Generic Drugs and the Struggle to Compete: The Role of Skinny Labels.

PURPOSE: The generic drug industry currently faces multiple, serious issues that threaten the US drug supply. So-called "skinny labels" are one of the few tools authorized by Congress to expedite entry into the market by generic competitors when the first patent for a brand's drug compound (only) expires. This article reviews the law on this expedited marketing pathway for generic competitors, as well as limitations on its use. METHODS: We examined the literature on patent protection of brand drugs, including the timelines for production of generic competitors. We also examined the law concerning skinny labels, including a recent decision of the US Federal Circuit Court that clearly articulates the guidelines concerning entry into the generic market, including labeling, marketing, and promotion. FINDINGS: Skinny labels that follow the regulations set forth in the Hatch-Waxman Act, including the necessary carve-out procedure for "methods of use" still protected by 1 or more active patents, do not infringe a brand drug's label. Furthermore, the skinny label does not induce or contribute to infringement merely because its label contains US Food and Drug Administration-required safety profile data-even when the data cross-reference superiority studies on still-patent protected methods of use elsewhere in the label. IMPLICATIONS: Generic drugs have become essential to the broad, general availability of clinical therapeutic agents. The Hatch-Waxman Act was intended to facilitate entry of generic competitors into the marketplace, and the skinny label is an important tool to accomplish that end. As long as the generic manufacturer follows the essential skinny-label rules, specifically including marketing the compound without promoting or advertising those methods of use still protected by ongoing patents, the law will not find induced or contributory infringement.

Pharmacokinetics and Bioequivalence of Fixed-Dose Combination of Simvastatin and Ezetimibe Tablets: A Randomized, Crossover, Open-Label Study in Healthy Volunteers.

The current study aimed to evaluate the bioequivalence of a new generic combination of simvastatin and ezetimibe with the reference formulation. An open-label, randomized, 3-period, 3-sequence, crossover study, including 60 healthy volunteers, was implemented. Participants received the test and reference formulation, each containing 20 mg of simvastatin and 10 mg of ezetimibe as a single-dose tablet, separated by a minimum of 2-week washout periods. Blood samples were collected for 20 time points from predose to 72 hours after the dose. The total ezetimibe assay was carried out using a validated liquid chromatography-tandem mass spectrometry, while unconjugated ezetimibe, simvastatin, and simvastatin ß-hydroxy acid determination was done via a validated ultra-performance liquid chromatography-tandem mass spectrometry. Each assay was preceded by a liquid-liquid extraction step. The pharmacokinetic parameters were derived using noncompartmental analysis and then compared between the reference and test formulations via a multivariate analysis of variance. No statistical difference was found in under the concentration-time curve from time 0 to the last quantifiable concentration and maximum concentration of unconjugated ezetimibe, total ezetimibe, and simvastatin between the reference and test formulations. The 90% confidence intervals of unconjugated ezetimibe, total ezetimibe, and simvastatin natural log-transformed under the concentration-time curve from time 0 to the last quantifiable concentration, and maximum concentration were in the range of 80%-125% as per the bioequivalence acceptance criteria. Therefore, the test formulation was bioequivalent to the reference formulation.

Tell me your (cognitive) budget, and I'll tell you what you value.

Consider the following two (hypothetical) generic causal claims: "Living in a neighborhood with many families with children increases purchases of bicycles" and "living in an affluent neighborhood with many families with children increases purchases of bicycles." These claims not only differ in what they suggest about how bicycle ownership is distributed across different neighborhoods (i.e., "the data"), but also have the potential to communicate something about the speakers' values: namely, the prominence they accord to affluence in representing and making decisions about the social world. Here, we examine the relationship between the level of granularity with which a cause is described in a generic causal claim (e.g., neighborhood vs. affluent neighborhood) and the value of the information contained in the causal model that generates that claim. We argue that listeners who know any two of the following can make reliable inferences about the third: 1) the level of granularity at which a speaker makes a generic causal claim, 2) the speaker's values, and 3) the data available to the speaker. We present results of four experiments (N = 1323) in the domain of social categories that provide evidence in keeping with these predictions.

Development of Mechanistic In Vitro-In Vivo Extrapolation to Support Bioequivalence Assessment of Long-Acting Injectables.

Long-acting injectable (LAI) formulations provide sustained drug release over an extended period ranging from weeks to several months to improve efficacy, safety, and compliance. Nevertheless, many challenges arise in the development and regulatory assessment of LAI drug products due to a limited understanding of the tissue response to injected particles (e.g., inflammation) impacting in vivo performance. Mechanism-based in silico methods may support the understanding of LAI-physiology interactions. The objectives of this study were as follows: (1) to use a mechanistic modeling approach to delineate the in vivo performance of DepoSubQ Provera® and formulation variants in preclinical species; (2) to predict human exposure based on the knowledge gained from the animal model. The PBPK model evaluated different elements involved in LAI administration and showed that (1) the effective in vivo particle size is potentially larger than the measured in vitro particle size, which could be due to particle aggregation at the injection site, and (2) local inflammation is a key process at the injection site that results in a transient increase in depot volume. This work highlights how a mechanistic modeling approach can identify critical physiological events and product attributes that may affect the in vivo performance of LAIs.

Synthetic polypeptides using a biologic as a reference medicinal product - the European landscape of regulatory approvals.

Recent advances in synthetic drug manufacturing have introduced a new dynamic to the European regulatory system, with chemically synthesized polypeptide products using biological originator products as their reference medicine. Whereas biosimilars are subject to a dedicated regulatory framework in the EU, synthetically produced follow-on products are not eligible for assessment through this pathway, requiring approval via the traditional generic pathway under Article 10 (1), or via the hybrid pathway under Article 10 (3). This review presents an overview of recent developments in the field of synthetic peptides referencing biological originators in the EU. The use of different regulatory procedures can have potential implications for regulatory assessments, clinical practice and pharmacovigilance. As more complex synthetic products referencing recombinant originator products are expected in the coming years, this study promotes more transparency as well as global alignment about regulatory procedures for chemically synthesised products referencing biological originator products to ensure approval of safe and high-quality generics.

Apixaban Pharmacokinetics and Bioequivalence of Two Tablet Formulations: A Randomized, Open-Label, Crossover Study, Fasting Condition in Healthy Indonesian Volunteers.

The present study aimed to assess the bioequivalence of a new apixaban generic with reference formulation. Twenty-six healthy volunteers were recruited for an open-label, balanced, randomized, 2-treatment, 2-sequence, 2-period, single oral dose study. Following overnight fasting, each volunteer received 5 mg of apixaban test and reference formulations as single doses, separated by a 1-week washout period. Twenty blood samples were collected at predose and multiple time points between 0.5 and 72 hours after dosing. A validated ultra-performance liquid chromatography-tandem mass spectrometry detection method following a protein precipitation step was implemented to determine apixaban concentrations. Noncompartmental analysis was used to derive the pharmacokinetic parameters, which were then compared between the test and reference products using a multivariate analysis of variance. The pharmacokinetic parameters of the test product were not statistically different from the reference product, and the 90% confidence intervals of apixaban natural log-transformed area under the concentration-time curve from time 0 to infinity, area under the concentration-time curve from time 0 to the last measurable concentration, and maximum concentration were within 80%-125% based on the bioequivalence acceptance range criteria. The test and reference formulations of apixaban are bioequivalent in healthy subjects under fasting conditions.

Dermatology medications with the highest cost burden on Medicare Part D: Potential implications of the Inflation Reduction Act.

Signed into law in August 2022, the Inflation Reduction Act includes provisions requiring the federal government to negotiate prices for medications covered under Medicare Part D. Initial negotiations will target drugs with the highest total spending and price increases relative to inflation. In this study, we identify dermatology prescriptions with the highest cost burden on Medicare Part D and analyze recent trends in total spending and unit costs.

Experience Learned and Perspectives on Using Model-Integrated Evidence in the Regulatory Context for Generic Drug Products-a Meeting Report.

This report summarizes relevant insights and discussions from a 2022 FDA public workshop titled Best Practices for Utilizing Modeling Approaches to Support Generic Product Development which illustrated how model-integrated evidence has been used and can be leveraged further to inform generic drug product development and regulatory decisions during the assessment of generic drug applications submitted to the FDA. The workshop attendees discussed that model-integrated evidence (MIE) approaches for generics are being applied in the space of long-acting injectable (LAI) products to develop shorter and more cost-effective alternative study designs for LAI products. Modeling and simulation approaches are utilized to support virtual BE assessments at the site of action for locally acting drug products and to assess the impact of food on BE assessments for oral dosage forms. The factors contributing to the success of the model-informed drug development program under PDUFA VI were discussed. The generic drug industry shared that decisions on formulation candidate/formulation variant selection, on pilot in vivo bioavailability studies, and on alternative study designs for BE assessment are informed by modeling and simulation approaches. There was agreement that interactions between the regulatory agencies and the industry are desirable because they improve the industry's understanding of scientific and other regulatory considerations on implementing modeling and simulation approaches in drug development and regulatory submissions.

Testimony and observation of statistical evidence interact in adults' and children's category-based induction.

Hearing generic or other kind-relevant claims can influence the use of information from direct observations in category learning. In the current study, we ask how both adults and children integrate their observations with testimony when learning about the causal property of a novel category. Participants were randomly assigned to hear one of four types of testimony: generic, quantified "all", specific, or only labels. In Study 1, adults (N = 1249) then observed that some proportion of objects (10%-100%) possessed a causal property. In Study 2, children (N = 123, Mage = 5.06 years, SD = 0.61 years, range 4.01-5.99 years) observed a sample where 30% of the objects had the causal property. Generic and quantified "all" claims led both adults and children to generalize the causal property beyond what was observed. Adults and children diverged, however, in their overall trust in testimony that could be verified by observations: adults were more skeptical of inaccurate quantified claims, whereas children were more accepting. Additional memory probes suggest that children's trust in unverified claims may have been due to misremembering what they saw in favor of what they heard. The current findings demonstrate that both child and adult learners integrate information from both sources, offering insights into the mechanisms by which language frames first-hand experience.

Immunosuppression with Generics in Liver and Kidney Transplantation: A Real-World Evidence Study.

Purpose: This study evaluates the use, benefit-risk profile, and economic impact of generic immunosuppressants (tacrolimus-TAC, cyclosporine-CsA, and mycophenolate-MYC) in kidney and liver transplant recipients compared to brand-name drugs. Patients and Methods: A retrospective multicentre observational study, involving four Italian regions, was conducted based on the national transplant Information system and regional healthcare claims data. The analysis focused on incident patients who received kidney and liver transplants between 2013 and 2019 and evaluated the use of generic of CsA, TAC, and MYC during the 30-day period following discharge. For each type of transplant and immunosuppressive agent, the benefit-risk profile of generic vs branded drugs in a two-year window was estimated by multivariate Cox models (HR; 95% CI). Furthermore, the potential cost savings per person associated with one year of treatment using generics were calculated. Results: The utilization of generic drugs showed a significant increase; over the study years, the proportion of users among kidney recipients ranged from 14.2% to 40.5% for TAC, from 36.9% to 56.7% for MYC, and from 18.2% to 94.7% for CsA. A great variability in generic uptake for region was found. A comparable risk-benefit profile between generic and branded formulations was shown for all immunosuppressors considered. Choosing generic immunosuppressants during maintenance could result in yearly savings of around 2000 euros per person for each therapy ingredient. Conclusion: The study shows an increasing proportion of patients using generic immunosuppressive drugs over time suggesting a growing acceptance of generics within the transplant community and reveals comparable risk-benefit profiles between the generic and branded formulations of TAC, CsA, and MYC. A significant variability in the use of generics immunosuppressive agents was found both at the regional level and among transplant centers and future research should delve into regional prescribing variations.

Untapped options to reduce waste from blister packaging for tablets and capsules.

PURPOSE: In Europe, most medicines are taken orally and primarily packaged as single solid oral dosage forms (SODF) in blister chambers (alveoli) arranged on blister cards. Blister cards are constructed as multilayer laminates of aluminum (Al) foils and/or various plastic polymers bonded together, forming the alveoli, which are separated by more or less large gaps. We calculated the amount of packaging material (and thus waste) generated annually for the packaging of the most commonly prescribed SODF in Germany and estimated how much waste could be saved by rearranging the alveoli. METHODS: For this purpose, we analysed the SODF of the 50 most frequently prescribed medicines that were packaged in alveoli (N = 45; 13 of aluminum-aluminum blisters, 32 of mixed materials), measured and weighed their packaging material and content, calculated the annual amount of waste produced from them, and estimated how much waste could be saved if the alveoli were optimally positioned on the blister cards. In addition, we examined the variability of the blister packaging of eight groups of commonly prescribed generics of the same strength. RESULTS: Detailed analysis of the blister cards revealed that most of the material (69%) was used for the space between blisters and that aluminum-aluminum alveoli were more than four times larger than the packaged SODF. The (conservatively) estimated annual amount of composite waste generated for the primary packaging of these SODF was 3868 t (and extrapolated to the entire German pharmaceutical market 8533 t), of which an optimized arrangement of the blister chambers, i.e., a 2-mm sealing area around each alveolus and the arrangement of the SODF in 2 rows, would save approximately 37%. CONCLUSION: Considering that other ecological strategies are not yet mature, the optimal arrangement of blister chambers would be a captivatingly simple and, above all, immediately implementable strategy to avoid large amounts of avoidable waste.

Trends in price for topical corticosteroids from 2017 to 2021 and the opportunity for cost savings identifiable at the point of care: A retrospective cross-sectional study.

BACKGROUND: Topical corticosteroids possess numerous generics and similar-strength substitutes. Affordability can impact obtaining the medication prescribed. OBJECTIVE: To determine recent trends in topical corticosteroid pricing and potential for cost saving. METHODS: A retrospective cross-sectional study analyzing all prescriptions dispensed for topical corticosteroids from January 1, 2017 through December 31, 2021, using a US all-payer pharmacy-claims database and commercial coupon dataset, was performed. RESULTS: Two hundred thirty-seven unique drug products (≥1 claim) were identified. Factors that predicted for higher cost (P < .05) were branded products (105% more expensive than generics) and ultrapotent class (55% more expensive than low potency) while ointments predicted for lower cost (19% less expensive than creams). Cash prices remained relatively stable, except for ultrapotent branded topical corticosteroids (63% increase). Cost savings were available for both brand-to-generic ($14.75 per unit) and generic-to-generic ($6.82 per unit) switching. Coupon prices were consistently lower than cash prices (r = 0.89). LIMITATIONS: Contracted rates through insurance plans were not included. CONCLUSIONS: Topical corticosteroid prices over the past 5 years have stabilized, the exception being branded ultrapotent corticosteroids. Savings from switching among similar-strength substitutes remain significant despite price stabilization. Coupon prices mirror the hierarchy of cash prices and can help assess real-time costs.

[Comparison of the effectiveness of rabeprazole original and generic products in the monotherapy of gastroesophageal reflux disease].

AIM: To compare the effectiveness of rabeprazole original and generic products in the treatment of gastroesophageal reflux disease (GERD) using impedance-pH monitoring. MATERIALS AND METHODS: Patients (n=35) diagnosed with GERD were divided into two groups. Group 1 patients (n=17, 45.2±1.7 years) received the rabeprazole original product (Pariet) 20 mg/day; Group 2 patients (n=18, 48.1±1.9 years) received 20 mg/day of a generic product. On Day 10 of therapy, all patients underwent 24-hour esophagus impedance-pH monitoring (Ohmega, Medical Measurement Systems, the Netherlands). The percentage of time with pH<4 in the esophagus, the total number and number of acidic, slightly acidic and slightly alkaline gastroesophageal refluxes (GERs), the latency period, and the duration of rabeprazole action were analyzed. The clinical efficacy of the drug was assessed using the GerdQ questionnaire. Statistical data were processed using Microsoft Office 2010 (Excel) and Biostat 2000 software packages. RESULTS: No significant differences were noted between the two groups of patients by gender, age, body mass index, smoking frequency, and GERD type (p>0.05). The average duration of action of the rabeprazole original product was significantly higher than that of the generics (13.2±0.6 and 8.8±0.7 h, respectively, p<0.05). In the rabeprazole original product group, compared to the generics group, the following values were lower: total GERs - 47.0 [43.3; 60.0] and 71.8 [54.3; 95.0], respectively, p<0.05; percentage of time with intraesophageal pH<4 - 1.8 [0.5; 2.3] and 2.1 [0.3; 6.8], respectively, p<0.05; the number of acidic GERs - 4.7 [2.2; 12.0] and 23.3 [12.6; 32.0], respectively, p<0.05. The total GerdQ questionnaire score in Group 1 was significantly lower than in Group 2 (5.4±0.1 vs 6.9±0.4, respectively; p>0.05). CONCLUSION: In treating GERD with the rabeprazole original product compared to generics, a significantly longer duration of acid production suppression, a more pronounced decrease in esophageal acidification, and a more statistically significant clinical improvement were observed.

Do Tofacitinib Generics Exhibit Conventional Synthetic Disease-Modifying Anti-rheumatic Drug and Non-steroidal Anti-inflammatory Drug-Sparing Ability in the Management of Axial Spondyloarthritis?

INTRODUCTION: Tofacitinib has emerged as a therapeutic option for axial spondyloarthritis (axSpA) following successful clinical trials. The evidence on the efficacy of tofacitinib generics in the management of axSpA is limited. In India, the usage of conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) is commonplace in the management of axSpA. Our primary aim was to identify the csDMARD and non-steroidal anti-inflammatory drug (NSAID)-sparing role of tofacitinib generics in an axSpA population. METHODS: This was a retrospective study in a real-world clinical setting. Data from nine rheumatology centers across India were analyzed for 168 patients with active axSpA who were initiated on generic tofacitinib 5 mg twice daily in conjunction with csDMARDs and NSAIDs, over a duration of six months. Our primary outcome was to evaluate the csDMARD and NSAID-sparing effect of tofacitinib generics, while the secondary outcome assessed safety profiles and efficacy at six months. RESULTS: The median Ankylosing Spondylitis Disease Activity Score (ASDAS) erythrocyte sedimentation rate (ESR) score of the study population was 3.91 (3.26, 4.56). Alongside tofacitinib generics, 121 (72%) patients were co-administered csDMARDs (methotrexate/sulfasalazine/both), and 90 (53.6%) patients were co-administered NSAIDs. The csDMARD, NSAID, and combined csDMARD + NSAID-sparing effects of tofacitinib generics were seen in 85 (50.6%), 156 (92.9%), and 81 (48.2%) patients, respectively. Adverse events were mild and well-tolerated. At six months, 124 (57.9%) patients had attained clinically important improvement in ASDAS ESR score, and the median decrease in ASDAS ESR score was 2.02 (1.18, 2.96). CONCLUSION: This real-world study provides evidence supporting the csDMARD and NSAID-sparing ability of tofacitinib generics in the treatment of axSpA. Tofacitinib generics displayed a good safety profile and showed signals of efficacy as well.

Authorized Generics In The US: Prevalence, Characteristics, And Timing, 2010-19.

Authorized generics are approved brand-name drugs that are sold by brand-name manufacturers or licensees without brands on their labeling. Despite their prevalence in prescription drug markets in the US, little is known about trends in their launches, their timing relative to traditional generics, and the characteristics of their respective brand-name drugs. We linked Food and Drug Administration and IQVIA data to investigate newly launched authorized generics during the period 2010-19. We found 854 launches over this period, with launches peaking in 2014. Marketing appears strategic: In markets with traditional generics, three-fourths of authorized generics launched after the respective generic competition started. When we focused on markets where generics were eligible for the 180-day exclusivity, about 70 percent of authorized generics launched before or during the exclusivity period. These findings provide insights for future research on the effect of authorized generics on competition, prices, and access to generics.

Integration of artificial neural network and physiologically based biopharmaceutic models in the development of sustained-release formulations.

Model-informed drug development is an important area recognized by regulatory authorities and is gaining increasing interest from the generic drug industry. Physiologically based biopharmaceutics modeling (PBBM) is a valuable tool to support drug development and bioequivalence assessments. This study aimed to utilize an artificial neural network (ANN) with a multilayer perceptron (MLP) model to develop a sustained-release matrix tablet of metformin HCl 500 mg, and to test the likelihood of the prototype formulation being bioequivalent to Glucophage® XR, using PBBM modeling and virtual bioequivalence (vBE). The ANN with MLP model was used to simultaneously optimize 735 formulations to determine the optimal formulation for Glucophage® XR release. The optimized formulation was evaluated and compared to Glucophage® XR using PBBM modeling and vBE. The optimized formulation consisted of 228 mg of hydroxypropyl methylcellulose (HPMC) and 151 mg of PVP, and exhibited an observed release rate of 42% at 1 h, 47% at 2 h, 55% at 4 h, and 58% at 8 h. The PBBM modeling was effective in assessing the bioequivalence of two formulations of metformin, and the vBE evaluation demonstrated the utility and relevance of translational modeling for bioequivalence assessments. The study demonstrated the effectiveness of using PBBM modeling and model-informed drug development methodologies, such as ANN and MLP, to optimize drug formulations and evaluate bioequivalence. These tools can be utilized by the generic drug industry to support drug development and biopharmaceutics assessments.