[Haemophilia B therapy: impact of the reimbursability of a long-acting recombinant factor on pharmaceutical expenditure in Italy]. / Terapia dell'emofilia B: impatto dell'ammissione alla rimborsabilità di un fattore ricombinante long-acting sulla spesa farmaceutica in Italia.

OBJECTIVES: to assess the variability in expenditure compared to 2022 assuming different rates of shifting of therapy days from current active ingredients used for the treatment of haemophilia B to nonacog beta pegolDesign: descriptive cross-sectional study. SETTING AND PARTICIPANTS: consumption in the year 2022 (data source: Medicines Utilisation Monitoring Centre, Italian Medicines Agency) of all medicinal products available in Italy containing coagulation factor IX. MAIN OUTCOMES MEASURES: for each active ingredient, the total number of therapy days and the variability in expenditure compared to 2022 were estimated on the basis of a switch of therapy days, between 5% and 20%, to nonacog beta pegol. RESULTS: on the basis of considered scenarios, the analysis shows that the total annual expenditure for clotting factors used in the treatment of haemophilia B could remain at most unchanged or reduced. Particularly, the extent of the reduction in spending could vary from 0.11% to 2.26%. This trend would be in contrast to the stable increase seen in recent years, particularly in 2022. CONCLUSIONS: this predictive spending assessment may be useful in evaluating the economic impact from new treatment options, such as etranacogene dezaparvovec gene therapy already approved by the European Medicines Agency and the Food and Drug Administration, and to improve pharmaceutical governance.

Analysis of long-term clinical and cost impact of etranacogene dezaparvovec for the treatment of hemophilia B population in the United States.

INTRODUCTION: Etranacogene dezaparvovec (EDZ), Hemgenix, is a gene therapy recently approved for people with hemophilia B (PwHB). OBJECTIVE: To estimate long-term clinical impact and cost of EDZ in the United States (US). METHODS: A decision-analytic model was developed to evaluate the long-term impact of introducing EDZ for PwHB over a 20-year time horizon. Factor IX (FIX) prophylaxis comparator was a weighted average of different FIX prophylaxis regimens based on US market share data. We compared a scenario in which EDZ is introduced in the US versus a scenario without EDZ. Clinical inputs (annualized FIX-treated bleed rate; adverse event rates) were obtained from HOPE-B phase 3 trial. EDZ durability input was sourced from an analysis predicting long-term FIX activity with EDZ. EDZ one-time price was assumed at $3.5 million. Other medical costs, including FIX prophylaxis, disease monitoring, bleed management, and adverse events were from literature. The model estimated annual and cumulative costs, treated bleeds, and joint procedures over 20 years from EDZ introduction. RESULTS: Approximately 596 PwHB were eligible for EDZ. EDZ uptake was estimated to avert 11,282 bleeds and 64 joint procedures over 20 years. Although adopting EDZ resulted in an annual excess cost over years 1-5 (mean: $53 million annually, total $265 million), annual cost savings were achieved beginning in year 6 (mean: $172 million annually; total $2.58 billion in years 6-20). The total cumulative 20-year cost savings was $2.32 billion, with cumulative cost savings beginning in year 8. CONCLUSION: Introducing EDZ to treat PwHB is expected to result in cost savings and patient benefit over 20 years. Initiating PwHB on EDZ sooner can produce greater and earlier savings and additional bleeds avoided. These results may be a conservative estimate of the full value of EDZ, as PwHB would continue to accrue savings beyond 20 years.

This analysis assessed the long-term clinical and financial impact of introducing EDZ in the United States of America for people with severe or moderately severe hemophilia B. A decision-analytic model was developed comparing a scenario with EDZ and one without EDZ over 20 years. Introducing EDZ would avert 11,292 bleeds and 64 joint procedures over 20 years and would achieve cumulative cost savings in year 8, with a total cumulative 20-year cost saving of $2.32 billion.

Cost-Effectiveness of Recombinant Factor IX Fc Prophylaxis and Recombinant Factor IX On-Demand Treatment in Patients with Haemophilia B Without Inhibitors.

INTRODUCTION: Recombinant factor IX (rFIX) and recombinant FIX Fc fusion protein (rFIXFc) are standard half-life and extended half-life FIX replacement therapies, respectively, and represent established treatment options indicated for adults and children with haemophilia B. These FIX replacement therapies can be administered as prophylaxis (to prevent bleeding) or 'on-demand' (to stop bleeding). This analysis aimed to estimate the cost-effectiveness of once-weekly prophylaxis with rFIXFc versus on-demand treatment with rFIX in patients with haemophilia B without inhibitors in the Italian healthcare setting. METHODS: A Markov model was developed to assess a hypothetical cohort of adolescent or adult male patients (≥ 12 years) with haemophilia B (FIX level of ≤ 2 IU/dL) without inhibitors. Model inputs were derived from the pivotal phase 3 clinical studies for rFIXFc and rFIX, published literature and assumptions when published data were unavailable. The model employed a lifelong time horizon with 6-monthly transitions between health states, and it estimated total costs, total quality-adjusted life years (QALYs), number of bleeds, number of surgeries and incremental cost-effectiveness ratio. RESULTS: rFIXFc prophylaxis was associated with lower total costs per patient (€5,308,625 versus €6,564,510) and greater total QALYs per patient (15.936 versus 11.943) compared with rFIX on-demand; rFIXFc prophylaxis was therefore the dominant treatment strategy. The model also demonstrated that rFIXFc prophylaxis was associated with fewer incremental bleeds (- 682.29) and surgeries (- 0.39) compared with rFIX on-demand. CONCLUSIONS: rFIXFc prophylaxis provides improved health outcomes and lower costs, and represents a cost-effective treatment option compared with rFIX on-demand for adolescent and adult male patients with haemophilia B. This comparative assessment of cost-effectiveness should help to inform both clinicians and healthcare policy makers when making treatment decisions for patients with haemophilia B.

Clinical, pharmacokinetic and economic analysis of the first switch to an extended half-life factor IX (albutrepenonacog alfa, rFIX-FP) in Spain.

Extended half-life of factor IX (FIX) demonstrated clinical benefit and lower treatment burden than standard half-life FIX products in clinical trials. We analysed the impact in efficacy, pharmacokinetics (PKs) and costs of the switch from nonacog alfa (rFIX) to albutrepenonacog alfa (rFIX-FP) in the first patient with haemophilia B (HB) treated in Spain outside clinical trials. A 7-year-old boy presented with HB with poor venous access and repetition infections using rFIX, which was switched to rFIX-FP. Prophylaxis was adjusted by PKs using WAPPS-Hemo tailoring from 100 IU/kg/week of rFIX to 80 IU/kg/3 weeks of rFIX-FP. Comparing 6 months before, rFIX-FP reduced 68.5% FIX consumption/kg and 58.3% infusion frequency, but total costs/weight showed a slight increase. Ratio of half-life between rFIX and rFIX-FP was 3.4-3.7. This case report revealed that switch to rFIX-FP decreased frequency and FIX consumption, without adverse events and bleeds.

Low Dose Prophylaxis vis-a-vis on-Demand Treatment Strategies for Hemophilia: A Cost Effective and Disability Attenuating Approach.

AIM: To assess effect of low dose prophylaxis in hemophilics in terms of bleeding, joint function, QoL and cost-effectiveness. METHODS: Analytic study done during one year among 70 adult hemophilics. In observation period (12 weeks), on-demand factor and during prophylaxis (12 weeks), low dose factor was given (Factor VIII 10 IU/KgBW biweekly for haemophilia A and Factor IX 20 IU/KgBW weekly for haemophilia B). Clinical joint assessment was done by Gilbert score and improvement by WFH definitions. RESULTS: Bleed reduced by 68.99% in moderate hemophilics (40 v/s 129) and 64.86% in severe hemophilics (26 v/s74) (p<0.05). During observation in moderate hemophilics, joint, soft tissue and mucosal bleeds occurred in frequency of 120, 1 and 8. This was reduced to 39 joint bleeds, 1 soft tissue bleed and no mucosal bleed during prophylaxis. In severe hemophilics, 70 joint, 2 soft tissue bleeds and 2 mucosal bleeds occurred during observation which reduced to 26 joint bleeds without soft tissue/mucosal bleed in prophylaxis. Bleeding episodes decreased by 65.79% in joints, 66.67% in soft tissues, 100% mucosal bleeds. After prophylaxis one joints (0.61 %) showed good improvement in joint function, thirty (18.18 %) joints showed moderate improvement and ninety two joints (55.76 %) showed mild improvement in joint function. Hospitalization reduced by 60.34% (163 v/s 411) and absenteeism by 53.73% (279 v/s 603). Factors consumption reduced by 12.33 % during prophylaxis period. CONCLUSION: The low dose prophylaxis strategy significantly decreased the subsequent episodes of total bleeds including joint bleeds and improved the joint function as well as quality of life.

Regional variation and cost implications of prescribed extended half-life factor concentrates among U.S. Haemophilia Treatment Centres for patients with moderate and severe haemophilia.

BACKGROUND: Extended half-life (EHL) factor VIII (FVIII) and IX (FIX) products are intended to decrease the burden of prophylaxis for patients with haemophilia A or B. Whether these newer concentrates have led to meaningful clinical practice change remains vague. AIM: To characterize the longitudinal use of standard (SHL) and EHL factor concentrates at haemophilia treatment centres (HTCs), using the ATHNdataset, a US database of 138 ATHN-affiliated HTCs. METHODS: Factor concentrate use among moderate and severe haemophilia A and B patients without inhibitors was analysed at three time points over 18 months. RESULTS: Use of EHL concentrates rose from 10% of patients to 22% during this study. EHL FVIII prophylaxis is prescribed to the minority of patients, 28%; EHL FIX now predominates for prophylaxis, 52%. Rates of prescribed EHL products varied significantly by age group and HTC region. Median prescribed prophylaxis for SHL compared to EHL products was FVIII 6240 and 5200 and FIX 6968 and FIX 3900 IU/kg/y, respectively. On-demand EHL use has grown but has minimal contribution to overall usage (2%). CONCLUSION: Haemophilia treatment centre region and patient age impact the rate of adoption of EHL products; however, EHL prescribing continues to rise nationally, particularly for EHL FIX. Careful attention to annual cost of prophylaxis is imperative as the decrease in median EHL prophylaxis consumption is not offset by the higher unit cost of these products. It is unclear how further growth in use of EHLs will be impacted by emerging non-factor replacement and gene therapies.

Real-World Analysis of Dispensed IUs of Coagulation Factor IX and Resultant Expenditures in Hemophilia B Patients Receiving Standard Half-Life Versus Extended Half-Life Products and Those Switching from Standard Half-Life to Extended Half-Life Products.

BACKGROUND: Hemophilia B requires replacement therapy with factor IX (FIX) coagulation products to treat and prevent bleeding episodes. A recently introduced extended half-life (EHL) recombinant FIX replacement product provided the opportunity to compare the amount of dispensed factor and expenditures for EHL treatment compared with a standard half-life (SHL) product. OBJECTIVE: To determine factor international units (IUs) dispensed and expenditures associated with switching from nonacog alfa, the most commonly used SHL replacement product, to eftrenonacog alfa, an EHL FIX replacement product. METHODS: Two U.S. claims databases were analyzed. A large national specialty pharmacy dispensation claims database was used to identify the number of IUs dispensed and monthly charges for all patients with hemophilia B from April 2015 to June 2016. Truven Health MarketScan Research Databases (January 2010-July 2016) were used to identify IUs and expenditures for patients with claims data for at least 3 months before and after switching from the SHL to the EHL product. Medians for IUs and expenditures are presented to accommodate for skewness of data distribution. RESULTS: The national specialty pharmacy database analysis included 296 patients with moderate or severe hemophilia B (233 on SHL; 94 on EHL). Median monthly factor dispensed was 11% lower (2,142 IU) in the EHL versus SHL cohort over the study period, while individual monthly reductions ranged from 32% to 47% (9,838 IU to 16,514 IU). Using the wholesale acquisition cost, the median per-patient monthly factor expenditures over the 15-month study period were 94% higher ($23,005) for the EHL than for the SHL product. Individual median monthly expenditure differences ranged from 15% ($6,562) to 49% ($19,624). In the Truven database, 14 patients switched from the SHL to the EHL product. The amount of factor dispensed was variable; in the 1-year period before and after the switch from the SHL to the EHL product, mean IUs dispensed decreased by 3,005 IU, while median IUs dispensed increased by 4,775 IU. Factor replacement expenditures were higher after switching from the SHL to the EHL product in each of the 3-month periods examined before versus after the switch. CONCLUSIONS: This analysis of real-world data showed that switching from the SHL to the EHL product was associated with higher expenditures. Increased expenditures noted in the first 3 months after switching may be related to initial stocking up of the EHL product, but expenditures were sustained throughout the 1-year period of data analysis. Further analysis of these findings with larger numbers of patients should be explored. DISCLOSURES: This study was sponsored by Pfizer. Pfizer employees were involved in the study design; the collection, analysis, and interpretation of data; the review of the manuscript; and the decision to submit for publication. All authors are employees of Pfizer. No author received an honorarium or other form of payment related to the development of this manuscript. All authors participated in the study design, data interpretation, and manuscript review and revisions and granted approval for the submission of the manuscript. Alvir, McDonald, and Tortella also participated in data analysis. Data from this paper were presented in part at the European Association for Haemophilia and Allied Disorders Annual Meeting, February 1-3, 2017, Paris, France; at the International Society for Pharmacoeconomics and Outcomes Research Annual Meeting, May 20-24, 2017, Boston, MA; and at the International Society on Thrombosis and Haemostasis Congress, July 8-13, 2017, Berlin, Germany.

A computer-based model to assess costs associated with the use of factor VIII and factor IX one-stage and chromogenic activity assays.

BACKGROUND: Measurement of coagulation factor factor VIII (FVIII) and factor IX (FIX) activity can be associated with a high level of variability using one-stage assays based on activated partial thromboplastin time (APTT). Chromogenic assays show less variability, but are less commonly used in clinical laboratories. In addition, one-stage assay accuracy using certain reagent and instrument combinations is compromised by some modified recombinant factor concentrates. Reluctance among some in the hematology laboratory community to adopt the use of chromogenic assays may be partly attributable to lack of familiarity and perceived higher associated costs. OBJECTIVES: To identify and characterize key cost parameters associated with one-stage APTT and chromogenic assays for FVIII and FIX activity using a computer-based cost analysis model. METHODS: A cost model for FVIII and FIX chromogenic assays relative to APTT assays was generated using assumptions derived from interviews with hematologists and laboratory scientists, common clinical laboratory practise, manufacturer list prices and assay kit configurations. RESULTS: Key factors that contribute to costs are factor-deficient plasma and kit reagents for one-stage and chromogenic assays, respectively. The stability of chromogenic assay kit reagents also limits the cost efficiency compared with APTT testing. Costs for chromogenic assays might be reduced by 50-75% using batch testing, aliquoting and freezing of kit reagents. CONCLUSIONS: Both batch testing and aliquoting of chromogenic kit reagents might improve cost efficiency for FVIII and FIX chromogenic assays, but would require validation. Laboratory validation and regulatory approval as well as education and training in the use of chromogenic assays might facilitate wider adoption by clinical laboratories.

Factor VIII/factor IX prophylaxis for severe hemophilia.

Experience with clotting factor concentrate (CFC) replacement products over several decades has shown that regular replacement (prophylaxis) is the only way to prevent musculoskeletal damage in hemophilia and impact the natural history of hemophilia. Yet there is a lack of data on the optimal age to start such replacement therapy and the regimens to be used. While very early administration of high doses is certainly more effective in preventing bleeding, cost and compliance are major constraints all over the world. Starting prophylaxis with even lower doses comparable to that used in episodic therapies leads to major reduction in bleeding. Recognition of the clinical heterogeneity of hemophilia even among patients with a label of severe hemophilia in terms of their spontaneous bleeding has led to efforts aimed at individualizing CFC replacement, based on clinical responses or pharmacokinetic data of the CFC. The importance of long-term outcome assessment being combined with CFC replacement therapy cannot be overemphasized.

Low cost industrial production of coagulation factor IX bioencapsulated in lettuce cells for oral tolerance induction in hemophilia B.

Antibodies (inhibitors) developed by hemophilia B patients against coagulation factor IX (FIX) are challenging to eliminate because of anaphylaxis or nephrotic syndrome after continued infusion. To address this urgent unmet medical need, FIX fused with a transmucosal carrier (CTB) was produced in a commercial lettuce (Simpson Elite) cultivar using species specific chloroplast vectors regulated by endogenous psbA sequences. CTB-FIX (∼1 mg/g) in lyophilized cells was stable with proper folding, disulfide bonds and pentamer assembly when stored ∼2 years at ambient temperature. Feeding lettuce cells to hemophilia B mice delivered CTB-FIX efficiently to the gut immune system, induced LAP(+) regulatory T cells and suppressed inhibitor/IgE formation and anaphylaxis against FIX. Lyophilized cells enabled 10-fold dose escalation studies and successful induction of oral tolerance was observed in all tested doses. Induction of tolerance in such a broad dose range should enable oral delivery to patients of different age groups and diverse genetic background. Using Fraunhofer cGMP hydroponic system, ∼870 kg fresh or 43.5 kg dry weight can be harvested per 1000 ft(2) per annum yielding 24,000-36,000 doses for 20-kg pediatric patients, enabling first commercial development of an oral drug, addressing prohibitively expensive purification, cold storage/transportation and short shelf life of current protein drugs.

Survey of coagulation factor concentrates tender and procurement procedures in 38 European Countries.

INTRODUCTION: Procurement of coagulation factor concentrates (CFCs) for the treatment of haemophilia is a vital process that determines the quantity and quality of factor replacement therapy. AIM: The aim of this study was to examine the different tender and procurement systems used in Europe for the procurement of CFCs and the outcomes produced by the various systems. METHODS: The survey questionnaire consisted of 30 items and explored various aspects of the procurement process including the prices of CFCs. In 2014, the survey was sent out by the European Haemophilia Consortium (EHC) to 45 national haemophilia patient organizations affiliated to the EHC in all European countries as well as to a designated clinician familiar with the procurement process. RESULTS: The survey was completed by 38 European countries. Nineteen countries use a tender process, 17 an alternative procurement process and 2 use a combination of methods. A wide variety of agencies and individuals are involved in the process. Factors associated with optimum outcome and lower prices include a tender process with a specific legal framework and a tender board including haemophilia clinicians and patient organization representatives. Safety was reported as the most important selection criterion but given the safety profile of almost all currently licensed products, price was the main criterion used in many countries. CONCLUSION: The involvement of both clinicians and patient organizations greatly improves the outcome of a tender or procurement process, as does the presence of a legal framework that governs the process.

EQOFIX: a combined economic and quality-of-life study of hemophilia B treatments in France.

BACKGROUND: EQOFIX is a medicoeconomic study that analyzed the health-related quality of life (HRQoL) and costs of care of the moderate and severe forms of hemophilia B, treated on demand or by prophylaxis with either plasma-derived Factor IX (pdFIX) or recombinant FIX (rFIX). STUDY DESIGN AND METHODS: The primary objectives were evaluations of the impact of hemophilia B on HRQoL and of the costs associated with its management. The secondary objectives were evaluations of the clinical efficacy and costs of care of pdFIX and rFIX. In this observational study we included and followed for 1 year severe and moderate hemophilia B patients without inhibitor. HRQoL was evaluated through generic and disease-specific questionnaires. Information on the health resources consumed was collected every 3 months. RESULTS: The EQOFIX cohort was composed of 155 patients, including 51 children and 104 adults, with 114 having severe disease and 41 having moderate disease. The regimens were prophylactic for 61 and on demand for 94. Altogether, 78 were treated with rFIX and 77 with pdFIX. There was no difference in the QoL between the pdFIX and rFIX treatments. The extra cost of prophylaxis was €22,605 per bleeding event prevented. The consumption of FIX was 1.4-fold higher for the patients treated with rFIX than for the patients treated with pdFIX. CONCLUSION: Our findings in a cohort composed of 25% of the French population of moderate and severe hemophilia B patients show, with similar clinical and HRQoL results, that treatment with rFIX is more expensive than treatment with pdFIX.

Public expenditure for plasma-derived and recombinant medicinal products in Italy.

BACKGROUND: In Italy, the supply of plasma-derived medicinal products funded by the National Health Service can be through public healthcare facilities, accredited pharmacies or toll fractionation agreements between Regions and the manufacturer. Pharmaceutical public expenditure includes the supply related to the first two channels and costs can significantly vary because of channel-specific price reductions. This paper describes 2011 public expenditure for plasma-derived medicinal products purchased on the market, as well as the cost analysis per active substance. MATERIALS AND METHODS: Analysis of the usage of plasma-derived medicinal products and of the related expenditure in public facilities has been carried out using medicinal product traceability data. The analysis related to the accredited pharmacies channel has been carried out using quantities for every medicinal package recorded by Pharmacy Associations and applying reference prices in force on March 1(st), 2012 as well as discounts for the accredited pharmaceutical expenditure imposed by law. RESULTS: At national and regional level, total and total per capita expenditures on plasma-derived medicinal products by market channel and funded by the National Health Service are shown. Analysis was conducted considering the active substances in three groups: substances included in toll fractionation agreements, recombinant coagulation factors, and other substances not included in toll fractionation agreements. In 2011, the national expenditure estimate for plasma-derived and recombinant medicinal product acquisition on the market was about € 535 million. DISCUSSION: The purchased volumes and mean purchased prices per unit of each substance have a significant influence on the observed regional variability of the pharmaceutical public expenditure. A strategy of regional comparison aimed at both sharing a national range of reference for purchase prices and evaluating modalities for centralised purchasing is desirable.

Models of prophylaxis.

Long-term, continuous prophylaxis for haemophilia began at a modest scale during the 1950s and 1960s in Sweden and The Netherlands. In the face of high cost and impediments to the performance of longitudinal, well-designed studies, it was decades before prophylaxis was considered to be the best practice in countries that could afford the cost. In 2007 and 2011, the only prospective randomized studies ever performed confirmed what large cohort studies in Europe had long since shown. Today, focus is on when to start prophylaxis, dosing and when/if to stop. Retrospective comparisons of the Swedish and Dutch cohorts, where different strategies have been used, indicate that a costly, high-dose regimen improves outcome, but not dramatically. A prospective comparison is now underway. Treatment, clinical outcome, clotting factor consumption and socioeconomic parameters will be compared between the two strategies. Results are expected to provide greater insight into the long-term consequences of the different prophylactic treatment strategies. The economic justification for prophylaxis has been addressed in several studies with varying results. While the majority (implicitly) suggest that prophylaxis is not cost effective at conventional willingness to pay for additional units in health thresholds, their results vary markedly. Closer inspection suggests that the primary reasons results differ include different definitions of prophylaxis, clotting factor price, discount rates, choice of outcome measures and time horizon.

Epidemiological survey of haemophiliacs with inhibitors in France: orthopaedic status, quality of life and cost--the 'Statut Orthopédique des Patients Hémophiles' avec Inhibiteur study.

The physical condition of severe haemophilia and the impact of advances in replacement therapy have been much studied, but little work has been done on patients who developed inhibitors. The 'Statut Orthopédique des Patients Hémophiles avec Inhibiteur' study was conducted in France in order to assess the orthopaedic status and quality of life of such patients, and the cost of their medical management. Fifty haemophiliacs aged 12-63 years with a history of high-responder inhibitors were included. Clinical assessment showed that only 12% of the patients had a nil pain score and 2% a nil clinical score, as per Gilbert scale. The mean clinical score was significantly higher in patients over 35 years of age than in younger ones. However, younger patients appeared to have a more impaired orthopaedic status than young haemophiliacs without inhibitors of similar age in previous published cohorts. Surprisingly, older haemophiliacs tended to have the best mental quality of life, contrasting with their highly impaired orthopaedic condition and physical quality of life. The mean cost of clinical resources consumed during the year preceding enrolment was Euro 268 999, 99% of which was related to clotting factor. Marked between-patient differences in cost were noted. Our study suggests that the management of haemophiliacs with inhibitors should be improved in order to prevent haemophilic arthropathy to an extent similar to that of patients without inhibitors. Cost-benefit assessment of any therapeutic strategy should always be combined with quality-of-life evaluation.

Primary prophylaxis in children with haemophilia.

Starting from the clinical observations that moderate haemophiliacs experienced only few bleeding episodes and rarely developed significant joint deterioration (haemophilic arthropathy), and the pioneer experience in Sweden, prophylaxis (i.e. the regular and long-term administration of clotting factor concentrate in order to prevent bleeding) has been practiced for more than forty years in severe haemophilia and is currently recommended as the first choice of treatment by the World Health Organisation and World Federation of Hemophilia and by many national medical/scientific organizations. Observational studies clearly established the superiority of prophylaxis over on-demand treatment in reducing the risk of arthropathy, also showing that starting prophylaxis earlier in life and after very few joint bleeds was associated with better joint outcomes, and led to the current definitions of primary (started before the age of 2 yrs and after no more than one joint bleed) and secondary prophylaxis. More recently, evidences from randomized trials, which were previously lacking in this setting, were also provided. This review summarizes available data from which current clinical practice of primary (and early secondary) prophylaxis in children with severe haemophilia was drawn. Open issues concerning optimal regimens and barriers to the implementation of prophylaxis are also discussed.