Will the EU Clinical Trials Regulation Support the Innovative Industry in Bringing New Medicines Faster to Patients?

Will the EU Clinical Trials Regulation Support the Innovative Industry in Bringing New Medicines Faster to Patients?

Pharmaceut Med. 2013 Apr; 27(2): 75-82
Atzor S, Gokhale S, Doherty M

A perspective from the innovative industry is provided in this article about the long awaited legal proposal for a Clinical Trial Regulation (“Proposal”), adopted in July 2012. With this Proposal, the European Commission reacted to a call by all stakeholders for more harmonization and streamlining of the provisions for conducting clinical trials in the EU. Discrepant approaches between Member States, a failure to respect legal timelines, and a lack of formal coordination mechanisms within and between Member States have resulted in an increased workload for the industry and contributed to a decline in Europe’s attractiveness as a place to carry out research and development. The Proposal introduces a concept whereby the sponsor makes a single submission of the clinical trial application dossier to an EU portal, which is followed by a single assessment based on cooperation between Member States. A possibility for the sponsor to choose a ‘reporting Member State’ to take the lead on key aspects of the assessment is expected to support excellence building and work sharing of Competent Authorities in the EU. The Proposal respects the fact that certain aspects need to be reviewed nationally. The new process aims to lead to a single decision per clinical trial per concerned Member State. The rules are built on the principle of strict adherence to timelines for authorization. The timelines are ambitious but at the same time competitive, as the process builds in mechanisms that strengthen compliance. The rules have been designed to encourage sponsors to file complete submission packages, since any substantial modification to a trial would lead to delays in its commencement. Sponsors need to streamline their internal processes accordingly. In the end, streamlining is an effort that needs to be accepted by all parties involved. The Proposal does not detail how Member States organize the involvement of different bodies, such as Competent Authorities and Ethics Committees, because according to the EU Treaty, the EU cannot legislate on aspects falling into pure Member State competence. The Proposal, however, establishes the assessment objectives on the basis of Good Clinical Practices set by the International Conference on Harmonisation (ICH) and the Declaration of Helsinki by the World Medical Association. As such, the new legislation is likely to have implications on Member States’ internal organization. In addition, Ethics Committees in Europe would benefit from an EU platform for best practice exchange-a concept that would need to be requested by the Council and the European Parliament through the legislative process. A single decision system for the entire EU per clinical trial has been discussed as an option, but such an approach was difficult to achieve while respecting national competencies. In this situation, the Proposal represents an acceptable compromise, provided its proposed mechanisms, processes, and timelines are retained upon implementation. As the Proposal is now on the table for discussion by the 27 Member States’ governments and by the European Parliament, co-legislators and stakeholders should be aware that any dilution of these provisions would be detrimental to the objective to ensure patient access and make the conditions for clinical research in Europe attractive and fit for the future. HubMed – drug


Drug Review: Safety and Efficacy of Bevacizumab for Glioblastoma and Other Brain Tumors.

Jpn J Clin Oncol. 2013 Apr 12;
Narita Y

Glioblastoma is a highly vascular tumor that expresses vascular endothelial growth factor, a key regulator of angiogenesis and tumor blood vessel permeability. Bevacizumab is a monoclonal antibody that inhibits vascular endothelial growth factor and the growth of gliomas. Bevacizumab monotherapy has proven effective for recurrent glioblastoma, and it extended progression-free survival and improved patient quality of life in various clinical trials. Some patients who receive bevacizumab experience improvements in neurological symptoms and steroid dose reductions. Bevacizumab induces a dramatic and rapid radiological response, but non-enhancing lesions are often detected on magnetic resonance imaging without enhancing lesions. Rebound phenomena such as rapid tumor regrowth are occasionally observed after the discontinuation of bevacizumab therapy. Therefore, Response Assessment in Neuro-Oncology criteria were recently devised to evaluate the efficacy and radiological response of bevacizumab treatment. Hypertension and proteinuria are characteristic adverse events associated with bevacizumab therapy. In addition, many fatal adverse events such as intracranial hemorrhage and venous thromboembolism are reported in patients treated with bevacizumab. However, these events are also associated with glioma itself, and careful attention needs to be paid to these events. Bevacizumab is used to treat various diseases including radiation necrosis and recurrent brain tumors such as brain metastases, schwannoma and meningioma, but additional clinical trials are necessary. The efficacy and current problems associated with bevacizumab in the treatment of glioblastoma and other brain tumors are reviewed. HubMed – drug


Mouse, but not Human STING, Binds and Signals in Response to the Vascular Disrupting Agent 5,6-Dimethylxanthenone-4-Acetic Acid.

J Immunol. 2013 Apr 12;
Conlon J, Burdette DL, Sharma S, Bhat N, Thompson M, Jiang Z, Rathinam VA, Monks B, Jin T, Xiao TS, Vogel SN, Vance RE, Fitzgerald KA

Vascular disrupting agents such as 5,6-dimethylxanthenone-4-acetic acid (DMXAA) represent a novel approach for cancer treatment. DMXAA has potent antitumor activity in mice and, despite significant preclinical promise, failed human clinical trials. The antitumor activity of DMXAA has been linked to its ability to induce type I IFNs in macrophages, although the molecular mechanisms involved are poorly understood. In this study, we identify stimulator of IFN gene (STING) as a direct receptor for DMXAA leading to TANK-binding kinase 1 and IFN regulatory factor 3 signaling. Remarkably, the ability to sense DMXAA was restricted to murine STING. Human STING failed to bind to or signal in response to DMXAA. Human STING also failed to signal in response to cyclic dinucleotides, conserved bacterial second messengers known to bind and activate murine STING signaling. Collectively, these findings detail an unexpected species-specific role for STING as a receptor for an anticancer drug and uncover important insights that may explain the failure of DMXAA in clinical trials for human cancer. HubMed – drug


Pharmacokinetics of Doripenem in Infected Patients Treated Within and Outside the Intensive Care Unit (May).

Ann Pharmacother. 2013 Apr 12;
Bhalodi AA, Keel RA, Quintiliani R, Lodise TP, Nicolau DP, Kuti JL

BACKGROUND:Doripenem often is used in the intensive care unit (ICU) to treat serious infections. However, pharmacokinetics in this population often are altered by various physiologic changes. Current pharmacokinetic data in critically ill patients receiving doripenem are limited.OBJECTIVE:To determine the pharmacokinetics of doripenem in patients treated in the ICU versus outside the ICU.METHODS:A total of 3-4 serum samples were collected from 25 infected patients receiving doripenem. A 2-compartment model was fit to serum pharmacokinetic data with nonparametric adaptive grid with adaptive ?. In the structural pharmacokinetic model, clearance (Cl) was made proportional to creatinine clearance (CrCl) and an intercept term. Bayesian pharmacokinetic parameters were compared between the 2 populations. A 5000-patient Monte Carlo simulation was performed for various CrCl ranges. The probability of pharmacodynamic target attainment was calculated over a range of minimum inhibitory concentrations (MICs), assuming a target of 35% of the dosing interval that unbound drug concentrations remain above the MIC.RESULTS:Mean (range) age, body mass index, and CrCl were 61 (31-90) years, 31.2 (15.1-55.5) kg/m(2), and 86 (15-221) mL/min, respectively. After the Bayesian step, r(2), bias, and precision were 0.97, 0.04, and 1.44 µg/mL, respectively. Mean (SD) parameters for ICU (n = 13) and non-ICU (n = 12) patients were not significantly different (p > 0.05): volume of central compartment (17.3 [11.2] vs 18.5 [11.7] L), Cl (10.1 [10.2] vs 15.5 [16.9] L/h), k12 (4.7 [4.7] vs 4.7 [4.8] h(-1)), and k21 (7.1 [5.5] vs 5.7 [5.3] h(-1)), respectively. Optimal target attainments were obtained for patients with normal renal function up to MICs of 2 µg/mL with a dose of 500 mg every 8 hours as 1-hour and 4-hour infusions.CONCLUSIONS:Doripenem pharmacokinetics were similar between ICU and non-ICU patients in this population. Optimal dosing regimens should be selected based on underlying renal function and suspected MIC of the infecting pathogen. HubMed – drug


Delivery of Optimized Inpatient Anticoagulation Therapy: Consensus Statement from the Anticoagulation Forum (May).

Ann Pharmacother. 2013 Apr 12;
Nutescu EA, Wittkowsky AK, Burnett A, Meril GJ, Ansell JE, Garcia DA

OBJECTIVE:To provide recommendations for optimized anticoagulant therapy in the inpatient setting and outline broad elements that need to be in place for effective management of anticoagulant therapy in hospitalized patients; the guidelines are designed to promote optimization of patient clinical outcomes while minimizing the risks for potential anticoagulation-related errors and adverse events.DATA SOURCES:The medical literature was reviewed using MEDLINE (1946-January 2013), EMBASE (1980-January 2013), and PubMed (1947-January 2013) for topics and key words including, but not limited to, standards of practice, national guidelines, patient safety initiatives, and regulatory requirements pertaining to anticoagulant use in the inpatient setting. Non-English-language publications were excluded. Specific MeSH terms used include algorithms, anticoagulants/administration and dosage/adverse effects/therapeutic use, clinical protocols/standards, decision support systems, drug monitoring/METHODS: Because of this document’s scope, the medical literature was searched using a variety of strategies. When possible, recommendations are supported by available evidence; however, because this paper deals with processes and systems of care, high-quality evidence (eg, controlled trials) is unavailable. In these cases, recommendations represent the consensus opinion of all authors and are endorsed by the Board of Directors of the Anticoagulation Forum, an organization dedicated to optimizing anticoagulation care. The board is composed of physicians, pharmacists, and nurses with demonstrated expertise and experience in the management of patients receiving anticoagulation therapy.DATA SYNTHESIS:Recommendations for delivering optimized inpatient anticoagulation therapy were developed collaboratively by the authors and are summarized in 8 key areas: (1) process, (2) accountability, (3) integration, (4) standards of practice, (5) provider education and competency, (6) patient education, (7) care transitions, and (8) outcomes. Recommendations are intended to inform the development of coordinated care systems containing elements with demonstrated benefit in improvement of anticoagulation therapy outcomes. Recommendations for delivering optimized inpatient anticoagulation therapy are intended to apply to all clinicians involved in the care of hospitalized patients receiving anticoagulation therapy. CONCLUSIONS:Anticoagulants are high-risk medications associated with a significant rate of medication errors among hospitalized patients. Several national organizations have introduced initiatives to reduce the likelihood of patient harm associated with the use of anticoagulants. Health care organizations are under increasing pressure to develop systems to ensure the safe and effective use of anticoagulants in the inpatient setting. This document provides consensus guidelines for anticoagulant therapy in the inpatient setting and serves as a companion document to prior guidelines relevant for outpatients. HubMed – drug



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