Assessing the Consequences of External Reference Pricing for Global Access to Medicines and Innovation: Economic Analysis and Policy Implications.

Background: External reference pricing (ERP) is used to set pharmaceutical prices to improve affordability, but its application may have negative consequences on patient access-thus, equity-across countries and on global innovation. With the United States contemplating ERP, negative effects could be magnified. Our aim: identify and quantify some major consequences of ERP. Research design, methods: Besides relying on databases and ERP modelling, we developed a heart failure case study. 4-step approach: 1) review ERP policies; 2) establish worldwide "price corridor"; 3) quantify patient access and health outcomes impact by ERP; 4) estimate ERP impact on innovation. Results: Our ERP referencing analysis highlights its perverse effects especially in lower-income countries. As counterstrategies to protect their revenues, manufacturers often implement tight list price corridors or launch avoidance/delays. Consequences include suboptimal patient access-hence, worse outcomes-illustrated by our case study: 500,000 + QALYs health loss. Additionally, the ensuing revenue reduction would likely cause innovation loss by one additional medicine that would have benefitted future patients. Conclusion: This research provides key insights on potential unintentional consequences of medicine price setting by ERP worldwide and under a new proposal for the United States. Our results can inform stakeholder discussions to improve patient access to innovative medicines globally.

Matching-adjusted indirect comparisons of annualized bleeding rate and utilization of BAY 94-9027 versus three recombinant factor VIII agents for prophylaxis in patients with severe hemophilia A.

Background: BAY 94-9027 is an extended half-life recombinant factor VIII (rFVIII) that prevents bleeding in persons with hemophilia A at twice-weekly, 5-day, and 7-day dosing intervals. In rare diseases such as hemophilia, where small populations preclude head-to-head comparisons in randomized controlled trials, outcomes from different studies can be compared by matching-adjusted indirect treatment comparisons (MAICs) via matched summary statistics of individual patient data. This study compared MAIC-adjusted outcomes of BAY 94-9027 with other FVIII agents for prophylaxis of hemophilia. Methods: Weighted patient data from the BAY 94-9027 PROTECT VIII trial were used to compare annualized bleeding rates (ABRs), percentage of patients with zero bleeds, and factor utilization against published data on rFVIII-Fc fusion protein (rFVIIIFc), BAX 855, and recombinant antihemophilic factor/plasma/albumin-free method (rAHF-PFM). Results: After matching BAY 94-9027 and comparators, the mean BAY 94-9027 utilization was significantly lower than rFVIIIFc pre- and post-matching (66.2 vs 82.2 IU/kg/week; 66.5 vs 82.2 IU/kg/week; both P<0.001). Median BAY 94-9027 utilization (IU/kg/week) trended lower than BAX 855 (64.3 vs 87.4) and rAHF-PFM (2004 study: 64.0 vs 107.5; 2012 study: 63.6 vs 109.9). Mean ABRs and percentages of patients with zero bleeds were similar post-matching between BAY 94-9027 and comparators. Conclusion: BAY 94-9027 demonstrated similar MAIC-adjusted ABR with lower utilization than rFVIIIFc, BAX 855, and rAHF-PFM.

Exploring the Impact of Infusion Frequency in Hemophilia A: Exit Interviews with Patients Participating in BAY 94-9027 Extension Studies (PROTECT VIII).

INTRODUCTION: Prophylactic treatment of severe hemophilia A is burdensome, requiring frequent intravenous injections. Extended half-life (EHL) factor VIII replacement therapies offer longer intervals between infusions while still meeting efficacy and safety outcomes; however, patient perspectives following long-term use of such products in the real-world remain unknown. OBJECTIVE: We aimed to explore the importance of infusion frequency and the potential benefits of reduced infusion frequency among patients receiving prophylactic treatment with an EHL product (BAY 94-9027). METHODS: Patients with severe hemophilia A participating in the PROTECT VIII extension study were invited to participate in a semi-structured, concept elicitation 'exit' interview to discuss their experiences. Participants were recruited from Israel, The Netherlands, and the US. Interview transcripts were translated into English and analyzed using thematic analysis methods. RESULTS: Sixteen participants (29-68 years of age) infusing with BAY 94-9027 once every 7 days, once every 5 days, or twice weekly were interviewed. Participants reported infusion frequency (alongside efficacy) as the most important treatment attribute influencing their satisfaction with therapy. Patient-reported benefits of reduced infusion frequency and longer duration of factor coverage included greater ability to participate in physical activities; better vein health; less time to schedule and administer factor VIII; reduced impact on work; and improved emotional well-being. CONCLUSIONS: This study provides rich insights into the experiences of patients with EHL products and the value of reduced infusion frequency. Such data could be of value to a range of stakeholders (e.g. regulators, payers) and facilitate patient-clinician discussions to promote tailored treatment decisions.

Change of initial oral antidiabetic therapy in type 2 diabetic patients.

OBJECTIVE: To explore the 'real-life' therapy of type 2 diabetes mellitus with oral antidiabetic drugs (OADs). METHODS: From the PHARMO Record Linkage System comprising linked drug dispensing and clinical laboratory data from approximately 2.5 million individuals in the Netherlands, among others, new users of OADs were identified in the period 1999-2004. New users, aged 30 years and older, without insulin use before cohort entry date and with at least one year follow-up were included. We determined per initial therapy patient characteristics and first therapy change. RESULTS: Overall 35,514 patients were included. Metformin and sulfonylureas (SU) were the most frequent initial therapy. Patients on thiazolidinedione (TZD) monotherapy had lower percentages baseline HbA1c >or= 7% compared to patients on metformin and SU. The proportion of patients still on initial therapy after one year ranged from 46% (TZDs) to around 60% (SU). Among patients starting on monotherapy, add-on (15-20%) and discontinuation (16-25%) of therapy occurred most frequently. In patients starting on combination therapy, a switch occurred in 30% of the patients. CONCLUSION: In more than 40% of the patients a change in initial OAD-therapy is already observed in the first year of therapy. Maintaining patients on initial therapy remains a challenge.

Effect of non-persistent use of oral glucose-lowering drugs on HbA1c goal attainment.

OBJECTIVES: The aim of this study was to quantify the effect of non-persistence with oral glucose-lowering drugs (OGLD) on HbA(1c) goal attainment (<7%) in daily practice. METHODS: From the PHARMO Record Linkage System comprising among others linked drug dispensing and clinical laboratory data from approximately 2.5 million individuals in the Netherlands, new users of OGLD in the period 1999-2004 were identified. Patients with a baseline HbA(1c) > or =7% and at least one HbA(1c) measurement in the period of 6-12 months after treatment onset were included in the study cohort. Persistence with OGLD in the first year of treatment was determined using the method of Catalan. In case the first treatment episode overlapped the first HbA(1c) measurement within 6-12 months after treatment onset, a patient was considered persistent at that measurement. Patients with a HbA(1c) <7% were defined as having attained goal. RESULTS: The study cohort included 2023 patients with a mean baseline HbA(1c) of 8.9 +/- 1.8%. Three-quarters (1512 patients) were persistent with any OGLD at the first HbA(1c) measurement within 6-12 months after treatment onset; of these, 861 (57%) were at goal. Of the 511 non-persistent patients, 239 (47%) were at goal. Non-persistent patients were about 20% less likely to attain goal (RRadj 0.82; 95%CI 0.74-0.91), compared to persistent OGLD users. CONCLUSION: Non-persistent use of OGLD leads to a 20% decreased probability of HbA(1c) goal attainment in daily practice. This effect of non-persistence seems modest, but represents around 12 000 new and 10 000 prevalent OGLD users a year in the Netherlands in whom OGLD use could be better controlled.