Drug Licensing Research Articles

A comparative analysis of licensing and reimbursement of anti-epileptic drugs in Canada and Australia (2804)

A comparative analysis of licensing and reimbursement of anti-epileptic drugs in Canada and Australia (2804)

Potency and stability of a trivalent, catalytically inactive vaccine against botulinum neurotoxin serotypes C, E and F (triCEF)

Botulism is an acute neuroparalytic affliction of the motor and autonomic neurons caused by the toxins produced from Clostridium botulinum and related bacterial strains. The botulinum neurotoxins, or BoNTs, consist of a phylogenetically diverse group of highly potent protein toxins. Current medical interventions for confirmed cases of botulism are limited to immediate administration of antitoxins and respiratory support. There is currently no licensed vaccine against botulism in the United States. The most widely distributed botulism vaccine was a pentavalent BoNT toxoid (PBT) against serotypes A-E administered until 2011 under an investigational new drug license. A binary vaccine composed of the recombinant, non-toxic, receptor binding domains (RBD) of serotypes/A1 and/B1 has completed a phase II clinical trial, but has yet to attain full licensure. We have previously published data demonstrating catalytically inactive, full length botulinum neurotoxin holoproteins (ciBoNT HPs) against serotypes/A1,/B1,/C1,/E1 and/F1 provide equivalent or superior potency against parental and dissimilar subtype toxins as compared the RBD vaccines. Here we describe the consistent potencies of the three independent lots each of ciBoNT/C1,/E1, and/F1 HPs against substantial monovalent challenges of the parental toxins. We also present data that a trivalent formulation of ciBoNT/C1,/E1 and/F1 (triCEF) maintains potency against both monovalent and polyvalent toxin challenges when stored as an adjuvanted vaccine at 4–8 °C for up to 2 years.

Implementing Health Technology Assessments in Latin America: Looking at the Past, Mirroring the Future. A Perspective from the ISPOR Health Technology Assessment Roundtable in Latin America

ObjectivesIn the last two decades, several countries in Latin America (LA) have shown an interest in developing health technology assessments (HTAs), but the process has not been uniform and has often been challenged by the health systems characteristics and the political or economic idiosyncrasies of these countries. MethodsThis article summarizes the discussions held by the participants at the 40th ISPOR HTA Council Roundtable for LA. An additional literature review was carried out to support some of the concepts included. ResultsThis article includes a brief description of the implementation of HTA over the last 30 years and then a conceptual analysis using examples of the broader use of HTA to support procurement decisions and risk-sharing agreements, which might play a future role in healthcare priority-setting in LA. ConclusionsFormerly, HTA processes and methods played important although mostly isolated roles (with drug licensing or reimbursement being examples of this). Nowadays, with more and more innovative technologies and the establishment of value frameworks to support the priority setting in healthcare, HTA features a promising panorama for the health systems sustainability.

Repurposing drugs in oncology: From candidate selection to clinical adoption.

Drug repurposing is a strategy that aims to develop novel cancer treatments through the reuse of existing medicines developed in other disease areas. Such a strategy includes the identification of candidate drugs, clinical development, drug licensing, reimbursement and clinical implementation. This review outlines a literature-based approach to candidate selection with illustrative examples in osteosarcoma, pancreatic cancer and perioperative therapies. Key issues related to the development of clinical trials, drug licensing/approval and clinical adoption are explored to highlight some of the obstacles that must be overcome to successfully repurpose a drug as a new therapeutic option.

Postoperativna analgezija kod dece

In many centres for pediatric surgery too many children still experience intense postoperative pain. Factors that contribute to inadequate postoperative pain control in children are: lack of the experience, inadequate use of pain scales, interpatient variability in pain perception and analgesic requirements, differences in pharmacodynamics and pharmacokinetics, age restricted drug licensing and a relative paucity of researches. The proper pain estimation scales are dependent on the child's age and their understanding of pain and of the scale. Most commonly used drugs in pediatric postoperative pain relief are opioid and nonopioid analgesics (nonsteroidal anti-inflammatory drugs, paracetamol, metamizole, ketamine, Dexamethasone and Alpha-2-agonists). The use of regional anesthesia techniques is becoming increasingly popular in postoperative analgesia following pediatric surgery. Severe acute postoperative pain in children can have significant long term effects such as chronic pain. Of great importance is that acute postoperative pain in children is optimally managed from the outset.

The Colombian Medical Oncologists Workforce.

As a result of population aging, the absolute number of new cancer cases will increase in Colombia during the next decades from about 101,893 per year in 2018 (excluding nonmelanoma skin cancer) to about 136,246 per year in 2040, still with an average annual percentage change of −1.5%.1 The country shows an epidemiologic transition with breast and prostate cancers as leading causes of cancer incidence and mortality, and a mortality reduction from infection and tobacco-associated cancers such as those from the cervix, liver, stomach, larynx, esophagus, and lung.2,3 However, the latter remain highly prevalent and, with a few exceptions, population-based survival shows a relative reduction for most types of cancer and with significant differences when compared with high-income countries.4 Despite the reduced survival, the 5-year prevalence for all cancer types was 466.4 per 100,000 in 2018 corresponding to approximately 230,726 prevalent cases.1 The relative reduction in survival may indicate scarce progress in cancer early detection or proper timely treatment. In this regard, some analyses show a variable number of visits to the oncologist depending upon the stage of the disease, with higher rates at the beginning of treatment (particularly if neoadjuvant protocols are used), lower rates among survivors with controlled disease, and higher rates again toward the end of life.5 Thus, a high proportion of advanced cases at diagnosis, as may be the case in Colombia,6 would require greater oncologist time to meet the demand. In addition to cancer incidence and stage at diagnosis, technologies used for cancer treatment also determine the demand of medical oncology. Currently target and immune therapies represent the highest investment in research and development by pharmaceutical companies,7 thus inducing permanent licensing of new oncology drugs and delivery of associated knowledge, which demands careful analysis by the medical oncologist workforce. Moreover, new technologies lead to relevant changes in oncology practice; for instance, trastuzumab combined with cytotoxic drugs for the management of HER2-positive breast cancer patients (approximately 20% of cases) reduces relapse in 50% of cases and increases survival rates.8 Furthermore, the addition of trastuzumab increases treatment adverse effects and modifies the treatment schedule from approximately 8 to 27 sessions during the first year of treatment compared to chemotherapy alone.5 Similarly, systemic therapy combined with other treatment modalities, such as in the case of neoadjuvant and adjuvant protocols or concomitant chemo-radiation, the administration of several lines of treatment, and consolidation with bone marrow transplantation, have also shown better disease control and longer survival for different types of cancer, thus resulting in increased medical oncologist time for cancer care. All factors described challenge the planning and supply of medical oncologist workforce, a situation critical to middle-income countries where better access to new cancer care technologies might take place, but the availability of resources to harmonize technology development with cancer care delivery is not a common situation. Hence, in this article, we review supply and demand of the medical oncologist workforce in Colombia using accredited sources of information and international standards.

Rushed Innovation: Reactive Licensing in the Pharmaceutical Industry

We study the drug licensing behavior (acquisition of rights for developing drugs) of large pharmaceutical firms in the aftermath of large negative shocks to their pipelines, Phase 3 failures (P3Fs). We find that P3Fs lead to increased licensing within a year of the event. This result is significant because one year is a short window given the usual timelines---licensing is a lengthy process that requires extensive planning and careful execution. Supported by a series of additional results, we interpret this finding as a reflection of rushed firm behavior. Correspondingly, our main finding is that drugs licensed in these circumstances (within a year of a P3F event) underperform in subsequent development: they are significantly less likely to reach the market compared to others licensed in normal conditions. Further analysis suggests that this underperformance may stem from the influence of rush on activities taking place in the last mile of the licensing process, and could hinge on the quality of the agreements that firms converge on during negotiation.

Orphan drugs—access and unmet needs in 194 countries and six regions: a comprehensive policy review with content analysis

BackgroundOrphaned because of low prevalence and barely recoverable medical costs, patients with rare diseases are disproportionately deprived of life-saving treatment. In China, an estimated 16·8 million patients suffer from rare diseases. This substantial burden could potentially be addressed through policies that optimise research and development, licensing, pricing, and reimbursement of orphan drugs. We aimed to review existing international orphan drug frameworks to inform policy formulation in China. MethodsPharmaceutical legislation, regulation, or policies related to the access and regulation of orphan drugs were examined from 194 WHO member countries and six regions. Relevant policies were identified through an internet search for governmental policy documents, email contacts to national pharmacovigilance centres participating in the WHO Programme for International Drug Monitoring, and a systematic literature search from academic publication databases. English publications were searched from PubMed, MEDLINE, Embase, Web of Science, and the Cochrane Library, and the search was updated to July 31, 2019. Findings171 drug regulation documents from 156 countries or regions and 77 full-text academic publications were retrieved and read in full. 89 (44·5%) of 200 countries or regions had documentation on orphan drug policy. 34 subthemes from content analysis were categorised into six policy themes: orphan drug designation, marketing authorisation, safety and efficacy requirements, price regulation, incentives that encourage market access, and incentives that encourage research and development. In the past 5 years, surges in the establishment of orphan drug policy were found in non-high income countries (ie, lower-middle-income countries, upper-middle-income countries, and low-income countries). InterpretationGlobally, patient access to orphan drugs has been boosted by government regulatory efforts and incentives. In China, priority review and tax reduction on orphan drug regulation are being initiated, along with the establishment of a national registry system for rare diseases, which are expected to positively effect patient access to orphan drugs. However, the current drug regulatory and insurance scheme in China still needs substantial improvement to achieve the accessibility and affordability of orphan drugs across the nation. A need for solid nation-wide epidemiological data on rare diseases, orphan drug designation, and systematic policy support is timely. FundingNone.

The Potential Role of Individual-Level Benefit-Risk Assessment in Treatment Decision Making: A DIA Study Endpoints Community Workstream.

Benefit-risk assessment is the cornerstone of decision making in medical care, playing a critical role in bringing treatments to market by informing decisions regarding drug development, licensing and reimbursement, and informing treatment decisions made by health care professionals and patients in clinical practice. In regulatory approval decision making, benefit and risk attributes are identified and defined based on available, aggregated clinical data from registration trials. In the context of major developments in recent years for involvement of patients as partners in all phases of drug development and in health care improvement, decision makers increasingly recognize the importance of informing treatment decisions by patient needs, values, experiences, and preferences. Using this as a basis, a DIA workstream was convened to explore the potential of individual-level benefit-risk assessment as a supplement to traditional group-level benefit-risk assessment for evaluating treatment. Various approaches as to how this information could be collected, including via patient-reported outcome measures, open-ended questioning, and stated-preference methods are presented. The utility of this information for various stakeholders is discussed.

Impact of the Avastin case on prescribing medicines off‐label

In 2018, the High Court ruled that CCGs can prescribe bevacizumab (Avastin) off‐label for wet age‐related macular degeneration (wet AMD). This article discusses the background to the case and its wider implications for drug licensing and clinical practice.

The role of validated analytical methods in JECFA drug assessments and evaluation for recommending MRLs.

The Joint Food and Agriculture Organization and World Health Organization (FAO/WHO) Expert Committee on Food Additives (JECFA) is one of three Codex committees tasked with applying risk analysis and relying on independent scientific advice provided by expert bodies organized by FAO/WHO when developing standards. While not officially part of the Codex Alimentarius Commission structure, JECFA provides independent scientific advice to the Commission and its specialist committees such as the Codex Committee on Residues of Veterinary Drugs in Foods (CCRVDF) in setting maximum residue limits (MRLs) for veterinary drugs. Codex methods of analysis (Types I, II, III, and IV) are defined in the Codex Procedural Manual as are criteria to be used for selecting methods of analysis. However, if a method is to be used under a single laboratory condition to support regulatory work, it must be validated according to an internationally recognized protocol and the use of the method must be embedded in a quality assurance system in compliance with ISO/IEC 17025:2005. This paper examines the attributes of the methods used to generate residue depletion data for drug registration and/or licensing and for supporting regulatory enforcement initiatives that experts consider to be useful and appropriate in their assessment of methods of analysis. Copyright © 2016 Her Majesty the Queen in Right of Canada. Drug Testing and Analysis © 2016 John Wiley & Sons, Ltd.

Current and Emerging Direct Oral Anticoagulants: State-of-the-Art.

Anticoagulant drugs comprise a specific subcategory of antithrombotic agents that act to inhibit blood coagulation at various stages, reducing clot development and ultimately lowering the risk of developing new-onset or recurrent thrombosis. Although the long history of anticoagulant drugs has been characteristically shaped by coumarin and heparin derivatives, a new generation of direct oral anticoagulants (DOACs), which specifically inhibit thrombin or activated factor X, combine many advantages of their progenitor drugs, and hence are prepotently revolutionizing the landscape of antithrombotic therapy. Several drugs (apixaban [BMS-562247], dabigatran [BIBR953], edoxaban [DU-1766], rivaroxaban [BAY 59-7939]) have already received widespread approval by national or supranational medicinal agencies. This narrative article provides a state-of-the-art for these and for several other DOACs at different stages of clinical evaluation (betrixaban, darexaban, eribaxaban, letaxaban, nokxaban), and certain others whose development has been discontinued (AZD-0837, fidexaban, LY517717, odiparcil, otamixaban, TTP889, and ximelagatran). What clearly emerges from our analysis is that DOACs sharing very similar mechanisms of action are still characterized by different efficacy and safety profiles. This not only depends on biochemical, biological, and pharmacokinetic characteristics, but also on lack of standardization between different clinical trials in terms of targeted disease, patient recruitment, sample size, duration and endpoints, as well as lack of harmonization around procedures used for drug licensing. These factors contribute to challenging the minds of physicians, who may find difficulty navigating their way through multiple indications, different pharmacological profiles, various side effects, and specific drug-to-drug interactions. Such considerations also burden laboratory professionals, who may face organizational and economic challenges in developing and/or implementing multiple assays to assess the pharmacodynamics (effect on coagulation) or pharmacokinetics (drug levels) of DOACs.

Optimal dose of selective serotonin reuptake inhibitors, venlafaxine, and mirtazapine in major depression: a systematic review and dose-response meta-analysis

SummaryBackgroundDepression is the single largest contributor to non-fatal health loss worldwide. Second-generation antidepressants are the first-line option for pharmacological management of depression. Optimising their use is crucial in reducing the burden of depression; however, debate about their dose dependency and their optimal target dose is ongoing. We have aimed to summarise the currently available best evidence to inform this clinical question.MethodsWe did a systematic review and dose-response meta-analysis of double-blind, randomised controlled trials that examined fixed doses of five selective serotonin reuptake inhibitors (SSRIs; citalopram, escitalopram, fluoxetine, paroxetine, and sertraline), venlafaxine, or mirtazapine in the acute treatment of adults (aged 18 years or older) with major depression, identified from the Cochrane Central Register of Controlled Trials, CINAHL, Embase, LILACS, MEDLINE, PsycINFO, AMED, PSYNDEX, websites of drug licensing agencies and pharmaceutical companies, and trial registries. We imposed no language restrictions, and the search was updated until Jan 8, 2016. Doses of SSRIs were converted to fluoxetine equivalents. Trials of antidepressants for patients with depression and a serious concomitant physical illness were excluded. The main outcomes were efficacy (treatment response defined as 50% or greater reduction in depression severity), tolerability (dropouts due to adverse effects), and acceptability (dropouts for any reasons), all after a median of 8 weeks of treatment (range 4–12 weeks). We used a random-effects, dose-response meta-analysis model with flexible splines for SSRIs, venlafaxine, and mirtazapine.Findings28 554 records were identified through our search (24 524 published and 4030 unpublished records). 561 published and 121 unpublished full-text records were assessed for eligibility, and 77 studies were included (19 364 participants; mean age 42·5 years, SD 11·0; 7156 [60·9%] of 11 749 reported were women). For SSRIs (99 treatment groups), the dose-efficacy curve showed a gradual increase up to doses between 20 mg and 40 mg fluoxetine equivalents, and a flat to decreasing trend through the higher licensed doses up to 80 mg fluoxetine equivalents. Dropouts due to adverse effects increased steeply through the examined range. The relationship between the dose and dropouts for any reason indicated optimal acceptability for the SSRIs in the lower licensed range between 20 mg and 40 mg fluoxetine equivalents. Venlafaxine (16 treatment groups) had an initially increasing dose-efficacy relationship up to around 75–150 mg, followed by a more modest increase, whereas for mirtazapine (11 treatment groups) efficacy increased up to a dose of about 30 mg and then decreased. Both venlafaxine and mirtazapine showed optimal acceptability in the lower range of their licensed dose. These results were robust to several sensitivity analyses.InterpretationFor the most commonly used second-generation antidepressants, the lower range of the licensed dose achieves the optimal balance between efficacy, tolerability, and acceptability in the acute treatment of major depression.FundingJapan Society for the Promotion of Science, Swiss National Science Foundation, and National Institute for Health Research.

Rushed Innovation: Evidence from Drug Licensing

We study the drug licensing behavior (acquisition of rights for developing drugs) of large pharmaceutical firms in the aftermath of large negative shocks to their pipelines, phase 3 failures (P3Fs). We find that P3Fs lead to increased licensing within a year of the event. This result is significant, because one year is a short window given the usual timelines—licensing is a lengthy process that requires extensive planning and careful execution. Supported by a series of additional results, we interpret this finding as a reflection of rushed firm behavior. Correspondingly, our main finding is that drugs licensed in these circumstances (within a year of a P3F event) underperform in subsequent development: they are significantly less likely to reach the market compared with others licensed in normal conditions. Further analysis suggests that this underperformance may stem from the influence of rush on activities taking place in the “last mile” of the licensing process and could hinge on the quality of the agreements that firms converge to during contract negotiations.This paper was accepted by Juanjuan Zhang, marketing.

Placebo Response in Rheumatoid Arthritis Clinical Trials.

Understanding the placebo response is critical to interpreting treatment efficacy, particularly for agents with a ceiling to their therapeutic effect, where an increasing placebo response makes it harder to detect potential benefit. The objective of this study is to assess the change in placebo responses over time in rheumatoid arthritis (RA) randomized placebo-controlled trials (RCT) for drug licensing authorization. The Cochrane Controlled Trials Register database was searched to identify RCT of biological or targeted synthetic disease-modifying antirheumatic drugs (DMARD) in RA. Studies were excluded if patients were conventional synthetic DMARD (csDMARD)-naive, not receiving background csDMARD therapy, or were biologic experienced. Metaregression model was used to evaluate changes in American College of Rheumatology (ACR) 20, ACR50, and ACR70 treatment response over time. There were 32 trials in total: anti-tumor necrosis factor therapy (n = 15), tocilizumab (n = 4), abatacept (n = 2), rituximab (n = 2), and Janus kinase inhibitors (n = 9). From 1999 to 2018, there was no significant trend in the age or sex of patients in the placebo arm. Disease duration, swollen joint count, and 28-joint count Disease Activity Score using erythrocyte sedimentation rate at baseline all significantly declined over time. There was a statistically significant increase in placebo ACR50 and ACR70 responses (ACR50 β = 0.41, 95% CI 0.09-0.74, p = 0.01; ACR70 β = 0.18, 95% CI 0.04-0.31, p = 0.01) that remained significant after controlling for potential confounders. There has been a rise in the placebo response in RA clinical trials over the last 2 decades. Shifting RA phenotype, changes in trial design, and expectation bias are possible explanations for this phenomenon. This observation has important implications when evaluating newer novel agents against established therapies.

Prevalence of baseline NS3 resistance-associated substitutions (RASs) on treatment with protease inhibitors in patients infected with HCV genotype 1

Treatment for hepatitis C has evolved significantly with the licensing of direct-acting antiviral drugs (DAAs). However, one of the limiting factors of the effectiveness of antiviral therapy with protease inhibitors (PIs) is the emergence of resistance caused by point mutations. The aim of this study was to determine the prevalence of resistance-associated substitutions (RASs) in HCV NS3 gene in patients infected with genotype 1 before therapy with simeprevir. A total of 73 serum samples from 15 treatment-experienced patients with boceprevir/telaprevir and 58 DAA-naïve patients were collected before therapy with DAAs simeprevir, daclatasvir and/or sofosbuvir. Presence of baseline resistance-associated substitutions (RAS) in the serine protease domain of HCV NS3 was analyzed by nucleotide sequencing followed by amino acid deduction. Overall RAS prevalence in this study was 13.7% (10/73). RAS prevalence for HCV subtype 1b was 17.4% (4/23) while for HCV subtype 1a was 12% (6/50). Primary mutations V36M/L and R155K were observed only in HCV subtype 1a, whereas T54S and Q80K were identified only in HCV subtype 1b. RAS V36M, which is related to reduction of susceptibility to second-generation PIs, was the most frequent in the study (6.9%; 5/73). Our results indicated that Brazilian isolates of HCV present a distinct pattern of RAS depending on the infecting viral subtype. In contrast to data from other countries, RAS Q80K prevalence in Brazil is low in HCV subtype 1a. This study improves the knowledge of genetic barrier for resistance to PIs involving RASs in chronically infected patients and its possible impact on an unsuccessful treatment outcome, information that might be crucial to upcoming decisions of incorporation of new DAAs in Brazilian guidelines of antiviral therapy against HCV infection.

Proposal for the International Society for Cell & Gene Therapy position statement on assays for the quality control and potency assessment of adoptive cellular immunotherapies

Translation of cell and gene therapies from pre-clinical experiments to clinical trials and final drug licensing brings requires the development, verification and even validation of the assays essential for the definition of the drug product. The technical and scientific challenges in doing this are far greater than they seem at first and are compounded by a lack of approved standards for assays used to support (c)GMP manufacture. This paper highlights some of those challenges and proposes solutions based on the experience of our colleagues using similar assay platforms in regulated pathology laboratories.

Choice of non-steroidal anti-inflammatory drugs in equine colic

While non-steroidal anti-inflammatory drugs (NSAIDs) can be used to manage abdominal discomfort in horses, they also are often a valid diagnostic tool to aid decision making around the need for surgery or referral of these patients. Knowledge of the pharmacokinetic properties and licensing of available drugs in the UK is of pivotal importance to select the most appropriate NSAID for the patient. This review focuses on the relevant characteristics of NSAIDs licensed for treatment of colic in horses: flunixin meglumine, metamizole, meloxicam and ketoprofen. Other NSAIDs such as phenylbutazone and firocoxib are licensed for use in horses but not for the treatment of colic; their role with colic is evaluated in light of available literature.

Added therapeutic value of new drugs approved in Brazil from 2004 to 2016.

This study aimed to assess the level of therapeutic innovation of new drugs approved in Brazil over 13 years and whether they met public health needs. Comparative descriptive analysis of therapeutic value assessments performed by the Brazilian Chamber of Drug Market Regulation (CMED) and the French drug bulletin Prescrire for new drugs licensed in Brazil, from January 1st 2004 to December 31st 2016. The extent to which new drugs met public health needs was examined by: checking inclusions into government-funded drug lists and/or clinical guidelines; comparing Anatomical Therapeutic Chemical Classification (ATC) codes and drug indications with the list of conditions contributing the most to the national disease burden; and assessing new medicines aimed to treat neglected diseases. 253 new drugs were approved. Antineoplastics, immunossupressants, antidiabetics and antivirals were the most frequent. Thirty-three (14%) out of 236 drugs assessed by the Brazilian chamber and sixteen (8.2%) out of 195 assessed by the French bulletin Prescrire were considered innovative. Thirty-six drugs (14.2%) were selected for coverage by the Brazilian Unified National Health System (SUS), seven of which were therapeutically innovative, and none were aimed to treat neglected disease. About 1/3 of the drugs approved aimed to treat conditions among the top contributors to Brazil's disease burden. Few therapeutically innovative drugs entered the Brazilian market, from which only a small proportion was approved to be covered by the SUS. Our findings suggest a divergence between public health needs, research & development (R&D) and drug licensing procedures.

Male infertility and environmental factors

Semen quality in men is decreasing. Numerous chemicals act as endocrine-disrupting agents and their detrimental effect on fertility and spermatogenesis has been shown in rodent studies. Consequences in humans are challenging to study and effects of fetal exposure on fertility are apparent only 2 decades later. Appropriate animal models are needed to study the reproductive effects of the thousands of chemicals that humans come in contact with. The burden of proof of chemical safety must shift from the individual and health care provider to the manufacturers similar to the licensing of medical drugs.