Poly(ADP-ribose) polymerase inhibitors in combination with anti-angiogenic agents for the treatment of advanced ovarian cancer.

Homologous recombination deficiency and VEGF expression are key pathways in high-grade ovarian cancer. Recently, three randomized practice changing trials were published: the PAOLA-1, PRIMA and VELIA trials. The use of PARP inhibitors (PARPi) following chemotherapy has become standard of care in first line. Combination of PARPi with anti-angiogenic agents has demonstrated synergistic activity in preclinical study. This review summarizes the body of evidence supporting the efficacy and safety of the combination of PARPi and anti-angiogenic drugs in first-line homologous recombination deficiency high-grade ovarian cancer leading to US FDA and EMA approvals. This double maintenance is supported by: a large benefit with bevacizumab + olaparib compared with olaparib alone, a rationale for additive effect, and a good safety and cost-effective profile.

Lay abstract Ovarian cancers often present difficulties to repair their DNA and are highly vascularized tumors. Recently, three randomized practice changing trials were published: the PAOLA-1, PRIMA and VELIA trials. They use one type of therapy to target the difficulty of ovarian cancer to repair their DNA which is called poly(ADP-ribose) polymerase inhibitor. This type of therapy has become standard of care after chemotherapy. In this review, we discuss the advantage of combining anti-angiogenic agents to poly(ADP-ribose) polymerase inhibitors to target the fact that tumors are highly vascularized. First, data from laboratory suggest synergistic activity of the combination. Then, clinical data are also in favor of the combination due to additive efficacy, and a good safety and cost-effective profile.

Lurbinectedin in the treatment of relapsed small cell lung cancer.

Lurbinectedin is a marine-derived drug that inhibits transcription, a process that is frequently dysregulated in small cell lung cancer. The activity of lurbinectedin has been studied in many solid tumors, showing not only promising results but also a favorable safety profile. In relapsed small cell lung cancer, the drug has shown encouraging activity both as a single agent and in combination with doxorubicin, paclitaxel or irinotecan. The USA FDA has recently granted accelerated approval to lurbinectedin monotherapy in this setting. This article provides an update on available data and ongoing studies of lurbinectedin in small cell lung cancer, including Phase I combination trials, the basket Phase II trial and the ATLANTIS Phase III trial.

Lay abstract Lung cancer is currently responsible for a large number of cancer deaths worldwide. Small cell lung cancer (SCLC) is considered the most aggressive subtype of lung cancer. When a patient presents with extensive SCLC, first-line treatment needs to be used. The most appropriate treatment option for the patient is selected; however, it is possible for the cancer to continue to get worse, even over a brief period of time. The patient will then be given another treatment; however, studies on the effectiveness of classical second-line drugs are scarce. For this reason, new therapies for SCLC are in development. One of these treatments is a marine-derived drug called lurbinectedin, which shows promising activity in some solid tumors, such as extensive SCLC, after failure of first-line treatment. Here the authors present the results of the main trials related to the activity of lurbinectedin either alone or in combination with other drugs for this type of cancer.

A General Propensity Score for Signal Identification Using Tree-Based Scan Statistics.

The tree-based scan statistic (TreeScan; Martin Kulldorff, Harvard Medical School, Boston, Massachusetts) is a data-mining method that adjusts for multiple testing of correlated hypotheses when screening thousands of potential adverse events for signal identification. Simulation has demonstrated the promise of TreeScan with a propensity score (PS)-matched cohort design. However, it is unclear which variables to include in a PS for applied signal identification studies to simultaneously adjust for confounding across potential outcomes. We selected 4 pairs of medications with well-understood safety profiles. For each pair, we evaluated 5 candidate PSs with different combinations of 1) predefined general covariates (comorbidity, frailty, utilization), 2) empirically selected (data-driven) covariates, and 3) covariates tailored to the drug pair. For each pair, statistical alerting patterns were similar with alternative PSs (≤11 alerts in 7,996 outcomes scanned). Inclusion of covariates tailored to exposure did not appreciably affect screening results. Inclusion of empirically selected covariates can provide better proxy coverage for confounders but can also decrease statistical power. Unlike tailored covariates, empirical and predefined general covariates can be applied "out of the box" for signal identification. The choice of PS depends on the level of concern about residual confounding versus loss of power. Potential signals should be followed by pharmacoepidemiologic assessment where confounding control is tailored to the specific outcome(s) under investigation.

Association between FDA and EMA expedited approval programs and therapeutic value of new medicines: retrospective cohort study.

OBJECTIVE: To characterize the therapeutic value of new drugs approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) and the association between these ratings and regulatory approval through expedited programs. DESIGN: Retrospective cohort study. SETTING: New drugs approved by the FDA and EMA between 2007 and 2017, with follow-up through 1 April 2020. DATA SOURCES: Therapeutic value was measured using ratings of new drugs by five independent organizations (Prescrire and health authorities of Canada, France, Germany, and Italy). MAIN OUTCOME MEASURES: Proportion of new drugs rated as having high therapeutic value; association between high therapeutic value rating and expedited status. RESULTS: From 2007 through 2017, the FDA and EMA approved 320 and 268 new drugs, respectively, of which 181 (57%) and 39 (15%) qualified for least one expedited program. Among 267 new drugs with a therapeutic value rating, 84 (31%) were rated as having high therapeutic value by at least one organization. Compared with non-expedited drugs, a greater proportion of expedited drugs were rated as having high therapeutic value among both FDA approvals (45% (69/153) v 13% (15/114); P<0.001) and EMA approvals (67% (18/27) v 27% (65/240); P<0.001). The sensitivity and specificity of expedited program for a drug being independently rated as having high therapeutic value were 82% (95% confidence interval 72% to 90%) and 54% (47% to 62%), respectively, for the FDA, compared with 25.3% (16.4% to 36.0%) and 90.2% (85.0% to 94.1%) for the EMA. CONCLUSIONS: Less than a third of new drugs approved by the FDA and EMA over the past decade were rated as having high therapeutic value by at least one of five independent organizations. Although expedited drugs were more likely than non-expedited drugs to be highly rated, most expedited drugs approved by the FDA but not the EMA were rated as having low therapeutic value.

Designing antifilarial drug trials using clinical trial simulators.

Lymphatic filariasis and onchocerciasis are neglected tropical diseases (NTDs) targeted for elimination by mass (antifilarial) drug administration. These drugs are predominantly active against the microfilarial progeny of adult worms. New drugs or combinations are needed to improve patient therapy and to enhance the effectiveness of interventions in persistent hotspots of transmission. Several therapies and regimens are currently in (pre-)clinical testing. Clinical trial simulators (CTSs) project patient outcomes to inform the design of clinical trials but have not been widely applied to NTDs, where their resource-saving payoffs could be highly beneficial. We demonstrate the utility of CTSs using our individual-based onchocerciasis transmission model (EPIONCHO-IBM) that projects trial outcomes of a hypothetical macrofilaricidal drug. We identify key design decisions that influence the power of clinical trials, including participant eligibility criteria and post-treatment follow-up times for measuring infection indicators. We discuss how CTSs help to inform target product profiles.

Evaluacion positiva de medicamentos: octubre, noviembre y diciembre 2019 / Positive assessment of drugs: October, November and December 2019

Se reseñan los medicamentos evaluados y con dictamen positivo por comisión de expertos de la Agencia Española de Medicamentos y Productos Sanitarios o de la Agencia Europea del Medicamento hechos públicos en octubre, noviembre y diciembre de 2019, y considerados de mayor interés para el profesional sanitario. Se trata de opiniones técnicas positivas que son previas a la autorización y puesta en el mercado del medicamento

The drugs assessed by the Spanish Agency for Medicines and Health Products or European Medicines Agency made public in October, November and December of 2019, and considered of interest to the healthcare professional, are reviewed. These are positive technical reports prior to the authorization and placing on the market of the product

Design and analysis of bridging studies with prior probabilities on the null and alternative hypotheses.

The pharmaceutical industry and regulatory agencies are increasingly interested in conducting bridging studies in order to bring an approved drug product from the original region (eg, United States or European Union) to a new region (eg, Asian-Pacific countries). In this article, we provide a new methodology for the design and analysis of bridging studies by assuming prior knowledge on how the null and alternative hypotheses in the original, foreign study are related to the null and alternative hypotheses in the bridging study and setting the type I error for the bridging study according to the strength of the foreign-study evidence. The new methodology accounts for randomness in the foreign-study evidence and controls the average type I error of the bridging study over all possibilities of the foreign-study evidence. In addition, the new methodology increases statistical power, when compared to approaches that do not use foreign-study evidence, and it allows for the possibility of not conducting the bridging study when the foreign-study evidence is unfavorable. Finally, we conducted extensive simulation studies to demonstrate the usefulness of the proposed methodology.

Moringa oleifera and glycemic control: A review of current evidence and possible mechanisms.

Maintaining glycemic control in diabetes and prediabetes is necessary to prevent many health complications and mortality. Although different hypoglycemic drugs are used for this purpose, there is still a growing interest in the use of medicinal plants due to their low price, easy availability, and fewer or no side effects. Moringa (Moringa oleifera Lam.) is a medicinal plant that has been traditionally used in the management of diabetes. This review aims to present the existing literature published until February 2019 on the role of moringa leaves in glycemia and their physiological mechanisms. In the conducted studies, moringa leaves have shown to reduce glycemia, without causing any adverse effects. The proposed mechanisms for reducing glycemia include inhibition of α-amylase and α-glucosidase activities, increased glucose uptake in the muscles and liver, inhibition of glucose uptake from the intestine, decreased gluconeogenesis in the liver, and increased insulin secretion and sensitivity. However, these studies are limited in numbers and mostly conducted in animals, in vitro and in vivo. Therefore, long-term human studies are required to determine the hypoglycemic effect of moringa leaves, their physiological mechanisms, active ingredients, and safety. Overall, this review provides evidence that moringa leaves have the possibility to be used as a glycemic control agent in diabetes and prediabetes.

Errata for trial publications are not uncommon, are frequently not trivial, and can be challenging to access: a retrospective review.

Objective: The research sought to determine the prevalence of errata for drug trial publications that are included in systematic reviews, their potential value to reviews, and their accessibility via standard information retrieval methods. Methods: The authors conducted a retrospective review of included studies from forty systematic reviews of drugs evaluated by the Canadian Agency for Drugs and Technologies in Health (CADTH) Common Drug Review (CDR) in 2015. For each article that was included in the systematic reviews, we conducted searches for associated errata using the CDR review report, PubMed, and the journal publishers' websites. The severity of errors described in errata was evaluated using a three-category scale: trivial, minor, or major. The accessibility of errata was determined by examining inclusion in bibliographic databases, costs of obtaining errata, time lag between article and erratum publication, and correction of online articles. Results: The 40 systematic reviews included 127 articles in total, for which 26 errata were identified. These errata described 38 errors. When classified by severity, 6 errors were major; 20 errors were minor; and 12 errors were trivial. No one database contained all the errata. On average, errata were published 211 days after the original article (range: 15-1,036 days). All were freely available. Over one-third (9/24) of online articles were uncorrected after errata publication. Conclusion: Errata frequently described non-trivial errors that would either impact the interpretation of data in the article or, in fewer cases, impact the conclusions of the study. As such, it seems useful for reviewers to identify errata associated with included studies. However, publication time lag and inconsistent database indexing impair errata accessibility.

Pharmacodynamic model for ß-lactam regimens used in surgical prophylaxis: model-based evaluation of standard dosing regimens.

Background Continual evolution of resistance among bacteria against methods of surgical prophylaxis may make currently used beta-lactam regimens inadequate. Objective To re-evaluate beta-lactam regimens in surgical prophylaxis. Setting A pharmacodynamic Monte Carlo simulation (MCS) model based on a number of patients in China. Methods Pharmacodynamic profiling using Monte Carlo simulation up to 4 hours postinfusion was conducted for standard-dose, short-term (0.5 h) and prolonged (2 to 4 h) infusions of ampicillin, cefazolin, cefotaxime, cefoxitin, cefuroxime, ertapenem, and piperacillin/tazobactam in adult patients with normal renal function. Microbiological data were incorporated. Cumulative fraction of response (CFR) was determined for each regimen against populations of S. aureus, coagulase-negative staphylococci and E. coli. The optimal CFR was defined as ≥ 90% response. Main Outcome Measure Cumulative fractions of response of pharmacodynamic target attainment. Results During the first 2 hours postinfusion, piperacillin/tazobactam 3.375 g exhibited consistently optimal cumulative fractions against S. aureus, CoNS and E. coli. Ampicillin 2 g (2 h) also displayed optimal CFRs for S. aureus and E. coli but not for coagulase-negative staphylococci. Cefoxitin 2 g didnot achieve any optimal CFRs, even via 2-h prolonged infusion (maximum 72.8% CFR for S. aureus and 64.5% CFR for E. coli). Cefazolin 2 g (4 h) and cefuroxime 1.5 g (4 h) provided desired CFRs across 4 h postinfusion for S. aureus but provided poor CFRs for coagulase-negative staphylococci and E. coli. Only ertapenem 1 g for E. coli and S. aureus and cefotaxime 1 g for E. coli consistently yielded ≥ 90% CFRs for 4 hour postinfusion. Conclusions Certain dosing regimens may warrant adjustment for improved prevention efficiency and enhanced empirical antibiotic regimens for surgical prophylaxis.

Foreword - Increase in clinical trials for probiotics and prebiotics.

After a steady increase over recent years, last year we experienced our first drop in Impact Factor (IF): from 3.301 to 2.923. Although last year I concluded that I was pretty awful at predicting the future (Venema, 2017; and I still haven't found a probiotic to improve that …), this result was not entirely unexpected. As a young journal (we have yet to celebrate our 10th anniversary), the IF will inevitably fluctuate a little. I keep track of the IF development over the course of the year and we are well on our way to achieving an IF of above 2 again (with still another 6 months to go until the end of June, when the new impact factors will be provided by Clarivate Analytics), which isn't bad at all for a young journal.

Evaluación positiva de medicamentos: septiembre, octubre y noviembre 2016 / Positive assessment of drugs: September, October and November 2016

Se reseñan los medicamentos evaluados y con dictamen positivo por comisión de expertos de la Agencia Española de Medicamentos y Productos Sanitarios (AEMPS) o de la Agencia Europea del Medicamento (EMA) hechos públicos en septiembre, octubre y noviembre de 2016. Se trata de opiniones técnicas positivas previas a la autorización y puesta en el mercado del medicamento

The drugs assessed by the Spanish Agency for Medicines and Health Products or European Medicines Agency made public in September, October and November of 2016, and considered of interest to the healthcare professional, are reviewed. These are positive technical reports prior to the authorization and placing on the market of the product

Statistical Approaches to Assess Biosimilarity from Analytical Data.

Protein therapeutics have unique critical quality attributes (CQAs) that define their purity, potency, and safety. The analytical methods used to assess CQAs must be able to distinguish clinically meaningful differences in comparator products, and the most important CQAs should be evaluated with the most statistical rigor. High-risk CQA measurements assess the most important attributes that directly impact the clinical mechanism of action or have known implications for safety, while the moderate- to low-risk characteristics may have a lower direct impact and thereby may have a broader range to establish similarity. Statistical equivalence testing is applied for high-risk CQA measurements to establish the degree of similarity (e.g., highly similar fingerprint, highly similar, or similar) of selected attributes. Notably, some high-risk CQAs (e.g., primary sequence or disulfide bonding) are qualitative (e.g., the same as the originator or not the same) and therefore not amenable to equivalence testing. For biosimilars, an important step is the acquisition of a sufficient number of unique originator drug product lots to measure the variability in the originator drug manufacturing process and provide sufficient statistical power for the analytical data comparisons. Together, these analytical evaluations, along with PK/PD and safety data (immunogenicity), provide the data necessary to determine if the totality of the evidence warrants a designation of biosimilarity and subsequent licensure for marketing in the USA. In this paper, a case study approach is used to provide examples of analytical similarity exercises and the appropriateness of statistical approaches for the example data.

Medicines use in hospitalised children: current status and outcome after an intervention.

INTRODUCTION: Challenges in rational use of medicines (RUM) in children are different from that of adults. In Sri Lanka, data on RUM in children are limited. OBJECTIVE: To assess the current status and to investigate effectiveness of an intervention in improving RUM in children. METHODS: Non-randomised controlled before and after study design was employed. Study settings were one paediatric unit in two Teaching Hospitals one for intervention (IU) and the other as a control (CU) unit. After assessing the current status in both units, a combined intervention (one-time training and distribution of a paediatric formulary) was offered to IU and medicine use was re-assessed in both units three months and one year after intervention. Fourteen indicators (7 WHO and 7 developed by investigators) were employed in the assessment. Any improvement was analysed using percentage changes, Chi-square or t tests as appropriate. RESULTS: A total of 1134 charts, 735 (3197 medicines) in IU and 399 (1539 medicines) in CU were subjected to analysis. At base level, of the 14 indicators, 9 were assessed satisfactory in both units. Four could not be assessed without knowing the clinical setting. The remaining indicator, reason for prescribing was recorded for 48% and 76% of medicines respectively in IU and CU. After intervention, only three indicators, medicines that had the reason for prescription recorded in the patient records, children treated without regular medicines, and children received the recommended doses of paracetamol, showed favourable changes in three months and one year. Percentage of medicines written in abbreviation showed an undesirable increase in IU (6.9, 16.2, 29.6) which was higher than what was observed in CU (3.2, 13.5, 18.4). CONCLUSIONS: Passive interventions appear to be ineffective in improving RUM in children. In addition, general medicine use indicators seem to be insensitive to capture the true challenges in paediatric pharmacotherapy.

Statistical evaluation of drug efficacy for bridging study in companion diagnostic test trials.

Personalized medicine is an area of growing attention in medical research and practice. A market-ready companion diagnostic test (CDx) is used in personalized medicine for identifying the best treatment for an individual patient. Unfortunately, development of CDx may lag behind the development of the drug, and consequently we use a clinical trial assay (CTA) to enroll patients into the drug pivotal clinical trial instead. Thus, when CDx becomes available, a bridging study will be required to assess the drug efficacy in the CDx intended use (CDx IU) population. Due to missingness of the CDx results that could be associated with randomization, one challenge we face in a bridging study is covariate imbalance between treatment arms for the subpopulation with both positive CDx and CTA. In this paper, we evaluate the performance of two methods in bridging studies under a causal inference framework. Particularly, we aim to use the propensity score method with doubly robust estimation and optimal matching to address the challenge. We extend under a current framework on drug efficacy estimation in the CDx IU population, using data from both the bridging study and the CTA drug pivotal clinical trial. Both approaches are discussed in the context of a randomized bridging study, and a targeted design clinical trial with simulations, followed by analyzing simulated data that mimic a real ongoing clinic trial.

A systematic review to investigate the measurement properties of goal attainment scaling, towards use in drug trials.

BACKGROUND: One of the main challenges for drug evaluation in rare diseases is the often heterogeneous course of these diseases. Traditional outcome measures may not be applicable for all patients, when they are in different stages of their disease. For instance, in Duchenne Muscular Dystrophy, the Six Minute Walk Test is often used to evaluate potential new treatments, whereas this outcome is irrelevant for patients who are already in a wheelchair. A measurement instrument such as Goal Attainment Scaling (GAS) can evaluate the effect of an intervention on an individual basis, and may be able to include patients even when they are in different stages of their disease. It allows patients to set individual goals, together with their treating professional. However, the validity of GAS as a measurement instrument in drug studies has never been systematically reviewed. Therefore, we have performed a systematic review to answer two questions: 1. Has GAS been used as a measurement instrument in drug studies? 2: What is known of the validity, responsiveness and inter- and intra-rater reliability of GAS, particularly in drug trials? METHODS: We set up a sensitive search that yielded 3818 abstracts. After careful screening, data-extraction was executed for 58 selected articles. RESULTS: Of the 58 selected articles, 38 articles described drug studies where GAS was used as an outcome measure, and 20 articles described measurement properties of GAS in other settings. The results show that validity, responsiveness and reliability of GAS in drug studies have hardly been investigated. The quality of the reporting of validity in studies in which GAS was used to evaluate a non-drug intervention also leaves much room for improvement. CONCLUSIONS: We conclude that there is insufficient information to assess the validity of GAS, due to the poor quality of the validity studies. Therefore, we think that GAS needs further validation in drug studies, especially since GAS can be a potential solution when a small heterogeneous patient group is all there is to test a promising new drug. TRIAL REGISTRATION: The protocol has been registered in the PROSPERO international prospective register for systematic reviews, with registration number CRD42014010619. http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42014010619 .

Comparison of Statistical Approaches for Dealing With Immortal Time Bias in Drug Effectiveness Studies.

In time-to-event analyses of observational studies of drug effectiveness, incorrect handling of the period between cohort entry and first treatment exposure during follow-up may result in immortal time bias. This bias can be eliminated by acknowledging a change in treatment exposure status with time-dependent analyses, such as fitting a time-dependent Cox model. The prescription time-distribution matching (PTDM) method has been proposed as a simpler approach for controlling immortal time bias. Using simulation studies and theoretical quantification of bias, we compared the performance of the PTDM approach with that of the time-dependent Cox model in the presence of immortal time. Both assessments revealed that the PTDM approach did not adequately address immortal time bias. Based on our simulation results, another recently proposed observational data analysis technique, the sequential Cox approach, was found to be more useful than the PTDM approach (Cox: bias = -0.002, mean squared error = 0.025; PTDM: bias = -1.411, mean squared error = 2.011). We applied these approaches to investigate the association of ß-interferon treatment with delaying disability progression in a multiple sclerosis cohort in British Columbia, Canada (Long-Term Benefits and Adverse Effects of Beta-Interferon for Multiple Sclerosis (BeAMS) Study, 1995-2008).

Estimation and approximation approaches for biosimilar index based on reproducibility probability.

In recent years, quantitative evaluation for biosimilarity has been taken seriously due to the development of biosimilar products. The concept for assessment of biological products is very different from that of small-molecule drug products because of the variability with respect to the manufacturing process and environmental factors of the biological products. In this article, we propose an estimate method for a biosimilar index and the related lower bound based on the concept of reproducibility probability by assessing power. In addition, some approximations are proposed and compared in regard to simplicity and accuracy.