Analysis of secondary pharmacology assays received by the US Food and Drug Administration.

Secondary pharmacology studies are a time-efficient and cost-effective method for determining the safety profile of a potential new drug before it enters human trials. The results of these multi-target screens are commonly submitted with Investigational New Drug (IND) applications, but there currently is little guidance on how such information is presented and which targets are chosen for testing. In this study, we expand on our previous analysis of secondary pharmacology reports by manually curating and analyzing all secondary pharmacology results received by the FDA received as part of an IND submission. A total of 1120 INDs submitted by 480 sponsors between 1999 and October 2020 were included in this study. The overall results were largely consistent with previous internal and external studies, showing that the most tested target in our set was the histamine 1 receptor (tested 938 times), the most hit target was sodium channel site 2 (hit 141 times), and the target with the highest hit percentage was the vesicular monoamine transporter 2 (hit 42.2% of the time). Additionally, this study demonstrated that improvements in the secondary pharmacology submission process, such as changes in formatting and nomenclature, could enhance the utility of these assays for regulatory review, including assisting with identifying the safety liabilities of a drug candidate early in development. This updated data set will allow FDA-industry collaborative working groups to continue developing the best methods for regulatory submission of secondary pharmacology data and evaluate the need for a standard target panel.

Considerations on chemistry, manufacturing, and control of stem cell products for Investigational New Drug application in China.

Tremendous progress has been made in recent years to produce functional cells for cell therapy products. Hundreds of clinical trials of stem cell products (SCPs) have shown promising therapeutic potential worldwide, including the products derived from human pluripotent stem cells (hPSCs), adult stem cells and mesenchymal stem cells (MSC). Before starting a clinical trial, comprehensive chemistry, manufacturing and control (CMC) study is required to assure the safety and quality consistency of SCPs. The heterogeneity of stem cell products arises from the variability in the donor tissues, isolation of cells and differentiation processes, and appropriate testing approaches are needed to characterize and release SCPs. Here we summarize the regulatory considerations of CMC study in Investigational New Drug (IND) application of SCPs in China based on the current knowledge, and they will be updated in the future with the advance of stem cell biology and regulatory science.

Anvisa autoriza testes da vacina contra o coronavírus: voluntários serão profissionais de saúde

Site do instituto Butantan dedicado a informações sobre a vacina contra o COVID-19. acesse o site para entender sobre os critérios de participação, como se inscrever, quais são os Centros de Pesquisa que participarão do estudo PROFISCOV, e muito mais

Coronavírus: como foi realizada a fase 2 da vacina?

Saiba mais em: www.saopaulo.sp.gov.br/coronavirus/planosp

Coronavírus: quantos centros farão os testes da vacina no Brasil?

Saiba mais em: www.saopaulo.sp.gov.br/coronavirus/planosp

Coronavírus: se a vacina for aprovada, como será a distribuição no Brasil?

Saiba mais em: www.saopaulo.sp.gov.br/coronavirus/planosp

Coronavírus: quem pode participar dos testes da vacina?

Saiba mais em: www.saopaulo.sp.gov.br/coronavirus/planosp

Coronavírus: Anvisa autoriza testes da vacina

Saiba mais em: www.saopaulo.sp.gov.br/coronavirus/planosp

Coletiva de Imprensa: Anúncios do Governo SP - 06/07/2020

O Governador João Doria confirmou nesta segunda-feira (6) que, pela segunda semana consecutiva, houve queda no número de mortes em decorrência do coronavírus em todo o estado de São Paulo. A nova redução reforça a tendência de achatamento progressivo da curva de óbitos da pandemia, que vem sendo apontada nas últimas semanas pelas autoridades de saúde. “São boas notícias, mas elas não devem ser celebradas com emoção. Mas, sim, com moderação para mantermos o foco em medidas de controle da pandemia, aumento da capacidade de atendimento do sistema de saúde, obrigatoriedade do uso de máscara e obediência à legislação e ao distanciamento social”, declarou o Governador. “Todos precisam ter paciência, resiliência e compreensão de que ainda estamos na pandemia”, reforçou Doria. De acordo com informações da Secretaria de Estado da Saúde e do Centro de Contingência do coronavírus, na semana entre 14 a 20 de junho, houve 1.913 mortes de pacientes contaminados no território paulista. Nos sete dias subsequentes, de 21 a 27 de junho, o número de vítimas fatais em decorrência da pandemia caiu para 1.769 óbitos. E no período entre 28 de junho a 4 de julho, foram 1.733 mortes. O número atual é 9,5% menor que o registrado há 16 dias. O Governador também apontou que São Paulo atingiu o menor índice da taxa de letalidade por coronavírus desde março, quando o estado registrou a primeira morte desde que a pandemia foi confirmada pela OMS (Organização Mundial de Saúde). Atualmente, a mortalidade é de 5% entre os casos confirmados de contaminação por coronavírus em todo o estado. “É o índice mais baixo de toda a série histórica”, destacou. “O objetivo principal é reduzir a curva de óbitos com a colaboração da maioria expressiva de prefeitas e prefeitos do interior, litoral e Grande São Paulo que têm nos ajudado neste sentido. Ao lado também do Ministério Público, Tribunal de Justiça e todos aqueles que respeitam a saúde, a medicina e fazem o correto enfrentamento da pandemia”, acrescentou Doria. Para o Secretário de Desenvolvimento Regional, Marco Vinholi, o aumento expressivo na testagem de coronavírus e o aumento robusto no número de leitos de UTI para pacientes com sintomas graves em hospitais públicos do estado são fatores fundamentais para a redução da mortalidade. “São Paulo não deixará ninguém sem atendimento. Já são mais de 2,5 mil respiradores distribuídos por todo o estado.” Saiba mais em: www.saopaulo.sp.gov.br/coronavirus/planosp

Iguratimod as an alternative induction therapy for refractory lupus nephritis: a preliminary investigational study.

OBJECTIVES: Iguratimod, a novel immunomodulatory agent for rheumatoid arthritis, has been shown to be effective against murine lupus. The aim of this study was to make a preliminary evaluation of the efficacy and safety of iguratimod as salvage therapy in patients with refractory lupus nephritis (LN). METHODS: We enrolled eligible patients with refractory LN, which we defined as having failed or relapsed on at least two immunosuppressant agents. After enrollment, we substituted iguratimod (25 mg twice daily) for their previous immunosuppressant agents without increasing the dose of steroids. The primary outcome was complete/partial remission (PR/CR) at week 24. Patients who achieved remission continued iguratimod as maintenance therapy over an extended follow-up. RESULTS: The study cohort comprised 14 patients with refractory LN, 10 of whom had recent treatment failure and 4 repeated relapses with inadequate initial responses. At enrollment, none of the patients had detectable evidence of extra-renal involvement. The median prednisone dosage was 10 mg/d (IQR 0-10 mg/day). Thirteen patients were eligible for response evaluation, with one patient missed. The renal response rate was 92.3% (12/13) at week 24, with 38.5% (5/13) achieving CR and 53.8% (7/13) achieving PR. We then continued to follow up the responding patients for up to 144 weeks. Twenty-five percent of the patients (3/12) had renal relapse after initial PR. The estimated glomerular filtration rate of all patients maintained stable during follow-up. One patient had a severe adverse reaction (anemia) but recovered fully after stopping iguratimod. CONCLUSIONS: Our study supports the potential of iguratimod for treatment of refractory LN. Iguratimod could be a promising candidate drug for this condition.

Sponsors' and investigative staffs' perceptions of the current investigational new drug safety reporting process in oncology trials.

BACKGROUND/AIMS: The Food and Drug Administration's final rule on investigational new drug application safety reporting, effective from 28 March 2011, clarified the reporting requirements for serious and unexpected suspected adverse reactions occurring in clinical trials. The Clinical Trials Transformation Initiative released recommendations in 2013 to assist implementation of the final rule; however, anecdotal reports and data from a Food and Drug Administration audit indicated that a majority of reports being submitted were still uninformative and did not result in actionable changes. Clinical Trials Transformation Initiative investigated remaining barriers and potential solutions to full implementation of the final rule by polling and interviewing investigators, clinical research staff, and sponsors. METHODS: In an opinion-gathering effort, two discrete online surveys designed to assess challenges and motivations related to management of expedited (7- to 15-day) investigational new drug safety reporting processes in oncology trials were developed and distributed to two populations: investigators/clinical research staff and sponsors. Data were collected for approximately 1 year. Twenty-hour-long interviews were also conducted with Clinical Trials Transformation Initiative-nominated interview participants who were considered as having extensive knowledge of and experience with the topic. Interviewees included 13 principal investigators/study managers/research team members and 7 directors/vice presidents of pharmacovigilance operations from 5 large global pharmaceutical companies. RESULTS: The investigative site's responses indicate that too many individual reports are still being submitted, which are time-consuming to process and provide little value for patient safety assessments or for informing actionable changes. Fewer but higher quality reports would be more useful, and the investigator and staff would benefit from sponsors'"filtering" of reports and increased sponsor communication. Sponsors replied that their greatest challenges include (1) lack of global harmonization in reporting rules, (2) determining causality, and (3) fear of regulatory repercussions. Interaction with the Food and Drug Administration has helped improve sponsors' adherence to the final rule, and sponsors would benefit from increased communication with the Food and Drug Administration and educational materials. CONCLUSION: The goal of the final rule is to minimize uninformative safety reports so that important safety signals can be captured and communicated early enough in a clinical program to make changes that help ensure patient safety. Investigative staff and sponsors acknowledge that the rule has not been fully implemented although they agree with the intention. Clinical Trials Transformation Initiative will use the results from the surveys and interviews to develop new recommendations and educational materials that will be available to sponsors to increase compliance with the final rule and facilitate discussion between sponsors, investigators, and Food and Drug Administration representatives.

Building a drug development database: challenges in reliable data availability.

CONTEXT: Policy and legislative efforts to improve the biomedical innovation process must rely on a detailed and thorough analysis of drug development and industry output. OBJECTIVE: As part of our efforts to build a publicly-available database on the characteristics of drug development, we present work undertaken to test methods for compiling data from public sources. These initial steps are designed to explore challenges in data extraction, completeness and reliability. Specifically, filing dates for Investigational New Drugs (IND) applications with the U.S. Food and Drug Administration (FDA) were chosen as the initial objective data element to be collected. MATERIALS AND METHODS: FDA's Drugs@FDA database and the Federal Register (FR) were used to collect IND dates for the 587 New Molecular Entities (NMEs) approved between 1994 and 2014. When available, the following data were captured: approval date, IND number, IND date and source of information. RESULTS: At least one IND date was available for 445 (75.8%) of the 587 NMEs. The Drugs@FDA database provided IND dates for 303 (51.6%) NMEs and the FR contributed with 297 (50.6%) IND dates. Out of the 445 NMEs for which an IND date was obtained, 274 (61.6%) had more than one date reported. DISCUSSION: Key finding of this paper is a considerable inconsistency in reliably available or reported data elements, in this particular case, IND application filing dates as assembled from publicly-available sources. CONCLUSION: Our team will continue to focus on finding ways to collect relevant information to measure impact of drug innovation.

Experience of an academic institute in importing a novel preclinical drug into India.

The article throws light on the process of importing a novel preclinical drug into India based on the real-life experience from one of our studies. A novel drug "X" acting through a new mechanism of action was hypothesized by us to function as a neuroprotectant. It was decided to import this novel drug from a university located in Brazil. An official collaboration pact was exchanged between both the sides. In accordance with the Indian Drug and Cosmetics Act 1940, unauthorized import of drug into India is not permitted. Hence, we decided to apply for the import license from Government of India. During the process of registration, we realized that the CDSCO SUGAM portal did not have facilities for the application from academic institute. We further faced challenges in different steps of import such as registration of the institute, individual drug application, fee transaction through the bank for Form 12, and customs duty clearance in the New Delhi airport. The process of import of drug for the purpose of testing by academic institutes has not been regularized by the CDSCO, and we suggest the apex organization to make separate provision for the academic institutes. This will encourage more academic institutes in India to opt for global collaborative works. This narration will further help them in following the same footsteps without facing significant hurdles. If more research on novel chemical entities is carried out in various academic institutes of India, it would not be far that we discover a blockbuster drug making the whole world turn toward us.

Obtaining i.v. fosfomycin through an expanded-access protocol.

PURPOSE: One hospital's experience with procuring i.v. fosfomycin via an expanded-access protocol to treat a panresistant infection is described. SUMMARY: In mid-2014, a patient at a tertiary care institution had an infection caused by a gram-negative pathogen expressing notable drug resistance. Once it was determined by the infectious diseases (ID) attending physician that i.v. fosfomycin was a possible treatment for this patient, the ID pharmacist began the process of drug procurement. The research and ID pharmacists completed an investigational new drug (IND) application, which required patient-specific details and contributions from the ID physician. After obtaining approval of the IND, an Internet search identified a product vendor in the United Kingdom, who was then contacted to begin the drug purchasing and acquisition processes. Authorization of the transaction required signatures from key senior hospital administrators, including the chief financial officer and the chief operating officer. Approximately 6 days after beginning the acquisition process, the research pharmacist arranged for the wholesaler to expedite product delivery. The ID pharmacist contacted the wholesaler's shipping company at the U.S. Customs Office, providing relevant contact information to ensure that any unexpected circumstances could be quickly addressed. The product arrived at the U.S. Customs Office 8 days after beginning the acquisition process and was held in the U.S. Customs Office for 2 days. The patient received the first dose of i.v. fosfomycin 13 days after starting the expanded-access protocol process. CONCLUSION: I.V. fosfomycin was successfully procured through an FDA expanded-access protocol by coordinating efforts among ID physicians, pharmacists, and hospital executives.

Development and Evaluation of a New Technological Way of Engaging Patients and Enhancing Understanding of Drug Tolerability in Early Clinical Development: PROACT.

INTRODUCTION: During early clinical testing of a new medication, it is critical to understand and characterise patient tolerability. However, in early clinical studies, it is difficult for patients to contribute directly to the sponsors' understanding of a new compound. Patient reported opinions about clinical tolerability (PROACT) provides a new, simple and innovative way in which patients can collaborate using an application downloaded to a mobile computer or smartphone. METHODS: PROACT was designed with special consideration given to patient confidentiality, patient engagement and data security. A pilot study was conducted to investigate patient uptake of PROACT and to characterize clinical trial information it captured. Patients recruited to Phase I oncology trials at a UK center were eligible to participate but were required to have a tablet computer or smartphone. Patients used PROACT to upload audio/video messages that became available instantly to their clinical team, who were able to reply to the patient within PROACT. The patient's message was also analyzed, personally-identifiable information removed and anonymized information then made available to the sponsor in an analytics module for decision-making. In parallel, a patient focus group was engaged to provide feedback on communication needs during early clinical trials and the PROACT concept. RESULTS: Of the 16 patients informed of PROACT, 8 had a smart device and consented to take part. Use of PROACT varied and all messages volunteered were relevant and informative for drug development. Topics disclosed included tolerability impacts, study design, and drug formulation. Alignment with the clinical study data provided a richer understanding of tolerability and treatment consequences. This information was available to be shared among the clinical team and the sponsor, to improve patient support and experience. Patient forum feedback endorsed the concept and provided further information to enhance the application. CONCLUSION: Overall, PROACT achieved proof of concept in this small pilot study and delivered a secure end-to-end system that protected patient privacy and provided preliminary insight into patient experiences beyond the usual clinical trial data set. The use of mobile devices to interact actively with participants in clinical trials may be a new way of engaging and empowering patients. Further validation of this technology in larger patient cohorts is ongoing. FUNDING: AstraZeneca.

Investigational New Drug applications: a 1-year pilot study on rates and reasons for clinical hold.

BACKGROUND: The Food and Drug Administration (FDA)'s Center for Drug Evaluation and Research (CDER) receives about 1500 initial Investigational New Drug applications (INDs) per year. In the first 30 days after initial IND submission, FDA conducts a review to determine whether the proposed investigation is safe to proceed, and if not, the IND may be placed on clinical hold. METHODS: A retrospective study of rates and reasons for clinical hold for all initial INDs submitted to CDER in fiscal year (FY) 2013 was performed. INDs were assessed for reasons that led to clinical hold, included chemistry, manufacturing and controls (CMC), animal toxicology or clinical issues. INDs were further categorized by commercial versus research sponsorship, and rare versus common disease indications. All INDs placed on hold were reassessed by whether they remained on hold within the first year following hold imposition. RESULTS: CDER received 1410 initial INDs in FY 2013, of which 125 (8.9%) were placed on hold during the first 30 days after initial submission. Of the INDs placed on hold, more than half became active within the first year after first imposition of hold. CMC reasons were most commonly cited, followed by clinical, then toxicology reasons. There were no substantive differences in rates and reasons for hold between INDs for rare or common disease indications, or between commercial or research INDs. CONCLUSIONS: The vast majority of initial INDs moved forward within 30 days after submission, and for those applications placed on hold, most became active within 1 year. The findings also suggest that many holds for new drug product programs can be avoided by following the available guidelines for investigational product development.

The Majority of Expedited Investigational New Drug Safety Reports Are Uninformative.

Sponsors of human drug and biologic products subject to an investigational new drug (IND) application are required to distribute expedited safety reports of serious and unexpected suspected adverse reactions to participating investigators and the FDA to assure the protection of human subjects participating in clinical trials. On September 29, 2010, the FDA issued a final rule amending its regulations governing expedited IND safety reporting requirements that revised the definitions used for reporting and clarified when to submit relevant and useful information to reduce the number of uninformative reports distributed by sponsors. From January 1, 2006, to December 31, 2014, the FDA's Office of Hematology and Oncology Products received an average of 17,686 expedited safety reports per year. An analysis of FDA submissions by commercial sponsors covering this time period suggested a slight increase in the number of expedited safety reports per IND per year after publication of the final rule. An audit of 160 randomly selected expedited safety reports submitted to the FDA's Office of Hematology and Oncology Products in 2015 revealed that only 22 (14%) were informative. The submission of uninformative expedited safety reports by commercial sponsors of INDs continues to be a significant problem that can compromise detection of valid safety signals. Clin Cancer Res; 22(9); 2111-3. ©2016 AACR.

Efficacy and safety concerns are important reasons why the FDA requires multiple reviews before approval of new drugs.

The regulatory approval of new drugs by the Food and Drug Administration (FDA) is a long and complex process and often requires multiple cycles of review, potentially delaying patients' access to new and effective therapeutics. We used qualitative methods to characterize the safety and efficacy reasons why applications for novel therapeutics approved by the FDA between 2001 and 2011 required multiple review cycles prior to approval. Among ninety-six applications approved between 2001 and 2011 that required multiple review cycles, safety concerns contributed to seventy-four (77.1 percent) and efficacy concerns to forty-three (44.8 percent). Our study suggests that multiple review cycles appear to play an important role in allowing the FDA to protect public health and in ensuring adequate understanding of clinical benefits and risks prior to approval.

La investigación biomédica: algunas orientaciones sobre cómo dar el primer paso / Biomedical research: guidance on how to take the first research steps

La creciente regulación de la investigación clínica, tanto nacional como europea, ha venido a incrementar los trámites administrativos necesarios para obtener las autorizaciones pertinentes previas al inicio de cualquier estudio de investigación biomédica. En función del tipo de estudio estos requisitos son más o menos complejos: los ensayos clínicos con medicamentos e investigaciones clínicas con productos sanitarios se encuentran entre los que disponen de más desarrollo normativo, mientras que los proyectos de investigación con procedimientos no invasivos están en la situación opuesta. Entre ambos, todo un abanico de normativas puede dificultar la labor del clínico a la hora de llevar a la práctica un estudio. Con este artículo pretendemos proporcionar unas instrucciones a seguir para cada tipo de estudio, así como informar de la legislación aplicable (AU)

The expanding body of regulations that affect biomedical research both in Spain and the rest of Europe have led to an increasing amount administrative work for obtaining approvals before a study can start. The complexity of the requirements will depend on the study design: clinical trials with medicines or other health care products are subject to the most highly developed regulations, whereas those affecting studies of non-invasive procedures are less complex. Between the 2 extremes, a range of requirements can complicate the clinical researcher's task. In this article we seek to provide instructions according to the type of study being planned and to explain relevant legislation (AU)