Gustavo Grampp

Comparability and biosimilarity: considerations for the healthcare provider

Abstract 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.

Drift, Evolution, and Divergence in Biologics and Biosimilars Manufacturing

Biological medicines (biologics) are produced in living cells and purified in complex, multi-step processes. Compared with chemically synthesized small-molecule drugs, biologics are more sensitive to changes in manufacturing conditions. Process and product consistency should be founded on rigorous design and control of manufacturing processes, but consistency is ultimately ensured through robust quality systems. Even a minor change in any component of a quality system could lead to product drift, evolution, and divergence, which may impact the quality, safety, efficacy, and/or interchangeability of biologics. Unintended or unexplained deviations in manufacturing processes can lead to excursions in product attributes (i.e., drift). Well-managed quality systems can help detect and mitigate drift. Occasionally, quality attributes could shift outside of established acceptable ranges as the result of a known manufacturing change (defined here as evolution). Such changes should be studied extensively for effects on product safety and efficacy. With the advent of biosimilars, similar biologics will be produced by multiple manufacturers with different quality systems. Different patterns of product drift and evolution could contribute, over time, to clinically meaningful differences among biologics, including among originator products across regions and among originator products and biosimilar products, a process defined here as divergence. Manufacturers and policymakers can minimize the potential impact of divergence by establishing robust pharmacovigilance systems; requiring distinguishable names for all biologics, including both originator products and biosimilars; adhering to high standards for designations of interchangeability; and ensuring that patient medical records accurately reflect the specific biologic dispensed, especially if the biologic could be sourced from multiple manufacturers.

Biosimilars 2.0: guiding principles for a global "patients first" standard.

In the European Union, biosimilar products have been approved since 2006 under an abbreviated pathway that leverages their similarity to an existing “reference” biological product. The products approved to date are based on recombinant versions of endogenous proteins with well-understood structures and pharmacology, but complicated safety and immunogenicity profiles. The period during the 2000s that included the first reviews, approvals, sale and use of biosimilars, is referred to herein as “Biosimilars 1.0.” Over the next several years, a new and advanced tranche of biosimilars will be developed for complex reference products, including medicines used in the treatment of cancer and autoimmune diseases. A global market for biosimilars is developing, and this may well foreshadow the beginning of the second era of product development. This Biosimilars 2.0 period will likely be characterized by the development of complex products, global harmonization of standards, and the increasing demand for long-term monitoring of pharmaceuticals. The products developed in this period should exhibit high levels of fidelity to the reference products and should be rigorously evaluated in analytical, non-clinical and clinical comparisons. Additionally, Biosimilars 2.0 manufacturers should strive for transparency in their labels and take proactive strides to be accountable to providers and patients for the quality of their products. An important opportunity now exists for the healthcare community, industry and regulators to work in partnership to outline the appropriate standards for these products to facilitate increased access while meeting patients’ needs.

Active and passive surveillance of enoxaparin generics: a case study relevant to biosimilars

Objective: This retrospective analysis assessed the capability of active and passive safety surveillance systems to track product-specific safety events in the USA for branded and generic enoxaparin, a complex injectable subject to immune-related and other adverse events (AEs). Methods: Analysis of heparin-induced thrombocytopenia (HIT) incidence was performed on benefit claims for commercial and Medicare supplemental-insured individuals newly treated with enoxaparin under pharmacy benefit (1 January 2009 – 30 June 2012). Additionally, spontaneous reports from the FDA AE Reporting System were reviewed to identify incidence and attribution of enoxaparin-related reports to specific manufacturers. Results: Specific, dispensed products were identifiable from National Drug Codes only in pharmacy-benefit databases, permitting sensitive comparison of HIT incidence in nearly a third of patients treated with brand or generic enoxaparin. After originator medicine’s loss of exclusivity, only 5% of spontaneous reports were processed by generic manufacturers; reports attributable to specific generics were approximately ninefold lower than expected based on market share. Conclusions: Claims data were useful for active surveillance of enoxaparin generics dispensed under pharmacy benefits but not for products administered under medical benefits. These findings suggest that the current spontaneous reporting system will not distinguish product-specific safety signals for products distributed by multiple manufacturers, including biosimilars.

Managing Unexpected Events in the Manufacturing of Biologic Medicines

The manufacturing of biologic medicines (biologics) requires robust process and facility design, rigorous regulatory compliance, and a well-trained workforce. Because of the complex attributes of biologics and their sensitivity to production and handling conditions, manufacturing of these medicines also requires a high-reliability manufacturing organization. As required by regulators, such an organization must monitor the state-of-control for the manufacturing process. A high-reliability organization also invests in an experienced and fully engaged technical support staff and fosters a management culture that rewards in-depth analysis of unexpected results, robust risk assessments, and timely and effective implementation of mitigation measures. Such a combination of infrastructure, technology, human capital, management, and a science-based operations culture does not occur without a strong organizational and financial commitment. These attributes of a high-reliability biologics manufacturer are difficult to achieve and may be differentiating factors as the supply of biologics diversifies in future years.

Identifying and Quantifying the Accuracy of Product Name Attribution of US-Sourced Adverse Event Reports in MedWatch of Somatropins and Insulins

Background: As of 2014, the US FDA was considering policy options to promote accurate attribution of adverse events for biosimilars. In order to assess the identification and traceability of biologics from multiple sources, Tufts University’s Center for the Study of Drug Development conducted a study reviewing the current FDA Adverse Event Reporting System (FAERS) for reports related to insulin and growth hormone products. Methods: For this study, all primary suspect reports that were received by FAERS for human growth hormone (hGH) and human insulin between the fourth quarter of 2005 and the third quarter of 2013 were extracted and analyzed. Results: The rates of “accurate” brand (ie, identifiable) drug names were generally high, with a higher incidence for hGH drugs than for insulin drugs (92% of hGH primary suspect reports vs 84% of insulin primary suspect reports). Lot number completion rates were generally low, with a higher incidence for insulin drugs than for hGH drugs (37% of insulin primary suspect reports vs 13% of hGH primary suspect reports). There were 13.5% of insulin reports that could not be linked to manufacturers, while 7.5% of hGH reports could not be linked to a manufacturer. Conclusions: The completion and accuracy rates of FAERS data on biologics observed in this study are consistent with those observed in earlier studies and suggest that traceability in adverse event reports can be improved through more consistent use of brand names or other product specific identifiers and through more frequent inclusion of lot numbers.

The Diversity of Biosimilar Design and Development: Implications for Policies and Stakeholders.

Biosimilars are required to be similar or highly similar in structure to their biologic reference product but are neither expected nor required to contain identical active substances. For example, glycosylated biosimilars approved to date demonstrate quantitative and qualitative structural differences from their reference product and exemplify the latitude of variations permitted for biosimilars. Although differences between a candidate biosimilar and its reference product will be evaluated for differential clinical effects during biosimilarity assessment, it is unlikely that potential differences between any two indirectly related biosimilars will be formally evaluated. Furthermore, biosimilar pathways permit variations in pharmaceutical attributes, clinical development approaches, and regulatory outcomes, resulting in further diversity of attributes among approved biosimilars. Because biosimilars may vary across the ranges of structural and functional acceptance criteria, they should not be treated like multisource, generic drugs.

Advancing Product Quality: a Summary of the Inaugural FDA/PQRI Conference

On September 16 and 17, 2014, the Food and Drug Administration (FDA) and Product Quality Research Institute (PQRI) inaugurated their Conference on Evolving Product Quality. The Conference is conceived as an annual forum in which scientists from regulatory agencies, industry, and academia may exchange viewpoints and work together to advance pharmaceutical quality. This Conference Summary Report highlights key topics of this conference, including (1) risk-based approaches to pharmaceutical development, manufacturing, regulatory assessment, and post-approval changes; (2) FDA-proposed quality metrics for products, facilities, and quality management systems; (3) performance-based quality assessment and clinically relevant specifications; (4) recent developments and implementation of continuous manufacturing processes, question-based review, and European Medicines Agency (EMA)-FDA pilot for Quality-by-Design (QbD) applications; and (5) breakthrough therapies, biosimilars, and international harmonization, focusing on ICH M7 and Q3D guidelines. The second FDA/PQRI conference on advancing product quality is planned for October 5–7, 2015.

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 products 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.

Preventing shortages of biologic medicines

Shortages of small-molecule injectable drugs have captured the attention of patients, healthcare providers, regulators and policy makers in recent years. While these shortages have several causes, non-compliance with current good manufacturing practice and subsequent shutdowns of manufacturing facilities have played a central role. Sterile injectable drugs are particularly susceptible to manufacturing quality disruptions because of their sensitivity to contamination. Biologics are subject to the same fill-finish contamination risk as sterile injectables, but their active ingredients are also sensitive to subtle changes in the manufacturing process and to storage and handling of their final dosage forms. Originator biologics will lose market exclusivity in the years ahead as patents expire and as competitors develop biosimilar products. The availability of therapeutic alternatives may provide opportunities to reduce costs and increase patient access, but this should not come at the expense of critical investments in the manufacturing of these complex and sensitive products.