Commentary
Guy's Hospital, London, UK
Correspondence and offprint requests to: David Goldsmith, Renal Unit, 6th Floor Guy's Hospital, London SE1 9RT, UK. Email: david.goldsmith{at}gstt.nhs.uk
Keywords: biopharmaceuticals; biosimilars; comparative testing; immunogenicity; pharmacovigilance; regulatory guidelines
We are now in the fifth decade of providing clinically useful medical and surgical care for patients with chronic kidney disease (CKD). The numbers of patients requiring a plan for renal replacement therapy has risen very sharply, as has the number of patients with a recognized impairment of kidney function. Progress in medicine, increasing economic wealth in industrialized and developing countries, societal pressures and above all the significant growth of a large ‘ageing’ cohort (prone to obesity, hypertension, diabetes and cardiovascular disease) have all conspired to challenge, as never before, those whose career it is to help patients with CKD.
Our specialty, possibly more than any other, is a child of technological advances. There would be no renal replacement therapy without ever more sophisticated machines, anti-coagulation and vascular access. We depend on input from radiology, pathology, infectious disease and intensive care to provide a fully integrated care pathway for all manifestations of CKD. Renal transplantation is now practised with a plethora of immunomodulatory drugs as our attempts to manipulate the immune system become more successful through greater sophistication. Most dialysis patients and a larger proportion of pre-dialysis patients routinely receive recombinant human erythropoietin with huge resultant benefit in quality of life.
But the environment in which these pharmaceutical ‘tools of our trade’ exist is also changing rapidly. ‘New’ therapies are mostly of increasing sophistication requiring evermore complex manufacturing processes (and much more financial ‘at risk’ investment). As the patents expire on many of the ‘first-generation’ therapies, opportunities have arisen for others to manufacture ‘generic’ versions of familiar compounds (e.g. enalapril, simvastatin, cyclosporin A). While ‘copying’ a fairly simple molecule certainly presents some challenges, it is achievable. However, when we come to the highly complex biologically active pharmaceutical agents such as recombinant human growth hormone, recombinant human erythropoietin or monoclonal antibodies to complex epitopes, the situation becomes much less predictable.
Biosimilars, or follow-on products of biotechnologically produced ‘biopharmaceuticals’, represent a complex issue that is becoming increasingly pertinent as the first generation of their innovator products reach the end of their patent protection periods. Recently, the European Medicines Agency (EMEA) granted approval to Omnitrope, a growth hormone biosimilar, and it may be anticipated that many more such products will emerge in the market in the near future. Our first challenge, one which must be successfully overcome, is nomenclature and definitions. It is important to clarify these; so this supplement includes a list of definitions for commonly used terms (Tables 1–5
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Like all pharmaceutical agents, safety is of paramount importance for biosimilars, but the dilemma of these products is that there is no legislative precedent for them. New guidelines for approval of biosimilars from the EMEA are still under review while no legal pathway exists at present in the US.
Biosimilars have little parallel with traditional chemical generics due to their inherent complexity and the complexity of the manufacturing processes necessary to produce them. Again, regulatory guidelines are yet to be defined and remain open for discussion.
Comprehensive analysis of biosimilars would include clinical data (pharmacokinetics and pharmacodynamics), efficacy and safety studies (comparison with a reference product in a relevant patient population, therapeutic indication, route and duration of administration) and testing using long-term immunogenicity data, validated antibody assays as well as a pre- and post-licensing pharmacovigilance plan.
Current technologies are being developed for such analyses but are still limited not only technically but also, theoretically. Fundamental questions are still unresolved—what parameters should be studied, what assays are appropriate to measure those parameters, what should be used to standardize results between manufacturers, what level of variation between products is acceptable and how sensitive is sensitive enough?
With all these unresolved issues, are we ready for biosimilars? More information and increased awareness about them are needed to ensure that we are in a position to make a rational and informed decision. The biosimilars situation is a rapidly evolving one and this supplement aims to overview the current situation in 2006, detailing the main reasons for concern and discussing what might be done to ensure their safe use and regulation. Experts experienced in the field present their perspectives in the context of four main issues—structural and molecular complexity of biosimilars, assays presently available for comparative analyses and pharmacovigilance, theoretical and practical bases for immunogenicity and the current regulatory situation. With this information, we hope to increase communication within the nephrological community so that we may achieve a sound knowledge-base. By so doing, we may allow ourselves the opportunity actively to participate in ensuring that regulations and testing of biosimilars meet appropriate safety requirements.
Conflict of interest statement. D.G. has received honoraria for speaking from Fujisawa, Novartis, Merck, Roche, Amgen, Abbott, Shire, Genzyme and Nabi, is a member of advisory boards for Nabi, Roche, Amgen, Abbott, Genzyme and Shire and holds unrestricted educational grants from Astra-Zeneca and Roche.
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