Biosimilar Development: Commonly asked Questions & Answers.
by Zeb Younes, Principal Consultant at Scendea
Introduction
A biosimilar is a biological medicine that is highly similar to another biological medicine already approved. The first European Medicines Agency (EMA) approved biosimilar was a somatotropin referred to as Omnitrope in 2006 and the first US Food and Drug Administration (FDA) approved biosimilar was a filgrastim product referred to Zarxio in 2015). Since the approval of these first biosimilars the EMA and FDA have recommended approval of over 65 and over 30 biosimilars respectively and the number is continuing to increase. With a large number of blockbuster innovator products reaching their patent expiry dates in the next 10 years, biosimilar development continues to be a highly lucrative field.
As biosimilars are developed to be highly similar to the originators, developers do not necessarily need to repeat all of the non-clinical and clinical studies and can use abbreviated programs saving substantial cost and time to approval. However, we know that amongst the success stories, there are also many that did not make it through development or failed at the last hurdle of regulatory review. There are specific aspects that must be accounted for during biosimilar development. Despite the established precedents and experience, it must be recognised that each case is different and must be evaluated on a case-by-case basis. Further to this, any non-standard approaches should be agreed with the regulators prior to execution. However, to aid developers, we have summarised some of the most common questions we receive on this topic along with the answers to help guide decision making during the development process.
What must be the same, similar and what can be different?
The label claimed strength, posology and indications must be within those defined by the originator product.
The product quality attributes of the biosimilar should be demonstrated to be highly similar to those of the originator. Minor differences may be acceptable as long as they have been demonstrated not to be clinically meaningful.
The formulation, container/closure, stability profiles may be different and can be optimised for improved shelf life and ease of administration. The impurity and safety profile may be improved, provided this does not lead to a difference in efficacy.
For a global development program with an initial focus on EU/US what is the major regional difference that we should be aware of?
The source of the originator product used in non-clinical and clinical evaluations is a major point that arises during global development programs.
Regulators recognise that repeating clinical studies using region specific originator product may not be cost effective, valuable or even ethical so agree that that as long as a 3-way (biosimilar/regional originator/other country originator), pair-wise analytical and functional bridge is in place between the region-specific originator and another ICH regions originator, then it may be possible to omit repeating studies using the region-specific reference.
How many batches of originator and biosimilar should we use to demonstrate analytical similarity?
Of all of the questions we are asked on this topic, this is the most common. There is no clear consensus from regulators on this and the changing originator profile could also impact the decision.
The number of batches of biosimilar and originator should each be a number that is amenable to statistical evaluation. For example, the final number could be between 5 and 25 and depends on a number of factors:
Variability in data
Any potential shifts in the originator data
Type of statistical analysis approach utilised
Side by side testing occasions
What are the most common issues observed by agencies during review/approval?
It should be emphasised that although the non-clinical and clinical programs for biosimilar development may be abbreviated, the CMC package must be as per a typical biologic and include the additional bio similarity evaluations. Often there are major gap in routine CMC requirements such as process development, photostability, shipping validation and stability which are raised during review.
The analytical procedures used in the similarity evaluations must be demonstrated to be fit-for-purpose and evidence is often requested if not provided in the dossier.
Additionally requests for isolation/enrichment of impurities of concern for evaluation of functional activity also come up and may take months to resolve.
One of the major issues that may arise if not agreed during earlier meetings with regulators is the choice of the source country of the originator used in the similarity evaluations, hence it is advised this is resolved early in development.
Could we waiver the non-clinical studies?
If it can be demonstrated that the biosimilar is highly similar to the originator in terms of physicochemical properties, primary structure, higher order structure and in vitro functional activity then it may be possible to waiver/abbreviate in vivo non-clinical studies.
Could we waiver clinical studies?
Depending on the molecule, manufacturing process and indication it may be possible to obtain approval on the basis of a single well designed pharmacokinetic/pharmacodynamic and safety study. In other cases, additional abbreviated immunogenicity and efficacy studies may be required.
Conclusion.
Given the large array of biosimilars under development it is not possible to take a single approach for each question, so we have provided a list of some of the most common questions we are asked by biosimilar drug developers and some answers to help guide the decision making process.