Biosimilars have now become commonplace in the clinic in many European countries. The first biosimilar product, Sandoz’s Omnitrope, a version of Lilly’s Humatrope (somatropin), was approved by the EMA in 2006 and, in the decade that followed, more than 20 biosimilars gained regulatory approval. The first biosimilar monoclonal antibody, to Janssen’s Remicade (infliximab) was approved in 2013. However, 2017 was a record year for such products, with 16 approvals for biosimilars referencing seven different innovator drugs. By mid-2018, EMA had approved over 40 biosimilars in total since 2006.

The U.S. has been much slower off the mark in this field. The FDA’s 351(k) pathway for biosimilar approval, part of the Biologics Price Competition and Innovation (BPCI) Act, was agreed in 2010, and draft guidance documents published two years later. It was not until 2015 though that Sandoz’s Zarxio, a biosimilar of Amgen’s Neupogen (filgrastim), was given the go-ahead for marketing using this pathway—outside of the U.S. the product is marketed under the brand name Zarzio. Multiple biosimilars to Neupogen had already been licensed in Europe, prior to the U.S. approval of Zarxio.

Since then, there has been a rapid acceleration in the pace of approvals with five in 2017, although legal and patent issues are still preventing some biosimilars accessing the U.S. market. Several of the big pharmaceutical companies have made substantial investments in developing further biosimilars, and many marketing authorization applications, particularly of monoclonal antibodies, are awaiting consideration by the FDA.

A biosimilar could be seen as a generic biologic product by some. However, this is not an accurate view, as biomolecules are ‘manufactured’ from living material and have a much more complex and intricate structure than small-molecule synthetic drugs. This is acknowledged in the requirements of various regulatory guidelines and pathways, which are somewhat more complex than for small-molecule generics. The path to market for a biosimilar involves a so-called “abbreviated” approval process, whereby a Phase II clinical trial is not required. Instead, there is intense focus on proving ‘biosimilarity’ to the reference originator product using a combination of physicochemical, biological and clinical data which is not required for a novel product.

Although the biosimilar will offer cost savings to patients over the originator product, in practice the price differential is unlikely to be quite as great as is the case for small-molecule generics. A clue to the other significant difference is in the name, biosimilar. The active ingredient in a small molecule generic has to be identical to that of the originator. However, for biosimilars, this is not achievable due to the different biological manufacturing processes. Even different batches of any originator biologic will have slight variations. Rather, the biosimilar product will be within the acceptable range of product attributes of the original biological but not exactly identical, hence the name ‘biosimilar.’ There will, inevitably, be some slight differences in structure between the two as a result of the different manufacturing process employed and hence the biosimilar producer must prove to the regulatory authorities that these structural differences have no influence on the safety and efficacy of the biosimilar compared to the originator.

Another important consideration is the selection of the indication for which approval will be sought. Many biologics, particularly monoclonal antibodies, are marketed for a number of different indications, so there is a decision to be made at the outset about which one offers the best route to initial approval.

If biosimilarity has been demonstrated in one indication, then it is possible that, with appropriate scientific justification, it could be extrapolated to the other indications for which the originator product is marketed. However, this is not a given.

Generation of the supporting CMC dossier for biosimilars
The Chemistry, Manufacturing and Control (CMC) dossier is an essential part of the submission package for a clinical trial and, in a later stage, for an application for market authorization for any pharmaceutical product. In the case of a biosimilar, the CMC part is even more important. The dossier must include a comprehensive head-to-head comparison of the biosimilar and the originator product. As part of this comparison, physicochemical and biological characterization is carried out on multiple batches of both the biosimilar and the originator in order to establish whether any differences exist. It is important that further investigation is then carried out to examine the possible impact of these differences on the safety and efficacy of the product. The dossier has to indicate where the differences between the two products are, and how these will potentially affect the performance of the biosimilar product. It will also include all details of the analytical and other methods that have been used to identify these differences. This will allow the assessor to decide just how “similar” the two products actually are. This comparison is the core part of the CMC dossier for a biosimilar.

The document should also include details of how the product was manufactured, including any cell lines that were used, and details such as the sources of all materials that went into the bioreactor. A description of the process control methods used must also be included, plus information about how the analytical data have been validated. All of this information will need to be included in any CMC dossier, regardless of whether it is for a small molecule or a biologic, a generic or a biosimilar.

The head-to-head comparison is an additional requirement for a biosimilar, and performing this is not a trivial endeavor. CMC data and product specification ranges are rarely available for originator products, which, in any case, may have changed during their ‘life time’ due to manufacturing changes that have been authorized, so the entire analytical exercise has to be performed many times on different batches to establish ranges of quality attributes to enable comparison to be made. This is a relatively costly process, and locating a source of the originator product batches can prove extremely difficult.

A comprehensive set of preclinical safety studies must also be carried out before any human volunteers or patients are dosed with the biosimilar drug candidate. These will include in-vitro assays and for some regulatory authorities, appropriate animal models designed to predict whether those small differences may have an impact on either the safety or efficacy of the product.

Immunogenicity is a particular concern, and both in-silico tools and in-vitro assessments using animal tissue can be used to predict whether it is likely to occur in humans. Some regulations require that animal immunogenicity studies be carried out before humans are dosed for the first time.

Biosimilar phase I studies
For an originator product, Phase I studies will typically be carried out on 30-48 healthy volunteers to establish its safety. The study group for a biosimilar Phase I study, in contrast, will involve between 120 and 200 healthy volunteers. The discrepancy arises not because the trial is looking to establish primary safety, but because it is designed to detect any differences in safety signals between the biosimilar and the originator product. Although the structural differences between the two products could be very small, they still introduce a potential risk, and even though analytical and preclinical animal studies may indicate that there should not be any differences in humans between the originator and the biosimilar, the Phase I study is necessary to show that the new product is safe but also, importantly, that it is just as safe as the originator. This requires statistical calculations, and for these calculations to be meaningful and valid, a larger group of subjects is required.

Some countries have proven to be better locations than others for carrying out these studies. It is important to select a location where the local health authorities and ethics committees understand what the aims of a Phase I biosimilar study are, and why so many subjects are required. The subjects will receive either the originator product, for which safety data are already available, and a safety profile established; or they will be dosed with the biosimilar, for which the safety profile is not certain.

There is a small, but potential chance that those small structural differences—or another minuscule difference that had not been detected in the analytical or preclinical work—could cause a major adverse event, such as an immune cascade. It could be argued whether it is ethically acceptable to expose healthy volunteers to these risks, in order to test a product that is essentially a copy of something that is already on the market, and for which the medical added value might be debatable. That said, the best place to run a study of this nature is in a country where there is already a good Phase I infrastructure, and a favorable regulatory environment where the timelines for study approval are not too long, such as the UK, Belgium, the Netherlands, and the U.S.

At the outset, it is important to open discussions with the relevant regulatory authority, to establish the acceptability of the study design and whether, based on the CMC dossier, the product may be considered biologically similar to the originator. If not, then there is little point in continuing with further development of the drug candidate as a biosimilar.

As well as the Phase I comparative safety study, a Phase III study proving equivalent efficacy will be required. It is again important to discuss the design of this study with the regulator, and together establish what endpoints will be required. The study needs to be carried out in a representative patient population and to be sufficiently well powered in terms of patient numbers to ensure that it is sensitive enough to detect any potential differences in efficacy between the two products.

In the U.S., the additional aspect of interchangeability needs to be established, whereas in the EU, there are important questions of pricing and reimbursement to be addressed. As with any application for a drug approval, discussions with the regulators will be required regarding the inevitable data differences that are observed, and how they should best be managed. If any deviations are being made from the reference product, such as its strength, the pharmaceutical form, or formulation, these will need to be justified to the regulator. However, it is important to note that the route of administration must be the same as for the reference product.

Some changes will not be compatible with biosimilarity, as they change the chemical nature of the product too much. Changes designed to improve safety may not preclude a biosimilar decision, however; these might include lower levels of known impurities than are present in the reference product or a reduction in its immunogenicity.

Case study: a change of clinical trial location
As an example of the difficulty in gaining approval to carry out a Phase I biosimilar study, a large generics company was looking to start a trial for a biosimilar to a monoclonal antibody drug. However, the proposed trial was rejected in the Netherlands.

The key to gaining the go-ahead to run this trial was twofold: completely reworking the CMC dossier; and applying to run the trial in a different country. The changes to the dossier used available information but provided an additional head-to-head comparison of analytical data. This was submitted to the health authority in Belgium, which gave the trial the green light within 15 days.

Conclusion: careful documentation wins the regulators over!
As more biosimilars reach the market, regulators will become more experienced and familiar with the concept of the biosimilar Phase I study. However, convincing them that the study will not put volunteers at risk will, quite rightly, remain an essential part of the process. Clear, careful documentation of the analytical and preclinical studies that have been carried out and open dialogue with regulators will go a long way in providing that reassurance.