Regulatory and Clinical Experiences with Biosimilar Filgrastim in the U.S., the European Union, Japan, and Canada.

Biosimilar filgrastims are primarily indicated for chemotherapy-induced neutropenia prevention. They are less expensive formulations of branded filgrastim, and biosimilar filgrastim was the first biosimilar oncology drug administered in European Union (EU) countries, Japan, and the U.S. Fourteen biosimilar filgrastims have been marketed in EU countries, Japan, the U.S., and Canada since 2008, 2012, 2015, and 2016, respectively. We reviewed experiences and policies for biosimilar filgrastim markets in EU countries and Japan, where uptake has been rapid, and in the U.S. and Canada, where experience is rapidly emerging. U.S. regulations for designating biosimilar interchangeability are under development, and such regulations have not been developed in most other countries. Pharmaceutical substitution is allowed for new filgrastim starts in some EU countries and in Canada, but not Japan and the U.S. In EU countries, biosimilar adoption is facilitated with favorable hospital tender offers. U.S. adoption is reportedly 24%, while the second filgrastim biosimilar is priced 30% lower than branded filgrastim and 20% lower than the first biosimilar filgrastim approved by the U.S. Food and Drug Administration. Utilization is about 60% in EU countries, where biosimilar filgrastim is marketed at a 30%-40% discount. In Japan, biosimilar filgrastim utilization is 45%, primarily because of 35% discounts negotiated by Central Insurance and hospital-only markets. Overall, biosimilar filgrastim adoption barriers are small in many EU countries and Japan and are diminishing in Canada in the U.S. Policies facilitating improved U.S. adoption of biosimilar filgrastim, based on positive experiences in EU countries and Japan, including favorable insurance coverage; larger price discount relative to reference filgrastim pricing; closing of the "rebate trap" with transparent pricing information; formal educational efforts of patients, physicians, caregivers, and providers; and allowance of pharmaceutical substitution of biosimilar versus reference filgrastim, should be considered. IMPLICATIONS FOR PRACTICE: We reviewed experiences and policies for biosimilar filgrastims in Europe, Japan, Canada, and the U.S. Postmarketing harmonization of regulatory policies for biosimilar filgrastims has not occurred. Acceptance of biosimilar filgrastims for branded filgrastim, increasing in the U.S. and in Canada, is commonplace in Japan and Europe. In the U.S., some factors, accepted in Europe or Japan, could improve uptake, including acceptance of biosimilars as safe and effective; larger cost savings, decreasing "rebate traps" where pharmaceutical benefit managers support branded filgrastim, decreased use of patent litigation/challenges, and allowing pharmacists to routinely substitute biosimilar for branded filgrastim.

Generic oncology drugs: are they all safe?

Although the availability of generic oncology drugs allows access to contemporary care and reduces costs, there is international variability in the safety of this class of drugs. In this Series paper, we review clinical, policy, safety, and regulatory considerations for generic oncology drugs focusing on the USA, Canada, the European Union (EU), Japan, China, and India. Safety information about generic formulations is reviewed from one agent in each class, for heavy metal drugs (cisplatin), targeted agents (imatinib), and cytotoxic agents (docetaxel). We also review regulatory reports from Japan and the USA, countries with the largest pharmaceutical expenditures. Empirical studies did not identify safety concerns in the USA, Canada, the EU, and Japan, where regulations and enforcement are strong. Although manufacturing problems for generic pharmaceuticals exist in India, where 40% of all generic pharmaceuticals used in the USA are manufactured, increased inspections and communication by the US Food and Drug Administration are occurring, facilitating oversight and enforcement. No safety outbreaks among generic oncology drugs were reported in developed countries. For developing countries, oversight is less intensive, and concerns around drug safety still exist. Regulatory agencies should collaboratively develop procedures to monitor the production, shipment, storage, and post-marketing safety of generic oncology drugs. Regulatory agencies for each country should also aim towards identical definitions of bioequivalence, the cornerstone of regulatory approval.

Comparative Risk of Anaphylactic Reactions Associated With Intravenous Iron Products.

IMPORTANCE: All intravenous (IV) iron products are associated with anaphylaxis, but the comparative safety of each product has not been well established. OBJECTIVE: To compare the risk of anaphylaxis among marketed IV iron products. DESIGN, SETTING, AND PARTICIPANTS: Retrospective new user cohort study of IV iron recipients (n = 688,183) enrolled in the US fee-for-service Medicare program from January 2003 to December 2013. Analyses involving ferumoxytol were limited to the period January 2010 to December 2013. EXPOSURES: Administrations of IV iron dextran, gluconate, sucrose, or ferumoxytol as reported in outpatient Medicare claims data. MAIN OUTCOMES AND MEASURES: Anaphylaxis was identified using a prespecified and validated algorithm defined with standard diagnosis and procedure codes and applied to both inpatient and outpatient Medicare claims. The absolute and relative risks of anaphylaxis were estimated, adjusting for imbalances among treatment groups. RESULTS: A total of 274 anaphylaxis cases were identified at first exposure, with an additional 170 incident anaphylaxis cases identified during subsequent IV iron administrations. The risk for anaphylaxis at first exposure was 68 per 100,000 persons for iron dextran (95% CI, 57.8-78.7 per 100,000) and 24 per 100,000 persons for all nondextran IV iron products combined (iron sucrose, gluconate, and ferumoxytol) (95% CI, 20.0-29.5 per 100,000) , with an adjusted odds ratio (OR) of 2.6 (95% CI, 2.0-3.3; P < .001). At first exposure, when compared with iron sucrose, the adjusted OR of anaphylaxis for iron dextran was 3.6 (95% CI, 2.4-5.4); for iron gluconate, 2.0 (95% CI 1.2, 3.5); and for ferumoxytol, 2.2 (95% CI, 1.1-4.3). The estimated cumulative anaphylaxis risk following total iron repletion of 1000 mg administered within a 12-week period was highest with iron dextran (82 per 100,000 persons, 95% CI, 70.5- 93.1) and lowest with iron sucrose (21 per 100,000 persons, 95% CI, 15.3- 26.4). CONCLUSIONS AND RELEVANCE: Among patients in the US Medicare nondialysis population with first exposure to IV iron, the risk of anaphylaxis was highest for iron dextran and lowest for iron sucrose.

Pain palliation measurement in cancer clinical trials: the US Food and Drug Administration perspective.

BACKGROUND: Pain palliation resulting from antitumor therapy provides direct evidence of treatment benefit when combined with evidence of antitumor activity. The US Food and Drug Administration (FDA) previously issued guidance regarding the use of patient-reported outcome (PRO) measures to support labeling claims. The purpose of this article is to identify common challenges and key design strategies when measuring pain palliation in antitumor therapy clinical trials that are consistent with PRO Guidance principles. METHODS: Antitumor clinical protocols submitted to the FDA between 1995 and 2012 that included pain palliation as a primary or secondary endpoint were reviewed. Challenges in critical trial design components were identified. Design strategies consistent with PRO Guidance principles are proposed. RESULTS: The challenges identified were measurement of pain intensity and analgesic use, enrollment eligibility criteria, data collection methods, responder definitions, missing data, and blinding. Strategies included the use of well-defined, reliable, PRO assessments of pain intensity and analgesics; ensuring that enrollment criteria define patients with clinically significant pain attributable to cancer on an optimal analgesic regimen; defining responders using both pain and analgesic use criteria; incorporating an analysis of tumor response to support evidence of pain response; and minimizing missing data and inadvertent unblinding. CONCLUSIONS: Improvement in cancer-related pain resulting from antitumor therapy is an important treatment benefit that can support drug approval and labeling claims when adequately measured if study results demonstrate statistically and clinically significant findings. Sponsors are encouraged to discuss pain palliation assessment methods with the FDA early in and throughout product development.

Cardiac imaging approaches to evaluate drug-induced myocardial dysfunction.

The ability to make informed benefit-risk assessments for potentially cardiotoxic new compounds is of considerable interest and importance at the public health, drug development, and individual patient levels. Cardiac imaging approaches in the evaluation of drug-induced myocardial dysfunction will likely play an increasing role. However, the optimal choice of myocardial imaging modality and the recommended frequency of monitoring are undefined. These decisions are complicated by the array of imaging techniques, which have varying sensitivities, specificities, availabilities, local expertise, safety, and costs, and by the variable time-course of tissue damage, functional myocardial depression, or recovery of function. This White Paper summarizes scientific discussions of members of the Cardiac Safety Research Consortium on the main factors to consider when selecting nonclinical and clinical cardiac function imaging techniques in drug development. We focus on 3 commonly used imaging modalities in the evaluation of cardiac function: echocardiography, magnetic resonance imaging, and radionuclide (nuclear) imaging and highlight areas for future research.

Sorafenib for the treatment of unresectable hepatocellular carcinoma.

PURPOSE: To describe the U.S. Food and Drug Administration (FDA) review and approval of sorafenib (Nexavar; Bayer Pharmaceuticals Corp., Montville, NJ, and Onyx Pharmaceuticals Corp., Emeryville, CA), an oral kinase inhibitor, for the treatment of patients with unresectable hepatocellular carcinoma (HCC). EXPERIMENTAL DESIGN: The FDA independently analyzed an international, double-blind, placebo-controlled trial comparing the effect of best supportive care plus sorafenib or matching placebo on overall survival. Eligible patients had unresectable, biopsy-proven HCC and had not received prior systemic therapy. RESULTS: Among the 602 randomized patients (placebo, 303; sorafenib, 299), baseline characteristics were well balanced, and 97% were Child-Pugh score A. HCC was "advanced" in 70% overall, as defined by extrahepatic metastases or by tumor radiographically visible in venous structures outside the liver. Underlying liver diseases included hepatitis B (18%), hepatitis C (28%), and alcohol-related (26%). The trial was stopped following a prespecified second interim analysis showing a statistically significant survival advantage for sorafenib [median, 10.7 vs 7.9 months; hazard ratio, 0.69 (95% confidence interval, (0.55, 0.87)), p = 0.00058]. Adverse events in sorafenib-treated patients included diarrhea in 55% (grade 3, 10%), hand-foot syndrome in 21% (grade 3, 8%), rash in 19% (grade 3, 1%), and cardiac ischemia or infarction in 2.7% (versus 1.3% for placebo). On sorafenib, treatment-emergent hypertension occurred in 9% of patients (placebo, 4%) and was grade 3 in 4% (placebo, 1%); elevated serum lipase occurred in 40% (placebo, 37%); hypophosphatemia occurred in 35% (placebo, 11%). CONCLUSIONS: Sorafenib is the first systemic therapy to demonstrate a survival benefit in a randomized trial for unresectable HCC and has received FDA approval for this indication.

The clinical significance of statistical significance.

Modern clinical trials provide the evidence for most therapeutic advances, and that evidence, expressed in a statistical format, is used to draw inferences about a population from the study's results. Clinician judgment translates these inferences for best individual patient care, but many clinicians struggle with the statistical interpretation of trial results. This review provides a clinical and non-Bayesian perspective on some key elements in the statistical design, analysis, and interpretation of randomized, comparative, phase III clinical trials intended to demonstrate a better outcome (superiority) than with a control treatment.

Bortezomib for the treatment of mantle cell lymphoma.

PURPOSE: To describe the Food and Drug Administration review and marketing approval considerations for bortezomib (Velcade) for the treatment of patients with mantle cell lymphoma. EXPERIMENTAL DESIGN: Food and Drug Administration reviewed a multicenter study of bortezomib in 155 patients with progressive mantle cell lymphoma after at least one prior therapy. RESULTS: Seventy-seven percent were stage IV, and 75% had one or more extranodal sites of disease. Prior therapy included an anthracycline or mitoxantrone, cyclophosphamide, and rituximab. Median age was 65 years. All received bortezomib 1.3 mg/m(2) i.v. on days 1, 4, 8, and 11 of each 3-week cycle. The primary end point was response. Response and progression were determined by independent review of serial computed tomography scans using International Lymphoma Workshop Response Criteria. The overall response rate was 31%, including complete response (CR) plus CR unconfirmed (CRu) plus partial response; median response duration was 9.3 months. The CR plus CRu response rate was 8% with a median duration of 15.4 months. Adverse events were similar to those observed previously for bortezomib. The most commonly reported treatment-emergent adverse events were asthenia (72%), peripheral neuropathies (55%), constipation (50%), diarrhea (47%), nausea (44%), and anorexia (39%). The most common adverse event leading to discontinuation was neuropathy. CONCLUSIONS: Bortezomib received regular approval for the treatment of patients with mantle cell lymphoma in relapse after prior therapy.

United States Food and Drug Administration approval summary: bortezomib for the treatment of progressive multiple myeloma after one prior therapy.

PURPOSE: On March 25, 2005, bortezomib (Velcade for Injection; Millennium Pharmaceuticals, Inc., Cambridge, MA, and Johnson & Johnson Pharmaceutical Research & Development, L.L.C.) received regular approval from the U.S. Food and Drug Administration (U.S. FDA) for the treatment of multiple myeloma (MM) progressing after at least one prior therapy. This approval was based on bortezomib's efficacy and safety which was shown in a single, large, comparative international open-label phase 3 trial that randomized 669 patients with MM previously treated with at least one systemic regimen to receive single-agent bortezomib or high-dose dexamethasone. The FDA analysis of the trial data and bortezomib's regulatory development are summarized here. EXPERIMENTAL DESIGN AND RESULTS: Following a preplanned interim analysis of time to disease progression (the primary end point), an independent data-monitoring committee advised the sponsor to halt the study and offer bortezomib to all dexamethasone-treated study patients. Time to progression was significantly prolonged in the bortezomib treatment arm (median, 6.2 months) compared with the dexamethasone arm (median, 3.5 months; log-rank test, P < 0.0001; hazard ratio, 0.55; 95% confidence interval, 0.44-0.69). Analysis of overall survival done on the interim database (with 20% of events) showed the superiority of bortezomib for patients (log-rank test, P < 0.05; hazard ratio, 0.57; 95% confidence interval, 0.40-0.81). Using criteria from the European Group for Blood and Marrow Transplantation, the response rate (complete plus partial response) with bortezomib was also superior to dexamethasone (38% versus 18%; P < 0.0001). Adverse events on the bortezomib arm were similar to those previously observed in phase 2 studies; some notable adverse events included asthenia, peripheral neuropathy, thrombocytopenia, and neutropenia. CONCLUSIONS: The U.S. FDA had earlier (May 2003) granted bortezomib accelerated approval for the treatment of patients with MM progressing after two prior therapies. The results of the phase 3 trial and the FDA analysis of the data, along with the sponsor's completion of other postmarketing commitments, confirm bortezomib's benefit and support regular approval.

Sorafenib for the treatment of advanced renal cell carcinoma.

PURPOSE: This report describes the U.S. Food and Drug Administration (FDA) review and approval of sorafenib (Nexavar, BAY43-9006), a new small-molecule, oral, multi-kinase inhibitor for the treatment of patients with advanced renal cell carcinoma (RCC). EXPERIMENTAL DESIGN: After meeting with sponsors during development studies of sorafenib, the FDA reviewed the phase 3 protocol under the Special Protocol Assessment mechanism. Following new drug application submission, FDA independently analyzed the results of two studies in advanced RCC: a large, randomized, double-blinded, phase 3 international trial of single-agent sorafenib and a supportive phase 2 study. RESULTS: In the phase 3 trial, 902 patients with advanced progressive RCC after one prior systemic therapy were randomized to 400 mg sorafenib twice daily plus best supportive care or to a matching placebo plus best supportive care. Primary study end points included overall survival and progression-free survival (PFS). A PFS analysis, pre-specified and conducted after a total of 342 events, showed statistically significant superiority for the sorafenib group (median = 167 days) compared with that for the controls (median = 84 days, log-rank P < 0.000001); the sorafenib/placebo hazard ratio was 0.44 (95% confidence interval, 0.35-0.55). Results were similar regardless of patient risk score, performance status, age, or prior therapy. The (partial) response rate to sorafenib was 2.1%. Overall survival results are preliminary. The principal toxicities in the sorafenib patients included reversible skin rashes in 40% and hand-foot skin reaction in 30%; diarrhea was reported in 43%, treatment-emergent hypertension was reported in 17%, and sensory neuropathic changes were reported in 13%. Grade 4 adverse events were uncommon. Grade 3 adverse events were hand-foot skin reaction (6%), fatigue (5%), and hypertension (3%). Laboratory findings included asymptomatic hypophosphatemia in 45% of sorafenib patients versus 11% in the placebo arm and elevation of serum lipase in 41% of sorafenib patients versus 30% in the placebo arm. Grade 4 pancreatitis was reported in two sorafenib patients, although both patients subsequently resumed sorafenib, with one at full dose. CONCLUSIONS: Sorafenib received FDA regular approval on December 20, 2005 for the treatment of advanced RCC based on the persuasive magnitude of improvement in PFS with acceptable safety. The recommended dose is 400 mg (two 200-mg tablets) twice daily taken either 1 h before or 2 h after meals. Adverse events were accommodated by temporary dose interruptions or reductions.

Interpretability of Cancer Clinical Trial Results Using Restricted Mean Survival Time as an Alternative to the Hazard Ratio.

Importance: In a comparative clinical study with progression-free survival (PFS) or overall survival (OS) as the end point, the hazard ratio (HR) is routinely used to design the study and to estimate the treatment effect at the end of the study. The clinical interpretation of the HR may not be straightforward, especially when the underlying model assumption is not valid. A robust procedure for study design and analysis that enables clinically meaningful interpretation of trial results is warranted. Objective: To discuss issues of conventional trial design and analysis and to present alternatives to the HR using a recent immunotherapy study as an illustrative example. Design, Setting, and Participants: By comparing 2 groups in a survival analysis, we discuss issues of using the HR and present the restricted mean survival time (RMST) as a summary measure of patients' survival profile over time. We show how to use the difference or ratio in RMST between 2 groups as an alternative for designing and analyzing a clinical study with an immunotherapy study as an illustrative example. Main Outcomes and Measures: Overall survival or PFS. Group contrast measures included HR, RMST difference or ratio, and the event rate difference. Results: For the illustrative example, the HR procedure indicates that nivolumab significantly prolonged patient OS and was numerically better than docetaxel for PFS. However, the median PFS time of docetaxel was significantly better than that of nivolumab. Therefore, it may be difficult to use median OS and/or PFS to interpret of the HR value clinically. On the other hand, using RMST difference, nivolumab was significantly better than docetaxel for both OS and PFS. We also provide details regarding design of a future study with RMST-based measures. Conclusions and Relevance: The design and analysis of a conventional cancer clinical trial can be improved by adopting a robust statistical procedure that enables clinically meaningful interpretations of the treatment effect. The RMST-based quantitative method may be used as a primary tool for future cancer trials or to help us to better understand the clinical interpretation of the HR even when its model assumption is plausible.

Melanoma complicating treatment with natalizumab for multiple sclerosis: A report from the Southern Network on Adverse Reactions (SONAR).

A 43-year-old female with multiple sclerosis developed urethral melanoma. The only potential risk factor was treatment with natalizumab, a humanized monoclonal antibody against α4 integrins. To investigate the risk-exposure relationship, we reviewed this case, all other published cases, and cases of natalizumab-associated melanoma reported to regulatory agencies. Data sources included the Food and Drug Administration's (FDA) Adverse Event Reporting System (FAERS) (2004-2014), a FDA Advisory Committee Meeting Report, and peer-reviewed publications. In the United States, the manufacturer maintains an FDA-mandated Tysabri Safety Surveillance Program (part of the Tysabri Outcomes Unified Commitment to Health (TOUCH)) of natalizumab-treated patients. We statistically compared reporting completeness for natalizumab-associated melanoma cases in FAERs for which information was obtained entirely from the TOUCH program versus cases where FAERS information was supplemented by TOUCH program information. FAERS included 137 natalizumab-associated melanoma reports in patients with multiple sclerosis. Median age at melanoma diagnosis was 45 years (range: 21-74 years). Changes in preexisting nevi occurred in 16%, history of cutaneous nevi occurred in 22%, diagnosis within 2 years of beginning natalizumab occurred in 34%, and 74% had primary surgical treatment. Among seven natalizumab-treated MS patients who developed biopsy-confirmed melanoma on treatment and reported in the literature, median age at diagnosis was 41 years (range: 38-48 years); and the melanoma diagnosis occurred following a median of 12 natalizumab doses (range: 1-77 doses). A history of mole or nevi was noted in four patients and a history of prior melanoma was noted in one patient. Completeness scores for reports were significantly lower for FAERS cases reported from the TOUCH program versus FAERS cases supplemented by TOUCH information (median score of 2 vs. 4 items out of 8-possible items, P < 0.0007). Clinicians should monitor existing nevi and maintain suspicion for melanoma developing in natalizumab-treated patients. The TOUCH Safety Surveillance Program, currently focused on progressive multifocal leukoencephalopathy, should be expanded to include information on other serious complications including malignancies, particularly if they are immunologic in nature.

FDA Approval: Blinatumomab.

On December 3, 2014, the FDA granted accelerated approval of blinatumomab (Blincyto; Amgen, Inc.) for treatment of Philadelphia chromosome-negative relapsed or refractory precursor B-cell acute lymphoblastic leukemia (R/R ALL). Blinatumomab is a recombinant murine protein that acts as a bispecific CD19-directed CD3 T-cell engager. The basis for the approval was a single-arm trial with 185 evaluable adults with R/R ALL. The complete remission (CR) rate was 32% [95% confidence interval (CI), 26%-40%], and the median duration of response was 6.7 months. A minimal residual disease response was achieved by 31% (95% CI, 25%-39%) of all patients. Cytokine release syndrome and neurologic events were serious toxicities that occurred. Other common (>20%) adverse reactions were pyrexia, headache, edema, febrile neutropenia, nausea, tremor, and rash. Neutropenia, thrombocytopenia, and elevated transaminases were the most common (>10%) laboratory abnormalities related to blinatumomab. A randomized trial is required in order to confirm clinical benefit.

FDA approval: idelalisib monotherapy for the treatment of patients with follicular lymphoma and small lymphocytic lymphoma.

On July 23, 2014, the FDA granted accelerated approval to idelalisib (Zydelig tablets; Gilead Sciences, Inc.) for the treatment of patients with relapsed follicular B-cell non-Hodgkin lymphoma or relapsed small lymphocytic lymphoma (SLL) who have received at least two prior systemic therapies. In a multicenter, single-arm trial, 123 patients with relapsed indolent non-Hodgkin lymphomas received idelalisib, 150 mg orally twice daily. In patients with follicular lymphoma, the overall response rate (ORR) was 54%, and the median duration of response (DOR) was not evaluable; median follow-up was 8.1 months. In patients with SLL, the ORR was 58% and the median DOR was 11.9 months. One-half of patients experienced a serious adverse reaction of pneumonia, pyrexia, sepsis, febrile neutropenia, diarrhea, or pneumonitis. Other common adverse reactions were abdominal pain, nausea, fatigue, cough, dyspnea, and rash. Common treatment-emergent laboratory abnormalities were elevations in alanine aminotransferase, aspartate aminotransferase, gamma-glutamyltransferase, absolute lymphocytes, and triglycerides. Continued approval may be contingent upon verification of clinical benefit in confirmatory trials.

FDA Approval: Ibrutinib for Patients with Previously Treated Mantle Cell Lymphoma and Previously Treated Chronic Lymphocytic Leukemia.

On November 13, 2013, the FDA granted accelerated approval to ibrutinib (IMBRUVICA capsules; Pharmacyclics, Inc.) for the treatment of patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. On February 12, 2014, the FDA granted accelerated approval for the treatment of patients with chronic lymphocytic leukemia (CLL) who have received at least one prior therapy. Ibrutinib is a first-in-class Bruton's tyrosine kinase (BTK) inhibitor that received all four expedited programs of the FDA: Fast-Track designation, Breakthrough Therapy designation, Priority Review, and Accelerated Approval. Both approvals were based on overall response rate (ORR) and duration of response (DOR) in single-arm clinical trials in patients with prior treatment. In MCL (N = 111), the complete and partial response rates were 17.1% and 48.6%, respectively, for an ORR of 65.8% [95% confidence interval (CI), 56.2%-74.5%]. The median DOR was 17.5 months (95% CI, 15.8-not reached). In CLL (N = 48), the ORR was 58.3% (95% CI, 43.2%-72.4%), and the DOR ranged from 5.6 to 24.2 months. The most common adverse reactions (≥ 30% in either trial) were thrombocytopenia, diarrhea, neutropenia, bruising, upper respiratory tract infection, anemia, fatigue, musculoskeletal pain, peripheral edema, and nausea.

FDA Approval: Belinostat for the Treatment of Patients with Relapsed or Refractory Peripheral T-cell Lymphoma.

On July 3, 2014, the FDA granted accelerated approval for belinostat (Beleodaq; Spectrum Pharmaceuticals, Inc.), a histone deacetylase inhibitor, for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL). A single-arm, open-label, multicenter, international trial in the indicated patient population was submitted in support of the application. Belinostat was administered intravenously at a dose of 1000 mg/m(2) over 30 minutes once daily on days 1 to 5 of a 21-day cycle. The primary efficacy endpoint was overall response rate (ORR) based on central radiology readings by an independent review committee. The ORR was 25.8% [95% confidence interval (CI), 18.3-34.6] in 120 patients that had confirmed diagnoses of PTCL by the Central Pathology Review Group. The complete and partial response rates were 10.8% (95% CI, 5.9-17.8) and 15.0% (95% CI, 9.1-22.7), respectively. The median duration of response, the key secondary efficacy endpoint, was 8.4 months (95% CI, 4.5-29.4). The most common adverse reactions (>25%) were nausea, fatigue, pyrexia, anemia, and vomiting. Grade 3/4 toxicities (≥5.0%) included anemia, thrombocytopenia, dyspnea, neutropenia, fatigue, and pneumonia. Belinostat is the third drug to receive accelerated approval for the treatment of relapsed or refractory PTCL.

A possible association between fetal/neonatal exposure to radiofrequency electromagnetic radiation and the increased incidence of autism spectrum disorders (ASD).

Recently disclosed epidemiological data indicate a dramatic increase in the incidence of autism spectrum disorders. Previously, the incidence of autism has been reported as 4-5 per 10000 children. The most recent evidence indicates an increased incidence of about 1 per 500 children. However, the etiology of autism is yet to be determined. The recently disclosed data suggest a possible correlation between autism incidence and a previously unconsidered environmental toxin. It is generally accepted in the scientific community that radiofrequency (RF) radiation is a biologically active substance. It is also readily acknowledged that human exposures to RF radiation have become pervasive during the past 20 years, whereas such exposures were uncommon prior to that time. It is suggested that fetal or neo-natal exposures to RF radiation may be associated with an increased incidence of autism.

Intravenous iron replacement with sodium ferric gluconate complex in sucrose for iron deficiency anemia in adults.

BACKGROUND: When oral iron replacement therapy is ineffective, IV or IM iron dextran products have been used successfully in many patients. However, adverse events, including urticaria, anaphylaxis, and death, sometimes are associated with the use of these products. OBJECTIVE: The aim of this study was to assess the efficacy and tolerability of sodium ferric gluconate complex (SFGC) in sucrose in the treatment of adults with iron deficiency anemia. METHODS: This was a single-center, open-label, uncontrolled study. Consecutive adults in need of IV iron replacement who experienced severe reactions to generic IV iron dextran and who had previously failed to respond to oral iron products were treated with a single dose of IV SFGC (312, 375, or 500 mg) infused over 2 hours. A second dose of SFGC could be administered 6 to 8 weeks later, if needed. RESULTS: Six patients (3 men, 3 women; mean [SD] age, 77.0 [10.4] years) were enrolled. All patients received a single-dose infusion of SFGC, and 2 patients received a second dose. No adverse events were observed at the lower doses (312 and 375 mg); however, both patients given the 500-mg dose reported transient nausea, and 1 had pruritus and the other had transient hypertension. CONCLUSION: The results of this study show that SFGC is a satisfactory alternative when IV iron replacement is needed by adults with iron deficiency anemia.