Integrated data acquisition system for medical device testing and physiology research in compliance with good laboratory practices

In seeking approval from the US Food and Drug Administration (FDA) for clinical trial evaluation of an experimental medical device, a sponsor is required to submit experimental findings and support documentation to demonstrate device safety and efficacy that are in compliance with Good Laboratory Practices (GLP). The objective of this project was to develop an integrated data acquisition (DAQ) system and documentation strategy for monitoring and recording physiological data when testing medical devices in accordance with GLP guidelines mandated by the FDA. Data aquisition systems were developed as stand-alone instrumentation racks containing transducer amplifiers and signal processors, analog-to-digital converters for data storage, visual display and graphical user-interfaces, power conditioners, and test measurement devices. Engineering standard operating procedures (SOP) were developed to provide a written step-by-step process for calibrating, validating, and certifying each individual instrumentation unit and the integrated DAQ system. Engineering staff received GLP and SOP training and then completed the calibration, validation, and certification process for the individual instrumentation components and integrated DAQ system. Eight integrated DAQ systems have been successfully developed that were inspected by regulatory affairs consultants and determined to meet GLP guidelines. Two of these DAQ systems were used to support 40 of the pre-clinical animal studies evaluating the AbiCor artificial heart (ABIOMED, Danvers, MA). Based in part on these pre-clinical animal data, the AbioCor clinical trials began in July 2001. The process of developing integrated DAQ systems, SOP, and the validation and certification methods used to ensure GLP compliance are presented in this article.     

Biochemical markers and the FDA Critical Path: How biomarkers may contribute to the understanding of pathophysiology and provide unique and necessary tools for drug development

The aim of this review is to discuss the potential usefulness of a novel class of biochemical markers, neoepitopes, in the context of the US Food and Drug Administration (FDA) Critical Path Initiative, which emphasizes biomarkers of safety and efficacy as areas of pivotal interest. Examples of protein degradation fragments – neoepitopes – that have proven useful for research on bone and cartilage are collagen type I and collagen type II degradation products, respectively. These markers have utility in the translational approach, as they can be used to estimate safety and efficacy in both preclinical models and clinical settings. Biochemical markers of tissue degradation may provide optimal tools, which in combination with other techniques, prove essential to drug discovery and development.     

Antidepressants are a rational complementary therapy for the treatment of Alzheimer's disease

There is a high prevalence rate (30-50%) of Alzheimer's disease (AD) and depression comorbidity. Depression can be a risk factor for the development of AD or it can be developed secondary to the neurodegenerative process. There are numerous documented diagnosis and treatment challenges for the patients who suffer comorbidity between these two diseases. Meta analysis studies have provided evidence for the safety and efficacy of antidepressants in treatment of depression in AD patients. Preclinical and clinical studies show the positive role of chronic administration of selective serotonin reuptake inhibitor (SSRI) antidepressants in hindering the progression of the AD and improving patient performance. A number of clinical studies suggest a beneficial role of combinatorial therapies that pair antidepressants with FDA approved AD drugs. Preclinical studies also demonstrate a favorable effect of natural antidepressants for AD patients. Based on the preclinical studies there are a number of plausible antidepressants effects that may modulate the progression of AD. These effects include an increase in neurogenesis, improvement in learning and memory, elevation in the levels of neurotrophic factors and pCREB and a reduction of amyloid peptide burden. Based on this preclinical and clinical evidence, antidepressants represent a rational complimentary strategy for the treatment of AD patients with depression comorbidity.     

Recognizing and reporting adverse drug reactions.

Although physicians in practice are most likely to see patients with adverse drug reactions, they may fail to recognize an adverse effect or to attribute it to a drug effect and, when recognized, they may fail to report serious reactions to the US Food and Drug Administration (FDA). To recognize and attribute an adverse event to a drug effect, physicians should review the patient''s clinical course, looking at patient risk factors, the known adverse reactions to the suspected drug, and the likelihood of a causal relationship between the drug and the adverse event-based on the temporal relationship, response to stopping or restarting the drug, and whether other factors could explain the reaction. Once an adverse drug reaction has been identified, the patient should be informed and appropriate documentation made in the patient''s medical record. Serious known reactions and all reactions to newly released drugs or those not previously known to occur (even if the certainty is low) should be reported to the FDA.     

High-throughput human metabolism and toxicity analysis

Poor drug candidate safety profiles are often identified late in the drug development process, manifesting themselves in the preclinical and clinical phases and significantly contributing to the high cost and low yield of drug discovery. As a result, new tools are needed to accelerate the assessment of drug candidate toxicity and human metabolism earlier in the drug development process, from primary drug candidate screening to lead optimization. Although high-throughput screens exist for much of the discovery phase of drug development, translating such screening techniques into platforms that can accurately mimic the human in vivo response and predict the impact of drug candidates on human toxicology has proven difficult. Nevertheless, some success has been achieved in recent years, which may ultimately yield widespread acceptance in the pharmaceutical industry.     

Phase 0 clinical trials in cancer drug development: from FDA guidance to clinical practice

The Food and Drug Administration (FDA) recently introduced the Exploratory Investigational New Drug Guidance to expedite the clinical evaluation of new therapeutic and imaging agents. Early clinical studies performed under the auspices of this guidance, so-called "Phase 0" trials, have been initiated at the National Cancer Institute to integrate qualified pharmacodynamic biomarker assays into first-in-human cancer clinical trials of molecularly targeted agents. The goal of this integration is to perform molecular proof-of-concept investigations at the earliest stage of cancer drug development. Phase 0 trials do not offer any possibility of patient benefit; instead, intensive, real-time pharmacodynamic and pharmacokinetic analyses of patient tumor samples and/or surrogate tissues are performed to inform subsequent trials. Phase 0 studies do not replace formal Phase I drug safety testing and require a substantial investment of resources in assay development early on; however, they offer the promise of more rational selection of agents for further, large-scale development as well as the molecular identification of potential therapeutic failures early in the development process.     

Preclinical safety evaluations supporting pediatric drug development with biopharmaceuticals: strategy,challenges, current practices

Evaluation of pharmaceutical agents in children is now conducted earlier in the drug development process. An important consideration for this pediatric use is how to assess and support its safety. This article is a collaborative effort of industry toxicologists to review strategies, challenges, and current practice regarding preclinical safety evaluations supporting pediatric drug development with biopharmaceuticals. Biopharmaceuticals include a diverse group of molecular, cell‐based or gene therapeutics derived from biological sources or complex biotechnological processes. The principles of preclinical support of pediatric drug development for biopharmaceuticals are similar to those for small molecule pharmaceuticals and in general follow the same regulatory guidances outlined by the Food and Drug Administration and European Medicines Agency. However, many biopharmaceuticals are also inherently different, with limited species specificity or immunogenic potential which may impact the approach taken. This article discusses several key areas to aid in the support of pediatric clinical use, study design considerations for juvenile toxicity studies when they are needed, and current practices to support pediatric drug development based on surveys specifically targeting biopharmaceutical development. Birth Defects Res (Part B) 92:359–380, 2011. © 2011 Wiley‐Liss, Inc.     

The belated US FDA approval of the adenosine A2A receptor antagonist istradefylline for treatment of Parkinson’s disease

Purinergic Signalling - After more than two decades of preclinical and clinical studies, on August 27, 2019, the US Food and Drug Administration (FDA) approved the adenosine A2A receptor antagonist...     

Regulatory Incentives for Antibiotic Drug Development: A Review of Recent Proposals

Two primary regulatory mechanisms have been proposed to incentivize new antibiotic development: (1) changing Food and Drug Administration (FDA) approval processes to expedite antibiotic approval; and (2) offering enhanced possibilities for market exclusivity. Changes to the FDA regulatory approval process include greater reliance on surrogate endpoints such as biomarkers, use of noninferiority hypothesis designs for key preapproval clinical trials, and development of an expedited development track specific for antibiotics called the Limited Population pathway. The second strategy intended to encourage new antibiotic development has been to provide additional market exclusivity incentives based on regulatory approval. While these pathways have some positive attributes, they also present enhanced risks to patients associated with lower regulatory barriers and the market exclusivity incentives may not efficiently direct resources to the true origins of antibiotic innovation.     

ROBERT TEMPLE: an eye for data. Interview

Robert Temple has spent more than thirty years of his career at the Food and Drug Administration-and he still likes it! After medical school, internship, and residency, Temple pursued endocrinology research at the NIH before deciding, in the early 70s, to apply his interests in science to consumer advocacy at the FDA. The FDA was undergoing enormous changes at that time, and Temple enjoyed the challenges associated with improving drug development and patient safety. Always relying on a critical evaluation of data, he is comfortable discussing mechanisms of drug action, experimental design, and regulatory policies, as well as the social implications of direct-to-consumer advertising of drugs. Currently, Temple is Director of one of the six Offices of Drug Evaluation and also serves as the Associate Director for Medical Policy.     

基于China GAP要求的花椒质量安全控制技术

根据中国良好农业规范（China GAP）标准相关控制点的要求,结合我国花椒的生产管理过程中存在质量安全风险的环节和因素,对花椒质量安全的良好农业规范（GAP）控制技术进行了阐述.     

National Institutes of Health phase I, Small Business Innovation Research applications: fiscal year 1983 results

A review of the 356 disapproved Small Business Innovation Research (SBIR) proposals submitted to the National Institutes of Health (NIH) for fiscal year 1983 funding was undertaken to identify the most common shortcomings of those disapproved applications. The shortcomings were divided into four general classes by using the scheme developed by other authors when describing the reasons for the disapproval of regular NIH research applications. Comparison of the reasons for disapproval of SBIR applications with regular applications suggests comparable difficulties in the areas of the problem and the approach. There is some indication, however, that the SBIR proposals may have been weaker in the category of the principal investigator (PI). In general, it is the responsibility of the PI to demonstrate that the work is timely and can be performed with available technology and expertise, and that the guidelines for the NIH SBIR program have been satisfied.     

Therapeutic bacteriophages as a rescue treatment for drug-resistant infections – an in vivo studies overview

Bacteriophages, highly prevalent in all environments, have found their use in medicine as an alternative or complement to antibiotics. The therapeutic use of bacteriophages was particularly popular in the 1920s and 1930s, until the discovery and introduction of antibiotics. Due to the dynamic growth of antibiotic resistance among bacterial strains, numerous international institutions (such as the FDA) have declared the search for novel treatment modalities to be of the highest priority. To date, bacteriophage therapy has not been registered for general use in Western countries. The regulation of biological medicinal products (within medicinal product regulation) does not contain a specific documentation frame for bacteriophages (only for vaccines, blood derived products, etc.) which, as active substances, need to meet specific requirements. Recently, the FDA allowed bacteriophage therapy to be used in the United States, via the Emergency Investigational New Drug scheme; clinical trials to compare the safety and efficacy of bacteriophage therapy are also permitted. To date, several therapeutic products of this type have made it to phase I or II; some clinical programmes have also been completed. This article cites numerous animal model studies and registered clinical trials, showing the safety and effectiveness of bacteriophage therapy, including infections caused by bacterial strains resistant to antibiotic treatment.     

The outlook for peptide drugs and the intricate relationship between the Active Pharmaceutical Ingredients manufacturer and their sponsors.

As research laboratories discover an ever-increasing number of peptides of pharmacological interest, there is an increased need for Good Manufacturing Practices (GMP) services, as these drugs candidates undergo clinical trials. It is therefore essential to understand the importance of the relationship with the Active Pharmaceutical Ingredients (API) manufacturer and its implications in the development and commercialization of the future peptide drug.     

The integration of investigative toxicology in the drug discovery process

Summary— Integrating toxicology early in the drug discovery process adds value by providing the earliest possible identification of a compound's potential for toxicological and pathological effects relevant to intended clinical use. With this approach true ‘lead’ candidates, with a high probability of clinical success, are identified and advanced while reducing effort and resources expended on compounds without the requisite therapeutic index. Resources are focussed on the speed of getting a discovery ‘lead’ into early clinical development, defining the mechanisms of observed preclinical toxicity and their relevance to human use, and developing early safety data with in vitro test systems ahead of in vivo systems where possible, thus reducing animal use.     

Improving Detection of Arrhythmia Drug-Drug Interactions in Pharmacovigilance Data through the Implementation of Similarity-Based Modeling

Identification of Drug-Drug Interactions (DDIs) is a significant challenge during drug development and clinical practice. DDIs are responsible for many adverse drug effects (ADEs), decreasing patient quality of life and causing higher care expenses. DDIs are not systematically evaluated in pre-clinical or clinical trials and so the FDA U. S. Food and Drug Administration relies on post-marketing surveillance to monitor patient safety. However, existing pharmacovigilance algorithms show poor performance for detecting DDIs exhibiting prohibitively high false positive rates. Alternatively, methods based on chemical structure and pharmacological similarity have shown promise in adverse drug event detection. We hypothesize that the use of chemical biology data in a post hoc analysis of pharmacovigilance results will significantly improve the detection of dangerous interactions. Our model integrates a reference standard of DDIs known to cause arrhythmias with drug similarity data. To compare similarity between drugs we used chemical structure (both 2D and 3D molecular structure), adverse drug side effects, chemogenomic targets, drug indication classes, and known drug-drug interactions. We evaluated the method on external reference standards. Our results showed an enhancement of sensitivity, specificity and precision in different top positions with the use of similarity measures to rank the candidates extracted from pharmacovigilance data. For the top 100 DDI candidates, similarity-based modeling yielded close to twofold precision enhancement compared to the proportional reporting ratio (PRR). Moreover, the method helps in the DDI decision making through the identification of the DDI in the reference standard that generated the candidate.     

Characteristics of Pivotal Trials and FDA Review of Innovative Devices

When patients lack sufficient treatment options for serious medical conditions, they rely on the prompt approval and development of new therapeutic alternatives, such as medical devices. Understanding the development of innovative medical devices, including the characteristics of premarket clinical trials and length of Food and Drug Administration (FDA) review, can help identify ways to expedite patient access to novel technologies and inform recent efforts by FDA to more quickly get these products to patients and physicians. We analyzed publicly available information on clinical trials and premarket FDA review for innovative medical devices that fill an unmet medical need. In this first-of-its-kind study focusing on these products, we extracted data on the length of the pivotal trials, primary study endpoint and FDA review; number of patients enrolled in trials; and in what country the device was available first. We identified 27 approved priority review devices from January 2006 through August 2013. The median duration of pivotal clinical trials was 3 years, ranging from 3 months to approximately 7 years. Trials had a median primary outcome measure evaluation time of one year and a median enrollment of 297 patients. The median FDA review time was 1 year and 3 months. Most priority review devices were available abroad before they were approved in the United States. Our study indicates that addressing the length of clinical studies—and contributing factors, such as primary outcome measures and enrollment—could expedite patient access to innovative medical devices. FDA, manufacturers, Congress and other stakeholders should identify the contributing factors to the length of clinical development, and implement appropriate reforms to address those issues.     

Incidence and nature of testicular toxicity findings in pharmaceutical development

BACKGROUND : Testicular toxicity (TT) is a sporadic and challenging issue in pharmaceutical drug development. Efforts to develop TT screening assays or biomarkers have been overshadowed by consortium efforts to predict drug‐induced toxicities such as hepatic injury, which are encountered more frequently. METHODS : To gauge the current state of the field and to prioritize future TT activities, the International Life Sciences Institute‐Health and Environmental Sciences Institute Developmental and Reproductive Toxicology (DART) Technical Committee sponsored a survey to better understand the incidence and nature of TT findings encountered during drug development. RESULTS : Highlights from the 16 survey respondents include: (1) Although preclinical TT was encountered relatively infrequently, half of the participants observed repeated problems with TT during pharmaceutical development, (2) despite control measures such as use of sexually mature animals to diminish confounding effects of spurious lesions, interpretation of TT remains a challenge, (3) “traditional” evaluation tools such as hormonal monitoring and newer approaches such as ‐omics are utilized to investigate testicular changes, and (4) an understanding of the risk and relevance of TT findings is achieved through joint consideration of factors such as species specificity, potential mode of action, and safety margins. CONCLUSIONS : TT remains a relatively uncommon but persistent challenge in pharmaceutical development. Although current preclinical TT approaches appear to be effective in limiting the occurrence of pharmaceutical candidate attrition in clinical trials, improved biomarker or screening platforms would allow companies to identify TT at an earlier stage, thus decreasing the time and resources expended on safety evaluation of pharmaceutical candidates. Birth Defects Res (Part B) 92: 511–525, 2011. © 2011 Wiley Periodicals, Inc.     

Haematotoxicology: scientific basis and regulatory aspects

Haematopoietic tissues are the targets of numerous xenobiotics. The purpose of in vitro haematotoxicology is the prediction of adverse haematological effects from toxicants on human haematopoietic targets under controlled experimental conditions in the laboratory. Building on its foundations in experimental haematology and the wealth of haematotoxicological data found in experimental oncology, this field of alternative toxicology has developed rapidly during the past decade. Preclinical and clinical drug development for anti-cancer drugs differs from that for other pharmaceuticals, because of the life-threatening nature of the disease. Treatment with anti-cancer drugs at clinically efficacious doses usually induces serious side-effects. The design of preclinical toxicology studies for anti-cancer drugs is intended to identify a safe clinical starting dose, characterise toxicities that could be encountered in human clinical trials, and determine whether these toxicities are reversible, manageable, and predictable. Although the myeloid colony-forming unit (CFU-GM) progenitor is most frequently evaluated, other defined progenitors and stem cells, as well as cell types found in the marrow stroma, can now be evaluated in vitro. Genetic damage to haematopoietic cells can occur in the absence of any overt haematological signs. The development of tissue-specific screening systems that are able to give information about the toxic effects of chemicals, drugs and environmental hazards on target genes is needed, in order to make preliminary decisions or to set priorities for selection among large groups of chemicals and possible drugs.     

A Modified Murine Embryonic Stem Cell Test for Evaluating the Teratogenic Effects of Drugs on Early Embryogenesis

Mammalian fetal development is easily disrupted by exogenous agents, making it essential to test new drug candidates for embryotoxicity and teratogenicity. To standardize the testing of drugs that might be used to treat pregnant women, the U.S. Food and Drug Administration (FDA) formulated special grade categories, labeled A, B, C, D and X, that define the level of risk associated with the use of a specific drug during pregnancy. Drugs in categories (Cat.) D and X are those with embryotoxic and/or teratogenic effects on humans and animals. However, which stages of pregnancy are affected by these agents and their molecular mechanisms are unknown. We describe here an embryonic stem cell test (EST) that classifies FDA pregnancy Cat.D and Cat.X drugs into 4 classes based on their differing effects on primitive streak formation. We show that ~84% of Cat.D and Cat.X drugs target this period of embryogenesis. Our results demonstrate that our modified EST can identify how a drug affects early embryogenesis, when it acts, and its molecular mechanism. Our test may thus be a useful addition to the drug safety testing armamentarium.