2016 White Paper on Recent Issues in Bioanalysis: Focus on Biomarker Assay Validation (BAV): (Part 3 – Lba, Biomarkers and Immunogenicity)
Susan RichardsLakshmi AmaravadiRenuka PillutlaHerbert BirnboeckAlbert TorriKyra J. CowanApollon PapadimitriouFabio GarofoloChristina SatterwhiteSteven P. PiccoliBonnie WuCorinna Krinos‐FiorottiJohn AllinsonFlora BerishaLaurent CoceaStephanie CroftStephanie FraserFabrizio GallicciaBoris GorovitsSwati GuptaVinita GuptaSam HaidarCharles HottensteinAkiko Ishii‐WatabeDarshana JaniJohn KadavilJohn KamerudDaniel KramerVirginia LitwinGustavo Mendes Lima SantosRobert NelsonNi YanJoão Pedras-VasconcelosYongchang QiuPaul RhyneAfshin SafaviYoshiro SaitoNatasha SavoieKara ScheibnerEginhard SchickPatricia SiguenzaJohn SmeragliaRoland F. StaackMeena SubramanyamGiane SumnerTheingi M. ThwayDavid J. UhlingerMartin UllmannAlessandra VitalitiJan WelinkChan C. WhitingXue LiRong Zeng
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Abstract:
The 2016 10th Workshop on Recent Issues in Bioanalysis (10th WRIB) took place in Orlando, Florida with participation of close to 700 professionals from pharmaceutical/biopharmaceutical companies, biotechnology companies, contract research organizations, and regulatory agencies worldwide. WRIB was once again a weeklong event - A Full Immersion Week of Bioanalysis for PK, Biomarkers and Immunogenicity. As usual, it is specifically designed to facilitate sharing, reviewing, discussing and agreeing on approaches to address the most current issues of interest including both small and large molecules involving LCMS, hybrid LBA/LCMS, and LBA approaches, with the focus on PK, biomarkers and immunogenicity. This 2016 White Paper encompasses recommendations emerging from the extensive discussions held during the workshop, and is aimed to provide the bioanalytical community with key information and practical solutions on topics and issues addressed, in an effort to enable advances in scientific excellence, improved quality and better regulatory compliance. This White Paper is published in 3 parts due to length. This part (Part 3) discusses the recommendations for large molecule bioanalysis using LBA, biomarkers and immunogenicity. Parts 1 (small molecule bioanalysis using LCMS) and Part 2 (Hybrid LBA/LCMS and regulatory inputs from major global health authorities) have been published in the Bioanalysis journal, issues 22 and 23, respectively.Keywords:
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Summary Biopharmaceuticals are biological medicinal products that have been developed through biotechnological practices, including recombinant human technology, gene technology or antibody methods. The imminent patent expiration of many biopharmaceutical products will produce the possibility for generic versions of these therapeutic agents (i.e.biosimilars). Biosimilars differ from generic low molecular weight chemical drugs in many important ways. These include the size and complexity of the active substance, which will affect the scientific requirement for testing; the nature of the starting materials (cell banks, tissues, and other biological products); the complexity of the manufacturing processes; and the limitations of state-ofthe-art methods to characterize proteins and to detect all product variations that can influence clinical efficacy, sideeffects like immunogenicity. Therefore, it was acknowledged that established legal and regulatory principles of ‘essential similarity’ that are applied to standard generics cannot be readily applied to biosimilars. Thus, verification of the similarity to or substitutability of biosimilars with reference innovator biopharmaceutical products will require much more than a demonstration of pharmacokinetic similarity, which is sufficient for
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Abstract: Biopharmaceuticals are complex molecules produced by living cells. Copies of these drugs, called biosimilars, are not identical to their reference medicine, and therefore specific regulatory requirements for registration apply. Pharmaceutical quality evaluation requires a complete dossier and a detailed comparative analysis to the reference drug. However, nonclinical and clinical requirements are much less extensive compared to the requirements for an innovator. Therefore, at the time of introduction onto the market, only limited clinical experience is available for the biosimilar. Differences of 15%–30% between the acquisition price of biosimilars and their corresponding reference biopharmaceuticals have been suggested in the literature. Although the percentage price difference between reference biopharmaceuticals and biosimilar medicines may be limited, absolute savings are still likely to be substantial when calculated with respect to expensive reference biopharmaceutical medicines. Although an economic evaluation needs to be carried out in an increasing number of European countries to inform reimbursement decisions, uncertainty exists about how such an economic evaluation should be conducted for a biosimilar. The assessment of the cost-effectiveness of a biosimilar for reimbursement purposes depends primarily on the relative efficacy, given that a biosimilar is likely to be less expensive than the reference biopharmaceutical. To date, the question of meaningful differences in efficacy between biosimilar and biopharmaceutical drugs has not been answered. Due to a lack of demand-side incentives, biosimilar medicines have enjoyed limited success in Europe to date. Other factors that inhibit the market accessibility of biosimilars include the limited number of companies that have the expertise and the financial ability to manufacture, gain marketing authorization for, and commercialize biosimilars; physician brand loyalty to reference biopharmaceutical medicines; application of rebate contracts to reference biopharmaceutical medicines following expiry of protection; and life-cycle management strategies of companies marketing reference biopharmaceutical medicines. Keywords: biopharmaceutical, biological medicine, registration, pricing, reimbursement
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Technical progress in the field of biology and medicine radically changed the forecast of numerous serious diseases and the fate of patients, which is associated with the evelopment and clinical application of biopharmaceutical drugs. Today, the term of a molecular patent is expired in a number of biological agents, that have become a key factor in the development of so-called biosimilars, representing reproduced versions of original biotechnological tools. Since biosynthetic drugs appearing as a biosimilar replacementcan, although slightly, differ in the production process (variations in immunogenicity, safety and / or efficacy), a clear understanding of the clinical and regulatory aspects of the original drugs and biological analogues is of the utmost importance. According to the forecasts of statisticians, the share of biosimilars from the volume of the biopharmaceutical market will constantly grow and by 2020 can reach 40%, which in money terms will be more than $100 billion. According to the forecasts of statisticians, the share of biosimilars in the volume of the biopharmaceutical market will constantly grow and by 2015-2020 can reach 40%, which in money terms will be more than $100 billion. Among the factors of the development of biosimilar market is a moderate price compared to that of original products, a wide range of applications, an increase of the state interest. The differences between the original preparation, generic and biosimilar are showed in the article. The regulatory base of biosimilars registration in Ukraine is also presented, which is now harmonized with European legislation. In general, the introduction of biosimilars into medical practice will significantly reduce the cost for health care, and, consequently, the cost of these medicines for the population. However, the peculiarities of the structure, synthesis and production of biopharmaceutical drugs require a careful approach to assess their quality, efficacy and safety.
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During the past decades, there has been a dramatic increase in the demand for biopharmaceutical products. Despite the great potential of these products in providing life-saving medications for patients, the clinical application of several protein-based therapeutics has been weakened due to the development of un-intended immune responses against the proteins, compromising their safety and effectiveness. Patients may develop persistent immune responses against protein-based therapeutic agents due to the formation of neutralizing antibodies. Therefore, the immunogenic potential of such agents remains a major safety concern for their therapeutic application. While it is known that product- and host-related factors affect immune responses, there is less information about other factors involved in the induction of such immune responses. This review aimed to provide an overview of the immunogenicity of protein-based therapeutics and explains the immune mechanisms and factors that affect immunogenicity, immunogenicity effects, preclinical screening techniques, as well as the methods used to mitigate immunogenicity.
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Importance of the field: Ever since the formation of the first biotechnology company almost three decades ago, more than 150 biopharmaceutical products have been marketed across the globe. The oldest of these biotechnology-derived products are now at the end of their patent lives, as a result of which, the development of 'biosimilars' is increasing.Areas covered in the review: The review highlights aspects in which biosimilars differ from generic drugs.What the reader will gain: The active substance of a biosimilar medicine is similar to the one of the biological reference medicine; however, biosimilars differ from generics of pharmacological drugs in aspects like size and complexity of the active substance, and the nature of the manufacturing process. The manufacture of a biopharmaceutical product is complex and involves several isolation and purification steps. These procedures are proprietary to the manufacturer of the originator product and hence even minor changes in production can have serious implications in terms of safety and efficacy of the product.Take home message: Biosimilars should not be brought to market using the same procedure applied to generics, and existing and future regulation should prevent inappropriate and automatic substitution of a biosimilar for a reference biopharmaceutical product.
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The formation of anti-drug antibodies represents a risk that should be assessed carefully during biopharmaceutical drug product (DP) development, as such antibodies compromise safety and efficacy and may alter the pharmacokinetic properties of a compound. This feature review discusses immunogenicity issues in biopharmaceutical DP development, with a focus on product quality. Excipient-induced and aggregate-induced immunogenicity are reviewed based on the concepts of 'aggregation-competent' species and 'provocative' aggregates. In addition, the influence of formulation parameters, such as particulates and contaminants appearing in the DP during processing and storage, on aggregate-induced immunogenicity are presented, including the role of fill-and-finish equipments and the effect of interactions with container materials. Furthermore, methods to detect and quantify aggregation and precursor conformational changes in a protein formulation are reviewed, and immunological mechanisms that may lead to aggregate-induced immunogenicity are proposed and discussed.
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Most biopharmaceuticals, including those proteins that are more or less identical to native human proteins, induce antibodies in a significant fraction of patients. The main factors contributing to immunogenicity are impurities and the presence of aggregates. Sequence divergence from the native proteins only plays a minor role except in proteins from microbial, plant or distant vertebrate origin. In the majority of cases the antibodies have no biological or clinical effects. The most common clinical effect is the loss of efficacy of the biopharmaceutical. Serious complications of immunogenicity are rare. The best method to prevent immunogenicity is optimizing production, purification and formulation of the biopharmaceutical protein to generate soluble, non-aggregated, native protein free of contaminating adjuvants. The best way to predict immunogenicity in humans is evaluation in immune tolerant transgenic mice.
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The imminent patent expiration of many biopharmaceutical products will produce the possibility for generic versions of these therapeutic agents (i.e. biosimilars). However, there are a number of issues that will make approval of biosimilars much more complicated than the approval of generic equivalents of conventional pharmaceuticals. These issues centre on the intrinsic complexity of biopharmaceutical agents, which are recombinant proteins in most cases, and the heterogeneity of proteins produced by different manufacturing processes (i.e. differences in host cells, purification and processing, formulation and packaging). The increased occurrence of antibody (Ab)-mediated pure red cell aplasia (PRCA) associated with a change in the formulation of one particular epoetin-α product highlights the potential for increased immunogenicity of recombinant proteins with different formulations, or those manufactured by different processes. Thus, verification of the similarity to or substitutability of biosimilars with reference innovator biopharmaceutical products will require much more than a demonstration of pharmacokinetic similarity, which is sufficient for conventional, small molecule generic agents. Regulatory requirements for the approval of biosimilars have not yet been fully established, but preliminary guidelines from the European Agency for the Evaluation of Medicinal Products (EMEA) state that the complexity of the product, the types of changes in the manufacturing process, and differences in quality, safety and efficacy must be taken into account when evaluating biosimilars. For most products, results of clinical trials demonstrating safety and efficacy are likely to be required. In addition, because of the unpredictability of the onset and incidence of immunogenicity, extended post-marketing surveillance is also important and may be required.
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