The United States Senate passed the \"FDA Modernization Act 2.0.\" on September 29, 2022. Although the effectiveness of this Bill, which aims to eliminate the mandatory use of laboratory animals in new drug development, is limited, it represents a significant trend that will change the shape of drug applications in the United States and other countries. However, pharmaceutical companies have not taken major steps towards the complete elimination of animal testing from the standpoint of product safety, where they prioritize patient safety. Nonetheless, society is becoming increasingly opposed to animal testing, and efforts will be made to use fewer animals and conduct fewer animal tests as a natural and reasonable response. These changes eventually alter the shape of new drug applications. Based on the assumption that fewer animal tests will be conducted or fewer animals will be used in testing, this study explored bioinformatics and new technologies as alternatives to compensate for reduced information and provide a picture of how future new drug applications may look. The authors also discuss the directions that pharmaceutical companies and nonclinical contract research organizations should adopt to promote the replacement, reduction, and refinement of animals used in research, teaching, testing, and exhibitions.

Phage therapy, a century-long treatment targeting bacterial infection, was widely abandoned after the clinical availability of antibiotics in the mid-20th century. However, the crisis of antimicrobial resistance today led to its revival in many countries. While many articles dive into its clinical application now, little research is presenting phage therapy from a regulatory perspective. Here, we focus on the regulations of phage therapy by dividing sections into Eastern Europe where it was never abandoned and Western Europe, Australia, the United States, India, and China where it only re-attracted researchers\' attention in recent decades. New insights about its regulations in China are provided as little English literature has specifically discussed this previously. Ultimately, by introducing the regulations in phage therapy for human health across representative countries, we hope to provide ideas of how countries may borrow each other\'s adapting legislation in phage therapy to best overcome the current regulatory hurdles.

Due to rapid development of biotechnology in recent years, the field of regenerative medicine has attracted considerable attention. Regenerative medicine-related regulations have been established in several countries to ensure the quality, safety, and efficacy of innovative treatments. Considering the diversity of regenerative medicine, the regulatory framework in Taiwan has been adjusted in response to global trend and local demand. Before 2010, cell and gene therapies were regarded as \"new medical practice\" under the \"Medical Care Act.\" Along with the establishment of Taiwan Food and Drug Administration (TFDA) in 2010, regenerative medicine was regulated as \"medicinal products\" under the \"Pharmaceutical Affairs Act.\" Then, the Ministry of Health and Welfare (MOHW) established a new dual-track regulatory pathway for regenerative medicine in 2016. The dual-track pathway divided regenerative medicine into medical practices and medicinal products, aiming to improve the accessibility of new treatments to patients and maintain the flexibility for clinical operations. In order to refine the regulation, the MOHW proposed two draft Acts for regenerative medicine in 2022. The two draft Acts are currently under legislative process. It is expected that the research and development of regenerative medicine can be further accelerated, thus providing early access to innovative therapies for patients in the future.

Cancer progression and mortality remain challenging because of current obstacles and limitations in cancer treatment. Continuous efforts are being made to explore complementary and alternative approaches to alleviate the suffering of cancer patients. Epidemiological and nutritional studies have indicated that consuming botanical foods is linked to a lower risk of cancer incidence and/or improved cancer prognosis after diagnosis. From these observations, a variety of preclinical and clinical studies have been carried out to evaluate the potential of botanical food products as anticancer medicines. Unfortunately, many investigations have been poorly designed, and encouraging preclinical results have not been translated into clinical success. Botanical products contain a wide variety of chemicals, making them more difficult to study than traditional drugs. In this review, with the consideration of the regulatory framework of the USFDA, we share our collective experiences and lessons learned from 20 years of defining anticancer foods, focusing on the critical aspects of preclinical studies that are required for an IND application, as well as the checkpoints needed for early-phase clinical trials. We recommend a developmental pipeline that is based on mechanisms and clinical considerations.

Previous clinical trials indicate that 10%-25% of patients received genomically matched therapy after comprehensive genomic profiling (CGP) tests. However, the clinical utility of CGP tests has not been assessed in clinical practice. We assessed the clinical utility of CGP tests for advanced or metastatic solid tumor and determined the proportion of patients receiving genomically matched therapy among those with common and non-common cancers. From August 2019 to July 2020, a total of 418 patients had undergone CGP tests, and the results were discussed through the molecular tumor board at our site. The median age of patients was 57 (range: 3-86) years. Colorectal cancer was the most common, with 47 (11%) patients. Actionable genomic alterations (median 3, range: 1-17) were identified in 368 (88.0%) of 418 patients. Druggable genomic alterations were determined in 196 (46.9%) of 418 patients through the molecular tumor board. Genomically matched therapy was administered as the subsequent line of therapy in 51 (12.2%) patients, which is comparable to the proportion we previously reported in a clinical trial (13.4%) (p = 0.6919). The proportion of patients receiving genomically matched therapy was significantly higher among those with common cancers (16.2%) than non-common cancers (9.4%) (p = 0.0365). Genomically matched therapy after the CGP tests was administered to 12.2% of patients, which is similar to the proportion reported in the previous clinical trials. The clinical utility of CGP tests in patients with common cancers greatly exceeded that in patients with non-common cancers.

The mission of the Food and Drug Administration (FDA) is to ensure the safety and effectiveness of dermatologic drugs, as authorized by the Federal Food, Drug, and Cosmetic Act (FD&CA). In this article, we discuss how the FDA\'s policies and practices have continued to evolve to incorporate scientific advances and to facilitate approval for dermatologic drugs in a timely manner for a broad spectrum of patients. We provide several examples to highlight areas where the Division of Dermatology and Dentistry found common ground with stakeholders to increase the therapeutic options for dermatologic patients, while still maintaining regulatory standards required for approval.

Background: This article describes the development and validation of a bioanalytical assay to quantify CPI-613 and its major metabolites, CPI-2850 and CPI-1810, in human plasma matrix using LC-MS/MS. Methodology: Sample extraction procedure following protein precipitation with acetonitrile was optimized to extract all three analytes from plasma with maximum recovery. The final extracted supernatants were diluted with water and injected onto an Xbridge C18 (50 × 2.1 mm; 5 μm) column for analysis. The analytes were separated by a gradient elution, and detection was performed on a triple quadrupole mass spectrometer (Sciex API 5000) operating in the negative ion mode. Results: The assay was linear over a range of 50-50,000 ng/ml for CPI-613, 250-250,000 ng/ml for CPI-2850 and 10-10,000 ng/ml for CPI-1810. Benchtop stability was established for 24 h, and four freeze-thaw cycles were evaluated for CPI-613 and its metabolites. Long-term freezer (-60 to -80°C) stability for about 127 days was established in this validation. Mean matrix recovery was more than 80% for all analytes. Conclusion: A robust LC-MS/MS method was developed for the quantification of CPI-613 and its major metabolites. The current assay will be used to support ongoing and future CPI-613 clinical trials.
To achieve the pharmacokinetic objectives of clinical trials, it was necessary to determine the concentrations of CPI-613 and its metabolites in human plasma samples. In this article, the authors describe the development and validation of a highly sensitive and selective LC-MS/MS assay method for the simultaneous quantification of CPI-613 and its major metabolites, CPI-2850 and CPI-1810, in human plasma. Concentration ranges were selected based on previous data where CPI-613 was detected using the HPLC method (rather than LC-MS/MS).

Fluorine 18 (18F) fluorthanatrace (18F-FTT) is a PET radiotracer for imaging poly (adenosine diphosphate-ribose) polymerase-1 (PARP-1), an important target for a class of drugs known as PARP inhibitors, or PARPi. This article describes the stepwise development of this radiotracer from its design and preclinical evaluation to the first-in-human imaging studies and the initial validation of 18F-FTT as an imaging-based biomarker for measuring PARP-1 expression levels in patients with breast and ovarian cancer. A detailed discussion on the preparation and submission of an exploratory investigational new drug application to the Food and Drug Administration is also provided. Additionally, this review highlights the need and future plans for identifying a commercialization strategy to overcome the major financial barriers that exist when conducting the multicenter clinical trials needed for approval in the new drug application process. The goal of this article is to provide a road map that scientists and clinicians can follow for the successful clinical translation of a PET radiotracer developed in an academic setting. Keywords: Molecular Imaging-Cancer, PET, Breast, Genital/Reproductive, Chemistry, Radiotracer Development, PARPi, 18F-FTT, Investigational New Drug © RSNA, 2022.

CE credit: For CE credit, you can access the test for this article, as well as additional JNMT CE tests, online at https://www.snmmilearningcenter.org Complete the test online no later than March 2025. Your online test will be scored immediately. You may make 3 attempts to pass the test and must answer 75% of the questions correctly to receive Continuing Education Hour (CEH) credit. Credit amounts can be found in the SNMMI Learning Center Activity. SNMMI members will have their CEH credit added to their VOICE transcript automatically; nonmembers will be able to print out a CE certificate upon successfully completing the test. The online test is free to SNMMI members; nonmembers must pay $15.00 by credit card when logging onto the website to take the test.The radiopharmaceutical development and approval process in the United States has changed dramatically over the past decade with the emergence of several new and exciting diagnostic and therapeutic drugs. This impressive expansion is a direct result of the symbiotic relationship that exists between drug development, clinical research, and improved regulatory guidance. The correlative increase in clinical research has introduced diverse opportunities for newcomers in medical and scientific professions. Knowing how to successfully navigate the clinical research process can be challenging for a novice. The pathway is highly regulated and, with the addition of radiopharmaceuticals, may be confusing and daunting. Moreover, very little clinical research education and training is provided in the typical collegiate curricula for these new initiates. This article will familiarize the reader with the U.S. regulatory process by providing basic definitions and understanding of how and when radiopharmaceuticals can be used in clinical research, including those involving investigational new drug applications and radioactive drug research committees. A later article will expand the reader\'s clinical research knowledge by focusing on the identity and role of the institutional review board.

Preeclampsia remains a major cause of maternal and neonatal morbidity and mortality. Biologic plausibility, compelling preliminary data, and a pilot clinical trial support the safety and utility of pravastatin for the prevention of preeclampsia.
We previously reported the results of a phase I clinical trial using a low dose (10 mg) of pravastatin in high-risk pregnant women. Here, we report a follow-up, randomized trial of 20 mg pravastatin versus placebo among pregnant women with previous preeclampsia who required delivery before 34+6 weeks\' gestation with the objective of evaluating the safety and pharmacokinetic parameters of pravastatin.
This was a pilot, multicenter, blinded, placebo-controlled, randomized trial of women with singleton, nonanomalous pregnancies at high risk for preeclampsia. Women between 12+0 and 16+6 weeks of gestation were assigned to receive a daily pravastatin dose of 20 mg or placebo orally until delivery. In addition, steady-state pravastatin pharmacokinetic studies were conducted in the second and third trimesters of pregnancy and at 4 to 6 months postpartum. Primary outcomes included maternal-fetal safety and pharmacokinetic parameters of pravastatin during pregnancy. Secondary outcomes included maternal and umbilical cord blood chemistries and maternal and neonatal outcomes, including rates of preeclampsia and preterm delivery, gestational age at delivery, and birthweight.
Of note, 10 women assigned to receive pravastatin and 10 assigned to receive the placebo completed the trial. No significant differences were observed between the 2 groups in the rates of adverse or serious adverse events, congenital anomalies, or maternal and umbilical cord blood chemistries. Headache followed by heartburn and musculoskeletal pain were the most common side effects. We report the pravastatin pharmacokinetic parameters including pravastatin area under the curve (total drug exposure over a dosing interval), apparent oral clearance, half-life, and others during pregnancy and compare it with those values measured during the postpartum period. In the majority of the umbilical cord and maternal samples at the time of delivery, pravastatin concentrations were below the limit of quantification of the assay. The pregnancy and neonatal outcomes were more favorable in the pravastatin group. All newborns passed their brainstem auditory evoked response potential or similar hearing screening tests. The average maximum concentration and area under the curve values were more than 2-fold higher following a daily 20 mg dose compared with a 10 mg daily pravastatin dose, but the apparent oral clearance, half-life, and time to reach maximum concentration were similar, which is consistent with the previously reported linear, dose-independent pharmacokinetics of pravastatin in nonpregnant subjects.
This study confirmed the overall safety and favorable pregnancy outcomes for pravastatin in women at high risk for preeclampsia. This favorable risk-benefit analysis justifies a larger clinical trial to evaluate the efficacy of pravastatin for the prevention of preeclampsia. Until then, pravastatin use during pregnancy remains investigational.