Global regulatory pathways for biosimilar development are continually evolving.  Many countries throughout the world have established legal and regulatory pathways which allow development of biosimilar products.

The European Union (EU) was the first region in the world to have set a legal framework and a regulatory pathway for biosimilars. To date, the European Medicines Agency (EMA) has approved 21 biosimilars within the product classes of human growth hormone, granulocyte colony-stimulating factor, erythtropoesis stimulating agent, insulin and tumour necrosis factor (TNF)-inhibitor, for use in the EU. The legislative route creating biosimilars for the United States  (US) market was created by the enacted healthcare reform law, the Patient Protection and Affordable Care Act (PPAC Act), signed into law in March 2010. The new law also included a pathway for an interchangeable biosimilar, which is a biological drug that can be automatically dispensed without specific prescriber authorisation. To date, the Food and Drug Administration  has approved one biosimilar, Zarxio (filgrastim-sndz), 06 March 2015.

But what are the key success factors for biosimilars in the market?

Clinical requirements

Biosimilars are approved on the basis of the ‘totality-of evidence’, quality, safety and efficacy. Clinical trials are costly and time consuming.  It is critical that the data package requirement is assessed on a case by case basis to determine what non-clinical and clinical studies are required to demonstrate similarity. There is no one-fit-for-all.  The result from each stage drives the next stage.  Significant advances in the scientific and analytical techniques e.g. in the field of physicochemical characterization are critical developments that help to reduce the clinical data package requirement. Human testing may not be an across the board requirement though it is more likely albeit shortened ones. Furthermore the clinical trials for biosimilars are not designed to prove efficacy per se, they are designed to demonstrate similarity using sensitive models and end points.


Overall all Regulatory Agencies have indicated that if biosimilarity has been demonstrated in one indication, extrapolation to other indications of the reference product could be acceptable with appropriate scientific justification.  If the relevant mechanism of action of the active substance and the target receptor(s) involved are the same then extrapolation can be justified. If different active sites of the biotherapeutic or different receptors of the target cells are involved in different therapeutic indications, or if the historical safety profile of the reference product differs qualitatively between the different therapeutic indications, additional data may have to be generated to justify the extrapolation of safety and efficacy data. This is critical as the cost of conducting clinical trials in each indication can be prohibitive.  However this concept is alien for prescribers. Various medical societies have indicated that they will not use biosimilars in extrapolated indications without clinical data. This could severely hinder uptake.


The World Health Organization established the International Nonproprietary Names (INN) system in 1953 to ensure the ‘clear identification, safe prescription and dispensing of medicines to patients, and for communication and exchange of information among health professionals and scientist worldwide’. The INN is intended to inform as to the active ingredient of a drug, otherwise known as the ‘generic’ name.

With the advent of biosimilars there has been ongoing debate on whether a biosimilar product proven through a comprehensive quality, non-clinical and clinical comparability studies to be similar to the originator should have the same INN. Some argue that biosimilars are not ‘identical’ and therefore should have unique INNs; traceability and attributions of adverse reactions have often been cited as a reason. The biosimilar drug makers argue that the rationale offered by those supporting unique identifiers, namely traceability, is just a tactic designed to put doubt in the minds of the prescribers and the consumers about the quality of a biosimilar product hence blunting competition. It is debatable whether unique naming for biosimilars offers any advantage to pharmacovigilance systems currently in place having been shown to work effectively. A distinct name for each biosimilar gives brand name drug makers a marketing advantage, as substitution will be more difficult for an already established product.


Biosimilars are similar but not identical.  To be considered interchangeable the safety and efficacy must not be greater than the risk of using the reference product.  The new law in the US under the 2010 Biosimilar Price Competition and Innovation (BCPI) Act includes a pathway for interchangeable biosimilars but the Agency so far has only released limited information on the principles of interchangeability. Guidelines are eagerly awaited.

Biosimilars developed in line with EU requirements can be considered therapeutic alternatives to their respective reference products but the decision lies outside the remit of the EMA/Committee for Medicinal Products for Human Use.  A number of countries have legal, regulatory and political provisions to prevent substitution and others have introduced policies for switching.  From 01 January 2014, French pharmacists are now legally permitted to substitute a biosimilar for the prescribed (reference) biological medicine as long as the prescribing physician has not marked the prescription as ‘non-substitutable’.

In Germany pharmacist may substitute a biosimilar as part of the obligatory generic substitution ‘Aut-idem-Regelung’ and practice specific prescription volume target agreements for doctors.  In April 2015 the Dutch Medicines Evaluation Board (MEB) has updated its position on biosimilars, stating that ‘biosimilars have been proven to have no relevant differences compared to an innovator biological medicinal product as far as quality, safety and efficacy are concerned’, a change from its position in 2010 which recommended to avoid switching. The Agency’s decision to change this position was based on ‘a careful study of the most recent literature and experiences in the evaluation of biosimilars’. This, says MEB, led it to the conclusion that ‘this strict condition is no longer valid’.

In May 2015 the Finnish Medicine Agency recommended switching and stated that there is no evidence for adverse effects due to a switch from a reference product to an approved biosimilars and the ‘theoretical basis of such adverse effects’ is weak. Switching is critical for the success of biosimilars as well as the opportunity to collect real data for the continuous support of biosimilars.


The high cost of biologics is an important issue in the battle concerning ever increasing healthcare cost. Biosimilars have the potential to curb health care cost as well as allow a robust and steady supply of biologics reaching far-flung patient populations.  However cost reductions have to be significant to encourage uptake.

Biosimilars in the EU are usually priced 15-30% below their reference products but they have achieved little market share because of lack of interchangeability.  A major exception is Germany where Germany’s Federal Healthcare Committee has encouraged the use of biosimilars and is able to negotiate for rebates.  There is reluctance to switch for a small cost saving in particular where the originator company is offering high level of patient support.  A significant price decrease could turn the tide. Recently in Norway Orion discounted its biosimilar infliximab (Remsima) by 69%.  The move paid off quickly and by March 2015 the biosimilar grabbed half the market.

Price does matter.


There has been a great deal of progress in developing the scientific pathway of biosimilars but the focus is shifting towards educating the stakeholders.  The paradigm of similarity is a difficult concept for prescribers and users.  There is a perception that biosimilars are inferior driven by lack of large studies in each indication.  To engage physicians, manufacturers must make sure prescribers truly understand the clinical and economic benefits of biosimilars.  Patients must be educated so they are willing to switch.  In the US most patients will value products that offer similar efficacy to their current treatment but at a lower out of pocket cost.  In other countries patients will have access to biologics that otherwise not available due to cost.


The regulatory pathways for the approval of biosimilars are well developed and tested globally.   The challenge is successful uptake in the market.  Understanding the science of biosimilars is crucial.  There is a perception that biosimilars are inferior to the originator and consequently not safe.  The evidence so far is clearly the opposite.  Biosimilars have been in the market for nearly 10 years in Europe and as evidenced by the Finnish Agency, the ‘theoretical basis for such adverse effects’ is weak.  Cost matters as clearly seen in Norway.  Education is key.  Robust pharmacovigilance monitoring is essential for continuous monitoring of the safety of biosimilars.  Member states of the EU have to apply biosimilar policies as they are critical for achieving sustainable health care systems.

Rodeina Challand Executive Director, 
Biosimilars Development – Scientific Affairs