Narasimharaju SN, senior manager — regulatory affairs and Mac Kella, senior regulatory affairs executive at ELC Group assess whether biosimilars are really interchangeable in the EU.
Narasimharaju SN, senior manager — regulatory affairs, ELC Group
Narasimharaju SN
Biological agents have revolutionised therapy and transformed treatment paradigms due to improved short- and long-term clinical and public health outcomes, and general patient care of chronic and debilitating autoimmune disorders.
Mac Kella, senior regulatory affairs executive, ELC Group
Mac Kella
Recent or impending expiry of patents for some key biologics has led to development of biosimilar products. With growing numbers of these products there are now more options for healthcare providers and patients not only to access biological products earlier but also to possibly switch from costly originator versions to bio-similar alternatives.
Regulatory requirements
In accordance with regulatory frameworks laid out by the European Medicines Agency (EMA), the US Food & Drug Administration (FDA), the World Health Organization (WHO) and other authorities with higher regulatory requirements, development of a bio-similar has to be accomplished by rigorous and comprehensive comparability exercises. This is to assure similarity of the bio-similar with the reference medicinal product in terms of quality characteristics, biological activity, safety and efficacy, which includes the absence of any clinically important differences.
The EMA has pioneered the legal, regulatory and scientific framework for approval of biosimilars, with 29 products approved via centralised procedure for use in the EU. However, the agency’s evaluations do not include recommendations if a bio-similar can be used interchangeably with its reference medicine. This decision is the sole responsibility of each of the EU Member States’ competent authorities. Recently, experts from national agencies in the EU issued their position statements welcoming the switch to bio-similar products and raising concerns over the scientific purpose, feasibility, utility and usefulness of over-complex and often un-surmountable interchangeability requirements, and how these fit with economically sustainable placement of these products onto the market.
It has been claimed that the switch from the reference product to the corresponding bio-similar may have an impact on the efficacy and safety. Ideally, changes in safety and efficacy might be associated with a switch from reference product to bio-similar if either of the products has a higher inter-individual variation in pharmacokinetics. However, such a difference has not been observed with current biosimilars.
Immunogenic issue
Considering the above, the remaining potential problem is immunogenicity. A biological product is immunogenic if the immune system of an individual will recognise it as a foreign substance. It is not always possible to avoid immunogenicity of biological medicinal products. A biosimilar is allowed to be as immunogenic or less than but not more immunogenic than the reference product.
Immunogenicity caused by a switch between a bio-similar and its reference product may, in principle, be caused by two mechanisms. First, the immune system may react to a structural difference between the products. However, such a reaction is highly unlikely with licensed biosimilars, as the products have been shown to have comparable structure and immunogenicity in pre-licensing clinical trials. Increased immunogenicity has, in rare cases, been associated with manufacturing changes of a given biological product.
The other possibility is that the reference product is immunogenic and the immunoglobulin class or specificity will change upon the switch to a bio-similar.
Changing one for the other
Interchangeability is a medical practice of changing one medicine for another that is expected to achieve the same clinical effect in a given clinical setting, and in any patient, on the initiative or with the agreement of the prescriber. Automatic substitution is a practice of dispensing one medicine instead of another equivalent and interchangeable medicine at the pharmacy level without consulting the prescriber. The term ‘switching’ is related to the decision taken by the treating physician to exchange one medicine for another with the same therapeutic intent in patients who are undergoing treatment.
Several EU national regulatory authorities, including those of the Netherlands, Finland, Scotland, Ireland and Germany have already taken national positions to endorse the interchangeability of biosimilars under the supervision of the prescriber.
Due to the medicinal product complexity the automatic substitution of a reference biological product by a bio-similar product is not allowed by any of the EU member states. The decision of substitution or switching lies in the hands of the doctor and not the pharmacist.