Comparison of Copaxone® and Synthon's therapeutically equivalent glatiramer acetate.

Glatiramer acetate is indicated for the treatment of patients with relapsing forms of multiple sclerosis (RMS). In 2016, an alternative to the originator product was approved in the EU through the hybrid procedure regulatory pathway. This paper reviews the scientifically rigorous and multifaceted program undertaken to demonstrate the equivalence of this glatiramer acetate follow-on product (GTR) and the reference product Copaxone®, which resulted in the EU approval of GTR 20 mg/mL and 40 mg/mL. Establishing therapeutic equivalence for non-biological complex drugs is not trivial and requires a complex and multidisciplinary effort. Ultimately, there is not a single test or study that establishes therapeutic equivalence of two heterogeneous products. Instead, it requires a good understanding of the synthesis process together with a full set of data that includes comparative physicochemical testing, nonclinical in vitro and in vivo studies, and a comparative clinical study to allow for a valid conclusion that two products are therapeutically equivalent. The detailed understanding of glatiramer's synthesis process and its impact on the characteristics of glatiramer, combined with the results of a scientifically rigorous and multifaceted physicochemical and biological characterization program, and the clinical data from the 794-patient Phase III GATE study, demonstrate that GTR and Copaxone are therapeutically equivalent. The data further demonstrate that Synthon's manufacturing process consistently yields drug substance of the same quality as Copaxone and that switching from Copaxone to GTR is safe and well-tolerated.

Effects of livestock grazing and well construction on prairie vegetation structure surrounding shallow natural gas wells.

Short and sparse vegetation near shallow gas wells has generally been attributed to residual effects from well construction, but other mechanisms might also explain these trends. We evaluated effects of distance to shallow gas wells on vegetation and bare ground in mixed-grass prairies in southern Alberta, Canada, from 2010 to 2011. We then tested three hypotheses to explain why we found shorter vegetation and more bare ground near wells, using cattle fecal pat transects from 2012, and our vegetation quadrats. We evaluated whether empirical evidence suggested that observed patterns were driven by (1) higher abundance of crested wheatgrass (Agropyron cristatum) near wells, (2) residual effects of well construction, or (3) attraction of livestock to wells. Crested wheatgrass occurrence was higher near wells, but this did not explain effects of wells on vegetation structure. Correlations between distance to wells and litter depth were the highest near newer wells, providing support for the construction hypothesis. However, effects of distance to wells on other vegetation metrics did not decline as time since well construction increased, suggesting that other mechanisms explained observed edge effects. Cattle abundance was substantially higher near wells, and this effect corresponded with changes in habitat structure. Our results suggest that both residual effects of well construction and cattle behavior may explain effects of shallow gas wells on habitat structure in mixed-grass prairies, and thus, to be effective, mitigation strategies must address both mechanisms.

Lymphogranuloma venereum among men who have sex with men in the Netherlands: regional differences in testing rates lead to underestimation of the incidence, 2006-2012.

Since 2003, an epidemic of lymphogranuloma venereum (LGV) has been ongoing in men who have sex with men (MSM) in Europe. Of 92,271 MSM consulting sexually transmitted disease (STI) clinics in the Netherlands between 2006 and 2011, 63,228 (68%) were tested for anorectal Chlamydia infection, with 6,343 (10%) positive diagnoses. In 4,776 of those (75%), LGV testing was performed, with regional variation from 7% to 97%. In total 414 LGV cases were diagnosed, a mean annual positivity rate of 8.7%, decreasing from 14% in 2007 to 6% in 2011, but increasing to 13.1% during 2012 (184 new cases). Risk factors for LGV were human immunodeficiency virus (HIV) positivity (odds ratio (OR)=4.1; 95% confidence interval (CI): 3.2­5.3), STI symptoms (OR=4.1; 95% CI: 3.1­5.4), more than 50 sex partners in the past six months (OR=3.7; 95% CI: 1.1­12.4), older age (40­44 years: OR=2.1; 95% CI: 1.5­2.8), no condom use (OR=2.2; 95% CI: 1.2­3.9) and homosexuality (as opposed to bisexuality; OR=2.2; 95% CI: 1.1­4.2). Regional differences in LGV testing rates limit national LGV surveillance, leading to an underestimation of the real incidence. Characteristics of MSM with LGV did not change over time, so existing prevention strategies should be intensified.

A double-blind, non-inferiority RCT comparing corifollitropin alfa and recombinant FSH during the first seven days of ovarian stimulation using a GnRH antagonist protocol.

BACKGROUND: Corifollitropin alfa, a fusion protein lacking LH activity, has a longer elimination half-life and extended time to peak levels than recombinant FSH (rFSH). A single injection of corifollitropin alfa may replace seven daily gonadotrophin injections during the first week of ovarian stimulation. METHODS: In this large, double-blind, randomized, non-inferiority trial the ongoing pregnancy rates were assessed after one injection of 150 microg corifollitropin alfa during the first week of stimulation and compared with daily injections of 200 IU rFSH using a standard GnRH antagonist protocol. RESULTS: The study population comprised 1506 treated patients with mean age of 31.5 years and body weight of 68.6 kg. Ongoing pregnancy rates of 38.9% for the corifollitropin alfa group and 38.1% for rFSH were achieved, with an estimated non-significant difference of 0.9% [95% confidence interval (CI): -3.9; 5.7] in favor of corifollitropin alfa. Stratified analyses of pregnancy rates confirmed robustness of this primary outcome by showing similar results regardless of IVF or ICSI, or number of embryos transferred. A slightly higher follicular response with corifollitropin alfa resulted in a higher number of cumulus-oocyte-complexes compared with rFSH [estimated difference 1.2 (95% CI: 0.5; 1.9)], whereas median duration of stimulation was equal (9 days) and incidence of (moderate/severe) ovarian hyperstimulation syndrome was the same (4.1 and 2.7%, respectively P = 0.15). CONCLUSION: Corifollitropin alfa is a novel and effective treatment option for potential normal responder patients undergoing ovarian stimulation with GnRH antagonist co-treatment for IVF resulting in a high ongoing pregnancy rate, equal to that achieved with daily rFSH. The trial was registered under ClinicalTrials.gov identifier NTC00696800.

Mutagen sensitivity in patients with familial and non-familial urothelial cell carcinoma.

Due to variation in individual susceptibility, only a fraction of all individuals exposed to environmental carcinogens will develop cancer. Our aim was to assess whether mutagen sensitivity plays a role in developing urothelial cell carcinoma (UCC) and whether this sensitivity is different in familial and non-familial cases. Intrinsic susceptibility was quantified by a mutagen sensitivity assay (mean number of chromatid breaks per cell after damage induction with bleomycin in the late S-G2 phase of the cell cycle). Patients were classified as sporadic (n = 25), familial (2 patients in 1 nuclear family, n = 23) or hereditary (2 patients <60 years or 3 patients in 1 nuclear family, n = 13) and compared with control subjects without a history of cancer. Information on demographic factors, smoking history and family history of UCC was collected by postal questionnaires. Differences in mutagen sensitivity were assessed by ANOVA and logistic regression analysis. Overall, UCC patients showed a higher mutagen sensitivity score compared with control subjects [mean number of chromatid breaks per cell 0.91, 95% confidence interval (CI) 0.84-0.97, and 0.74, 95% CI 0.69-0.79, respectively; p = 0.001). Sporadic and familial patients exhibited the highest susceptibility (0.94, 95% CI 0.82-1.06, and 0.93, 95% CI 0.83-1.03, respectively). Hereditary patients (0.79, 95% CI 0.72-0.86) showed a susceptibility similar to controls. Mutagen sensitivity increases the risk of non-hereditary UCC. The relatively low mutagen sensitivity score among hereditary patients points to a different carcinogenic pathway.

An illustration of the clinical relevance of detecting human antimouse antibody interference by affinity chromatography.

Elevated Cancer antigen 125 (CA 125) serum concentrations (up to 221 kU/1) were measured in a 39 year old woman with a positive family history of breast cancer. The serum determinations were performed with the automated Immulite OM-MA chemiluminescent enzyme immunoassay system (Diagnostic Products). Laparoscopic evaluation of the ovaries did not reveal any abnormalities. CA 125 measurements in the same patient using the automated IMx immunoassay system (Abbott) demonstrated normal serum levels. Using a previously reported chromatography procedure IgG type human antimouse antibody activity was found to be present in the serum samples explaining the falsely elevated levels. To prevent this interference the manufacturer modified the assay system by replacing the monoclonal M11 detection antibody with a rabbit polyclonal antibody. Using the modified OM-MA CA 125 assay results were comparable with the IMx values.

Serum CA 125 measurements to identify patients with endometrial cancer who require lymphadenectomy.

BACKGROUND: Most studies evaluating the role of serum CA 125 measurements in endometrial cancer report a positive correlation with prognostic factors. The present study investigates the role of serum CA 125 measurements as a preoperative aid in the decision whether lymphadenectomy or sampling should be part of the surgical procedure. PATIENTS AND METHODS: We retrospectively studied clinical data of 98 patients with endometrial cancer (FIGO stage I to III), who had serum samples available for analysis of IMx CA 125. Clinical information was included in the analysis in the order in which it became available to the clinician. Patients were grouped retrospectively on the basis of histopathologically determined factors. Those with grade 3 tumors, and/or myometrial invasion > or = 1/2, and/or cervical involvement, and/or parametrial or adnexal tissue involvement, and/or blood vessel invasion, were retrospectively assigned to require lymphadenectomy or sampling (N = 60). All other patients were classified as not requiring such a procedure (N = 38). RESULTS: Serum IMx CA 125 concentrations correlated with all factors included in the surgical FIG0 classification. The sensitivity to identify patients who would have required a lymphadenectomy or sampling on the basis of precurretage serum CA 125 measurements ranged between 17% (10/60) with cut-off of 35 U/ml, and 53% (32/60) with a 15 U/ml cut-off. Corresponding specificity to exclude patients for lymphadenectomy or sampling ranged from 95% (36/28) to 76% (29/38), respectively. After curettage, information regarding histological grade became available. Using only this information, 17 out of 60 patients who would have required a lymphadenectomy or sampling could be identified because of their grade 3 tumor. The combination of serum CA 125 and histological grade could identify between 37% (22/60) and 65% (39/60) of the patients who required a lymphadenectomy or sampling cut-offs again ranging from 35 to 15 U/ml. CONCLUSIONS: CA 125 serum levels may provide additional information in the preoperative assessment of endometrial cancer patients. More studies are needed to establish the appropriate cut-off level for serum CA 125 in this respect.

Quantitation of IgG and IgM human anti-mouse antibodies (HAMA) interference in CA 125 measurements using affinity chromatography.

Currently no available immunoassay system offers complete protection against spuriously elevated or lowered results due to interference by Human Anti-Mouse Antibodies (HAMA). Although routine use of chromatography procedures is not an acceptable option because of the extra cost and workload involved, such a procedure would be highly desirable to ensure accurate immunoassay results. The present report describes a relatively simple affinity chromatography procedure using a HiTrap Protein G column to isolate immunoglobulin G (IgG) HAMA, followed by a HiTrap N-hydroxy-succinimide (NHS)-activated column coupled to goat-anti human immunoglobulin M (IgM) to bind IgM HAMA. To examine the usefulness of this purification procedure we determined CA 125 in forty serum samples prior to and following chromatography. Pre- and post-injection samples were obtained from 20 patients injected with 1 mg of 111In-labelled murine OC 125 F(ab')2 fragments in an immunoscintigraphy study. It is shown that this analytical procedure provides a technique to determine the extent and the nature of the existing HAMA interference in samples of patients after in vivo use of monoclonal antibodies for diagnostic or therapeutic purposes. The procedure can also contribute to the clarification of clinically discordant CA 125 results. Finally, the availability of such a procedure in the clinical laboratory provides an opportunity to test the robustness of newly developed immunoassay systems towards HAMA interference.

Comparison of four 'second generation' immunoassay systems to determine CA 125 in serum by using a graphical approach to method comparison analysis.

Clinical management of ovarian cancer patients is facilitated by CA 125 determinations in serum. Presently, several assay systems based on different concepts and different methodologies are available to measure CA 125. Method comparison analysis of such assay systems is usually performed through (linear) regression analysis, which requires assumptions about the distribution of experimental data and its measurement error. The aim of the present study was to compare four newly developed second generation assay systems for quantitation of CA 125 by utilizing an alternative simple approach to method comparison analysis. This alternative comprises the construction of relative difference plots and mountain plots, previously described by Krouwer et al. (Eur J Clin Chem Clin Biochem 1995; 33:525-7). In addition, the diagnostic value of the assays was illustrated through receiver-operating-characteristic (ROC) curves. Sera obtained from 300 women were assayed for CA 125 using the Abbott IMx CA 125 assay (Abbott), the Centocor CA 125 II RIA assay (Centocor), the Berilux Ov testing kit for CA 125 (Behringwerke), and the CA 125 TR-FIA assay (Wallac Oy). Both the relative difference plots and the mountain plots revealed higher serum concentrations with the Centocor RIA II (Median +33%, P2.5 to P97.5: -25% to 161%) and Berilux (Median +28%, P2.5 to P97.5: -17% to 108%) compared to the Abbott IMx system. The TR-FIA assay system showed lower serum concentrations (Median - 17%, P2.5 to P97.5: -74% to 229%). The combination of relative difference plots and mountain plots demonstrated clearly the wide range of differences between CA 125 assays measuring the same analyte. The relative difference plots provided insight into the distribution of the differences over the range of measurement as well as the identification of outliers. A simple quantitative assessment of the median differences could be made from the overlaying mountain plots. The close correspondence observed between the ROC curves illustrated that assay systems for CA 125 differing in design (type of antibodies used) and format can produce similar results on group level. However, the results of the clinical evaluation underline the importance of the application of assay specific cut-off values.

Improvement of clinical staging in cervical cancer with serum squamous cell carcinoma antigen and CA 125 determinations.

Staging of cervical cancer is routinely performed by means of examination under anesthesia in combination with radiographic and/or endoscopic techniques. This "clinical" staging leads to 10-25% misclassification, mostly due to positive lymph nodes or lymph or blood vessel invasion. Determination of pretreatment squamous cell carcinoma antigen (SCC) and CA 125 serum levels may solve part of this staging problem and may improve the selection of the most appropriate individual therapy. Using 2.5 ng/ml (SCC) and 35 U/ml (CA 125) as cutoff levels, we studied 99 patients retrospectively. Elevated levels were found in 27% (SCC) and 23% (CA 125). In clinical stage IB or IIA disease 45/81 patients had positive nodes or lymph or blood vessel invasion at operation. Of these patients 49% had elevated serum levels of SCC or CA 125. Strongest correlation was found with blood vessel invasion (57%). Only 19% of low-stage patients without evidence of vascular spread of disease had positive levels. The positive predictive value of SCC and CA 125 for detection of vascular spread of disease in low-stage cervical cancer was 76%. In most centers surgery is the primary treatment of choice in low-stage cervical cancer. Nevertheless, with respect to patient survival, results of primary surgery and primary radiotherapy are comparable. Radiotherapy given in an adjuvant setting leads to a high incidence of severe complications. In order to overcome part of these complications one should consider radiotherapy as the primary therapy of choice in patients with clinical stage IB or IIA cervical cancer with elevated pretreatment SCC or CA 125 levels.

Ovarian cancer incidence (1989-1991) and mortality (1954-1993) in The Netherlands.

OBJECTIVE: To examine ovarian cancer incidence and mortality in the Netherlands, and to relate trends in mortality to changes in parity and use of oral contraceptives. METHODS: Age-standardized and age-specific incidence and mortality rates are presented using incidence data from the Netherlands Cancer Registry, 1989-1991, and mortality data from the Netherlands Central Bureau of Statistics, 1954-1993. RESULTS: In the period 1989-1991, age-standardized incidence of ovarian cancer was 14.9 per 10(5) woman-years. The majority (89%) of these tumors had an epithelial origin. Two-thirds of all newly diagnosed ovarian cancers already showed extension to the pelvis or beyond at diagnosis. From the period 1954-1958 to 1969-1973, age-standardized mortality rates increased from 10.6 to 13.1 per 10(5) woman-years. Thereafter, a decline was noted to 11.4 per 10(5) woman-years in the period 1989-1993. Age-specific mortality rates showed a pattern of rising mortality in the elderly, whereas mortality in the younger age categories was declining. The number of live births has declined gradually, and oral contraceptive use has increased. CONCLUSION: Incidence of ovarian cancer is high in the Netherlands, but comparable to other countries in north-western Europe and North America. Mortality rates are rising in the elderly and declining in the young. Further research is needed concerning the effects of oral contraceptives, fertility drugs, and hormone replacement therapy on the incidence and mortality of ovarian cancer.

Should random urothelial biopsies be taken from patients with primary superficial bladder cancer? A decision analysis. Members of the Dutch South-East Co-Operative Urological Group.

OBJECTIVE: To evaluate whether it is worthwhile to implement routine random biopsies from the normal-looking urothelium in the management of patients with primary superficial bladder cancer. PATIENTS AND METHODS: Two hypothetical management policies were compared, one of which incorporated random biopsies as an additional prognostic test. In the 'no-biopsy policy', all patients were treated with transurethral resection (TUR) alone, except for patients with a pT1G3 tumour who were treated with adjuvant prophylactic intravesical therapy. In the 'biopsy policy', the choice of treatment was influenced by the presence or absence of dysplastic urothelium in random biopsy specimens, except in patients with a pT1G3 tumour who received adjuvant treatment, irrespective of the result of random biopsies. Decision analysis was used to compare the outcome of these hypothetical policies with respect to the expected 3-year risks of recurrence and progression. Baseline data used in the analysis originated from a large unselected case series, prospectively documented in the Netherlands. RESULTS: The 'biopsy policy' resulted in a 3 year risk of recurrence and a 3 year risk of progression of 52% and 11%, respectively. These 3 year risks were almost identical to the 'no-biopsy policy': 54% and 11%, respectively. In a sensitivity-analysis, the expected 3 year risks of recurrence as well as the expected 3 year risks of progression were found to remain similar with both policies, even with quite extreme assumptions favouring the 'biopsy policy'. CONCLUSION: In view of the expected small difference in disease outcome between the two management policies, taking random biopsies of normal-looking urothelium at the time of the TUR has no practical value.

Bladder cancer incidence and survival in the south-eastern part of The Netherlands, 1975-1989.

Trends in cancer occurrence and survival may reflect changing risks and prognosis, respectively, but may also be caused by changes in detection, classification and registration. Changed classification of low-stage papillary carcinomas may have a material effect on observed trends in the occurrence of bladder cancer. We studied the effect of the implementation of the WHO grading system and the third edition of the TNM staging system on bladder cancer incidence in the south-eastern part of the Netherlands. Data on superficial and invasive bladder cancer incidence between 1975 and 1989 were derived from the population-based Eindhoven cancer registry. Data on survival of patients with stages I-IV bladder cancer were derived from the municipal population registers. Age-adjusted bladder cancer incidence per 100,000 person-years rose from 25.9 to 40.7 in males and from 3.1 to 8.5 in females. This increasing trend was caused almost entirely by non-invasive pTa papillary carcinoma. A considerable shift was observed towards lower disease stages, which was less evident within the group of invasive tumours. The relative 5-year survival of patients with stages I-IV invasive bladder cancer was 59% in 1975-1977 and 70% in 1984-1986. After stratification by stage, however, no striking improvement was observed in the prognosis. We conclude that the increasing trend of bladder cancer occurrence in the Netherlands since 1975 has largely been caused by changed classification systems and reporting procedures for pTa tumours (formerly classified as papillomas).