifer Myers, MD, FHM, director of quality and safety education for Penn Medicine in Philadelphia.

Addressing hospitalists at the seventh annual Mid-Atlantic Hospital Medicine Symposium at Mount Sinai School of Medicine in New York, Dr. Myers said that while the challenges associated with quality improvement (QI) are many, HM leaders have the in-house relationships and respect to push the issue.

"There's really no other specialty more perfectly poised to lead this work," she told more than 180 symposium attendees Friday.

Dr. Myers, in an address titled "Enhancing Patient Safety," told The Hospitalist that HM leaders pursue three broad goals: to participate in QI programs already in place, to help create or foster a culture focused on addressing mistakes, and to teach those lessons to young physicians.

She urged physicians to actively report on mistakes and near misses, and earnestly address the processes that led to them. If a vehicle to discuss the mistakes doesn't exist at an institution, hospitalists can push to start one, she said. If a hospital doesn't have an electronic incident reporting system, a hospitalist can push to get one. "This is the goal," Dr. Myers added. "People coming to work and feeling they can be safe and report errors in the spirit of improvement."

She noted that many hospitalists already oversee quality and safety programs without any formal training. She recommended some of those physicians consider the Quality and Safety Educators Academy (QSEA), a three-day academy designed as a faculty development program and sponsored by SHM and the Alliance for Academic Internal Medicine (AAIM). The academy is March 7-9, 2013, in Tempe, Ariz.

NEW YORK—Hospitalists are poised to become key allies with hospital quality and safety officers nationwide, according to veteran hospitalist Jennifer Myers, MD, FHM, director of quality and safety education for Penn Medicine in Philadelphia.

Addressing hospitalists at the seventh annual Mid-Atlantic Hospital Medicine Symposium at Mount Sinai School of Medicine in New York, Dr. Myers said that while the challenges associated with quality improvement (QI) are many, HM leaders have the in-house relationships and respect to push the issue.

"There's really no other specialty more perfectly poised to lead this work," she told more than 180 symposium attendees Friday.

Dr. Myers, in an address titled "Enhancing Patient Safety," told The Hospitalist that HM leaders pursue three broad goals: to participate in QI programs already in place, to help create or foster a culture focused on addressing mistakes, and to teach those lessons to young physicians.

She urged physicians to actively report on mistakes and near misses, and earnestly address the processes that led to them. If a vehicle to discuss the mistakes doesn't exist at an institution, hospitalists can push to start one, she said. If a hospital doesn't have an electronic incident reporting system, a hospitalist can push to get one. "This is the goal," Dr. Myers added. "People coming to work and feeling they can be safe and report errors in the spirit of improvement."

She noted that many hospitalists already oversee quality and safety programs without any formal training. She recommended some of those physicians consider the Quality and Safety Educators Academy (QSEA), a three-day academy designed as a faculty development program and sponsored by SHM and the Alliance for Academic Internal Medicine (AAIM). The academy is March 7-9, 2013, in Tempe, Ariz.

NEW YORK—Hospitalists are poised to become key allies with hospital quality and safety officers nationwide, according to veteran hospitalist Jennifer Myers, MD, FHM, director of quality and safety education for Penn Medicine in Philadelphia.

Addressing hospitalists at the seventh annual Mid-Atlantic Hospital Medicine Symposium at Mount Sinai School of Medicine in New York, Dr. Myers said that while the challenges associated with quality improvement (QI) are many, HM leaders have the in-house relationships and respect to push the issue.

"There's really no other specialty more perfectly poised to lead this work," she told more than 180 symposium attendees Friday.

Dr. Myers, in an address titled "Enhancing Patient Safety," told The Hospitalist that HM leaders pursue three broad goals: to participate in QI programs already in place, to help create or foster a culture focused on addressing mistakes, and to teach those lessons to young physicians.

She urged physicians to actively report on mistakes and near misses, and earnestly address the processes that led to them. If a vehicle to discuss the mistakes doesn't exist at an institution, hospitalists can push to start one, she said. If a hospital doesn't have an electronic incident reporting system, a hospitalist can push to get one. "This is the goal," Dr. Myers added. "People coming to work and feeling they can be safe and report errors in the spirit of improvement."

She noted that many hospitalists already oversee quality and safety programs without any formal training. She recommended some of those physicians consider the Quality and Safety Educators Academy (QSEA), a three-day academy designed as a faculty development program and sponsored by SHM and the Alliance for Academic Internal Medicine (AAIM). The academy is March 7-9, 2013, in Tempe, Ariz.

Using localized inpatient teams of hospitalists and physician assistants in single nursing units can boost physicians' productivity, hospital efficiency, and patient outcomes, according to a study in the Journal of Hospital Medicine.

The study, "Impact of Localizing General Medical Teams to a Single Nursing Unit," compared the effectiveness of using localized medical teams with nonlocalized teams in caring for patients in the nursing unit of an academic medical center from April to mid-July 2010. The localized team members received 51% fewer paged messages, logged more encounters with patients, and generated more relative value units (RVUs) during the workday compared with the nonlocalized teams, researchers reported.

These findings point to an overall significant increase in team productivity. The risk of 30-day readmissions and the patient charges incurred remained the same.

Lead author Siddhartha Singh, MD, MS, associate chief medical officer at Froedtert Hospital and the Medical College of Wisconsin in Milwaukee, says the study's most surprising finding was that patients averaged longer length of stay (LOS) under localized team care. However, Dr. Singh says, "if somebody wants to try out localization, the big message from our study is that it's a good thing as far as workflow is concerned."

Dr. Singh hopes the research will spark future studies about localized hospitalist teams and the optimal amount of localization needed to improve productivity and efficiency.

"When others try to localize patients, they need to be careful of 100% localization," he says. "My sense is, without having studied this any further, there's a sweet spot that optimizes the care provided to the patients [and maximizes] hospital efficiency and physician assistant productivity. I'm hoping that the next set of research on this topic tries to investigate that."

Using localized inpatient teams of hospitalists and physician assistants in single nursing units can boost physicians' productivity, hospital efficiency, and patient outcomes, according to a study in the Journal of Hospital Medicine.

The study, "Impact of Localizing General Medical Teams to a Single Nursing Unit," compared the effectiveness of using localized medical teams with nonlocalized teams in caring for patients in the nursing unit of an academic medical center from April to mid-July 2010. The localized team members received 51% fewer paged messages, logged more encounters with patients, and generated more relative value units (RVUs) during the workday compared with the nonlocalized teams, researchers reported.

These findings point to an overall significant increase in team productivity. The risk of 30-day readmissions and the patient charges incurred remained the same.

Lead author Siddhartha Singh, MD, MS, associate chief medical officer at Froedtert Hospital and the Medical College of Wisconsin in Milwaukee, says the study's most surprising finding was that patients averaged longer length of stay (LOS) under localized team care. However, Dr. Singh says, "if somebody wants to try out localization, the big message from our study is that it's a good thing as far as workflow is concerned."

Dr. Singh hopes the research will spark future studies about localized hospitalist teams and the optimal amount of localization needed to improve productivity and efficiency.

"When others try to localize patients, they need to be careful of 100% localization," he says. "My sense is, without having studied this any further, there's a sweet spot that optimizes the care provided to the patients [and maximizes] hospital efficiency and physician assistant productivity. I'm hoping that the next set of research on this topic tries to investigate that."

Using localized inpatient teams of hospitalists and physician assistants in single nursing units can boost physicians' productivity, hospital efficiency, and patient outcomes, according to a study in the Journal of Hospital Medicine.

The study, "Impact of Localizing General Medical Teams to a Single Nursing Unit," compared the effectiveness of using localized medical teams with nonlocalized teams in caring for patients in the nursing unit of an academic medical center from April to mid-July 2010. The localized team members received 51% fewer paged messages, logged more encounters with patients, and generated more relative value units (RVUs) during the workday compared with the nonlocalized teams, researchers reported.

These findings point to an overall significant increase in team productivity. The risk of 30-day readmissions and the patient charges incurred remained the same.

Lead author Siddhartha Singh, MD, MS, associate chief medical officer at Froedtert Hospital and the Medical College of Wisconsin in Milwaukee, says the study's most surprising finding was that patients averaged longer length of stay (LOS) under localized team care. However, Dr. Singh says, "if somebody wants to try out localization, the big message from our study is that it's a good thing as far as workflow is concerned."

Dr. Singh hopes the research will spark future studies about localized hospitalist teams and the optimal amount of localization needed to improve productivity and efficiency.

"When others try to localize patients, they need to be careful of 100% localization," he says. "My sense is, without having studied this any further, there's a sweet spot that optimizes the care provided to the patients [and maximizes] hospital efficiency and physician assistant productivity. I'm hoping that the next set of research on this topic tries to investigate that."

Adalimumab, a subcutaneously administered tumor necrosis factor blocker, has been approved for treating adults with moderately to severely active ulcerative colitis who have not had an adequate response with conventional treatments, the Food and Drug Administration announced.

The safety and effectiveness of adalimumab for this patient population was established in two clinical studies of 908 patients with moderately to severely active ulcerative colitis (UC).

Adalimumab, marketed as Humira by Abbott Laboratories, was first approved for treating rheumatoid arthritis in 2002, followed by psoriatic arthritis in 2005, ankylosing spondylitis in 2006, Crohn’s disease in 2007, and plaque psoriasis and juvenile idiopathic arthritis in 2008.

Adalimumab is the second TNF blocker to be approved for ulcerative colitis; infliximab (Remicade), an intravenous TNF blocker, was previously approved for treating ulcerative colitis.

Clinical remission rates in the two studies were significantly greater among patients treated with infliximab than among those who received placebo: In an 8-week study, which did not include patients who had previously been treated with a TNF blocker, the clinical remission rate at 8 weeks was 18.5% among those on adalimumab vs. 9.2% in those on placebo, a 9.3% difference.

In the second study, which followed patients for 1 year and included some who had been treated with infliximab, the clinical remission rate at 8 weeks was 16.5% among those on adalimumab, vs. 9.3% among those on placebo, a 7.2% difference.

At a meeting on Aug. 28 held to review these data, the majority of the FDA’s Gastrointestinal Drugs Advisory Committee agreed that these differences represented clinically meaningful benefits and supported approval of adalimumab for this indication – adults with moderately to severely active ulcerative colitis who have not had an adequate response to conventional treatment.

Panelists cited the need for more treatments for ulcerative colitis and for a subcutaneous TNF blocker for these patients, as well as its potential steroid-sparing effects.

In the studies, no new side effects were identified, the agency said.

The FDA statement points out that the effectiveness of adalimumab "has not been established in patients with ulcerative colitis who have lost response to or were intolerant to TNF blockers."

The approved dosing regimen for adalimumab is a starting dose of 160 mg, followed by a second dose of 80 mg 2 weeks later and then a maintenance dose of 40 mg every other week.

"The drug should only continue to be used in patients who have shown evidence of clinical remission by 8 weeks of therapy," according to the FDA statement.

Adalimumab is the first self-administered biologic treatment for ulcerative colitis to be approved.

Adalimumab, a subcutaneously administered tumor necrosis factor blocker, has been approved for treating adults with moderately to severely active ulcerative colitis who have not had an adequate response with conventional treatments, the Food and Drug Administration announced.

The safety and effectiveness of adalimumab for this patient population was established in two clinical studies of 908 patients with moderately to severely active ulcerative colitis (UC).

Adalimumab, marketed as Humira by Abbott Laboratories, was first approved for treating rheumatoid arthritis in 2002, followed by psoriatic arthritis in 2005, ankylosing spondylitis in 2006, Crohn’s disease in 2007, and plaque psoriasis and juvenile idiopathic arthritis in 2008.

Adalimumab is the second TNF blocker to be approved for ulcerative colitis; infliximab (Remicade), an intravenous TNF blocker, was previously approved for treating ulcerative colitis.

Clinical remission rates in the two studies were significantly greater among patients treated with infliximab than among those who received placebo: In an 8-week study, which did not include patients who had previously been treated with a TNF blocker, the clinical remission rate at 8 weeks was 18.5% among those on adalimumab vs. 9.2% in those on placebo, a 9.3% difference.

In the second study, which followed patients for 1 year and included some who had been treated with infliximab, the clinical remission rate at 8 weeks was 16.5% among those on adalimumab, vs. 9.3% among those on placebo, a 7.2% difference.

At a meeting on Aug. 28 held to review these data, the majority of the FDA’s Gastrointestinal Drugs Advisory Committee agreed that these differences represented clinically meaningful benefits and supported approval of adalimumab for this indication – adults with moderately to severely active ulcerative colitis who have not had an adequate response to conventional treatment.

Panelists cited the need for more treatments for ulcerative colitis and for a subcutaneous TNF blocker for these patients, as well as its potential steroid-sparing effects.

In the studies, no new side effects were identified, the agency said.

The FDA statement points out that the effectiveness of adalimumab "has not been established in patients with ulcerative colitis who have lost response to or were intolerant to TNF blockers."

The approved dosing regimen for adalimumab is a starting dose of 160 mg, followed by a second dose of 80 mg 2 weeks later and then a maintenance dose of 40 mg every other week.

"The drug should only continue to be used in patients who have shown evidence of clinical remission by 8 weeks of therapy," according to the FDA statement.

Adalimumab is the first self-administered biologic treatment for ulcerative colitis to be approved.

Adalimumab, a subcutaneously administered tumor necrosis factor blocker, has been approved for treating adults with moderately to severely active ulcerative colitis who have not had an adequate response with conventional treatments, the Food and Drug Administration announced.

The safety and effectiveness of adalimumab for this patient population was established in two clinical studies of 908 patients with moderately to severely active ulcerative colitis (UC).

Adalimumab, marketed as Humira by Abbott Laboratories, was first approved for treating rheumatoid arthritis in 2002, followed by psoriatic arthritis in 2005, ankylosing spondylitis in 2006, Crohn’s disease in 2007, and plaque psoriasis and juvenile idiopathic arthritis in 2008.

Adalimumab is the second TNF blocker to be approved for ulcerative colitis; infliximab (Remicade), an intravenous TNF blocker, was previously approved for treating ulcerative colitis.

Clinical remission rates in the two studies were significantly greater among patients treated with infliximab than among those who received placebo: In an 8-week study, which did not include patients who had previously been treated with a TNF blocker, the clinical remission rate at 8 weeks was 18.5% among those on adalimumab vs. 9.2% in those on placebo, a 9.3% difference.

In the second study, which followed patients for 1 year and included some who had been treated with infliximab, the clinical remission rate at 8 weeks was 16.5% among those on adalimumab, vs. 9.3% among those on placebo, a 7.2% difference.

At a meeting on Aug. 28 held to review these data, the majority of the FDA’s Gastrointestinal Drugs Advisory Committee agreed that these differences represented clinically meaningful benefits and supported approval of adalimumab for this indication – adults with moderately to severely active ulcerative colitis who have not had an adequate response to conventional treatment.

Panelists cited the need for more treatments for ulcerative colitis and for a subcutaneous TNF blocker for these patients, as well as its potential steroid-sparing effects.

In the studies, no new side effects were identified, the agency said.

The FDA statement points out that the effectiveness of adalimumab "has not been established in patients with ulcerative colitis who have lost response to or were intolerant to TNF blockers."

The approved dosing regimen for adalimumab is a starting dose of 160 mg, followed by a second dose of 80 mg 2 weeks later and then a maintenance dose of 40 mg every other week.

"The drug should only continue to be used in patients who have shown evidence of clinical remission by 8 weeks of therapy," according to the FDA statement.

Adalimumab is the first self-administered biologic treatment for ulcerative colitis to be approved.

Ustekinumab induced a clinical response in patients with moderate to severe Crohn’s disease that was resistant to tumor necrosis factor antagonists, in a phase IIb clinical trial published online Oct. 17 in the New England Journal of Medicine.

However, the agent did not improve remission rates, compared with placebo, said Dr. William J. Sandborn, AGAF, who is professor of medicine and chief of the division of gastroenterology at the University of California San Diego, La Jolla, and his associates.

"A sizable proportion" of patients with moderate to severe Crohn’s disease do not respond to TNF antagonists, have an unsustained response, or must discontinue the medications because of adverse effects. After ustekinumab showed efficacy in such patients in a phase IIa clinical study, Dr. Sandborn and his colleagues performed a 36-week double-blind phase IIb trial in 526 adults at 153 medical centers in 12 countries.

Ustekinumab, a human IgG monoclonal antibody that inhibits the receptors for interleukin-12 and interleukin-23 on T cells, natural killer cells, and antigen-presenting cells, has Food and Drug Administration approval for use in plaque psoriasis. This clinical trial was sponsored by an affiliate of the manufacturer, Janssen Biotech.

During an 8-week induction phase, the study subjects were randomly assigned to receive intravenous placebo (132 patients) or ustekinumab in 1-mg/kg (131 patients), 3-mg/kg (132 patients), or 6-mg/kg (131 patients) doses. Then, during weeks 8-36, the study subjects who showed a response to induction therapy and those who did not show a response were separately randomized to receive either subcutaneous ustekinumab (90 mg) or placebo at week 8 and week 16, as maintenance therapy.

Treatment efficacy was assessed at week 22, and patients were followed through week 36 for a safety analysis. A total of 36.1% of the subjects discontinued the study before week 36.

The primary end point was a clinical response, defined as a decrease of 100 points or more on the Crohn’s Disease Activity Index (CDAI) score.

A total of 39.7% of patients receiving the 6-mg induction dose showed a clinical response, which was significantly greater than the 23.5% of patients receiving placebo, the investigators said (N. Engl. J. Med. 2012 [doi:10.1056/NEJMoa1203572]).

A greater number of patients receiving the lower doses of ustekinumab than receiving placebo showed a clinical response, but the differences between these low-dose groups and the placebo group did not reach statistical significance.

The 6-mg/kg dose was effective across most demographic and disease characteristics, judging from the findings of a subgroup analysis. It was consistently effective in patients who had failed on their first attempt at therapy with TNF antagonists, patients who had failed on two or more TNF antagonists, and patients who had only a transient response to TNF antagonists.

However, rates of clinical remission did not differ significantly between patients receiving ustekinumab and those receiving placebo, Dr. Sandborn and his associates said.

At all follow-up visits, the proportion of patients who had a 70-point clinical response was significantly higher, the reductions in mean CDAI scores were significantly greater, and the reductions in C-reactive protein levels were significantly greater in patients receiving 6 mg per kg of ustekinumab than in the placebo group.

As a maintenance therapy, 90 mg of subcutaneous ustekinumab appeared to be effective in patients who responded to the induction dose of the agent. The proportion of patients who showed a clinical response at week 22 was 69.4% in those receiving maintenance ustekinumab, significantly greater than the 42.5% response rate among those receiving maintenance placebo.

Among patients who responded to induction-phase ustekinumab, 41.7% of those who also received maintenance ustekinumab achieved clinical remission at week 22, compared with only 27.4% of those who received maintenance placebo.

Similarly, among patients who showed a response to induction ustekinumab, reductions in both CDAI scores and CRP levels were sustained if they continued on maintenance ustekinumab but were not sustained if they continued on placebo for the maintenance period.

However, patients who did not show a response to induction ustekinumab also did not benefit from additional ustekinumab in the maintenance phase of the study.

The results of the safety analysis were "somewhat limited" by the small sample size and the short duration of treatment. No deaths, serious opportunistic infections, or major adverse cardiovascular events were reported, "but large studies of longer duration are needed to assess uncommon adverse events," the investigators said.

Of note, one patient receiving ustekinumab as both induction and maintenance therapy developed a basal cell carcinoma. Among patients taking ustekinumab in the induction phase of the study, six developed serious infections: Clostridium difficile, viral gastroenteritis, UTI, anal abscess, vaginal abscess, and a staph infection of a central catheter.

Ustekinumab induced a clinical response in patients with moderate to severe Crohn’s disease that was resistant to tumor necrosis factor antagonists, in a phase IIb clinical trial published online Oct. 17 in the New England Journal of Medicine.

However, the agent did not improve remission rates, compared with placebo, said Dr. William J. Sandborn, AGAF, who is professor of medicine and chief of the division of gastroenterology at the University of California San Diego, La Jolla, and his associates.

"A sizable proportion" of patients with moderate to severe Crohn’s disease do not respond to TNF antagonists, have an unsustained response, or must discontinue the medications because of adverse effects. After ustekinumab showed efficacy in such patients in a phase IIa clinical study, Dr. Sandborn and his colleagues performed a 36-week double-blind phase IIb trial in 526 adults at 153 medical centers in 12 countries.

Ustekinumab, a human IgG monoclonal antibody that inhibits the receptors for interleukin-12 and interleukin-23 on T cells, natural killer cells, and antigen-presenting cells, has Food and Drug Administration approval for use in plaque psoriasis. This clinical trial was sponsored by an affiliate of the manufacturer, Janssen Biotech.

During an 8-week induction phase, the study subjects were randomly assigned to receive intravenous placebo (132 patients) or ustekinumab in 1-mg/kg (131 patients), 3-mg/kg (132 patients), or 6-mg/kg (131 patients) doses. Then, during weeks 8-36, the study subjects who showed a response to induction therapy and those who did not show a response were separately randomized to receive either subcutaneous ustekinumab (90 mg) or placebo at week 8 and week 16, as maintenance therapy.

Treatment efficacy was assessed at week 22, and patients were followed through week 36 for a safety analysis. A total of 36.1% of the subjects discontinued the study before week 36.

The primary end point was a clinical response, defined as a decrease of 100 points or more on the Crohn’s Disease Activity Index (CDAI) score.

A total of 39.7% of patients receiving the 6-mg induction dose showed a clinical response, which was significantly greater than the 23.5% of patients receiving placebo, the investigators said (N. Engl. J. Med. 2012 [doi:10.1056/NEJMoa1203572]).

A greater number of patients receiving the lower doses of ustekinumab than receiving placebo showed a clinical response, but the differences between these low-dose groups and the placebo group did not reach statistical significance.

The 6-mg/kg dose was effective across most demographic and disease characteristics, judging from the findings of a subgroup analysis. It was consistently effective in patients who had failed on their first attempt at therapy with TNF antagonists, patients who had failed on two or more TNF antagonists, and patients who had only a transient response to TNF antagonists.

However, rates of clinical remission did not differ significantly between patients receiving ustekinumab and those receiving placebo, Dr. Sandborn and his associates said.

At all follow-up visits, the proportion of patients who had a 70-point clinical response was significantly higher, the reductions in mean CDAI scores were significantly greater, and the reductions in C-reactive protein levels were significantly greater in patients receiving 6 mg per kg of ustekinumab than in the placebo group.

As a maintenance therapy, 90 mg of subcutaneous ustekinumab appeared to be effective in patients who responded to the induction dose of the agent. The proportion of patients who showed a clinical response at week 22 was 69.4% in those receiving maintenance ustekinumab, significantly greater than the 42.5% response rate among those receiving maintenance placebo.

Among patients who responded to induction-phase ustekinumab, 41.7% of those who also received maintenance ustekinumab achieved clinical remission at week 22, compared with only 27.4% of those who received maintenance placebo.

Similarly, among patients who showed a response to induction ustekinumab, reductions in both CDAI scores and CRP levels were sustained if they continued on maintenance ustekinumab but were not sustained if they continued on placebo for the maintenance period.

However, patients who did not show a response to induction ustekinumab also did not benefit from additional ustekinumab in the maintenance phase of the study.

The results of the safety analysis were "somewhat limited" by the small sample size and the short duration of treatment. No deaths, serious opportunistic infections, or major adverse cardiovascular events were reported, "but large studies of longer duration are needed to assess uncommon adverse events," the investigators said.

Of note, one patient receiving ustekinumab as both induction and maintenance therapy developed a basal cell carcinoma. Among patients taking ustekinumab in the induction phase of the study, six developed serious infections: Clostridium difficile, viral gastroenteritis, UTI, anal abscess, vaginal abscess, and a staph infection of a central catheter.

Ustekinumab induced a clinical response in patients with moderate to severe Crohn’s disease that was resistant to tumor necrosis factor antagonists, in a phase IIb clinical trial published online Oct. 17 in the New England Journal of Medicine.

However, the agent did not improve remission rates, compared with placebo, said Dr. William J. Sandborn, AGAF, who is professor of medicine and chief of the division of gastroenterology at the University of California San Diego, La Jolla, and his associates.

"A sizable proportion" of patients with moderate to severe Crohn’s disease do not respond to TNF antagonists, have an unsustained response, or must discontinue the medications because of adverse effects. After ustekinumab showed efficacy in such patients in a phase IIa clinical study, Dr. Sandborn and his colleagues performed a 36-week double-blind phase IIb trial in 526 adults at 153 medical centers in 12 countries.

Ustekinumab, a human IgG monoclonal antibody that inhibits the receptors for interleukin-12 and interleukin-23 on T cells, natural killer cells, and antigen-presenting cells, has Food and Drug Administration approval for use in plaque psoriasis. This clinical trial was sponsored by an affiliate of the manufacturer, Janssen Biotech.

During an 8-week induction phase, the study subjects were randomly assigned to receive intravenous placebo (132 patients) or ustekinumab in 1-mg/kg (131 patients), 3-mg/kg (132 patients), or 6-mg/kg (131 patients) doses. Then, during weeks 8-36, the study subjects who showed a response to induction therapy and those who did not show a response were separately randomized to receive either subcutaneous ustekinumab (90 mg) or placebo at week 8 and week 16, as maintenance therapy.

Treatment efficacy was assessed at week 22, and patients were followed through week 36 for a safety analysis. A total of 36.1% of the subjects discontinued the study before week 36.

The primary end point was a clinical response, defined as a decrease of 100 points or more on the Crohn’s Disease Activity Index (CDAI) score.

A total of 39.7% of patients receiving the 6-mg induction dose showed a clinical response, which was significantly greater than the 23.5% of patients receiving placebo, the investigators said (N. Engl. J. Med. 2012 [doi:10.1056/NEJMoa1203572]).

A greater number of patients receiving the lower doses of ustekinumab than receiving placebo showed a clinical response, but the differences between these low-dose groups and the placebo group did not reach statistical significance.

The 6-mg/kg dose was effective across most demographic and disease characteristics, judging from the findings of a subgroup analysis. It was consistently effective in patients who had failed on their first attempt at therapy with TNF antagonists, patients who had failed on two or more TNF antagonists, and patients who had only a transient response to TNF antagonists.

However, rates of clinical remission did not differ significantly between patients receiving ustekinumab and those receiving placebo, Dr. Sandborn and his associates said.

At all follow-up visits, the proportion of patients who had a 70-point clinical response was significantly higher, the reductions in mean CDAI scores were significantly greater, and the reductions in C-reactive protein levels were significantly greater in patients receiving 6 mg per kg of ustekinumab than in the placebo group.

As a maintenance therapy, 90 mg of subcutaneous ustekinumab appeared to be effective in patients who responded to the induction dose of the agent. The proportion of patients who showed a clinical response at week 22 was 69.4% in those receiving maintenance ustekinumab, significantly greater than the 42.5% response rate among those receiving maintenance placebo.

Among patients who responded to induction-phase ustekinumab, 41.7% of those who also received maintenance ustekinumab achieved clinical remission at week 22, compared with only 27.4% of those who received maintenance placebo.

Similarly, among patients who showed a response to induction ustekinumab, reductions in both CDAI scores and CRP levels were sustained if they continued on maintenance ustekinumab but were not sustained if they continued on placebo for the maintenance period.

However, patients who did not show a response to induction ustekinumab also did not benefit from additional ustekinumab in the maintenance phase of the study.

The results of the safety analysis were "somewhat limited" by the small sample size and the short duration of treatment. No deaths, serious opportunistic infections, or major adverse cardiovascular events were reported, "but large studies of longer duration are needed to assess uncommon adverse events," the investigators said.

Of note, one patient receiving ustekinumab as both induction and maintenance therapy developed a basal cell carcinoma. Among patients taking ustekinumab in the induction phase of the study, six developed serious infections: Clostridium difficile, viral gastroenteritis, UTI, anal abscess, vaginal abscess, and a staph infection of a central catheter.

Rapid diagnostic and point-of-care tests for hepatitis C virus are accurate enough to be used in first-line HCV screening worldwide, according to results from the first systematic review of evidence on such tests.

Blood-based point-of-care tests (POCTs) had better sensitivity and specificity overall than did blood-based rapid diagnostic tests (RDTs), Sushmita Shivkumar of McGill University, Montreal, Quebec, and her colleagues reported.

POCTs do not require sample processing or refrigeration, and have a shelf life of 6 months or more. Rapid diagnostic tests, or RDTs, require refrigeration and sample processing. Manufactured by a variety of firms under various marketing names, all the tests can detect HCV infection in under 30 minutes, with many taking less than 5 minutes, according to the investigators, who conducted a meta-analysis of 18 studies evaluating the accuracy of one or more RDT or POCT, compared with standard assays (Ann. Intern. Med. 2012;157:558-66).

Ms. Shivkumar and her colleagues found blood-based POCTs (using serum, plasma, or whole blood) to be the most accurate of the tests evaluated in the included studies, showing 98.9% sensitivity with a 95% confidence interval [CI] of 94.5%-99.8% for whole blood and 96.8%-99.6% for serum or plasma). RDTs of serum or plasma had 98.4% sensitivity (95% CI 88.9%-99.8%). Specificity was highest in POCTs of serum or plasma at 99.7% (95% CI, 99.3%-99.9%), followed by POCTs of whole blood at 99.5% (95% CI, 97.5%-99.9%), RDTs of serum or plasma at 98.6% (95% CI, 94.9%-99.6%). POCTs for oral fluids had a sensitivity of 97.1% (95% CI, 94.7%-98.4%) and specificity of 98.2% (95% CI, 92.2%-99.6%).

POCTs and RDTs cannot distinguish between acute and chronic HCV infections, which is one of the reasons that public health organizations continue to favor conventional assays. The Food and Drug Administration currently approves the use of a single POCT for HCV, and for use only in nontraditional settings; in the United Kingdom and Canada such tests have not yet been approved.

However, by being fast, accurate, and cheaper than conventional tests, the rapid diagnostic and point-of-care tests offer "great potential for expanded first-line screening for hepatitis C infection and demonstrate the utility of blood-based singleton POCTs and of multiplex POCTs designed to provide integrated HIV and HCV screening of at-risk populations," Ms. Shivkumar and her associates wrote in their analysis. "Their rapid turnaround time limits loss to follow-up and facilitates early linkages."

The authors also concluded that their findings showed that the rapid and point-of-care tests could play a "substantial role" in expanded global screening initiatives for HCV.

The blood-based POCTs, besides being the most accurate, have the advantage of not requiring refrigeration, the investigators wrote. This feature is key in developing countries in Africa and Asia, where prevalence of HCV infection is highest.

Ms. Shivkumar and her colleagues noted several weaknesses in their meta-analysis, mostly related to the quality of studies included. Only three of the studies they evaluated were blinded, while four received industry funding; the conventional assays used as reference varied in the studies, and HCV genotype information was not collected in most.

The study was supported by grants from the Canadian Institutes of Health Research. None of the authors declared conflicts of interest.

Rapid diagnostic and point-of-care tests for hepatitis C virus are accurate enough to be used in first-line HCV screening worldwide, according to results from the first systematic review of evidence on such tests.

Blood-based point-of-care tests (POCTs) had better sensitivity and specificity overall than did blood-based rapid diagnostic tests (RDTs), Sushmita Shivkumar of McGill University, Montreal, Quebec, and her colleagues reported.

POCTs do not require sample processing or refrigeration, and have a shelf life of 6 months or more. Rapid diagnostic tests, or RDTs, require refrigeration and sample processing. Manufactured by a variety of firms under various marketing names, all the tests can detect HCV infection in under 30 minutes, with many taking less than 5 minutes, according to the investigators, who conducted a meta-analysis of 18 studies evaluating the accuracy of one or more RDT or POCT, compared with standard assays (Ann. Intern. Med. 2012;157:558-66).

Ms. Shivkumar and her colleagues found blood-based POCTs (using serum, plasma, or whole blood) to be the most accurate of the tests evaluated in the included studies, showing 98.9% sensitivity with a 95% confidence interval [CI] of 94.5%-99.8% for whole blood and 96.8%-99.6% for serum or plasma). RDTs of serum or plasma had 98.4% sensitivity (95% CI 88.9%-99.8%). Specificity was highest in POCTs of serum or plasma at 99.7% (95% CI, 99.3%-99.9%), followed by POCTs of whole blood at 99.5% (95% CI, 97.5%-99.9%), RDTs of serum or plasma at 98.6% (95% CI, 94.9%-99.6%). POCTs for oral fluids had a sensitivity of 97.1% (95% CI, 94.7%-98.4%) and specificity of 98.2% (95% CI, 92.2%-99.6%).

POCTs and RDTs cannot distinguish between acute and chronic HCV infections, which is one of the reasons that public health organizations continue to favor conventional assays. The Food and Drug Administration currently approves the use of a single POCT for HCV, and for use only in nontraditional settings; in the United Kingdom and Canada such tests have not yet been approved.

However, by being fast, accurate, and cheaper than conventional tests, the rapid diagnostic and point-of-care tests offer "great potential for expanded first-line screening for hepatitis C infection and demonstrate the utility of blood-based singleton POCTs and of multiplex POCTs designed to provide integrated HIV and HCV screening of at-risk populations," Ms. Shivkumar and her associates wrote in their analysis. "Their rapid turnaround time limits loss to follow-up and facilitates early linkages."

The authors also concluded that their findings showed that the rapid and point-of-care tests could play a "substantial role" in expanded global screening initiatives for HCV.

The blood-based POCTs, besides being the most accurate, have the advantage of not requiring refrigeration, the investigators wrote. This feature is key in developing countries in Africa and Asia, where prevalence of HCV infection is highest.

Ms. Shivkumar and her colleagues noted several weaknesses in their meta-analysis, mostly related to the quality of studies included. Only three of the studies they evaluated were blinded, while four received industry funding; the conventional assays used as reference varied in the studies, and HCV genotype information was not collected in most.

The study was supported by grants from the Canadian Institutes of Health Research. None of the authors declared conflicts of interest.

Rapid diagnostic and point-of-care tests for hepatitis C virus are accurate enough to be used in first-line HCV screening worldwide, according to results from the first systematic review of evidence on such tests.

Blood-based point-of-care tests (POCTs) had better sensitivity and specificity overall than did blood-based rapid diagnostic tests (RDTs), Sushmita Shivkumar of McGill University, Montreal, Quebec, and her colleagues reported.

POCTs do not require sample processing or refrigeration, and have a shelf life of 6 months or more. Rapid diagnostic tests, or RDTs, require refrigeration and sample processing. Manufactured by a variety of firms under various marketing names, all the tests can detect HCV infection in under 30 minutes, with many taking less than 5 minutes, according to the investigators, who conducted a meta-analysis of 18 studies evaluating the accuracy of one or more RDT or POCT, compared with standard assays (Ann. Intern. Med. 2012;157:558-66).

Ms. Shivkumar and her colleagues found blood-based POCTs (using serum, plasma, or whole blood) to be the most accurate of the tests evaluated in the included studies, showing 98.9% sensitivity with a 95% confidence interval [CI] of 94.5%-99.8% for whole blood and 96.8%-99.6% for serum or plasma). RDTs of serum or plasma had 98.4% sensitivity (95% CI 88.9%-99.8%). Specificity was highest in POCTs of serum or plasma at 99.7% (95% CI, 99.3%-99.9%), followed by POCTs of whole blood at 99.5% (95% CI, 97.5%-99.9%), RDTs of serum or plasma at 98.6% (95% CI, 94.9%-99.6%). POCTs for oral fluids had a sensitivity of 97.1% (95% CI, 94.7%-98.4%) and specificity of 98.2% (95% CI, 92.2%-99.6%).

POCTs and RDTs cannot distinguish between acute and chronic HCV infections, which is one of the reasons that public health organizations continue to favor conventional assays. The Food and Drug Administration currently approves the use of a single POCT for HCV, and for use only in nontraditional settings; in the United Kingdom and Canada such tests have not yet been approved.

However, by being fast, accurate, and cheaper than conventional tests, the rapid diagnostic and point-of-care tests offer "great potential for expanded first-line screening for hepatitis C infection and demonstrate the utility of blood-based singleton POCTs and of multiplex POCTs designed to provide integrated HIV and HCV screening of at-risk populations," Ms. Shivkumar and her associates wrote in their analysis. "Their rapid turnaround time limits loss to follow-up and facilitates early linkages."

The authors also concluded that their findings showed that the rapid and point-of-care tests could play a "substantial role" in expanded global screening initiatives for HCV.

The blood-based POCTs, besides being the most accurate, have the advantage of not requiring refrigeration, the investigators wrote. This feature is key in developing countries in Africa and Asia, where prevalence of HCV infection is highest.

Ms. Shivkumar and her colleagues noted several weaknesses in their meta-analysis, mostly related to the quality of studies included. Only three of the studies they evaluated were blinded, while four received industry funding; the conventional assays used as reference varied in the studies, and HCV genotype information was not collected in most.

The study was supported by grants from the Canadian Institutes of Health Research. None of the authors declared conflicts of interest.

I had a thought experiment based on two truths about myself: I am all for universal health care, and I would not have strong objections to receiving a fixed salary.

But I know a lot of doctors who oppose Obamacare. I can see how having to see more patients and accept lower reimbursement rates, all while filling out disability paperwork for people you believe actually do have the capacity to work might leave a bad taste in any doctor’s mouth.

So here is the thought experiment: In this increasingly interdependent world, what if we could open up licensing regulations for physicians that would allow those of us who favor universal health care to practice in Canada or other parts of the United Kingdom, for example, and those who believe in traditional insurance-based health care to practice in the United States?

Wouldn’t that be ideal? Win-win.

I thought about the lung cancer patient in Wales whose surgery, radiation, and chemotherapy were all paid for by the National Health Service. Were he to develop metastatic disease, the NHS would not pay for Tarceva (erlotinib), because the National Institute for Health and Clinical Excellence (NICE) has decided that the cost of the drug is not worth the 8 extra weeks that the patient gets.

To some, this is the very definition of fairness. Health care is universal and is paid for by taxes. What is deemed reasonable is given to you completely free, and what is not, well, isn’t. It seems to be a more thoughtful, compassionate, and just way to practice medicine, and perhaps more practical as well. Everyone gets standard of care.

For others, the above scenario is inherently unfair. Why should a government agency decide what will be good for the individual? Why should government decide that an extra 8 weeks for any individual is futile and not worth taxpayer money? People should be able to buy what they can afford, regardless of outcome. It is their money after all.

And then I realized that it is in such societies where capitalism is unbridled that pharmaceuticals thrive. Capitalism provides pharmaceutical companies with the incentives to invest in research and development. And it is precisely that R&D that leads to the kind of information that NICE needs to make decisions about drug utilization.

Said another way, the information and innovation that come from cutthroat capitalist societies is precisely what allows the nationalized health care systems to succeed.

So while I may dislike the unabashed concern for profit that I imagine motivates health insurance agencies and pharmaceutical companies (who among us, left or right leaning, didn’t find the increase in colchicine pricing offensive?), I recognize their necessity and am ultimately grateful that what they do allows societies that do provide universal health care to do so.

Bonus: Interestingly enough, I found a paper from the economics department at MIT that says basically the same thing, not just about health care, but about welfare in general.

Dr. Chan practices rheumatology in Pawtucket, R.I.

I had a thought experiment based on two truths about myself: I am all for universal health care, and I would not have strong objections to receiving a fixed salary.

But I know a lot of doctors who oppose Obamacare. I can see how having to see more patients and accept lower reimbursement rates, all while filling out disability paperwork for people you believe actually do have the capacity to work might leave a bad taste in any doctor’s mouth.

So here is the thought experiment: In this increasingly interdependent world, what if we could open up licensing regulations for physicians that would allow those of us who favor universal health care to practice in Canada or other parts of the United Kingdom, for example, and those who believe in traditional insurance-based health care to practice in the United States?

Wouldn’t that be ideal? Win-win.

I thought about the lung cancer patient in Wales whose surgery, radiation, and chemotherapy were all paid for by the National Health Service. Were he to develop metastatic disease, the NHS would not pay for Tarceva (erlotinib), because the National Institute for Health and Clinical Excellence (NICE) has decided that the cost of the drug is not worth the 8 extra weeks that the patient gets.

To some, this is the very definition of fairness. Health care is universal and is paid for by taxes. What is deemed reasonable is given to you completely free, and what is not, well, isn’t. It seems to be a more thoughtful, compassionate, and just way to practice medicine, and perhaps more practical as well. Everyone gets standard of care.

For others, the above scenario is inherently unfair. Why should a government agency decide what will be good for the individual? Why should government decide that an extra 8 weeks for any individual is futile and not worth taxpayer money? People should be able to buy what they can afford, regardless of outcome. It is their money after all.

And then I realized that it is in such societies where capitalism is unbridled that pharmaceuticals thrive. Capitalism provides pharmaceutical companies with the incentives to invest in research and development. And it is precisely that R&D that leads to the kind of information that NICE needs to make decisions about drug utilization.

Said another way, the information and innovation that come from cutthroat capitalist societies is precisely what allows the nationalized health care systems to succeed.

So while I may dislike the unabashed concern for profit that I imagine motivates health insurance agencies and pharmaceutical companies (who among us, left or right leaning, didn’t find the increase in colchicine pricing offensive?), I recognize their necessity and am ultimately grateful that what they do allows societies that do provide universal health care to do so.

Bonus: Interestingly enough, I found a paper from the economics department at MIT that says basically the same thing, not just about health care, but about welfare in general.

Dr. Chan practices rheumatology in Pawtucket, R.I.

I had a thought experiment based on two truths about myself: I am all for universal health care, and I would not have strong objections to receiving a fixed salary.

But I know a lot of doctors who oppose Obamacare. I can see how having to see more patients and accept lower reimbursement rates, all while filling out disability paperwork for people you believe actually do have the capacity to work might leave a bad taste in any doctor’s mouth.

So here is the thought experiment: In this increasingly interdependent world, what if we could open up licensing regulations for physicians that would allow those of us who favor universal health care to practice in Canada or other parts of the United Kingdom, for example, and those who believe in traditional insurance-based health care to practice in the United States?

Wouldn’t that be ideal? Win-win.

I thought about the lung cancer patient in Wales whose surgery, radiation, and chemotherapy were all paid for by the National Health Service. Were he to develop metastatic disease, the NHS would not pay for Tarceva (erlotinib), because the National Institute for Health and Clinical Excellence (NICE) has decided that the cost of the drug is not worth the 8 extra weeks that the patient gets.

To some, this is the very definition of fairness. Health care is universal and is paid for by taxes. What is deemed reasonable is given to you completely free, and what is not, well, isn’t. It seems to be a more thoughtful, compassionate, and just way to practice medicine, and perhaps more practical as well. Everyone gets standard of care.

For others, the above scenario is inherently unfair. Why should a government agency decide what will be good for the individual? Why should government decide that an extra 8 weeks for any individual is futile and not worth taxpayer money? People should be able to buy what they can afford, regardless of outcome. It is their money after all.

And then I realized that it is in such societies where capitalism is unbridled that pharmaceuticals thrive. Capitalism provides pharmaceutical companies with the incentives to invest in research and development. And it is precisely that R&D that leads to the kind of information that NICE needs to make decisions about drug utilization.

Said another way, the information and innovation that come from cutthroat capitalist societies is precisely what allows the nationalized health care systems to succeed.

So while I may dislike the unabashed concern for profit that I imagine motivates health insurance agencies and pharmaceutical companies (who among us, left or right leaning, didn’t find the increase in colchicine pricing offensive?), I recognize their necessity and am ultimately grateful that what they do allows societies that do provide universal health care to do so.

Bonus: Interestingly enough, I found a paper from the economics department at MIT that says basically the same thing, not just about health care, but about welfare in general.

Dr. Chan practices rheumatology in Pawtucket, R.I.

SILVER SPRING, MD. – A Food and Drug Administration advisory panel unanimously supported the approval of teduglutide, a recombinant analogue of human glucagon-like peptide-2 (GLP-2), as a treatment to improve the intestinal absorption of fluid and nutrients in adults with short bowel syndrome, with recommendations to follow the drug’s long-term safety, at a meeting on Oct. 16.

At a meeting in September, the FDA’s Gastrointestinal Drugs Advisory Committee voted 12 to 0 that the benefits of teduglutide outweighed the potential risks in patients with short bowel syndrome (SBS). In phase III studies of 169 adults with SBS, whose estimated small bowel length was a mean of 72 cm and who had been on parenteral nutrition and IV therapy for a mean of 7 years, teduglutide significantly reduced the volume of parenteral nutrition and IV fluids they needed after 6 months of treatment, compared with placebo.

While the panelists unanimously agreed that the results represented a clinically meaningful benefit for these patients and generally felt comfortable with the drug’s safety profile, they recommended that more safety data are needed, including determining whether the risk of colorectal cancer is increased with treatment.

Produced in the distal small intestine and proximal large intestine, GLP-2 is "an intestinotrophic peptide that stimulates mucosal epithelium," increasing absorption of fluids and nutrients, according to the manufacturer, NPS Pharmaceuticals. In studies, patients treated with teduglutide, administered subcutaneously once a week, had evidence of increased villus height after 21 days of treatment, according to the company.

In the main phase III study of 86 adults with SBS, 63% of those treated with 0.05 mg/kg daily had at least a 20% reduction in the volume of parenteral nutrition and IV fluids (the primary end point) required after 24 weeks of treatment, compared with 30% of those on placebo; this was a statistically significant difference. The volume of parenteral nutrition and IV fluids from baseline to the 24th week of treatment was reduced by a median of 4.4 L/week among patients on teduglutide, compared with 2.3 L/week for patients on placebo. Teduglutide treatment also led to a higher percentage of patients with at least one day less on therapy than did placebo (54% vs. 23%). An extension study indicated that this effect was maintained through 1 year of treatment.

While the FDA reviewers agreed that the drug had clinically meaningful effects in the studies, they raised some safety issues, mainly potential tumor-promoting effects, as well as potential GI side effects that included biliary and pancreatic disease and GI stenosis and obstruction. To date, there have been no reports of small bowel malignancies in treated patients; the three malignancies reported in treated patients have been a metastatic adenocarcinoma in a patient who had been on treatment for almost a year and lung cancer in two patients who had a history of smoking. Adenomas were seen in the bile duct and jejunum of rats at 700 times the human dose, findings that are "consistent with the pharmacological effects of the drug," according to the FDA.

There was also a low incidence of intestinal obstruction and stenosis, cholecystitis, and pancreatic disease in treated patients, compared with no cases among those on placebo.

NPS has proposed a registry of treated patients to evaluate the long-term safety and effectiveness of teduglutide, and a risk evaluation and mitigation strategy (REMS) aimed at educating prescribers about the potential and known risks of treatment. The REMS would include a letter to health care professionals and professional societies, including the American Gastroenterological Association and the American College of Gastroenterology; and drug labeling that includes contraindications in patients with a history of malignancy or with active or currently suspected malignancy, as well as warnings and precautions about the possible acceleration of neoplastic growth, colorectal polyps, and small bowel neoplasia.

The panel voted 10 to 1, with one abstention, that the company’s plans were adequate for addressing the safety concerns, although they pointed out that the number of patients in the studies was small and recommended close follow-up of treated patients.

"It seems like it’s a fairly safe drug," but follow-up is short term and fewer than 200 patients have been treated with teduglutide, said panelist Dr. Kevin Kelly, director of the division of solid tumor oncology at Thomas Jefferson University, Philadelphia. He and others recommended that patients be followed for up to 10 years.

"My gut feeling is that this is probably a very safe drug" that does not increase the risk of carcinogenesis, said another panelist, Dr. Ronald Fogel of the Digestive Health Center of Michigan in Chesterfield. He recommended more aggressive follow-up of treated patients than was proposed by the company, which he said could include serial colonoscopies at 2-year intervals with multiple biopsies at areas of dysplasia.

If teduglutide is approved, the company will market it as Gattex. About 10,000-15,000 adults in the United States with SBS are dependent on parenteral nutrition and IV fluids for fluid and nutrient replacement, according to NPS. Teduglutide was recently approved in Europe for the same indication. The FDA is expected to make a decision on approval by Dec. 30; if the drug is approved, the company plans to pursue studies in pediatric patients with SBS.

The two drugs currently approved by the FDA for people with SBS who are dependent on parenteral nutrition are somatropin rhGH (Zorbtive), a growth hormone approved in 2003, and L-glutamine powder for oral solution (Nutrestore), an adjunctive treatment approved in 2004.

The FDA usually follows the recommendations of its advisory panels, which are not binding. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting. Occasionally, a panelist may be given a waiver, but not at this meeting.

SILVER SPRING, MD. – A Food and Drug Administration advisory panel unanimously supported the approval of teduglutide, a recombinant analogue of human glucagon-like peptide-2 (GLP-2), as a treatment to improve the intestinal absorption of fluid and nutrients in adults with short bowel syndrome, with recommendations to follow the drug’s long-term safety, at a meeting on Oct. 16.

At a meeting in September, the FDA’s Gastrointestinal Drugs Advisory Committee voted 12 to 0 that the benefits of teduglutide outweighed the potential risks in patients with short bowel syndrome (SBS). In phase III studies of 169 adults with SBS, whose estimated small bowel length was a mean of 72 cm and who had been on parenteral nutrition and IV therapy for a mean of 7 years, teduglutide significantly reduced the volume of parenteral nutrition and IV fluids they needed after 6 months of treatment, compared with placebo.

While the panelists unanimously agreed that the results represented a clinically meaningful benefit for these patients and generally felt comfortable with the drug’s safety profile, they recommended that more safety data are needed, including determining whether the risk of colorectal cancer is increased with treatment.

Produced in the distal small intestine and proximal large intestine, GLP-2 is "an intestinotrophic peptide that stimulates mucosal epithelium," increasing absorption of fluids and nutrients, according to the manufacturer, NPS Pharmaceuticals. In studies, patients treated with teduglutide, administered subcutaneously once a week, had evidence of increased villus height after 21 days of treatment, according to the company.

In the main phase III study of 86 adults with SBS, 63% of those treated with 0.05 mg/kg daily had at least a 20% reduction in the volume of parenteral nutrition and IV fluids (the primary end point) required after 24 weeks of treatment, compared with 30% of those on placebo; this was a statistically significant difference. The volume of parenteral nutrition and IV fluids from baseline to the 24th week of treatment was reduced by a median of 4.4 L/week among patients on teduglutide, compared with 2.3 L/week for patients on placebo. Teduglutide treatment also led to a higher percentage of patients with at least one day less on therapy than did placebo (54% vs. 23%). An extension study indicated that this effect was maintained through 1 year of treatment.

While the FDA reviewers agreed that the drug had clinically meaningful effects in the studies, they raised some safety issues, mainly potential tumor-promoting effects, as well as potential GI side effects that included biliary and pancreatic disease and GI stenosis and obstruction. To date, there have been no reports of small bowel malignancies in treated patients; the three malignancies reported in treated patients have been a metastatic adenocarcinoma in a patient who had been on treatment for almost a year and lung cancer in two patients who had a history of smoking. Adenomas were seen in the bile duct and jejunum of rats at 700 times the human dose, findings that are "consistent with the pharmacological effects of the drug," according to the FDA.

There was also a low incidence of intestinal obstruction and stenosis, cholecystitis, and pancreatic disease in treated patients, compared with no cases among those on placebo.

NPS has proposed a registry of treated patients to evaluate the long-term safety and effectiveness of teduglutide, and a risk evaluation and mitigation strategy (REMS) aimed at educating prescribers about the potential and known risks of treatment. The REMS would include a letter to health care professionals and professional societies, including the American Gastroenterological Association and the American College of Gastroenterology; and drug labeling that includes contraindications in patients with a history of malignancy or with active or currently suspected malignancy, as well as warnings and precautions about the possible acceleration of neoplastic growth, colorectal polyps, and small bowel neoplasia.

The panel voted 10 to 1, with one abstention, that the company’s plans were adequate for addressing the safety concerns, although they pointed out that the number of patients in the studies was small and recommended close follow-up of treated patients.

"It seems like it’s a fairly safe drug," but follow-up is short term and fewer than 200 patients have been treated with teduglutide, said panelist Dr. Kevin Kelly, director of the division of solid tumor oncology at Thomas Jefferson University, Philadelphia. He and others recommended that patients be followed for up to 10 years.

"My gut feeling is that this is probably a very safe drug" that does not increase the risk of carcinogenesis, said another panelist, Dr. Ronald Fogel of the Digestive Health Center of Michigan in Chesterfield. He recommended more aggressive follow-up of treated patients than was proposed by the company, which he said could include serial colonoscopies at 2-year intervals with multiple biopsies at areas of dysplasia.

If teduglutide is approved, the company will market it as Gattex. About 10,000-15,000 adults in the United States with SBS are dependent on parenteral nutrition and IV fluids for fluid and nutrient replacement, according to NPS. Teduglutide was recently approved in Europe for the same indication. The FDA is expected to make a decision on approval by Dec. 30; if the drug is approved, the company plans to pursue studies in pediatric patients with SBS.

The two drugs currently approved by the FDA for people with SBS who are dependent on parenteral nutrition are somatropin rhGH (Zorbtive), a growth hormone approved in 2003, and L-glutamine powder for oral solution (Nutrestore), an adjunctive treatment approved in 2004.

The FDA usually follows the recommendations of its advisory panels, which are not binding. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting. Occasionally, a panelist may be given a waiver, but not at this meeting.

SILVER SPRING, MD. – A Food and Drug Administration advisory panel unanimously supported the approval of teduglutide, a recombinant analogue of human glucagon-like peptide-2 (GLP-2), as a treatment to improve the intestinal absorption of fluid and nutrients in adults with short bowel syndrome, with recommendations to follow the drug’s long-term safety, at a meeting on Oct. 16.

At a meeting in September, the FDA’s Gastrointestinal Drugs Advisory Committee voted 12 to 0 that the benefits of teduglutide outweighed the potential risks in patients with short bowel syndrome (SBS). In phase III studies of 169 adults with SBS, whose estimated small bowel length was a mean of 72 cm and who had been on parenteral nutrition and IV therapy for a mean of 7 years, teduglutide significantly reduced the volume of parenteral nutrition and IV fluids they needed after 6 months of treatment, compared with placebo.

While the panelists unanimously agreed that the results represented a clinically meaningful benefit for these patients and generally felt comfortable with the drug’s safety profile, they recommended that more safety data are needed, including determining whether the risk of colorectal cancer is increased with treatment.

Produced in the distal small intestine and proximal large intestine, GLP-2 is "an intestinotrophic peptide that stimulates mucosal epithelium," increasing absorption of fluids and nutrients, according to the manufacturer, NPS Pharmaceuticals. In studies, patients treated with teduglutide, administered subcutaneously once a week, had evidence of increased villus height after 21 days of treatment, according to the company.

In the main phase III study of 86 adults with SBS, 63% of those treated with 0.05 mg/kg daily had at least a 20% reduction in the volume of parenteral nutrition and IV fluids (the primary end point) required after 24 weeks of treatment, compared with 30% of those on placebo; this was a statistically significant difference. The volume of parenteral nutrition and IV fluids from baseline to the 24th week of treatment was reduced by a median of 4.4 L/week among patients on teduglutide, compared with 2.3 L/week for patients on placebo. Teduglutide treatment also led to a higher percentage of patients with at least one day less on therapy than did placebo (54% vs. 23%). An extension study indicated that this effect was maintained through 1 year of treatment.

While the FDA reviewers agreed that the drug had clinically meaningful effects in the studies, they raised some safety issues, mainly potential tumor-promoting effects, as well as potential GI side effects that included biliary and pancreatic disease and GI stenosis and obstruction. To date, there have been no reports of small bowel malignancies in treated patients; the three malignancies reported in treated patients have been a metastatic adenocarcinoma in a patient who had been on treatment for almost a year and lung cancer in two patients who had a history of smoking. Adenomas were seen in the bile duct and jejunum of rats at 700 times the human dose, findings that are "consistent with the pharmacological effects of the drug," according to the FDA.

There was also a low incidence of intestinal obstruction and stenosis, cholecystitis, and pancreatic disease in treated patients, compared with no cases among those on placebo.

NPS has proposed a registry of treated patients to evaluate the long-term safety and effectiveness of teduglutide, and a risk evaluation and mitigation strategy (REMS) aimed at educating prescribers about the potential and known risks of treatment. The REMS would include a letter to health care professionals and professional societies, including the American Gastroenterological Association and the American College of Gastroenterology; and drug labeling that includes contraindications in patients with a history of malignancy or with active or currently suspected malignancy, as well as warnings and precautions about the possible acceleration of neoplastic growth, colorectal polyps, and small bowel neoplasia.

The panel voted 10 to 1, with one abstention, that the company’s plans were adequate for addressing the safety concerns, although they pointed out that the number of patients in the studies was small and recommended close follow-up of treated patients.

"It seems like it’s a fairly safe drug," but follow-up is short term and fewer than 200 patients have been treated with teduglutide, said panelist Dr. Kevin Kelly, director of the division of solid tumor oncology at Thomas Jefferson University, Philadelphia. He and others recommended that patients be followed for up to 10 years.

"My gut feeling is that this is probably a very safe drug" that does not increase the risk of carcinogenesis, said another panelist, Dr. Ronald Fogel of the Digestive Health Center of Michigan in Chesterfield. He recommended more aggressive follow-up of treated patients than was proposed by the company, which he said could include serial colonoscopies at 2-year intervals with multiple biopsies at areas of dysplasia.

If teduglutide is approved, the company will market it as Gattex. About 10,000-15,000 adults in the United States with SBS are dependent on parenteral nutrition and IV fluids for fluid and nutrient replacement, according to NPS. Teduglutide was recently approved in Europe for the same indication. The FDA is expected to make a decision on approval by Dec. 30; if the drug is approved, the company plans to pursue studies in pediatric patients with SBS.

The two drugs currently approved by the FDA for people with SBS who are dependent on parenteral nutrition are somatropin rhGH (Zorbtive), a growth hormone approved in 2003, and L-glutamine powder for oral solution (Nutrestore), an adjunctive treatment approved in 2004.

The FDA usually follows the recommendations of its advisory panels, which are not binding. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting. Occasionally, a panelist may be given a waiver, but not at this meeting.