WHO/KFDA joint workshop on implementing WHO guidelines on evaluating similar biotherapeutic products, Seoul, Republic of Korea 24–26 August, 2010

AbstractIn August 2010, the World Health Organization and the Korea Food & Drug Administration jointly organized the first implementation workshop of WHO guidelines on evaluating similar biotherapeutic products (SBPs) at the global level. The objective of the Workshop was to facilitate implementation of the newly adopted WHO Guidelines into the practice of national regulatory authorities (NRAs). WHO Guidelines were recognized by the workshop participants as a tool for harmonizing regulatory requirements worldwide. By reviewing and practicing several case studies, better understanding and consensus on the principles of clinical trial designs were reached. However, variations in terms of the national requirements for quality, safety and efficacy of these products revealed diversity in the regulatory expectations in different countries and regions. In addition, lack of terminology for the products developed as copy products (so called "me too" products) with a partial comparability to an RBP, led to a great diversity in evaluating as well as naming these products. The workshop participants proposed the following actions: a) NRAs should make efforts to build their capacities for regulation of SBPs; b) WHO should revise WHO Guidelines for assuring the quality of products prepared by recombinant DNA technology (WHO TRS 814) and continue monitoring progress with the implementation of the Guidelines on evaluating SBPs. Publication of the outcome of the Workshop was recognized as another action that WHO should coordinate

AN OVERVIEW OF BIOSIMILARS

Biosimilars are surmounting pharmaceutical market from last three decades and sale increasing progressively. Advances in the biotechnologylead to development and discovery of new biological products to treat various life-threatening diseases. Biosimilars are biological drugs that areproduced after expiry of the patent of approved innovator. This review attempt to highlight the differences between biosimilars and chemical generics,development stages, issues of concern with the use of biosimilars and need of appropriate regulations for their approval. Generic approach is notscientifically useful to manufacture biosimilars. Biosimilars have more structural complexity, multi-layered manufacturing or scale-up process andrisk of immunogenicity; therefore required unique regulatory pathways to introduce them in the market. Safety and efficacy of biosimilar are essentialparameter to increase access in the population. Biosimilars can ensure the cost-effective treatment to invade incurable diseases due to enhancedcompetition in pharma/biotech industries to manufacture it.Keywords: Biosimilars, Biologics, Follow-on biologics, Generic drugs, Subsequent-entry biologics

Impact of successive post-authorisation changes on the dissolution profile of solid oral dosage forms

Tese de mestrado, Regulação e Avaliação do Medicamento e Produtos de Saúde, 2021, Universidade de Lisboa, Faculdade de Farmácia.A equivalência terapêutica de medicamentos genéricos (MG) é a principal premissa para a obtenção da autorização de introdução do medicamento no mercado (AIM). Aquando a apresentação de um pedido de AIM, a prova de equivalência do medicamento genérico em comparação com o seu medicamento de referência (MR) deve ser irrefutavél. A mesma é confirmada através de testes in-vitro, incluindo testes de desempenho, como por exemplo, o perfil de dissolução comparativo. Quando aplicável no âmbito do pedido de AIM, a confirmação da bioequivalência é confirmada através de testes in-vivo. Este tipo de ensaios permite a extrapolação tanto dos dados de eficácia (clínicos) como de segurança (pré-clínicos e farmacovigilância) do MR comparativamente ao produto genérico proposto. Durante o ciclo de vida do produto, o desempenho do mesmo deve ser reavaliado a cada necessidade de alteração de qualquer condição aprovada na AIM, provando que o medicamento genérico continua a ser um equivalente terapêutico ao seu MR. Testes comparativos de desempenho, tais como a dissolução, são úteis na simulação do comportamento do medicamento no corpo humano, tornando possível a comparação da sua absorção com a de um MR. A necessidade de repetir o estudo alargado de bioequivalência (BE) pode ser substancialmente reduzida quando se estabelece uma relação entre dados de desempenho in-vitro e dados de desempenho in-vivo. O controlo destas características é da responsabilidade dos titulares da AIM, e cada autoridade reguladora tem a sua própria regulamentação, o que permite avaliar o nível de impacto da alteração e apresentar as provas adequadas durante a gestão do ciclo de vida do medicamento. Contudo, após sucessivas alterações menores ao medicamento genérico e medicamento de referência, devido a directrizes e regulamentos de testes não padronizados, é possível o surgimento de uma potencial bio-inequivalência do medicamento genérico após a sua aprovação inicial. O presente trabalho pode ser dividido em três objectivos principais. Primeiramente, confirmar a presença de divergências de desempenho entre MR e MG, que potencialmente resultam em bio-inequivalencia, após mudanças pós-AIM sucessivas durante todo o ciclo de vida do medicamento. Simultaneamente, identificar lacunas no panorama regulamentar das autoridades reguladoras ANVISA (Agência Nacional de Vigilância Sanitária) do Brasil, a EMA (Agência Europeia de Medicamentos) da Europa e a FDA (Food and Drug Administration) dos Estados Unidos da América, que potenciam possíveis divergências de desempenho e, portanto, bio-inequivalência. O último objectivo deste trabalho é sugerir e analisar possíveis alterações de regulação que atenuem este risco. Para este efeito, foi realizada uma pesquisa bibliográfica aprofundada, analisando regulamentação local, directrizes, documentação e publicações oficiais, bases de dados públicas das autoridades de saúde com AIM aprovadas e teses académicas, utilizando termos, definições e linguagem adaptados para os efeitos desta pesquisa. Os principais instrumentos de pesquisa aplicados às publicações indexadas foram PubMed, Science.gov, Google books, Science Direct e Research Gate. Esta pesquisa permitiu a comparação dos critérios de aceitação de BE, perfil comparativo de dissolução (PCD), requisitos para o desenvolvimento do método de dissolução juntamente com a regulamentação da alteração dos termos do AIM no que respeita à sua classificação, provas a apresentar e forma de apresentação para a implementação de alterações. Em termos de critérios de aceitação do perfil comparativo de dissolução e bioequivalência, não foram observadas diferenças entre as directrizes das autoridades reguladoras estudadas. Entre as principais semelhanças nos diferentes regulamentos para alterações aos termos da AIM estão: a necessidade de realizar o PCD entre a condição anterior aprovada e a condição proposta; e a exigência de factor de semelhança, f2, com um valor superior a 50. Estas conclusões estão de acordo com a hipótese proposta para este trabalho, isto é, após sucessivas pequenas alterações ao medicamento genérico e ao MR, para as quais apenas foram apresentadas provas comparativas in-vitro versus a condição previamente aprovada, o perfil de dissolução pode se tornar distinto do perfil do seu MR, o que pode levar à bio-inequivalência do medicamento genérico após a sua aprovação inicial. Uma simulação de PCD foi proposta, considerando um aumento de 10 vezes no tamanho do lote do medicamento genérico em comparação com o bio-lote, concomitantemente com uma pequena alteração no processo de produção e uma mudança no equipamento. Neste cálculo, foram consideradas mesma classe e subclasse de um produto com principios activos de baixa solubilidade (classe II ou IV) do sistema de classificação biofarmacêutico, para o qual a dissolução é sempre um factor crítico. Este conjunto de alterações foi classificado como menor e moderado pelas autoridades de saúde avaliadas neste trabalho. Considerando que o critério de semelhança entre o PCD proposto e o aprovado se restringia ao valor f2 superior a 50, através da simulação de uma única alteração, foi possível demonstrar que, quando comparado com a referência, a curva de dissolução proposta divergia da curva da mesma. Numa tentativa de mitigação dos riscos encontrados, várias soluções foram estudadas e propostas, desde a simples realização do estudo contra o medicamento de referência no seu estado actual (assumindo todas as alterações) para qualquer tipo de alteração, até um programa de monitorização específico para avaliar uma possível bio-inequivalência dos medicamentos do mercado. Atendendo à premissa desta obra de avaliar os requisitos regulamentares para a hipótese levantada de perda de bioequivalência, foi considerado confirmado que existe uma lacuna regulamentar para a prova de comparação necessária para alterações menores e moderadas na AIM de uma forma farmacêutica sólida genérica de libertação imediata. Foi possível concluir que, tendo em consideração que a isenção da necessidade de bioequivalência utiliza principalmente o critério f2, genéricos das classes II e IV BCS, podem ser introduzidos no mercado com perfis de dissolução que diferem dos do seu medicamento de referência. Foi possível constatar, também, que os produtos de libertação imediata são mais vulneráveis do que os produtos de libertação modificada, tendo em vista um menor número de condicionantes para a classificação da mudança como menores e moderadas.Therapeutic equivalence is the main premise for obtaining Marketing Authorization (MA) for generic drugs. Proof of equivalence is presented in the submission of an MA application. Pharmaceutical equivalence is confirmed through in vitro testing, including performance tests such as comparative dissolution profile. When applicable in the scope of the MA application, bioequivalence confirmation is asserted by in vivo testing. This testing supports the extrapolation of both efficacy (clinical) and safety (pre-clinical and pharmacovigilance) data of the reference product (RP) to the proposed generic product. During its life cycle, product performance must be re-evaluated at every need to change any condition approved in the MA, proving that the generic product continues to be a therapeutic equivalent to its RP. Comparative performance tests, such as dissolution, are useful in simulating the behaviour of the drug in the human body, making it possible to compare its absorption against a RP. The need to repeat the extended bioequivalence study (BE) can be substantially reduced when a relationship between in-vitro performance data and in-vivo performance data is established. The monitoring of these characteristics is responsibility of the MA holders, and each regulatory agency has its own regulation, which allows the level of impact of the change to be assessed and the appropriate evidence to be submitted during the life cycle management of the drug. However, after successive minor changes to the generic drug and RP, due to unstandardized guidelines and regulations of testing, a potential bio-inequivalence of the generic drug after its initial approval may arise. The present work is axed in three main goals. The first to attest the presence of performance divergences between RP and generic solid oral products, after successive post-authorisation changes throughout their lifecycle, possibly resulting in bio-inequivalence. This while identifying gaps in the regulatory landscape of the regulatory authorities ANVISA (Agência Nacional de Vigilância Sanitária) from Brazil, the EMA (European Medicines Agency) from Europe and the FDA (Food and Drug Administration) from the United States of America that potentiate possible performance divergences and thus, bio-inequivalence. The last goal of this body of work is to suggest and analyse possible regulation changes that mitigate this risk. A comprehensive literature search was performed by analysing local regulations, guidelines, official documentation and publications, health authorities’ public online databases of approved MAs, academic thesis, using adapted terms, definitions, and language for the research purpose. Main research tools applied to indexed publications were PubMed, Science.gov, Google books, Science Direct and Research Gate. This allowed for the comparison of the acceptance criteria of BE, comparative dissolution profile (CDP), requirements for development of the dissolution method along with the regulation of change to the terms of the MA regarding its classification, evidence to be presented and form of submission for the implementation of changes. In terms of acceptance criteria for comparative dissolution profile and bioequivalence, no differences between regulatory authorities’ guidelines were observed. Among the main similarities in the different regulations for changes to the terms of the MA researched are: the need to perform the CDP between the previous approved condition and the proposed condition; and requiring similarity factor, f2, with a value greater than 50. These findings are in line with the proposed hypothesis of this work, that is, after successive minor changes to the generic drug and RP, for which only in-vitro comparative evidence has been presented against the previously approved condition, this dissolution profile may no longer be similar to its reference drug, which may lead to bio-inequivalence of the generic drug after its initial approval. A simulation of CDP was performed considering a 10-fold increase in the batch size of the generic drug compared to the bio-batch, concomitant with a minor change in the production process and a change in equipment. Same class and subclass of a product with low solubility assets (class II or IV) of the biopharmaceutical classification system, for which dissolution is always a critical factor was assumed. This set of changes was rated as minor and moderate by the health authorities subject in this work. Considering that the similarity criterion between proposed and approved CDP was restricted to f2 value greater than 50, by simulating a single change, it was possible to demonstrate that, when compared to the reference, the proposed dissolution curve diverged from the curve of the reference drug. To mitigate the risks found, a number of solutions were studied and proposed, ranging from simply conducting the study against the RP in its current condition (assuming all changes) for all of the changes categories, to a specific monitoring program for possible bio-inequivalence. As the aim of this research was to assess the regulatory requirements for the hypothesis raised, it was considered confirmed that there is a regulatory gap for the evidence of comparison required for minor and moderate changes in the MA acceptance of an immediate release generic solid dosage form. It was possible to conclude that, taking into consideration that the exemption of the need for bioequivalence uses mainly the f2 criterion, generics of classes II and IV BCS, may be available the market with dissolution profiles that differ from those of their reference product during its lifecycle. Immediate release products were found to be more vulnerable than modified release products, given fewer constraints on the classification of change as minor and moderate

Implementing quality by design for biotech products: are regulators on track?

Quality by design (QbD) is an innovative approach to drug development that has started to be implemented into the regulatory framework, but currently mainly for chemical drugs. The recent marketing authorization of the first monoclonal antibody developed using extensive QbD concepts in the European Union paves the way for future further regulatory approvals of complex products employing this cutting-edge technological concept. In this paper, we report and comment on insights and lessons learnt from the non-public discussions in the European Medicines Agency's Biologicals Working Party and Committee for Medicinal Products for Human Use on the key issues during evaluation related to the implementation of an extensive QbD approach for biotechnology-derived medicinal products. Sharing these insights could prove useful for future developments in QbD for biotech products in general and monoclonal antibodies in particular

Scientific and Regulatory Perspective on Monoclonal Antibody Biosimilars

Similar biotherapeutic products (SBPs), also called biosimilars, exhibit similar biological and clinical properties to authorized reference products. Biosimilars, including small molecules like erythropoietin and complex macromolecules like monoclonal antibodies (mAbs), have been used extensively in disease treatment. Monoclonal antibody biosimilars have gradually become a dominant development in the global pharmaceutical industry since their patents or data protection have been expired or nearing expiration. Since the mAb biosimilars are complex biological macromolecules with various post-translation modifications, it is important to evaluate whether these tiny differences significantly affect the quality. From a regulatory perspective, the comparability study needs to be performed to demonstrate that the quality, safety, and efficacy are similar to the biological reference. Based on these comprehensive comparative results, the indicated extrapolation might be acceptable. Post-market surveillance is also required because of unexpected biological variation caused by slightly different manufacturing processes. This chapter presents the scientific and regulatory considerations for monoclonal antibody biosimilar products for manufactures and for the regulatory authorities to administrate wisely and comprehensively

Biosimilars

Introduced in the 1980s, biologic medications have since become important tools in modern medicine. However, biologics are expensive, greatly affecting the healthcare budgets of both underdeveloped and developed countries. Fortunately, biosimilars, which are highly similar, reverse-engineered versions of existing biological medicines and their active ingredients, are now available as more affordable options for patients treated with biologics. This book discusses biosimilars with chapters on clinical trials, regulation, pharmacovigilance, and the interchangeability of biosimilars with biologics. It also addresses future trends in the biosimilars market

Unofficial Legislative History of the Biologics Price Competition and Innovation Act 2009, An

On March 23, 2010, President Obama signed into law the Biologics Price Competition and Innovation Act of 2009 (BPCIA) which created a regulatory pathway for, and scheme for litigation of patent issues relating to, “biosimilar” biological products. This article discusses the history of the BPCIA and explains its provisions. Section I provides background and a history of the regulation of drugs and biological products in the United States. Section II describes the growing interest in biosimilar approval from the early 2000s through September 2006, when the legislative debate began in earnest. Section III describes the legislative and stakeholder process from September 2006 to enactment, and section IV discusses the BPCIA in some detail. These sections show, and the conclusion in section V explains, that the regulatory and intellectual property issues addressed in the final 2010 legislation were debated, discussed, explored, and vetted by stakeholders — including the Food and Drug Administration (FDA), the Federal Trade Commission (FTC), Democrats and Republicans in both House and Senate, the United States Pharmacopoeia, the generic industry, the biosimilar industry, trade associations, professional organizations like the Drug Information Association (DIA), and European regulators — for (in some cases) as many as ten years. Moreover, as these sections also show, like the Hatch-Waxman amendments of 1984, the final legislation represents a true compromise of competing interests

A Techno-Economic Framework for Assessing Manufacturing Process Changes in the Biopharmaceutical Industry

Industry pressures encourage and sometimes ‘force’ biopharmaceutical companies to implement process changes throughout a product’s lifecycle, so as to enhance yields, purity, robustness and cost-effectiveness. However, making a change involves technical, regulatory, and clinical risks. Possible changes to a product’s quality mean that all changes must be backed-up either with non-clinical bioequivalence studies or with lengthy and costly clinical trials and approved by regulatory authorities. These hurdles combined with the upfront costs can results in a tendency to avoid changes, whereas they may represent economic opportunity if evaluated holistically. This thesis explores the possibility of creating a systematic evaluation framework that captures the technical and regulatory activities involved in process changes to rapidly gauge the potential cost and risk implications. Fundamentaldrivers and consequencesof making bioprocesses changes were benchmarked in a survey to help create the framework model. Key technical activities were captured, namely development, manufacturing, retrofitting and validation at all stages of development. Impacts of changes were linked to regulatory activities needed to assess comparability. Resulting uncertainties such as the likelihood of repeating clinical trials, market losses, delays to market from retrofit, revalidation, or regulatory approval disruptions, and the costs involved in proving product equivalence were captured. The framework was translated into Microsoft Excel with macros for Monte Carlo simulations to account for the uncertainties. Minor and major change scenarios based on the purification of polyclonal IVIG by means of a blood-plasma fractionation process were used to demonstrate the usefulness of the proposed framework. The impact of ‘forced’ and optional changes were compared at different stages of development. Changes made during late-phase development resulted in market share losses and delays that outweighed any yield improvement modifications. The model predicted that it would be more profitable to make process modifications either during early phase development or post-product approval assuming stockpiling of approved product was feasible. The feasibility of purifying a new product, alpha-1 antitrypsin (AAT) from a waste fraction, Fraction IV precipitate, was another process change scenario explored using scale-down studies. Experimental trials of the preliminary filtration and anion exchange purification steps were carried out, yielding low recoveries of AAT. Ciphergen®’s SELDI-TOF-MS ProteinChip technology was used to investigate the value of using a high throughput optimisation method to improve the isolation of AAT. Quantitative analysis of the protein samples using the Ciphergen® was compared to well-established protein concentration determination methods, eliminating variability in samples and differences in MS intensity by normalising the data. The work in this thesis has demonstrated the usefulness of a combined business, technical and risk approach for evaluating the risks and benefits of implementing process changes

The implications of regulatory framework for topical semisolid drug products: From critical quality and performance attributes towards establishing bioequivalence

Due to complex interdependent relationships affecting their microstructure, topical semisolid drug formulations face unique obstacles to the development of generics compared to other drug products. Traditionally, establishing bioequivalence is based on comparative clinical trials, which are expensive and often associated with high degrees of variability and low sensitivity in detecting formulation differences. To address this issue, leading regulatory agencies have aimed to advance guidelines relevant to topical generics, ultimately accepting different non-clinical, in vitro/in vivo surrogate methods for topical bioequivalence assessment. Unfortunately, according to both industry and academia stakeholders, these efforts are far from flawless, and often upsurge the potential for result variability and a number of other failure modes. This paper offers a comprehensive review of the literature focused on amending regulatory positions concerning the demonstration of (i) extended pharmaceutical equivalence and (ii) equivalence with respect to the efficacy of topical semisolids. The proposed corrective measures are disclosed and critically discussed, as they span from mere demands to widen the acceptance range (e.g., from 10% to 20%/25% for rheology and in vitro release parameters highly prone to batch-to-batch variability) or reassess the optimal number of samples required to reach the desired statistical power, but also rely on specific data modeling or novel statistical approaches