Efficacy Of New Drugs Research Articles

Biomarkers of translational medicine

The development of new medicines is one of the priority areas of translational medicine. A significant role for biomarkers (BM) that assess the safety and efficacy of new drugs. The right choice of BM reduces the time and costs necessary for the development of drugs and transfer them to the clinic. The review is devoted to the analysis of modern scientific literature on the role of previously known and newly discovered BM in translational research. Translational BM (TBM) established during preclinical studies and are applicable at all stages of the study. TBM should have a high sensitivity and specificity, be easily measured in real time in an easily accessible biological fluids, to evaluate the same process in different species of animals (including humans), make it possible to compare the results of clinical trials with preclinical. The main role of the TBM toxicity to predict, identify and monitor the toxicity of drugs at all stages of their study. The international consortium (Predictive Safety Testing Consortium, PSTC) whose main task is the qualification of new TBM toxicity and the search for new, more advanced than existing methods for testing markers, was established. Under PSTC formed 6 working groups, each of which coordinates research for the study and selection of TBM toxicity caused by the administration of drugs in the liver, kidney, heart and blood vessels, skeletal muscle, testes. The first qualified consortium markers were 7 contained in the urine markers for preclinical studies on rats with the goal of establishing early lesions in the kidney induced by drugs. Only a small number of BM used in the study of new drugs, can be translational.

ScFv-conjugated superparamagnetic iron oxide nanoparticles for MRI-based diagnosis in transgenic mouse models of Parkinson’s and Huntington’s diseases

It is widely accepted that amyloid oligomers are the most toxic species to initiate the pathologic processes of Parkinson’s disease (PD) and Huntingdon’s disease (HD). But there is no definitive diagnosis for PD and HD at their early stages. Here, we conjugated an amyloid oligomer-specific scFv antibody (W20) to PEGylated superparamagnetic iron oxide nanoparticles (SPIONs) and detected the properties of the SPIONs conjugated with W20. The results showed that W20-SPIONs, with the size of around 11.8 nm in diameter, were stable and nontoxic, and had enough relaxation capacity to be used as an MRI contrast agent. When applied to the transgenic mouse models of PD and HD, W20-SPIONs crossed the blood-brain barrier and specifically bound to the oligomer area to give MRI signal, distinguishing PD and HD from healthy controls. These results indicated that W20-SPIONs had potential in early-stage diagnosis for PD and HD and also opened up a new strategy for evaluating the efficacy of new drugs.

Cost recovery by Health Canada and drug safety: a time-series analysis.

In 1995, Health Canada started collecting fees from pharmaceutical companies for various drug regulatory activities. This study investigated whether this change in the source of revenue affected the postmarket safety of drugs. A list of all new active substances approved in the 5 years before (1990-1994) and after (1995-1999) the introduction of cost recovery was compiled. Drug safety warnings and market withdrawals due to safety reasons were identified from the Health Canada Web site and other sources. Information about total funding for Health Canada's drug regulatory program came from a report by KPMG, a global professional service company providing financial audit, tax and advisory services. Time-series analyses and Kaplan-Meier curves were used to determine whether cost recovery affected postmarket safety. The introduction of cost recovery made no difference in the proportion of new active substances that received a safety warning, the number of safety warnings per new active substance or the time until the first safety warning or the likelihood that a drug would have a safety problem. Median drug review times decreased significantly after cost recovery was implemented (p = 0.02). The introduction of cost recovery and the associated reduction in review times did not affect the postmarket safety of drugs. Further changes to cost recovery, as are currently being proposed by Health Canada, need to be evaluated for any potential effects on the approval process that might influence decisions that Health Canada makes about the safety and efficacy of new drugs.

Antimicrobial Therapy in Community-Acquired Pneumonia in Children.

Empirical antibiotic therapy remains the cornerstone of treatment in community-acquired pneumonia (CAP). However, the best option for empirical antibiotics for treatment on an ambulatory basis, as well as in those requiring hospitalization, is still unclear. This review tries to answer the question regarding the most appropriate antibiotics in different settings in children with CAP as well as duration of therapy. Recent studies have provided insights regarding use of oral antibiotics in children with mild to moderate CAP, and severe CAP with lower chest retractions but no hypoxia. In view of rapidly emerging resistance among various causative pathogens, several new drugs have been currently approved, or are under trial for CAP in children. Current knowledge suggests that the choice of antibiotics for ambulatory treatment of CAP is oral amoxicillin with a duration of 3-5days. Children with CAP with lower chest retractions but no hypoxia can be treated with oral amoxicillin. Severe pneumonia can be treated with intravenous antibiotics consisting of penicillin/ampicillin with or without an aminoglycoside. Several new drugs have been developed and approved for use in CAP caused by multidrug-resistant organisms, but these should be used judiciously to avoid emergence of further resistance. Future research is needed regarding the safety and efficacy of newer drugs in children.

Abstract 4096: Stage-defined, transgenic immunocompetent mouse model (ASV-B) to investigate new drugs for hepatocellular carcinoma

Abstract Background: Hepatocellular carcinoma (HCC) is a complex multistep malignancy in need of new therapeutic options often arising on underlying chronic liver disease. HCC animal models relevant to clinical situations are crucial to investigate new anticancer drugs, alone or in combination. Mice bearing xenografts and transgenic mice are the two main models used for preclinical drug development, but most of them fail to mimic the different step of HCC observed in patients. In this study, we aim to describe a stage-defined, transgenic immunocompetent HCC mouse model. Methods: ASV-B is a transgenic mouse model that spontaneously develops, upon SV40 T-Ag oncogene expression in hepatocytes, a reproducible stage-defined HCC. Hyperplasia at week(W)8 is followed by nodular stage at W12 (multiple well-delimited tumor nodules of about 1 mm, growing progressively up to 1 cm), then diffuse carcinoma stage at W16-20. HCC is restricted to male, backcrossed with C57BL/6J mice, the female littermates being used as controls. Results: Liver volume assessed by ultrasound at each step of carcinogenesis showed a 2.7-, 2.7-, 3.9-, and 5.8-fold increase (p<0.001) in transgenic mice compared to controls (CTRL) at W8, 12, 16, and 20, respectively. ASV-B model displays marked arterialization with intense arterial flow in liver tumor similar to human HCC. Sinusoids in tumor nodules are tortuous and dilated, surrounded by activated hepatic stellate cells (HSCs) expressing smooth muscle actin (SMA) while HSCs surrounding normal sinusoids only express desmin. In addition, ASV-B livers develop along carcinogenesis a mesenchymal phenotype (increased vimentin and decreased e-cadherin staining), mimicking certain clinical situations of acquired resistance to VEGFR inhibitors. Angiogenesis, monitored using Doppler assessing blood flow velocity (BFV) in the hepatic artery, is enhanced by 29%, 51% and 156% at W8, W12 and W16, respectively, in transgenic liver animals as compared to CTRL. Increased angiogenesis was confirmed by CD31 staining in tumor specimen showing increased number of vessels per field. ASV-B model has been used to investigate the toxicity and efficacy of new drugs (galunisertib, MET/AXL inhibitor), including antiangiogenic agents (sorafenib and ramucirumab) alone or in combination, and may be relevant to explore the effects of immunotherapy agents. At the conference, we will display further characterization of liver tumors regarding vascularization, and immune cells localization using IHC. Conclusion: ASV-B transgenic mouse model mimics several characteristics of human HCC developing on healthy liver including multinodular disease, vessel abnormalities, and dedifferentiation toward mesenchymal phenotype. Further steps will consist of characterizing the adjacent nontumor liver, and developing nonalcoolic steatohepatitis (NASH) on ASV-B model using specific diets. Citation Format: Annemilaï Tijeras-Raballand, Patricia Hainaud, Christian Hobeika, Clarisse Eveno, Marc Pocard, Philippe Bonnin, Valérie Paradis, Mohamed Bouattour, Eric Raymond, Armand de Gramont, Evelyne Dupuy, Sandrine Faivre. Stage-defined, transgenic immunocompetent mouse model (ASV-B) to investigate new drugs for hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4096.

In silico clinical trials: concepts and early adoptions.

Innovations in information and communication technology infuse all branches of science, including life sciences. Nevertheless, healthcare is historically slow in adopting technological innovation, compared with other industrial sectors. In recent years, new approaches in modelling and simulation have started to provide important insights in biomedicine, opening the way for their potential use in the reduction, refinement and partial substitution of both animal and human experimentation. In light of this evidence, the European Parliament and the United States Congress made similar recommendations to their respective regulators to allow wider use of modelling and simulation within the regulatory process. In the context of in silico medicine, the term 'in silico clinical trials' refers to the development of patient-specific models to form virtual cohorts for testing the safety and/or efficacy of new drugs and of new medical devices. Moreover, it could be envisaged that a virtual set of patients could complement a clinical trial (reducing the number of enrolled patients and improving statistical significance), and/or advise clinical decisions. This article will review the current state of in silico clinical trials and outline directions for a full-scale adoption of patient-specific modelling and simulation in the regulatory evaluation of biomedical products. In particular, we will focus on the development of vaccine therapies, which represents, in our opinion, an ideal target for this innovative approach.

Ocular Blood Flow in Rabbits under Deep Anesthesia: A Real-Time Measurement Technique and Its Application in Characterizing Retinal Ischemia

In this study, we reported a new technique based on laser speckle flowgraphy to record the ocular blood flow in rabbits under deep anesthesia, and proposed parameters to characterize retinal ischemia. We applied the proposed technique to study the correlation of blood flow between the eyes of normal non-anesthetized animals, and to characterize the occlusion of the internal carotid artery (ICA) and external carotid artery (ECA). We established a correlation in blood flow between the eyes of non-anesthetized animals, and derived two new parameters, namely, the laterality index and vascular perfusion estimate (VPE). Our experimental results from 16 eyes (of 13 New Zealand white rabbits) showed a reduction in ocular blood flow with a significant decrease in the VPE after the occlusion of the ECA (p < 0.001). A low/minimal effect on blood flow was observed with the occlusion of the ICA. In conclusion, we demonstrated a means for the real-time measurement of the ocular blood flow in rabbits under deep anesthesia by using laser speckle flowgraphy and the VPE as an indicator of successful occlusion. The proposed technique might be applicable in quantifying the efficacy of new drugs and interventions for the treatment of retinal ischemia.

Study of the Serum Metabolomic Profile in Nonalcoholic Fatty Liver Disease: Research and Clinical Perspectives.

In recent years, metabolomics has attracted great scientific attention. The metabolomics methodology might permit a view into transitional phases between healthy liver and nonalcoholic steatohepatitis. Metabolomics can help to analyze the metabolic alterations that play a main role in the progression of nonalcoholic steatohepatitis. Lipid, glucose, amino acid, and bile acid metabolism should be widely studied to understand the complex pathogenesis of nonalcoholic steatohepatitis. The discovery of new biomarkers would be important for diagnosis and staging of liver disease as well as for the assessment of efficacy of new drugs. Here, we review the metabolomics data regarding nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. We analyzed the main studies regarding the application of metabolomics methodology in the complex context of nonalcoholic steatohepatitis, trying to create a bridge from the basic to the clinical aspects.

Drug approval based on randomized phase 3 trials for relapsed malignancy: analysis of oncologic drugs granted accelerated approval, publications and clinical trial databases.

Background As relapsed disease is frequently the first target of newly developed therapies, it is vital to address the difficulty in demonstrating the efficacy of new drugs for relapsed malignancy in randomized phase 3 trials. Methods We analyzed the approved indications, target populations, and development status of post-marketing confirmatory trials of all oncology-related drugs that were granted accelerated approval for both hematological and solid malignancies. Furthermore, we searched for randomized phase 3 trials for adult patients with relapsed lymphoid malignancy, other than chronic lymphocytic leukemia (CLL) and multiple myeloma (MM). Results Thirty-one (81.6%) of the 38 hematological indications and 23 (53.5%) of the 43 solid malignancy indications were in the relapsed settings. The target population of post-marketing studies was different from the approved indication in 18 (47.4%) of 38 hematological indications and 11 (25.6%) of 43 solid malignancy indications; all 18 hematological indications involved relapsed settings. Improved time-to-event outcome for relapsed patients was the primary endpoint in 6 (19.3%) of the 31 relapsed hematological indications. In 4 published studies of relapsed lymphoid malignancy, the medication significantly improved outcomes. From 33 trials listed at Clinicaltrials.gov , 2 were positive and 13 were negative. Five out of the 13 negative trials were terminated due to poor accrual. Conclusion Our analysis indicates that drug approval based on phase 3 trials is more challenging for relapsed hematological malignancies than for solid malignancies. Therefore, determining proper evaluation methods for the efficacy and safety of drugs for relapsed malignancy, without randomized trials, is important.

Recommendations for pharmacological clinical trials in children with functional constipation: The Rome foundation pediatric subcommittee on clinical trials.

Evidence for the efficacy of commonly used drugs in the treatment of childhood functional constipation (FC) is scarce, studies are often of low quality and study designs are heterogeneous. Thus, recommendations for the design of clinical trials in childhood FC are needed. Members of the Rome Foundation and a member of the Pediatric Committee of the European Medicines Agency formed a committee to create recommendations for the design of clinical trials in children with FC. This committee recommends conducting randomized, double-blind, placebo-controlled, parallel-group clinical trials to assess the efficacy of new drugs for the treatment of childhood FC. Pediatric study participants should be included based on fulfilling the Rome IV criteria for FC. A treatment free run-in period for baseline assessment is recommended. The trial duration should be at least 8weeks. Treatment success is defined as no longer meeting the Rome IV criteria for FC. Stool consistency should be reported based on the Bristol Stool Scale. Endpoints of drug efficacy need to be tailored to the developmental age of the patient population.

Assessing treatment outcomes in multiple sclerosis trials and in the clinical setting.

Increasing numbers of drugs are being developed for the treatment of multiple sclerosis (MS). Measurement of relevant outcomes is key for assessing the efficacy of new drugs in clinical trials and for monitoring responses to disease-modifying drugs in individual patients. Most outcomes used in trial and clinical settings reflect either clinical or neuroimaging aspects of MS (such as relapse and accrual of disability or the presence of visible inflammation and brain tissue loss, respectively). However, most measures employed in clinical trials to assess treatment effects are not used in routine practice. In clinical trials, the appropriate choice of outcome measures is crucial because the results determine whether a drug is considered effective and therefore worthy of further development; in the clinic, outcome measures can guide treatment decisions, such as choosing a first-line disease-modifying drug or escalating to second-line treatment. This Review discusses clinical, neuroimaging and composite outcome measures for MS, including patient-reported outcome measures, used in both trials and the clinical setting. Its aim is to help clinicians and researchers navigate through the multiple options encountered when choosing an outcome measure. Barriers and limitations that need to be overcome to translate trial outcome measures into the clinical setting are also discussed.

Abstract A008: Establishment of novel gastric cancer PDX models and cell lines for developing new therapeutics

Abstract It is essential to have appropriate preclinical models for developing new drugs for gastric cancer (GC). Cell lines have been the most commonly used model for this purpose. However, the numbers of gastric cancer cell lines established and available for this purpose are limited and not enough to deal with variety of gastric cancer molecular subtypes such as recently proposed by The Cancer Genome Atlas (TCGA). In addition, patient-derived xenograft (PDX) models have been considered more appropriate models for evaluating the efficacy of new drugs in vivo. For contributing to develop new drugs as well as to seek more effective biomarkers, we have been conducting an intramural project, called DEF study, for establishing new GC PDXs as well as new GC cell lines. So far, 30 multi-passage-competent new PDXs have been successfully established from surgically removed gastric cancer tissues or ascites. Twenty-two (22) new GC cell lines have also been established from PDX tissue (16 lines) or directly from ascites (6 lines). All GC PDXs have been examined by immunohistochemistry for HER2, EGFR, and Met expressions, and we identified 5 cases overexpressing HER2 (corresponding to Score3+) and 1 case overexpressing both EGFR and MET. Comprehensive gene mutation analysis has been performed in 21 PDX tissues, and repetitive mutations (SNV/Indel) have been observed in ERBB2, ERBB3, BRAF, APC, ARID1A, and p53. Copy number alternations have also been identified; examples include KRAS and ERBB2 for amplification and PTEN and CDKN2A for deletion. Citation Format: Takeshi Kuwata, Kazuyoshi Yanagihara. Establishment of novel gastric cancer PDX models and cell lines for developing new therapeutics [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A008.

Morphological analysis of human umbilical vein endothelial cells co-cultured with ovarian cancer cells in 3D: An oncogenic angiogenesis assay.

Antiangiogenic therapy for cancer is a strategy targeted at tumour vasculature, often in combination with conventional cytotoxicity treatments. Animal testing is still the most common method used for evaluating the efficacy of new drugs but tissue-engineered in vitro models are becoming more acceptable for replacing and reducing the use of animals in anti-cancer drug screening. In this study, a 3D co-culture model of human endothelial cells and ovarian cancer cells was developed. This model has the potential to mimic the interactions between endothelial cells and ovarian cancer cells. The feasibility of applying this model in drug testing was explored here. The complex morphology of the co-culture system, which features development of both endothelial tubule-like structures and tumour structures, was analysed quantitatively by an image analysis method. The co-culture morphology integrity was maintained for 10 days and the potential of the model for anti-cancer drug testing was evaluated using Paclitaxel and Cisplatin, two common anti-tumour drugs with different mechanisms of action. Both traditional cell viability assays and quantitative morphological analyses were applied in the drug testing. Cisplatin proved a good example showing the advantages of morphological analysis of the co-culture model when compared with mono-culture of endothelial cells, which did not reveal an inhibitory effect of Cisplatin on the tubule-like endothelial structures. Thus, the tubule areas of the co-culture reflected the anti-angiogenesis potential of Cisplatin. In summary, in vitro cancer models can be developed using a tissue engineering approach to more closely mimic the characteristics of tumours in vivo. Combined with the image analysis technique, this developed 3D co-culture angiogenesis model will provide more reproducible and reliably quantified results and reveal further information of the drug’s effects on both tumour cell growth and tumour angiogenesis.

SULCAL MORPHOLOGY CHANGES AS A MARKER OF ALZHEIMER’S DISEASE AND COGNITIVE DECLINE

Sulcal morphology analysis provides insights into the subtle structural brain changes in Alzheimer's disease (AD). This study aimed to investigate the clinical utility of sulcal morphology measurements for identifying AD and to analyse their link with cognition. We included 51 AD patients with progressive episodic memory deficits associated with biological evidence of underlying AD pathophysiology based on the cerebrospinal fluid profile and amyloid imaging (PET using 11C-PiB), and 27 healthy controls with negative amyloid imaging. Patients were classified into prodromal (n=19) and moderate (n=32) stages. The Morphologist software was used as an automated method to provide fold opening (FO) and cortical thickness (CT) individual measures for 18 groups of sulci in each hemisphere. In parallel, SPM was used to compute volumetric measures of each cerebral lobe through a widely used cortical parcellation atlas (AAL). Direct intra-group comparison showed that AD was characterized by reduced CT and increased FO in temporal and parietal sulci, as a function of disease stage. Logistic regressions showed that CT/FO measures in 9 temporal and parietal sulci yielded together 100% of diagnosis accuracy between patients and controls. Post-hoc analysis showed that sulcal morphology provided better diagnosis accuracy than AAL-based lobe volumetric measures (5–11%) and hippocampal volume segmentation (21–26%). We observed significant correlations between cognitive - memory, executive and instrumental – principal components and reduced CT or increased FO in temporal, frontal and parietal regions respectively, with sulcal changes being significant determinants of reduced performance. No correlation was found with regional Pib retention. Sulcal morphology measures such as cortical thickness and fold opening of the temporal and parietal sulci are useful to detect early and moderate AD. The diagnosis accuracy is better than hippocampal volume. Because regional morphologic sulcal measures are correlated to specific cognitive functions but not with amyloid load, sulcal changes analysis may be considered as a potential marker of neuronal injury due the progression of tau pathology and could provide new surrogate markers to evaluate the efficacy of new drugs.

Clinical Neurophysiology in Neuromuscular Disorders: Old Fashioned or Still Relevant?

AbstractClinical neurophysiology still has a role in the diagnostic process of pediatric neuromuscular disorders. It should be integrated into a stepwise diagnostic process which includes a first step clinical examination to build a clinical hypothesis, followed by muscle ultrasound, and finally clinical neurophysiology where it is necessary. There is still a need for further research if new techniques such as impedance myography, motor unit counting, and others give additional information and if they can be used to evaluate the efficacy of new drugs.

Status epilepticus in dogs and cats, part 2: treatment, monitoring, and prognosis.

To discuss current anticonvulsant drug options and advances in treatment of status epilepticus (SE) and to review the prognosis associated with SE. When treating a patient with SE, the main goals are to halt seizure activity, prevent further seizures, identify the cause of the seizures, and manage any complications. The veterinary literature indicates that benzodiazepines are the most common class of drugs used for the initial treatment of SE. Although many anticonvulsant drugs are currently available for treatment of SE, there is a lack of evidence demonstrating clear benefit to the use of specific therapeutics for benzodiazepine-refractory SE. Several multicenter, randomized, and placebo-controlled clinical trials are currently investigating the efficacy of new drugs, such as fosphenytoin, for use in canine SE. Another active area of research is the investigation of nonpharmacologic methods of seizure treatment including percutaneous vagal nerve stimulation and transcranial ultrasonic neuromodulation. Electroencephalography (EEG) is underutilized in the management of veterinary seizure disorders. However, recent advances in EEG technology may allow for earlier and proactive therapeutic interventions in epileptic patients, provide objective data collection regarding treatment efficacy, and yield insight into the neurologic status of patients with SE. Most importantly, use of EEG in patients with SE will lead to increased recognition of nonconvulsive seizures and nonconvulsive SE. Mortality associated with SE is as high as 25% in dogs due to direct and indirect causes of death. Dogs with seizure disorders have a decreased lifespan compared to the general population, and epileptic dogs with SE have a significantly abbreviated lifespan compared to epileptics that do not experience SE. In people, nonconvulsive SE has a higher morbidity and mortality than convulsive SE, regardless of patient age or underlying diagnosis.

Molecular Imaging of Huntington's Disease.

The onset and the clinical progression of Huntington Disease (HD) is influenced by several events prompted by a genetic mutation that affects several organs tissues including different regions of the brain. In the last decades years, Positron Emission Tomography (PET) and Magnetic Resonance Imaging (MRI) helped to deepen the knowledge of neurodegenerative mechanisms that guide to clinical symptoms. Brain imaging with PET represents a tool to investigate the physiopathology occurring in the brain and it has been used to predict the age of onset of the disease and to evaluate the therapeutic efficacy of new drugs. This article reviews the contribution of PET and MRI in the research field on Huntington's disease, focusing in particular on some most relevant achievements that have helped recognize the molecular changes, the clinical symptoms and evolution of the disease. J. Cell. Physiol. 232: 1988-1993, 2017. © 2016 Wiley Periodicals, Inc.

Clinical trials in antineutrophil cytoplasmic antibody-associated vasculitis: what we have learnt so far, and what we still have to learn.

The prognosis of the antineutrophil cytoplasmic antibody associated vasculitides (AAV), microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA) and eosinophilic GPA (EGPA), has been fundamentally improved over the last five decades by the use of glucocorticoids and immunosuppressants, turning them from consistently fatal diseases into chronic conditions. The long-term course is now largely determined by the frequency of disease flares and by accruing damage caused by disease activity and treatment-related comorbidities. This review summarizes the evidence derived from clinical trials performed during the last 30 years and the remaining clinical unmet needs that new studies aim to address. In MPA and GPA, ongoing studies assess (i) different strategies to reduce cumulative glucocorticoid doses currently used for induction and maintenance of remission, (ii) the efficacy of new drugs and (iii) the optimal duration of immunosuppression and the use of biomarkers to individualize therapy. Prospective randomized trials also target disease-associated cardiovascular risk and infections. The first prospective controlled trials specifically designed for EGPA have recently been launched and could lead to new therapeutic options for patients diagnosed with this rare disease. This is an exciting time for researchers in the field of AAV, and for patients as collaborative efforts raise the hope of developing new therapies and more individualized approaches to the management of the diseases, maximizing efficacy while minimizing treatment toxicities.

ANIMAL EXPERIMENTS IN THE ERA OF TRANSLATIONAL MEDICINE. WHAT WOULD THEY BE?

Currently, laboratory animals are used in biomedical research to test hypotheses about the mechanisms of development and progression of the diseases, to search the new targets for pharmacotherapy, to test the safety and efficacy of new drugs. However, the results of experimental studies, with the established practice of their planning and performing, do not provide a sufficient level of evidence to go to performance of clinical trials. Key concepts, that allow the analysis of the current situation and outline the way out of the crisis, are the concepts of internal and external validity and bias. This review briefly describes the main types of systematic errors that reduce the validity of experimental research. Tools, that improve the translational potential of experimental studies, are systematic reviews and meta-analyzes, international guidelines and checklists, as well as the «reverse» translation of failed clinical trials. Guidelines and checklists that help researchers to assess the compliance of the planned and ongoing research to «gold standard», should be implemented at various levels, starting with the grantmaking organizations, bioethics committees and editorial boards of scientific journals. Pre-registration of experimental works and access of a wide range of researchers to the primary data after publication should make the research process more open and therefore objective. The above approaches might help to overcome the crisis of translatability of experimental results in practice and regain the trust of the general public to the results of biomedical experimental studies.

Assessing the Therapeutic Response to Pirfenidone in Idiopathic Pulmonary Fibrosis: Can We Do Better than with Forced Vital Capacity Alone?

New anti-fibrotic agents for idiopathic pulmonary fibrosis (IPF) were approved based on the results of forced vital capacity (FVC) trends, although concerns were raised about the reliability of FVC as the only endpoint parameter. We hypothesized that IPF-specific multi-dimensional scores (Composite Physiologic Index-CPI; gender-age-physiology-GAP; risk stratification score-RISE) would better capture response to therapy. In this pilot study, treated and untreated cohorts of IPF patients, matched for demographic and functional characteristics were prospectively followed for 1year, at 4-month intervals. Progression-free survival was significantly improved in treated patients (p=0.0093). While no difference in FVC longitudinal trends was observed, MRC dyspnea score (p=0.0347), diffusing lung capacity (p=0.0015), 6-min walk distance (p=0.0007), CPI (p=0.0457) and RISE (p=0.0005) were significantly stabilized in treated patients, compared to steady worsening in untreated subjects. Multi-dimensional scores provide broader spectrum of prognostic information and may facilitate the assessment of efficacy of new drugs for IPF.