Qualitative analysis of actual Standard for Exchange of Nonclinical Data (SEND) datasets for Data Domains: Proposition from Japan Pharmaceutical Manufacturers Association SEND Taskforce Team on standardization of nonclinical data.

The Standard for Exchange of Nonclinical Data (SEND) has been adopted by the US FDA, which has required pharmaceutical companies who are developing new drugs for the US market to implement SEND. The Japan Pharmaceutical Manufacturers Association (JPMA) SEND Taskforce Team responded to this situation by starting a project to better understand the contents of SEND datasets. The project focused on domains generally included in the SEND domains for single- and repeat-dose general toxicology studies, and surveyed what kind of information are populated in which domains and in what way. The qualitative analysis of the results indicated that variations exist based on whether or not an individual variable was populated and on how the variable was populated. The Taskforce Team recommends reducing variations not only in the SEND datasets but also in the descriptions in the study protocol and/or final study report. Reduction of such variations should lead to higher quality datasets with powerful and increased searchability so that accumulated SEND datasets should become more valuable. These efforts would provide regulatory agencies with easier review of SEND datasets, which contributes to efficient development of new drug candidates.

Evaluación positiva de medicamentos: abril, mayo y junio 2020 / Positive assessment of drugs: April, May and June 2020

Se reseñan los medicamentos evaluados y con dictamen positivo por comisión de expertos de la Agencia Española de Medicamentos y Productos Sanitarios o de la Agencia Europea del Medicamento hechos públicos en abril, mayo y junio de 2020, y considerados de mayor interés para el profesional sanitario. Se trata de opiniones técnicas positivas que son previas a la autorización y puesta en el mercado del medicamento

The drugs assessed by the Spanish Agency for Medicines and Health Products or European Medicines Agency made public in April, May and June 2020, and considered of interest to the healthcare professional, are reviewed. These are positive technical reports prior to the authorization and placing on the market of the product

Quality Management Model for Phase I Clinical Drug Trials: A Structural Equation Model.

This study aimed to construct a quality management model for phase I clinical drug trials. A cross-sectional survey was conducted and data were collected from 604 respondents at 69 institutions in China engaged in phase I clinical drug trials. Exploratory and confirmatory factor analyses were used to develop the survey tool. Structural equation modeling was used to construct a quality management model for phase I clinical drug trials. The results showed that the final survey tool had good reliability and validity (Cronbach's α=0.938, root mean square error of approximation=0.074, comparative fit index=0.962, and Tucker-Lewis index=0.955). The model included five dimensions: government regulation, industry management, medical institution management, research team management, and contract research organization (CRO) management. In total, 22 measurement items were obtained. The structural equation model indicated government regulation, industry management, medical institution management, and CRO management significantly affected the quality of phase I clinical drug trials (ß=0.195, ß=0.331, ß=0.279, and ß=-0.267, respectively; P<0.05). Research team management had no effect on the quality of trials (ß=0.041, P=0.610). In conclusion, the model is valuable for identifying factors influencing phase I clinical drug trials and guiding quality management practices.

Investigational drug labeling variability.

BACKGROUND/AIMS: In comparison with commercial drugs, there are few regulations concerning the labeling of investigational drugs. This leads to variability in their content and layout. This increases the risk of errors during storage, validation, compounding, dispensing and administration. The aim of this study was to evaluate the conformity and variability of investigational drug labels. Additional exploratory aims were to evaluate the use of an automated script to describe the labels and to identify the factors associated with the ease of finding a kit number. METHODS: An 87-criterion list was developed to evaluate content, format and readability. It included eight criteria to evaluate the conformity to the Canadian Food and Drugs Regulation. A systematic cross-sectional evaluation of all investigational drug labels in our 500-bed mother-child center was performed. All active protocols during the period of 14-22 February 2018 were included. Labels from drugs that were sourced locally were excluded. Labels affixed to the outside (external) and inside (internal) containers, as well as labels from American and European sponsors, were compared with the chi-square and Student's t tests. A script was developed in Python to automatically determine key information (number of words, main colors and their proportion). A short survey was conducted with a convenience sample of pharmacists to rate the ease of finding the kit number on labels. Correlation was evaluated with different factors. RESULTS: A total of 27 protocols were included (24 internal and 34 external labels). The majority (33/34) of external labels were compliant with the Regulation. Some internal labels did not state the expiry date (9/13), the sponsor address (2/13) or storing conditions (1/13). A total of 10 criteria were different between internal and external labels, for instance, the number of languages was higher on external labels (median 3 (2-14) vs 10 (2-50); p = 0.013). Five criteria were different depending on the sponsors' location, for instance, European sponsors were more prone to use bold characters (25% vs 61%, p = 0.034). There was a mean of 146 ± 111 words and 78.3% ± 7.3% empty space per label. These were positively correlated (p < 0.001). The proportion of free space on a label was also correlated with the ease of finding the kit number (p = 0.002). CONCLUSION: We measured a high variability in the labeling of investigational drugs. Key information was missing from labels affixed to internal containers, despite the use of a high number of pages. The automation worked well and further work is needed to identify criteria that may improve readability and reduce error risk. Detailed and harmonized international guidelines are needed.

Ready for Germany's revised radiation rules?

The assessment of the benefit-risk ratio of investigational medicinal products (IMPs) and the approval of clinical trial applications (CTAs) conducted in the European Union (EU) is a remit of national competent authorities (NCAs) of the 28 member states. The aim of this article is to shed light on clinical studies for oncology drugs carried out in Germany which involve diagnostic radiation tests. The authorisation process surrounding diagnostic radiology accompanying clinical investigations and used for measuring IMP related treatment effects is not well understood. The procedure appears to be complicated because the scientific evaluation of the application is carried out by an independent agency, the Federal Office for Radiation Protection (Bundesamt für Strahlenschutz, BfS). To avoid delays and failures in conducting studies in Germany knowledge of the scope, procedural steps and associated timelines is crucial for project management purposes. Reliable planning is a pre-requisite for timely study initiation. Novelties of the recently implemented law and key aspects relevant to CTAs should facilitate obtaining BfS clearance. Integrating this additional regional requirement in drug development plans is of importance for timely commencement of multi-national clinical trials.

Principales implicaciones del nuevo Real Decreto de ensayos clínicos para los urgenciólogos investigadores / New Royal Decree on clinical trials: main implications for emergency medicine physicians who do research

La puesta en marcha de una nueva regulación europea para la realización de ensayos clínicos con medicamentos ha supuesto cambios importantes en España, que se han traducido en la publicación de un Real Decreto que regula la realización de ensayos clínicos y que entró en vigor en enero de 2016. El nuevo Real Decreto pretende sentar las bases para trabajar de acuerdo con la normativa europea, regula los comités de ética de investigación con medicamentos (CEIm) que deben evaluar los estudios, introduce medidas para facilitar la investigación clínica y clarifica el Registro Español de Estudios Clínicos, entre otras cosas. Se revisan las modificaciones más importantes, sobre todo las que van dirigidas a facilitar la investigación, como las nuevas figuras que se crean de «Ensayo clínico de bajo nivel de intervención» e «Investigación clínica sin ánimo comercial». Estas figuras pueden resultar especialmente positivas para la realización de ensayos clínicos por parte de los urgenciólogos. También se comentan los cambios que se establecen para la investigación en poblaciones vulnerables y las modificaciones en la documentación que hay que presentar tanto al CEIm como a la Agencia Española de Medicamentos y Productos Sanitarios (AU)

The new European Union directives affecting clinical trials of medicines introduced important changes for Spain, leading to the publication of a Royal Decree regulating the conduct of clinical trials that went into effect in January 2016. The decree sets out the principles for complying with the EU directives, regulates the work of institutional review boards (IRBs) or ethics committees that review research proposals, introduces means to facilitate clinical research, and clarifies the role of the Spanish register of clinical trials, among other topics. This paper discusses the main changes that have been introduced, especially those intended to facilitate research, such as the new concepts of low intervention trial and noncommercial clinical research. These concepts may be particularly useful for clinical trials designed by emergency medicine physicians. We also comment on changes affecting vulnerable populations and the documents that must be presented to both the researchers’ IRB and the Spanish Agency for Medicines and Health Care Products (AU)

La acreditación de los comités de ética de la investigación / Accreditation of Independent Ethics Committees

Objetivo: Según la Ley 14/2007 y el Real Decreto 1090/2015, la investigación biomédica debe ser evaluada por un comité de ética de la investigación (CEI), que deberá estar acreditado como comité de ética de la investigación con medicamentos (CEIm) si el dictamen recae sobre un estudio clínico con medicamentos o una investigación clínica con productos sanitarios. El objetivo de este estudio es comprobar cómo se regula la acreditación de los CEI y de los CEIm. Métodos: Se ha analizado la legislación estatal y autonómica sobre investigación biomédica. Resultados: Ni los CEI ni los CEIm tienen un procedimiento de acreditación definido con claridad en la legislación estatal o autonómica. Discusión: Los CEI son fundamentales en el desarrollo de la investigación biomédica básica o clínica, y deben estar acreditados por un órgano externo para evitar que la independencia, la composición multidisciplinaria y la revisión se vean afectadas (AU)

Objective: According to Law 14/2007 and Royal Decree 1090/2015, biomedical research must be assessed by an Research Ethics Committee (REC), which must be accredited as an Research ethics committee for clinical trials involving medicinal products (RECm) if the opinion is issued for a clinical trial involving medicinal products or clinical research with medical devices. The aim of this study is to ascertain how IEC and IECm accreditation is regulated. Methods: National and regional legislation governing biomedical research was analysed. Results: No clearly-defined IEC or IECm accreditation procedures exist in the national or regional legislation. Discussion: Independent Ethics Committees are vital for the development of basic or clinical biomedical research, and they must be accredited by an external body in order to safeguard their independence, multidisciplinary composition and review procedures (AU)

Development of drugs for severe malaria in children.

Over 90% of deaths attributable to malaria are in African children under 5 years old. Yet, new treatments are often tested primarily in adult patients and extrapolations have proven to be sometimes invalid, especially in dosing regimens. For studies in severe malaria an additional complication is that the decline in severe malaria in adult patients precludes sufficiently powered trials in adults, before the intervention can be tested in the ultimate target group, paediatric severe malaria. In this paper we propose an alternative pathway to the development of drugs for use in paediatric severe malaria. We argue that following the classical phase I and II studies, small safety and efficacy studies using well-chosen surrogate endpoints in adult severe malaria be conducted, instead of larger mortality endpoint trials. If the drug appears safe and promising small pilot studies in paediatric severe malaria using the same endpoints can follow. Finally, with carefully observed safeguards in place to ensure high ethical standards, promising candidate interventions can be taken forward into mortality endpoint, well-powered, large paediatric studies in African children with severe malaria. Given the available research capacity, limited numbers of prudently selected interventions can be studied in phase III trials, and adaptive designs should be considered.

Use of Placebo in Pediatric Inflammatory Bowel Diseases: A Position Paper From ESPGHAN, ECCO, PIBDnet, and the Canadian Children IBD Network.

Performing well-designed and ethical trials in pediatric inflammatory bowel diseases (IBD) is a priority to support optimal therapy and reduce the unacceptable long lag between adult and pediatric drug approval. Recently, clinical trials in children have been incorporating placebo arms into their protocols under conditions that created controversy. Therefore, 4 organizations (the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition; European Crohn's and Colitis Organization; the Canadian Children IBD Network; and the Global Pediatric IBD Network) jointly provide a statement on the role of placebo in pediatric IBD trials. Consensus was achieved by 94 of 100 (94%) voting committees' members that placebo should only be used if there is genuine equipoise between the active treatment and placebo; for example, this may be considered in trials of drugs with new mechanisms of action without existing adult data, especially when proven effective alternatives do not exist outside the trial. Placebo may also be used in situations where it is an "add-on" to an effective therapy or to evaluate exit-strategies of maintenance therapy after long-term deep remission. It has been, however, agreed that no child enrolled in a trial should receive a known inferior treatment both within and outside the trial. This also includes withholding therapy in children who show clinical response after a short induction therapy. Given the similarity between pediatric and adult IBD regarding pathophysiology and response to treatments, drugs generally cannot be considered being in genuine equipoise with placebo if it has proven efficacy in adults. Continued collaboration of all stakeholders is needed to facilitate drug development and evaluation in pediatric IBD.

PCMO L01-Setting Specifications for Biological Investigational Medicinal Products.

UNLABELLED: This paper provides overall guidance and best practices for the setting of specifications for clinical biological drug substances and drug products within the framework of ICH guidelines on pharmaceutical development [Q8(R2) and Q11], quality risk management (Q9), and quality systems (Q10). A review is provided of the current regulatory expectations for the specification setting process as part of a control strategy during product development, pointing to existing challenges for the investigational new drug/investigational medicinal product dossier (IND/IMPD) sponsor. A case study illustrates how the investigational medicinal product specification revision process can be managed within a flexible quality system, and how specifications can be set and justified for early and late development stages. LAY ABSTRACT: This paper provides an overview for the setting of product specifications for investigational medicinal products used in clinical trials. A case study illustrates how product specifications of investigational medicinal products can be justified and managed within a modern product quality system.

The Food and Drug Administration and pragmatic clinical trials of marketed medical products.

Pragmatic clinical trials can help answer questions of comparative effectiveness for interventions routinely used in medical practice. Pragmatic clinical trials may examine outcomes of one or more marketed medical products, and they are heterogeneous in design and risk. The Food and Drug Administration is charged with protecting the rights, safety, and welfare of individuals enrolled in clinical investigations, as well as assuring the integrity of the data upon which approval of medical products is made. The Food and Drug Administration has broad jurisdiction over drugs and medical devices (whether or not they are approved for marketing), and as such, clinical investigations of these products are subject to applicable Food and Drug Administration regulations. While many pragmatic clinical trials will meet the criteria for an exemption from the requirements for an investigational new drug application or investigational device exemption, in general, all clinical investigations of medical products that fall under Food and Drug Administration jurisdiction must adhere to regulations for informed consent and review by an institutional review board. We are concerned that current Food and Drug Administration requirements for obtaining individual informed consent may deter or delay the conduct of pragmatic clinical trials intended to develop reliable evidence of comparative safety and effectiveness of approved medical products that are regulated by the Food and Drug Administration. Under current regulations, there are no described mechanisms to alter or waive informed consent to make it less burdensome or more practicable for low-risk pragmatic clinical trials. We recommend that the Food and Drug Administration establish a risk-based approach to obtaining informed consent in pragmatic clinical trials that would facilitate the conduct of pragmatic clinical trials without compromising the protection of enrolled individuals or the integrity of the resulting data.

Strategic Regulatory Evaluation and Endorsement of the Hollow Fiber Tuberculosis System as a Novel Drug Development Tool.

The first nonclinical drug development tool (DDT) advanced by the Critical Path to TB Drug Regimens (CPTR) Initiative through a regulatory review process has been endorsed by leading global regulatory authorities. DDTs with demonstrated predictive accuracy for clinical and microbiological outcomes are needed to support decision making. Regulatory endorsement of these DDTs is critical for drug developers, as it promotes confidence in their use in Investigational New Drug and New Drug Application filings. The in vitro hollow fiber system model of tuberculosis (HFS-TB) is able to recapitulate concentration-time profiles (exposure) observed in patients for single drugs and combinations, by evaluating exposure measures for the ability to kill tuberculosis in different physiologic conditions. Monte Carlo simulations make this quantitative output useful to inform susceptibility breakpoints, dosage, and optimal combination regimens in patients, and to design nonclinical experiments in animal models. The Pre-Clinical and Clinical Sciences Working Group within CPTR executed an evidence-based evaluation of the HFS-TB for predictive accuracy. This extensive effort was enabled through the collaboration of subject matter experts representing the pharmaceutical industry, academia, product development partnerships, and regulatory authorities including the Food and Drug Administration (FDA) and the European Medicines Agency (EMA). A comprehensive analysis plan following the regulatory guidance documents for DDT qualification was developed, followed by individual discussions with the FDA and the EMA. The results from the quantitative analyses were submitted to both agencies, pursuing regulatory DDT endorsement. The EMA Qualification Opinion for the HFS-TB DDT was published 26 January 2015 (available at: http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document_listing_000319.jsp).

Standardizing terms, definitions and concepts for describing and interpreting unwanted immunogenicity of biopharmaceuticals: recommendations of the Innovative Medicines Initiative ABIRISK consortium.

Biopharmaceuticals (BPs) represent a rapidly growing class of approved and investigational drug therapies that is contributing significantly to advancing treatment in multiple disease areas, including inflammatory and autoimmune diseases, genetic deficiencies and cancer. Unfortunately, unwanted immunogenic responses to BPs, in particular those affecting clinical safety or efficacy, remain among the most common negative effects associated with this important class of drugs. To manage and reduce risk of unwanted immunogenicity, diverse communities of clinicians, pharmaceutical industry and academic scientists are involved in: interpretation and management of clinical and biological outcomes of BP immunogenicity, improvement of methods for describing, predicting and mitigating immunogenicity risk and elucidation of underlying causes. Collaboration and alignment of efforts across these communities is made difficult due to lack of agreement on concepts, practices and standardized terms and definitions related to immunogenicity. The Innovative Medicines Initiative (IMI; www.imi-europe.org), ABIRISK consortium [Anti-Biopharmaceutical (BP) Immunization Prediction and Clinical Relevance to Reduce the Risk; www.abirisk.eu] was formed by leading clinicians, academic scientists and EFPIA (European Federation of Pharmaceutical Industries and Associations) members to elucidate underlying causes, improve methods for immunogenicity prediction and mitigation and establish common definitions around terms and concepts related to immunogenicity. These efforts are expected to facilitate broader collaborations and lead to new guidelines for managing immunogenicity. To support alignment, an overview of concepts behind the set of key terms and definitions adopted to date by ABIRISK is provided herein along with a link to access and download the ABIRISK terms and definitions and provide comments (http://www.abirisk.eu/index_t_and_d.asp).

El ensayo clínico en Radiología: claves para su interpretación / Key aspects in interpreting clinical trials in radiology

Un ensayo clínico (EC) es un estudio experimental que evalúa un tratamiento o técnica diagnóstica en seres humanos en términos de eficacia y seguridad. Para asegurar su calidad metodológica y que sus resultados sean ciertos, se han elaborado varios listados de comprobación con la finalidad de identificar si el EC tiene sesgos importantes que invaliden sus conclusiones. El objetivo de este artículo es describir cuáles son los puntos que debemos abordar a la hora de realizar la lectura crítica de un EC. Normalmente, la respuesta a estas cuestiones las encontramos leyendo detenidamente la sección 'Material y métodos', y la de 'Resultados'. La aleatorización, el seguimiento de pacientes (o análisis de las pérdidas), el enmascaramiento y la equivalencia entre los grupos (a excepción de la intervención) son algunos de los aspectos claves en cuanto al diseño. En los resultados debemos valorar qué medidas de eficacia clínica se han utilizado (riesgo relativo, odds ratio o número de pacientes necesario a tratar entre otras) y la precisión de los resultados (intervalos de confianza). Una vez que hemos comprobado que el EC cumple todos estos requisitos, se valorará si los resultados se pueden aplicar en nuestro medio y si los beneficios que se han obtenido justifican los riesgos y costes (AU)

A clinical trial is an experimental study to evaluate the efficacy and safety of a treatment or diagnostic technique in human beings. To ensure the methodological quality of a clinical trial and the validity of its results, various checklists have been elaborated to identify biases that could invalidate its conclusions. This article focuses on the points we need to consider in the critical evaluation of a clinical trial. We can usually find this information in the 'materials and methods' and 'results' sections of articles. Randomization, follow-up (or analysis of losses), blinding, and equivalence between groups (apart from the intervention itself) are some key aspects related to design. In the 'results' section, we need to consider what measures of clinical efficacy were used (relative risk, odds ratio, or number needed to treat, among others) and the precision of the results (confidence intervals). Once we have confirmed that the clinical trial fulfills these criteria, we need to determine whether the results can be applied in our environment and whether the benefits obtained justify the risks and costs involved (AU)

Design of phase I combination trials: recommendations of the Clinical Trial Design Task Force of the NCI Investigational Drug Steering Committee.

Anticancer drugs are combined in an effort to treat a heterogeneous tumor or to maximize the pharmacodynamic effect. The development of combination regimens, while desirable, poses unique challenges. These include the selection of agents for combination therapy that may lead to improved efficacy while maintaining acceptable toxicity, the design of clinical trials that provide informative results for individual agents and combinations, and logistic and regulatory challenges. The phase I trial is often the initial step in the clinical evaluation of a combination regimen. In view of the importance of combination regimens and the challenges associated with developing them, the Clinical Trial Design (CTD) Task Force of the National Cancer Institute Investigational Drug Steering Committee developed a set of recommendations for the phase I development of a combination regimen. The first two recommendations focus on the scientific rationale and development plans for the combination regimen; subsequent recommendations encompass clinical design aspects. The CTD Task Force recommends that selection of the proposed regimens be based on a biologic or pharmacologic rationale supported by clinical and/or robust and validated preclinical evidence, and accompanied by a plan for subsequent development of the combination. The design of the phase I clinical trial should take into consideration the potential pharmacokinetic and pharmacodynamic interactions as well as overlapping toxicity. Depending on the specific hypothesized interaction, the primary endpoint may be dose optimization, pharmacokinetics, and/or pharmacodynamics (i.e., biomarker).