Efficacy and safety of generic pomalidomide plus low-dose dexamethasone in relapsed or refractory multiple myeloma: a multicenter, open-label, single-arm trial.

This multicenter, open-label, single-arm trial (ClinicalTrials.gov, NCT05236621) was conducted to confirm the efficacy and safety of generic pomalidomide plus dexamethasone in Chinese patients with relapsed or refractory multiple myeloma (RRMM). Total 79 eligible RRMM patients were planned to be included. Patients were treated with generic pomalidomide (4 mg daily on days 1-21, orally) and low-dose dexamethasone (40 mg/day on days 1, 8, 15, and 22, orally; 20 mg for patients aged > 75 years) in 28-day cycles until disease progression with a maximum treatment duration of 2 years. The primary endpoint is the overall response rate (ORR) assessed by the independent review committee per the 2016 International Myeloma Working Group guidelines. A total of 85 eligible patients were included in this study from 32 centers in China, with a median age of 62.0 (range, 39-76) years, a median prior line of therapy of 4 (range, 1-16), and 41.2% patients with high-risk cytogenetics. The ORR was 38.8% (95% confidence interval (CI), 28.44-50.01). The disease control rate was 67.1% (95% CI, 56.02-76.87), meanwhile, the median progression-free survival was 5.55 months (95% CI, 3.68-7.52). Among the treatment-related adverse events (TRAEs), infective pneumonia (17.6%) was the most frequent non-hematologic adverse event, while a decrease in neutrophil count (52.9%) was the most common grade ≥ 3 TRAE. The study results indicated that the generic pomalidomide demonstrated consistent efficacy and a safety profile similar to the branded pomalidomide when combined with low-dose dexamethasone in Chinese RRMM patients.Registration number ClinicalTrials.gov NCT05236621, retrospectively registered on February 11, 2022.

Pharmaceutical equivalent 5-aminolevulinic acid fluorescence guided resection of central nervous system tumors: feasibility, safeness and cost-benefit considerations.

PURPOSE: 5-aminolevulinic acid (5-ALA) fluorescence-guided resection (FGR) has been an essential tool in the 'standard of care' of malignant gliomas. Over the last two decades, its indications have been extended to other neoplasms, such as metastases and meningiomas. However, its availability and cost-benefit still pose a challenge for widespread use. The present article reports a retrospective series of 707 cases of central nervous system (CNS) tumors submitted to FGR with pharmacological equivalent 5-ALA and discusses financial implications, feasibility and safeness. METHODS: From December 2015 to February 2024, a retrospective single institution series of 707 cases of 5-ALA FGR were analyzed. Age, gender, 5-ALA dosage, intraoperative fluorescence finding, diagnosis and adverse effects were recorded. Financial impact in the surgical treatment cost were also reported. RESULTS: there was an additional cost estimated in $300 dollars for each case, increasing from 2,37 to 3,28% of the total hospitalization cost. There were 19 (2,69%) cases of asymptomatic photosensitive reaction and 2 (0,28%) cases of photosensitive reaction requiring symptomatic treatment. 1 (0,14%) patient had a cutaneous rash sustained for up to 10 days. No other complications related to the method were evident. In 3 (0,42%) cases of patients with intracranial hypertension, there was vomiting after administration. CONCLUSION: FGR with pharmacological equivalent 5-ALA can be considered safe and efficient and incorporates a small increase in hospital expenses. It constitutes a reliable solution in avoiding prohibitive costs worldwide, especially in countries where commercial 5-ALA is unavailable.

Developing Prioritization Criteria to Identify Target Drugs for CalRx, the California Generic Drugs Initiative.

OBJECTIVES: This study aimed to establish criteria to identify priority drugs for CalRx, a California-sponsored initiative to support the manufacture and distribution of affordable generic drugs. METHODS: A web-based ranking exercise was implemented with key stakeholders in August 2020, using pricing, spending, and public health criteria identified through a review of academic literature and public health agency reports. A total of 39 of 40 invited stakeholders in 4 different categories-patient advocates, healthcare providers, health insurers, and health policy and economic experts-participated in this study (98% response rate). RESULTS: Drugs that treat large populations, drugs that represent high cost to payors, and drugs that represent high cost to consumers were ranked a priority, receiving > 10% of ranking weights. Drugs that treat conditions with high morbidity or mortality, drugs without therapeutic alternatives, and drugs treating vulnerable populations represented criteria of further interest (9%-10% of weights). Shortage risk and curative effect (8%-9% of the weights), high price increases, communicable disease treatments, and high unit prices (< 8% of the weights) represented the bottom of the priority distribution. CONCLUSIONS: This study suggests that drugs that treat large populations, drugs that represent large costs to payors, and drugs that represent large costs to consumers should be the priority for California's CalRx generic drug initiative. A prioritizing algorithm will assist California in determining top drugs to target from a public health and spending perspective as it plans the rollout of the CalRx initiative and negotiates with drug manufacturers.

Synthesis and characterization of two potential impurities (des-ethyl-Ganirelix) generated in the Ganirelix manufacturing process.

Controlling certain diseases using peptide drugs has remarkably increased in the past two decades. In this regard, a generic formulation is an upfront solution to fulfill market demands. Ganirelix, a leading peptide active pharmaceutical ingredient (API) primarily used as a gonadotropin-releasing hormone antagonist (GnRH), has established a potential market value worldwide. But its generic formulation mandates detailed impurity profiles from a synthetic source and contemplates the sameness of a reference-listed drug (RLD). Post-chemical synthesis and processing of Ganirelix, some commercial sources have revealed two new potential impurities among many known, which show the deletion of an ethyl group from the hArg(Et)2 residue at the sixth and eighth positions, named des-ethyl-Ganirelix. These impurities are unprecedented in traditional peptide chemistry, and such monoethylated-hArg building blocks are not easily accessible commercially to synthesize these two impurities. Here, we have outlined the synthesis, purification, and enantiomeric purity characterization of the amino acids and their incorporation in the Ganirelix peptide sequence to synthesize these potential peptide impurities. This methodology will enable the convenient synthesis of side-chain substituted Arg and hArg derivatives in peptide drug discovery platforms.

Within-subject pharmacokinetic variability has a strong influence on individual exposure ratios in bioequivalence studies, hence on drug formulation interchangeability.

INTRODUCTION: Bioequivalence between a reference and a generic drug is based on the hypothesis that a ± 20% change in blood exposure (or ± 10% for drugs with narrow therapeutic index, NTI) following the generic/reference switch will not have any therapeutic consequences. However, the individual exposure ratio between generic and reference can be higher than 1.20 (or 1.10). This study aims to analyse the different parameters influencing the individual exposure ratio, hence the conditions for reference/generic interchangeability. METHODS: Bioequivalence studies with a double cross-over design for a virtual drug were simulated using 100 random sets of 12, 24, 48 or 100 pairs of areas under the curve (AUC), varying the generic/reference AUC geometric mean ratios between 0.80 and 1.25 and the within-subject exposure variance of the reference and the generic formulations. RESULTS: The proportion of subjects with an exposure generic/reference ratio outside the ± 10% or ± 20% acceptance intervals increases when (1) the reference within-subject variance increases; (2) the ratio of the generic within-subject variance on the reference within-subject variance increases; and (3) the generic/reference mean AUC ratio diverges from 1.0. When only considering replicated administrations of the reference, the individual exposure ratio increases with the within-subject variance, yielding values outside the usually accepted individual exposure ratio range of 0.5 to 2 for drugs with narrow therapeutic index as soon as the within-subject variance standard deviation is ≥ 0.25 (equivalent to within-patient CV% > 25%). CONCLUSIONS: Interchangeability between reference and generic formulations, especially for drugs with narrow therapeutic index can only be assumed if, the within-subject variance of generic is less or equal to the within-subject variance of reference or, if this is not the case, if the distribution of the generic/generic individual exposure ratios is included within the therapeutic margins of the reference drug.

Factors influencing drug switching and changes in low-density lipoprotein-cholesterol levels with atorvastatin: a real-world observational study.

BACKGROUND: Although generic drugs have been approved with the assurance of interchangeable applications with original drugs, some physicians, and patients still view their efficacy and interchangeability negatively. Using real-world data, we aimed to determine factors that impact switching between drugs that contain the same active ingredient, i.e., atorvastatin, and, in turn, whether this 'switch' could alter clinical outcomes. METHODS: Using the National Health Insurance Service senior cohort, a retrospective cohort study was conducted to assess patients who had newly started atorvastatin 10 mg and had at least two records of national health examinations from 2010 to 2014. Drug switching, which was defined as a change in the atorvastatin product administered 90 days before the first and second examinations, was assessed. Greedy propensity score matching (1:2) was performed between switchers and non-switchers to control for potential confounders. Factors influencing switching were analyzed using multivariate logistic regression to estimate odds ratios and 95% confidence intervals (CIs). Changes in low-density lipoprotein-cholesterol (LDL-C) levels attributable to drug switching were evaluated using difference-in-differences regression. RESULTS: A total of 1,588 patients were included, of whom 25.3% switched drugs (1,187 non-switchers and 401 switchers). Compared to patients taking generics before the first examination, those taking the original drugs had a lower odds ratio (0.31; 95% CI [0.21, 0.46]) for subsequent drug switching. A change in medical institution was associated with a significantly higher odds ratio (6.83; 95% CI [4.66, 10.02]). There were no significant differences in LDL-C alterations between switchers and non-switchers (0.42 mg/dL; 95% CI [-2.29, 3.13]). CONCLUSION: The type of first-time drug administered and changes in medical institution can influence drug switching. No significant changes in LDL-C values were observed in the various switching scenarios between the original and generic drugs, suggesting their interchangeable application in real-world clinical practice.

Legal Approaches to New Psychoactive Substances: First Empirical Findings.

BACKGROUND: Generic drug legislation, i.e., simultaneously banning groups of drugs, has been introduced worldwide to counteract the trade and use of emerging "new psychoactive substances" (NPSs) more effectively. SUMMARY: The potential and de facto positive and negative effects of generic drug legislation have been described using an analysis based on documented evaluations of the experiences in the UK and Germany, supplemented with data from other publicly available sources. In particular, the effects of generic drug legislation on availability, use, sales, and overall health harms of NPS, and switches from NPS to traditional (classical) drugs are addressed. The results show that the introduction of generic drug legislation in the UK and Germany has enabled stricter regulation of NPS but has also led to some major harms within the domain of public health. Depending on the population considered, the rate of NPS use remained stable, slightly declined, or increased following the banning of NPS. Once banned, NPSs were more often purchased on the black market, often together with other (more harmful) drugs. Moreover, NPS-related harms did not reduce following the ban, and in some cases even increased. Finally, when harmful NPS, like potent synthetic opioids and cannabinoids, become substantially used and endanger public health, legislators already have the legal means to ban the problem drug, thus overruling the need for a generic ban. KEY MESSAGES: Generic drug legislation may facilitate drug law enforcement, but it is not (very) effective in counteracting NPS use and it may increase NPS-related public health problems. It is concluded that, overall, the advantages of generic drug legislation are overshadowed by its serious disadvantages.

Transitioning Long-Acting Products to a Generic Marketplace: What's Missing?

Development of and increased access to generic oral medications to treat high-burden diseases including human immunodeficiency virus (HIV), tuberculosis, viral hepatitis, and malaria have had a major impact on reducing global morbidity and mortality. However, access and adherence to these life-saving treatments remains limited for some of the most vulnerable and underserved populations, for whom stigma, control, and discretion are critical to decisions around care. Current efforts to develop long-acting formulations to treat and prevent these conditions could overcome many of these barriers. However, generic manufacturing of these innovative products will be required to ensure affordable access to the communities and patients in greatest need. Strategic investments in new infrastructure will be required even before markets and manufacturing costs are clear, to ensure that access to these new products is not delayed, particularly for patients in low- and middle-income countries. Unlike conventional oral medications, long-acting products require greater investment for formulation, packaging, and delivery. The requirement for long-term bioequivalence studies will introduce additional delays in regulatory approval of generic long-acting products, and expedited approval pathways must be developed. Lessons learned from the development of long-acting hormonal contraceptives and long-acting antiretroviral products may provide a way forward.

Interchangeability of generic drugs for subpopulations: Bioequivalence simulation from a nonparametric PK model of gabapentin generic drugs.

Patients are often switched between generic formulations of the same drug, but in some cases generic interchangeability is questioned. For generic drugs to be approved, bioequivalence with the innovator drug should be demonstrated, but evidence of bioequivalence is not required in the intended patient population or relative to other approved generics. AIM: We aim to identify pathophysiological pharmacokinetic subpopulations for whom there is a difference in comparative bioavailability compared to a healthy population. METHODS: We used simulated exposures from a nonparametric model of multiple generics and the originator gabapentin. Exposure was simulated for virtual populations with pharmacokinetic characteristics beyond those of healthy subjects with regard to rate of absorption, volume of distribution and reduced renal function. Virtual parallel design bioequivalence studies were performed using a random sample of 24 simulated subjects, with standard acceptance criteria. RESULTS: Results indicated increased pharmacokinetic variability for patient populations with a lower rate of absorption or a reduced renal function, but no change in the average comparable bioavailability ratio. This increased variability results in a reduced likelihood of demonstrating bioequivalence. Observations were similar for comparisons between all different formulations, as well as between subjects who received the identical formulation in a repeated fashion. No relevant effect was observed for simulations with increased volume of distribution. CONCLUSION: Our simulations indicate that the reduced likelihood of demonstrating bioequivalence for subjects with altered pharmacokinetics is not influenced by a formulation switch, nor does the average comparable bioavailability ratio change, therefore these results support generic interchangeability and current approval requirements for generics.

Harmonization of summaries of product characteristics (SmPCs) of drugs with the same active ingredients: an evaluation of SmPCs of the most frequently prescribed active substances.

PURPOSE: In aut-idem or generic substitution, discrepancies between summaries of product characteristics (SmPCs) referring to the same active substance (AS) may cause difficulties regarding informed consent and medical liability. The qualitative and quantitative characteristics of such discrepancies are insufficiently studied, impeding harmonization of same-substance SmPCs and compromising safe drug treatment. METHODS: SmPCs of the one hundred most frequently prescribed ASs in Germany were analyzed for discrepancies in the presentation of indications (Inds) and contraindications (CInds). Inclusion and exclusion criteria of drugs/SmPCs were chosen according to the standards of the aut-idem substitution in Germany. RESULTS: According to the study protocol, we identified 1486 drugs, of which 1426 SmPCs could be obtained. 41% respectively 65% of the ASs had same-substance SmPCs that differed from the respective reference SmPC in the number of listed Inds respectively CInds. The number of listed Inds/CInds varied considerably between same-substance SmPCs with maximum ranges in Inds of 7 in amoxicillin, and in CInds of 11 in lisinopril. Many ASs had large proportions (> 50%) of associated same-substance SmPCs that differed from the respective reference SmPC. A considerable proportion of ASs had same-substance SmPCs with formal and content-related differences other than the discrepancy in the number of Inds/CInds. CONCLUSION: This evaluation of same-substance SmPCs shows a clear lack of harmonization of same-substance SmPCs. Considering that generic substitution has become the rule and that physicians usually do not know which drug the patient receives in the pharmacy, these discrepancies raise several questions, that require a separate legal evaluation.

Current status of biosimilars in Turkey: A survey among medical oncologists.

INTRODUCTION: To evaluate biosimilar understanding and preference trends of medical oncologists in Turkey. METHODS: A survey consisting of 24 multiple-choice questions with checkbox answers was conducted among medical oncologists. The questionnaire was divided into five parts to some intentions: demographic characteristics, general knowledge about biosimilars, knowledge about local approval and reimbursement issues, individual preference trends, and ranking the knowledge of their own. All answers were analyzed as whole cohort, specialists and fellows. RESULTS: Fellows (n = 47) consisted 42%, and academic clinicians (n = 37) consisted 35% of the participants. In the whole cohort, the overall rate of correct answers was 55.1% in the general knowledge about the biosimilars part, and 26.7% in the local approval and reimbursement issues part. At all, 57.7% of the participants declared that they object to switch from a reference product to a biosimilar product. The rate of those who defined themselves as extremely knowledgeable decreased from 8.1% to 2.7% in the whole cohort at the end of the survey. CONCLUSION: The need for more accurate and clarified local regulations and education emerging in the biotechnology era must be met.

Consumption and cost trends of EGFR TKIs: influences of reimbursement and national price negotiation.

BACKGROUND: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been widely used in the treatment of EGFR mutation non-small-cell lung cancer. The Chinese government has made great efforts to improve the availability and affordability of these drugs. The aim of this study was to investigate the trends in the consumption and cost of EGFR TKIs in Nanjing, a developed city in China, and evaluate the influence of health insurance coverage and national price negotiation on drug consumption. METHODS: Data about EGFR TKIs applications in 2010-2019 were extracted from Jiangsu Medicine Information Institute. Five types of EGFR TKIs were included. Consumption was expressed in defined daily doses (DDDs) and expenditure. The correlation between defined daily cost (DDC) and DDDs was analyzed by Pearson's correlation test. RESULTS: The DDC, number of DDDs and expenditure of EGFR TKIs changed little from 2010 to 2015. National price negotiation was initiated as a policy and low-price generic gefitinib came into the market in 2016. Three types of EGFR TKIs moved into the coverage of the national health insurance since 2017. Hence, the DDC decreased, and the number of DDDs increased significantly year by year since 2016. The first generation TKIs always made up of comprised the majority of the total consumption. The predominantly prescribed TKIs were gefitinib and icotinib. DDC was negatively correlated with the number of DDDs. The number of DDDs increased significantly after health insurance enrollment, price negotiation and generic drug replacement. CONCLUSION: The consumption of EGFT TKIs has increased and the DDC of EGFR TKIs has decreased since 2016. These trends may be attributed to drug reimbursement, price negotiation and generic drug replacement. Further efforts are needed to translate the high consumption of EGFR TKIs into clinical benefits.

The impact of National Centralised Drug Procurement policy on the use of policy-related original and generic drugs in China.

AIMS: To evaluate the effects of the first round of National Centralised Drug Procurement pilot (so-called '4+7' policy) on the use of policy-related original and generic drugs. METHODS: This study used drug purchasing order data from the Centralised Drug Procurement Survey in Shenzhen 2019, covering 24 months from January 2018 to December 2019. '4+7' policy-related drugs were selected as study samples, including 25 drugs in the '4+7' procurement list and 69 alternative drugs that have an alternative relationship with '4+7' List drugs in clinical use. '4+7' List drugs were then divided into bid-winning and bid-non-winning products according to the bidding results. Included drugs were sorted into original and generic drugs. Purchase volume, expenditures, and daily costs were selected as outcome variables, and were measured using Defined Daily Doses (DDDs), Chinese Yuan (CNY), and Defined Daily Drug cost (DDDc). A single-group Interrupted Time Series analysis was adopted to quantify policy effect. RESULTS: After policy intervention, the overall policy-related original drugs significantly decreased by 0.39 CNY (95% CI: -0.62 to -0.17, p < 0.01) in DDDc, 5949.36 thousand DDDs (95% CI: -8276.67 to -3622.05, p < 0.001) in volume, and 31,575.08 thousand CNY (95% CI: -41,812.68 to -21,337.49, p < 0.001) in expenditures. The volume proportion of generic drugs increased from 78.6% to 91.0%, and the expenditure proportion of increased from 30.9% to 49.8%. CONCLUSION: '4+7' policy promoted the substitution use of domestic generics against original branded drugs and played positive effects on drug price cut and medication burden reduction. The proportion of original branded drugs and generics that passed generic consistency evaluation significantly increased after policy intervention, indicating the improvement of the overall quality level of drug use in China.

Efficacy and safety of switching from brand-name to domestic generic levetiracetam in children with epilepsy. / å·¦ä¹™æ‹‰è¥¿å¦çš„å›½äº§ä»¿åˆ¶è¯æ›¿æ¢æ²»ç–—å„¿ç«¥ç™«ç—«çš„ç–—æ•ˆåŠå®‰å ¨æ€§ç ”ç©¶.

OBJECTIVES: To study the efficacy and safety of domestic generic levetiracetam in replacement of brand-name levetiracetam in the treatment of children with epilepsy. METHODS: A retrospective analysis was performed on the medical data of 154 children with epilepsy who received domestic generic levetiracetam in the inpatient or outpatient service of Guangdong Provincial People's Hospital from May 2019 to December 2020. Domestic generic levetiracetam and brand-name levetiracetam were compared in terms of efficacy and safety. RESULTS: For these 154 children, the epilepsy control rate was 77.3% (119/154) at baseline. At 6 months after switching to domestic generic levetiracetam, the epilepsy control rate reached 83.8% (129/154), which showed a significant increase (P<0.05). There was no significant change in the frequency of seizures from baseline to 6 months after switching (P>0.05). The incidence of refractory epilepsy in children with no response after switching treatment was significantly higher than that in children with response (P<0.05). Before switching, only 1 child (0.6%) experienced somnolence, while after switching, 3 children (1.9%) experienced mild adverse drug reactions, including dizziness, somnolence, irritability, and bad temper. CONCLUSIONS: Switching from brand-name to generic levetiracetam is safe and effective and holds promise for clinical application, but more prospective randomized controlled trials are required in future.

Widespread skeptic attitudes among people with epilepsy toward generic antiseizure drugs - A Swedish survey study.

PURPOSE: To explore associations between the characteristics of people with epilepsy (PWE) and their attitudes toward generic substitution of antiseizure drugs (ASDs) in epilepsy. METHODS: This was a cross-sectional survey study directed at adults with epilepsy using selected brand drugs: Keppra®, Lamictal®, Lyrica® or Topimax®. Symptoms of anxiety and depression, sense of self-efficacy, and beliefs about medicines were assessed. Caregivers were asked to answer for persons with intellectual or communicative difficulties. RESULTS: The total response rate was 41% (n = 178). Almost half (46%) of subjects stated that they would oppose generic substitution (Gen-NEG) if suggested by their neurologist, while 71% would worry about adverse effects and/or increased seizure frequency after a putative switch. Age ≥50 increased the odds of being Gen-NEG (adjusted OR: 2.20, 95% CI: 1.18-4.11). Negative associations with both Gen-NEG and worriers were found for education level of high-school diploma or above, employment/studies, and prior experience of generic ASD switch. The proportion of worriers was much higher among caregivers (21/22) compared to subjects with epilepsy (106/156). CONCLUSION: High proportions of PWE express concerns regarding generic substitution of ASDs. The elderly and caregivers seem to express particular concerns. Identifying ways to diminish negative outcomes and worries in connection with a switch is an important future field of research in order to ensure high quality, cost-effective health care for the most vulnerable people in our societies.

Knowledge, opinions and attitudes of primary care physicians about generic drugs: a cross-sectional study.

BACKGROUND: Generic drug (GD) use is affected by many factors, including physicians' approach. OBJECTIVE: This study aimed to investigate the knowledge, opinions and attitudes of primary care physicians (PCPs) about GDs and potentially associated factors. METHODS: An adequately representative sample (n = 354) of PCPs was determined via stratified and simple random sample selection method in this descriptive, cross-sectional study. The research data were collected through a face-to-face 40-item survey, where the knowledge, opinions and attitudes about GDs were questioned. The prescribing percentage of GDs overall was also examined. RESULTS: The survey was completed by 305 PCPs (mean age: 49.2 ± 7.9 years; 57.4% male). The rate of correct responses about GDs was 67.6% for basic knowledge and 46.6% for the development process. The percentages of PCPs who declared that GDs were 'less efficacious', 'of lower quality' and 'less safe' than original drugs were 65.2%, 53.4% and 35.4%, respectively. More than half (60.3%) of the PCPs declared not to pay attention to whether the drug is generic while prescribing. It was observed that, as the knowledge level of the physicians increased, negative opinions and prescribing attitudes regarding the effectiveness, quality and safety of the GDs decreased. The rate of GD prescribing (51.6%) in Izmir was lower than the rest of the country (54.6%; P < 0.001). CONCLUSION: This study shows that the knowledge of PCPs about GDs is generally inadequate, which reflects negatively on their opinions and attitudes regarding the use of GDs. Educational activities can help establish awareness that GDs can be used without doubt of their effectiveness, quality and safety.

Application of the 3Rs principles in the development of pharmaceutical generics.

Although the 3Rs are broadly applied in nonclinical testing, a better appreciation of the 3Rs is needed in the field of differentiated or value-added pharmaceutical generics because the minor changes in formulation, dosage form, indication, and application route often do not require additional safety testing. The US FDA and the EU EMA have comprehensive regulations for such drugs based on quality, therapeutic equivalence, and safety guidelines. However, no scientific publications on how the concept of replacement and reduction from 3Rs principles can be applied in the safety assessment of differentiated generics were found in the public domain. In this review, we discuss the application of 3Rs in nonclinical testing requirements for differentiated generics. Practical examples are provided in the form of case studies from regulated markets. We highlight the need for utilization of existing data to establish equivalence (differentiated generic vs innovator) in efficacy and safety. The case studies indicate that data requirements from animal experiments have been reduced to a large extent in some major markets without compromising quality and safety. In this context, we also highlight the problem that on a global scale, a true reduction of animal experiments will only be achieved when all countries adopt similar practices.

A Bayesian population physiologically based pharmacokinetic absorption modeling approach to support generic drug development: application to bupropion hydrochloride oral dosage forms.

We propose a Bayesian population modeling and virtual bioequivalence assessment approach to establishing dissolution specifications for oral dosage forms. A generalizable semi-physiologically based pharmacokinetic absorption model with six gut segments and liver, connected to a two-compartment model of systemic disposition for bupropion hydrochloride oral dosage forms was developed. Prior information on model parameters for gut physiology, bupropion physicochemical properties, and drug product properties were obtained from the literature. The release of bupropion hydrochloride from immediate-, sustained- and extended-release oral dosage forms was described by a Weibull function. In vitro dissolution data were used to assign priors to the in vivo release properties of the three bupropion formulations. We applied global sensitivity analysis to identify the influential parameters for plasma bupropion concentrations and calibrated them. To quantify inter- and intra-individual variability, plasma concentration profiles in healthy volunteers that received the three dosage forms, each at two doses, were used. The calibrated model was in good agreement with both in vitro dissolution and in vivo exposure data. Markov Chain Monte Carlo samples from the joint posterior parameter distribution were used to simulate virtual crossover clinical trials for each formulation with distinct drug dissolution profiles. For each trial, an allowable range of dissolution parameters ("safe space") in which bioequivalence can be anticipated was established. These findings can be used to assure consistent product performance throughout the drug product life-cycle and to support manufacturing changes. Our framework provides a comprehensive approach to support decision-making in drug product development.

An iterative method to protect the type I error rate in bioequivalence studies under two-stage adaptive 2×2 crossover designs.

Bioequivalence studies are the pivotal clinical trials submitted to regulatory agencies to support the marketing applications of generic drug products. Average bioequivalence (ABE) is used to determine whether the mean values for the pharmacokinetic measures determined after administration of the test and reference products are comparable. Two-stage 2×2 crossover adaptive designs (TSDs) are becoming increasingly popular because they allow making assumptions on the clinically meaningful treatment effect and a reliable guess for the unknown within-subject variability. At an interim look, if ABE is not declared with an initial sample size, they allow to increase it depending on the estimated variability and to enroll additional subjects at a second stage, or to stop for futility in case of poor likelihood of bioequivalence. This is crucial because both parameters must clearly be prespecified in protocols, and the strategy agreed with regulatory agencies in advance with emphasis on controlling the overall type I error. We present an iterative method to adjust the significance levels at each stage which preserves the overall type I error for a wide set of scenarios which should include the true unknown variability value. Simulations showed adjusted significance levels higher than 0.0300 in most cases with type I error always below 5%, and with a power of at least 80%. TSDs work particularly well for coefficients of variation below 0.3 which are especially useful due to the balance between the power and the percentage of studies proceeding to stage 2. Our approach might support discussions with regulatory agencies.

Safety and efficacy of combined sofosbuvir/daclatasvir treatment of children and adolescents with chronic hepatitis C Genotype 4.

Direct-acting antivirals have become available for treating chronic HCV (hepatitis C virus) infection in adults and, recently, in children at least 12 years old. Our aim was to investigate the safety and efficacy of combined sofosbuvir (SOF)/daclatasvir (DCV) for HCV Genotype 4 in children aged 8 to 18 years or weighing 17 kg or more. A total of 40 chronic HCV-infected, treatment-naïve children with well compensated livers were recruited from two sites. Patients received combined therapy of SOF (400 mg/d for patients weighing greater than 45 kg; 200 mg/d for patients weighing 17 to 45 kg) and DCV (60 mg/d for patients weighing greater than 45 kg; 30 mg/d for patients weighing 17 to 45 kg) for 12 weeks. They were followed up regularly by clinical examination and laboratory tests during treatment (weekly in the first month then monthly to the end of treatment), every 3 months for 6 months post-treatment, and at 48 weeks post-treatment. In our cohort, which included 45% of children below the age of 12 years (72.5% genotype 4 and 27.5% mixed genotype 4 and 1), end of treatment response (ETR) was 97.5%. Sustained virologic response for weeks 12 and 24 post-treatment (SVR12 and SVR24) were 97.5% and 95%, respectively, on an intention to treat basis, and 100% and 100% for those who completed the study protocol. Observed side effects were mild and none required drug cessation. Combined SOF/DCV was found to be effective and safe for treating HCV Genotype 4-infected children, 8 years of age and above.