most inhibitors occur at an early age and usually within the first 50 exposure days . as such however , it should be acknowledged that there are no clear data that demonstrate an increased risk of inhibitor when switching fviii concentrate in patients prior to 50 exposure days . certain clinical scenarios have been associated with an increased risk of inhibitor development , and for some patients with haemophilia a , switching products requires careful consideration . haemophilia patients with a history of inhibitors , including those in whom the inhibitor has been eradicated with immune tolerance induction ( iti ) , may relapse and constitute a group of individuals at higher risk of inhibitor development . there may be similar concerns for haemophilia patients with a family history of inhibitor and/or a higher risk mutation in the f8 gene . as such , there may be reluctance on the part of the physician and the patient to consider switching products when they have been shown to be tolerant of their current therapeutic product . if such individuals are to have the opportunity to benefit from advances in therapy such as those with increased safety profiles or extended duration of action , they would need to consider switching products . in this situation , it should be noted that there is no evidence of increased risk of inhibitor development 6 . lastly , intensive treatment ( including surgery ) is reported to be associated with an increased risk of inhibitor development 7 . as such , patients scheduled to have elective orthopaedic surgery should remain on their current product and switching in the intraoperative or early postoperative period should be avoided . however , for all patients , following discussions with patients or their caregivers , a product switch may be undertaken if there is a clinical need ; there are no absolute contraindications for switching . for patients for whom product switching may be appropriate , a reluctance to switch products may be associated with concerns regarding the potential negative outcomes of such a switch . in addition , some patients with haemophilia often develop a strong psychological link with their current product 2 . to investigate patient concerns regarding switching , a semi - structured , non - random , brief , online survey was conducted using the web research platform surveymonkey. participants from seven national haemophilia organisations ( argentina , brazil , chile , santo domingo , mexico , nicaragua and spain ) were informally invited ( by e.r . ) through social media during 15  days in april 2013 . survey participation was voluntary and a total of 46 participants ( of whom 27.5% were parents of a child with haemophilia ) anonymously completed the online survey ( response rate 85% ) . ethical standards for online behavioural research were strictly followed and all participants gave their electronic consent before taking the survey . data were provided regarding haemophilia a ( n  =  37 ) and b ( n  =  9 ) , of which the majority of patients had severe haemophilia ( n  =  27 ) , and some patients had been diagnosed with an inhibitor ( n  =  9 ) . of note , 57% of the respondents believed that the probability of inhibitor development was high or very high when switching product . moreover , when asked to list up to five concerns related to switching product , inhibitor development appeared first in the list ( 25.3% of respondents ) , followed by potential product side effects ( 21.8% ) , product effectiveness ( 17.2% ) , safety / purity ( 17.2% ) , and finally , product quality and longevity ( 4.6% ) . the original survey and complete report in spanish are available by email request to eduardo.remor@uam.es . to explore concerns regarding product switching by healthcare professionals , a recently conducted delphi consensus exercise was undertaken to canvass expert opinion on the topic 6 . briefly , the delphi process is a structured group communication in which a complex problem is considered by a group of experts . the procedure usually begins with a face - to - face meeting to set the context of the communication , after which experts input their thoughts / opinions through several rounds of questions and answers . the delphi panel noted that currently available studies are often retrospective , characterised by a mixture of methodological approaches , and frequently lack appropriate control groups . given this background , and the modest amount of data available on product switching , the delphi process provided an alternative approach to addressing the complex problem of assessing the risk of immunogenicity associated with product switching . the group addressed 14 separate items relating to the issue of product switching and the risk of inhibitor development and reached a high level of consensus on most items . they , too , concluded that much of current clinical practice regarding treatment switching in haemophilia was not based on evidence , but on the fear of developing an inhibitor 6 . treatment - related factors , including treatment intensity as briefly mentioned above , therapeutic regimen ( i.e. prophylaxis vs. on - demand treatment ) and product type have been proposed as possible influences on inhibitor development 712 . for example , a systematic literature review concluded that inhibitor incidence was lower in patients treated with one pd - fviii vs. those who had used multiple pd - fviii concentrates or a single rfviii product 12 . although a more recent systematic review using multi - way analysis of variance concluded that source of concentrate did not significantly influence inhibitor development 11 , suggestions of an increased incidence of inhibitor development and treatment with rfviii products , and also those with a b - domain deletion / modification , may continue to contribute to patient and physician reluctance to switch to new rfviii products . three early studies in previously untreated patients ( pups ) suggested that the incidence of inhibitor development was less for those treated with pd - fviii than in patients treated with rfviii 1315 . however , significant differences in inhibitor development were only observed in two of these three studies 13,14 . in the uk study , inhibitors developed more frequently in patients initially treated with rfviii when compared with pd - fviii ( p  =  0.006 ) 13 . in a french cohort study , the risk of inhibitor development was reported to be higher in patients treated with rfviii than those treated with pd - fviii , regardless of other risk factors ( e.g. f8 genotype , history of inhibitors in patients with a family history of haemophilia , age at first fviii infusion ) 14 . however , in sweden , no significant increase in the incidence of inhibitors was reported for haemophilia a patients in the 1990s who were mainly treated with recombinant products ( n  =  10/48 , total incidence 21% ) , as compared with the 1980s ( n  =  9/52 , 17% ) , when patients received intermediate / high - purity plasma - derived concentrates 15 . the concerted action on neutralising antibodies in severe haemophilia a ( canal ) study was a retrospective , multi - centre cohort study designed to further describe the relationship between treatment and inhibitor development in 366 pups with severe haemophilia ( residual fviii activity < 2% ) born between 1990 and 2000 9,16 . a total of 82 patients ( 26% ) developed clinically relevant inhibitors ; of 181 patients first treated with rfviii product , 53 ( 29% ) developed inhibitors , while inhibitors were reported in 29 of the 135 ( 21% ) patients treated with pd - fviii , and the relative risk ( rr ) of inhibitors in pd - fviii vs. rfviii products was 0.8 ( 95% confidence interval [ ci ] , 0.51.3 ) 16 . in addition , switching between fviii products did not appear to increase the risk of inhibitor development ( rr , 1.1 ; ci , 0.61.6 ) . hence , the canal study results do not support previous findings suggesting an increased risk of inhibitor development with rfviii products , nor that switching products may influence inhibitor development 16 . more recently , the potential influence of rfviii vs. pd - fviii product type on inhibitor development was also explored in the rodin ( research of determinants of inhibitor development ) study , which used data from the pednet registry that comprised 29 centres in europe , canada and israel . overall , there was no difference in inhibitor risk between pd - fviii and rfviii products ( adjusted hazard ratio 0.96 ; 95% ci , 0.621.49 ) , and switching between different fviii products was not associated with an increased risk of inhibitor development ( adjusted hazard ratio 0.99 ; 95% ci , 0.631.56 ) . however , a significantly increased risk of inhibitor development was found to be associated with second - generation ( produced in baby hamster kidney [ bhk ] cells ) vs. third - generation full - length rfviii products ( adjusted hazard ratio 1.60 ; 95% ci , 1.082.37 ) 7 . although this latter finding is intriguing , there is no clear biological explanation for the difference in inhibitor development between second- vs. third - generation full - length rfviii . concerns regarding a potential increase in immunogenicity associated with b - domain deleted rfviii were raised by an early italian study of previously treated patients ( ptps ) 17 . of 25 low - risk ptps , one patient developed an inhibitor after switching from pd - fviii to b - domain - deleted rfviii 17 . results from a more recent meta - analysis by aledort and colleagues of prospective clinical studies on product switching appeared to demonstrate an increased risk of inhibitor development with b - domain - deleted rfviii in ptps 8 . however ,  good results for meta - analyses come from inclusion of good data  18 , and in this respect , of the two studies that contributed the most to the final odds ratio for the aledort meta - analysis , one consisted only of case reports 19 and the other contained only the prospective arm from the italian study 17 . the ongoing european haemophilia safety surveillance ( euhass ) , a prospective adverse event reporting system , is exploring the incidence of inhibitors in pups and ptps and the potential factors that may be contributing to inhibitor development . data reported from the first 2  years of the study , provided by 64 haemophilia centres from 27 european countries ( caring for 22  242 patients ) , showed that the inhibitor rate in pups with severe haemophilia a was 25% overall , with a similar incidence of inhibitors in patients treated with rfviii ( 25% ) as compared with those treated with pd - fviii ( 27% ) 20 . for ptps , no significant difference was observed in inhibitor incidence between different rfviii products ( including full - length and b - domain - deleted products ) 20 . a more recent evaluation of data now available from the first 3  years of euhass has confirmed that in pups , there are no significant differences in inhibitor development between pd - fviii and rfviii products , or between different rfviii products 21 . of note , the second - generation full - length rfviii product associated with increased inhibitor incidence in the rodin study was also one produced in bhk cells ; together , these findings may lead to speculations that products may be associated with inhibitor development in pups . however , such speculation should be made with caution as many other variables may contribute to immunogenicity . although early studies suggested a potential for increased inhibitor incidence in patients treated with rfviii and b - domain deleted product , the findings summarised above from canal , rodin and euhass do not provide support for these earlier suppositions . to date , studies on three national product switches ( ireland , canada and the uk ) have been published ( table1 ) 2224 . while all three studies examined product switching , the product switches were different , and only the uk study investigated inhibitor incidence in both switchers and non - switchers . summary of data from the three national product switches one patient had previously documented inhibitors , and one child who had been on prophylaxis with kogenate developed an inhibitor during intense therapy for treatment of an acute bleed . patients remaining on kogenate. the difference in inhibitor incidence rates between switchers and non - switchers was not significant ( p  =  0.12 ) . the national irish product switch resulted from a national tender process in 2006 in which all patients with haemophilia a changed their fviii treatment product en masse to a plasma and albumin - free recombinant full - length fviii product ( advate ) 22 . in this study , case records of irish ptps were retrospectively reviewed to evaluate the risk of inhibitor formation following this treatment switch . only one of the 96 patients without a previous history of inhibitors developed an inhibitor following the switch . however , as this patient had only received three exposure days prior to the switch 22 , the inhibitor might also have developed if the patient had remained on his previous treatment . in addition , there were no cases of recurrent inhibitor formation in any of 16 patients with previously documented inhibitors . the canadian national product switch surveillance study comprised 460 haemophilia a paediatric and adult patients from 17 canadian comprehensive haemophilia care centres , of whom 274 had evaluable data 24 . this study was conducted by the inhibitor subcommittee of the association of hemophilia clinic directors of canada to evaluate inhibitor development in patients with haemophilia a following the switch to a second - generation rfviii product ( table1 ) . an inhibitor was detected in four of the 274 ( 1.5% ) evaluable patients at the time of the switch , but no additional patients with inhibitors were reported afterwards 24 . this finding highlights the importance of studying patients prospectively and testing for inhibitors before and after switching . a national tendering exercise conducted in the uk in 20092010 required half of patients receiving rfviii to change rfviii brands 23 . based on the contractual requirements of the exercise , patients were randomly selected for switching in each local treatment centre . centres were requested to test all patients for inhibitors prior to the switching date and 6-monthly thereafter . a total of 1217 patients with severe haemophilia a lacking an inhibitor history were analysed ; 535 patients switched rfviii product and 682 patients did not . four patients who switched , two from kogenate and two from advate , developed inhibitors ; in two cases , the inhibitors were transient , while for the other two cases , patients were rapidly tolerised . the incidence of inhibitors reported ( 7.5/1000 treatment per years ) did not significantly differ from the 5.31/1000 treatment year incidence observed during the 20-year period preceding the study ( p  =  0.24 ) , although the study was underpowered . of note , among the 682 non - switchers , one patient developed inhibitors . as these three studies employed different methodologies and studied heterogeneous patient populations , the findings of each can not be directly compared , nor can the data be pooled for a combined analysis . however , all three studies suggest that switching is not associated with an increased risk of inhibitor formation relative to the very low background frequency of immunogenicity of these products , although the results are not conclusive and should be interpreted with caution . the implementation of prospective , controlled surveillance programmes on switching and not switching is imperative , as there is insufficient evidence currently available to support the development of clear  best practice in addition , such surveillance programmes will provide researchers with the data needed to address the many unanswered questions regarding the patient - related and treatment - related factors that contribute to the risk of inhibitor development . most importantly , for the full potential of surveillance programmes to be realised , all data on inhibitor development and products received should be submitted to a centralised , unbiased database to establish a baseline on the current inhibitor risk and include all new patients , regardless of which product they receive . this is the only way to ensure that the field is able to utilise all of the data in the service of our patients . given the limitations of the existing evidence base , we can make a number of recommendations for the conduct of future studies on product switching . first , inhibitor testing should be performed before and after the switch to determine if any new inhibitors detected may be in association with switching to the new treatment . similarly , inhibitor testing should also be performed before and after intensive treatment / surgery . concerning routine patient care , educational materials addressing patients concerns about switching are needed because some of patients concerns are not supported by the actual evidence about the consequences of switching products . more importantly , physicians are encouraged to discuss directly with patients and parents their therapeutic approach and the other treatment options that are available before a more urgent need arises to consider switching . doing so may increase patient satisfaction with treatment and foster more informed and positive attitudes when and if the need arises to address switching to a new product . in the future , it may become feasible in routine practice to calculate an inhibitor risk score and identify patients at high risk , thus aiding the evaluation of which patients to consider for switching treatments . among patients with haemophilia ( and their physicians ) , there is often a reluctance to switch factor concentrates because of concerns about increasing the risk of inhibitors . however , current evidence does not suggest that switching products significantly influences inhibitor development . with the forthcoming arrival of new haemophilia treatments , elena santagostino has received speaker fees for meetings organised by bayer , baxter , pfizer , csl behring , novo nordisk , biotest , kedrion , octapharma and grifols , acted as paid consultant for bayer , pfizer , csl behring , novo nordisk and grifols and has received unrestricted research grants from novo nordisk and pfizer . victor jimnez - yuste has received reimbursement for attending symposia / congresses and/or honoraria for speaking and/or honoraria for consulting and/or funds for research from baxter , bayer , csl behring , grifols , novo nordisk , octapharma and pfizer . thierry lambert has acted as a board member for baxter , bayer , csl behring , novo nordisk and pfizer . rolf ljung has during the last five  years received consultancy / speaker fees from novo nordisk , bayer , baxter and octapharma . massimo morfini has served as a consultant and invited speaker for novo nordisk a / s , csl behring , wyeth / pfizer , baxter and bayer . gnter auerswald , gary benson , gerry dolan and silva zupani alek have no conflict of interests to declare .
patients with haemophilia a ( and their physicians ) may be reluctant to switch factor viii ( fviii ) concentrates , often due to concerns about increasing the risk of inhibitors ; this reluctance to switch may contribute to patients missing the clinical benefits provided by the arrival of new factor viii products . 
 this topic was explored at the eleventh zrich haemophilia forum . 
 clinical scenarios for which product switching may be cause for concern were discussed ; when there is a clinical need , there are no absolute contraindications to switching , but some patients ( e.g. previously untreated patients and those undergoing elective surgery ) may require more careful consideration . 
 both patient and physician surveys indicate that the reluctance to switch , and the fear of inhibitor development , does not appear to be evidence based . 
 the evaluation of more recent data did not support previous studies suggesting that particular products ( e.g. recombinant vs. plasma - derived and full length vs. b - domain modified ) may be associated with increased risk . 
 in addition , data from three national product switches showed that switching was not associated with increased inhibitor risk , but highlighted the need for regular inhibitor testing and for a centralised , unbiased database of inhibitor incidence . 
 to conclude , current evidence does not suggest that switching products significantly influences inhibitor development .