Optimizing The Clinical Efficacy And Safety Of Biological Medicines And Their Biosimilars Within Available Resources In Europe

Introduction: Biological medicines contain active principles made by large and complex molecular structures, produced or extracted from a biological source. Biosimilars offer significant opportunities to reduce the price of biological medicines especially in an area of spiralling healthcare expenditure. Given the complexity of these medicines, their role in the management of many diseases, and their high price, there is the need to promote their appropriate use and develop tools and policies to increase access to high quality and affordable medicines. Aims: With a multidisciplinary approach, I took into account different facets this topic. 1. Analysis of the development and marketing authorisation of biosimilars in the EU to explore how the regulatory framework affects biosimilar clinical development, policies and uptake. 2. Analysis of the evidence supporting the switch between originator and biosimilars and the switch among biosimilars, in chronic clinical conditions. 3. Development and testing of an innovative analytical technique to monitor the appropriate use of biological medicines in order to maximise patient outcomes. 4. Development of education and training programmes for healthcare professionals regarding biological medicines and biosimilars in collaboration with local health authorities. Methods: I applied a combination of different methodologies, tailored to each different aim. 1. Analysis of pivotal clinical trials of EU approved biosimilars that compare their efficacy and safety to originators. 2. Series of systematic reviews that evaluate efficacy and safety of switching between biologics and their biosimilars of insulin analogues and anti-TNFs. Identification of studies through systematic searches on Medline, EMBASE, and The Cochrane Library. Update of anti-TNFs review (2022) to retrieve studies on switching among biosimilars. 3. Measurement of serum concentrations of therapeutic antibodies and anti-drug antibodies using the innovative Surface Plasmon Resonance-based immunoassay. 4. Definition of training objectives and modalities of educational sessions on biological medicines. Identification of clinical areas where these medicines are commonly used. Development of key metrics of prescription performance used as starting point for the course content. Main results: 1. Up to April 2022, I retrieved 68 biosimilars approved in the EU, corresponding to 18 active principles. The comparability exercise and subsequent approval of the majority of them is based on one or more pivotal phase III trials comparing their clinical efficacy to the originators. Often trials adopted an equivalence design, while insulin analogue biosimilars approval based on non-inferiority trial design. Two third of these trials included data on immunogenicity. The requirement for showing similarity in terms of clinical efficacy and safety provides a robust demonstration of comparable clinical outcomes. 2. I retrieved 22 studies addressing the insulin review questions. Three randomised controlled trials, on insulin glargine, collected evidence on equivalent efficacy, safety and immunogenicity when switching to biosimilar. Data on switching between different analogues, or from analogues to human insulins are very limited (one RCT). Studies comparing switching from originators to biosimilars of anti-TNF (infliximab, adalimumab, etanercept) in chronic inflammatory diseases are many and consistent. I included 32 records, corresponding to three systematic reviews, 14RCTs, 8 OLEs and three cohort studies. Substantial amount of evidence from RCTs is available for IFX and ADMB, versus one RCT of ETN. All these studies suggest switching is safe and effective. With regards of switching among biosimilars, I included 19 clinical studies: 11 cohort studies and 8 single-arm studies: none of these studies highlights significant concerns on switching between biosimilars. 3. The study involved 76 patients receiving infliximab for IBD. Concentration of biological drug and anti-drug-antibodies in each sample determined by SPR in triplicate by two researchers with different experience. Measurements with both ELISA and SPR indicated very similar IFX serum concentrations, with differences of ADA. All the sera showing ADA by ELISA also showed ADA by SPR. 8 patients showed ADA only with SPR: these ADA had significantly faster dissociation rate constants than those detectable by both methods. Measurement of IFX and ADA can support informed decisions for a more rational management of biological therapies. 4. Education programme was replied four times with 30-40 participants each. There was a case-mix of specialties: gastroenterologists, dermatologists, rheumatologists but also oncologists, internal medicine physicians and general practitioners. The majority was confident in prescribing biosimilars in naïve patients, with some restraint to switching. All the participants were in favour of better integration of the gained experience with different specialities. Conclusions: Altogether, the different strategies exploited in my project could support a clinical decision-making based on a more rational use of biological medicines, with benefits for both the patient’s outcome and the health budgets

Key patient related factors in the management of inflammatory bowel disease

Background: Inflammatory Bowel Disease (IBD) is a lifelong illness typically starting during the teen years in patients with an appreciable negative impact on health-related-quality-of-life (HRQoL). However, more needs to be known about the effects of IBD on work productivity, daily activities and HRQoL to guide future decision making including priorities for resource allocation with an increasing prevalence of IBD as well as years with disability. In addition, concerns that indirect costs may not always be considered by payers within reimbursement and funding decisions. Methods: Survey among Austrian patients with IBD using robust instruments. Results and Conclusion: IBD does have a substantial burden reducing HRQoL and work productivity and increasing work absenteeism, with differences between those with ulcerative colitis and Chron’s disease. Productivity reduction was associated with reduced HRQoL. Improved HRQoL should be a focus of future treatments and funding decisions, which is particularly important for patients with IBD. However, indirect costs may not always be a focus among reimbursement authorities

Can local policies on biosimilars optimize the use of freed resources – experiences from Italy

There is an increasing need to prescribe biosimilars to fund new medicines and increasing medicine volumes. Bertolani and Jommi document successful measures introduced regionally in Italy

Ever-changing landscape of biosimilars in Canada; findings and implications from a global perspective

Siu et al. have comprehensively assessed the rapidly changing regulation and reimbursement environment for biologicals and biosimilars in Canada and the resultant implications

Switching among biosimilars : a review of clinical evidence

Biological medicines have improved patients' outcomes, but their high costs may limit access. Biosimilars, alternatives which have demonstrated high similarity in terms of quality, safety and efficacy to an already licensed originator biological product, could increase competition and decrease prices. Given the expanding number of biosimilars, patients may switch from originator to biosimilar or among biosimilars. Randomized trials and observational studies conducted with multiple biosimilars over many disease areas confirmed the safety and efficacy of switching from originator to biosimilar. This study summarizes evidence on switching between biosimilars for which there are concerns to provide future guidance. Systematic search (Medline, Embase, Cochrane Library) for studies on anti-TNF agents, assessing clinical efficacy and safety of biosimilar-to-biosimilar switch in chronic inflammatory diseases. We retrieved 320 records and included 19 clinical studies. One study with historical control compared switching between biosimilars to maintenance of the same biosimilar. Ten were controlled cohort studies comparing switching between two biosimilars vs switching from originator to a biosimilar or vs multiple switches. Eight were single-arm cohort studies, where participants switched from one biosimilar to another and the outcomes were compared before and after the switch. Overall, these studies did not highlight significant concerns in switching between biosimilars. Therefore, switching studies seem difficult to perform and unnecessary with the body of evidence suggesting no real problems in practice coupled with stringent regulatory requirements. Monitoring the use of biosimilars in clinical practice could support clinical decision making, rational use of biologic medicines, and help to further realize possible savings

The current situation regarding long-acting insulin analogues including biosimilars among selected African, Asian, European and South American countries : findings and implications for the future

Background: Diabetes mellitus rates continue to rise, which coupled with increasing costs of associated complications has appreciably increased global expenditure in recent years. The risk of complications are enhanced by poor glycaemic control including hypoglycaemia. Long-acting insulin analogues were developed to reduce hypoglycaemia and improve adherence. Their considerably higher costs though have impacted their funding and use. Biosimilars can help reduce medicine costs. However, their introduction has been affected by a number of factors. These include the originator company dropping its price as well as promoting patented higher strength 300 IU/ml insulin glargine. There can also be concerns with different devices between the manufacturers. Objective: To assess current utilisation rates for insulins, especially long-acting insulin analogues, and the rationale for patterns seen, across multiple countries to inform strategies to enhance future utilisation of long-acting insulin analogue biosimilars to benefit all key stakeholders. Our approach: Multiple approaches including assessing the utilisation, expenditure and prices of insulins, including biosimilar insulin glargine, across multiple continents and countries. Results: There was considerable variation in the use of long-acting insulin analogues as a percentage of all insulins prescribed and dispensed across countries and continents. This ranged from limited use of long-acting insulin analogues among African countries compared to routine funding and use across Europe in view of their perceived benefits. Increasing use was also seen among Asian countries including Bangladesh and India for similar reasons. However, concerns with costs and value limited their use across Africa, Brazil and Pakistan. There was though limited use of biosimilar insulin glargine 100 IU/ml compared with other recent biosimilars especially among European countries and Korea. This was principally driven by small price differences in reality between the originator and biosimilars coupled with increasing use of the patented 300 IU/ml formulation. A number of activities were identified to enhance future biosimilar use. These included only reimbursing biosimilar long-acting insulin analogues, introducing prescribing targets and increasing competition among manufacturers including stimulating local production. Conclusions: There are concerns with the availability and use of insulin glargine biosimilars despite lower costs. This can be addressed by multiple activities

Ongoing efforts to improve the management of patients with diabetes in Bangladesh and the implications

Background: Prevalence rates of patients with diabetes are growing across countries, and Bangladesh is no exception. Associated costs are also increasing, driven by costs associated with the complications of diabetes including hypoglycaemia. Long-acting insulin analogues were developed to reduce hypoglycaemia as well as improve patient comfort and adherence. However, they have been appreciably more expensive reducing their affordability and use. Biosimilars offer a way forward. Consequently, there is a need to document current prescribing and dispensing rates for long-acting insulin analogues across Bangladesh, including current prices and differences, as a result of affordability and other issues. Methods: Mixed method approach including surveying prescribing practices in hospitals coupled with dispensing practices and prices among community pharmacies and drug stores across Bangladesh. This method was adopted since public hospitals only dispense insulins such as soluble insulins free-of-charge until funds run out and all long-acting insulin analogues have to be purchased from community stores. Results: There has been growing prescribing and dispensing of long-acting insulins in Bangladesh in recent years, accounting for over 80% of all insulins dispensed in a minority of stores. This has been helped by growing prescribing and dispensing of biosimilar insulin glargine at lower costs that the originator, with this trend likely to continue with envisaged growth in the number of patients. Consequently, Bangladesh can serve as an exemplar to other low- and middle-income countries struggling to fund long-acting insulins for their patients. Conclusions: It was encouraging to see continued growth in the prescribing and dispensing of long-acting insulin analogues in Bangladesh via the increasing availability of biosimilars. This is likely to continue benefitting all key stakeholder groups

Availability and use of long-acting insulin analogues including their biosimilars across Africa; findings and implications

Background: Prevalence rates of diabetes mellitus are growing across Africa with an appreciable number likely to be on insulin to manage their condition. This has significant implications on future morbidity and mortality exacerbated by high complication rates. Complication rates in patients requiring insulins are enhanced by hypoglycaemia. Long-acting insulin analogues were developed to reduce hypoglycaemia and improve patient compliance. However, they are typically appreciably more expensive than human and other insulins in Africa, and continuing controversies surrounding their benefits limits their listing on national essential medicine lists (EMLs). Biosimilars can reduce the prices long-acting insulin analogues. This needs assessing. Methods: Mixed methods approach including documentation of insulin utilisation patterns and prices among a range of African countries. In addition, input from senior level government, academic, and healthcare professionals from across Africa on the current situation with long-acting insulin analogues as well as potential changes needed to enhance future funding of long-acting analogue biosimilars. Results: There is variable listing of long-acting insulin analogues on national EMLs across Africa due to their high prices and issues of affordability. Even when listed, utilisation of long-acting insulin analogues is limited by similar issues including affordability. Appreciably lowering the prices of long-acting insulin analogues via biosimilars should enhance future listing on EMLs and use accompanied by educational and other initiatives. However, this will require increased competition to lower prices. Conclusion: There are concerns with value and funding of long-acting insulin analogues across Africa including biosimilars. A number of activities have been identified to improve future funding and listing on EMLs

Corrigendum to "Utilisation trend of long-acting insulin analogues including biosimilars across Europe: findings and implications"

In the article titled "Utilisation Trend of Long-Acting Insulin Analogues including Biosimilars across Europe: Findings and Implications" [1], the captions of Figures 3 and 4 were incorrect. The corrected captions for Figures 3 and 4 appear below

Variation in the prices of oncology medicines across Europe and the implications for the future

Introduction/ Objectives: There are increasing concerns among health authorities regarding the sustainability of healthcare systems with growing expenditure on medicines including new high-priced oncology medicines. Medicine prices among European countries may be adversely affected by their population size and economic power to negotiate. There are also concerns that prices of patented medicines do not change once the prices of medicines used for negotiations substantially change. This needs to be investigated as part of the implications of low-cost generic oncology medicines. Methodology: Analysing principally reimbursed prices of patented oral oncology medicines (imatinib, erlotinib and fludarabine) between 2013 and 2017 across Europe and exploring correlations between GDP, population size, and prices. Comparing the findings with previous research regarding prices of oral generic oncology medicines. Results: The prices of imatinib, erlotinib and fludarabine did vary among European countries but showed limited price erosion over time in the absence of generics. There appeared to be no correlation between population size and prices. However, higher prices were seen among countries with higher GDP per capita which is a concern for lower income countries referencing these. Discussion and Conclusion: It is likely that the limited price erosion for patented oncology medicines will change across Europe with increased scrutiny over their prices and value as more medicines used for pricing decisions lose their patents combined with growing pressures on the oncology drug budget. In addition, discussions will continue regarding fair pricing for new oncology medicines and other approaches given ever rising prices with research showing substantial price reductions for oral oncology medicines (up to -97.8% for imatinib) once generics become available. We are also seeing appreciable price reductions for biosimilars further increasing the likelihood of these developments