No two classes of biosimilars: Urgent advice to the US Congress and the FDA.

WHAT IS KNOWN AND OBJECTIVE: The United States is the only country with legislation to approve two classes of biosimilars. One has "no clinically meaningful difference" from the reference product, and when it is tested for switching and alternating, it can receive an interchangeable status. The objective of this review is to establish whether it is possible from the switching and alternating studies to evaluate additional safety or efficacy. METHODS: Analysed published data to ascertain if the testing with switching and alternating provide additional proof of safety or efficacy. Political and scientific rationale of creating a new class of biosimilars and how this affects the confidence in biosimilars. RESULTS AND DISCUSSION: There is no safety or efficacy concern when switching or alternating biosimilars with the reference product. Unfortunately, the rationale for interchangeability is more political than scientific, and it has brought more confusion and mistrust in using biosimilars in the United States. WHAT IS NEW AND CONCLUSION: The US Congress is requested to remove the interchangeability clause from the Biological Price and Competition Act to enable faster acceptance of biosimilars and remove the threat of lack of confidence in the safety of biosimilars.

On clinical thresholds, clinical equivalents and indirect comparisons of biological treatments for moderate-to-severe psoriasis.

WHAT IS KNOWN AND OBJECTIVE: To assess the equivalent efficacy of two or more treatments, clinical relevance must be adequately established, but there appears to be some confusion between clinical relevance and differences in absolute risk reduction or effect size, which quantifies the size of the difference between two groups. Delta values used for sample size calculation in clinical trials should take account of clinical relevance. We aim to illustrate this confusion as regards biologics for treatment of moderate-to-severe psoriasis. COMMENT: In psoriasis, treatment success has been defined as achieving lesion response to 'clear or almost clear', ≥ 90% improvement with respect to baseline Psoriasis Area and Severity Index (PASI), or achieving a PASI score lower than 3 on treatment. A PASI 75 response (≥ 75% improvement with respect to baseline) is often taken as a meaningful cut-off for clinical relevance. A recently published meta-analysis using a random-effects model showed that ustekinumab use was associated with statistically significantly higher odds for achieving PASI 75 response compared with adalimumab use (OR, 1·84; 95% credible interval, 1·01-3·54) and etanercept use (2·07; 1·42-3·06), but lower odds for achieving PASI 75 compared with infliximab use (0·36; 0·14-0·82). The inference is that this magnitude of response in PASI will translate into a perceptible clinical improvement by patients. This need not be the case. In particular, this measure does not take account of the adverse effect profiles of the different agents. Only by taking account of these different and opposing effects, such as through use of validated quality-of-life indices, can one make robust inferences on clinical equivalence. WHAT IS NEW AND CONCLUSION: From a clinical perspective, biologics for the treatment of plaque psoriasis should not be considered equivalents solely on the basis of PASI responses. Choice between these agents requires accounting for their relative safety and efficacy profiles, as well as patient-reported outcome measures. At the individual patient level, other factors such as individual contraindications must be taken into account.

Biologic therapies for moderate to severe psoriasis are not interchangeable.

Health care managers and hospital pharmacists are increasingly compelling prescribers to use medication substitutes. This policy becomes particularly evident when the agents are biologics with shared indications based on their assumed clinical equivalence and efficiency (cost-effectiveness), and in these cases the involvement of clinicians in decision making is often minimal or nonexistent. Lacking head-to-head clinical trials comparing various drugs, the prescriber can use indirect comparisons to define 2 or more agents as clinically equivalent therapeutic alternatives. This denomination of clinical equivalence does not imply that 2 such medications are truly therapeutically equivalent, or therapeutic equivalents, as this type of equivalence is defined by the absence of statistically significant differences between the drugs on all measures of effect in most patients, meaning that neither one is preferable to the other in different situations. Although real patients are not entirely comparable to those in clinical trials, the choice of a biologic agent to treat psoriasis is largely based on the findings of such trials. A recently published meta-analysis shows that not all the biologics currently available to treat moderate to severe psoriasis can be considered therapeutic equivalents, in spite of the authors' claim to the contrary; indeed, infliximab and etanercept can in no way be considered equivalent therapeutic alternatives based on the data provided. Biologics do display real differences with respect to efficacy at different time points and in the time required to onset of effect. In any case, therapeutic decisions should be made by an experienced clinician and tailored to each individual patient.

Effect of storage temperature and time on measurement of serum symmetric dimethylarginine concentration using point-of-care and commercial laboratory analyzers in cats and dogs.

BACKGROUND: Stability of serum symmetric dimethylarginine (sSDMA) during short- and long-term storage has not been assessed for the immunoassay of the Point-of-Care IDEXX Catalyst DX (POC) analyzer and the Enzyme Multiplied Immunoassay Technique of IDEXX commercial laboratory (CL). Also, the agreement between both analyzers is questioned. OBJECTIVES: To determine (a) the effect of storage time and temperature on sSDMA measured by POC and CL; (b) the agreement between sSDMA measured by POC and CL; and (c) the imprecision of the POC. ANIMALS: Serum of cats (n = 17) and dogs (n = 18) with a range of SDMA concentrations (6 to >100 µg/dL). METHODS: Based on an equivalence trial with predefined equivalence range (-3.0 to +3.0 µg/dL) and using T0 as baseline, stability was evaluated after 24 hours at 22°C and 4°C (POC); after 7 days at 4°C (POC and CL) and after 10 and 24 months at -24°C and -80°C (CL). Bland-Altman plots enabled method comparison. Imprecision of the POC was assessed by duplicate sSDMA measurements at T0. RESULTS: The POC analyzer produced equivalent sSDMA measurements if samples were stored for 24 hours at 4°C (95% confidence interval [CI]: -2.5-2.0 µg/dL), but not when stored for 24 hours at room temperature (RT; 95% CI: -4.1 to 0.5 µg/dL) or after 7 days at 4°C (95% CI: -3.6-1.0 µg/dL). The CL analyzer was less affected by preanalytical variation with clinically similar results obtained when samples were stored for 7 days at 4°C (95% CI: -2.2 to 2.4 µg/dL) and for at least 24 months at -24°C (95% CI: -1.7 to 2.9 µg/dL) and -80°C (95% CI: -1.5 to 3 µg/dL). A relevant mean difference of -2.3 µg/dL between both analyzers was found. Duplicate POC measurements were equivalent (95% CI: -2.6 to 2.0 µg/dL). CONCLUSIONS: Delayed analysis may significantly change sSDMA depending on storage and measurement conditions. Interchangeable use of assays should be done with caution because analytical variation could be interpreted as clinically relevant change.

Efficacy and Safety of CMAB008 Compared with Innovator Infliximab in Patients with Moderate-to-Severe Rheumatoid Arthritis Receiving Concomitant Methotrexate: A Randomized, Double-blind, Multi-center, Phase III Non-inferiority Study.

OBJECTIVES: The aim of this work is to verify the non-inferior efficacy and safety of CMAB008 compared with innovator infliximab in rheumatoid arthritis patients combined with methotrexate. METHODS: We conducted a randomized, double-blinded, parallel, positive control design, multicenter study, with a stable dose of methotrexate. Patients were enrolled randomly with a ratio of 1:1 to receive intravenously CMAB008 3 mg/kg or innovator infliximab 3 mg/kg at weeks 0, 2, 6, 14, 22 and 30. The primary efficacy endpoint was American College of Rheumatology 20% improvement criteria (ACR20) response rate at week 30. The non-inferiority was established if the lower limit of the one-sided 97.5% confidence interval (CI) for the difference was more than - 15% and the equivalence was established if the two-sided 95% CI was within ± 15% in an exploratory equivalence analysis. The secondary endpoints included other efficacy assessment parameters, as well as immunogenicity, safety, and pharmacokinetics. RESULTS: In the full analysis population (FAS), 110 (57.6%) of 191 patients in the CMAB008 group and 120 (62.2%) of 193 patients in the innovator infliximab group reached the primary outcome of ACR20 at week 30. The differences of the rates were - 4.6% and the lower limit of one-sided 97.5% confidence interval was - 14.29%, not less than the lower limit of the non-inferiority margin (- 15%); so CMAB008 was non-inferior to innovator infliximab. Further, CMAB008 was equivalent to innovator infliximab both in FAS (difference - 4.6%, 95% CI - 14.29% to 5.12%) and PPS (difference - 3.3%, 95% CI - 13.18% to 6.62%). The efficacy, safety, immunogenicity, and pharmacokinetics are highly similar between CMAB008 and innovator infliximab. CONCLUSIONS: Non-inferior efficacy of CMAB008 to innovator infliximab is illustrated with similar early and lasting therapeutic effects, and the equivalence is further demonstrated. CMAB008 is well tolerated and has semblable safety compared with the innovator infliximab. TRIAL REGISTRATION NUMBER: NCT03478111.

Clinical Equivalence between Generic Versus Branded Antibiotics: Systematic Review and Meta-Analysis.

Regulatory authorities authorize the clinical use of generic drugs (GD) based on bioequivalence studies, which consist of the evaluation of pharmacokinetics after a single dose in vitro or in healthy individuals. There are few data on clinical equivalence between generic and branded antibiotics. Our aim was to synthesize and analyze the available evidence on the clinical efficacy and safety of generic antibiotics compared to their original formulations. A systematic review was performed on Medline (PubMed) and Embase and validated through Epistemonikos and Google Scholar. The last search was conducted on 30 June 2022. Meta-analyses of clinical cure and mortality outcomes were performed. One randomized clinical trial (RCT) and 10 non-randomized intervention studies were included. No differences in clinical cure were observed between groups in the meta-analysis (OR = 0.89, 95% CI [0.61-1.28]; I2 = 70%, p = 0.005). No difference was observed between groups when considering the use of carbapenems for overall mortality (OR = 0.99, 95% CI [0.63-1.55]; I2 = 78%) or death associated with infections (OR = 0.79, 95% CI [0.48-1.29], I2 = 67%). Most of the studies were observational, and the duration of follow-up, the characteristics of the participants, and the sites of infections were heterogeneous. Due to the uncertainty of the evidence, it is not possible to contraindicate the use of generics, which is an important strategy to expand access.

Scientific Rationale for Waiving Clinical Efficacy Testing of Biosimilars.

After 18 years and the administration of billions of doses, there is little doubt about biosimilars' safety and efficacy. Yet, only 14 molecules in the EU and 9 in the US are available as biosimilars, among the 200+ targets, due mainly to the high development cost attributed to clinical efficacy testing after extensive analytical assessment, nonclinical testing, and clinical pharmacology comparisons. So far, none of the hundreds of clinical efficacy testing has failed because it cannot fail due to its lack of sensitivity for multiple reasons, as argued in this paper. This analysis is unique since biosimilars are the first category of products that are put to comparative testing as if these were new biological drugs. Clinical efficacy testing used to overcome differences in the analytical, nonclinical, and clinical pharmacology comparisons can lead to the approval of unsafe products. Only recently the regulatory agencies have begun to talk about this risk and shown their willingness to waive these studies. However, a clear change in the regulatory guidelines is required to change the mindset of all biosimilar stakeholders to bring a pivotal change in the availability of affordable biosimilars.

Equivalency of In vitro fertilization Success Rates in Elective Single Blastocyst Transfer and Elective Double Blastocyst Transfer: An Example of Equivalence Methodology in Clinical Reproductive Health.

CONTEXT: When comparing success rates between treatments, it is more appropriate to structure analyses in terms of equivalence rather than traditional analyses that assess differences. Unfortunately, no studies of elective single blastocyst transfer (eSBT) have been conducted in this manner. AIMS: The objective of this study was to assess clinical equivalence of in vitro fertilization success rates among patients undergoing eSBT. SETTINGS AND DESIGN: A historical prospective study was conducted at a private fertility center. METHODS: Medical records were reviewed to identify patients eligible for eSBT. Equivalency of success rates, defined as no more than a 10% difference based on 95% confidence intervals (CIs), was compared between eSBT (n = 125) and eDBT (n = 213) groups. RESULTS: Using traditional analysis techniques, no differences in pregnancy or live-birth rates were seen (eSBT: 84.6% vs. eDBT: 84.5%, P = 0.99; eSBT: 65.3% vs. eDBT: 72.3%, P = 0.23). The 95% CI around the difference in pregnancy rates ranged from -7.9 to 8.1, suggesting clinically equivalent pregnancy rates. Clinical equivalence was not established for live-births (95% CI = -18.5-4.5). CONCLUSIONS: Findings suggest comparable pregnancy rates can be achieved in a clinical setting when utilizing eSBT in good-prognosis patients. Although live-birth rate equivalence was not demonstrated, it is thought the additional complications associated with multiple gestations outweigh the potentially higher live-birth rate. The present study highlights the importance of utilizing equivalence analyses when making statements regarding the similarity of two treatments in reproductive health, rather than relying on superiority analyses alone.

Clinical equivalence of budesonide dry powder inhaler and pressurized metered dose inhaler.

INTRODUCTION: A delivery device is the most important factor that determines the local/systemic bioavailability of inhaled corticosteroids. Dry powder inhalers (DPIs) and pressurized metered dose inhalers (pMDIs) are the most commonly used delivery devices for localized drug delivery to the airways. OBJECTIVE: This study was to compare the clinical equivalence of budesonide delivered by the Pulmicort Turbuhaler (DPI) and the Aeronide inhaler (pMDI). MATERIALS AND METHODS: The two inhalers were compared for their pharmaceutical equivalence and clinical equivalence. The in vitro test included the uniformity of the delivered dose and determination of the aerodynamic particle size of budesonide. The in vivo test was carried out in 36 patients with mild to moderate asthma. This was a randomized, single-blinded study conducted for a period of 3 months. This included assessment of the spirometric parameters [forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), peak expiratory flow rate (PEFR), forced expiratory flow 25-75% (FEF25-75)], the severity of asthma symptoms, adverse events, frequency of short-acting inhaled bronchodilator usage and measurement of urinary cortisol levels. RESULTS: The aerodynamic particle size was slightly different between the two inhalers (2.3 ± 0.2 µm for Pulmicort Turbuhaler and 2.2 ± 0.2 µm for Aeronide inhaler). Both inhalers passed the uniformity of delivered dose (95.4% and 97.4%) specified in the British Pharmacopoeia. There was no statistically significant difference observed between the two inhalers in terms of the spirometric parameters, symptom-free days, frequency of bronchodilator usage and the level of urinary cortisol. CONCLUSION: In addition to pharmaceutical equivalence, no clinical difference observed between the two budesonide inhalers.

Fixed-dose combination ezetimibe+atorvastatin lowers LDL-C equivalent to co-administered components in randomized trials: use of a dose-response model.

Co-administration of ezetimibe with atorvastatin is a generally well-tolerated treatment option that reduces LDL-C levels and improves other lipids with greater efficacy than doubling the atorvastatin dose. The objective of the study was to demonstrate the equivalent lipid-modifying efficacy of fixed-dose combination (FDC) ezetimibe/atorvastatin compared with the component agents co-administered individually in support of regulatory filing. Two randomized, 6-week, double-blind cross-over trials compared the lipid-modifying efficacy of ezetimibe/atorvastatin 10/20 mg (n = 353) or 10/40 mg (n = 280) vs. separate co-administration of ezetimibe 10 mg plus atorvastatin 20 mg (n = 346) or 40 mg (n = 280), respectively, in hypercholesterolemic patients. Percent changes from baseline in LDL-C (primary endpoint) and other lipids (secondary endpoints) were assessed by analysis of covariance; triglycerides were evaluated by longitudinal-data analysis. Expected differences between FDC and the corresponding co-administered doses were predicted from a dose-response relationship model; sample size was estimated given the expected difference and equivalence margins (±4%). LDL-C-lowering equivalence was based on 97.5% expanded confidence intervals (CI) for the difference contained within the margins; equivalence margins for other lipids were not prespecified. Ezetimibe/atorvastatin FDC 10/20 mg was equivalent to co-administered ezetimibe+atorvastatin 20 mg in reducing LDL-C levels (54.0% vs. 53.8%) as was FDC 10/40 mg and ezetimibe+atorvastatin 40 mg (58.9% vs. 58.7%), as predicted by the model. Changes in other lipids were consistent with equivalence (97.5% expanded CIs <±3%, included 0); triglyceride changes varied more. All treatments were generally well tolerated. Hypercholesterolemic patients administered ezetimibe/atorvastatin 10/20 and 10/40 mg FDC had equivalent LDL-C lowering. This FDC formulation proved to be an efficacious and generally well-tolerated lipid-lowering therapy.