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Deborah Robertson provides an overview of recently published articles that may be of interest to non-medical prescribers. Should you wish to look at any of the papers in more detail, a full reference is provided [ABSTRACT FROM AUTHOR]

Background: Summaries of product characteristics (SmPCs) are regulatory documents published upon drug approval. They should report all relevant study data and advise how to use drugs safely and effectively. Patient-reported outcomes (PROs) are increasingly used in clinical trials to incorporate the patient perspective—SmPCs should thus adequately report PROs. In Germany, new drugs undergo mandatory early benefit assessment. Pharmaceutical companies submit dossiers containing all evidence; the subsequent dossier assessments focus on patient-relevant outcomes and comprehensively report PROs. Objective: The primary aim was to investigate to what extent PROs recorded as outcomes in clinical trials of new drugs are reported in SmPCs. Methods: We analysed dossier assessments with randomized controlled trials (RCTs) of new drugs entering the market between 01/2014 and 07/2018 and the corresponding SmPCs, and compared PRO reporting in both document types. For this purpose, we evaluated dossier assessment characteristics (e.g. drug name, indication, disease category) and study characteristics (e.g. evaluable PROs available?). PROs were divided into symptoms and health-related quality of life (HRQoL). SmPCs were screened to identify RCTs. We conducted 3 main evaluation steps: (1) Did the RCT included in the dossier assessment contain evaluable PROs? (2) If yes, was the RCT included in the SmPC? (3) If yes, were the PROs reported in the SmPC? Results are presented descriptively. Results: 88 dossier assessments including 143 RCTs on 72 drugs were considered: 109 (76.2%) RCTs included evaluable PROs, of which 89 were included in SmPCs. 38 RCTs (42.7%) investigated oncologics, 18 (20.2%) anti-infectives, and 33 (37.1%) other drugs. The RCTs considered symptoms more often than HRQoL (82 vs. 66 RCTs). In SmPCs, PROs were reported for 41 RCTs (46.1%), with a slightly higher reporting rate for RCTs considering HRQoL (43.9%) than for RCTs considering symptoms (41.5%). In oncologic indications, PROs were reported for 36.7% of RCTs considering HRQoL and 33.3% of RCTs considering symptoms. In infectious diseases, the rates were 21.4% (symptoms) and 0% (HRQoL), and for other diseases about 60% (symptoms) to 70% (HRQoL). Conclusion: Even though a large amount of PRO data on new drugs is available from clinical trials included in SmPCs, the corresponding results are underreported. [ABSTRACT FROM AUTHOR]

The 2011 German Pharmaceutical Market Restructuring Act subjected brand-name drugs for nonrare diseases to price regulation based on an assessment of their clinical benefit. Indication-specific assessment outcomes range from major added benefit to less benefit than the appropriate comparator(s) and affect price negotiations beyond the first year on the market. Using data on drugs that entered the market in the period 2012-16, we evaluated benefit assessment findings, subsequent drug exits, and their correlates. We considered 171 drug-indication pairs, corresponding to 138 different drugs. Of these, 66 drug-indication pairs (55 different drugs) were found to have added benefit. Almost all drugs with a positive benefit assessment (98 percent) remained on the market, while drugs without a positive benefit assessment were over ten times more likely to exit (25 percent versus 2 percent). US policy makers considering how to address rapidly increasing drug costs may draw valuable lessons from the German experience. [ABSTRACT FROM AUTHOR]

Background Desmoid tumours describe a rare monoclonal, fibroblastic proliferation characterised by an often unpredictable clinical course. Surgery is one therapeutic option for progressing patients, except if mutilating and associated with considerable function loss. Different systemic treatment approaches have been investigated and promising results could be demonstrated using imatinib. Patients and methods We initiated a phase II trial within the German Interdisciplinary Sarcoma Group (GISG) evaluating imatinib to induce progression arrest in desmoid tumour patients being Response Evaluation Criteria in Solid Tumours (RECIST) progressive, not amenable to surgical resection with R0 intent or accompanied by unacceptable function loss (NCT01137916). Thirty-eight patients (median age 44 years [range: 19–80]; 68% female; 90% Eastern Cooperative Oncology Group (ECOG) performance status 0) were treated with a daily dose of 800 mg imatinib planned over 2 years. The progression arrest rate after 6 months of imatinib treatment (PAR 6mo ) was the primary end-point. Patients showing disease progression under imatinib could be treated with nilotinib 800 mg daily. Accrual started in July 2010 in four GISG centres and finalised in September 2013. Results The final analysis for the primary end-point in the evaluable patients of the full analysis set revealed a PAR 6mo of 65%. Subsequent progression arrest rates at 9, 12, 15, 18, 21 and 24 months were 65%, 59%, 53%, 53%, 50% and 45%, respectively. None of the patients died within the study observational period. Best reported response was seven partial responses at 21 months revealing an overall response rate of 19%. Eight patients treated with nilotinib demonstrated a PAR at 3 months of 88% (7/8); no more disease progressions occurred until end of study. In general imatinib adverse events were mild to moderate. Conclusions Imatinib induces sustained progression arrest in RECIST progressive desmoid tumour patients. In addition, nilotinib had the potential to stabilise desmoid tumour growth after treatment failure with imatinib. [ABSTRACT FROM AUTHOR]

Introduction/Methods : A discussion forum was hosted by the German not-for-profit Association for Applied Human Pharmacology (AGAH e.V.) to critically review key eligibility criteria and stopping rules for clinical trials with healthy subjects, enrolling stakeholders from the pharmaceutical industry, contract research organisations, academia, ethics committees and competent authority. Results : Pivotal eligibility criteria were defined for trials with new investigational medicinal products (IMPs) or with clinically established IMPs. In general, a pulse rate ranging between 50 and 90 beats/min is recommended for first-in-human (FIH) trials, while wider ranges seem acceptable for trials with clinically established IMPs, provided there are no indications of thyroid dysfunction. Hepatic laboratory parameters not to exceed the upper limit of normal (ULN) comprise ALT (alanine aminotransferase) and AST (aspartate aminotransferase) in FIH trials, whereas slight elevations (10% above ULN) seem acceptable in trials with clinically established IMPs without known hepatotoxicity. A normal renal function is required for any clinical trial in healthy subjects. A risk-adapted approach for stopping rules was adopted. Stopping rules for an individual subject are one adverse event of severe intensity or one serious adverse event. In case of a severe adverse event, some stakeholders demand a causal relationship with the IMP (i.e. an adverse reaction). Stopping rules for a cohort are one serious adverse reaction or ≥50% of subjects experiencing any adverse reaction of moderate or severe intensity. Consequences : The application of this consensus resulted in a reduction in protocol deficiencies issued by the competent authority. [ABSTRACT FROM AUTHOR]

Background Bone remains one of the most common anatomic sites for cancer metastases, and the limited therapeutic options aggravate cancer-related morbidity and mortality in multiple malignancies. The covalent conjugation of the amino-bisphosphonate alendronate (ale) with the antimetabolite 5-fluoro-2′-desoxyuridine (5-FdU) results in N-(butyl-(4-hydroxy-4-phosphono)phosphate)-5-fluoro-2′-desoxyuridine (5-FdU-alendronat, 5-FdU-ale), an effective, novel bone-targeting duplex drug directed against skeletal cancer manifestations. Methods In vitro cytotoxicity of ale, 5-FdU or 5-FdU-ale was measured with Alamar Blue and MUH cell viability assays in 14 malignant melanoma, multiple myeloma, bone marrow-derived stromal cell and osteoblast-like cell lines. In vivo toxicity was evaluated using the chicken embryo assay and evaluation of nephrotoxicity and the systemic toxicity in Balb/c nude mice. The effect of 5-FdU-ale on osteoclast was evaluated with Balb/c nude mice in a metastatic breast cancer mouse model. Results A cell line-specific, dose-related cytotoxicity was observed for 5-FdU-ale in all cancer cell lines tested, which was significantly less toxic than 5-FdU alone when compared to the benign osteoblasts or stromal cells. The embryotoxicity of 5-FdU-ale was significantly less than that of the parental drugs alendronate or 5-FdU. 5-FdU-ale showed no signs of unwanted side effects, weight loss or nephrotoxicity in mice. In a bone metastasis mouse model, 5-FdU-ale reduced the number of tumor-associated osteoclasts. Conclusion The coupling of an amino-bisphosphonate with an antimetabolite via an N-alkyl-bonding offers a new strategy for the preparation of amino-bisphosphonates conjugates with a cancer cell-specific, efficacious cytotoxic bone-targeting potential along with a reduced systemic toxicity. The innovative duplex drug 5-FdU-ale therefore warrants further clinical investigation. [ABSTRACT FROM AUTHOR]

Ibrutinib (formerly PCI-32765) is a specific, irreversible, and potent inhibitor of Burton's tyrosine kinase (BTK) developed for the treatment of several forms of blood cancer. It is now an FDA-approved drug marketed under the name Imbruvica (Pharmacyclics, Inc.) and successfully used as an orally administered second-line drug in the treatment of mantle cell lymphoma. Since BTK is predominantly expressed in hematopoietic cells, the sensitivity of solid tumor cells to Ibrutinib has not been analyzed. In this study, we determined the effect of Ibrutinib on breast cancer cells. We demonstrate that Ibrutinib efficiently reduces the phosphorylation of the receptor tyrosine kinases ErbB1, ErbB2 and ErbB3, thereby suppressing AKT and MAPK signaling in ErbB2-positive (ErbB2+) breast cancer cell lines. Treatment with Ibrutinib significantly reduced the viability of ErbB2+ cell lines with IC values at nanomolar concentrations, suggesting therapeutic potential of Ibrutinib in breast cancer. Combined treatment with Ibrutinib and the dual PI3K/mTOR inhibitor BEZ235 synergistically reduces cell viability of ErbB2+ breast cancer cells. Combination indices below 0.25 at 50 % inhibition of cell viability were determined by the Chou-Talalay method. Therefore, the combination of Ibrutinib and canonical PI3K pathway inhibitors could be a new and effective approach in the treatment of breast cancer with activated ErbB receptors. Ibrutinib could thus become a valuable component of targeted therapy in aggressive ErbB2+ breast cancer. [ABSTRACT FROM AUTHOR]

Purpose We evaluated the safety, tolerability, and pharmacokinetics (PK) of EMD 525797 (DI17E6), a humanized monoclonal antibody targeting αv-integrins, in healthy subjects. Methods In this first-in-human, double-blind, placebo-controlled, randomized Phase 1 study, healthy male volunteers were consecutively assigned to 6 ascending single-dose cohorts of 35, 100, 250, 500, 1000, or 1500 mg. Per dose cohort, EMD 525797 or placebo was administered over 1 h as an intravenous 250-mL infusion to 6 and 3 volunteers, respectively. Escalation to the next dose level was based on evaluation of safety, tolerability, and PK data. Results Fifty-five subjects (aged 18-45 years) were randomized. Twenty-seven of 37 (73 %) subjects receiving EMD 525797 reported a total of 61 adverse events (AEs), including 38 events (in 17 subjects) considered by the investigator to be treatment related. A total of 35 AEs were reported by 14 of 18 (78 %) placebo-treated subjects. The most commonly occurring AEs were gastrointestinal disorders, abnormal laboratory values, and increased or decreased biochemistry and/or hematology values, as well as headaches, which occurred at a slightly higher frequency in the EMD 525797 group compared with placebo. There were no serious AEs or deaths. EMD 525797 PK appeared to be dose dependent, especially at lower doses. Conclusion Ascending single doses of EMD 525797 were shown to be safe and well tolerated. No safety concerns were identified. This study supports the ongoing investigation of EMD 525797. [ABSTRACT FROM AUTHOR]

Aim AZD8931 is an oral equipotent inhibitor of EGFR (erbB1), HER2 (erbB2) and HER3 (erbB3) signaling. This Phase I, open-label study evaluated the safety, tolerability, and pharmacokinetics of multiple ascending doses of AZD8931 in patients with advanced solid tumors (). Methods Patients received AZD8931 as a single oral dose followed by 4 days of observation, then twice-daily dosing for 21 consecutive days. Using a standard 3 + 3 design, AZD8931 doses were escalated from 40 mg bid until the maximum tolerated dose (MTD) was established. Results Twenty-eight patients received AZD8931 (n = 5, 40 mg bid; n = 8, 80 mg bid; n = 6, 160 mg bid; n = 6, 240 mg bid; n = 3, 300 mg bid). Ovary ( n = 8) and breast ( n = 5) were the most common primary tumor types. The most frequent adverse events were treatment-emergent cutaneous ( n = 27) and diarrhea ( n = 21). Dose-limiting toxicities (DLTs) were identified in one patient in the 240 mg bid cohort (Grade 3 rash) and two patients in the 300 mg bid cohort (Grade 3 and 4 diarrhea). The pharmacokinetic profile of AZD8931 supported twice-daily dosing. AZD8931 was rapidly absorbed (median t 1-3 h), was well distributed and had moderate to high clearance with an elimination half-life of approximately 11 h. Exposure appeared to increase approximately proportionally with dose up to 160 mg. Of 21 patients evaluable for response at day 21, 12 had stable disease and nine had disease progression. Conclusion The MTD of AZD8931 determined from the 21-day DLT period was 240 mg bid, although more long-term data are needed to confirm a dose of AZD8931 suitable for chronic treatment. [ABSTRACT FROM AUTHOR]

Background PLD is a standard treatment in patients with recurrent platinum-resistant or refractory ovarian cancer. Vandetanib is an oral once daily administered inhibitor of VEGFR-, EGFR- and RET-signaling with activity in combination with chemotherapy in some solid tumours. We aimed to establish a feasible combination therapy of PLD and vandetanib in ovarian cancer. Methods Eligible patients were treated with PLD 50 mg/m q28 and vandetanib 100 mg/d po. It was planned to recruit at least 10 patients evaluable for toxicity over 2 treatment cycles. Primary endpoints were tolerability and safety; secondary endpoint was efficacy. Results Fourteen of 15 registered patients started treatment and were evaluable for toxicity. Three patients (21 %) stopped after first cycle (PD, withdrawal of consent, nausea/vomiting). The remaining 11 patients were treated for at least 2 cycles. Dose reductions of PLD and vandetanib were indicated in 4 (29 %) and 5 patients (36 %), respectively. The following G3/4 toxicities occurred per patient: 2 (14 %) elevated liver enzymes G3, 2 (14 %) neutropenia G3/4, 5 (36 %) PPE G3/4, 2 (14 %) mucositis G3. Tyrosine kinase inhibitor attributed side effects like hypertension or bowel perforations were not reported. Toxicity led to cessation of treatment in 4 patients (29 %). Ten patients were evaluable for response: PR 1, SD 4. The median PFS was 6.7 months and median OS was 11.1 months. Conclusions The combination of PLD 50 mg/mq28 and vandetanib 100 mg/d is feasible, but may be intolerable due to reported toxicity. [ABSTRACT FROM AUTHOR]

Simple Summary: This opinion paper describes the regulatory hurdles for a clinical oncologist and physician scientist to activate an Investigator-Initiated Trial (IIT) before and after 2004 with German regulation as an example. Changes in legal framework with impacts on time and costs to activate a clinical trial are described. Evidence needed to reach the objective of higher patient safety and trial quality by European Union (EU) Clinical Trial Directive (CTD) 2001/20 is discussed. Shortly after the beginning of the year 2000, multiple legal changes with impacts on the regulatory framework of clinical trials became effective almost simultaneously. They included the European Union (EU) Clinical Trial Directive (CTD) 2001/20 followed by major changes in national drug laws, the change in the legal status of German University Hospitals (1998), and a new disease-related groups (DRG)-based reimbursement system for hospitals in Germany (2000). Together, these changes created enormous bureaucratic and financial inhibition of activation and conduct of academic investigator-initiated clinical trials (IIT). Examples for activating clinical trials in oncology before and after 2004 are outlined and discussed, focussing on extended time frames, the establishment of centralized responsibility structures and the exploding financial consequences. In addition, the evolution of trial numbers and the distribution of trial initiators between "commercial" and "academic" over time are discussed together with the occurrence of clinical registries. At the same time, progress in molecular biology led to a plethora of new targets for effective pharmacological therapy of life-threatening diseases such as cancer, and the overall number of clinical trials has not decreased. Yet, judging the regulatory and administrative hurdles between scientific study design and first-patient on trial before and after 2004 and weighing these against the lack of evidence that this regulation has achieved its goal to enhance patient safety and trial quality, the necessity to completely overhaul this CTD becomes obvious. A main goal of such an initiative should be to minimize bureaucracy. For the specific situation in Germany, relocation of responsibility and freedom to operate in University Hospitals and Medical Faculties back to the physician–scientists and reduction in interference by legal divisions should be a goal as well as increasing the public financial support for IITs. [ABSTRACT FROM AUTHOR]

The methods used for detection of prostate cancer and prostate cancer lymph node metastases in medical diagnostics leave room for improvement. Currently, no means of identifying metastasized lymph nodes other than biopsies is available. Markers which are exclusively found on prostate cancer cells present a focal point for potential imaging methods. To complement the established markers like e.g. PCA3-a noncoding mRNA sequence-and PSA-a serine protease-we investigated the ectopically expressed G-protein coupled olfactory receptor OR1D2 as a possible target for prostate-specific detection with its agonist bourgeonal which has been conjugated to two different fluorescent dyes. We performed mRNA expression analysis of the OR1D2 receptor mRNA by reverse transcriptase polymerase chain reaction on LNCaP prostate carcinoma cells and three other non-prostate derived carcinoma cell lines. Additionally, we used flow cytometry to investigate the uptake of fluorescent-dye-bound OR1D2-ligand bourgeonal into the examined carcinoma cell lines. Finally, confocal laser scanning microscopy of in vitro cell culture and in vivo tumor xenografts on mice was performed. We could confirm OR1D2 receptor mRNA overexpression as well as stronger uptake of both bourgeonal conjugates in vitro and in vivo for LNCaP cells compared to the non-prostate derived cell lines. Cytoplasmic accumulation and no adverse effects after in vitro and in vivo application of the conjugates were observed. The conjugates represent a platform for the development of future prostate-specific imaging applications, e.g. detection of metastasized lymph nodes during surgery by intraoperative laser examination. [ABSTRACT FROM AUTHOR]

Purpose: The aim of non-interventional studies (NIS) with medicinal products is to investigate the use of authorized medicinal products in daily routine. In the past, this type of study has been subject to frequent criticism, and many recommendations have been published. The aim of our study was to assess the quality of NIS study protocols. Methods: Nearly all NIS study protocols submitted to the German Federal Institute for Drugs and Medical Devices (BfArM) within a period of one year could be analyzed. The protocols were evaluated in terms of objectives, methods and included patients, as well as with regard to their compliance with quality recommendations for NIS by federal authorities and pharmaceutical industry associations. Results: The 136 NIS available for study were scheduled to enroll approximately 330,000 patients (2,500 patients per study) and 43,000 healthcare professionals. Of these NIS, 58 % were performed with medicinal products that had been authorized within the past 5 years; however, 68 % of the investigated active pharmaceutical ingredients were older than 5 years, and 19 % were even older than 19 years. Only 56 % of the protocols provided information on publication policy, and 65 % required the involvement of ethic committees. The adherence to current quality recommendations was average, but the compliance of NIS performed by member companies of the Association of Research-Based Pharmaceutical Companies was significantly higher than that of other sponsors. Conclusions: Current quality recommendations are still not fully implemented in most NIS protocols. Therefore, the scientific value of many NIS is still questionable, and the criticism that NIS are mainly conducted for marketing reasons could not be refuted by the data analyzed here. [ABSTRACT FROM AUTHOR]

A mechanistic drug-disease model was developed on the basis of a previously published integrated glucose-insulin model by Jauslin et al. A glucokinase activator was used as a test compound to evaluate the model’s ability to identify a drug’s mechanism of action and estimate its effects on glucose and insulin profiles following oral glucose tolerance tests. A kinetic-pharmacodynamic approach was chosen to describe the drug’s pharmacodynamic effects in a dose-response-time model. Four possible mechanisms of action of antidiabetic drugs were evaluated, and the corresponding affected model parameters were identified: insulin secretion, glucose production, insulin effect on glucose elimination, and insulin-independent glucose elimination. Inclusion of drug effects in the model at these sites of action was first tested one-by-one and then in combination. The results demonstrate the ability of this model to identify the dual mechanism of action of a glucokinase activator and describe and predict its effects: Estimating a stimulating drug effect on insulin secretion and an inhibiting effect on glucose output resulted in a significantly better model fit than any other combination of effect sites. The model may be used for dose finding in early clinical drug development and for gaining more insight into a drug candidate’s mechanism of action. [ABSTRACT FROM PUBLISHER]

The aim of this study was to evaluate the effect of food on the oral bioavailability of preladenant, a novel adenosine A2A receptor antagonist. This open-label, randomized, single-dose, 2-way crossover study evaluated the effects of a high-fat, high-calorie meal on the pharmacokinetics of preladenant and its metabolite (SCH434748) following oral administration of a single 25-mg preladenant capsule to 24 healthy subjects. When administered with food, the time of maximum concentration (Tmax) of preladenant was prolonged compared with administration in the fasting state. Whereas Tmax was increased from 0.9 hours to 2.6 hours and maximum concentration (Cmax) was decreased (from 212 ng/mL to 128 ng/mL), the extent of absorption (area under the plasma concentration–time curve from time 0 to time of final quantifiable sample, or AUC[tf]) was unaffected by the meal. Similarly, SCH434748 Tmax was prolonged in the fed state, and Cmax decreased from 43.7 ng/mL to 28.6 ng/mL. The assessment of AUC[tf] and area under the plasma concentration–time curve from time 0 to infinity [AUC[I]] together suggests that the AUC for the metabolite remained unchanged. No serious, significant, or unexpected adverse events occurred. In summary, food delays absorption and reduces peak exposure (Cmax) but does not alter the extent of preladenant exposure (AUC). These small changes are unlikely to be of clinical importance. A single 25-mg dose of preladenant is safe and well tolerated in healthy subjects under both fed and fasting conditions. [ABSTRACT FROM PUBLISHER]

In a study reported herein, the marketing approval dates of 214 drugs newly introduced into the world market from January 1990 through December 1994 were compared in 4 countries. The analysis reveals that the United States and the United Kingdom have similar patterns of drug availability, although the United States has a number of therapies with significant public health benefits that are not yet available in the United Kingdom. The findings also show that the United States outpaces both Germany and Japan in approving important new drugs. Various strategies adopted by the Food and Drug Administration to expedite its pharmaceutical review process, including the use of industry user fees, are described. [ABSTRACT FROM AUTHOR]