ensure continued access to the same type of medicine . 3 , 7 , 8
Substitution occurs at the point of dispensing in the pharmacy and involves changing to an equivalent or interchangeable medicine without the need to contact the prescriber . 4 , 8 , 9 Automatic substitution occurs when a pharmacist is obliged to dispense an equivalent and interchangeable medicine in accordance with local or national regulations .
An overview of definitions , requirements and regulations of switching and substitution of biosimilars in the US and Europe is presented in Table 1 .
In general , switching and substitution are largely dependent on national legislation and recommendations , which can lead to a variance across member states . For example , in the majority of member states , a switch made under the the supervision of the prescriber from an RP to its biosimilar and vice versa has become standard practice . By contrast , the practice of ( automatic ) substitution for biologic medicines at the pharmacy level , is currently either not practised or permitted in most European member states . 1 , 2 , 4 , 5
Types of switches There are many scenarios for switching biosimilars as described below .
Reverse switching is the change from a biosimilar to its originator . It has also been used for a switch that occurs after prior exposure to an RP ( RP to biosimilar to RP ) as well as one that does not ( biosimilar to RP ).
Multiple switching describes at least three therapy transitions , or alternating between the RP and its biosimilar product or between biosimilars .
Cross-switching is the process of switching between biosimilars , for example , switching between two biosimilars or a transition of therapy from one biosimilar to another biosimilar of the same RP .
Definition and concept of an interchangeable biosimilar Here , there are clear differences between the US and Europe . 1 , 2 , 8 – 14
In the US , interchangeability is legally defined in the Biologics Price Competition and Innovation Act ( BPCIA ). To be designated as interchangeable , a biosimilar : a Must meet the previously mentioned criteria for biosimilarity b Be expected to produce the same clinical result as the reference biologic in any given patient , and c The risk in terms of safety or reduced efficacy of switching ( back and forth ) between the use of the biologic and the RP must not be greater than the risk of using the reference biologic without such alternation or switching .
An interchangeability study is generally expected by the
2 , 12 , 13
FDA for risk assessment . At time of writing , three products have been granted the designation of interchangeability by the FDA : in diabetes ,
2 , 12 , 13
inflammatory disease and ophthalmology , respectively .
Substitution of an interchangeable product and the RP can be performed at the pharmacy level without contacting the prescribing healthcare provider , but this does depend on state
4 , 12 , 13 pharmacy laws .
In Europe , a different approach to interchangeability has been adopted . In general , interchangeability refers to the possibility of exchanging one medicine for another that is expected to have the same clinical effect . In the case of biosimilars , interchangeability could mean replacing the originator with a biosimilar ( or vice versa ) or replacing one biosimilar of the same RP with another . 1 , 5 , 6 Replacement can be done at two different levels : switching ( by the physician ) and ( automatic ) substitution ( by the pharmacist ). 1
The EMA and the Heads of Medicines Agencies have now issued a joint statement confirming that biosimilar medicines approved in the EU are interchangeable with their RP or with an equivalent biosimilar . 15 Information regarding questions on prescribing or interchangeability practices are available from the national competent authority in the relevant member states and listed on the EMA website . 14
Considerations when examining interchangeable biosimilars While the first interchangeable biosimilars have been designated in the US , there are still many questions and much debate on the requirements necessary to demonstrate interchangeability . One of the main concerns related to the use of interchangeable biosimilars is the suggested risk of immunogenicity when switching between non-identical but highly similar biologicals .
More and more data , however , show that it is highly unlikely that harmful immunogenicity would be triggered by a switch when biosimilars approved to rigorous regulatory
5 , 6 , 16 , 17
standards are used .
A review by Strand et al 16 summarised the immunogenicity data for biosimilars used in the setting of rheumatic diseases , plaque psoriasis and inflammatory bowel disease by assessing the incidence of anti-drug antibodies ( ADAs ), which is a recognised measure of immunogenicity . The effect of switching on the incidence of ADAs was established based on data collected for infliximab , etanercept , rituximab and adalimumab . The data revealed no changes in quantitative or qualitative immunogenicity when switching between RPs and corresponding biosimilars . 4 – 6 , 16 Many switch studies have been undertaken in the Nordic states which demonstrated no worsening of disease or any specific safety concerns in patients one year after a switch . 17 – 19 Recent evidence has also revealed no robust data indicating that switching between an RP and its biosimilar leads to immunogenicity ( heightened or altered immunogenic response ) and the risk associated with switching between an RP and its biosimilar ( from a clinical
5 , 6 , 17 – 20 perspective ).
In addition to the risk of immunogenicity , there are also practical considerations , such as the delivery device , that might vary between products ( e . g ., subcutaneously selfadministered products ). Different administration devices ( e . g ., autoinjector or prefilled syringe ) can present an obstacle to switching for many patients . 21 In such circumstances , education , training and counselling of the patient or the caregiver is necessary to familarise them with the new device to ensure appropriate administration of the product . 6 , 21
To ensure an appropriate transition , healthcare providers should receive support and guidance , with transparency on the potential gains from use of biosimilars and how any possible cost savings will be allocated to incentivise involved stakeholders . 21
The case of interchangeability in the EU , Australia and Asia Worldwide , different regulatory views are in place in terms of designating biosimilars as interchangeable with their RPs . In Europe , the EMA assesses marketing authorisation for most biologics under the centralised procedure in the current European regulatory framework . Their marketing authorisation is centrally discussed by experts affiliated to the EU national medicines agencies .
According to the EMA , interchangeability is a broad term referring to “ the possibility of exchanging one medicine
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