The possibility of obtaining marketing authorization of orphan pharmaceutical compounding preparations: 3,4-DAP for Lambert-Eaton Myasthenic Syndrome.

BACKGROUND: Pharmaceutical compounding preparations, produced by (hospital) pharmacies, usually do not have marketing authorization. As a consequence, some of these pharmaceutical compounding preparations can be picked-up by a pharmaceutical company to obtain marketing authorization, often leading to price increases. An example is the 3,4-diaminopyridine slow release (3,4-DAP SR) tablets for Lambert-Eaton Myasthenic Syndrome (LEMS). In 2009 marketing authorization was given for the commercial immediate release phosphate salt of the drug, including a fifty-fold price increase compared to the pharmaceutical compounding preparation. Obtaining marketing authorization for 3,4-DAP SR by academia might have been a solution to prevent this price increase. To determine whether the available data of a pharmaceutical compounding preparation with long-term experience in regular care are adequate to obtain marketing authorization, 3,4-DAP SR is used as a case study. METHODS: A retrospective qualitative case-study was performed. Initially, document analysis was executed by collecting the required data for marketing authorization in general and whether data of Firdapse® and 3,4-DAP SR met these requirements. Secondly, the (non-) available data of the two formulations were compared with each other to determine the differences in availability. RESULTS: At the time of approval, almost all data were available for both Firdapse® and 3,4-DAP SR. Conversely, much of the data used for the approval of Firdapse® originated from the 3,4-DAP immediate release (3,4-DAP IR) formulation. Only two bioequivalence studies and one pharmacology safety study was performed with Firdapse® before marketing authorization application. CONCLUSIONS: In conclusion, at time Firdapse® obtained approval, the data available did not differ substantially from 3,4-DAP SR, indicating that approval with 3,4-DAP SR would have been possible. We make a plea for approval of orphan medicinal products developed and manufactured by academic institutions as to keep utilization of these products affordable.

Inpatient Admissions and Costs Associated with Persistent Use of Dalfampridine Extended-Release in Multiple Sclerosis: A Claims Database Analysis.

BACKGROUND: While the clinical benefits of dalfampridine extended-release (D-ER) have been established in patients with multiple sclerosis (MS) through multiple clinical trials, there is limited real-world data on D-ER use, in particular the persistent use of D-ER, and associated acute care resource utilization and costs. OBJECTIVE: To examine the real-world association of D-ER use and inpatient admissions and costs among patients with MS. METHODS: This study was a retrospective observational claims analysis of the MarketScan database (April 2009-March 2014). Eligible patients consisted of adult enrollees aged 18-64 years who had (a) 12 months of continuous private plan enrollment preceding (baseline) and following (follow-up) the first D-ER claim; (b) ≥ 2 MS diagnosis codes with ≥ 1 during the baseline period; (c) ≥ 2 consecutive D-ER claims; and (d) no alternate gait-impairing etiologies during the baseline and follow-up periods. Patients were separated into 2 D-ER cohorts in the main analysis: persistent (≥ 360 days of D-ER supply) and nonpersistent (< 360 days of supply) users. Sensitivity analyses were conducted, examining additional breakdowns of days of supply within the nonpersistent cohort. Inpatient admissions (all-cause and MS-related) and health care expenditures were calculated and compared between the cohorts during follow-up using Wilcoxon rank-sum and chi-square tests. Regression models were conducted, controlling for age, sex, MS relapses, comorbidities, disease-modifying therapy use, and other baseline factors, including inpatient admissions and costs. RESULTS: Of 1,598 eligible patients, 719 (45.0%) were persistent D-ER users, and 879 (55.0%) were nonpersistent D-ER users. The 2 cohorts had similar demographic and clinical characteristics, with mean (SD) ages of 51.0 (8.4) and 50.6 (8.6) years and were 71.3% and 66.6% female, respectively. Compared with nonpersistent D-ER use, persistent D-ER use was associated with lower odds of all-cause inpatient admissions (OR = 0.58, P = 0.010) and MS-related inpatient admissions (OR = 0.50, P = 0.004). Persistent use was also associated with lower inpatient expenditures for all-cause admissions ($669 vs. $1,515, P = 0.002) and MS-related admissions ($388 vs. $891, P = 0.008). CONCLUSIONS: Persistent D-ER use was associated with significantly lower rates of all-cause and MS-related inpatient admissions and costs. DISCLOSURES: Funding for this research and medical writing assistance was provided by Acorda Therapeutics. The study sponsor was involved in all stages of the study research and manuscript preparation. Guo and Niyazov were employees of Acorda Therapeutics at the time of this study and may own stock/stock options. Wu, Macaulay, Terasawa, and Schmerold are employees of Analysis Group, which received consultancy fees from Acorda Therapeutics for this project. Krieger was a consultant for Acorda Therapeutics for this project and has the following additional financial interests to report: consulting/advisory board work with Bayer, Biogen, EMD Serono, Novartis, Genentech, Genzyme, and Teva. Study concept and design were contributed by Guo, Niyazov, Macaulay, and Wu. Macaulay, Terasawa, Schmerold, and Wu helped prepare the data, and data interpretation was performed by Krieger, Guo, Niyazov, and Macaulay, along with Terasawa and Wu. The manuscript was written by Terasawa and Schmerold, along with Macaulay, and revised by all the authors. A portion of the current research was presented in poster format at the 2106 American Academy of Neurology Annual Meeting, which took place in Vancouver, BC, Canada, on April 15-21, 2016.

Healthcare resource use and costs of multiple sclerosis patients in Germany before and during fampridine treatment.

BACKGROUND: Multiple sclerosis (MS) patients often suffer from gait impairment and fampridine is indicated to medically improve walking ability in this population. Patient characteristics, healthcare resource use, and costs of MS patients on fampridine treatment for 12 months in Germany were analyzed. METHODS: A retrospective claims database analysis was conducted including MS patients who initiated fampridine treatment (index date) between July 2011 and December 2013. Continuous insurance enrollment during 12 months pre- and post-index date was required, as was at least 1 additional fampridine prescription in the fourth quarter after the index date. Patient characteristics were evaluated and pre- vs post-index MS-related healthcare utilization and costs were compared. RESULTS: A total of 562 patients were included in this study. The mean (standard deviation [SD]) age was 50.5 (9.8) years and 63% were female. In the treatment period, almost every patient had at least 1 MS-related outpatient visit, 24% were hospitalized due to MS, and 79% utilized MS-specific physical therapy in addition to the fampridine treatment. Total MS-related healthcare costs were significantly higher in the fampridine treatment period than in the period prior to fampridine initiation (€17,392 vs €10,960, P < 0.001). While this difference was driven primarily by prescription costs, MS-related inpatient costs were lower during fampridine treatment (€1,333 vs €1,565, P < 0.001). CONCLUSIONS: Physical therapy is mainly used concomitant to fampridine treatment. While healthcare costs were higher during fampridine treatment compared to the pre-treatment period, inpatient costs were lower. Further research is necessary to better understand the fampridine influence.

Dalfampridine prior authorization program: a cohort study.

BACKGROUND: Dalfampridine (Ampyra) is indicated to improve walking in patients with multiple sclerosis (MS) and was found to be effective in 35%-43% of individuals with MS in clinical trials. Dalfampridine may increase seizure risk, particularly in patients with renal impairment. A U.S. managed care expert consensus panel agreed that patient access to dalfampridine is best managed by a prior authorization (PA) in accordance with the FDA-approved labeling. To ensure safe and appropriate dalfampridine use, a health plan developed and implemented a 2-phase point-of-sale PA program. OBJECTIVES: To evaluate dalfampridine PA review decisions, utilization, and pharmacy expenditures following the implementation of a dalfampridine safety and clinical PA program compared with a group of dalfampridine utilizers unexposed to a PA program. METHODS: The study utilized retrospective administrative pharmacy claims data from a commercial health plan averaging 1.3 million members per month. The plan implemented a 2-phase dalfampridine safety and effectiveness PA program on August 1, 2010. A comparison group that did not implement the dalfampridine PA program was identified from a commercially insured population with approximately 350,000 members per month. Members in both groups were required to be continuously enrolled from August 1, 2010, through January 31, 2011. A member's earliest paid or rejected claim found from August 1, 2010, through October 31, 2010, was defined as the index claim. Dalfampridine-weighted 30-day supply claims were summed and compared between groups from index date through January 31, 2011. A pharmacy cost avoidance estimate was calculated using the difference in average claims per member from index claim through January 31, 2011, multiplied by dalfampridine wholesale acquisition cost. Overall, dalfampridine utilization was evaluated between the intervention and comparison populations from August 2010 (implementation of PA in intervention group) through December 2011. Linear regression and Poisson models were used to test the trend differences. RESULTS: The 60 PA-exposed dalfampridine members' average follow-up was 157 days. Phase 1 approval was obtained by 32 (53.3%) members; 4 (6.7%) members received a denial because of renal impairment; 8 (13.3%) members received a denial due to inability to obtain walking time; 1 (1.7%) member with relapse-remitting MS was denied a PA due to no concomitant disease-modifying agent; and 15 (25.0%) members did not initiate the PA process. Phase 2 approval was obtained by 23 (38.3%) of the 60 members. The 60 PA members had a total of 126 claims and an average utilization of 2.1 (SD 1.8) claims per member. The 20 non-PA dalfampridine members' average follow-up was 157 days. The comparison group members had a total of 84 claims and an average utilization of 4.2 (SD 2.0) claims per member. The PA program resulted in an average of 2.1 (P less than 0.001) fewer claims per member in the PA group. The total dalfampridine cost avoidance estimate was $143,010 or $0.03 per member per month. The overall measure of a monthly claims utilization difference over time was statistically significantly different at P less than 0.001, using the linear regression slope trend test. The trend line slope was not statistically significantly different, P = 0.841, between the intervention and comparison populations. CONCLUSIONS: The study indicates that a dalfampridine PA program potentially improved safety and minimized dalfampridine costs. A PA program is effective in selecting appropriate utilizers for initial therapy. Addition of care management may further optimize use by encouraging adherence and tracking patient response.

Clinical overview of dalfampridine: an agent with a novel mechanism of action to help with gait disturbances.

BACKGROUND: Medication used to treat multiple sclerosis (MS) can be categorized as disease-modifying therapies, symptomatic therapies, or treatment of acute exacerbations. Dalfampridine is the first symptomatic therapy approved by the Food and Drug Administration to improve walking in patients with MS. OBJECTIVE: This article reviews the pharmacology, pharmacodynamic properties, and pharmacokinetic properties of dalfampridine, as well as its clinical efficacy, safety profile, pharmacoeconomic considerations, and place in therapy. METHODS: Three PubMed searches were conducted for original articles published in English between 1966 and August 2012 with human study participants. Articles concerning the pharmacology, pharmacokinetic properties, pharmacodynamic properties, efficacy, and safety profile of dalfampridine were evaluated. RESULTS: Dalfampridine theoretically works to improve conduction and enhance walking by inhibiting potassium channels in the axonal membrane and by prolonging action potentials in demyelinated neurons. The efficacy of dalfampridine has been reported in 2 Phase III clinical trials in patients with MS. When comparing dalfampridine 10 mg twice daily with placebo, these studies found a statistically significant improvement in walking (42.9% vs 9.3% and 35% vs 8%; P < 0.001). However, clinical trials and postmarketing surveillance have shown an increased risk of seizures with dalfampridine use that appears to be dose related [corrected]. CONCLUSIONS: Dalfampridine has a unique mechanism of action, leading to its approval as the first symptomatic therapy for MS to improve walking speed. The increased risk of seizures can be a safety concern and will require health care providers to be diligent in monitoring patients and to ensure adequate patient education [corrected]. The addition of dalfampridine as symptomatic therapy for MS may lead to additional novel products in the future.