An overview of biosimilars and non-biologic complex drugs in Europe, the United States, and Canada and their relevance to multiple sclerosis.

The advent of biological medicines has significantly transformed the landscapes of many disease spaces and improved the lives of millions around the world. However, the structural complexity and sensitivity of such products result in a high price tag, adding to already financially strained healthcare systems. As these and other expensive complex drugs lose market exclusivity, stakeholders eagerly await the arrival of lower cost alternatives, such as biosimilars and subsequent entry non-biological complex drugs (NBCDs). Nevertheless, stakeholders remain uncertain about key issues which have resulted in heterogeneous reimbursement policies and varying levels of biosimilar uptake and subsequent entry NBCD approval processes between different markets. With the imminent introduction of both subsequent entry NBCDs and biosimilars for multiple sclerosis (MS), it is important to get a better understanding of this new class of products and how healthcare systems have been adapting to their use. This article defines biosimilars and subsequent entry NBCDs and provides an overview of how these products have been introduced in Europe, the United States, and Canada from a regulatory, health technology, and reimbursement perspective. In addition, this article briefly explores the potential impact and outlook of biosimilar and NBCD products related to MS.

Topiramate use during pregnancy and major congenital malformations in multiple populations.

BACKGROUND: We measured birth prevalence of major congenital malformations (MCMs) after topiramate use during pregnancy to screen for a possible signal of increased risk. METHODS: Using four healthcare databases, we identified three cohorts of pregnant women: cohort 1, used topiramate during the first trimester; cohort 2, used topiramate or another antiepileptic drug previously but not during pregnancy; and cohort 3, were pregnant and did not use topiramate but had indications for use individually matched to those of users. Cohort 1 was compared with cohorts 2 and 3. MCMs were a code for any major congenital malformation dated within 30 days of the delivery date on the mother's claims or within 365 days after infant birth date, excluding a genetic or syndromic basis, and with procedure or healthcare usage consistent with the MCM diagnosis code in the 365 days after infant birth. RESULTS: Of the 10 specific common MCMs evaluated, 1 (conotruncal heart defects) had a prevalence ratio greater than 1.5 for both primary comparisons, and 4 (ventricular septal defect, atrial septal defect, hypospadias, coarctation of the aorta) had a prevalence ratio greater than 1.5 for one of the two comparisons. Following screening of organ systems with elevated MCMs, the prevalence ratio was greater than 1.5 for patent ductus arteriosus in both comparisons and for obstructive genitourinary defects in one comparison. CONCLUSION: To evaluate a large number of MCMs across many pregnancies, we used crude methods for detecting potential signals. Therefore, these results should be seen as potential signals, not causal.

Topiramate use in pregnancy and the birth prevalence of oral clefts.

PURPOSE: First marketed in the USA in 1996, topiramate (TPM) is an antiepileptic drug later approved for migraine prophylaxis, and in 2012 for weight loss in combination with phentermine. Some studies indicate an elevated prevalence of oral cleft (OC) in infants exposed to TPM in utero. We evaluated the association between TPM use in early pregnancy and the risk of OC. METHODS: This retrospective cohort study used 1997-2011 automated data from four sources: HealthCore and OptumInsight (commercial insurance claims), Truven Health (Medicaid claims), and Kaiser Permanente Northern California Region (electronic medical records). We compared the prevalence of OCs in infants of women exposed to TPM in the first trimester (TPM cohort) with the prevalence in infants of women formerly exposed to TPM or other antiepileptic drugs (formerly exposed [FE] cohort) and infants of women with similar medical profiles (SMPs) to the TPM cohort that were not exposed to TPM (SMP cohort). To control for confounding, we used stratification and standardization for individual variables and propensity score deciles. RESULTS: The birth prevalence of OCs was 0.36% (7/1945) in the TPM cohort, 0.14% (20/13 512) in the FE cohort, and 0.07% (9/13 614) in the SMP cohort. Standardized by site, the prevalence ratio (PR) for TPM versus FE was 2.5 (95% CI: 1.0-6.0) and for TPM versus SMP was 5.4 (95% CI: 2.0-14.6). Adjustment for covariates one at a time or by propensity score yielded similar results. CONCLUSION: Consistent with other recent epidemiologic research, first-trimester TPM exposure was associated with an elevated birth prevalence of OC.

The Zelnorm epidemiologic study (ZEST): a cohort study evaluating incidence of abdominal and pelvic surgery related to tegaserod treatment.

BACKGROUND: Pre-marketing clinical studies of tegaserod suggested an increased risk of abdominal surgery, particularly cholecystectomy. We sought to quantify the association between tegaserod use and the occurrence of abdominal or pelvic surgery, including cholecystectomy. METHODS: This cohort study was conducted within an insured population. Tegaserod initiators and similar persons who did not initiate tegaserod were followed for up to six months for the occurrence of abdominal or pelvic surgery. Surgical procedures were identified from health insurance claims validated by review of medical records. The incidence of confirmed outcomes was compared using both as-matched and as-treated analyses. RESULTS: Among 2,762 tegaserod initiators, there were 94 abdominal or pelvic surgeries (36 gallbladder): among 2,762 comparators there were 134 abdominal or pelvic surgeries (37 gallbladder) (hazard ratio HR] = 0.70, 95% confidence interval [C.I.] = 0.54-0.91 overall, HR = 0.98, 95% C.I. = 0.62-1.55 for gallbladder). Current tegaserod exposure compared to nonexposure was associated with a rate ratio [RR] of 0.68 (95% C.I. = 0.48-0.95) overall, while the RR was 0.99 (95% C.I. = 0.56-1.77) for gallbladder surgery. CONCLUSIONS: In this study, tegaserod use was not found to increase the risk of abdominal or pelvic surgery nor the specific subset of gallbladder surgery.

Tegaserod and the risk of cardiovascular ischemic events: an observational cohort study.

OBJECTIVES: Tegaserod, a partial 5-HT(4) agonist previously approved for treatment of irritable bowel syndrome with constipation and chronic idiopathic constipation, was suspended from US marketing in 2007, based on pooled clinical trial results which contained a signal suggesting increased risk of cardiovascular ischemic events (CVIEs). We sought to evaluate whether there was an association between tegaserod and CVIE in a setting of routine clinical practice. METHODS: This was a matched cohort study conducted within a large US health insurance database, involving 52 229 patients who initiated tegaserod and 52 229 patients with similar characteristics who did not initiate tegaserod. Participants were followed for up to 6 months for the occurrence of CVIE (myocardial infarction, acute coronary syndrome, coronary revascularization, and stroke). Outcomes were identified using insurance claims and were confirmed by review of medical records. We conducted as-matched analyses providing hazard ratios (HRs) along with 95% confidence intervals (95% CI) and as-treated analyses accounting for changes in dispensed therapy. RESULTS: There was no increased risk of CVIE associated with tegaserod treatment. The as-matched association between tegaserod and ischemic cardiovascular outcomes (HR = 0.95, 95% CI 0.73-1.23) and stroke (HR = 0.90, 95% CI 0.46-1.77) did not change substantially in the as-treated analyses (cardiovascular relative risk [RR] = 1.14, 95% CI 0.83-1.56; stroke: RR = 1.09, 95% CI = 0.49-2.02). The results were largely unaffected by adjustment for characteristics or subgroup analyses. CONCLUSION: In this observational study of tegaserod use, we found no evidence for an increased risk of CVIE in tegaserod users.

The risk of coronary heart disease in type 2 diabetic patients exposed to thiazolidinediones compared to metformin and sulfonylurea therapy.

PURPOSE: To evaluate whether the risk of coronary heart disease (CHD) differs among adult diabetic patients treated with thiazolidinediones (TZDs) and similar patients treated with combined oral metformin and sulfonylurea (M + S) therapy. METHODS: We conducted a retrospective cohort study involving 25 140 diabetic patients aged 18 and older who had at least one pharmacy claim for a TZD or combined M + S therapy between 1 January 1999 and 30 June 2002. We used propensity score matching to adjust for observable differences between initiators of combined M + S therapy and TZD initiators. The data were analyzed in two ways: first based on the original matched groups, 'as balanced', without accounting for switching to another medication during follow-up, and second based on actual antidiabetic drug use during follow-up, 'as treated'. Cox proportional hazards regression and multivariable Poisson regression were performed to compare the risk of CHD events. RESULTS: In the 'as balanced' analysis, the risk for CHD among TZD users relative to combination drug users was close to the null value (adjusted hazard ratio: 1.02, 95% confidence intervals (CI): 0.87-1.20). In the 'as treated' analysis, the risk of CHD was similar for periods of current use of TZDs compared to periods of non-use (incidence rate ratio: 1.10, 95%CI: 0.96-1.25). CONCLUSIONS: These results do not suggest a cardioprotective or deleterious effects of TZDs compared with combined M + S oral therapy on the short-term CHD event risk in persons with type 2 diabetes after accounting for the greater baseline CHD risk in TZD initiators.

The comparative safety of rosuvastatin: a retrospective matched cohort study in over 48,000 initiators of statin therapy.

PURPOSE: The purpose of this study was to compare incidence rates of hospitalization associated with rhabdomyolysis, myopathy, renal, or hepatic dysfunction, and of in-hospital death, between initiators of rosuvastatin and other statins. METHODS: This was a matched cohort study of statin initiators from the administrative database of a large health insurer in the US, during the first 6 months of rosuvastatin availability with up to 18 months of follow-up. All outcome events were verified by medical record review. Incidence rates, risk ratios, and associated 95% confidence intervals were estimated. RESULTS: From an initial pool of 12,217, 11,249 eligible rosuvastatin initiators were matched to 37,282 initiators of other statins. The incidence rate (IR) per 1000 person-years for rhabdomyolysis was 0.10 [0.00, 0.55] for rosuvastatin initiators (n = 1) and 0.06 [0.01, 0.22] for other statin initiators (n = 2), for a hazard ratio (HR) of 1.98 [0.18, 21.90]. The IR for myopathy was 0.20 [0.02, 0.71] for rosuvastatin initiators (n = 2) and 0.00 [0.00, 0.09] for other statin initiators (n = 0). The IR for renal dysfunction was 1.18 [0.61, 2.06] for rosuvastatin initiators (n = 12) and 1.26 [0.91, 1.71] for other statin initiators (n = 42), for a HR of 0.90 [0.47, 1.73]. The IR for hepatic dysfunction was 0.20 (0.02, 0.71) for rosuvastatin initiators (n = 2) and 0.24 (0.10, 0.47) for other statin initiators (n = 8), for a HR of 0.87 (0.18, 4.14). CONCLUSIONS: This study found no difference between rosuvastatin and the other statins in the incidence of hospitalizations associated with renal or hepatic events, or death. The absolute incidence rates of rhabdomyolysis and myopathy were reassuringly low among all statin initiators but remain too small for firm conclusions to be drawn on any difference between the statins.