Scent dog identification of SARS-CoV-2 infections in different body fluids.

BACKGROUND: The main strategy to contain the current SARS-CoV-2 pandemic remains to implement a comprehensive testing, tracing and quarantining strategy until vaccination of the population is adequate. Scent dogs could support current testing strategies. METHODS: Ten dogs were trained for 8 days to detect SARS-CoV-2 infections in beta-propiolactone inactivated saliva samples. The subsequent cognitive transfer performance for the recognition of non-inactivated samples were tested on three different body fluids (saliva, urine, and sweat) in a randomised, double-blind controlled study. RESULTS: Dogs were tested on a total of 5242 randomised sample presentations. Dogs detected non-inactivated saliva samples with a diagnostic sensitivity of 84% (95% CI: 62.5-94.44%) and specificity of 95% (95% CI: 93.4-96%). In a subsequent experiment to compare the scent recognition between the three non-inactivated body fluids, diagnostic sensitivity and specificity were 95% (95% CI: 66.67-100%) and 98% (95% CI: 94.87-100%) for urine, 91% (95% CI: 71.43-100%) and 94% (95% CI: 90.91-97.78%) for sweat, 82% (95% CI: 64.29-95.24%), and 96% (95% CI: 94.95-98.9%) for saliva respectively. CONCLUSIONS: The scent cognitive transfer performance between inactivated and non-inactivated samples as well as between different sample materials indicates that global, specific SARS-CoV-2-associated volatile compounds are released across different body secretions, independently from the patient's symptoms. All tested body fluids appear to be similarly suited for reliable detection of SARS-CoV-2 infected individuals.

The effect of exposure misclassification in spontaneous ADR reports on the time to detection of product-specific risks for biologicals: a simulation study.

BACKGROUND AND OBJECTIVE: The availability of accurate product-specific exposure information is essential in the pharmacovigilance of biologicals, because differences in the safety profile may emerge between products containing the same active substance. In spontaneous adverse drug reaction (ADR) reports, drug exposure may, however, be misclassified, that is, attributed to the incorrect product. The aim of this study was to explore the effect of exposure misclassification on the time to detection of product-specific risks in spontaneous reporting systems. METHODS: We used data simulations to explore the effect of exposure misclassification. We simulated an active substance-specific subset of a spontaneous reporting system and used the proportional reporting ratio for signal detection. The effect of exposure misclassification was evaluated in three test cases representing product-specific ADRs that may occur for biologicals and studied in relative terms by varying the model parameters (market share and relative risk). RESULTS: We found that exposure misclassification results in the largest delay in identification of risks that have a weak association (relative risk < 2 or 3) with the product of interest and in situations where the product associated with the unique risk has a large (>50%) market share. The absolute public health impact of exposure misclassification, in terms of cases/time to detection, varied considerably across the test cases. CONCLUSION: Exposure misclassification in ADR reports may result in a delayed detection of product-specific risks, particularly in the detection of weak drug-event associations. Our findings can help inform the future implementation and refinement of product-specific and batch-specific signal detection procedures.

An analysis of marketing authorisation applications via the mutual recognition and decentralised procedures in Europe.

PURPOSE: The aim of this study is to provide a comprehensive overview of the outcomes of marketing authorisation applications via the mutual recognition and decentralised procedures (MRP/DCP) and assess determinants of licensing failure during CMDh referral procedures. METHODS: All MRP/DCP procedures to the Co-ordination group for Mutual recognition and Decentralised procedures-human (CMDh) during the period from January 2006 to December 2013 were analysed. Reasons for starting referral procedures were scored. In addition, a survey under pharmaceutical companies was performed to estimate the frequency of licensing failure prior to CMDh referrals. RESULTS: During the study period, 10392 MRP/DCP procedures were finalized. Three hundred seventy-seven (3.6%) resulted in a referral procedure, of which 70 (19%) resulted in licensing failure, defined as refusal or withdrawal of the application. The frequency of CMDh referrals decreased from 14.5% in 2006 to 1.6% in 2013. Of all referrals, 272 (72%) were resolved through consensus within the CMDh, the remaining 105 (28%) were resolved at the level of the CHMP. Most referrals were started because of objections raised about the clinical development program. Study design issues and objections about the demonstration of equivalence were most likely to result in licensing failure. An estimated 11% of all MRP/DCP procedures resulted in licensing failure prior to CMDh referral. CONCLUSION: Whereas the absolute number of MRP/DCP procedures resulting in a referral has reduced substantially over the past years, no specific time trend could be observed regarding the frequency of referrals resulting in licensing failure. Increased knowledge at the level of companies and regulators has reduced the frequency of late-stage failure of marketing applications via the MRP/DCP.

A Retrospective Analysis of the Potential Impact of Differences in Aggregates on Clinical Immunogenicity of Biosimilars and their Reference Products.

Aggregates, in particular high molecular weight species (HMWs), have been linked to increased immunogenicity. The current understanding on the impact of HMWs is mainly based on in vitro and nonclinical studies and there are only limited data available associating differences in HMWs in marketed monoclonal antibodies (mAbs) to clinical outcomes. Biosimilars offer a unique opportunity to study the potential association between quality parameters and clinical outcomes. We performed a retrospective evaluation to investigate the association between HMW content and reported antidrug-antibody (ADA) incidence in 30 full-length biosimilar mAbs approved in the European Union and the United States. Information for HMW content and ADA incidence were collected from publicly available sources. Differences in HMW content between biosimilars and their reference products (RPs) ranged from -0.75 to 1.65% with slightly higher differences observed in antineoplastic products as compared with immunosuppressant products. The difference in the ADA incidence between the RP and the biosimilar for the programs studied ranged from -11.0 to 18.5%. No association was observed between differences in HMW content and reported ADA incidence, in neither phase I nor phase III studies. Our results show that the limited differences in the content of HMWs between marketed biosimilars and reference mAbs were not associated with differences in reported immunogenicity, determined as incidence of ADAs and neutralizing ADAs in comparative clinical studies.

Demonstration of Physicochemical and Functional Similarity of the Biosimilar BAT1806/BIIB800 to Reference Tocilizumab.

BACKGROUND AND OBJECTIVE: Tocilizumab is an immunoglobulin G1 monoclonal antibody targeting the interleukin-6 receptor (IL-6R). BAT1806/BIIB800 (tocilizumab-bavi) has been developed as a biosimilar to the reference product tocilizumab (TCZ). The objective of this study was to demonstrate physicochemical and functional similarity between BAT1806/BIIB800 and TCZ in a comprehensive comparability exercise. METHODS: A comprehensive panel of over 20 methods was used to generate datasets comparing critical and non-critical product quality attributes for 10 BAT1806/BIIB800 lots and 44 TCZ lots (16 sourced from China, 16 from the EU, and 12 from the US). Primary structure, higher-order structure, and physicochemical properties were assessed using liquid chromatography, mass spectrometry, various spectroscopy techniques/methods, capillary electrophoresis, and thermoanalytical techniques. Fragment antigen-binding (Fab)- and fragment crystallizable (Fc)-mediated biological properties were assessed using cell-based assays, immunoassays, flow cytometry, and kinetic binding assays. RESULTS: BAT1806/BIIB800 and TCZ (irrespective of source) were shown to be similar in terms of structural and functional properties. No differences were observed in terms of the most critical quality attributes, that is, soluble-IL-6R binding and inhibition of IL-6-mediated cell proliferation. BAT1806/BIIB800 and TCZ demonstrated similarity in terms of Fab- and Fc-mediated binding and biological activity. Minor differences were observed in glycosylation (afucosylation and sialylation), glycation, aggregation, and charge variants, which were demonstrated to be not clinically relevant. CONCLUSION: BAT1806/BIIB800 and TCZ were highly similar for all critical quality attributes. Where differences were observed in less critical quality attributes, additional analytical assessments and clinical study results determined these to be not clinically meaningful.

The role of Periodic Safety Update Reports in the safety management of biopharmaceuticals.

PURPOSE: To describe and assess the outcomes of Periodic Safety Update Report (PSUR) evaluations of biopharmaceuticals. METHODS: A cross-sectional analysis was performed of follow-up requirements of PSURs submitted for centrally approved biopharmaceuticals in the European Union between 1 July 2008 and 30 June 2010. A follow-up analysis on a subset of products that submitted multiple PSURs within the study period was also performed. RESULTS: The cross-sectional analysis included 70 PSURs. Potential safety concerns occurred in 57 (83 %) of all PSURs, and 26 (37 %) concluded a need to change the Summary of Product Characteristics (SPC). In comparison to newer products, products authorized for more than 10 years contained significantly fewer potential safety concerns (60 vs. 92 %; p < 0.01) and required fewer SPC changes (15 vs. 46 %; p = 0.03). For 45 products, multiple PSURs were submitted that could be included in a follow-up analysis. For this subset of products, of the 106 newly identified safety potential safety issues, 7 (7%) resulted in requirements for label changes in the following PSUR. CONCLUSIONS: PSURs facilitate communication between regulators and marketing authorization holders. Potential safety concerns occur for the majority of biopharmaceuticals and throughout their lifecycle, but for established products PSUR evaluations rarely lead to regulatory actions.

Antibody-mediated pure red cell aplasia in chronic kidney disease patients receiving erythropoiesis-stimulating agents: new insights.

Antibody-mediated pure red cell aplasia is a very rare but devastating condition affecting patients receiving treatment with erythropoiesis-stimulating agents. New cases continue to emerge, generally in clusters, consistent with an 'environmental' trigger to its pathogenesis. Defining the causes of antibody-mediated pure red cell aplasia is clearly of importance for patients with chronic kidney disease, but any developments in this area may also have relevance to other disease areas as therapeutic delivery of endogenous proteins rapidly increases. This review focuses on the current knowledge regarding the etiology of antibody-mediated pure red cell aplasia and the current approach to therapy.

Current evidence on the use of the adalimumab biosimilar SB5 (ImraldiTM): a multidisciplinary perspective.

INTRODUCTION: This review provides an overview of data from trials and real-world studies available for SB5 (ImraldiTM) across three main therapeutic areas: rheumatology, gastroenterology, and dermatology. AREAS COVERED: A literature search for publications on data for SB5 efficacy/effectiveness, safety, and immunogenicity was undertaken. EXPERT OPINION: Evidence derived from clinical studies suggest that the biosimilar SB5 is a safe and effective alternative to reference adalimumab. Considering that patients suffering from immune-mediated inflammatory diseases such as inflammatory arthritis, inflammatory bowel disease and psoriasis often require long-term biologic treatment, biosimilar medicines (such as SB5) can reduce healthcare costs while increasing access to effective treatments.

An Introduction to Biosimilars for the Treatment of Retinal Diseases: A Narrative Review.

Biological therapies have revolutionized the treatment of disease across a number of therapeutic areas including retinal diseases. However, on occasion, such treatments may be relatively more expensive compared to small molecule therapies. This can restrict patient access and treatment length leading to suboptimal clinical outcomes. Several biosimilar candidates of ranibizumab and aflibercept are currently in development and the first biosimilar of ranibizumab received EMA approval in August and FDA approval in September 2021. Biosimilars are biological medicines that are highly similar to an already-approved biological medicine (reference product). The physicochemical and clinical similarity of a biosimilar is determined by a rigorous analytical and clinical program, including extensive pharmacokinetic and pharmacodynamic analysis with phase III equivalence studies where appropriate. These phase III studies are carried out in a patient population that is representative of all of the potential approved therapeutic indications of the originator product and the most sensitive for detecting potential differences between the biosimilar and the reference product. Biosimilars have been used successfully across a wide range of therapeutic areas for the past 15 years where they have achieved substantial cost savings that can be reinvested into healthcare systems without affecting the quality of patient care. The current review provides an introduction to biosimilars with the aim of preparing retinal specialists for discussing these products with their patients.

Detection of Post-COVID-19 Patients Using Medical Scent Detection Dogs-A Pilot Study.

There is a growing number of COVID-19 patients experiencing long-term symptoms months after their acute SARS-CoV-2 infection. Previous research proved dogs' ability to detect acute SARS-CoV-2 infections, but has not yet shown if dogs also indicate samples of patients with post-COVID-19 condition (Long COVID). Nine dogs, previously trained to detect samples of acute COVID-19 patients, were confronted with samples of Long COVID patients in two testing scenarios. In test scenario I (samples of acute COVID-19 vs. Long COVID) dogs achieved a mean sensitivity (for acute COVID-19) of 86.7% (95%CI: 75.4-98.0%) and a specificity of 95.8% (95%CI: 92.5-99.0%). When dogs were confronted with Long COVID and negative control samples in scenario IIa, dogs achieved a mean sensitivity (for Long COVID) of 94.4 (95%CI: 70.5-100.0%) and a specificity of 96.1% (95%CI: 87.6-100.0%). In comparison, when acute SARS-CoV-2 positive samples and negative control samples were comparatively presented (scenario IIb), a mean sensitivity of 86.9 (95%CI: 55.7-100.0%) and a specificity of 88.1% (95%CI: 82.7-93.6%) was attained. This pilot study supports the hypothesis of volatile organic compounds (VOCs) being long-term present after the initial infection in post-COVID-19 patients. Detection dogs, trained with samples of acute COVID-19 patients, also identified samples of Long COVID patients with a high sensitivity when presented next to samples of healthy individuals. This data may be used for further studies evaluating the pathophysiology underlying Long COVID and the composition of specific VOC-patterns released by SARS-CoV-2 infected patients throughout the course of this complex disease.

Use of trained scent dogs for detection of COVID-19 and evidence of cost-saving.

Background: One of the lessons learned from the coronavirus disease 2019 (COVID-19) pandemic is the importance of early, flexible, and rapidly deployable disease detection methods. Currently, diagnosis of COVID-19 requires the collection of oro/nasopharyngal swabs, nasal turbinate, anterior nares and saliva but as the pandemic continues, disease detection methods that can identify infected individuals earlier and more quickly will be crucial for slowing the spread of the virus. Previous studies have indicated that dogs can be trained to identify volatile organic compounds (VOCs) produced during respiratory infections. We sought to determine whether this approach could be applied for detection of COVID-19 in Rwanda and measured its cost-saving. Methods: Over a period of 5 months, four dogs were trained to detect VOCs in sweat samples collected from human subjects confirmed positive or negative for COVID-19 by reverse transcription polymerase chain reaction (RT-PCR) testing. Dogs were trained using a detection dog training system (DDTS) and in vivo diagnosis. Samples were collected from 5,253 participants using a cotton pad swiped in the underarm to collect sweat samples. Statistical analysis was conducted using R statistical software. Findings: From August to September 2021 during the Delta wave, the sensitivity of the dogs' COVID-19 detection ranged from 75.0 to 89.9% for the lowest- and highest-performing dogs, respectively. Specificity ranged from 96.1 to 98.4%, respectively. In the second phase coinciding with the Omicron wave (January-March 2022), the sensitivity decreased substantially from 36.6 to 41.5%, while specificity remained above 95% for all four dogs. The sensitivity and specificity by any positive sample detected by at least one dog was 83.9, 95% CI: 75.8-90.2 and 94.9%; 95% CI: 93.9-95.8, respectively. The use of scent detection dogs was also found to be cost-saving compared to antigen rapid diagnostic tests, based on a marginal cost of approximately $14,000 USD for testing of the 5,253 samples which makes 2.67 USD per sample. Testing turnaround time was also faster with the scent detection dogs, at 3 h compared to 11 h with routine diagnostic testing. Conclusion: The findings from this study indicate that trained dogs can accurately identify respiratory secretion samples from asymptomatic and symptomatic COVID-19 patients timely and cost-effectively. Our findings recommend further uptake of this approach for COVID-19 detection.

Canine real-time detection of SARS-CoV-2 infections in the context of a mass screening event.

INTRODUCTION: Previous research demonstrated that medical scent detection dogs have the ability to distinguish SARS-CoV-2 positive from negative samples with high diagnostic accuracy. To deploy these dogs as a reliable screening method, it is mandatory to examine if canines maintain their high diagnostic accuracy in real-life screening settings. We conducted a study to evaluate the performance of medical scent detection dogs under real-life circumstances. METHODS: Eight dogs were trained to detect SARS-CoV-2 RT-qPCR-positive samples. Four concerts with a total of 2802 participants were held to evaluate canines' performance in screening individuals for SARS-CoV-2 infection. Sweat samples were taken from all participants and presented in a line-up setting. In addition, every participant had been tested with a SARS-CoV-2 specific rapid antigen test and a RT-qPCR and they provided information regarding age, sex, vaccination status and medical disease history. The participants' infection status was unknown at the time of canine testing. Safety measures such as mask wearing and distance keeping were ensured. RESULTS: The SARS-CoV-2 detection dogs achieved a diagnostic specificity of 99.93% (95% CI 99.74% to 99.99%) and a sensitivity of 81.58% (95% CI 66.58% to 90.78%), respectively. The overall rate of concordant results was 99.68%. The majority of the study population was vaccinated with varying vaccines and vaccination schemes, while several participants had chronic diseases and were under chronic medication. This did not influence dogs' decisions. CONCLUSION: Our results demonstrate that SARS-CoV-2 scent detection dogs achieved high diagnostic accuracy in a real-life scenario. The vaccination status, previous SARS-CoV-2 infection, chronic disease and medication of the participants did not influence the performance of the dogs in detecting the acute infection. This indicates that dogs provide a fast and reliable screening option for public events in which high-throughput screening is required.

Discrimination of SARS-CoV-2 Infections From Other Viral Respiratory Infections by Scent Detection Dogs.

Background: Testing of possibly infected individuals remains cornerstone of containing the spread of SARS-CoV-2. Detection dogs could contribute to mass screening. Previous research demonstrated canines' ability to detect SARS-CoV-2-infections but has not investigated if dogs can differentiate between COVID-19 and other virus infections. Methods: Twelve dogs were trained to detect SARS-CoV-2 positive samples. Three test scenarios were performed to evaluate their ability to discriminate SARS-CoV-2-infections from viral infections of a different aetiology. Naso- and oropharyngeal swab samples from individuals and samples from cell culture both infected with one of 15 viruses that may cause COVID-19-like symptoms were presented as distractors in a randomised, double-blind study. Dogs were either trained with SARS-CoV-2 positive saliva samples (test scenario I and II) or with supernatant from cell cultures (test scenario III). Results: When using swab samples from individuals infected with viruses other than SARS-CoV-2 as distractors (test scenario I), dogs detected swab samples from SARS-CoV-2-infected individuals with a mean diagnostic sensitivity of 73.8% (95% CI: 66.0-81.7%) and a specificity of 95.1% (95% CI: 92.6-97.7%). In test scenario II and III cell culture supernatant from cells infected with SARS-CoV-2, cells infected with other coronaviruses and non-infected cells were presented. Dogs achieved mean diagnostic sensitivities of 61.2% (95% CI: 50.7-71.6%, test scenario II) and 75.8% (95% CI: 53.0-98.5%, test scenario III), respectively. The diagnostic specificities were 90.9% (95% CI: 87.3-94.6%, test scenario II) and 90.2% (95% CI: 81.1-99.4%, test scenario III), respectively. Conclusion: In all three test scenarios the mean specificities were above 90% which indicates that dogs can distinguish SARS-CoV-2-infections from other viral infections. However, compared to earlier studies our scent dogs achieved lower diagnostic sensitivities. To deploy COVID-19 detection dogs as a reliable screening method it is therefore mandatory to include a variety of samples from different viral respiratory tract infections in dog training to ensure a successful discrimination process.

The Efficacy, Safety, and Immunogenicity of Switching Between Reference Biopharmaceuticals and Biosimilars: A Systematic Review.

To date, no consensus exists among stakeholders about switching patients between reference biological products (RPs) and biosimilars, which may have been curbing the implementation of biosimilars in clinical practice. This study synthesizes the available data on switching and assesses whether switching patients from a RP to its biosimilar or vice versa affects efficacy, safety, or immunogenicity outcomes. A total of 178 studies, in which switch outcomes from a RP to a biosimilar were reported, was identified. Data were derived from both randomized controlled trials and real-world evidence. Despite the limitations stemming from a lack of a robust design for most of the studies, the available switching data do not indicate that switching from a RP to a biosimilar is associated with any major efficacy, safety, or immunogenicity issues. Some open-label and observational studies reported increased discontinuation rates after switching, which were mainly attributed to nocebo effects. Involvement of the prescriber in any decision to switch should remain and attention should be paid to the mitigation of a potential nocebo effect.

Batch-to-Batch Consistency of SB4 and SB2, Etanercept and Infliximab Biosimilars.

BACKGROUND: Biosimilars must meet stringent regulatory requirements, both at the time of authorization and during their lifecycle. Yet it has been suggested that divergence in quality attributes over time may lead to clinically meaningful differences between two versions of a biologic. Therefore, this study investigated the batch-to-batch consistency across a range of parameters for released batches of the etanercept biosimilar (SB4) and infliximab biosimilar (SB2). METHODS: SB4 (Benepali®) and SB2 (Flixabi®) were both developed by Samsung Bioepis and are manufactured in Europe by Biogen at their facility in Hillerød, Denmark. A total of 120 batches of SB4 and 25 batches of SB2 were assessed for consistency and compliance with specified release parameters, including purity, post-translational glycosylation (SB4 only), protein concentration, and biological activity. RESULTS: The protein concentration, purity, tumor necrosis factor-α (TNF-α) binding, and TNF-α neutralization of all batches of SB4 and SB2 were within the strict specification limits set by regulatory agencies, as was the total sialic acid (TSA) content of all batches of SB4. CONCLUSIONS: Quality attributes of SB4 and SB2 batches showed little variation and were consistently within the rigorous specifications defined by regulatory agencies.

Are we ready to close the discussion on the interchangeability of biosimilars?

Since the introduction of the first biosimilar the discussion about their interchangeability has persisted. The body of evidence gathered for biosimilars provides reassurance that they are approved based on a rigorous comparability exercise and do not show clinically meaningful differences to their reference products. There are no data suggesting that the risk of switching to a biosimilar in terms of increased immunogenicity is greater than switching between two batches of any biologic. The key concern around switching biosimilars is the nocebo effect, which reinforces the need for physician involvement when switching. Whereas this might argue against automatic substitution of biosimilars, it is not a biosimilars-specific concern. To increase physician confidence in biosimilars, regulators should acknowledge that biosimilars are interchangeable.

Real-World Evidence on Etanercept Biosimilar SB4 in Etanercept-Naïve or Switching Patients: A Systematic Review.

INTRODUCTION: In 2016, SB4 (Benepali®) became the first etanercept (ETN) biosimilar to obtain marketing authorisation in Europe. Despite robust analytical and clinical comparisons, outstanding questions remain on SB4 use in routine practice. METHODS: A systematic search for publications on real-world evidence of SB4 effectiveness, safety and drug survival was undertaken using search terms (SB4 OR Benepali OR biosimilar etanercept OR innovator etanercept) in the BIOSIS® Toxicology, BIOSIS Previews®, Embase® and MEDLINE® databases up to 17 January 2019. RESULTS: Of 959 articles identified, eight journal articles, two journal letters and 23 congress abstracts were selected on criteria of original real-world evidence with a clinical focus. As expected with real-world evidence, quality scoring showed that the evidence had high external validity but lower internal validity. A total of 13,552 patients were described across nine European countries and all approved SB4 indications: 2499 were ETN-naïve and 11,053 switched from reference ETN to SB4 (switchers). Switch acceptance rates (a combination of clinicians offering and patients accepting initiation on SB4) ranged between 51.6% and 99.0%; patient support programmes positively contributed to acceptance. Disease activity was generally similar pre- and post-switch (typically 3-month timeframe). Retention rates across studies were at least 75% (up to 12 months follow-up). No new safety signals were identified. Differences in discontinuation rates versus historic controls reported in some studies may have been influenced by differences in treatment practices, lack of clinician confidence and nocebo effects. CONCLUSION: Nearly 2500 ETN-naïve patients have been initiated on SB4 and outcomes are similar to those patients receiving reference ETN. Overall this systematic review of real-world evidence provides additional reassurance that SB4 is as effective and safe as reference ETN in both switched and naïve patients. FUNDING: Biogen International GmbH.

Controversies in Establishing Biosimilarity: Extrapolation of Indications and Global Labeling Practices.

The principles of establishing biosimilarity are to demonstrate structural and functional similarity to a reference product using the most discriminatory analytical methods. There is still considerable controversy on the scientific basis for extrapolation of indications for biosimilars, which has been strengthened by diverging global regulatory decision making. Closely related to the question of extrapolation is the question of how to communicate the evidence base for authorizing biosimilars to healthcare professionals. In this paper we will consider some of the discussions around extrapolation of indications and the implications of decisions of various regulatory agencies in the world regarding the authorization and labeling of biosimilars.

Characteristics of product recalls of biopharmaceuticals and small-molecule drugs in the USA.

Compared with chemically synthesized small-molecule drugs, the manufacturing process of biopharmaceuticals is more complex. Unexpected changes to product characteristics following manufacturing changes have given rise to calls for robust systems to monitor the postauthorization safety of biopharmaceuticals. We compared quality-related product recalls in the USA of biopharmaceuticals and of small molecules. Although the reasons for recalls for biopharmaceuticals differed from those for small molecules, adverse events were rarely reported. The relative contribution of recalls that could cause serious adverse health consequences was not greater for biopharmaceuticals than for small molecules. Therefore, these data do not give rise to concerns that biopharmaceuticals are more frequently associated with unexpected safety concerns.