Biosimilars - what does a primary care clinician need to know?

Generics can be made to have the exact same active ingredient, biosimilars cannot

Generic pharmaceutical medicines can usually be chemically synthesised to have the exact same molecular structure as the original patented pharmaceutical.⁵ This is not the case for biosimilar medicines. The processes used to manufacture innovator biologics or biosimilars use living systems and are inherently variable. These medicines exhibit what is known as “microheterogeneity”, where small differences in the protein or antibody may be detectable between batches of the same biologic produced by one manufacturer.¹ For example, a protein could have the same amino acid sequence but have differences in glycosylation patterns.¹ In addition, once an original biological medicine has come off patent, it is unlikely that a competing manufacturer will be able to exactly replicate the full manufacturing and production process of the innovator, especially as some aspects of the process may not be available in the public domain.

As a result of this complexity, no two batches of an original biologic medicine are identical, and similarly alternative versions of a biologic medicine cannot be identical to the original; hence the name “biosimilars”.^{1, 5} These medicines are also referred to as subsequent entry biologics, follow-on biologics, or similar biotherapeutic products.

Evaluating and approving biosimilars: a new challenge in medicine requires a new approach

The regulatory approval of generically equivalent medicines is dependent on demonstrating that the generic has an identical chemical structure and pharmacokinetic bioequivalence via the same route of administration in healthy volunteers as the original patented medicine.⁵ Clinical trials to demonstrate that the generic medicine has equivalent clinical efficacy and safety as the innovator medicine are not required.

Due to variability in biosimilars, criteria for regulating generic medicines are insufficient to ensure that a biosimilar has the same clinical efficacy and safety as a previously patented biologic medicine.⁵ In addition, since biologics can be large and structurally complex, it is difficult to analyse whether they have the same physical and chemical structure as the innovator biologic.¹

This leads to the key questions which regulatory authorities face regarding the evaluation and approval of biosimilars:

• How much change can there be in a biosimilar, relative to the original biologic, before clinical efficacy and safety are affected?
• What is the best way to ascertain potential differences and evaluate the efficacy and safety of biosimilars?

Biosimilars are a relatively new area of medical science, and new regulatory frameworks for how to best answer these questions have been required and come into use over the last decade. In 2015, new guidelines on the approval of biosimilars from the Europe Medicines Agency and guidance from the Food and Drug Administration (FDA) to manufacturers in the United States have been released.^6–8 Increased market competition from off-patent biologic medicines has the potential to reduce costs and widen access so more patients can use them, which could be a desirable outcome; the challenge is to ensure that this can happen without compromising patient safety or reducing efficacy.

To address the question of how much difference there can be between a biosimilar and the originator biologic before clinical efficacy and safety are affected, many regulatory agencies around the world have devised processes for evaluating and approving biosimilars. In New Zealand, Medsafe has adopted the guidelines of the European Medicines Agency for the approval of biosimilars.⁹ These guidelines require the manufacturer of a biosimilar product to demonstrate that the biosimilar:¹⁰

A. Is similar to the reference medicine in terms of chemical and physical properties (the already approved, “original” biological medicine) This is assessed by a range of laboratory experiments, such as antigen binding tests for antibodies. In general, there is no “gold standard” to quantify chemical and physical similarity; the purpose of these tests is to identify any differences between the biosimilar and the original biologic.

B. Does not have any meaningful differences from the reference medicine in terms of quality, safety or efficacy This is assessed by a variety of tests including pharmacodynamic and pharmacokinetic studies, as well as clinical trials of efficacy compared to the reference biologic. These tests must demonstrate that any detected differences in chemical or physical properties do not have a meaningful impact on clinical efficacy and safety.⁶ For example, biosimilar versions of epoetins are known to have different glycosylation profiles, but have been demonstrated to have the same clinical efficacy and safety, so are approved for use.¹ In the assessment of a biosimilar version of recombinant human follicle stimulating hormone (Ovaleap), the European Medicines Agency noted minor chemical differences are present compared to the innovator biologic (Gonal-f), but approved the biosimilar on the basis of clinical evidence of similar efficacy and safety.¹¹

The European Medicines Agency has additional specific criteria depending on the type of biologic medicine under consideration, e.g. chemical and clinical efficacy criteria for biosimilar insulins, epoetins and filgrastims.^{12, 13}

Multiple indications

A biological medicine may be used to treat patients with different conditions and be approved for multiple indications. The question which then arises is whether a biosimilar needs to be assessed in clinical trials for every indication of the original biologic, or could it be approved for all of the indications held by the original biologic medicine once similar efficacy and safety is shown for a subset of those indications?

When a biosimilar is approved for an indication which has not been directly assessed in clinical trials, regulatory agencies refer to these as “extrapolated indications”. Authorities, including the World Health Organisation (WHO) and European Medicines Agency, have provided guidance on the scenarios that would form a sound scientific basis for approving a biosimilar for extrapolated indications, such as when a medicine is believed to have similar mechanisms of action in different conditions and is used in similar doses or durations.^{7, 14} However, the interpretation of evidence can differ between regulatory authorities, e.g. a biosimilar version of Remicade (infliximab) is approved for a more limited range of indications in Canada than in most other countries.¹⁵

Extrapolated indications are likely to be an area of ongoing debate where there may be disagreements between regulatory authorities or clinicians depending on the biosimilar and indications in question.¹⁴ Ultimately, for any medicine, safety and efficacy can only be demonstrated through the accumulated evidence of appropriate clinical trials and real world data on rates of clinical response and adverse effects.

Immunogenicity and tolerance

One of the key concerns with biologics and biosimilars is the potential for unforeseen adverse effects resulting from variability, especially immune reactions. The immunogenicity of biological products is likely to arise from their biological complexity but predicting whether a biological product will produce an immune reaction is difficult.^{1, 7} The potential clinical impact of an immune reaction can also be highly variable; consequences can range from little clinical impact, to influencing the achieved dose and efficacy of the medicine or leading to the development of antibodies which cause autoimmune reactions.¹⁴ As is the case with any new medicine, long-term data on the safety of biosimilars in large numbers of patients will not be available until these have been in clinical use for some time.

The lesson from Eprex

An example of an unforeseen adverse effect from a biological medicine comes from changes in the manufacture and use of the innovator biologic Eprex (epoetin alfa, a recombinant erythropoietin). Until the late 1990s bovine serum albumin (sourced from cows) was used as a vehicle in Eprex production. Due to concerns about the potential development of Creutzfeldt–Jakob disease, bovine serum albumin was swapped for another compound, polysorbate-80. Adverse reaction monitoring detected an increased occurrence of a rare condition in patients treated with Eprex: pure red-cell aplasia due to the presence of anti-erythropoietin antibodies. Subsequent investigation implicated the change in vehicle as a cause of increased immunogenicity leading to the development of anti-erythropoietin antibodies in some patients. Other factors also implicated in the increased occurrence of pure red-cell aplasia included a change in clinical practice with increasing subcutaneous instead of intravenous administration, variable storage conditions and possible leaching of compounds from rubber stoppers in syringes.^{16, 17}

This case involved a change in manufacturing process and administration of the original patented medicine, rather than the introduction of a biosimilar. However, it highlights that small alterations in the preparation of biologics could have important clinical effects, and this has informed current approaches to the safety of biologics and biosimilars. Firstly, changes in the manufacturing process of approved biologics are now more tightly regulated.¹⁶ Secondly, it is recognised that biosimilars could have important differences in clinical effect even if they have little difference in terms of composition to the original biologic; thus, clinical tests of efficacy and immunogenicity in sensitive populations are included in current approval guidelines around the world.

Immunogenicity in European guidelines

The approval process for biosimilars in Europe requires that a manufacturer demonstrates comparable (or lower) immunogenicity to the reference product. For any medicines which are used long-term, the European Medicines Agency has stated that immunogenicity data for one year of use will normally be required for approval.⁷ One of the concerns with extrapolated indications is that use in different patient populations (such as people with different autoimmune conditions) could influence immunogenicity.¹⁴ The FDA and WHO recommend that immunogenicity tests performed to support an approval application are conducted in patients with the greatest expected risk of developing adverse immune reactions, so that any extrapolated indications are for uses and patient populations where a lower risk would be expected, e.g. due to lower doses or shorter durations of use.^{8, 14} As is the case with any medicine, including innovator biologics and biosimilars, regulatory authorities can request post-marketing surveillance studies to collect additional data on safety during routine clinical use, and some biosimilars have been approved in Europe with post-marketing surveillance requirements in place.

Assessing biosimilar safety in New Zealand

In New Zealand, manufacturers of all biological medicines (either original innovator medicines or biosimilars) are required to submit Periodic Benefit Risk Evaluation Reports, which compile new and emerging evidence about the risks and benefits of a medicine for approved indications.¹⁸