The effect of generic market entry on antibiotic prescriptions in the United States.

When patented, brand-name antibiotics lose market exclusivity, generics typically enter the market at lower prices, which may increase consumption of the drug. To examine the effect of generic market entry on antibiotic consumption in the United States, we conducted an interrupted time series analysis of the change in the number of prescriptions per month for antibiotics for which at least one generic entered the US market between 2000 and 2012. Data were acquired from the IQVIA Xponent database. Thirteen antibiotics were analyzed. Here, we show that one year after generic entry, the number of prescriptions increased for five antibiotics (5 to 406%)-aztreonam, cefpodoxime, ciprofloxacin, levofloxacin, ofloxacin-and decreased for one drug: cefdinir. These changes were sustained two years after. Cefprozil, cefuroxime axetil and clarithromycin had significant increases in trend, but no significant level changes. No consistent pattern for antibiotic use following generic entry in the United States was observed.

Characteristics and Price Increases Among Sole-Source, Off-Patent Drugs in the United States, 2008 to 2018.

Importance: Some sole-source, off-patent drugs in the United States have undergone substantial price hikes in recent years. Despite increased attention by lawmakers, there are limited data to guide policy. Objectives: To describe key attributes of sole-source, off-patent, off-exclusivity drugs; to characterize the prevalence of price increases; and to identify attributes associated with price increases. Design, Setting, and Participants: In this cross-sectional study, 300 sole-source, off-patent, off-exclusivity drug products met inclusion criteria and were selected for analysis from January 1, 2008, to December 31, 2018. Attributes were identified from multiple sources, and yearly wholesale acquisition cost prices were determined from First Databank. Main Outcomes and Measures: The association of drug attributes with the following 2 price change thresholds was measured after adjusting for inflation: 25% or more price increase in a calendar year (wholesale acquisition cost) and 50% or more price increase in a calendar year. The rate of annual price increase over time was also measured. Results: Of the 300 drug products and 2242 observations analyzed, the overall inflation-adjusted mean increase in drug prices was 8.8% (95% CI, 7.8%-9.8%) per year. Ninety-five drugs (31.7%) increased by 25% or more during any calendar year, and 66 drugs (22.0%) increased by 50% or more during any calendar year. An initial price of less than $2 per unit (adjusted odds ratio [aOR], 2.36; 95% CI, 1.69-3.29), antineoplastic and immunomodulatory class (aOR, 2.72; 95% CI, 1.31-5.65), dermatologic class (aOR, 2.95; 95% CI, 1.80-4.84), oral route (aOR, 2.01; 95% CI, 1.45-2.79), and US Food and Drug Administration (FDA) approval before 1990 (aOR, 1.52; 95% CI, 1.14-2.03) were attributes of drugs that were more likely to be associated with a 25% or more price increase in a calendar year after adjusting for by initial price. Similarly, an initial price of less than $2 per unit (aOR, 2.68; 95% CI, 1.76-4.09), antineoplastic and immunomodulatory class (aOR, 3.07; 95% CI, 1.54-6.12), oral route of administration (aOR, 1.70; 95% CI, 1.11-2.60), and FDA approval before 1990 (aOR, 2.02; 95% CI, 1.40-2.94) were attributes of drugs that were more likely to be associated with a 50% or more price increase in a calendar year after adjusting for by initial price. Price increases of 25% or more were most common in 2014, and price increases of 50% or more were most common in 2013. Conclusions and Relevance: Price increases among sole-source, off-patent drugs are common, and policy interest in this practice is warranted. These findings should inform state drug pricing legislation.

Medicare beneficiaries' out-of-pocket costs for commonly used generic drugs, 2009-2017.

OBJECTIVES: To examine differences in the out-of-pocket costs for common generic drugs used to treat chronic conditions when individuals used their Medicare prescription drug plan (PDP) or when purchased through Walmart's generic drug discount programs (GDDPs) from 2009 to 2017. STUDY DESIGN: A retrospective analysis of Medicare PDP Formulary files and Walmart's GDDP retail drug lists from 2009 to 2017. METHODS: We identified all generic drugs used to treat chronic conditions that were on Walmart's GDDP retail drug list from 2009 to 2017. We then determined the out-of-pocket costs for each drug for each Medicare PDP and compared those costs with Walmart's GDDP cash price. RESULTS: There were 62 and 43 generic medications used to treat common chronic diseases available through Walmart's GDDP in 2009 and 2017, respectively. Across all PDPs, the median beneficiary out-of-pocket expenditure for a 30-day supply of the GDDP-available medications for chronic diseases decreased from $5.70 (interquartile range [IQR], $2.55-$7.98) in 2009 to $2.00 (IQR, $0.00-$4.00) in 2017 (P <.001) Approximately three-fifths (60.2%) of PDPs required beneficiaries to pay out-of-pocket costs higher than those of Walmart's GDDP in 2009, but only one-third (33.4%) did so in 2017. CONCLUSIONS: Although Medicare beneficiary out-of-pocket costs for commonly used generic drug prescriptions generally decreased over time, Medicare beneficiaries may still be paying more for the same drugs than they would through Walmart's GDDP. Increased generic drug price transparency, including enforcing bans on gag clauses, is needed to ensure that Medicare beneficiaries obtain drugs using the most affordable options.

Current Regulatory Standpoint on Evaluating the Bioequivalence of Different Classes of Generic Drugs - Is the Evaluation in the Right Direction?

BACKGROUND: The concept of evaluating bioequivalence has changed over a period of time. Currently, the Average Bioequivalence approach (ABE) is the gold standard tool for the evaluation of generics. Of late, many debates had arisen about employing ABE approach for the appraisal of all drug categories. This review aims to examine the limitations of ABE approach and the significances of Population Bioequivalence (PBE) and Individual Bioequivalence (IBE) approach, current regulatory thinking for assessing different categories of the drug, whether they are adequately assessed, and the evaluation is in the right direction. METHODS: We carried out an organized search of bibliographic databases for peer-reviewed research literatures, regulatory recommendations, guidance documents using a focused review question and eligibility criteria. The standard tools were used to appraise the quality of retrieved documents and to make sure the authenticity of the data. RESULTS: In total 73 references were used in the review, the majority of the references (guidance documents) were from the different regulatory agencies and product-specific guidance. There were 29 product-specific guidance from USFDA and EMA. The limitations of the ABE approach were discussed in detail along with the significances of Population Bioequivalence (PBE) approach and Individual Bioequivalence (IBE) approaches. CONCLUSION: It is apparent from the review that IBE approach is a precise method for evaluating the drugs as it answers drug interchangeability (prescribability and switchability). IBE approach is followed by PBE approach and ABE approach for the evaluation of different categories of drugs in terms of precision.

Comparison of malaria treatment outcome of generic and innovator's anti-malarial drugs containing artemether-lumefantrine combination in the management of uncomplicated malaria amongst Tanzanian children.

BACKGROUND: In 2006, artemether-lumefantrine (ALU), specifically Coartem® (Novartis Pharma AG, Basel Switzerland), was approved as the first-line drug for treatment of uncomplicated malaria in Tanzania. Due to poor availability and affordability of the innovator's product, the government of Tanzania in 2013 prequalified the use of generic anti-malarial drugs, whereby Artefan® (Ajanta, Pharma Ltd, India) was the first to be approved. METHODS: This was an equivalence prospective study that aimed to determine the effectiveness of anti-malarial generic Artefan® in comparison with innovator's product Coartem®. Patients aged 6 to 59 months with uncomplicated malaria were recruited and randomized to either receive Artefan® or Coartem® as a control. Participants were required to revisit clinic five times as follow up to monitor treatment outcome as per World Health Organization recommendations. On each visit, thick and thin blood smears, dried blood spot (DBS), haemoglobin concentrations and auxiliary temperature were performed and documented. RESULTS: Out of 230 recruited participants, 200 met inclusion criteria and were randomized equally to receive Artefan® and Coartem®. The overall PCR uncorrected cure rate were 80% for Artefan® and 75% for Coartem® (p = 0.44). Adequate clinical and parasitological response were 82.1% for Artefan® and 74.7% for Coartem®, and there was no early treatment failure (ETF) observed in both arms of treatment. Both drugs showed excellent early parasite clearance, whereby no participants had peripheral parasitaemia on day 3. Late clinical failures (LCF) were 3.6% for Artefan® and 1.3% for Coartem® (p = 0.31), and late parasitological failure (LPF) were 15.4% for Artefan® and 22.7% for Coartem® (p = 0.32). Mean haemoglobin (g/dl) concentrations observed on day 28 were higher compared to day 0 for both drugs, although not statistically significant. Only one (1.3%) participant on Artefan® had temperature ≥ 37.5 °C on day 3. CONCLUSION: The findings of this study indicate that both Artefan® and Coartem® are equivalent and effective in the management of uncomplicated malaria amongst children in the Coast part of Tanzania.

Regulatory Requirements and Innovation: A Comparison of the Dermatologic Antifungal Drug Product Markets in Brazil and United States.

BACKGROUND: Development of novel dermatological topical products for the treatment of cutaneous fungal infections is a constant necessity, especially in developing countries. Through public health policies, many developing countries have facilitated in the last decades the entry of generic products, which can be superficially seen as a threat to innovation. To verify whether regulatory requirements, or the waiving of some requirements, could have an impact on innovation, we performed a detailed technical comparison of the dermatologic antifungal markets of Brazil and of the United States, taking Brazil as an example of a developing country with more lenient requirements regarding the registration of generic topical drug products. METHODS: The official databank of ANVISA (DATAVISA) and of US Food and Drug Administration (Orange Book) were assessed for valid topical dermatological antifungal drug products registered. RESULTS: The Brazilian market has a greater number of registered drug products encompassing a greater variety of drug substances than the US, but the latter comprises more products with novel technologies. In both countries, cream was the predominant dosage form and imidazoles were the major substance group. Ketoconazole was the lead active substance in Brazil and ciclopirox was the lead drug in the US. Generic products dominated both markets. CONCLUSIONS: Despite the great number of registered products, the Brazilian market lacks the latest technologies, reflecting that the ease of generics registration is not accompanied by innovation.

Overview of the European Medicines Agency's Development of Product-Specific Bioequivalence Guidelines.

The European Medicines Agency's (EMA) product-specific bioequivalence guidelines outline harmonized regulatory requirements for studies to demonstrate bioequivalence for products that may have particular needs due to their pharmacokinetics, in addition to those outlined in general guidance. As such they are potentially very useful to the pharmaceutical industry in the development of generic medicinal products and to regulatory authorities for harmonized decision-making. Since their introduction in 2013, EMA product-specific bioequivalence guidelines continue to increase in number, and as of June 2017, encompass a number of different pharmacotherapeutic groups and pharmaceutical forms. This article further elucidates the processes involved for stakeholders and reviews the Agency's experience with the development of these guidelines, including the scientific issues witnessed with their advancement. A comparison with the United States Food and Drug Administration approach to similar guidelines is also provided.

Biosimilars in Oncology in the United States: A Review.

IMPORTANCE: Biosimilars are biological medicines that contain a highly similar version of the active substance of an already approved biologic reference product. The availability of biosimilars might provide an opportunity to lower health care expenditures as a result of the inherent price competition with their reference product. Understanding how biosimilar cancer drugs are regulated, approved, and paid for, as well as their impact in a value-based care environment, is essential for physicians and other stakeholders in oncology. OBSERVATIONS: Important structural and regulatory differences exist between biosimilar and generic medications. Minor differences in clinically inactive components with no clinically meaningful differences between biosimilars and their reference biologic are allowed. A biosimilar uses the same mechanism of action as the reference biologic, and its condition of use is the same as the approved indication, although extrapolation is permitted across indications under regulatory guidance. A biosimilar has to have a similar route of administration, dosage, and strength as the reference biologic. As patent expiration of multiple cancer biologics will occur in the next few years, more biosimilars might enter the market. Whether the approval and use of biosmilars as replacements for these heavily prescribed reference biologics will ultimately lead to cost savings is unknown and requires longer follow-up. Two biosimilars with an oncology supportive care indication are currently approved in the United States; both are myeloid growth factors. CONCLUSIONS AND RELEVANCE: The financial impact of generic drug competition can be dramatic, but significant differences in regulatory and development processes between generics and biosimilars limit such comparisons and likely present significant challenges for biosimilar approval and adoption in the US market. However, a value-based care environment and their cost-savings potential make biosimilars an attractive option for the therapeutic arsenal. Oncologists' understanding of biosimilars is critical to moving forward.

Impact of the US FDA "Biopharmaceutics Classification System" (BCS) Guidance on Global Drug Development.

The FDA guidance on application of the biopharmaceutics classification system (BCS) for waiver of in vivo bioequivalence (BE) studies was issued in August 2000. Since then, this guidance has created worldwide interest among biopharmaceutical scientists in regulatory agencies, academia, and industry toward its implementation and further expansion. This article describes how the review implementation of this guidance was undertaken at the FDA and results of these efforts over last dozen years or so across the new, and the generic, drug domains are provided. Results show that greater than 160 applications were approved, or tentatively approved, based on the BCS approach across multiple therapeutic areas; an additional significant finding was that at least 50% of these approvals were in the central nervous system (CNS) area. These findings indicate a robust utilization of the BCS approach toward reducing unnecessary in vivo BE studies and speeding up availability of high quality pharmaceutical products. The article concludes with a look at the adoption of this framework by regulatory and health policy organizations across the globe, and FDA's current thinking on areas of improvement of this guidance.

Examining patterns in medication documentation of trade and generic names in an academic family practice training centre.

BACKGROUND: Studies in the United States have shown that physicians commonly use brand names when documenting medications in an outpatient setting. However, the prevalence of prescribing and documenting brand name medication has not been assessed in a clinical teaching environment. The purpose of this study was to describe the use of generic versus brand names for a select number of pharmaceutical products in clinical documentation in a large, urban academic family practice centre. METHODS: A retrospective chart review of the electronic medical records of the St. Michael's Hospital Academic Family Health Team (SMHAFHT). Data for twenty commonly prescribed medications were collected from the Cumulative Patient Profile as of August 1, 2014. Each medication name was classified as generic or trade. Associations between documentation patterns and physician characteristics were assessed. RESULTS: Among 9763 patients prescribed any of the twenty medications of interest, 45% of patient charts contained trade nomenclature exclusively. 32% of charts contained only generic nomenclature, and 23% contained a mix of generic and trade nomenclature. There was large variation in use of generic nomenclature amongst physicians, ranging from 19% to 93%. CONCLUSIONS: Trade names in clinical documentation, which likely reflect prescribing habits, continue to be used abundantly in the academic setting. This may become part of the informal curriculum, potentially facilitating undue bias in trainees. Further study is needed to determine characteristics which influence use of generic or trade nomenclature and the impact of this trend on trainees' clinical knowledge and decision-making.

Burden of neurological diseases in the US revealed by web searches.

BACKGROUND: Analyzing the disease-related web searches of Internet users provides insight into the interests of the general population as well as the healthcare industry, which can be used to shape health care policies. METHODS: We analyzed the searches related to neurological diseases and drugs used in neurology using the most popular search engines in the US, Google and Bing/Yahoo. RESULTS: We found that the most frequently searched diseases were common diseases such as dementia or Attention Deficit/Hyperactivity Disorder (ADHD), as well as medium frequency diseases with high social impact such as Parkinson's disease, MS and ALS. The most frequently searched CNS drugs were generic drugs used for pain, followed by sleep disorders, dementia, ADHD, stroke and Parkinson's disease. Regarding the interests of the healthcare industry, ADHD, Alzheimer's disease, MS, ALS, meningitis, and hypersomnia received the higher advertising bids for neurological diseases, while painkillers and drugs for neuropathic pain, drugs for dementia or insomnia, and triptans had the highest advertising bidding prices. CONCLUSIONS: Web searches reflect the interest of people and the healthcare industry, and are based either on the frequency or social impact of the disease.

Hot Topics in Primary Care: Demystifying the Differences: Follow-on Biologics, Biosimilars, and Generics.

Sponsors of follow-on biologics can submit their applications for approval by the US Food and Drug Administration (FDA) under 2 distinct pathways. The submission pathway is determined by the pathway previously used by the reference biologic product, which is the biologic product upon which the follow-on product relies for evidence of safety and efficacy.

Proton pump inhibitors while belonging to the same family of generic drugs show different anti-tumor effect.

CONTEXT: Tumor acidity represents a major cause of chemoresistance. Proton pump inhibitors (PPIs) can neutralize tumor acidity, sensitizing cancer cells to chemotherapy. OBJECTIVE: To compare the anti-tumor efficacy of different PPIs in vitro and in vivo. MATERIALS AND METHODS: In vitro experiments PPIs anti-tumor efficacy in terms of cell proliferation and cell death/apoptosis/necrosis evaluation were performed. In vivo PPIs efficacy experiments were carried out using melanoma xenograft model in SCID mice. RESULTS: Lansoprazole showed higher anti-tumor effect when compared to the other PPIs. The lansoprazole effect lasted even upon drug removal from the cell culture medium and it was independent from the lipophilicity of the PPIs formulation. DISCUSSION: These PPIs have shown different anti-tumoral efficacy, and the most effective at low dose was lansoprazole. CONCLUSION: The possibility to contrast tumor acidity by off-label using PPIs opens a new field of oncology investigation.

A comparison of the intrasubject variation in drug exposure between generic and brand-name drugs: a retrospective analysis of replicate design trials.

AIMS: The aim of the present study was to investigate whether differences in total and peak drug exposure upon generic substitution are due to differences between formulations or to intrasubject pharmacokinetic variability of the active substance. METHODS: The study was designed as a retrospective reanalysis of existing studies. Nine replicate design bioequivalence studies representing six drug classes - i.e. for alendronate, atorvastatin, cyclosporin, ebastine, exemestane, mycophenolate mofetil, and ropinirole - were retrieved from the Dutch Medicines Regulatory Authority. RESULTS: In most studies, the intrasubject variability in total and peak drug exposure was comparable for the brand-name [in the range 0.01-0.24 for area under the concentration-time curve (AUCt ) and 0.02-0.29 for peak plasma concentration (Cmax ) on a log scale] and generic (0.01-0.23 for AUCt and 0.08-0.33 for Cmax ) drugs, and was comparable with the intrasubject variability upon switching between those drugs (0.01-0.23 for AUCt and 0.06-0.33 for Cmax ). The variance related to subject-by-formulation interaction could be considered negligible (-0.069 to 0.047 for AUCt and -0.091 to 0.02 for Cmax ). CONCLUSION: In the investigated studies, the variation in total and peak exposure seen when a patient is switched from a brand-name to a generic drug is comparable with that seen following repeated administration of the brand-name drug in the patient. Only the intrasubject variability seems to play a crucial and decisive role in the variation in drug exposure seen; no additional formulation-dependent variation in exposure is observed upon switching. Thus, our data support that, for the medicines that were included in the present investigation, from a clinical pharmacological perspective, the benefit-risk balance of a generic drug is comparable with that of the brand-name drug.

Definition and Classification of Generic Drugs Across the World.

Our aim was to systematically identify and compare how generic medications, as defined by the US Food and Drug Administration (FDA), World Health Organization (WHO), and European Medicines Agency (EMA), are classified and defined by regulatory agencies around the world. We focused on emerging markets and selected the most populated countries in each of the WHO regions: Africa, the Americas, Eastern Mediterranean, Europe, Southeast Asia, and Western Pacific. A structured review of published literature was performed through December 2013. Direct information from regulatory agencies and Ministries of Health for each country was extracted. Additionally, key informant interviews were performed for validation. Of the 21 countries selected, approximately half provided an official country-level definition for generic pharmaceuticals. The others did not have any definition or referred to the WHO. Only two-thirds of the countries had specific requirements for generic pharmaceuticals, often associated with clinical interchangeability. Most countries with requirements mention bioequivalence, but few required bioavailability studies explicitly. Over 30% of the countries had other terms associated with generics in their definitions and processes. In countries with generic drug policies, there is reference to patent and/or data protection during the drug registration process. Several countries do not mention good manufacturing practices as part of the evaluation process. Countries in Africa and Eastern Mediterranean regions appear to have a less developed regulatory framework. In summary, there is significant variability in the definition and classification of generic drugs in emerging markets. Standardization of the definitions is necessary to make international comparisons viable.