Drug Competition Research Articles

A model-based analysis of phenytoin and carbamazepine toxicity treatment using binding-competition during hemodialysis

Hemodialysis (HD) has limited efficacy towards treatment of drug toxicity due to strong drug-protein binding. In this work, we propose to infuse a competitor drug into the extracorporeal circuit that increases the free fraction of a toxic drug and thereby increases its dialytic removal. We used a mechanistic model to assess the removal of phenytoin and carbamazepine during HD with or without binding-competition. We simulated dialytic removal of (1) phenytoin, initial concentration 70 mg/L, using 2000 mg aspirin, (2) carbamazepine, initial concentration 35 mg/L, using 800 mg ibuprofen, in a 70 kg patient. The competitor drug was infused at constant rate. For phenytoin (~ 13% free at t = 0), HD brings the patient to therapeutic concentration in 460 min while aspirin infusion reduces that time to 330 min. For carbamazepine (~ 27% free at t = 0), the ibuprofen infusion reduces the HD time to reach therapeutic concentration from 265 to 220 min. Competitor drugs with longer half-life further reduce the HD time. Binding-competition during HD is a potential treatment for drug toxicities for which current recommendations exclude HD due to strong drug-protein binding. We show clinically meaningful reductions in the treatment time necessary to achieve non-toxic concentrations in patients poisoned with these two prescription drugs.

The effect of patent expiration on sales of branded competitor drugs in a therapeutic class

BackgroundGeneric entry can lower pharmaceutical prices and yield significant cost savings for both patients and health systems. The effect of generic entry has often been measured by sales of the ...

A study of the value of requesting information from drug manufacturers for systematic reviews; 9 years of experience from the drug effectiveness review project

BackgroundSystematic reviews (SRs) depend on comprehensive searches for evidence to provide balanced, accurate results. Requesting published and unpublished studies from pharmaceutical manufacturers has been proposed as a method to engage industry stakeholders and potentially reduce reporting bias. The Drug Effectiveness Review Project (DERP) has been requesting such evidence since 2003; the purpose of this study was to retrospectively evaluate the type and impact of the evidence received.MethodsData from “dossiers” submitted by pharmaceutical manufacturers for a set of 40 SRs conducted for DERP from July 2006 to June 2015 were retrospectively evaluated. Characteristics of data submitted in dossiers, including numbers, types, and characteristics of studies submitted and then included in DERP SRs, were abstracted. Time trends, study quality, publication status, and whether the submission represented a unique study or supplemental data to a published study were assessed. The impact of this evidence on SR conclusions was assessed using dual review. Differences were resolved through a consensus.ResultsOver 9 years, 160 dossiers were received, relating to 40 DERP SRs. Out of 7360 studies/datasets submitted, 2.2% (160) were included in a SR. The ratio of submitted-to-included increased over time. Most were unique studies (23% were supplemental data sets), and almost 42% of the studies were unpublished. The majority of the studies were rated fair quality, with 7.3% rated good and 14% rated poor quality by the original SR authors. Considering all literature search sources, 7.2% of all studies included in the 40 SRs came from a dossier, and 16% of dossier studies were included in a meta-analysis. The dossier studies resulted in changes to conclusions in 42% of the SRs. Out of 46 unpublished unique studies included in a SR, 25 (54%) influenced the conclusions in favor of the manufacturers drug, 8% favored a competitor drug, and 40% favored neither. In 92% of cases favoring the manufacturer’s drug, the dossier study was the only evidence for that drug in a specific population or outcome.ConclusionsIn SRs conducted for DERP, few studies submitted by pharmaceutical manufacturers were ultimately included in a SR. The included data helped to reduce reporting and publication bias by filling important gaps and in some cases led to altered conclusions.

Glecaprevir + pibrentasvir (ABT493 + ABT-530) for the treatment of Hepatitis C

ABSTRACTIntroduction: Glecaprevir (formerly ABT-493, pangenotypic NS3/4A protease inhibitor) and pibrentasvir (formerly ABT-530, pangenotypic NS5A inhibitor) are second generation direct acting antivirals (DAA) for the treatment of chronic Hepatitis C (HCV). It is a fixed dose ribavirin (RBV)-free regimen with activity against genotypes (GT) 1–6. In vitro the two antivirals have synergistic activity with a high barrier to resistance and potent activity against common polymorphisms. It is once daily oral dosing with minimal absorption, primary biliary excretion, and negligible renal excretion, making it safe for patients with renal impairment. This regimen is being reviewed because it is the first pangenotypic regimen suitable for those with renal impairment and prior DAA failure.Areas covered: The key phase 2 and 3 trials which investigated the efficacy and safety of glecaprevir/pibrentasvir are reviewed by methodology, primary end point, baseline demographic data, response rates, and adverse events. Literature search methodology involved reviewing key abstracts presented at the American Association for the Study of Liver Disease and European Association for the Study of Liver.Expert commentary: The advantages and limitations of glecaprevir/pibrentasvir will be reviewed in comparison to its competitor drug on the market.

Alogliptin-A Narrative Review

Diabetes mellitus is a metabolic disorder that is characterised by raised blood glucose level in the body as a result of insulin resistance and pancreatic beta-cell failure and defects in insulin secretion or insulin action. Pharmacological therapy for the management of type II diabetes currently includes six classes of Oral Antidiabetic drugs. They are Biguanides, Sulfonylureas, Meglitinides, Thiazolidinediones, Dipeptidyl peptidase IV inhibitors (DPP4) and α-Glucosidase inhibitors. The five accessible DPP-4 inhibitors are sitagliptin, vildagliptin, saxagliptin, linagliptin, alogliptin, which are also called as “Gliptins”. Alogliptin has been well established as the treatment option in the management of type 2 diabetes. Alogliptin is available as three new combination which is used with diet and exercise which helps in further improvement of glycemic control. Alogliptin is a Pro-drug, in which the active substance is alogliptin benzoate. The main advantage of using alogliptin over other drugs in its class is that the selectivity for DPP-IV is much higher than the next closest competitor drug. The cost of drug acquisition is low and affordable both as a single drug or in combination when compared to other DPP4 inhibitors.

Steady Increase In Prices For Oral Anticancer Drugs After Market Launch Suggests A Lack Of Competitive Pressure.

The cost of treating cancer has risen to unprecedented heights, putting tremendous financial pressure on patients, payers, and society. Previous studies have documented the rising prices of cancer drugs at launch, but less critical attention has been paid to the cost of these drugs after launch. We used pharmacy claims for commercially insured individuals to examine trends in postlaunch prices over time for orally administered anticancer drugs recently approved by the Food and Drug Administration (FDA). In the period 2007-13, inflation-adjusted per patient monthly drug prices increased 5percent each year. Certain market changes also played a role, with prices rising an additional 10percent with each supplemental indication approved by the FDA and declining 2percent with the FDA's approval of a competitor drug. Our findings suggest that there is currently little competitive pressure in the oral anticancer drug market. Policy makers who wish to reduce the costs of anticancer drugs should consider implementing policies that affect prices not only at launch but also later.

PRM145 - Reviewing Clinical Outcome Assessment Usage In Clinical Trials: Introducing The Cola Methodology

It is widely accepted that, as well as developing new Clinical Outcome Assessments (COAs) for clinical trials, using existing COAs to evaluate treatment benefit from the patient perspective is often a more pragmatic, time- and cost-effective strategy. However, the suitability of a COA (whether new or existing) is dependent on evidence of content and psychometric validity in a specific context and for specific concepts of interest. Determining which existing COA is most suitable based upon these criteria is particularly challenging when a large pool of instruments is available. For example, a recent MEDLINE search for COAs in head and neck cancer yielded more than 100 instruments. To shortlist from here, the logical next step is to review which COAs have been used (successfully and unsuccessfully) by sponsors in previous and ongoing trials. However, there is no clear guidance that explains how to identify relevant products or trials and what information to review to support measurement selection and ensure regulatory acceptance. Thus we outline an approach that is systematic, robust and pragmatic to support the selection of an existing COA for inclusion in upcoming studies. The Competitor Outcomes Landscape Analysis (COLA) methodology is a four-step approach: 1) identify relevant competitor drugs using a global clinical trial database, 2) review the [email protected] database and the EMA’s European Public Assessment Reports to establish approval status and identify COAs included in labelling, 3) review FDA’s Drug Approval Packages to document regulatory decision-making and 4) identify COAs included in trial protocols for drugs in development. The COLA approach helps sponsors to select the most appropriate COA for studies in a specific population and disease area. We believe this framework allows for more confidence, transparency and credibility in the decision-making process and as such COLA is a systematic approach to support an optimal COA strategy.

When Does FDAMA Section 114 Apply? Ten Case Studies

BackgroundSection 114 of the Food and Drug Administration Modernization Act of 1997 regulates the promotion of health economic information by pharmaceutical companies to US health plans. Greater clarity is important given demands by payers and other stakeholders for evidence of value. ObjectivesTo develop hypothetical case studies of health economic promotions to examine legal and policy implications. MethodsWe constructed for pedagogical purposes 10 categories of potential health economic promotions. We generated hypothetical case studies for each category, including questions about whether each might be allowable under Section 114. The case studies were developed around the following categories: 1) costing out on-label clinical end points; 2) promotion of a costing exercise to physicians working in an accountable care organization setting; 3) burden-of-illness claims; 4) economic analysis of a formulary restriction policy; 5) extrapolations to doses, populations, or settings not covered in trials; 6) adherence claims; 7) “utilization of care” as a secondary end point in randomized clinical trials; 8) costing out a competitor drug’s adverse event; 9) economic analysis of comparative effectiveness claims using an indirect treatment comparison; and 10) extrapolating from surrogate to long-term outcomes in an economic model. DiscussionMost cases seem to fall into a gray zone given haziness around what constitutes “competent and reliable evidence” and “directly relate[d]” to an approved indication. In practice, it is difficult to know what the section allows given the imprecision of the statute and lack of guidance about its scope. ConclusionIdeally, future guidance will provide clarity and flexibility.

A linearization approach for the model‐based analysis of combined aggregate and individual patient data

The application of model-based meta-analysis in drug development has gained prominence recently, particularly for characterizing dose-response relationships and quantifying treatment effect sizes of competitor drugs. The models are typically nonlinear in nature and involve covariates to explain the heterogeneity in summary-level literature (or aggregate data (AD)). Inferring individual patient-level relationships from these nonlinear meta-analysis models leads to aggregation bias. Individual patient-level data (IPD) are indeed required to characterize patient-level relationships but too often this information is limited. Since combined analyses of AD and IPD allow advantage of the information they share to be taken, the models developed for AD must be derived from IPD models; in the case of linear models, the solution is a closed form, while for nonlinear models, closed form solutions do not exist. Here, we propose a linearization method based on a second order Taylor series approximation for fitting models to AD alone or combined AD and IPD. The application of this method is illustrated by an analysis of a continuous landmark endpoint, i.e., change from baseline in HbA1c at week 12, from 18 clinical trials evaluating the effects of DPP-4 inhibitors on hyperglycemia in diabetic patients. The performance of this method is demonstrated by a simulation study where the effects of varying the degree of nonlinearity and of heterogeneity in covariates (as assessed by the ratio of between-trial to within-trial variability) were studied. A dose-response relationship using an Emax model with linear and nonlinear effects of covariates on the emax parameter was used to simulate data. The simulation results showed that when an IPD model is simply used for modeling AD, the bias in the emax parameter estimate increased noticeably with an increasing degree of nonlinearity in the model, with respect to covariates. When using an appropriately derived AD model, the linearization method adequately corrected for bias. It was also noted that the bias in the model parameter estimates decreased as the ratio of between-trial to within-trial variability in covariate distribution increased. Taken together, the proposed linearization approach allows addressing the issue of aggregation bias in the particular case of nonlinear models of aggregate data.

Application pratique de la charte de la visite médicale

Visits from pharmaceutical representatives are controlled in France by regulations, but also by a Charter of good practice. The goal of this study was to measure compliance to the conditions of this charter by participating pharmaceutical companies. An assessment grid was drafted to determine compliance to interdictions and obligations concerning the information provided during visits from pharmaceutical representatives. We studied 20 visits from pharmaceutical representatives. All of the documents and obligatory information were only provided in 5% of cases. During 80% of these meetings, the pharmaceutical representatives made a comparison with competitor's drugs, which was associated with negative remarks in 44% of cases. The pharmaceutical representatives promoted cases of use outside those, which had received marketing approval in 35%. Gifts or samples were offered at the end of these meetings in 20% of cases. Prohibited practices were observed in a total of 85% of cases. This study shows that meetings are respected by pharmaceutical representatives in terms of regulations related to donations. In opposite, there is a very low compliance concerning the proper use of the drug, whether to provide official documentation, to give information respectful of other pharmaceutical companies or to promote the proper use. Our results suggest that, at present hospital visits by pharmaceutical representatives do not respect the commitments made by the pharmaceutical industry, and do not make it possible to ensure that honest information is provided to favor the proper use of drugs.

Conformity to the charter for visits from pharmaceutical representatives

BackgroundVisits from pharmaceutical representatives (PRs) are controlled in France by regulations, but also by a Charter of good practice, drafted by an organisation which represents 270 drug companies (LEEM). The...

Inhibition of RNase L and RNA-dependent Protein Kinase (PKR) by Sunitinib Impairs Antiviral Innate Immunity

RNase L and RNA-dependent protein kinase (PKR) are effectors of the interferon antiviral response that share homology in their pseudokinase and protein kinase domains, respectively. Sunitinib is an orally available, ATP-competitive inhibitor of VEGF and PDGF receptors used clinically to suppress angiogenesis and tumor growth. Sunitinib also impacts IRE1, an endoplasmic reticulum protein involved in the unfolded protein response that is closely related to RNase L. Here, we report that sunitinib is a potent inhibitor of both RNase L and PKR with IC(50) values of 1.4 and 0.3 μM, respectively. In addition, flavonol activators of IRE1 inhibited RNase L. Sunitinib treatment of wild type (WT) mouse embryonic fibroblasts resulted in about a 12-fold increase in encephalomyocarditis virus titers. However, sunitinib had no effect on encephalomyocarditis virus growth in cells lacking both PKR and RNase L. Furthermore, oral delivery of sunitinib in WT mice resulted in 10-fold higher viral titers in heart tissues while suppressing by about 2-fold the IFN-β levels. In contrast, sunitinib had no effect on viral titers in mice deficient in both RNase L and PKR. Also, sunitinib reduced mean survival times from 12 to 6 days in virus-infected WT mice while having no effect on survival of mice lacking both RNase L and PKR. Results indicate that sunitinib treatments prevent antiviral innate immune responses mediated by RNase L and PKR.

Lixisenatide for type 2 diabetes mellitus

Introduction: Type 2 diabetes mellitus (T2DM) is an increasing health problem worldwide. Glucagon-like peptide-1 (GLP-1) receptor agonists are an expanding drug class that target several of the pathophysiological traits of T2DM. Lixisenatide is a GLP-1 receptor agonist in development for once-daily treatment of T2DM.Areas covered: Pharmacological, preclinical and clinical evidence demonstrating the applicability of lixisenatide for the treatment of T2DM are reviewed. Available data and pending clinical development are summarized, critically appraised and compared to competitor drugs. The most relevant papers and meeting abstracts published up to November 2010 are used as sources for this review.Expert opinion: Efficacy and safety in T2DM are demonstrated with lixisenatide in monotherapy and in combination with metformin. However, limited data with the intended once-daily 20 μg subcutaneous dosing necessitate further evaluation of lixisenatide as add-on to various antidiabetic treatments. It remains to be established whether the slightly differing chemical properties compared to other GLP-1 receptor agonists including a rather short duration of action will be a disadvantage or maybe even an advantage, for example, when combined with long-acting insulin.

FDA Wants M.D.s to Enlist in War Against Illegal Ads

Back to table of contents Previous article Next article Professional NewsFull AccessFDA Wants M.D.s to Enlist in War Against Illegal AdsJun YanJun YanSearch for more papers by this authorPublished Online:18 Jun 2010https://doi.org/10.1176/pn.45.12.psychnews_45_12_002AbstractThe Food and Drug Administration (FDA) has launched a campaign to recruit physicians and health care professionals to report potentially illegal advertisements and promotions by drug companies.This outreach effort, termed the “Bad Ad” program, is being implemented by the FDA's Division of Drug Marketing, Advertising, and Communications (DDMAC).A Web site at <www.fda.gov/badad> has been set up to educate health care professionals about the types of drug advertisements and promotions that violate the law. Among the examples are overstating efficacy, omitting or downplaying safety risks, and promoting off-label indications.Drug companies are prohibited from discussing or promoting unapproved indications of their products, but it is not illegal for them to distribute articles published in peer-reviewed medical journals that investigate or review unapproved uses of a medication.The FDA is encouraging physicians and other professionals to report suspected violations they encounter at medical conferences, in professional and lay media, in materials they receive, at company-sponsored presentations, and during sales-representatives' visits. Complaints can be submitted, with supporting materials or other evidence, to the agency by e-mail at [email protected]gov, telephone at (877) RX-DDMAC, or mail. The reports can be submitted anonymously, but the agency recommends that those filing a complaint provide their name and contact information for follow-up and collection of additional materials.“This is a reasonable effort on the part of the FDA,” said David Fassler, M.D., APA treasurer and a child and adolescent psychiatrist in Vermont. He is also a clinical professor of psychiatry at the University of Vermont. “At a minimum, it may help educate physicians about the regulations governing ads and promotions.”He suggested, however, that the initiative indicates the FDA's lack of resources when it comes to reviewing drug-marketing activities. “Improving compliance will ultimately require a substantial increase in the resources available for monitoring and enforcement,” he said.The DDMAC, housed in the FDA's Center for Drug Evaluation and Research, is in charge of monitoring and regulating the advertisements and promotional activities for prescription drugs. Medical devices and over-the-counter drugs are not regulated by this division.Although spontaneous reports from health care professionals have occasionally led to investigation and regulatory actions, the DDMAC has traditionally focused its reviews on advertising materials voluntarily submitted by drug companies, complaints filed by competitor drug companies, and surveillance of medical conferences. In a public letter posted on the Bad Ad program Web site, FDA Commissioner Margaret Hamburg, M.D., wrote that the “FDA's ability to monitor other promotional activities, which may occur in any number of settings, is limited.”In 2009, the DDMAC issued 38 enforcement letters to pharmaceutical companies, up from 22 letters in 2008.According to Hamburg's letter, the DDMAC will have exhibits at major medical conferences to educate physicians and others about drug-marketing regulations and to promote the Bad Ad program. She urged practitioners to assist the FDA in identifying and stopping misleading drug promotion. ISSUES NewArchived

The use of placebo control in clinical trials: An overview of the ethical issues involved for the protection of human research participants.

A placebo-controlled clinical trial is a trial where some of the volunteers are given the new drug being tested, and the other volunteers are given a placebo. A placebo looks exactly like the experimental drugs in every respect both in appearance and wrappings which, is prescribed in identical way to the real drug. The experimental group receives the real drugs while the control group receives the placebo. When patients believe that a certain medication will improve their condition, that fact alone can cause certain positive effects when combine with pill, an injection or even a surgical procedure. Researchers can utilize such adventitious effects and more precisely determine the actual therapeutic benefit of a new treatment. However, the use of placebo in clinical trials has been controversial with many stake holders in clinical research expressing different opinions. It is usually not problematic to use a placebo in clinical trials when testing a new treatment in absence of a known treatment. On the other hand, resort to placebo controls becomes ethically controversial when researchers wish to introduce a new treatment as a possible successor or competitor drugs whose use is currently a standard practice. More problematic and controversial is the use of invasive placebo in interventions in surgical trials. This article is therefore, a critical presentation of the ethical issues involved in the protection of human research participants in the presence of placebo controlled clinical trials

At the Heart of Controversy: Genentech Markets a Genetically Engineered Drug

This case, developed from a wide variety of publicly available information, presents ethical and economic issues arising from the development, marketing, and pricing of a biotech drug. Genentech developed TPA, the first genetically engineered drug that could be used in clot-dissolving therapy for heart attack, and marketed it as Activase. Public outrage focused on the disparity between the drug's $10 direct manufacturing cost and what Genentech charged for its drug. Activase/TPA was priced at $2200 a dose, raising immediate concerns about its affordability and therefore availability to those who needed it. Additional issues arise from other events, including concern over related-party relationships between the company and organizations which researched and recommended TPA, as well as aggressive marketing of TPA to physicians and the company's refusal to participate in an international drug study to compare TPA with competitor drugs.

Quality specifications in thyroid diseases

Background: Laboratory tests to support the diagnosis and management of thyroid diseases have undergone significant changes with the introduction of highly sensitive assays for thyroid stimulating hormone (TSH) and free T4 and T3 concentrations in plasma. Given the importance of these measurements, quality specifications are needed to ensure accurate results. Goals for precision and accuracy are available based on known intraindividual and interindividual biological variation. Methods: Results of external quality assurance (EQA) schemes are sufficient to document precision goals but survey materials are not commutable for use in determining bias or detect the presence of unusual antibodies on a case-by-case basis. Because TSH concentrations are inversely related to free T4, this physiologic relationship can be exploited for quality assurance purposes. Results: Significant discordance between this relationship can be caused by subclinical and potentially unrecognized disease, dysequilibrium caused by recent therapy, the presence of abnormal binding proteins or protein binding competitor drugs, and antibody interferences such as human antimouse antibody (HAMA) or rheumatoid factor. Conclusion: A mechanism to automatically track discordances for subsequent follow and investigation can be an effective part of a quality assurance program for thyroid hormone measurements.

Erlotinib: CP 358774, NSC 718781, OSI 774, R 1415.

Erlotinib: CP 358774, NSC 718781, OSI 774, R 1415.

Facing migraine in the new millennium

The launch of sumatriptan in 1991 represented the most significant development in the acute treatment of migraine in 50 years, establishing it as the ‘gold standard’ in migraine care. The reward for Glaxo Wellcome has been sales worth $US580 million in 1996. However, with the recent launch of 2 competitor drugs, Glaxo Wellcome’s own naratriptan and Zeneca’s zolmitriptan, and the imminent approval of at least 3 more selective serotonin (5-HT)1receptor agonists, the migraine therapy market is becoming increasingly crowded as patients and physicians are suddenly faced with an array of treatment options. This weekInpharmatakes a look at what sets these new agents apart and differentiates them from the standard set by sumatriptan.

Candida: a review of clinical experience with Lamisil.

Pharmaceutical companies sometimes quote the MICs of antifungal agents to make favourable or unfavourable comparisons with competitor drugs. To the doctor, however, the clinical outcome is important. In this light it can be seen that topical terbinafine is certainly as effective as, if not more effective than, any other anticandidal agent available.