Patterns of Tumor Necrosis Factor Inhibitor (TNFi) Biosimilar Use Across United States Rheumatology Practices.

ObjectiveIt is unclear if biosimilars of biologics for inflammatory arthritis are realizing their promise to increase competition and improve accessibility. This study evaluates biosimilar tumor necrosis factor inhibitor (TNFi) utilization across rheumatology practices in the United States and compares whether patients initiating biosimilars remain on these treatments at least as long as new initiators of bio-originators.MethodsWe identified a cohort of patients initiating a TNFi biosimilar between January 2017 and September 2018 from an electronic health record registry containing data from 218 rheumatology practices and over 1 million rheumatology patients in the United States. We also identified a cohort of patients who initiated the bio-originator TNFi during the same period. We calculated the proportion of biosimilar prescriptions compared with other TNFi's and compared persistence on these therapies, adjusting for age, sex, diagnoses codes, and insurance type.ResultsWe identified 909 patients prescribed the biosimilar infliximab-dyyb, the only biosimilar prescribed, and 4413 patients with a new prescription for the bio-originator infliximab. Biosimilar patients tended to be older, have a diagnosis code for rheumatoid arthritis, and covered by Medicare insurance. Over the study period, biosimilar prescriptions reached a maximum of 3.5% of all TNFi prescriptions. Patients persisted on the biosimilar at least as long as the bio-originator infliximab (hazard ratio [HR] 0.83, P = 0.07).ConclusionThe uptake of biosimilars in the United States remains low despite persistence on infliximab-dyyb being similar to the infliximab bio-originator. These results add to clinical studies that should provide greater confidence to patients and physicians regarding biosimilar use

Proceedings of the biosimilars workshop at the International Symposium on Oncology Pharmacy Practice 2019.

The International Society of Oncology Pharmacy Practitioners organized a workshop to create learning opportunities on biosimilars in pharmacy practice on 10 October 2019. The topics that were covered included (i) the development and testing of biosimilars, (ii) the challenges of bringing biosimilars to market, and (iii) real-world data on patient safety and perceptions during biosimilar implementation. The development of biosimilars can take up to eight years and the extensiveness of the process depends on several factors, such as the complexity of the production process and regulatory requirements. Compared to generic products of small-molecule drugs, there is a higher barrier to market entry for biosimilars, explaining the small number of biosimilars in the market. Appraisal of biosimilars for inclusion in hospital formularies is also different from the review process of originator biologics, where the former is usually institution-led and has fewer restrictions on use. When several biosimilar products are available, factors that should be considered besides cost are licensed indications, supply chain confidence, clinical data, and product attributes. Real-world data have shown that biosimilars are well-tolerated and have safety data that are comparable to that of the originator product. Oncology pharmacists from the United Kingdom, Kenya, and Canada also presented their respective experiences with biosimilar use. Different countries at varying stages of biosimilar implementation faced distinct challenges. Nevertheless, resources to assist biosimilar implementation can potentially be shared between different regions. International Society of Oncology Pharmacy Practitioners is well-positioned to foster professional cooperation at an international level to drive biosimilar implementation

Emergence of the Biosimilar Sector and Opportunities of Developing Country Suppliers

As biologic products begin to come off-patent, a market is emerging for biosimilars (also known as biogenerics or follow-on biologics). Firms from emerging countries such as India and China have dominated the production of active ingredients in pharmaceutical industries all over the world and are now developing capabilities in biosimilar production. This emergence of a new market dynamic is disruptive to current key players as it has potential challenge their current dominant hold over the market, while for firms from developing countries it creates a sea of opportunities. This rise of biosimilars and capabilities for cheap production in developing country firms has potential to transform patient care in developing countries as well as advanced countries. This paper reviews study data collected at Innogen and the most recent literature to understand how the sector for biosimilars is evolving and the opportunities and challenges faced by emerging suppliers. The aim of the paper is to identify the gaps in the current literature and opportunities for further study in this area

Heterogeneity in learning processes and the evolution of dynamic managerial capabilities as a response of emergence of biosimilar market: evidence from the Indian pharmaceutical industry

This paper examines heterogeneity in the response of Indian firms to the emergence of a new segment in the pharmaceutical generics market – biosimilars. The necessary diversity of the knowledge base and regulatory requirements underlying biosmilar products have created significant technological capability and market access challenges for Indian firms. This is but the latest development which adds to an existing catalogue of challenges including the decline of the traditional generics markets, regulatory hurdles in advanced country markets and failures in managing new drug development. Using case studies of three Indian firms we show that dynamic managerial capability is a key driver of heterogeneity in learning processes involved in acquisition of technological capabilities for biosimilars and market access strategies. It further highlights the important role of pre-existing capabilities in enabling and constraining the development of new biosimilar capabilities

Quality, Non-clinical and Clinical Considerations for Biosimilar Monoclonal Antibody Development: EU, WHO, USA, Canada, and BRICS-TM Regulatory Guidelines

Objective: The aim was to critically evaluate well-established regulatory agencies mAb biosimilar guidelines for development and marketing authorization about quality, efficacy and safety and compare to BRICS-TM regulations to identify challenges. Materials and Methods: The current valid guidelines of EMA, WHO, USFDA, BGTD/HC, ICH, and BRICS-TM were obtained from official websites and comparative qualitative review was performed. Results: The review revealed that Health Canada uses mAb specific guidelines from EMA or USFDA when necessary. The BRICS agencies (except Russia) have incorporated some or most of the WHO SBP TRS and related annexes in similar national biotechnological/biological guidelines; however, gaps or insufficient information have been identified. The Russian Federation has issued general product registration guideline/s with very brief information about mAbs. The TMMDA (Turkey) has published an updated biosimilar guideline which parallels those of the EMA and the ones from WHO; however, no mAb specific guidelines are published. COFEPRIS (Mexico) has published a biotechnological/biological product registration guideline with no information about mAb. The SAHPRA biosimilar guideline has an annex on mAbs which focuses on non-clinical and clinical aspects. The comparative evaluation of BRICS-TM agencies indicates a gap pertaining to clarification for physico-chemical characterization, manufacturing process, overages and compatibility requirements between biological substances and excipients specifically on mAbs. In vitro assay requirements seem quite aligned with those of WHO, whereas in vivo studies mostly have disparity in terms of necessity, type of studies as well as design and criteria. Clinical safety and efficacy studies are indicated in emerging regulatory agencies, however detailed information pertaining to design, size of populations, requirements for primary and secondary endpoints, clarity and evaluation criteria differ. In general, BRICS-TM agencies allow extrapolation of indications provided that pre-defined conditions are met. Interchangeability, switching and substitution of biosimilars are not defined in most of BRIC-TM guidelines whereas South Africa, by law, allows neither interchangeability nor substitution. Pediatric research remains questionable across BRICS-TM. Conclusions: EMA, USFDA guidelines are broadly aligned with WHO and in addition, they also contain specific requirements pertaining to their own region. BRICS-TM has considerably less defined mAb specific biosimilar development and comparability parameters in their published guidelines.Peer reviewedFinal Published versio

Switching from reference infliximab to CT-P13 in patients with inflammatory bowel disease: 12 months results

Background: Biological agents, such as infliximab, have transformed the outcomes of patients with immune-mediated inflammatory diseases. The advent of biosimilar treatment options such as CT-P13 promises to improve the availability of biological therapy, yet real-world switching data are currently limited. Here, we assess the effectiveness and safety of switching to CT-P13 from infliximab reference product (RP) in patients with inflammatory bowel disease. Materials and methods: This was a prospective single-center observational study in patients with moderate to severe Crohn’s disease (CD) and ulcerative colitis (UC). All patients were switched from infliximab RP (Remicade) to CT-P13 treatment and followed up for up to 12 months. The efficacy endpoint was the change in clinical response assessed at 3-monthly intervals, according to the Harvey–Bradshaw score and partial Mayo score for patients with CD and UC, respectively. C-reactive protein (CRP) was also measured. Adverse events were monitored and recorded throughout the study. Results: A total of 98 patients with inflammatory bowel disease (67 CD/31 UC) were included. A total of 83.6% (56/67) of patients with CD were in remission at the time of the switch and 62.7% were in remission at 12 months. The Harvey–Bradshaw score showed a significant change at 12 months (P =0.007) but no significant change was observed in median CRP at this timepoint (P= 0.364). A total of 80.6% (25/31) of patients with UC were in remission at the time of the switch and 65.3% (18/28) were in remission at 12 months. No significant changes in the median partial Mayo score (P=0.058) or CRP (P =0.329) were observed at 12 months. Serious adverse events related to medication were reported in 11 (11.2%) patients. Conclusion: Switching from infliximab RP to CT-P13 is efficacious and well tolerated in patients with CD or UC for up to 12 months

Manufacturing Barriers to Biologics Competition and Innovation

As finding breakthrough small-molecule drugs gets harder, drug companies are increasingly turning to “large molecule” biologics. Although biologics represent many of the most promising new therapies for previously intractable diseases, they are extremely expensive. Moreover, the pathway for generic-type competition set up by Congress in 2010 is unlikely to yield significant cost savings. In this Article, we provide a fresh diagnosis of, and prescription for, this major public policy problem. We argue that the key cause is pervasive trade secrecy in the complex area of biologics manufacturing. Under the current regime, this trade secrecy, combined with certain features of FDA regulation, not only creates high barriers to entry of indefinite duration but also undermines efforts to advance fundamental knowledge. In sharp contrast, offering incentives for information disclosure to originator manufacturers would leverage the existing interaction of trade secrecy and the regulatory state in a positive direction. Although trade secrecy, particularly in complex areas like biologics manufacturing, often involves tacit knowledge that is difficult to codify and thus transfer, in this case regulatory requirements that originator manufacturers submit manufacturing details have already codified the relevant tacit knowledge. Incentivizing disclosure of these regulatory submissions would not only spur competition but it would provide a rich source of information upon which additional research, including fundamental research into the science of manufacturing, could build. In addition to provide fresh diagnosis and prescription in the specific area of biologics, the Article contributes to more general scholarship on trade secrecy and tacit knowledge. Prior scholarship has neglected the extent to which regulation can turn tacit knowledge not only into codified knowledge but into precisely the type of codified knowledge that is most likely to be useful and accurate. The Article also draws a link to the literature on adaptive regulation, arguing that greater regulatory flexibility is necessary and that more fundamental knowledge should spur flexibility. A vastly shortened version of the central argument that manufacturing trade secrecy hampers biosimilar development was published at 348 Science 188 (2015), available online

The Future of Generic Biologics: Should the United States “Follow-On” the European Pathway?

The United States is embarking on a biotechnology drug revolution. In the last few decades, biotech drugs have saved millions of lives, and the market for these miracle cures continues to grow at an astronomical rate. Unfortunately, as the market for biotech drugs is skyrocketing, drug prices are following suit. As Congress strives to make these new drugs more affordable, it must not ignore significant safety concerns unique to these revolutionary therapies. Congress should follow the lead of the European Union to create an accessible pathway for generic forms of biotech drugs that includes strict regulatory measures to ensure drug safety and efficacy

Forced Degradation Testing as Complementary Tool for Biosimilarity Assessment

Oxidation of monoclonal antibodies (mAbs) can impact their efficacy and may therefore represent critical quality attributes (CQA) that require evaluation. To complement classical CQA, bevacizumab and infliximab were subjected to oxidative stress by H2O2 for 24, 48, or 72 h to probe their oxidation susceptibility. For investigation, a middle-up approach was used utilizing liquid chromatography hyphenated with mass spectrometry (LC-QTOF-MS). In both mAbs, the Fc/2 subunit was completely oxidized. Additional oxidations were found in the light chain (LC) and in the Fd’ subunit of infliximab, but not in bevacizumab. By direct comparison of methionine positions, the oxidized residues in infliximab were assigned to M55 in LC and M18 in Fd’. The forced oxidation approach was further exploited for comparison of respective biosimilar products. Both for bevacizumab and infliximab, comparison of posttranslational modification profiles demonstrated high similarity of the unstressed reference product (RP) and the biosimilar (BS). However, for bevacizumab, comparison after forced oxidation revealed a higher susceptibility of the BS compared to the RP. It may thus be considered a useful tool for biopharmaceutical engineering, biosimilarity assessment, as well as for quality control of protein drugs