Biosimilares: situación regulatoria para su autorización

Biotecnological drugs represents the future treatment in medicine. Since the expiry of the patent of the fi rst approved biotech drug, “copying” and marketing of them can be offered by any other biotech company, these new medicines are known as biosimilar medicines. They are approved by the EMEA (European Medicines Evaluation Agency) through the European centralised procedure, the EMEA issued several stringent guidelines to approve a biosimilar drug on the European market, preclinical and clinical studies are necessary to asses the highest standards in quality, efficacy and patient safety. The World Health Organization has determined that biosimilar have the same INN than the original product.     

On safety margin for drug interchangeability

ABSTRACT

As more and more generic (or biosimilar) drug products become available in the market place, it is a concern whether the approved generic (or biosimilar) drug products are safe and efficacious and hence can be used interchangeably. According to current regulation, most regulatory agencies such as the United States Food and Drug Administration (FDA) indicate an approved generic (or biosimilar) drug product can serve as a substitute for the innovative drug product. Bioequivalence (biosimilarity) assessment for regulatory approval among generic copies (or biosimilars) of the innovative drug product are not required. In practice, approved generic (or biosimilar) drugs are commonly used interchangeably without any mechanism of safety monitoring. In this article, current bioequivalence (or biosimilarity) limit is adjusted according to the observed geometric mean ratio and corresponding variability for development of safety margins for monitoring of drug interchangeability by minimizing the relative change in response with and without the switching.     

Are biosimilars approved for use in psoriasis safe enough to replace leading biologic therapies? A review

ABSTRACT

Introduction: Many tumor necrosis factor (TNF)-alpha ‘biosimilar’ agents have been approved for the treatment of psoriasis and other autoinflammatory conditions. These biosimilars have the same structure as the originator biologic and have been shown to be equivalent in terms of safety and efficacy. However, given the method by which biosimilars are manufactured, they are not exact replicas of the originator, unlike generic forms of non-biologic medications. Therefore, there is controversy regarding whether these agents should be considered interchangeable with their originator biologics.

Areas covered: The objective of this review is to summarize the safety data for each of the approved TNF-alpha biosimilars to determine whether or not these agents have appropriate safety profiles to replace their originator biologics.

Expert opinion: Based on extrapolation of phase III investigations in patients with rheumatologic diseases, each of the approved anti-TNF agents have comparable efficacy, tolerability, and safety profiles to their originators. Studies in patients with psoriasis are more limited. Transitioning from a biologic to its biosimilar has also been shown to be similarly safe and immunogenetic compared to maintenance therapy with the originator. More post-marketing studies are needed to demonstrate the long-term safety in patients with psoriasis.     

Hybridoma technology a versatile method for isolation of monoclonal antibodies,its applicability across species,limitations, advancement and future perspectives

The advancements in technology and manufacturing processes have allowed the development of new derivatives, biosimilar or advanced improved versions for approved antibodies each year for treatment regimen. There are more than 700 antibody-based molecules that are in different stages of phase I/II/ III clinical trials targeting new unique targets. To date, approximately more than 80 monoclonal antibodies (mAbs) have been approved. A total of 7 novel antibody therapeutics had been granted the first approval either in the United States or European Union in the year 2019, representing approximately 20% of the total number of approved drugs. Most of these licenced mAbs or their derivatives are either of hybridoma origin or their improvised engineered versions. Even with the recent development of high throughput mAb generation technologies, hybridoma is the most favoured method due to its indigenous nature to preserve natural cognate antibody pairing information and preserves innate functions of immune cells. The recent advent of antibody engineering technology has superseded the species level barriers and has shown success in isolation of hybridoma across phylogenetically distinct species. This has led to the isolation of monoclonal antibodies against human targets that are conserved and non-immunogenic in the rodent. In this review, we have discussed in detail about hybridoma technology, its expansion towards different animal species, the importance of antibodies isolated from different animal sources that are useful in biological applications, advantages, and limitations. This review also summarizes the challenges and recent progress associated with hybridoma development, and how it has been overcome in these years to provide new insights for the isolation of mAbs.     

Comparability and biosimilarity: considerations for the healthcare provider

BACKGROUND: Healthcare providers use recombinant biologics such as monoclonal antibodies to treat a variety of serious illnesses. Manufacturing of approved biotechnology products is complex, and the quality of the resulting biologic is dependent on careful control of process inputs and operating conditions. Biosimilars, which are similar but not identical to innovator biologics, are entering regulatory evaluation, approval, and marketing in regions with biosimilar approval pathways. SCOPE AND FINDINGS: This article describes the evaluation and potential impact of manufacturing process changes and biosimilar product development, and explores the similarities and distinctions between the two. Regulatory agencies generally require a comparability exercise following a manufacturing process change. This comparability is focused primarily on analytical characterization of the approved product before and after the manufacturing process change, with non-clinical and clinical confirmation required when determined necessary. When developing a biosimilar, the manufacturer does not have access to key information including the innovator manufacturer's cell line, cell culture conditions, purification procedures, and fill and finish processes. Further, the biosimilar manufacturer does not have access to information about the innovator manufacturer's product development history, including knowledge about the quality attributes of lots used in non-clinical and clinical development. We define the biosimilar manufacturer's lack of information as the knowledge gap. As a result, a biosimilarity exercise to compare a biosimilar to an approved innovator biologic requires a rigorous evaluation to ensure the safety and efficacy of the biosimilar. CONCLUSION: Given the knowledge gap under which biosimilars are developed, data to establish biosimilarity should go beyond a simple comparability exercise.     

The safety of emerging biosimilar drugs for the treatment of rheumatoid arthritis

Introduction: Biological disease-modifying anti-rheumatic drugs (bDMARDs), often administered in combination with methotrexate, target specific inflammatory mediators and have transformed the treatment of rheumatic diseases, especially rheumatoid arthritis (RA) but also the spondyloarthritides. However, the high cost of these drugs in many countries restricts patient access. As many bDMARDs have reached or are near to patent expiration, numerous biosimilar drugs are in development and some have already been approved. Biosimilars are generally priced lower than their reference products (RPs), or bio-originators, and as prices come down it is hoped that patient access to these drugs will increase, making the safety of these drugs an area of major interest.

Areas covered: This article reviews publicly available safety data on biosimilars in RA.

Expert opinion: Most available data for biosimilars in RA relate to tumor necrosis factor inhibitors (TNFi) and rituximab (an anti-CD20 monoclonal antibody). As biosimilar use around the world increases, evidence supporting the clinical safety of the biosimilars compared with their RPs also grows. To date, no new safety concerns have been raised in studies with TNFi or rituximab biosimilars for the treatment of RA; safety profiles have been consistent with those of their RPs. However, careful post-marketing pharmacovigilance remains necessary.     

对医疗机构开展药物警戒工作的认识与探讨

通过研究医疗机构药品使用与安全监管现状,分析药物警戒体系在药品使用环节对安全、有效、合理用药的重要作用,探索医疗机构开展药物警戒工作的内容与方法,建议制定相关法规,保障该项工作的开展。     

Pharmacovigilance during the pre-approval phases: an evolving pharmaceutical industry model in response to ICH E2E, CIOMS VI, FDA and EMEA/CHMP risk-management guidelines.

Pharmacovigilance science has traditionally been a discipline focussed on the postmarketing or post-authorisation period, with due attention directed towards pre-clinical safety data, clinical trials and adverse events. As the biological sciences have evolved, pharmacovigilance has slowly shifted toward earlier, proactive consideration of risks and potential benefits of drugs in the pre- and peri-approval stages of drug development, leading to a maturing of drug safety risk management. Further advances in biology, pharmacology and improvements in computational applications to medicine have led to the development of more complex medicines previously unobtainable and have also permitted a more thorough assessment of risks and potential benefits even earlier in the development process. Elevated public concern with the safety of more sophisticated medicines, combined with new science, have led pharmaceutical innovators, regulators and healthcare professionals to collaborate to develop guidelines, which drive enhanced pharmacovigilance and safety risk management earlier in drug development. In this paper, we review international guidelines on pharmacovigilance planning applicable to the pre-approval phases of medicines development and provide author opinion on these guidelines' potential drug safety implications. We discuss the possible evolution of a pharmaceutical industry model to respond to these guidelines; a view on multidisciplinary safety management teams is provided to encourage refinement of safety-signal identification and risk assessment early in drug development and to communicate important safety concerns to internal research efforts, patients, investigators and regulators. We further describe these functions in the context of the complexities of vulnerable populations, including the example of medicines research for paediatric populations. We also discuss the special role of epidemiology in pre-approval drug development and the impact on epidemiological science of changes to the pharmacovigilance paradigm.     

Selective activation of anticancer prodrugs by monoclonal antibody-enzyme conjugates.

A great deal of interest has surrounded the activities of monoclonal antibodies (mAbs), and mAb-drug, toxin and radionuclide conjugates for the treatment of human cancers. In the last few years, a number of new mAb-based reagents have been clinically approved (Rituxan, Herceptin, and Panorex), and several others are now in advanced clinical trials. Successful therapeutic treatment of solid tumors with drug conjugates of such macromolecules must overcome the barriers to penetration within tumor masses, antigen heterogeneity, conjugated drug potency, and efficient drug release from the mAbs inside tumor cells. An alternative strategy for drug delivery involves a two-step approach to cancer therapy in which mAbs are used to localize enzymes to tumor cell surface antigens. Once the conjugate binds to the cancer cells and clears from the systemic circulation, antitumor prodrugs are administered that are catalytically converted to active drugs by the targeted enzyme. The drugs thus released are capable of penetrating within the tumor mass and eliminating both cells that have and have not bound the mAb-enzyme conjugate. Significant therapeutic effects have been obtained using a broad range of enzymes along with prodrugs that are derived from both approved anticancer drugs and highly potent experimental agents. This review focuses on the activities of several mAb-enzyme/prodrug combinations, with an emphasis on those that have provided mechanistic insight, clinical activity, novel protein constructs, and the potential for reduced immunogenicity.     

抗体类生物类似药命名管理及其影响分析

目的 规范我国抗体类生物类似药命名,完善其全生命周期管理体系。方法 深入研究世界卫生组织（World Health Organization,WHO）、欧盟、美国、日本及我国关于抗体类生物类似药的命名要求,分析不同命名方式对药品全生命周期管理的影响。结果 目前,国内外抗体类生物类似药的命名原则不尽相同,但总体遵循WHO的国际非专利药名系统不同的命名方式将对处方安全性、药物警戒、医保准入与支付等方面产生影响。结论 建议药品监管部门逐步与国际接轨,基于国际非专利药名系统并结合我国实际情况尽快出台生物类似药命名相关文件,以明确抗体类生物类似药命名。此外,建议加强药物警戒管理、制定科学审慎的生物类似药医保支付决策,从而构建生物类似药尤其是抗体类药物的全生命周期管理体系。     

Pharmacovigilance regulations in India: A Step forward

Robust regulatory arrangements provide the foundation for a national method of medicine safety, and for public confidence in medicines. This article focuses on the need to sharpen the regulatory requirements for pharmacovigilance in India. To be effective the remit of drug regulatory authorities needs to go further than the approval of new medicines, to encompass a wider range of issues related to the safety of medicines. In order to achieve their respective objectives pharmacovigilance programs and drug regulatory authorities must be mutually supporting. On one hand, pharmacovigilance programs need to maintain strong links with the drug regulatory authorities to ensure that the latter are well briefed on safety issues in everyday clinical practice, whether these issues are relevant to future regulatory action or concerns that emerge in the public domain. On the other, regulators need to understand the pivotal role that pharmacovigilance plays in ensuring the ongoing safety of medicinal products. Despite global focus on the Development Safety Update Report, Indian regulators are not yet insistent on real-time update of a drug’s cumulative safety profile. Hence, the present article concludes with a strong urge to postulate regulations that create a comprehensive medicine safety system through careful strategic planning that envelope all aspects of pharmacovigilance.     

江苏省药品生产企业药物警戒工作现状抽样调查研究

目的 本文立足于药品不良反应监测工作向药物警戒过渡的发展阶段,调查分析江苏省药品生产企业药物警戒工作的现状,为提升药品生产企业药物警戒工作能力提供依据与建议.方法 采用问卷调查法,选取江苏省内药品生产企业代表,对其在药物警戒体系、药品安全性监测、药品风险管理等方面的工作现状进行调查,运用SPSS 22.0软件进行数据录...     

Biosimilares: balance de eficacia,seguridad y coste

A biosimilar medicinal product is a successor to a biological medicinal product for which patent protection no longer applies. Manufactured by recombinant DNA technology (insertion of gene into the host cell to produce the protein). Comparable with the selected comparator, reference product, in terms of quality, safety and efficacy. The biosimilar product is usually approved for the same indications as the comparator reference product given that they share the same mode of actions.     

药物警戒体系在医疗机构安全用药中的作用

目的:建立和运行药物警戒体系,保障临床安全用药。方法:介绍我院建立的药物警戒体系及开展药物警戒的工作模式。结果:我院的药物警戒体系由药品不良反应监测、药品安全评价、合理用药监测等与临床安全用药相关的各项工作及相关部门整合而成。随着对药物警戒理解的不断加深,逐步形成了从药品购入到临床应用全过程的药物警戒体系和运行模式。结论:药物警戒体系的建立和运行,可发挥保障患者临床用药安全的作用,医疗机构有必要建立临床用药全过程的药物警戒体系。     

Pharmacovigilance in a rare disease: example of the VIGIAPATH program in pulmonary arterial hypertension

Spontaneous reporting is the primary method used in pharmacovigilance (PV) to detect drug safety signal. Specific criteria used in pharmacovigilance to prove accountability of a drug are rarely present in rare disease. The low number of alerts also makes it challenging. The aim of this commentary is to raise awareness among pharmacists on issues and opportunities for pharmacovigilance in rare diseases, taking pulmonary arterial hypertension (PAH) as example, from which a subset of cases are drug-induced. It is demonstrated how a dedicated program named VIGIAPATH created to reinforce pharmacovigilance of drug-induced pulmonary arterial hypertension at a national level, led to increase self-reporting and confirm safety signals. Thanks to a specific program such as VIGIAPATH, pharmacists can play an important role in communication with clinicians, patients and regulatory agencies, facilitating the detection of potential safety signals at an early stage in rare disease.     

Improving the understanding of originator and biosimilar biologics among healthcare providers in Saudi Arabia

The loss of patentability of many originator biologics has led to the rapid introduction of biosimilar agents. The anticipated economic benefit of introducing such agent has been accompanied by vagueness surrounding their biotechnology, approval requirements, positioning in treatment paradigms and potential for adverse events. The Second Symposium on Biologics and Biosimilars “Beyond Clinical Practice” was held on 24th-26th January 2020 aiming at improving the understanding of these new agents in a diverse interactive conference and to guide stakeholders how to introduce biosimilars into clinical practice. The symposium consisted of 4 tracks and 3 workshops. A total of 217 participants attended the meeting. The majority were pharmacists (78.8%) followed by physicians (18.9%) and other healthcare providers (2.3%). The workshops covered the following topics: basics of pharmacoeconomics, pharmacovigilance and patients’ perspective toward biosimilar biologics. While, the 4 main tracks included: Introduction to biosimilars, challenges in clinical practice, regulatory and pharmacoeconomic aspects and Challenges in biosimilar pharmacovigilance.