LAUSR

The development of biologic agents, proteins engineered to specifically target key components of the inflammatory pathway, heralded a new era in the management of rheumatic diseases. With impressively high efficacy, especially in combination with methotrexate, they have lowered mortality [1] and raised the bar for supressing disease activity in rheumatoid arthritis (RA) so that induction and maintenance of remission is now realistic for many patients – something that would have been unheard of some decades ago [2]. However, despite their undoubted efficacy, the high pricing of these drugs, driven partly by the need for expensive biosynthetic manufacturing plants and partly by the ability of rich countries to pay, resulted in an inequitable usage world-wide. Health care organisations in richer, developed countries, paid the premium prices requested by Industry. Yet even many rich countries limited biologics use, requiring some level of co-payment, or limiting funding to the more severe forms of disease (such as the UK, where reimbursement for biologics in RA only occurs if DAS 28 > 5.1). If rich countries experienced a struggle to provide ready access of these important drugs, what chance did developing countries have? From the first filing of patents on biologic drugs and their subsequent introduction into clinical practice, it was clear that, on patent expiry, there would be an opportunity to copy these drugs and, exploiting advances in efficiency of biological manufacturing techniques and a likely requirement for smaller clinical trials, cost would drop significantly, in the broadly similar manner to that observed with generics. However, this was not to be as simple as might have initially appeared. There are many important issues in copying biologics: complex proteins are very different to small molecule generics and reverseengineering large molecular weight monoclonal antibodies is a major technological challenge. On top of that, further equally important hurdles to overcome include developing an appropriate regulatory system to ensure quality and consistent molecular structure, assess in vitro and in vivo effects and establish an optimal clinical trial evaluation to guarantee similarity to the bio-originator. The FDA [3] and EMA [4] therefore developed stringent standards to approve Bbiosimilars^ as biologic drugs that had no significant analytical or pharmacological differences (within pre-approved tolerance limits) to the reference product. Yet not all regulatory environments are the same. Countries such as India and some Latin American countries allow the manufacture of drugs that have not been developed to the same level of rigour and scrutiny, in the hope of driving cost down yet further and supporting home industries. These drugs are not biosimilars, but rather termed Bbiomimics^, Bcopy drugs^ or Bintended copies^. And life gets yet more complicated as we consider what trials are needed to assure quality, safety [5], and potential immunogenicity (a constant fear in biologics) [6]. Should the original and costly pivotal trials be replicated in full, or are more abbreviated (and hence cheaper) trials acceptable? If a biosimilar has been shown to be not significantly different from the biooriginator/ reference product in one disease, should it be automatically be approved and licenced for all of the conditions that the originator is approved for (extrapolation of indication)? These issues have been debated across the world for some years now, but still cause much confusion. Who should be responsible for choosing a biologic (including biosimilar) drug? Physician? Pharmacist? Hospital? Payer? Does the person responsible for drug acquisition understand the disease and drug sufficiently well – or is cost the only driver? Does any of this matter? Within this background, the PANLAR consensus statement on biosimilars has been devised and published [7]. This important development is to be applauded. It resulted from a well-designedmodifiedDelphi process, involving participants from each of the PANLAR countries and represented health See related article, https://doi.org/10.1007/s10067-019-04496-3.