Search

The US Food and Drug Administration (FDA) is open to accepting real-world evidence (RWE) to support its assessment of medical products. However, RWE stakeholders lack a shared understanding of FDA's evidentiary expectations for the use of RWE in applications for new drugs and biologics. We conducted a systematic review of publicly available FDA approval documents from January 2019 to June 2021. We sought to quantify, by year, how many approvals incorporated RWE in any form, and the intended use of RWE in those applications. Among approvals with RWE intended to support safety and/or effectiveness, we classified whether and how those studies impacted FDA's benefit-risk considerations, whether those studies were incorporated into the product label, and the therapeutic area of the medical product. Finally, we qualified FDA's documented feedback where available. We found that 116 approvals incorporated RWE in any form, with the proportion of approvals incorporating RWE increasing each year. Of these approvals, 88 included an RWE study intended to provide evidence of safety or effectiveness. Among these 88 approvals, 65 of the studies influenced FDA's final decision and 38 were included in product labels. The 88 approvals spanned 18 therapeutic areas. FDA's feedback on RWE study quality included methodological issues, sample size concerns, omission of patient level data, and other limitations. Based on these findings, we would anticipate that future guidance on FDA's evidentiary expectations of RWE use will incorporate fit-for-purpose real-world data selection and careful attention to study design and analysis., (© 2021 Aetion, Inc. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Pharmacometrics is an emerging science that interprets drug, disease, and trial information in a mathematical fashion to inform and facilitate efficient drug development and/or regulatory decisions. Pharmacometrics study is increasingly adopted in the regulatory review of new antimicrobial agents. We summarized the 31 antimicrobial agents approved by the US Food and Drug Administration (FDA) and the 26 antimicrobial agents approved by European Medicines Agency (EMA) from January 2001 to May 2019. We also reviewed recent examples of utilizing pharmacometrics to support antimicrobial agent's registration in China, including modeling and simulation methods, effects of internal/external factors on pharmacokinetic (PK) parameters, safety and efficacy evaluation in terms of exposure-response analysis, refinement of the wording of product labeling and package leaflet, and possible postmarketing clinical trial. Ongoing communication among regulator, academia, and industry regarding pharmacometrics is encouraged to streamline and facilitate the development of new antimicrobial agents. The industry can maximize its benefit in drug development through continued pharmacometrics education/training., (© 2021 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

The first (2017) and sixth (2021) multistakeholder Paediatric Strategy Forums focused on anaplastic lymphoma kinase (ALK) inhibition in paediatric malignancies. ALK is an important oncogene and target in several paediatric tumours (anaplastic large cell lymphoma [ALCL], inflammatory myofibroblastic tumour [IMT], neuroblastoma and hemispheric gliomas in infants and young children) with unmet therapeutic needs. ALK tyrosine kinase inhibitors have been demonstrated to be active both in ALK fusion-kinase positive ALCL and IMT. ALK alterations differ, with fusions occurring in ALCL, IMT and gliomas, and activating mutations and amplification in neuroblastoma. While there are many ALK inhibitors in development, the number of children diagnosed with ALK driven malignancies is very small. The objectives of this ALK Forum were to (i) Describe current knowledge of ALK biology in childhood cancers; (ii) Provide an overview of the development of ALK inhibitors for children; (iii) Identify the unmet needs taking into account planned or current ongoing trials; (iv) Conclude how second/third-generation inhibitors could be evaluated and prioritised; (v) Identify lessons learnt from the experience with ALK inhibitors to accelerate the paediatric development of other anti-cancer targeted agents in the new regulatory environments. There has been progress over the last four years, with more trials of ALK inhibitors opened in paediatrics and more regulatory submissions. In January 2021, the US Food and Drug Administration approved crizotinib for the treatment of paediatric and young adult patients with relapsed or refractory ALCL and there are paediatric investigation plans (PIPs) for brigatinib and for crizotinib in ALCL and IMT. In ALCL, the current goal is to investigate the inclusion of ALK inhibitors in front-line therapy with the aim of decreasing toxicity with higher/similar efficacy compared to present first-line therapies. For IMT, the focus is to develop a joint prospective trial with one product in children, adolescents and adults, taking advantage of the common biology across the age spectrum. As approximately 50% of IMTs are ALK-positive, molecular analysis is required to identify patients to be treated with an ALK inhibitor. For neuroblastoma, crizotinib has not shown robust anti-tumour activity. A focused and sequential development of ALK inhibitors with very good central nervous system (CNS) penetration in CNS tumours with ALK fusions should be undertaken. The Forum reinforced the strong need for global academic collaboration, very early involvement of regulators with studies seeking possible registration and early academia-multicompany engagement. Innovations in study design and conduct and the use of 'real-world data' supporting development in these rare sub-groups of patients for whom randomised clinical trials are not feasible are important initiatives. A focused and sequenced development strategy, where one product is evaluated first with other products being assessed sequentially, is applicable for ALK inhibitors and other medicinal products in children., Competing Interests: Conflict of interest statement EB is an employee of Day One Biopharmaceuticals and was an employee of Pfizer. HC is an employee of Hoffmann-La Roche. SGD has consulted for Bayer and received travel expenses from Loxo Oncology, Roche, and Salarius. FD is the European principal investigator of the Roche Alectinib study and participated in advisory boards for Bayer, BMS, Roche, Celgene, LOXO Oncology, Servier and Tesaro and received travel expenses from Bayer, BMS, Roche and consultancy from Servier and received funding for research projects from Onxeo, Synth-Innove. LVM has consulted for Bayer and participated in advisory boards for BMS and Tesaro, and been a Data Monitoring Committee Member for Eisai and Merck. YM is an employee of Takeda Pharmaceuticals International. YPM has been a consultant for Pfizer. KN participated in advisory boards, consulted and taught for Bayer, Y-mAbs, and EUSA. GS is an employee of Xcovery. ADJP has participated in advisory boards for Novartis, Takeda, Merck, Lilly and Celgene and consulted for Lilly and Developmental Therapeutics Consortium Limited. KW is an employee of Pfizer. WW has consulted for Takeda and participated in an advisory board for Takeda Pharmaceuticals International. ZFZ is an employee of Turning Point Therapeutics. All remaining authors have declared no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Deciding on the smallest change in an outcome that constitutes a clinically meaningful treatment effect (ie, the minimum clinically important difference [MCID]) is fundamental to interpreting clinical trial outcomes, making clinical decisions, and designing studies with sufficient statistical power to detect any such effect. There is no consensus on MCIDs for outcomes in Alzheimer's disease trials, but the US Food and Drug Administration's consideration of aducanumab clinical trials data has exposed the uncertainty of the clinical meaning of statistically significant but small improvements. Although MCIDs for outcomes, including Clinical Dementia Rating-Sum of Boxes and Mini-Mental State Examination in Alzheimer's disease have been reported, the Food and Drug Administration's guidelines, drafted in 1989 to facilitate regulatory approval of substantially effective antidementia drugs, do not specify quantified minimum differences. Although it is important that regulatory requirements encourage drug development and approval, without MCIDs, sponsors are motivated to power trials to detect statistical significance for only small and potentially inconsequential effects on clinical outcomes. MCIDs benefit patients, family members, caregivers, and health-care systems and should be incorporated into clinical trials and drug development guidance for Alzheimer's disease., Competing Interests: Declaration of interests Outside of this Personal View, LSS reports grants and personal fees from Eli Lilly, Merck, and Roche/Genentech; personal fees from Boehringer Ingelheim, Neurim, Ltd, Neuronix, Ltd, Cognition, Eisai, Takeda, vTv, IBC, Abbot, and Samus; and grants from Biogen, Novartis, Biohaven, and Washington Univ/ NIA DIAN-TU. RH and KYL declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

On 7 June 2021, aducanumab was granted accelerated approval for the treatment of Alzheimer disease (AD) by the FDA on the basis of amyloid-lowering effects considered reasonably likely to confer clinical benefit. This decision makes aducanumab the first new drug to be approved for the treatment of AD since 2003 and the first drug to ever be approved for modification of the course of AD. Many have questioned how scientific evidence, expert advice and the best interests of patients and families were considered in the approval decision. In this article, we argue that prior to approval, the FDA and Biogen's shared interpretation of clinical trial data - that high-dose aducanumab was substantially clinically effective - avoided conventional scientific scrutiny, was prominently advanced by patient representative groups who had been major recipients of Biogen funds, and raised concerns that safeguards were insufficient to mitigate regulatory capture within the FDA. Here, we reflect on events leading to the FDA's decision on 7 June 2021 and consider whether any lessons can be learned for the field., (© 2021. Springer Nature Limited.)

Aducanumab (Aduhelm), the first new drug to treat Alzheimer's disease since 2003, has received accelerated approval from the Food and Drug Administration (FDA).This drug's approval has been highly contentious in the medical and scientific community owing to contradictory study findings and the FDA's advisory panel not recommending its approval., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Importance: As of May 2021, more than 32 million cases of COVID-19 have been confirmed in the United States, resulting in more than 615 000 deaths. Anaphylactic reactions associated with the Food and Drug Administration (FDA)-authorized mRNA COVID-19 vaccines have been reported., Objective: To characterize the immunologic mechanisms underlying allergic reactions to these vaccines., Design, Setting, and Participants: This case series included 22 patients with suspected allergic reactions to mRNA COVID-19 vaccines between December 18, 2020, and January 27, 2021, at a large regional health care network. Participants were individuals who received at least 1 of the following International Statistical Classification of Diseases and Related Health Problems, Tenth Revision anaphylaxis codes: T78.2XXA, T80.52XA, T78.2XXD, or E949.9, with documentation of COVID-19 vaccination. Suspected allergy cases were identified and invited for follow-up allergy testing., Exposures: FDA-authorized mRNA COVID-19 vaccines., Main Outcomes and Measures: Allergic reactions were graded using standard definitions, including Brighton criteria. Skin prick testing was conducted to polyethylene glycol (PEG) and polysorbate 80 (P80). Histamine (1 mg/mL) and filtered saline (negative control) were used for internal validation. Basophil activation testing after stimulation for 30 minutes at 37 °C was also conducted. Concentrations of immunoglobulin (Ig) G and IgE antibodies to PEG were obtained to determine possible mechanisms., Results: Of 22 patients (20 [91%] women; mean [SD] age, 40.9 [10.3] years; 15 [68%] with clinical allergy history), 17 (77%) met Brighton anaphylaxis criteria. All reactions fully resolved. Of patients who underwent skin prick tests, 0 of 11 tested positive to PEG, 0 of 11 tested positive to P80, and 1 of 10 (10%) tested positive to the same brand of mRNA vaccine used to vaccinate that individual. Among these same participants, 10 of 11 (91%) had positive basophil activation test results to PEG and 11 of 11 (100%) had positive basophil activation test results to their administered mRNA vaccine. No PEG IgE was detected; instead, PEG IgG was found in tested individuals who had an allergy to the vaccine., Conclusions and Relevance: Based on this case series, women and those with a history of allergic reactions appear at have an elevated risk of mRNA vaccine allergy. Immunological testing suggests non-IgE-mediated immune responses to PEG may be responsible in most individuals.

Due to the sheer number of COVID-19 (coronavirus disease 2019) cases there is a need for increased world-wide SARS-CoV-2 testing capability that is both efficient and effective. Having open and easy access to detailed information about these tests, their sensitivity, the types of samples they use, etc. would be highly useful to ensure their reproducibility, to help clients compare and decide which tests would be best suited for their applications, and to avoid costs of reinventing similar or identical tests. Additionally, this resource would provide a means of comparing the many innovative diagnostic tools that are currently being developed in order to provide a foundation of technologies and methods for the rapid development and deployment of tests for future emerging diseases. Such a resource might thus help to avert the delays in testing and screening that was observed in the early stages of the pandemic and plausibly led to more COVID-19-related deaths than necessary. We aim to address these needs via a relational database containing standardized ontology and curated data about COVID-19 diagnostic tests that have been granted Emergency Use Authorizations (EUAs) by the FDA (US Food and Drug Administration). Simple queries of this actively growing database demonstrate considerable variation among these tests with respect to sensitivity (limits of detection, LoD), controls and targets used, criteria used for calling results, sample types, reagents and instruments, and quality and amount of information provided., Competing Interests: JDB is a founder and director of the following: Neochromosome, Inc., the Center of Excellence for Engineering Biology, and CDI Labs, Inc. and serves on the Scientific Advisory Board of the following: Sangamo, Inc., Modern Meadow, Inc., and Sample6, Inc. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Patients with multiple chronic conditions, including more advanced chronic kidney disease (CKD), are often excluded from clinical trials, creating challenges in deriving appropriate dosing information and labeling. This article summarizes the May 7, 2019, US Food and Drug Administration Pharmaceutical Science and Clinical Pharmacology Advisory Committee Meeting, which solicited expert opinions on how to enroll patients with more advanced CKD into clinical trials as well as the assumptions behind and different approaches of exposure-matching., (© 2021 The Authors. Clinical Pharmacology & Therapeutics © 2021 American Society for Clinical Pharmacology and Therapeutics.)

The Food and Drug Administration has granted emergency use authorization to sotrovimab for the treatment of mild to moderate COVID-19 in patients at increased risk for progression to severe illness.Sotrovimab is a monoclonal antibody that works directly against the spike protein of SARS-CoV-2 to block its attachment and entry into a human cell., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

The US Food and Drug Administration's Sentinel System was established in 2009 to use routinely collected electronic health data for improving the national capability to assess post-market medical product safety. Over more than a decade, Sentinel has become an integral part of FDA's surveillance capabilities and has been used to conduct analyses that have contributed to regulatory decisions. FDA's role in the COVID-19 pandemic response has necessitated an expansion and enhancement of Sentinel. Here we describe how the Sentinel System has supported FDA's response to the COVID-19 pandemic. We highlight new capabilities developed, key data generated to date, and lessons learned, particularly with respect to working with inpatient electronic health record data. Early in the pandemic, Sentinel developed a multi-pronged approach to support FDA's anticipated data and analytic needs. It incorporated new data sources, created a rapidly refreshed database, developed protocols to assess the natural history of COVID-19, validated a diagnosis-code based algorithm for identifying patients with COVID-19 in administrative claims data, and coordinated with other national and international initiatives. Sentinel is poised to answer important questions about the natural history of COVID-19 and is positioned to use this information to study the use, safety, and potentially the effectiveness of medical products used for COVID-19 prevention and treatment., (© 2021 John Wiley & Sons Ltd.)

The pharmaceutical industry is actively applying quantitative systems pharmacology (QSP) to make internal decisions and guide drug development. To facilitate the eventual development of a common framework for assessing the credibility of QSP models for clinical drug development, scientists from US Food and Drug Administration and the pharmaceutical industry organized a full-day virtual Scientific Exchange on July 1, 2020. An assessment form was used to ensure consistency in the evaluation process. Among the cases presented, QSP was applied to various therapeutic areas. Applications mostly focused on phase 2 dose selection. Model transparency, including details on expert knowledge and data used for model development, was identified as a major factor for robust model assessment. The case studies demonstrated some commonalities in the workflow of QSP model development, calibration, and validation but differ in the size, scope, and complexity of QSP models, in the acceptance criteria for model calibration and validation, and in the algorithms/approaches used for creating virtual patient populations. Though efforts are being made to build the credibility of QSP models and the confidence is increasing in applying QSP for internal decisions at the clinical stages of drug development, there are still many challenges facing QSP application to late stage drug development. The QSP community needs a strategic plan that includes the ability and flexibility to Adapt, to establish Common expectations for model Credibility needed to inform drug Labeling and patient care, and to AIM to achieve the goal (ACCLAIM).

The Food and Drug Administration's (FDA's) "Animal Rule" provides a unique regulatory pathway for drugs and biologics intended to treat serious or life-threatening conditions caused by exposure to lethal or permanently disabling chemical, biological, radiological, or nuclear agents when human efficacy studies are not ethical and field trials are not feasible. Human dose selection under the Animal Rule is based on integrating the totality of clinical pharmacology evidence collected in in vitro, animal, and human studies. This review discusses the necessary pharmacokinetic and pharmacodynamic information and methods for determining the effective human dose of antimicrobials under the Animal Rule and presents case studies illustrating the utility of a totality of evidence approach for different methods., (© 2021 The Authors Clinical Pharmacology & Therapeutics © 2021 American Society for Clinical Pharmacology and Therapeutics.)

The value of model-based translation in drug discovery and development is now effectively being recognized in many disease areas and among various stakeholders. Such quantitative approaches are expected to facilitate the selection on which compound to prioritize for successful development, predict the human efficacious dose based on preclinical data with adequate precision, guide design, and de-risk later development stages. The importance of time-dependencies, which are typically species-dependent due to different turnover rates of biological processes, is, however, often neglected. For bacterial infections, the choice of dosing regimen is typically relying on preclinical pharmacokinetic (PK) and pharmacodynamic (PD) data, because the bacterial load and disease severity, and consequently the PK/PD relationship, cannot be quantified well on clinical data, given the low-information end points used. It is time to recognize the limitations of using time-collapsed approaches for translation (i.e., methods where targets are based on summary measures of exposure and response). Models describing the full time-course captures important quantitative information of drug distribution, bacterial growth, antibiotic killing, and resistance development, and can account for species-differences in the PK profiles driving the killing. Furthermore, with a model-based approach for translation, we can take a holistic approach in development of a joint model for in vitro, in vivo, and clinical data, as well as incorporating information on the contribution of the immune system. Such advancements are anticipated to facilitate rational decision making during various stages of drug development and in the optimization of treatment regimens for different groups of patients., (© 2021 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Model-informed drug development (MIDD) has a long and rich history in infectious diseases. This review describes foundational principles of translational anti-infective pharmacology, including choice of appropriate measures of exposure and pharmacodynamic (PD) measures, patient subpopulations, and drug-drug interactions. Examples are presented for state-of-the-art, empiric, mechanistic, interdisciplinary, and real-world evidence MIDD applications in the development of antibacterials (review of minimum inhibitory concentration-based models, mechanism-based pharmacokinetic/PD (PK/PD) models, PK/PD models of resistance, and immune response), antifungals, antivirals, drugs for the treatment of global health infectious diseases, and medical countermeasures. The degree of adoption of MIDD practices across the infectious diseases field is also summarized. The future application of MIDD in infectious diseases will progress along two planes; "depth" and "breadth" of MIDD methods. "MIDD depth" refers to deeper incorporation of the specific pathogen biology and intrinsic and acquired-resistance mechanisms; host factors, such as immunologic response and infection site, to enable deeper interrogation of pharmacological impact on pathogen clearance; clinical outcome and emergence of resistance from a pathogen; and patient and population perspective. In particular, improved early assessment of the emergence of resistance potential will become a greater focus in MIDD, as this is poorly mitigated by current development approaches. "MIDD breadth" refers to greater adoption of model-centered approaches to anti-infective development. Specifically, this means how various MIDD approaches and translational tools can be integrated or connected in a systematic way that supports decision making by key stakeholders (sponsors, regulators, and payers) across the entire development pathway., (© 2021 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Most crises, though difficult and challenging to address, offer opportunities for change and for development of new perspectives or approaches to deal with traditional strategies. The reaction to and the managing of the COVID-19 pandemic has provided a platform for evaluating how we quantify disease prevalence, incidence, time courses and sequellae as well as how well we plan, design, analyze and interpret health care associated data, including clinical trials and electronic medical records and health claims data. Whether the Covid-19 crisis provides opportunities to advance the fields of biostatistics and epidemiology in select ways remains to be seen. This article describes three areas of crises experienced by the author during a career in the regulation of pharmaceutical products and how they were responded to. Some suggestions for potential future opportunities in reaction to the Covid-19 crises are provided., (Copyright © 2020. Published by Elsevier Inc.)

Importance: Clinical trial evidence used to support drug approval is typically the only information on benefits and harms that patients and clinicians can use for decision-making when novel cancer therapies become available. Various evaluations have raised concern about the uncertainty surrounding these data, and a systematic investigation of the available information on treatment outcomes for cancer drugs approved by the US Food and Drug Administration (FDA) is warranted., Objective: To describe the clinical trial data available on treatment outcomes at the time of FDA approval of all novel cancer drugs approved for the first time between 2000 and 2016., Design, Setting, and Participants: This comparative effectiveness study analyzed randomized clinical trials and single-arm clinical trials of novel drugs approved for the first time to treat any type of cancer. Approval packages were obtained from drugs@FDA, a publicly available database containing information on drug and biologic products approved for human use in the US. Data from January 2000 to December 2016 were included in this study., Main Outcomes and Measures: Regulatory and clinical trial characteristics were described. For randomized clinical trials, summary treatment outcomes for overall survival, progression-free survival, and tumor response across all therapies were calculated, and median absolute survival increases were estimated. Tumor types and regulatory characteristics were assessed separately., Results: Between 2000 and 2016, 92 novel cancer drugs were approved by the FDA for 100 indications based on data from 127 clinical trials. The 127 clinical trials included a median of 191 participants (interquartile range [IQR], 106-448 participants). Overall, 65 clinical trials (51.2%) were randomized, and 95 clinical trials (74.8%) were open label. Of 100 indications, 44 indications underwent accelerated approval, 42 indications were for hematological cancers, and 58 indications were for solid tumors. Novel drugs had mean hazard ratios of 0.77 (95% CI, 0.73-0.81; I2 = 46%) for overall survival and 0.52 (95% CI, 0.47-0.57; I2 = 88%) for progression-free survival. The median tumor response, expressed as relative risk, was 2.37 (95% CI, 2.00-2.80; I2 = 91%). The median absolute survival benefit was 2.40 months (IQR, 1.25-3.89 months)., Conclusions and Relevance: In this study, data available at the time of FDA drug approval indicated that novel cancer therapies were associated with substantial tumor responses but with prolonging median overall survival by only 2.40 months. Approval data from 17 years of clinical trials suggested that patients and clinicians typically had limited information available regarding the benefits of novel cancer treatments at market entry.

Background: Adverse drug reactions (ADRs) can occur any time someone uses a medication. ADRs are systematically tracked and cataloged, with varying degrees of success, in order to better understand their etiology and develop methods of prevention. The US Food and Drug Administration (FDA) has developed the FDA Adverse Event Reporting System (FAERS) for this purpose. FAERS collects information from myriad sources, but the primary reporters have traditionally been medical professionals and pharmacovigilance data from manufacturers. Recent studies suggest that information shared publicly on social media platforms related to medication use could be of benefit in complementing FAERS data in order to have a richer picture of how medications are actually being used and the experiences people are having across large populations., Objective: The aim of this study is to validate the accuracy and precision of social media methodology and conduct evaluations of Twitter ADR reporting for commonly used pharmaceutical agents., Methods: ADR data from the 10 most prescribed medications according to pharmacy claims data were collected from both FAERS and Twitter. In order to obtain data from FAERS, the SafeRx database, a curated collection of FAERS data, was used to collect data from March 1, 2016, to March 31, 2017. Twitter data were manually scraped during the same time period to extract similar data using an algorithm designed to minimize noise and false signals in social media data., Results: A total of 40,539 FAERS ADR reports were obtained via SafeRx and more than 40,000 tweets containing the drug names were obtained from Twitter's Advanced Search engine. While the FAERS data were specific to ADRs, the Twitter data were more limited. Only hydrocodone/acetaminophen, prednisone, amoxicillin, gabapentin, and metformin had a sufficient volume of ADR content for review and comparison. For metformin, diarrhea was the side effect that resulted in no difference between the two platforms (P=.30). For hydrocodone/acetaminophen, ineffectiveness as an ADR that resulted in no difference (P=.60). For gabapentin, there were no differences in terms of the ADRs ineffectiveness and fatigue (P=.15 and P=.67, respectively). For amoxicillin, hypersensitivity, nausea, and rash shared similar profiles between platforms (P=.35, P=.05, and P=.31, respectively)., Conclusions: FAERS and Twitter shared similarities in types of data reported and a few unique items to each data set as well. The use of Twitter as an ADR pharmacovigilance platform should continue to be studied as a unique and complementary source of information rather than a validation tool of existing ADR databases., (©Zeyun Zhou, Kyle Emerson Hultgren. Originally published in JMIR Public Health and Surveillance (http://publichealth.jmir.org), 30.09.2020.)

Purpose: Prior literature reviews have identified gaps in understanding of how postmarketing safety labeling changes and related FDA communications impact key clinical and behavioral outcomes. We conducted a review of newly published studies on this topic to determine what new evidence exists and to identify which gaps may still remain. We believe that this information can support FDA as it develops and implements future risk communication approaches., Methods: We searched PubMed and Embase for studies published between January 1, 2010, and August 7, 2017 that examined the impact of labeling changes or associated FDA safety-related communications. For each study, we extracted information on research design and findings for key clinical outcomes and behaviors. We also conducted a ROBINS-I review to identify potential for bias in the research design of each study., Results: We found that the estimated impacts of FDA labeling changes on several key outcomes-including adverse events-varied. Labeling changes also yielded unintended consequences on drug prescribing in some cases, despite low provider adherence. Finally, some studies we reviewed exhibited potential for bias due to confounding, among other factors., Conclusions: The new studies we reviewed contain many of the same limitations identified in previously published reviews. While there are several challenges to conducting this research there is substantial room for improvement in the quality of the evidence base. More information, particularly with respect to the types of populations and medications affected by labeling changes, is needed to support the development of more effective and targeted safety communications., (© 2020 John Wiley & Sons Ltd.)

The Psychopharmacologic Drug Advisory Committee (PDAC) is one of 33 advisory committees of the Food and Drug Administration (FDA). During committee meetings, an open public hearing takes place where speakers provide testimonies about the drug in question and are asked, not required, to disclose any conflicts of interests (COIs) before speaking. These speakers may present with COIs which include, but are not limited to, reimbursement for travel and lodging by the pharmaceutical company to attend the meeting; previous or current payments for consulting from the pharmaceutical company and compensation as a paid investigator in previously conducted clinical trials for the drug under review. Our study aimed to investigate the characteristics and COIs of public speakers at PDAC meetings of the FDA. We evaluated 145 public speakers at FDA committee meetings over a 10-year period. We found a total of 52 public speakers disclosed a COI with travel and lodging being the most prominent. Among these speakers, 82.4% provided a positive testimony regarding the psychiatric drug in question. Speakers who had the condition in question were not more likely to provide a positive statement than those who did not. Our results showed that disclosing a COI was associated with increased odds of public speakers providing a favourable testimony for the recommendation of psychiatric drugs. The implications of these findings are concerning since COIs have the potential to skew public speaker's testimonies and persuade committee members to recommend a drug through emotionally charged tactics., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: In recent years, metastatic castration-resistant prostate cancer (MCRPC) and studies related to MCRPC have drawn global attention. The main objective of this bibliometric study was to provide an overview of MCRPC, explore clusters and trends in research and investigate the future direction of MCRPC research., Methods: A total of 4089 publications published between 1979 and 2018 were retrieved from the Web of Science (WoS) Core Collection database. Different aspects of MCRPC research, including the countries/territories, institutions, journals, authors, research areas, funding agencies and author keywords, were analyzed., Results: The number of annual MCRPC publications increased rapidly after 2010. American researchers played a vital role in this increase, as they published the most publications. The most productive institution was Memorial Sloan Kettering Cancer Center. De Bono, JS (the United Kingdom [UK]) and Scher, HI (the United States of America [USA]) were the two most productive authors. The National Institutes of Health (NIH) funded the largest number of published papers. Analyses of keywords suggested that therapies (abiraterone, enzalutamide, etc.) would attract global attention after US Food and Drug Administration (FDA) approval., Conclusions: Developed countries, especially the USA, were the leading nations for MCRPC research because of their abundant funding and frequent international collaborations. Therapy was one of the most vital aspects of MCRPC research. Therapies targeting DNA repair or the androgen receptor (AR) signing pathway and new therapies especially prostate-specific membrane antigen (PSMA)-based radioligand therapy (RLT) would be the next focus of MCRPC research.

Up to 40% of patients with primary biliary cholangitis have an incomplete response to first-line treatment with ursodeoxycholic acid. Obeticholic acid was approved by the US Food and Drug Administration in 2016 as a second-line treatment for patients with primary biliary cholangitis who are unresponsive to ursodeoxycholic acid; however, approximately 50% of patients might need additional treatments to reach therapeutic goals. A considerable need exists for effective treatment options to prevent progression to liver transplantation or death in these patients. Drugs that might modulate immunological abnormalities in primary biliary cholangitis have been studied but their effectiveness varies. Budesonide, ciclosporin, and rituximab have shown potential in modifying the disease process. Bezafibrate, a pan-peroxisome proliferator-activated receptor agonist, has been shown to ameliorate deranged bile acid homoeostasis and attenuate raised concentrations of liver enzymes associated with primary biliary cholangitis. As the mechanisms underlying the pathogenesis and progression of primary biliary cholangitis are further clarified, specific targeted therapies are under development with promising early results. Various therapeutic target bile acid homeostasis, immune dysfunction, and fibrogenetic pathways are being studied. A better understanding of the biochemical and clinical effects of the therapies in development bear discussion, both to guide the discovery of new therapies and to inform clinicians so that rational treatment regimens can be tailored to patients once they become available., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

FDA has launched a Real World Evidence (RWE) Program for using real-world evidence (RWE) to help support new indications for already approved drugs or biologics and postapproval studies. The plan also includes stakeholder engagement efforts, demonstration projects, leadership activities, and development of guidance documents to assist developers interested in using real-world data (RWD) to develop RWE to support FDA regulatory decisions. This plan was mandated by the Cures Act passed in 2016. Over the 24-month period from passage of the law until FDA officially announced their program, FDA has gone to considerable efforts to educate the public about the benefits of RWE and encourage researchers to consider situations where RWE trials can generate useful information. Through a variety of stakeholder engagement projects, including publication of articles in medical journals, participation in public meetings, and development of initiatives, FDA has put more effort into preparing the medical community for its new emphasis on RWE than any other new policy that I can recall.

The Transplant Therapeutics Consortium (TTC), a public-private partnership (PPP) led by the Critical Path Institute (C-Path), recently published a whitepaper titled "The Importance of Drug Safety and Tolerability in the Development of New Immunosuppressive Therapy for Transplant Recipients" by Stegall et al in the American Journal of Transplantation. As staff members of the Food and Drug Administration's (FDA), Center for Drug Evaluation and Research (CDER), Office of New Drugs and Office of Translational Science, and the Oncology Center of Excellence, we would like to provide our perspective on the TTCs efforts and the whitepaper., (Published 2019. This article is a U.S. Government work and is in the public domain in the USA.)