Regulatory Considerations Toward Orphan Drug Designation and Orphan Drug Exclusivity in the United States and European Union: Structural Similarity, Clinical Superiority/Significant Benefit, and Case Studies.

The U.S. Food and Drug Administration and European Commission have developed successful orphan drug legislation to promote the research, development, and marketing approval of drugs to treat rare diseases. Central to these regulations are the concepts of structural similarity and clinical superiority/significant benefit to achieve orphan drug exclusivity. However, differences in health authority expectations remain regarding the qualification for an orphan drug designation, defining structural similarity, and demonstrating clinical superiority/significant benefit. These differences can create sponsor company uncertainty regarding the approvability of products (e.g., blocking risk by an existing orphan product) and divergent orphan drug decisions among health authorities. A comprehensive assessment of current regulations, case studies in exclusivities, and recommendations for improvement are presented.

Meeting report: Advancing accelerated regulatory review with Real-Time Oncology Review (RTOR), Project Orbis, and the Product Quality Assessment Aid.

The American Association of Pharmaceutical Scientists (AAPS) Chemistry, Manufacturing, and Controls (CMC) Community hosted two virtual panel discussions focusing on several novel regulatory review pathways for innovative oncology products: Real-Time Oncology Review (RTOR), Project Orbis, and the Product Quality Assessment Aid (PQAAid). The panel sessions were held on August 27, 2021, for the discussion of RTOR, and January 21, 2022, for the discussion of Project Orbis and the PQAAid. Both panel sessions included representatives from the US Food and Drug Administration (FDA) and subject matter experts from the pharmaceutical and biotechnology industries, with the aim of facilitating knowledge sharing on CMC-specific advantages, challenges, eligibility criteria for participation, and operational modifications instituted through the utilization of these acceleration initiatives. Key topics included managing cross-regional regulatory CMC requirements, adapting to expedited development timelines, coordinating interactions between health authorities and industry, and potential opportunities for future improvement and expansion of these programs. As RTOR, Project Orbis, and PQAAid are relatively new initiatives, the experiences shared by the panel experts are valuable for providing deeper insight into these new regulatory pathways and processes.

An evidence-based definition of anemia for singleton, uncomplicated pregnancies.

BACKGROUND: The definition for anemia in pregnancy is outdated, derived from Scandinavian studies in the 1970's to 1980's. To identity women at risk of blood transfusion, a common cause of Severe Maternal Morbidity, a standard definition of anemia in pregnancy in a modern, healthy United States cohort is needed. OBJECTIVE: To define anemia in pregnancy in a United States population including a large county vs. private hospital population using uncomplicated patients. MATERIALS AND METHODS: Inclusion criteria were healthy women with the first prenatal visit before 20 weeks. Exclusion criteria included preterm birth, preeclampsia, hypertension, diabetes, short interval pregnancy (<18 months), multiple gestation, abruption, and fetal demise. All women had iron fortification (Ferrous sulfate 325 mg daily) recommended. The presentation to care and pre-delivery hematocrits were obtained, and the percentiles determined. A total of 2000 patients were included, 1000 from the public county hospital and 1000 from the private hospital. Each cohort had 250 patients in each 2011, 2013, 2015, and 2018. The cohorts were compared for differences in the fifth percentile for each antepartum epoch. Student's t-test and chi-squared statistical tests were used for analysis, p-value of ≤0.05 was considered significant. RESULTS: In the public and private populations, 777 and 785 women presented in the first trimester while 223 and 215 presented in the second. The women at the private hospital were more likely to be older, Caucasian race, nulliparous, and present earlier to care. The fifth percentile was compared between the women in the private and public hospitals and were clinically indistinguishable. When combining the cohorts, the fifth percentile for hemoglobin/hematocrit was 11 g/dL/32.8% in the first trimester, 10.3 g/dL/30.6% in the second trimester, and 10.0 g/dL/30.2% pre-delivery. CONCLUSIONS: Fifth percentile determinations were made from a combined cohort of normal, uncomplicated pregnancies to define anemia in pregnancy. Comparison of two different cohorts confirms that the same definition for anemia is appropriate regardless of demographics or patient mix.

Meeting Report: N-Nitrosamine Impurity Control Strategies in the Pharmaceutical and Biotechnology Industries.

The American Association of Pharmaceutical Scientists (AAPS) Chemistry, Manufacturing, and Control (CMC) Community hosted a virtual panel discussion on December 9, 2020, to provide a forum to discuss N-nitrosamine control strategies in the pharmaceutical and biotechnology industries. The panel included staff from the US Food and Drug Administration (FDA) and industry subject matter experts. Meeting topics included acceptable intake levels for nitrosamine impurities, definitions of "acceptable level of risk," water as a contributor in nitrosamine risk assessments, nitrosamine impurity control strategies based upon fate/purge data, early vs. late development assessment expectations, application to oncology programs developed under ICH S9, and Drug Master File (DMF) regulatory expectations. During the meeting, divergence in global health authority expectations was additionally discussed. One of the most important outputs from this AAPS panel discussion was the criticality of continued dialog between industry and health authorities to help understand actual versus perceived risks and provide pragmatic, scientifically justified solutions to ensure patients are provided with an uninterrupted supply of safe medicines based on globally harmonized requirements.

Effectiveness of Chlamydia trachomatis expedited partner therapy in pregnancy.

BACKGROUND: Expedited partner therapy for Chlamydia trachomatis has had mixed efficacy in different populations, but limited data exist on the efficacy of the therapy in a pregnant population. OBJECTIVE: This study aimed to evaluate the real-world effectiveness of establishing a prenatal expedited partner therapy program in eradicating chlamydia before delivery and to examine the maternal and neonatal outcomes between women who received expedited partner therapy for chlamydia and women who received standard partner referral testing and treatment during pregnancy. STUDY DESIGN: An expedited partner therapy program was implemented on August 21, 2019, at a public hospital in a county with high chlamydia prevalence. Pregnant women were provided with single-dose packets of azithromycin to treat partners following a diagnosis of chlamydia infection. We prospectively observed pregnant women treated in the expedited partner therapy program who delivered at our institution in the same year and compared the outcomes with a historic cohort from the previous year that had traditional partner referral testing and treatment. We excluded women with concurrent gonorrhea, HIV, syphilis, or current intimate partner violence. The primary outcome was chlamydia reinfection or no-cure rates at repeat testing in 4 to 6 weeks following treatment or at the 36-week prenatal care screening. Secondary outcomes included obstetrical, maternal, and neonatal outcomes, including premature rupture of membranes, chorioamnionitis, endometritis, neonatal intensive care unit admission, neonatal sepsis, pneumonia, and conjunctivitis. RESULTS: The rate of chlamydia infection was 3.6% over a 2-year period in our delivered population. In the year following the implementation of the expedited partner therapy, compared with 419 women (mean±standard deviation, 23.4±5.5 years) who were diagnosed with chlamydia infection in the previous year, 471 women (mean±standard deviation age, 23.8±5.3 years) who delivered at our institution were diagnosed with chlamydia infection. There was no difference in race, parity, prenatal care attendance, or concomitant sexually transmitted infections. Compared with the pre-expedited partner therapy group, the rate of reinfection in the post-expedited partner therapy group was not statistically different (60/471 [13%] vs 61/419 [15%]; odds ratio, 0.86 [95% confidence interval 0.58-1.26]). In a per-protocol analysis, 72 women (17%) in the pre-expedited partner therapy group and 389 women (83%) in post-expedited partner therapy group received expedited partner therapy; reinfection was not statistically different between groups (P=.47). There was no difference in secondary outcomes, although a trend toward improved rates of endometritis was noted in the post-expedited partner therapy group (odds ratio, 0.13; 95% confidence interval, 0.02-1.02). CONCLUSION: The implementation of a prenatal expedited partner therapy program did not affect the rate of chlamydia reinfection before delivery. Treatment of chlamydia in an inner-city population has multiple factors that lead to successful treatment. Future efforts to reduce sexually transmitted infection and chlamydia reinfection rates in an at-risk population should include exploring patient education and safe sex practices beyond expedited partner therapy alone during pregnancy.

Syphilis Immunoassay Signal Strength Correlates with Active Infection in Pregnant Women.

OBJECTIVE: This study aimed to evaluate the association of ARCHITECT chemiluminescent immunoassay (CIA) signal strength (signal-to-cutoff [S/CO] ratio), with maternal syphilis stage, rapid plasma reagin (RPR) reactivity, and congenital syphilis. STUDY DESIGN: A prospective observational study of reverse syphilis screening was conducted. Pregnant women were screened with CIA. Reactive CIA was reflexed to RPR; particle agglutination test (Treponema pallidum particle agglutination [TPPA]) was performed for CIA+/RPR- results. Clinical staging with history and physical was performed, and disease stage was determined. Prior treatment was confirmed. We compared S/CO ratio and neonatal outcomes among the following groups: Group 1: CIA+/RPR+/TPPA+ or CIA+/RPR-/TPPA+ with active syphilis; Group 2: CIA+/RPR-/TPPA+ or CIA+/serofast RPR/TPPA+, previously treated; Group 3: CIA+/RPR-/TPPA+, no history of treatment or active disease; Group 4: CIA+/RPR-/TPPA-, false-positive CIA. RESULTS: A total of 144 women delivered with reactive CIA: 38 (26%) in Group 1, 69 (48%) in Group 2, 20 (14%) in Group 3, and 17 (12%) in Group 4. Mean (±standard deviation) S/CO ratio was 18.3 ± 5.4, 12.1 ± 5.3, 9.1 ± 4.6, and 1.9 ± 0.8, respectively (p < 0.001). Neonates with overt congenital syphilis occurred exclusively in Group 1. CONCLUSION: Women with active syphilis based on treatment history, clinical staging, and laboratory indices have higher CIA S/CO ratio and are more likely to deliver neonates with overt evidence of congenital syphilis.

Closed Incision Negative Pressure Therapy in Morbidly Obese Women Undergoing Cesarean Delivery: A Randomized Controlled Trial.

OBJECTIVE: To evaluate the efficacy of incisional negative pressure wound therapy in the prevention of postoperative wound morbidity in women with class III obesity undergoing cesarean delivery. METHODS: In an open label randomized controlled trial, women admitted for delivery with class III obesity (body mass index 40 or higher) measured within 2 weeks of admission for delivery were offered participation in the study. They were consented either in the outpatient maternal-fetal medicine specialty clinic, during admission to labor and delivery and before a decision to perform cesarean delivery, or in the preoperative area of the hospital before scheduled cesarean delivery. Exclusion criteria included anticoagulation therapy, human immunodeficiency virus infection, and silver or acrylic allergy. Those who ultimately underwent cesarean delivery were randomized to standard surgical dressing or incisional negative pressure wound therapy dressing. The primary outcome was wound morbidity. Preplanned secondary outcomes included characteristics of composite wound morbidity, and hospital, emergency room, and clinic utilization. The sample size estimate required randomization of 440 women to detect a 50% decrease in composite outcome. RESULTS: Between January 1, 2015, and July 31, 2016, 850 women were screened and 677 women with class III obesity were enrolled. Of these, 441 underwent cesarean delivery and were subsequently randomized (219 to standard dressing and 222 to incisional negative pressure wound therapy). The primary outcome, overall composite wound morbidity rate, was 18%. This was not different between the two cohorts (incisional negative pressure wound therapy 17% vs standard dressing 19%, relative risk 0.9 [95% CI 0.5-1.4]). CONCLUSION: Prophylactic incisional negative pressure wound therapy use did not reduce postoperative wound morbidity when compared with a standard surgical dressing in women with class III obesity. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02289157.

Factors Associated with Postpartum Loss to Follow-Up and Detectable Viremia After Delivery Among Pregnant Women Living with HIV.

Pregnant women living with HIV are at risk for loss to follow-up and viral rebound after delivery. We conducted a retrospective cohort study of women with HIV who delivered at Parkland Hospital, Dallas, to identify factors associated with postpartum loss to HIV care 1 year after delivery. Logistic regression was used to identify factors predicting loss to follow-up. For a subset of women, we compared odds of viremia detectable at delivery and postpartum among women with higher versus lower pill burden regimens. We included 604 women with HIV who delivered between 2005 and 2015. Three hundred ninety-one (65%) women completed at least one visit with an HIV provider within 1 year of delivery. The follow-up rate among black, non-Hispanic women was 65%; 57% for white, non-Hispanic women; and 78% for Hispanic women. Women without follow-up presented for prenatal care later (17 vs. 11 weeks, p < 0.001), and were less likely to be on antiretroviral therapy at initial prenatal visit (29% vs. 49%, p < 0.001). Factors predicting loss to follow-up in multivariate analysis included low-level viremia at delivery [adjusted odds ratio (aOR) = 2.85, 95% confidence interval (CI) = 1.73-4.71] and failure to return for a postpartum visit (aOR = 3.19, 95% CI = 2.07-4.94). High antiretroviral pill burden (≥6 pills daily) was associated with viremia (>1000 copies/mL) at the first prenatal visit (OR = 8.7, 95% CI = 4.6-16.6) through 1 year postpartum (OR = 2.3, 95% CI = 1.2-4.4). Viremia at delivery, failure to return for a postpartum visit, and high pill burden during pregnancy are predictors of postpartum loss to HIV care.

Diagnostic accuracy of fourth-generation ARCHITECT HIV Ag/Ab Combo assay and utility of signal-to-cutoff ratio to predict false-positive HIV tests in pregnancy.

BACKGROUND: False-positive HIV screening tests in pregnancy may lead to unnecessary interventions in labor. In 2014, the Centers for Disease Control and Prevention released a new algorithm for HIV diagnosis using a fourth-generation screening test, which detects antibodies to HIV as well as p24 antigen and has a shorter window period compared with prior generations. A reactive screen requires a differentiation assay, and supplemental qualitative RNA testing is necessary for nonreactive differentiation assay. One screening test, the ARCHITECT Ag/Ab Combo assay, is described to have 100% sensitivity and >99% specificity in nonpregnant populations; however, its clinical performance in pregnancy has not been well described. OBJECTIVE: The objective of the study was to determine the performance of the ARCHITECT assay among pregnant women at a large county hospital and to assess whether the relative signal-to-cutoff ratio can be used to differentiate between false-positive vs confirmed HIV infections in women with a nonreactive differentiation assay. STUDY DESIGN: This is a retrospective review of fourth-generation HIV testing in pregnant women at Parkland Hospital between June 1, 2015, and Jan. 31, 2017. We identified gravidas screened using the ARCHITECT Ag/Ab Combo assay (index test), with reflex to differentiation assay. Women with reactive ARCHITECT and nonreactive differentiation assay were evaluated with a qualitative RNA assay (reference standard). We calculated sensitivity, specificity, predictive value, and false-positive rate of the ARCHITECT screening assay in our population and described characteristics of women with false-positive HIV testing vs confirmed infection. Among women with a nonreactive differentiation assay, we compared interventions among women with and without a qualitative RNA assay result available at delivery and examined relative signal-to-cutoff ratios of the ARCHITECT assay in women with false-positive vs confirmed HIV infection. RESULTS: A total of 21,163 pregnant women were screened using the ARCHITECT assay, and 190 tested positive. Of these, 33 of 190 (17%) women had false-positive HIV screening tests (28 deliveries available for analysis), and 157 of 190 (83%) had confirmed HIV-1 infection (140 available for analysis). Diagnostic accuracy of the ARCHITECT HIV Ag/Ab Combo assay in our prenatal population (with 95% confidence interval) was as follows: sensitivity, 100% (97.7-100%); specificity, 99.8% (99.8-99.9%); positive likelihood ratio, 636 (453-895); negative likelihood ratio, 0.0 (NA); positive predictive value, 83% (77-88%); and false positive rate, 0.16% (0.11-0.22%), with a prevalence of 7 per 1000. Women with false-positive HIV testing were younger and more likely of Hispanic ethnicity. A qualitative RNA assay (reference standard) was performed prenatally in 24 (86%) and quantitative viral load in 22 (92%). Interventions occurred more frequently in women without a qualitative RNA assay result available at delivery, including intrapartum zidovudine (75% vs 4%, P = .002), breastfeeding delay (75% vs 8%, P = .001), and neonatal zidovudine initiation (75% vs 4%, P = .002). The ARCHITECT signal-to-cutoff ratio was significantly lower for women with false-positive HIV tests compared with those with established HIV infection (1.89 [1.27, 2.73] vs 533.65 [391.12, 737.22], respectively, P < .001). CONCLUSION: While the performance of the fourth-generation ARCHITECT HIV Ag/Ab Combo assay among pregnant women is comparable with that reported in nonpregnant populations, clinical implications of using a screening test with a positive predictive value of 83% in pregnancy are significant. When the qualitative RNA assay result is unavailable, absence of risk factors in combination with an ARCHITECT HIV Ag/Ab assay S/Co ratio <5 and nonreactive differentiation assay provide sufficient evidence to support deferral of unnecessary intrapartum interventions while awaiting qualitative RNA results.

Pharmacokinetics of amlodipine besylate at delivery and during lactation.

BACKGROUND: Amlodipine is rarely used in the treatment of pregnant hypertensive women due to limited pharmacokinetic data during pregnancy and the postpartum period. OBJECTIVE: To evaluate the pharmacokinetics of amlodipine besylate in the peri-partum period including quantities of placental passage, breast milk excretion and infant exposure. STUDY DESIGN: This was a prospective study of pregnant women who were prescribed 5 mg of amlodipine daily for treatment of chronic hypertension and delivered at term. Cord and maternal blood samples were collected at delivery. On postpartum day 2, six paired maternal plasma and breast milk samples were obtained at 4, 6, 8, 12, 15 and 24 h following amlodipine dosing. Infant plasma samples were collected 24-48 h after delivery. All samples were analyzed for amlodipine concentration. A one compartment, first-order model was used to calculate pharmacokinetic estimates for maternal plasma. RESULTS: Of the 16 patients enrolled in the study, 11 had cord blood and maternal serum collected at delivery, of which only 6 produced sufficient breast milk for sampling. Amlodipine was detected in infant cord blood plasma with a mean concentration of 0.49 ±â€¯0.29 ng/mL compared to mean maternal serum level of 1.27 ±â€¯0.84 ng/mL. Amlodipine concentrations in both in breast milk and infant plasma were undetectable at the lower limit of assay detection (<0.1 ng/mL). In the immediate postpartum period, the amlodipine elimination half-life was 13.7 ±â€¯4.9 h, the area under the curve was 53.4 ±â€¯19.8 ng*h/mL and the peak concentration was 2.0 ±â€¯1.0 ng/mL. CONCLUSIONS: Amlodipine does cross the placenta in measurable quantities, but is not detected in breast milk or infant plasma at 24-48 h of life indicating that it is likely safe to use during the peripartum period.

Perinatal outcomes associated with abnormal cardiac remodeling in women with treated chronic hypertension.

BACKGROUND: Adverse maternal outcomes associated with chronic hypertension include accelerated hypertension and resultant target organ damage. One example is long-standing hypertension leading to maternal cardiac dysfunction. Our group has previously identified that features of such injury manifest as cardiac remodeling with left ventricular hypertrophy. Moreover, these features of cardiac remodeling identified in women with chronic hypertension during pregnancy were associated with adverse perinatal outcomes. Recent definitions of maternal cardiac remodeling using echocardiography have been expanded to include measurements of wall thickness. We hypothesized that these new features characterizing cardiac remodeling in women with chronic hypertension may also be associated with adverse perinatal outcomes. OBJECTIVE: There were 3 aims in this study of women with treated chronic hypertension during pregnancy: to (1) apply the updated definitions of maternal cardiac remodeling; (2) elucidate whether these features of cardiac remodeling were associated with adverse perinatal outcomes; and (3) determine which, if any, of the newly defined cardiac remodeling strata were most damaging when compared to women with normal cardiac geometry. STUDY DESIGN: This was a retrospective study of women with treated chronic hypertension during pregnancy delivered from January 2009 through January 2016. Cardiac remodeling was categorized by left ventricular mass index and relative wall thickness into 4 groups determined using the 2015 American Society of Echocardiography guidelines: normal geometry, concentric remodeling, eccentric hypertrophy, and concentric hypertrophy. Perinatal outcomes were analyzed according to each category of cardiac remodeling compared with outcomes in women with normal geometry. RESULTS: A total of 314 women with treated chronic hypertension underwent echocardiography at a mean gestational age of 17.9 weeks. There were no differences between maternal age (P = .896), habitus (P = .36), or duration of chronic hypertension (P = .212) among the 4 groups. Abnormal cardiac remodeling was found in 51% and was significantly associated with increased rates of superimposed preeclampsia (P = .015), preterm birth (P < .001), and neonatal intensive care admission (P = .003). These outcomes reached the greatest significance when comparisons were made between eccentric hypertrophy and normal geometry. CONCLUSION: Using current American Society of Echocardiography guidelines, 51% of women with treated chronic hypertension during pregnancy have some degree of abnormal cardiac remodeling. Any suggestion of maternal cardiac remodeling, regardless of subtype, was associated with increased risks for superimposed preeclampsia and preterm birth with its resultant perinatal sequelae. Eccentric ventricular hypertrophy, previously thought to mimic exercise physiology, appears to be the most associated with adverse perinatal outcomes. Despite evidence of cardiac remodeling, ejection fraction was preserved.

Frequency and consequences of ventricular hypertrophy in pregnant women with treated chronic hypertension.

BACKGROUND: Ventricular hypertrophy is a known sequela of long-standing chronic hypertension with associated morbidity and mortality. OBJECTIVE: We sought to assess the frequency and importance of left ventricular hypertrophy in gravidas treated for chronic hypertension during pregnancy. STUDY DESIGN: This was a retrospective study of pregnant women with chronic hypertension who were delivered at our hospital from January 2009 through February 2015. All women who were given antihypertensive therapy underwent maternal echocardiography and were managed in a dedicated, high-risk prenatal clinic. Left ventricular hypertrophy was defined using the criteria of the American Society of Echocardiography as left ventricular mass indexed to maternal body surface area with a value of >95 g/m2. Maternal and infant outcomes were then analyzed according to the presence or absence of left ventricular hypertrophy. RESULTS: Of 253 women who underwent echocardiography, 48 (19%) met criteria for left ventricular hypertrophy. Women in this latter cohort were significantly more likely to be African American (P = .031), but there were no other demographic differences. More than 85% of the entire cohort had a body mass index >30 kg/m2 and a third of all women had class III obesity with a body mass index of >40 kg/m2. Importantly, duration of chronic hypertension (P = .248) and gestational age at time of echocardiography (P = .316) did not differ significantly between the groups. Left ventricular function was preserved in both groups as measured by left ventricular ejection fraction (P = .303). Those with ventricular hypertrophy were at greater risk to be delivered preterm (P = .001), to develop superimposed preeclampsia (P = .028), and to have an infant requiring intensive care (P = .023) when compared with women without ventricular hypertrophy. These findings persisted after adjustment for age, race, and parity. The gestational age at delivery according to measured left ventricular size was also examined and with increasing ventricular mass there was a significant association with the severity of preterm birth (P < .001). CONCLUSION: Left ventricular hypertrophy was identified in 1 in 5 women given antepartum treatment for chronic hypertension. Further analysis showed that these women were at significantly greater risk for superimposed preeclampsia and its attendant perinatal sequelae of preterm birth.

Infant outcomes among women with Zika virus infection during pregnancy: results of a large prenatal Zika screening program.

BACKGROUND: Zika virus infection during pregnancy is a known cause of congenital microcephaly and other neurologic morbidities. OBJECTIVE: We present the results of a large-scale prenatal screening program in place at a single-center health care system since March 14, 2016. Our aims were to report the baseline prevalence of travel-associated Zika infection in our pregnant population, determine travel characteristics of women with evidence of Zika infection, and evaluate maternal and neonatal outcomes compared to women without evidence of Zika infection. STUDY DESIGN: This is a prospective, observational study of prenatal Zika virus screening in our health care system. We screened all pregnant women for recent travel to a Zika-affected area, and the serum was tested for those considered at risk for infection. We compared maternal demographic and travel characteristics and perinatal outcomes among women with positive and negative Zika virus tests during pregnancy. Comprehensive neurologic evaluation was performed on all infants delivered of women with evidence of possible Zika virus infection during pregnancy. Head circumference percentiles by gestational age were compared for infants delivered of women with positive and negative Zika virus test results. RESULTS: From March 14 through Oct. 1, 2016, a total of 14,161 pregnant women were screened for travel to a Zika-affected country. A total of 610 (4.3%) women reported travel, and test results were available in 547. Of these, evidence of possible Zika virus infection was found in 29 (5.3%). In our population, the prevalence of asymptomatic or symptomatic Zika virus infection among pregnant women was 2/1000. Women with evidence of Zika virus infection were more likely to have traveled from Central or South America (97% vs 12%, P < .001). There were 391 deliveries available for analysis. There was no significant difference in obstetric or neonatal morbidities among women with or without evidence of possible Zika virus infection. Additionally, there was no difference in mean head circumference of infants born to women with positive vs negative Zika virus testing. No microcephalic infants born to women with Zika infection were identified, although 1 infant with hydranencephaly was born to a woman with unconfirmed possible Zika disease. Long-term outcomes for infants exposed to maternal Zika infection during pregnancy are yet unknown. CONCLUSION: Based on a large-scale prenatal Zika screening program in an area with a predominantly Hispanic population, we identified that 4% were at risk from reported travel with only 2/1000 infected. Women traveling from heavily affected areas were most at risk for infection. Neonatal head circumference percentiles among infants born to women with evidence of possible Zika virus infection during pregnancy were not reduced when compared to infants born to women without infection.

Association of Baseline Proteinuria and Adverse Outcomes in Pregnant Women With Treated Chronic Hypertension.

OBJECTIVE: To assess the importance of baseline proteinuria in women treated for chronic hypertension during pregnancy. METHODS: This retrospective cohort study included women with chronic hypertension who received antihypertensive therapy in the first half of pregnancy and completed urine protein quantification before 20 weeks of gestation. Maternal and neonatal outcomes were analyzed according to the presence or absence of baseline proteinuria, defined as 300 mg or greater per 24 hours identified before 20 weeks of gestation. Frequencies of superimposed preeclampsia, preterm birth, and small-for-gestational-age neonates were further evaluated according to stratified urine protein excretion levels from less than 50 mg to greater than 1,000 mg/24 hours. RESULTS: Between January 2002 and December 2014, a total of 447 women met inclusion criteria. Of these, 56 (13%) had baseline proteinuria. Women with baseline proteinuria were statistically significantly more likely to develop superimposed preeclampsia (79% compared with 49%), deliver preterm (18% compared with 6% 30 weeks of gestation or less, 34% compared with 17% 34 weeks of gestation or less, and 48% compared with 26% less than 37 weeks of gestation), and deliver an small-for-gestational-age neonate (41% compared with 22% less than the 10th percentile, 20% compared with 9% less than the third percentile) when compared with women who did not have proteinuria (all P<.05). Furthermore, the rates of superimposed preeclampsia and small for gestational age were significantly increased as 24-hour protein excretion levels increased across stratified levels (P for trend .002 and .015, respectively). When proteinuria levels less than 300 mg/d were analyzed separately, a significant association was observed for rates of superimposed preeclampsia and preterm birth. CONCLUSION: In pregnant women with treated chronic hypertension, baseline proteinuria was significantly associated with increased rates of preeclampsia, preterm birth, and growth restriction-even at proteinuria values previously considered to be within normal range (less than 300 mg/d).

Blood Pressure Profiles Across Pregnancy in Women with Chronic Hypertension.

Objective To examine blood pressure patterns across pregnancy in women with treated chronic hypertension according to the occurrence of severe preeclampsia, growth restriction, and preterm birth <34 weeks. Methods This retrospective descriptive case study included only pregnant women receiving antihypertensive therapy. Using a random effects model, mean arterial pressures were plotted across gestation for women with and without preeclampsia, fetal growth restriction, and preterm birth <34 weeks with differences analyzed for each curve. Results Between January 2002 and December 2014, 447 women met inclusion criteria. Of these women, 65% developed severe preeclampsia, 24% delivered an infant weighing <10th percentile, and 15% had a preterm birth <34 weeks. Women diagnosed with either preeclampsia (23.3 vs 26.4 weeks; mean difference, 3.1 weeks; 95% confidence interval [CI], 2.3-4.3), fetal growth restriction (23.5 vs 24.9 weeks; mean difference, 1.4 weeks; 95% CI, 0.2-2.6), or preterm birth (19.8 vs 24.9 weeks; mean difference, 5.1 weeks; 95% CI, 3.7-6.9) reached a blood pressure nadir at a significantly earlier gestational age than those who did not. Conclusion For pregnant women with treated chronic hypertension, blood pressure patterns differ significantly in those who develop severe preeclampsia, fetal growth restriction, and preterm birth <34 weeks.

Telescoped Process to Manufacture 6,6,6-Trifluorofucose via Diastereoselective Transfer Hydrogenation: Scalable Access to an Inhibitor of Fucosylation Utilized in Monoclonal Antibody Production.

IgG1 monoclonal antibodies with reduced glycan fucosylation have been shown to improve antibody-dependent cellular cytotoxicity (ADCC) by allowing more effective binding of the Fc region of these proteins to T cells receptors. Increased in vivo efficacy in animal models and oncology clinical trials has been associated with the enhanced ADCC provided by these engineered mAbs. 6,6,6-Trifluorofucose (1) is a new inhibitor of fucosylation that has been demonstrated to allow the preparation of IgG1 monoclonal antibodies with lower fucosylation levels and thus improve the ADCC of these proteins. A new process has been developed to support the preparation of 1 on large-scale for wide mAb manufacture applications. The target fucosylation inhibitor (1) was synthesized from readily available d-arabinose in 11% overall yield and >99.5/0.5 dr (diastereomeric ratio). The heavily telescoped process includes seven steps, two crystallizations as purification handles, and no chromatography. The key transformation of the sequence involves the diastereoselective preparation of the desired trifluoromethyl-bearing alcohol in >9/1 dr from a trimethylsilylketal intermediate via a ruthenium-catalyzed tandem ketal hydrolysis-transfer hydrogenation process.

1,1'-Carbonyldiimidazole (CDI) Mediated Coupling and Cyclization To Generate [1,2,4]Triazolo[4,3-a]pyridines.

An operationally efficient CDI mediated tandem coupling and cyclization reaction to generate [1,2,4]triazolo[4,3-a]pyridines has been reported. The reaction conditions and scope were investigated, and the methodology was demonstrated in batch mode as well as in a continuous process.

Manufacturing of [(14)C]-Labeled Drug Substance and Drug Product Utilized in Clinical Research: A Case Study of Omecamtiv Mecarbil.

This mini-review describes the Chemistry, Manufacturing and Control activities associated with the manufacture of [(14)C]-labeled drug substance and subsequent drug compounding activities to generate clinical trial material utilized in human absorption, distribution, metabolism, and excretion clinical studies. Due to the unstable nature and increased decomposition rates observed with [(14)C]-labeled compounds, the manufacture, testing, release, formulation, and regulatory filings are uniquely challenging. A case study of the cardiac myosin activator AMG 423 (omecamtiv mercarbil), utilized in a dual oral/intravenous infusion clinical study is presented.