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When a patent expires alternative versions will be produced and are referred to as biosimilars but what does the future hold for these newly approved versions of biopharmaceutical products?
Hakan Mellstedt
MD PhD
Department of Oncology
and Haematology
Cancer Centre Karolinska
Karolinska University
Hospital
Solna
Stockholm, Sweden
Recombinant technologies have provided a means to produce therapeutic proteins. When the patents expire, alternative versions will be produced, referred to as biosimilars. They are similar to the reference product but not identical copies. Biosimilars might have biological properties not identical to the innovator drugs such as immunogenicity and clinical effects in extrapolated indications, which might not be detected until a huge patient population has been treated and carefully monitored in the pharmacovigilance programme. Biosimilars will contribute significantly to the protein drugs arsenal, although caution should be taken until a large number of patients has been treated. Price reduction will not be at the level of chemical generics. It is anticipated that the discount may be in the range of 30 ±10% compared with the innovator drug.
Recombinant technologies have provided a means of producing a variety of therapeutic proteins, allowing biopharmaceuticals to become important therapeutic options for a variety of indications. Patent expirations for a number of biopharmaceuticals have prompted the study and development of alternative versions of biological products called biosimilars.[1]
Biosimilars are new biopharmaceutical agents that are ‘similar’ but not identical to the innovator biopharmaceutical product. Characteristics of biopharmaceuticals are closely related to the manufacturing process, which cannot be duplicated. Thus, biosimilars are unique molecules and not generic versions of the innovator biopharmaceuticals.
The primary and secondary structures of a biosimilar are, however, supposed to be the same as the reference product[2] as well as many biological functions shown in preclinical testing systems, indicating the same mechanisms of action.
In the clinical trials with a rather small number of patients and short observation periods, the biosimilars have shown a similar clinical effect as the reference product. This can be shown by the effect on haemoglobin concentration of erythropoietins tested in chronic renal failure and chemotherapy-induced
anaemia. Similarly, G-CSF biosimilars have a similar effect as the reference product on chemotherapyused neutropenia and CD34+ cell mobilisation in healthy donors. The ‘acute’ safety profiles are also similar.
However, the tertiary structures may be different from the innovator drug. Identity, similarity and/or difference in tertiary structures are difficult to prove. Such differences may have consequences especially with regard to immunogenicity but also possibly to biological functions. These differences may not be
witnessed until a substantial number of patients has been treated and followed over an extended time period. Pharmacovigilance programmes are therefore extremely important for biologicals, much more than for small chemical molecules. We should be aware that induced antibodies against biologicals may interact with the corresponding endogenously produced proteins and cause severe side-effects (such as pure
cell aplasia). These effects might only be seen in a minority of patients but they are still of significant clinical importance.
Another problem is extrapolation,[1] which may be linked to the non-identity of the biochemical structures of the biosimilars compared with the innovator drug. Extrapolation to indications of the innovator drug is allowed even though the biosimilar drug has formally not been tested for a given indication. Extrapolation is probably acceptable. However, it is extremely important that in the Summary of Product Characteristics it is clearly noted which indications are based on extrapolation. Moreover, the number of patients who have been included in the pivotal studies of the biosimilars and the indications should also be shown. A special concern is the use of granulocyte
colony-stimulating factor (G-CSF) in healthy donors. A number of patients should be treated with G-CSF biosimilars before they are given to healthy donors. A careful long-term monitoring of healthy donors treated with G-CSF biosimilars should be mandatory with regard to side-effects such as immunogenicity, normal WBC functions and leukemogenesis.
Automatic substitutions are allowed for chemical generics. In principle this rule could also be applied to biosimilars. However, authorities in most European countries do not recommend or allow automatic substitution of biosimilars.[1] This is a very interesting standpoint indicating that the authorities are aware
that biosimilars are not identical drugs and the mixing of different biosimilars should not be done. This may render pharmacovigilance programmes difficult to accomplish and evaluate. Side-effects and the clinical inferiority of biosimilars may not be possible to trace if automatic substitution is allowed. Important clinical information on individual protein drugs may be lost.
Patents on monoclonal antibodies (MAb) will soon expire and a huge market for monoclonal antibodies’ biosimilars (BMAb) is expected. Compared with growth factors, MAb are much more complex in structure and similarities/comparability to the innovator drugs will be more difficult to prove than for
growth factors. MAbs have multifunctional mechanisms of action and biochemical characteristics have a significant effect on biological functions.
It will probably not be possible to duplicate the amino-acid sequences of the complementarity determining regions (CDR) I−III defining the antigen binding site. The affinity binding constant will differ. It will also not be possible to copy the biological active part of the immunoglobulin molecule, the Fc-part, with its complex amino-acid sequences and carbohydrate contents determining antibody dependent cellular
cytotoxicity (ADCC) and complement dependent cytolysis (CDC). The multifunctionality of MAbs and the uncertainty of the relative contribution of signalling inhibition and ADCC efficacy of, for example, trastuzumab and ADCC, CDC and apoptosis induction to the efficacy of various anti-CD20 antibodies in B cells malignancies, should make it almost impossible to produce a BMAb with claims to be similar to the innovator drug. Moreover, clinical surrogate endpoints such as erypoietin and G-CSF increase in haemoglobin, and white blood cell counts are easy to establish. Validated clinical surrogate endpoints for MAbs in oncology have not yet been established. Randomised clinical studies are probably required to measure both response rates and time to progression/ overall survival to show favourable comparisons with the innovator drug. All these obstacles will force biopharmaceutical companies to accomplish extensive developmental programmes for BMAb and ensure that the authorities proceed with care and attention.
Economics is a driving force in the introduction of biosimilars, as there are great hopes for cost reductions. However, these reductions will not be in the range of small molecule chemical generics, where a 80-90% discount might be seen. It is anticipated, and based on current experience, that it is realistic to expect 20-30% lower costs for a biosimilar compared with the reference product. There are several reasons for this discrepancy in pricing. Generics are manufactured by chemical synthesis and biosimilars by living organism. Bioequivalence only is required to be shown for generics, while phase I and III clinical trials are requested for biosimilars. The developmental
time for a chemical generic is, on average, 3 years but for biosimilars the period is between 6 and 9 years. The developmental costs for biosimilars are 50 to 100 times higher than for generics. These main differences in the production process will remain and explain why cost reductions for biosimilars will probably be in the range of 30±10% compared to the innovator drug. Moreover, a small price differential
reduces the incentive to switch. Probably less than 20% discount is not sufficient to switch to a biosimilar product.
The biopharmaceutical market will be characterised by price competition, even when there is a limited number of players for a given product. This holds for both original and biosimilar protein drugs. The market for biosimilars is huge, particularly so when biosimilars enter the US market. The annual market value is expected to be more than $20 billion in 5 years’ time.
Biopharmaceuticals, especially biosimilars, will be important drugs and represent a substantial part of the health economy. To demonstrate value for money, it is important that health economics are involved early in the developmental process of biopharmaceuticals and biosimilars. It is also important that health professionals such as physicians, pharmacists and other health care decision makers are aware of the advantages, but also the potential drawbacks, of biosimilars so as to apply an optimal use of these novel innovative drugs.
Soon pharmaceutical companies will also start to produce the second generation of biopharmaceuticals with improved properties, such as more convenient administration schedules and better clinical efficacy. A switch to second-generation biopharmaceuticals with a long expiration time is expected. In the future there might be competition between well established first-generation biosimilars and secondgeneration innovative biopharmaceuticals.
The future will bring rapidly growing access to various biopharmaceuticals and require a novel competence among healthcare providers, and care and attention from the authorities. It will require an intense dialogue between health care professionals and the industry, and the inclusion of health economics in the evaluation process to establish the optimal
use of these drugs.
References
1. Mellstedt H, Niederwieser D et al . Ann Oncol 2008;19:411-419.
2. Brockmeyer C, Seidl A. Eur J Hosp Pharm Prac 2009;15(2):34-40.
