by Giuliana Miglierini

The undergoing revision of the pharmaceutical legislation aims, among others, to redefine data protection to better support competitiveness of generics and biosimilars and to favour the timely access of patients to treatments.

While the innovator pharma industry is claiming the proposed reform would reduce the attractiveness of Europe for R&D activities, a recent report from Iqvia analysed the status of biosimilar competition. According to the document, not all biological medicines experiencing loss of exclusivity (LoE) in the next decade would automatically face competition by the corresponding biosimilars. This would result in the creation of a “biosimilar void” on the market, with many originators losing protection without seeing the parallel development of their biosimilar versions.

Competition is not guaranteed

“Biosimilar competition is not necessarily guaranteed, and emerging dynamics pose a risk to conventional notions of medicines lifecycles”, states the report since its very beginning. The analysis refers to biological medicines that will lose protection in the period 2023-2032.

Despite the approx. 8-fold expected increase in LoE opportunity by value between 2012 and 2032 (from €4.4 billion to €32.2 bln, as result of loss of exclusivity for 110 biological medicines), data show a declining trend for years 2021-2023 (€4.3 bln). According to Iqvia, more than a half (55%) of biologics with LoE in the period 2023-2027 might experience the lack of a biosimilar in development.

The report highlights five areas of common perception to be addressed to better define the issue. The increasing complexity of many biological medicines coupled to new barriers to entry is one of the factors making the development of biosimilars interesting only for products referred to originators with large market shares. According to Iqvia, 27% of the 26 high-sales products that will reach loss of exclusivity by the end of 2032 do not have yet a biosimilar candidate in development in Europe (vs 45% at the global level), corresponding to a potential loss of approx. €8 bln market opportunity. The number of biosimilar candidates in the pipeline for high-sales biologics is also expected to decrease from 2027 onwards.

Regulatory hurdles, therapeutic classes, and disease indication are expected to play a greater role in guiding decisions on biosimilar development, indicates the report. The attractiveness of the European market should also be considered. Oncology will remain the more interesting area, with 44% of all candidates in early to late development for LoE events occurring between 2023 and 2027. Immunology and ophthalmology are other therapeutic areas that might experience growing competition.

The current barriers to biosimilar development

According to Iqvia, the main constraints limiting the decision on biosimilars development are represented by cost and time. In the oncology area, for example, high costs have to be considered to purchase the reference comparator biologic medicine, and large patients populations are required to demonstrate relevant clinical endpoints. New therapeutic classes, i.e., PD-L1/PD-1 inhibitors, may also pose challenges for the design of pharmacokinetic and equivalence studies. From the manufacturing perspective, the increasing use of antibody-drug conjugates (ADC) would result in new barriers to entry.

According to Iqvia, the least attractive products for biosimilars development are those with less than €500 million annual sales in Europe. The report shows 93% of these products might fail to see biosimilar competition, compared to 27% of high-sales medicines. This negative trend would result in a “biosimilar void” corresponding to approx. €15 bln in lost savings. Iqvia also identified some exceptions that might experience a niche development, on the basis of specific technological and manufacturing know-how, platforms and market access excellence.

Another factor to be considered is reimbursement rate, that the report identifies in 51% for low-sales biologics with no biosimilar pipeline (approx. 30% lower than for products with a biosimilar pipeline). The management of the intellectual property referred to the originator should be also taken into consideration.

Orphan and one-off medicines

Despite the growing number of new biologics reaching marketing authorisation as orphan medicines, according to Iqvia biosimilar development is undergoing by now for only one product (eculizumab). No other orphan biologics are expected to face biosimilar competition in future, as annual sales of the 39 orphan medicines currently on the market are too low (approx. €105 mln).

A major factor limiting the development of biosimilars for orphan medicines is linked to the fact many of these therapies fall in the antibody-drug conjugates (ADC) and cell- or gene-therapies (ATMPs) categories (wave 3 biologics). This implies many challenges from the development and manufacturing point of view, higher upfront investments and a more complex setup for analytical and clinical testing.

According to Iqvia, there are currently 16 non-orphan biosimilar candidates under development, corresponding to wave 3 biologics. A limiting factor for this pipeline is identified in the still present fragmentation of the European regulatory system, e.g., reimbursement policies, incentives, and clinical standards. ATMPs, also referred to as one-off therapies, represent a particular case, being relatively young on the market. This leads to no expectation of LoE events in the next five years. The trend would then change, with some 10 products losing protection by 2040, but it should be considered together with the parallel declining of the number of eligible patients, as many of them might have been already treated with the one-off originator medicine.

Shifting standards of care

Another factor analysed by Iqvia is the impact on biosimilars development of the possible changes in the current standards of care, for example resulting from the availability of new and more user-friendly formulations of the originator (i.e., subcutaneous vs intravenous injections). The availability of second- and third generation versions of the original biologic should be considered as another factor limiting the possible market share of a biosimilar of the first-generation product. The picture is indeed furthermore complicated, as another frequent possibility, especially in the oncology area, sees the development of combination therapies based on the use of two or more biologics. As already said, some of them might be very costly (i.e. monoclonal antibodies and PD-1 inhibitors), and require a larger study population to demonstrate equivalence of the add-off effect.

The proposed solutions to fill the biosimilar void

The Iqvia report proposes several possible solutions to overcome the expected biosimilar void, starting from horizon scanning activities aimed at early identification of upcoming LoE events in order to prevent contractions in biosimilar development. Horizon scanning may also support market entry and granting of incentives based on demand. The development of biosimilars of orphan medicines might benefit of a default waiver of comparative efficacy studies, a suggested measure that according to Iqvia would not compromise the demonstration of biosimilarity. Improvements at the regulatory level might also help to streamline development, together with global convergence of regulatory guidance. Iqvia also suggests the adoption of clear regulatory pathways to incentivise the development of the next-generation, one-off biosimilar gene- and cellular treatments. Access might be improved by optimisation of market conditions, with incentives for clinicians combined with the introduction of prescription targets. New tender models would also be needed to favour multi-winner procurement practices.