issues have to be addressed by the decision-making committees .
When the evaluation of biosimilars and tenders are organised on a national level , hospital pharmacists manage the implementation of the biosimilar use and educate other healthcare professionals . In any case , the process of switching ( single , multiple , cross-switching ) has to be defined and communicated for each entity of biosimilars in the individual setting .
Single switching from the reference product to the biosimilar product and subsequent switching back are an integrated part of modern Phase III biosimilar studies . Multiple ( unintended ) switches and cross-switching between different biosimilars of the same reference product have not yet been studied and should be avoided . Additional studies and greater experience will increase confidence about interchangeability and switching . Meanwhile , the nocebo effect ( a negative reaction to a treatment that cannot be explained on the basis of the known pharmacology of the drug ) associated with switching and educational needs for varying devices ( pens for subcutaneous administration ) should not be neglected . Other points to consider are the therapeutic equivalence in extrapolated indications , naming and traceability . In the hospital , local guidelines for prescribing , substitution , switching and pharmacovigilance have to be developed in an appropriate and pragmatic manner . Useful information is available in the European Public Assessment Reports ( EPARs ) and various position statements of associations of healthcare professionals . Post-marketing pharmacovigilance is mandatory to determine the benefit – risk profile of biologics and biosimilars throughout their life cycles . Different post-marketing commitments for different biosimilars regarding the same reference product are to be considered . In the case of switching , patients should be monitored particularly closely for adverse drug reactions , and hospital pharmacists should encourage reporting .
Prescribing of EMA-approved biosimilars Since 2006 , approximately 60 biosimilar products across 15 different biological entities have been approved by the EMA ( Table 1 ). 2 , 4
An EPAR is published for every medicine granted central marketing authorisation . Each EPAR is a valuable and useful information tool for health care professionals . In addition , the EMA and the European Commission have published an information guide to provide reference information on the science and regulation of biosimilar medicines . 5 However , the EMA ’ s evaluation of biosimilars does not include recommendations on interchangeability . Automatic interchange of biosimilars at the pharmacy level is a national prerogative and regulations are different throughout the EU . Up to now , automatic substitution at the pharmacy level is not widely practised in Europe . Restricted substitution can occur , for example , in Baltic countries , France and Poland . Typical restrictions are that physicians have the possibility to declare the prescription as ‘ non-substitutable ’ or that substitution can only occur on the initiation of treatment . 6 In a recent discussion of automatic substitution of biosimilars in German pharmacies , the key stakeholders concluded that the decision regarding interchange should be made by the prescribing physician . The prescribing decision should remain the responsibility of the prescribing physician , with patients being well informed and monitored . Additional challenges arise from the availability of more than one biosimilar of mAbs , and when tenders might lead to cross-switches of biosimilars . These scenarios could be used to implement a Phase IV pharmacovigilance study .
It is essential that all biologics are identifiable by a unique name . This applies to biosimilars as well as originator products and is particularly important for prescribing , product traceability and pharmacovigilance . Currently , the unique identifier is the trade name . Therefore , the trade name has to be used for prescribing , documentation and pharmacovigilance issues . The reference product , biosimilars and bioidenticals contain the same active substance with the same international nonproprietary name ( INN ) related to the World Health Organization nomenclature system . Besides the WHO nomenclature system , the US Food and Drug Administration implemented a unique identifier ( four-letter suffix added to the INN ) for each active substance . This approach is controversial and perhaps another cause for confusion . 7
Bioidentical products Some of the authorised products are based on the same regulatory dossier ( same date of authorisation ) and are manufactured in the same cell line using the same manufacturing process . These so-called ‘ bioidenticals ’ are the same ( not similar ) products but carry different brand names and are marketed by different manufacturers . In fact , substitution of bioidenticals is allowed at the pharmacy level . The identification of bioidenticals is not easy for physicians and pharmacists and differing regulations for the substitution of biosimilars and bioidenticals make it even more complex . Of course , the bioidenticals can be identified by their trade name , but it is not easy to discern which product is a biosimilar brand product and , moreover , is bioidentical to another biosimilar brand product . Identification would be much easier if the term biosimilar or bioidentical were part of the label .
Biosimilars in the future Most of the innovative medicinal products approved in the recent past are biologics , especially mAbs , are costly . The recently introduced advanced therapy medicinal products are even more expensive and will affect the sustainability of the healthcare systems . The continuing pressure on the healthcare budgets is expected to force a change in attitudes and will result in an increase in the use of lower cost biosimilars across Europe . Additional mAbs will lose patent protection in the future ( for example , ranibizumab , aflibercept ) and other biologics will follow . Therefore , we will have to evaluate new biosimilars continuously and each active substance will contain its own specifics and challenges . Some experts are of the opinion that planning should start six months before a new biosimilar comes to the market in order to reduce expenditures from the very beginning of the market access of a new biosimilar .
By contrast , the acceptance of biosimilars depends on the availability of evidence for safety and efficacy ( including real-world studies ), effective communication of the evidence by healthcare professionals and patients as well as an incentive for an adequate prospect of profit . 2 The widening use of biosimilars makes it necessary for hospital pharmacists to keep continuously updated in order to advise physicians and patients about these drugs and the concept of biosimilarity . At the same time , pharmacists have to develop ‘ good practices ’ for the use of biosimilars , together with other healthcare professionals .
References 1 Mitrokostas N et al . End of a Humira battle : Observations from the AbbVie-Amgen armistice . www . biosimilardevelopment . com / doc / end-of-a-humirabattle-observations-from-theabbvie-amgen-armistice-0001 ( accessed July 2019 ) 2 Wolff-Holz E et al . Preparing for the incoming wave of biosimilars in oncology . ESMO Open 2018 ; 3 : e000420 3 Boone N et al . How to select a biosimilar . Eur J Hosp Pharm 2013 ; 20:275 – 86 . 4 European Medicines Agency . www . ema . europa . eu / en / medicines / ema _ group _ types / ema _ medicine / field _ ema _ web _ categories % 253Aname _ field / Human / ema _ medicine _ types / field _ ema _ med _ biosimilar / ema _ group _ types / ema _ smops / ema _ group _ types / ema _ withdrawn _ applications ? sort = field _ ema _ med _ market _ auth _ date & order = asc ( accessed July 2019 ). 5 European Medicines Agency . Biosimilars in the EU . Information for healthcare professionals . www . ema . europa . eu / documents / leaflet / biosimilars-eu-informationguide-healthcare-professionals _ en . pdf ( accessed July 2019 ) 6 Larkin H et al . Pharmacymediated substitution of biosimilars – a global survey benchmarking country substitution policies . GaBI J 2017 ; 6:157 – 64 . 7 Thorpe R . Nomenclature for biosimilars ; a continuing thorny issue . GaBI J 2018 ; 7:141 .
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