RESUMO
Hemax® is an epoetin alfa product developed by Biosidus S.A. in Argentina at the end of the 1980s and has been present in that market since 1991. The initial presentation was a lyophilized powder containing albumin as stabilizer, to best adapt to environmental conditions in developing countries; more recently, a prefilled syringe, albumin-free presentation was developed, since this presentation has become the preferred standard in many markets. The primary objective was to compare the pharmacokinetic profile of different formulations of epoetin alfa after a single subcutaneous administration to healthy volunteers of 40 000 IU of Eprex/Erypo® and Hemax® PFS. This clinical trial was conceived following an open-label, randomized, three-way three-period cross-over balanced, and sequential design. The study was conducted on 24 healthy volunteers. To analyze similarity between Hemax® PFS and the innovator product, Eprex®, area under the curve (AUC) and Cmax of both products have been compared. The 90% CI lower limit for the geometric mean ratios was higher than 80% for any comparisons, and the 90% CI upper limit for these geometric ratios was below 125% for all the comparisons made, thus demonstrating equivalence between both products. The comparison between Hemax® PFS and Eprex® resulted in similar 90% CI for Cmax , AUC(0-120 h) and AUC(0-inf) ratios, all of them within the 80-125% interval, with a power above 95% for each ratio. These findings suggest biosimilar patterns for absorption velocity (with Tmax close to 15 h), absorption extent, and elimination (with an elimination half-life close to 25-30 h for each formulation).
Assuntos
Eritropoetina , Humanos , Epoetina alfa/farmacocinética , Voluntários Saudáveis , Área Sob a Curva , Proteínas Recombinantes , Equivalência Terapêutica , Injeções SubcutâneasRESUMO
The manufacture of biologics is a complex process involving numerous steps. Over time, differences may arise as a result of planned changes to the manufacturing processes of a biologic from the same manufacturer. Comparability is the regulatory process that outlines the scope of an assessment required of an already licensed biologic after a manufacturing process change made by the same manufacturer. The aim of a comparability assessment is to demonstrate that any pre-manufacturing and post-manufacturing changes have no adverse impact on quality, safety, and efficacy of the biologic. A comparability assessment is distinct from a biosimilarity assessment, which involves extensive assessment of a biologic that is highly similar to the originator (reference product) in terms of quality, safety, and efficacy. The US Food and Drug Administration, European Medicines Agency, and World Health Organization have applied the fundamental comparability concepts into their respective biosimilarity guidance documents. In this review, we examine the rationale behind the distinct, highly regulated approval processes governing changes that may occur over time to an originator biologic due to planned manufacturing changes (as described by a comparability exercise) and those that outline the approval of a proposed biosimilar drug, based on its relationship with the reference product (biosimilarity evaluations).
Assuntos
Medicamentos Biossimilares/química , Medicamentos Biossimilares/uso terapêutico , Descoberta de Drogas/métodos , Aprovação de Drogas , Descoberta de Drogas/legislação & jurisprudência , Indústria Farmacêutica/legislação & jurisprudência , Indústria Farmacêutica/tendências , Humanos , Valores de Referência , Equivalência Terapêutica , Estados Unidos , United States Food and Drug Administration , Organização Mundial da SaúdeRESUMO
Much of the testing required for the regulatory approval of a biosimilar is focused on proving that the new drug is sufficiently similar to the reference biologic in structure, pharmacokinetics or pharmacodynamics, clinical efficacy, and safety. However, the reference drug may itself have gone through some changes in the years since its approval, including those caused by alterations in the manufacturing process. Do these changes increase the risk that the reference drug may cause unexpected outcomes? It is up to the US Food and Drug Administration to decide whether the changes merit the need for additional studies to confirm that the drug meets the structural or clinical outcomes standard for the reference agent. Although it is extremely rare, a change in the production of one biologic drug (ie, epoetin alfa) did result in unanticipated serious immunologic side effects.