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.     

Are biosimilars patentable?

Introduction: This paper explores whether, and under what circumstances, a biosimilar approved in the United States under the Biologics Price Competition and Innovation Act (hereafter ‘BPCIA’) can be patented. The possibility that a biosimilar product could have meaningful patent protection arises from specific requirements for biosimilarity under the BPCIA, which account for the fact that manufacturing processes of biologics are inherently imprecise. The requirements for biosimilar approval may provide sufficient leeway to a biosimilar applicant to patent structural or formulation differences that provide non-clinical but business-relevant advantages over the reference molecule, such as improved shelf-life or ease of manufacture, without compromising clinical biosimilarity.

Areas covered: Examination of the BPCIA and related Acts, Food and Drug Administration (FDA) guidance papers, case law, patent database searching, and relevant scholarly articles.

Expert opinion: Legislative and regulatory requirements for the approval of a biosimilar under the BPCIA are focused on clinical results and allow a degree of leeway for differences to exist between a biosimilar’s structure and non-clinical components and those of the biosimilar’s reference molecule. This leeway can be exploited to provide the biosimilar with potentially patentable business-relevant advantages over its reference product while maintaining clinical biosimilarity to the reference product.     

Analytical Similarity Assessment in Biosimilar Studies

For assessment of biosimilarity, the US Food and Drug Administration (FDA) recommends a stepwise approach for obtaining the totality-of-the-evidence for demonstrating biosimilarity between a proposed biosimilar product and an innovative (reference) biological product. The stepwise approach starts with analytical studies for functional and structural characterization at various stages of manufacturing process of the proposed biosimilar product. Analytical similarity assessment involves identification of critical quality attributes (CQAs) that are relevant to clinical outcomes. FDA proposes first classifying the identified CQAs into three tiers according to their criticality or risking ranking relevant to clinical outcomes and then performing equivalence test (for CQAs in Tier 1), quality range approach (for CQAs in Tier 2), and raw data or graphical presentation (for CQAs in Tier 3) for obtaining totality-of-the-evidence for demonstrating biosimilarity between the proposed biosimilar product with the reference product. In practice, some debatable issues are evitably raised due to this complicated process of analytical similarity assessment. In this article, these debatable are described and discussed.     

Improving the power to establish clinical similarity in a Phase 3 efficacy trial by incorporating prior evidence of analytical and pharmacokinetic similarity

ABSTRACT

To improve patients’ access to safe and effective biological medicines, abbreviated licensure pathways for biosimilar and interchangeable biological products have been established in the US, Europe, and other countries around the world. The US Food and Drug Administration and European Medicines Agency have published various guidance documents on the development and approval of biosimilars, which recommend a “totality-of-the-evidence” approach with a stepwise process to demonstrate biosimilarity. The approach relies on comprehensive comparability studies ranging from analytical and nonclinical studies to clinical pharmacokinetic/pharmacodynamic (PK/PD) and efficacy studies. A clinical efficacy study may be necessary to address residual uncertainty about the biosimilarity of the proposed product to the reference product and support a demonstration that there are no clinically meaningful differences. In this article, we propose a statistical strategy that takes into account the similarity evidence from analytical assessments and PK studies in the design and analysis of the clinical efficacy study in order to address residual uncertainty and enhance statistical power and precision. We assume that if the proposed biosimilar product and the reference product are shown to be highly similar with respect to the analytical and PK parameters, then they should also be similar with respect to the efficacy parameters. We show that the proposed methods provide correct control of the type I error and improve the power and precision of the efficacy study upon the standard analysis that disregards the prior evidence. We confirm and illustrate the theoretical results through simulation studies based on the biosimilars development experience of many different products.     

Recommendations and requirements for the design of bioanalytical testing used in comparability studies for biosimilar drug development

With the imminent expiry of patents on a number of biological products on the market, the development of biosimilars (or 'follow-on biologics') creates an increasing opportunity in the biotechnology industry. Although general guidelines on the quality and safety of biological products also apply to biosimilars, there is a need to address specific requirements for developing biosimilar drugs. Since it is critical to show comparability of the biosimilar products to their reference (or innovator) products, developing the appropriate bioanalytical methods to support such preclinical and clinical comparability studies is of great importance. The present work recommends the requirements for the development and validation for both pharmacokinetic and immunogenicity assays to support the biosimilar drug development.     

Risk-Based Comparability Assessment for Monoclonal Antibodies During Drug Development: A Clinical Pharmacology Perspective

Due to complexities in the structure, function, and manufacturing process of antibody-based therapeutic proteins, comparability assessment for supporting manufacturing changes can sometimes be a challenging task. Regulatory guidance recommends a hierarchical risk-based approach, starting with Chemistry, Manufacturing, and Controls (CMC) analytical characterizations, followed by non-clinical and/or clinical studies to ensure that any potential changes in quality attributes have no adverse impact on efficacy and safety of the product. This review focuses on the changes in quality attributes which may potentially affect the pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of a monoclonal antibody (mAb) product, and provides general guidelines in designing non-clinical and clinical PK/PD studies to help support comparability assessments. A decision tree for comparability assessment is proposed depending on the nature of the changes in quality attributes, the potential impact of such changes, and the timing of the manufacturing change relative to the development process. Ideally, the optimization of manufacturing process should take place in the early stage of drug development (i.e., preclinical to phase 2a) as more stringent comparability criteria would have to be met if manufacturing changes occur in the late stage of drug development (i.e., phase 2b and after), and consequently, major changes in manufacturing process should be avoided during confirmatory phase 3 studies and post-approval of drug products.     

Adjustment for unbalanced sample size for analytical biosimilar equivalence assessment

ABSTRACT

Large sample size imbalance is not uncommon in the biosimilar development. At the beginning of a product development, sample sizes of a biosimilar and a reference product may be limited. Thus, a sample size calculation may not be feasible. During the development stage, more batches of reference products may be added at a later stage to have a more reliable estimate of the reference variability. On the other hand, we also need a sufficient number of biosimilar batches in order to have a better understanding of the product. Those challenges lead to a potential sample size imbalance. In this paper, we show that large sample size imbalance may increase the power of the equivalence test in an unfavorable way, giving higher power for less similar products when the sample size of biosimilar is much smaller than that of the reference product. Thus, it is necessary to make some sample size imbalance adjustments to motivate sufficient sample size for biosimilar as well. This paper discusses two adjustment methods for the equivalence test in analytical biosimilarity studies. Please keep in mind that sufficient sample sizes for both biosimilar and reference products (if feasible) are desired during the planning stage.     

Sample size requirement in analytical studies for similarity assessment

ABSTRACT

For the assessment of biosimilar products, the FDA recommends a stepwise approach for obtaining the totality-of-the-evidence for assessing biosimilarity between a proposed biosimilar product and its corresponding innovative biologic product. The stepwise approach starts with analytical studies for assessing similarity in critical quality attributes (CQAs), which are relevant to clinical outcomes at various stages of the manufacturing process. For CQAs that are the most relevant to clinical outcomes, the FDA requires an equivalence test be performed for similarity assessment based on an equivalence acceptance criterion (EAC) that is obtained using a single test value of some selected reference lots. In practice, we often have extremely imbalanced numbers of reference and test lots available for the establishment of EAC. In this case, to assist the sponsors, the FDA proposed an idea for determining the number of reference lots and the number of test lots required in order not to have imbalanced sample sizes when establishing EAC for the equivalence test based on extensive simulation studies. Along this line, this article not only provides statistical justification of Dong, Tsong, and Weng’s proposal, but also proposes an alternative method for sample size requirement for the Tier 1 equivalence test.     

Nanoparticle iron medicinal products – Requirements for approval of intended copies of non-biological complex drugs (NBCD) and the importance of clinical comparative studies

Currently, most countries apply the standard generic approach for the approval of intended copies of originator nanoparticle iron medicinal products, requiring only demonstration of bioequivalence to a reference medicinal product by bioavailability studies. However, growing evidence suggests that this regulatory approach is not appropriate. Clinical and non-clinical studies have shown that intended copy preparations of nanoparticle iron medicinal products can differ substantially from the originator product in their efficacy and potentially in their safety profile. An adapted regulatory pathway (separate from the standard generic approach) with defined data requirements is needed for approval of intended copies of iron medicinal products. Here, we discuss the difficulties involved in assessing therapeutic equivalence of nanoparticle iron medicinal products and suggest key concepts of a regulatory approach. Standardized non-clinical comparative studies are necessary but, as demonstrated in the reported clinical data, they may not be sufficient to demonstrate a comparable efficacy and safety profile. Validated, prospective, comparative clinical studies might be needed, in addition to non-clinical studies, in order to enable appropriate assessment of therapeutic equivalence. Furthermore, including brand names in addition to the International Non-proprietary Names (INNs) in safety reports could enable effective safety monitoring of intended copies and originator products.     

Role of Modeling and Simulation in the Development of Novel and Biosimilar Therapeutic Proteins

Modeling and simulation (M&S) is an important enabler of knowledge integration in novel biological product development programs. Given the volume of data generated from clinical trials and the complexity of pharmacokinetic (PK) and pharmacodynamic (PD) properties for reference products, extending the use of M&S to biosimilar development is logical. Assessing PK and PD similarity is normally a critical part of demonstrating biosimilarity to a reference product. Thoughtful considerations are necessary in study design to minimize the PK and PD variability, thereby increasing the sensitivity for detecting potential differences between products. In addition, the sensitivity of PD biomarkers depends partly on their relevance to the mechanism(s) of action and the dynamic range of PD response(s), including the impact of certain structural differences on PD in the relevant population. As such, opportunities exist for leveraging the available M&S knowledgebase to maximize the efficiency in the design and interpretation of PK and PD similarity studies. This article describes M&S applications which have contributed to and can continue to enhance biosimilar development programs.     

Rational Selection,Criticality Assessment,and Tiering of Quality Attributes and Test Methods for Analytical Similarity Evaluation of Biosimilars

Leading regulatory agencies recommend biosimilar assessment to proceed in a stepwise fashion, starting with a detailed analytical comparison of the structural and functional properties of the proposed biosimilar and reference product. The degree of analytical similarity determines the degree of residual uncertainty that must be addressed through downstream in vivo studies. Substantive evidence of similarity from comprehensive analytical testing may justify a targeted clinical development plan, and thus enable a shorter path to licensing. The importance of a careful design of the analytical similarity study program therefore should not be underestimated. Designing a state-of-the-art analytical similarity study meeting current regulatory requirements in regions such as the USA and EU requires a methodical approach, consisting of specific steps that far precede the work on the actual analytical study protocol. This white paper discusses scientific and methodological considerations on the process of attribute and test method selection, criticality assessment, and subsequent assignment of analytical measures to US FDA’s three tiers of analytical similarity assessment. Case examples of selection of critical quality attributes and analytical methods for similarity exercises are provided to illustrate the practical implementation of the principles discussed.     

Biosimilar: what it is not

A biosimilar is a high quality biological medicine shown to be in essence the same as an original product. The European Medicines Agency (EMA) paved the way in the regulatory arena by creating a safeguarding framework for the development of biosimilars. Biosimilar is thus a regulatory term that alludes to the evidence-based studies required to demonstrate such very high similarity. They are therefore not innovative products but the pathway laid down by the EMA for their approval represented a new paradigm. This has brought some confusion and has cast doubts among healthcare professionals about the scientific evidence behind their authorization. Many papers have been published to clarify the concept, and to reassure those professionals, but misconceptions frequently still arise. Unfortunately, this prevents biosimilars from deploying their full therapeutic added value. This paper is intended to approach those misconceptions from a new angle, by explaining what a biosimilar is not…and why. A biosimilar is neither a generic, nor an original product. It is not a biobetter or a ‘stand-alone’. Therefore, it should not be managed as such therapeutically, commercially or from a healthcare policy viewpoint. The EMA''s criteria were acknowledged by other agencies, but a significant regulatory gap with a vast majority of regulatory bodies still remains. This leaves room for the so-called non-original biologics (NOB), i.e. non-biosimilar biologics, to be launched in many regions. Raising awareness of what a biosimilar is and what it is not, will generate trust in biosimilars among healthcare professionals and will ultimately benefit patients     

Non-clinical safety studies on biosimilar recombinant human erythropoietin

Recombinant human erythropoietin (rhEPO) is widely used for the treatment of patients with anaemia and its loss of patent protection has stimulated the development of cheaper biosimilar products. However, the quality and comparability of rhEPO products recently marketed in several developing countries is questionable. Paying attention to quality in its isolation, purification and analytical characterization, it has been possible to produce a biosimilar rhEPO that is comparable with the originator product. Non-clinical safety testing was initially carried out in the absence of a regulatory framework and contributed to the receipt of marketing approval for biosimilar rhEPO in Eastern Europe. Subsequently, this non-clinical testing was extended to take into account the recent guidelines for similar biological medicinal products published by the European regulatory authorities, which were markedly influenced by the intervening occurrence of pure red cell aplasia in patients taking what proved to be an impure rhEPO product. This Mini Review discusses the challenges faced, approaches taken and lessons learned in developing a biosimilar rhEPO product, both before and after the publication of the regulatory guidelines.     

Managing uncertainty: A perspective on risk pertaining to product quality attributes as they bear on immunogenicity of therapeutic proteins

The critical question addressed in this paper regards how industry and regulatory agencies should manage the risk of adverse events to patients posed by product quality attributes for which a preponderance of evidence from clinical and/or non-clinical studies supports it as a risk, but for which the probability of clinical adverse events arising from the attribute is uncertain. We here provide our perspective on the principles that can be applied to determine the need for and the manner in which to control quality attributes when their impact on safety and/or efficacy is suspected, but uncertain. As an example, we use the risk of immune responses to protein therapeutics posed by sub-visible protein particulates in therapeutic proteins. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:3560–3567, 2012     

Understanding Pharmaceutical Quality by Design

This review further clarifies the concept of pharmaceutical quality by design (QbD) and describes its objectives. QbD elements include the following: (1) a quality target product profile (QTPP) that identifies the critical quality attributes (CQAs) of the drug product; (2) product design and understanding including identification of critical material attributes (CMAs); (3) process design and understanding including identification of critical process parameters (CPPs), linking CMAs and CPPs to CQAs; (4) a control strategy that includes specifications for the drug substance(s), excipient(s), and drug product as well as controls for each step of the manufacturing process; and (5) process capability and continual improvement. QbD tools and studies include prior knowledge, risk assessment, mechanistic models, design of experiments (DoE) and data analysis, and process analytical technology (PAT). As the pharmaceutical industry moves toward the implementation of pharmaceutical QbD, a common terminology, understanding of concepts and expectations are necessary. This understanding will facilitate better communication between those involved in risk-based drug development and drug application review.     

The Use of Pharmacometrics to Optimize Biosimilar Development

Pharmacometric approaches can assist in biosimilar development by leveraging quantitative knowledge of the originator product characteristics such as dose–exposure and exposure–response information to support a targeted approach to clinical studies. The degree to which these approaches can be applied relies on the level of information known about the originator and information that supports application of the originator model to the biosimilar. A model-based approach testing the hypothesis that the biosimilar PK and/or PK/PD profile is similar to the originator in the target patient population is aligned with the central comparability exercise required for the biosimilar approval. This Commentary details the key opportunities in study design and study analysis where pharmacometrics approaches can aid biosimilar development.     

Structure-Function Relationships for Recombinant Erythropoietins: A Case Study From a Proposed Manufacturing Change With Implications for Erythropoietin Biosimilar Study Designs

Comparability studies used to assess a proposed manufacturing change for a biological product include sensitive analytical studies to confirm there are no significant differences in structural or functional attributes that may contribute to clinically meaningful changes in efficacy or safety. When a proposed change is relatively complex or when clinically relevant differences between the product before and after the change cannot be ruled out based on analytical studies, nonclinical and clinical bridging studies are generally required to confirm overall comparability. In this study, we report findings from a comparability assessment of epoetin alfa before and after a proposed manufacturing process change. Although differences in glycosylation attributes were observed, these were initially believed to be irrelevant to the product's pharmacology. This assumption was initially supported via nonclinical and clinical pharmacology studies, but a clinically meaningful difference in potency was ultimately observed in a phase 3 clinical study conducted in a sensitive patient population using a sensitive study design. These results indicate that the nonclinical assessments of structure-function relationships were insufficiently sensitive to identify clinically relevant differences resulting from differences in the glycosylation profile. This case study highlights important findings that may be relevant in the development of biosimilar epoetin alfa products.     

Regulatory considerations for generic or biosimilar low molecular weight heparins

The aim of the present paper is to address the legal aspects, technical requirements and possible conditions of use associated to low molecular weight heparin generics and biosimilars that are arriving to the market in United States and the European Union, respectively. To this end the concept of "similar biological medicinal product" that was coined in 2003 by the pharmaceutical legislation of the European Union is compared to the concept of generic in the United States and the concept of generic in the European Union. This different legal basis determines directly the technical requirements to obtain a marketing authorisation. Therefore, the chemical/biological, non-clinical and clinical requirements to demonstrate therapeutic equivalence are different in these two Regulatory Authorities, FDA and EMA. Consequently, the possible conditions of use are different. In the United States the products approved as generics by the FDA are considered interchangeable to the Reference Listed Drug. In contrast, the EMA legislation only deals with the approvability or prescribability of the medicines and it is a national / regional decision of the member States to consider these biosimilar products as interchangeable or not.