Infliximab discontinuation in patients with originator retransition vs biosimilar continuation

Posted on

Submitted: 4 November 2023; Revised: 24 November 2023; Accepted: 27 November 2023; Published online first: 28 November 2023

A study by Meijboom et al. aimed to compare the risk of and reasons for infliximab discontinuation between retransitioned patients and those remaining on biosimilar [1].

When the market exclusivity of the originator infliximab (Remicade) expired in 2014, many patients with inflammatory bowel disease (IBD) transitioned from the originator infliximab to an infliximab biosimilar, driven by cost containment reasons. Transitioning has been proven safe and effective in several double-blind studies, with numerous patients successfully making the switch in clinical practice.

However, approximately 7% of these patients subsequently retransitioned to the originator infliximab (i.e. they stopped the biosimilar and reinitiated the originator), mainly due to a (perceived) increase in disease activity or adverse events after transitioning to the biosimilar. It is unclear whether this sign of potential unsatisfactory treatment response is specifically related to the infliximab biosimilar, the patient, and/or the disease, including patients’ beliefs about the biosimilar.

Therefore, Meijboom et al. conducted a study with the aim of comparing the risk and reasons for infliximab discontinuation between two groups of patients: those who retransitioned to the originator and those who remained on biosimilar. The study included patients with IBD who had initially transitioned from infliximab originator to the corresponding biosimilar.

The risk and reason for retransitioning were assessed in all IBD patients who transitioned from infliximab originator to biosimilar between January 2015 and September 2019 in two Dutch hospitals. Retransitioned patients were matched with patients remaining on biosimilar (biosimilar remainder patients). The authors categorized patients’ reasons for discontinuing as either an unwanted response (i.e. loss of effect and/or adverse events) or as disease remission. A comparison of the risk of discontinuation due to an unwanted response was conducted between the two cohorts using a Cox proportional hazards model.

The study findings revealed that 22.7% of patients in the retransitioning cohort vs 13.4% in the biosimilar remainder cohort discontinued infliximab due to an unwanted response, and 2.3% vs 9.4% of patients, respectively, discontinued because their disease was in remission. The authors noted that retransitioned patients had more than threefold increased risk of discontinuing due to an unwanted response compared with biosimilar remainder patients (adjusted HR 3.7, 95% CI: 1.0–13.9).

Meijboom et al. further zoomed in on the retransitioned patients. About one in six retransitioned patients retransitioned due to objectively measured increased disease activity, e.g. elevated calprotectin and/or active disease seen on endoscopy, the other patients due to (subjective) symptoms only. Patients who retransitioned due to objectively increased disease activity discontinued their infliximab treatment more often than patients who retransitioned due to symptoms only (66.7% versus 23.7%).

In conclusion, the study demonstrated that patients who retransitioned were more likely to discontinue infliximab treatment due to an unwanted response compared to patients who remained on biosimilar. On the other hand, patients who remained on the biosimilar were more likely to discontinue infliximab due to remission. Patients who retransitioned had more than a threefold increased risk of discontinuing infliximab due to an unwanted response compared to patients who remained on the biosimilar. These findings indicate that retransitioning is mainly related to the patient and/or their disease, including the patients’ beliefs about the biosimilar. It is less likely to be related to the infliximab biosimilar itself.

The reason for retransitioning, which might have an impact on the course of infliximab originator treatment, is objectively measured disease activity or symptoms only, and it could be of importance in clinical decision-making. Clinicians could consider patients who opt for retransitioning to another treatment option.

Competing interests: The authors of the research paper [1] declared that there were no conflicts of interest.

Provenance and peer review: Commissioned; internally peer reviewed.

Reference
1. Meijboom RW, Gardarsdottir H, Becker ML, Movig KLL, Kuijvenhoven J, Egberts TCG, et al. Discontinuation of infliximab treatment in patients with inflammatory bowel disease who retransitioned to originator and those who remained on biosimilar. Therap Adv Gastroenterol. 2023 Sep 11;16:17562848231197923. doi: 10.1177/17562848231197923.

Author: Rosanne Meijboom, Trainee Researcher, Pharmacy Foundation of Haarlem Hospitals (SAHZ), Boerhaavelaan 24, 2035 RC, Haarlem, The Netherlands

Disclosure of Conflict of Interest Statement is available upon request.

Copyright © 2023 Pro Pharma Communications International

Permission granted to reproduce for personal and non-commercial use only. All other reproduction, copy or reprinting of all or part of any ‘Content’ found on this website is strictly prohibited without the prior consent of the publisher. Contact the publisher to obtain permission before redistributing.

Last update: 10/05/2024

Go Back

Print

Switches between biosimilars and their reference products

Posted on

Submitted: 22 November 2023; Revised: 24 November 2023; Accepted: 27 November 2023; Published online first: 28 November 2023

Biologics are the fastest-growing class of medications in the United States and account for a substantial and growing portion of healthcare costs. The Biologics Price Competition Act of 2009 created an abbreviated approval pathway for the U.S. Food and Drug Administration (FDA) to help provide patients with greater access to safe and effective biological products. As of 1 November 2023, FDA has approved 44 biosimilar products, 7 of which are interchangeable biosimilars. These products can be used to treat many conditions such as chronic skin and bowel diseases, arthritis, kidney conditions, diabetes, multiple sclerosis, macular degeneration, and cancer.

Despite the rigorous requirements for comparative structural and functional analytical characterization data and one or more clinical studies that demonstrate a proposed biosimilar is highly similar to and has no clinically meaningful differences from the reference product, concerns of immune system mediated safety events associated with switching between biosimilars and their reference products persist.

Switching between biosimilars and reference products has been addressed in FDA guidance [1, 2]. As part of the demonstration of biosimilarity, a clinical immunogenicity assessment is expected to evaluate potential differences in immune responses and in some instances whether a single cross-over from the reference product to the proposed biosimilar would result in a major risk in terms of hypersensitivity, immunogenicity, or other reactions [1]. For interchangeable biosimilars, FDA guidance states that applications generally will include data from a switching study or studies and FDA anticipates that the data will be useful in assessing the risk, in terms of safety and diminished efficacy, of alternating or switching between the products [2].

Since the publication of these FDA guidances, experience with biosimilars and interchangeable biosimilars has increased considerably. While switching of biosimilars has been addressed in descriptive reviews, statistical methods have not been employed in a definitive fashion. This systematic review and meta-analysis [3] includes all of the identified randomized studies with one or more switches of biosimilars that were approved by FDA. Randomized controlled studies and their extension studies containing a switch treatment period (STP) to or from a biosimilar and its corresponding reference biological were identified from publicly available information maintained by FDA. These findings were augmented with data from peer-reviewed publications containing information not captured in FDA reviews. Forty-four STPs were identified from 31 unique studies for 21 different biosimilars. Data were extracted and synthesized according to PRISMA guidelines.

Meta-analyses were conducted to estimate the overall risk difference across studies. A total of 5,252 patients who were switched to or from a biosimilar and its reference biological were identified and 5,770 patients who served as no switch controls. Safety data, including deaths, serious adverse events, and treatment discontinuation showed an overall risk difference (95% CI) of -0.00 (-0.00, 0.00), 0.00 (-0.01, 0.01), -0.00 (-0.01, 0.00), respectively, across STPs. Immunogenicity data showed a similar incidence of anti-drug antibodies and neutralizing antibodies in patients within a STP who were switched to or from a biosimilar to its reference biological and patients who were not switched. Immune related adverse events such as anaphylaxis, hypersensitivity reactions, and injections site reactions were similar in switched and non-switched patients.

Safety and immunological concerns with switching between a biosimilar and its reference product, once or multiple times, have not been demonstrated in controlled clinical studies for FDA-approved biosimilars. This work adds to the growing body of evidence that switching between biosimilars and their corresponding reference products has not been associated with a greater risk of immunogenicity or safety concerns and is expected to reassure patients and their care providers. Regulatory recommendations on the need for studies with switches as part of the demonstration of biosimilarity and interchangeability are under review.

Competing interests: The authors of the research paper [3] declared that there were no conflicts of interest.

Provenance and peer review: Commissioned; internally peer reviewed.

References

  1. Guidance for Industry: Scientific Considerations in Demonstrating Biosimilarity to a Reference Product (May 2019) found at: https://www.fda.gov/media/82647/download
  2. Guidance for Industry: Considerations in Demonstrating Interchangeability with a Reference Product (May 2019) found at: https://www.fda.gov/media/124907/download
  3. Herndon TM, Ausin C, Brahme NN, Schrieber SJ, Luo M, Andrada FC, Kim C, Sun W, Zhou L, Grosser S, Yim S, Ricci MS. Safety outcomes when switching between biosimilars and reference biologics: A systematic review and meta-analysis. PLoS One. 2023;18(10):e0292231.

Author: Dr Sarah Schrieber, PharmD, Office of Therapeutic Biologics and Biosimilars, Center for Drug Evaluation and Research, U.S. Food and Drug Administration

Disclosure of Conflict of Interest Statement is available upon request.

Copyright © 2023 Pro Pharma Communications International

Permission granted to reproduce for personal and non-commercial use only. All other reproduction, copy or reprinting of all or part of any ‘Content’ found on this website is strictly prohibited without the prior consent of the publisher. Contact the publisher to obtain permission before redistributing.

Last update: 19/07/2024

Go Back

Print

Biosimilar epoetin for cancer and chemotherapy-induced anaemia in the US

Posted on

Biosimilars are biological drug products that are highly similar to reference products in analytic features, pharmacokinetics and pharmacodynamics, immunogenicity, safety and efficacy. Biosimilar epoetin received US Food and Drug Administration (FDA) approval in 2018 [1]. The manufacturer received an FDA non-approval letter in 2017, despite receiving a favourable review by the FDA’s Oncologic Drugs Advisory Committee (ODAC) and an FDA non-approval letter in 2015 for an earlier formulation.

Oncologists from the US reviewed relevant peer-reviewed articles with use of MEDLINE (PubMed), Embase (Ovid), and Web of Science. Search terms included ‘erythropoietin’, ‘biosimilars’, ‘follow-on biologics’, ‘similar biologic products’, ‘subsequent entry biologics’, ‘follow-on biologic products’ and ‘similar biologic medicinal products’. The search was carried out on articles published between January 2005 and January 2021, in English or Japanese.

From the results of their search the authors discuss the 2018 FDA approval, the 2017 FDA ODAC Committee review and the FDA complete response letters in 2015 and 2017; review concepts of litigation, naming, labelling, substitution, interchangeability and pharmacovigilance; review European and US oncology experiences with biosimilar epoetin and review the safety of erythropoiesis-stimulating agents [2].

In 2020, policy statements from health insurance providers Aetna, UnitedHealthcare and Humana indicated that new patients starting epoetin oncology must use biosimilar epoetin unless medical need for other epoetins is documented.

Empirical studies report that as of 2012, reference epoetin use decreased from 40%–60% of all patients with cancer with chemotherapy-induced anaemia to < 5% of such patients because of safety concerns. Between 2018 and 2020, biosimilar epoetin use varied, increasing to 81% among one private insurer’s patients covered by Medicare# whose cancer care is administered with Oncology Analytics and to 41% with the same private insurer’s patients with cancer covered by commercial health insurance and administered by the private insurer, to 0% in several Veterans Administration Hospitals, increasing to 100% in one large county hospital in California and with yet-to-be-reported data from most oncology settings.

The authors conclude that biosimilar epoetin appears to have overcome some barriers since 2015, although current uptake in the US is variable. Pricing and safety considerations for all erythropoiesis-stimulating agents are primary determinants of biosimilar epoetin oncology uptake.

Implications for practice

Few oncologists understand substitution and interchangeability of biosimilars with reference drugs. Epoetin biosimilar is new to the market and physician and patient understanding is limited. The development of epoetin biosimilar is not familiar to oncologists [2].

Article [2] abstracted by Article abstracted by Charles L Bennett, Toni Stephenson Lymphoma Center, the Hematologic Malignancies Research Institute, the Beckman Research Institute, of the City of Hope Comprehensive Cancer Center, Duarte, California and the College of Pharmacy, University of South Carolina, Columbia, South Carolina, USA.

#Medicare is a national social insurance programme, administered by the US federal government since 1966. It provides health insurance for Americans aged 65 and older who have worked and paid into the system, as well as to younger people with disabilities.

Competing interests: The authors of the research paper [2] reported conflicts of interest, including having financial relationships with various pharmaceutical companies. For full details of the authors’ conflict of interest, see the research paper [2].

Provenance and peer review: Commissioned; internally peer reviewed.

References
1. GaBI Online – Generics and Biosimilars Initiative. FDA approves epoetin alfa biosimilar Retacrit [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2021 Aug 20]. Available from: www.gabionline.net/biosimilars/news/FDA-approves-epoetin-alfa-biosimilar-Retacrit
2. Bennett CL, Nagai S, Bennett AC, Hoque S, Nabhan C, Schoen MW, et al. The first 2 years of biosimilar epoetin for cancer and chemotherapy-induced anemia in the U.S.: a review from the Southern Network on Adverse Reactions. Oncologist.

Last update: 10/05/2024

Go Back

Print

Poor traceability of biologicals in UK ADR reporting indicates the need for improvements to ensure patient safety

Posted on

Submitted: 27 January 2020; Revised: 29 January 2020; Accepted: 29 January 2020; Published online first: 25 February 2020

Biological medical products (biologicals) are derived from living cells or organisms. Due to their complex structures and the inherent challenges for manufacturing, a degree of minor variability may exist between different batches of the same product and between original biological and follow-on versions, so-called biosimilars. Thus, when adverse drug reactions (ADRs) occur, it is important to know the precise brand name and batch number of the biological involved.

Several studies have concluded, however, that specific product details are not always provided in ADR reports. Consequently, the aim of this study (UK BIO-TRAC) was to assess the extent to which biologicals are traceable by brand name and batch number in UK hospital practice and in reports of ADRs submitted by patients and healthcare professionals [1]. We performed an online hospital pharmacist survey to capture information on how specific product details are recorded in routine UK hospital practice and assessed the proportion of ADR reports specifying brand name and batch number submitted to the UK national spontaneous reporting database, the Yellow Card Scheme, between 1 January 2009 and 30 September 2017.

In the survey, 61 hospital pharmacists from 40 different National Health Service (NHS) Trusts (representing 23% of the 174 eligible NHS Trusts), reported that systematic brand name recording in routine hospital processes (dispensing and administration) ranged from 91% to 79%. Batch numbers were less routinely recorded, ranging from 38% to 58%. Paper-based recording of product details was more commonly used for recording information in the UK hospital setting. A total of 6,108 electronic ADR reports, submitted to the Yellow Card Scheme for recombinant biologicals, were analysed. We found that 38% of these ADR reports had an identifiable brand name whereas only 15% of these ADR reports contained batch numbers. Brand name and batch number traceability was slightly increased for biologicals for which a biosimilar has been approved, although still only 56% of the ADR reports contained an identifiable brand name. Batch number traceability in electronic ADR reports improved slightly after the implementation of the European Union Pharmacovigilance Legislation in 2012. However, no improvement was observed for brand-name traceability.

We therefore conclude that the Pharmacovigilance Legislation from 2012 to strengthen product identification for biologicals in ADR reports has not yet achieved its objective. The traceability of biologicals in UK clinical practice is not always ensured, particularly for batch numbers. The shortcomings in the recording and tracing of product details, such as batch numbers, in UK clinical practice could partially explain the limited traceability of biologicals found in ADR reports. Education and training on the importance of traceability for biologicals in ADR reporting can further support improving the traceability. The findings from this study are in line with an earlier study from The Netherlands [2, 3]. Further research is needed to evaluate how the use of electronic-based routine recording of detailed product information may help to improve traceability in clinical practice and eventually in ADR reporting, and in turn help to build a robust pharmacovigilance system that allows for the timely identification of any manufacturing-related safety issues.

Competing interests: None.

Provenance and peer review: Not commissioned; internally peer reviewed.

Author

Kevin Klein1,2,3, PhD

1Foundation Lygature, 6 Jaarbeursplein, NL-3521 AL Utrecht, The Netherlands
2Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, 99 Universiteitsweg, NL-3584 CG Utrecht, The Netherlands
3Exon Consultancy, Amsterdam, The Netherlands

References
1. Klein K. Hazell l, Stolk P, Shakir S. The UK BIO-TRAC study: a cross-sectional study of product and batch traceability for biologics in clinical practice and electronic adverse drug reaction reporting in the UK. Drug Saf. 2020;43(3):255-63.
2. Klein K, Scholl JHG, Vermeer NS, Broekmans AW. Traceability of biologics in The Netherlands: an analysis of information-recording systems in clinical practice and spontaneous ADR reports. Drug Saf. 2016;39:185.
3. GaBI Online – Generics and Biosimilars Initiative. Pharmacovigilance for biologicals in The Netherlands [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2020 Jan 29]. Available from: www.gabionline.net/Biosimilars/Research/Pharmacovigilance-for-biologicals-in-The-Netherlands

Disclosure of Conflict of Interest Statement is available upon request.

Copyright © 2020 Pro Pharma Communications International

Permission granted to reproduce for personal and non-commercial use only. All other reproduction, copy or reprinting of all or part of any ‘Content’ found on this website is strictly prohibited without the prior consent of the publisher. Contact the publisher to obtain permission before redistributing.

Last update: 17/11/2020

Go Back

Print

HIV patients will accept generic treatments

Posted on

Human immunodeficiency virus (HIV) patients in high-income countries are likely to accept the introduction of generic antiretroviral (ARV) drugs, according to a study carried out by researchers in Ireland [1].

Between July and August 2015, a survey of 66 patients was carried out in one-to-one interviews at St James Hospital, Dublin, Ireland. Descriptive and univariate analysis revealed information on cohort demographics, knowledge of generic medicine and facilitators of generics substitution.

The analysis identified an ethnically diverse group of patients that broadly reflected the overall diversity of those attending the clinic. 94% of patients were taking ARVs, of whom 95% were taking a once-daily regimen of three pills and 50% were on a single-tablet regimen. 35% were prescribed medicines, other than ARVs. Only 21% of the patients had ever discussed generic medicines with a healthcare
professional.

The patients’ view of generics

Only patients familiar with generic medicines were asked to complete questions related to their attitude on these products. The majority of these patients agreed that generic medicines contained the same drug as the branded alternative and are as safe and effective. 71% said that they would have no concerns over the introduction of generic ARVs. However, 61% of those interviewed said that an increase in frequency of administration would affect their acceptance of generic medications, and 53% would be concerned over an increase in pill burden. Results also showed that patients would be more willing to accept substitution introduced by their hospital doctor rather than their pharmacist.

The authors believe that the results show that generics substitution would be acceptable to the majority of patients in Ireland. Targeted education programmes should be implemented to ease transition and reduce misconceptions about generic ARVs. Barriers to substitution are likely to be encountered with increased dosing regime or pill burden. However, if advised by their hospital doctor, patients would be more likely to accept generic medications. They also state that the savings made through administration of generic ARVs can be reinvested into HIV services.

A summary of the attitude of healthcare professionals towards the introduction of generic ARVs is presented in an earlier article in GaBI Journal [2].

References
1.Kieran JA, O’Reilly E, O’Dea S, Bergin C, O’Leary A. Generic substitution of antiretrovirals: patients’ and health care providers’ opinions. Int J STD AIDS. 2017:956462417696215.
2.Healthcare professionals will accept generic HIV treatments. Generics and Biosimilars Initiative Journal (GaBI Journal). 2017;6(3):148. doi:10.5639/gabij.2017.0603.029

Copyright © 2018 Pro Pharma Communications International

Permission granted to reproduce for personal and non-commercial use only. All other reproduction, copy or reprinting of all or part of any ‘Content’ found on this website is strictly prohibited without the prior consent of the publisher. Contact the publisher to obtain permission before redistributing.

Last update: 04/04/2022

Go Back

Print

Healthcare professionals will accept generic HIV treatments

Posted on

Healthcare professionals working with HIV patients in high-income countries are likely to accept the introduction of generic antiretroviral drugs (ARVs), according to a study carried out by researchers in Ireland [1].

Between the end of August and November 2015, 30 healthcare professionals completed an online survey about the introduction of generic ARVs. Descriptive and univariate analysis revealed information on cohort demographics, knowledge of generic medicine and facilitators of generics substitution.

The sample of healthcare professionals that completed the survey included 22 physicians, four nurse specialists and four pharmacists. 66% of the healthcare professionals had been working in the field of HIV treatment for over five years. They expressed good knowledge of the terms associated with generic medicines and the majority stated that generic medicines contained the same drug as the branded alternative and are as safe and effective.

The healthcare professionals view
The majority of the healthcare professionals that completed the survey expressed concerns about the supply chain of generics. They also noted that the main disadvantages in switching to generic ARVs were related to the loss of fixed-dose combinations of medication, potential negative effects on adherence and the use of older medications. In addition, the majority of healthcare professionals noted that an increase in dosing frequency or pill burden would affect their willingness to prescribe a generic ARV.

Despite concerns, the overall results showed that healthcare professionals would be willing to prescribe generic ARVs if they became available, with 30% stating ‘Yes’, 43% stating ‘Yes, in some cases’, and 27% stating ‘Yes, on a case-by-case basis’. The survey also showed that healthcare professionals have good understanding of the cost of ARVs and generics alternatives, and saw financial advantages in making a switch to generics.

The authors believe that the results show that generics substitution would be acceptable to the majority of healthcare professionals in Ireland. Education programmes targeted at healthcare professionals should be implemented to ease transition and reduce misconceptions about generic ARVs. However, barriers to substitution are likely to be encountered with increased dosing regime or pill burden. The authors also state that the savings made through administration of generic ARVs that can be reinvested into HIV services, will be a powerful motivation for their implementation by healthcare professionals.

Reference
1. Kieran JA, O’Reilly E, O’Dea S, Bergin C, O’Leary A. Generic substitution of antiretrovirals: patients’ and health care providers’ opinions. Int J STD AIDS. 2017:956462417696215.

Disclosure of Conflict of Interest Statement is available upon request.

Copyright © 2017 Pro Pharma Communications International

Permission granted to reproduce for personal and non-commercial use only. All other reproduction, copy or reprinting of all or part of any ‘Content’ found on this website is strictly prohibited without the prior consent of the publisher. Contact the publisher to obtain permission before redistributing.

Last update: 04/04/2022

Go Back

Print