Journal articles: 'Early phase studies'

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Catapano, Alberico L. "Pitavastatin – pharmacological profile from early phase studies." Atherosclerosis Supplements 11, no. 3 (December 2010): 3–7. http://dx.doi.org/10.1016/s1567-5688(10)71063-1.

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Ramkumar, Anupama. "Early phase studies in India: Are we too early to explore?" Indian Journal of Pharmacology 40, no. 5 (2008): 189. http://dx.doi.org/10.4103/0253-7613.44149.

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Sivasubramanian, Parijatham S., and Katherine D. Crew. "Biomarker Endpoints for Early-Phase Cancer-Prevention Studies." Current Breast Cancer Reports 5, no. 3 (June 15, 2013): 194–201. http://dx.doi.org/10.1007/s12609-013-0116-x.

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Gullapalli, Rampurna P., Carolyn L. Mazzitelli, Christina M. Charriez, David J. Carpenter, Rebecca D. Crean, Bobbie Carter, and Phil Perera. "Extemporaneous preparation strategy for early phase clinical studies." International Journal of Pharmaceutics 549, no. 1-2 (October 2018): 150–60. http://dx.doi.org/10.1016/j.ijpharm.2018.07.059.

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Hughes, George S. "Challenges in the Design of Phase I and Early Phase II Studies." Drug Information Journal 23, no. 4 (October 1989): 693–97. http://dx.doi.org/10.1177/009286158902300425.

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Zaks, T. Z., A. Akkari, L. Briley, M. Mosteler, A. G. Stead, K. M. Koch, C. Sampson, M. Ehm, E. Harris, and A. Roses. "Role of pharmacogenetic studies in early clinical development: Phase I studies with lapatinib." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 3029. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.3029.

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3029 Background: Rash and diarrhea are a class effect of ERBB1 inhibitors. These events are relatively mild with Lapatinib (a dual ERBB1/ERBB2 kinase inhibitor). Finding a genetic basis for patients who may be predisposed to these adverse events, from the outset of clinical development, may improve the understanding of the mechanisms of these side effects and may have implications for use and dosing. Methods: DNA was isolated from peripheral blood of 107 Caucasian subjects from eight monotherapy phase I studies including 73 healthy volunteers and 34 cancer patients, 100 of whom had associated pharmacokinetic data. 284 single nucleotide polymorphisms (SNPs) from five candidate genes of transporters (ABCB1, ABCG2) and enzymes (CYP 3A4 and 3A5, and 2C19) for which lapatinib is a substrate were genotyped and examined for associations with pharmacokinetic variables (dose-normalized AUC, Cmax, and Tmax) as well as rash (15 cases) and diarrhea (18 cases). Results: Skin rash and diarrhea in this phase I cohort were only mild, (i.e. grade I or II). Statistically significant associations were observed between 34 SNPs in CYP2C19, rash (22 SNPs) and diarrhea (6 SNPs), and between 15 SNPs in ABCB1 and Tmax. Notably, 3/3 subjects (2 healthy volunteers, one patient) homozygous for the CYP2C19*2 allele experienced both mild rash and diarrhea. Extensive linkage disequilibrium was observed among these associated SNPs. Conclusions: Our results suggest that it is possible to determine pharmacogenetic associations with side effect phenotypes during the earliest phase of clinical drug development. These results are currently being validated on a larger cohort of patients from phase II lapatinib clinical trials. [Table: see text]

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Morrissey, Malcolm. "RTSM (Randomization and Trial Supply Management) for Early Phase Studies." Open Clinical Trials Journal 3, no. 1 (November 18, 2011): 26–31. http://dx.doi.org/10.2174/1876821001103010026.

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Burström, Thommie, Jussi Harri, and Timothy L. Wilson. "Nascent Entrepreneurs Managing in Networks: Equivocality, Multiplexity and Tie Formation." Journal of Enterprising Culture 26, no. 01 (March 2018): 51–83. http://dx.doi.org/10.1142/s0218495818500036.

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This paper studies the dynamics of network development in early phases of venture development. Seven ventures were studied through interviews and visualization techniques. An equivocal three-phase process was studied — conceptualization, early foundation and early establishment. This paper defines network equivocality, draw on multiplexity theory and contributes by fine-tuning the concept of tie formation. The paper presents a conceptual model where the dynamics behind network development in early phases of venture development is explained. It is proposed that each phase of development is divided by knowledge boundaries. As ventures mature, they pass knowledge boundaries, and this passage triggers network transformation. Thus, the roles of both nascent firms and of multiplex network contacts change, and consequently tie formation also change. Three distinct tie formations are identified; esoteric, enlarged and exoteric.

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Arato, Teruyo, Takashi Daimon, Yuji Heike, Ken Ishii, Kyogo Itho, Shinichi Kageyama, Yutaka Kawakami, et al. "2015 Guidance on cancer immunotherapy development in early‐phase clinical studies." Cancer Science 106, no. 12 (December 2015): 1761–71. http://dx.doi.org/10.1111/cas.12819.

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Kacprowska, Agata, and Jacek Jassem. "Hypofractionated radiotherapy for early breast cancer: Review of phase III studies." Reports of Practical Oncology & Radiotherapy 17, no. 2 (March 2012): 66–70. http://dx.doi.org/10.1016/j.rpor.2011.10.003.

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Patterson, Scott, Stephen Francis, Mick Ireson, Dawn Webber, and John Whitehead. "A NOVEL BAYESIAN DECISION PROCEDURE FOR EARLY-PHASE DOSE-FINDING STUDIES." Journal of Biopharmaceutical Statistics 9, no. 4 (January 11, 1999): 583–97. http://dx.doi.org/10.1081/bip-100101197.

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Marton, Matthew J., and Russell Weiner. "Practical Guidance for Implementing Predictive Biomarkers into Early Phase Clinical Studies." BioMed Research International 2013 (2013): 1–9. http://dx.doi.org/10.1155/2013/891391.

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The recent U.S. Food and Drug Administration (FDA) coapprovals of several therapeutic compounds and their companion diagnostic devices (FDA News Release, 2011, 2013) to identify patients who would benefit from treatment have led to considerable interest in incorporating predictive biomarkers in clinical studies. Yet, the translation of predictive biomarkers poses unique technical, logistic, and regulatory challenges that need to be addressed by a multidisciplinary team including discovery scientists, clinicians, biomarker experts, regulatory personnel, and assay developers. These issues can be placed into four broad categories: sample collection, assay validation, sample analysis, and regulatory requirements. In this paper, we provide a primer for drug development teams who are eager to implement a predictive patient segmentation marker into an early clinical trial in a way that facilitates subsequent development of a companion diagnostic. Using examples of nucleic acid-based assays, we briefly review common issues encountered when translating a biomarker to the clinic but focus primarily on key practical issues that should be considered by clinical teams when planning to use a biomarker to balance arms of a study or to determine eligibility for a clinical study.

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Tsay, Jonathan S., and Carolee J. Winstein. "Five Features to Look for in Early-Phase Clinical Intervention Studies." Neurorehabilitation and Neural Repair 35, no. 1 (November 26, 2020): 3–9. http://dx.doi.org/10.1177/1545968320975439.

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Neurorehabilitation relies on core principles of neuroplasticity to activate and engage latent neural connections, promote detour circuits, and reverse impairments. Clinical interventions incorporating these principles have been shown to promote recovery and demote compensation. However, many clinicians struggle to find interventions centered on these principles in our nascent, rapidly growing body of literature. Not to mention the immense pressure from regulatory bodies and organizational balance sheets that further discourage time-intensive recovery-promoting interventions, incentivizing clinicians to prioritize practical constraints over sound clinical decision making. Modern neurorehabilitation practices that result from these pressures favor strategies that encourage compensation over those that promote recovery. To narrow the gap between the busy clinician and the cutting-edge motor recovery literature, we distilled 5 features found in early-phase clinical intervention studies—ones that value the more enduring biological recovery processes over the more immediate compensatory remedies. Filtering emerging literature through this lens and routinely integrating promising research into daily practice can break down practical barriers for effective clinical translation and ultimately promote durable long-term outcomes. This perspective is meant to serve a new generation of mechanistically minded and caring clinicians, students, activists, and research trainees, who are poised to not only advance rehabilitation science, but also erect evidence-based policy changes to accelerate recovery-based stroke care.

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Shih, Weichung Joseph, Pamela A. Ohman-Strickland, and Yong Lin. "Analysis of pilot and early phase studies with small sample sizes." Statistics in Medicine 23, no. 12 (June 8, 2004): 1827–42. http://dx.doi.org/10.1002/sim.1807.

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ÖZKAN, Abuzer. "Ideal predictor studies." Journal of Experimental and Clinical Medicine 39, no. 2 (March 18, 2022): 595–96. http://dx.doi.org/10.52142/omujecm.39.2.64.

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We have read the article titled “Evaluation of Covid-19 cases that applied to the hospital at the first peak of the pandemic” prepared by Akdoğan et al. with great interest. Firstly, we thank authors for their research from Turkey that aims create an alternative diagnosis method by using some laboratory parameters in the early phase of COVID-19. Although the study resulted in negative results, these studies of academics from Turkey for humanity at a time when the whole world was affected by the pandemic are commendable. Secondly, we thank the authors and the editorial board for their courage in publishing this negative article that is informative and successful manuscript. As mentioned in an article published in nature, highlighting negative results will improve science. We also would like to mention a few important points about ideal predictor studies in the early phase of COVID-19.

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Akpinar, Erol, and Antônio Figueiredo Neto. "Experimental Conditions for the Stabilization of the Lyotropic Biaxial Nematic Mesophase." Crystals 9, no. 3 (March 19, 2019): 158. http://dx.doi.org/10.3390/cryst9030158.

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Nematic phases are some of the most common phases among the lyotropic liquid crystalline structures. They have been widely investigated during last decades. In early studies, two uniaxial nematic phases (discotic, ND, and calamitic, NC) were identified. After the discovery of the third one, named biaxial nematic phase (NB) in 1980, however, some controversies in the stability of biaxial nematic phases began and still continue in the literature. From the theoretical point of view, the existence of a biaxial nematic phase is well established. This review aims to bring information about the historical development of those phases considering the early studies and then summarize the recent studies on how to stabilize different nematic phases from the experimental conditions, especially, choosing the suitable constituents of lyotropic mixtures.

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Brown, Stan. "Clinical Antimicrobial Photodynamic Therapy: Phase II Studies in Chronic Wounds." Journal of the National Comprehensive Cancer Network 10, Suppl_2 (October 2012): S—80—S—83. http://dx.doi.org/10.6004/jnccn.2012.0182.

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Microbiologically based diseases continue to pose serious global health problems. Effective alternative treatments that are not susceptible to resistance are sorely needed, and the killing of photosensitized bacteria through photodynamic therapy (PDT) may ultimately emerge as such an option. In preclinical research and early in vivo studies, PDT has demonstrated the ability to kill an assortment of microorganisms. Antimicrobial PDT has the potential to accelerate wound healing and prevent clinical infection, particularly in patients with chronic leg ulcers. Larger trials are needed to confirm its early promise and suggest its ultimate role in caring for chronic wounds.

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Keshavan, Matcheri S., Gregor Berger, Robert B. Zipursky, Christos Pantelis, Stephen J. Wood, and Christos Pantelis. "Neurobiology of early psychosis." British Journal of Psychiatry 187, S48 (August 2005): s8—s18. http://dx.doi.org/10.1192/bjp.187.48.s8.

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BackgroundNeurobiological studies of the early course of psychoses, such as schizophrenia, allow investigation of pathophysiology without the confounds of illness chronicity and treatment.AimsTo review the recent literature on the biology of the early course of psychoses.MethodWe carried out a critical appraisal of the recent findings in the neurobiology of early psychoses, using structural, functional and neurochemical imaging techniques.ResultsBrain structural alterations are present early in the illness and may predate symptom onset. Some changes, notably those in frontal and temporal lobes, can progress during the early phases of the illness. Functional and neurochemical brain abnormalities can also be seen in the premorbid and the early phases of the illness. Some, although not all, changes can be trait-like whereas some others might progress during the early years.ConclusionsA better understanding of such changes, especially during the critical periods of the prodrome, around the transition to the psychotic phase and during the early phases of the illness is crucial for continued research into preventive intervention strategies.

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Ruhrmann, Stephan, Frauke Schultze-Lutter, Wolfgang Maier, and Joachim Klosterkötter. "Pharmacological intervention in the initial prodromal phase of psychosis." European Psychiatry 20, no. 1 (January 2005): 1–6. http://dx.doi.org/10.1016/j.eurpsy.2004.11.001.

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AbstractEarly identification and treatment of schizophrenia may alleviate the symptoms, delay the onset and improve the outcome of psychosis. Thus, detection of individuals at risk during the prodromal phase is an important task. Universal approaches to screen the general population or healthy subjects at risk have not proven possible to-date. However, clinical criteria for detecting ultra-high risk individuals have been developed for specialized settings, with their implementation in interventional studies. This article examines the rationale for early detection and intervention of psychosis, along with a review of some of the current studies. These target prevention using psychological and/or pharmacological intervention strategies have demonstrated promising results in high risk individuals. The German Research Network on Schizophrenia (GRNS) is conducting two multicenter early intervention studies; one with early psychological intervention in subjects who manifest early prodromal symptoms; with the second trial applying clinical management and pharmacological early intervention in subjects experiencing late prodromal symptoms (high risk subjects). Despite the promising results, many of the current studies have small sample sizes with study durations of a short period. The full benefits of early detection and intervention should be revealed once larger and longer studies are conducted.

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English, Brett A., Kelan Thomas, Jack Johnstone, Adam Bazih, Lev Gertsik, and Larry Ereshefsky. "Use of translational pharmacodynamic biomarkers in early-phase clinical studies for schizophrenia." Biomarkers in Medicine 8, no. 1 (January 2014): 29–49. http://dx.doi.org/10.2217/bmm.13.135.

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Araujo, Daniel V., Marc Oliva, Kecheng Li, Rouhi Fazelzad, Zhihui Amy Liu, and Lillian L. Siu. "Contemporary dose-escalation methods for early phase studies in the immunotherapeutics era." European Journal of Cancer 158 (November 2021): 85–98. http://dx.doi.org/10.1016/j.ejca.2021.09.016.

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Rissmann, Robert, Matthijs Moerland, and Martijn B. A. Doorn. "Blueprint for mechanistic, data‐rich early phase clinical pharmacology studies in dermatology." British Journal of Clinical Pharmacology 86, no. 6 (April 6, 2020): 1011–14. http://dx.doi.org/10.1111/bcp.14293.

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Karacalioglu, Ozgur, Seyfettin Ilgan, Nuri Arslan, and Mehmet Ozguven. "Uterine doughnut in early proliferating phase: Potential pitfall in gastrointestinal bleeding studies." Annals of Nuclear Medicine 17, no. 8 (December 2003): 685–87. http://dx.doi.org/10.1007/bf02984975.

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Markopoulos, C., D. M. Hyams, H. L. Gomez, M. Harries, S. Nakamura, T. Traina, and A. Katz. "Multigene assays in early breast cancer: Insights from recent phase 3 studies." European Journal of Surgical Oncology 46, no. 4 (April 2020): 656–66. http://dx.doi.org/10.1016/j.ejso.2019.10.019.

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Lempke, Landon, Abbis Jaffri, and Nicholas Erdman. "The Effects of Early Physical Activity Compared to Early Physical Rest on Concussion Symptoms." Journal of Sport Rehabilitation 28, no. 1 (January 1, 2019): 99–105. http://dx.doi.org/10.1123/jsr.2017-0217.

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Clinical Scenario: Currently, rest following concussion serves as the keystone of concussion treatment, but substantial evidence to support it is lacking. Recent literature suggests that early physical activity may be beneficial in reducing concussion symptoms which may influence clinical recovery time. Clinical Question: Does early physical activity decrease postconcussion symptoms compared to physical rest following concussion? Summary of Key Findings: A total of 5 articles were included that examined symptom duration changes at multiple time points. All 5 studies utilized follow-up time points compared to initial examination, but there was variance in the specific time points reported. Two studies employed control groups and compared strict or recommended rest to early activity or limited rest. Three studies were observational studies that directly compared baseline measurements to follow-up assessments. Clinical Bottom Line: Current evidence suggests that early physical activity in the acute phase following a concussion may decrease the time needed for symptom resolution compared to immediate rest. Strength of Recommendation: Using Centre for Evidence-Based Medicine 2011 level 3 evidence and higher, the results suggest that early physical activity during the acute phase of a concussion may decrease symptom duration; however, a lack of high-quality studies and inconsistent interventions are limitations to this recommendation.

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Hattan, David G. "In Utero Phase Carcinogenicity Testing." International Journal of Toxicology 17, no. 3 (April 1998): 337–53. http://dx.doi.org/10.1080/109158198226611.

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Early experimentation with transplacental exposure (1940s) demonstrated that expression of lung tumors in mice was enhanced when urethane was given during development in utero. In 1970, a U. S. Food and Drug Administration (FDA) expert panel on the safety evaluation of food additives and pesticides met and recommended that an in utero exposure phase be added to carcinogenicity testing (U.S. FDA, 1 971). An analysis was conducted of studies in the open scientific literature, in food additive studies available in FDA files and in studies performed by the National Institute of Environmental Health Sciences (NIEHS). While exposure to rodents during only the adult phase provided qualitatively similar results, early neonatal exposure typically provided slightly higher incidences of turnors, and decreased latency to turn or onset in certain scientific studies. In a series of studies recently performed by the NIEHS with three known animal carcinogens, neonatal or adult exposure produced similar tumors in similar tissues. The food additive saccharin, which shows bladder tumors, and eugenol reliably produced tumors only with neonatal exposure. Implieations for carcinogenicity testing of food additives are discussed in light of these experi-mental findings.

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Subramanian, Deejesh, Cintia V. Cruz, and Facundo Garcia-Bournissen. "Systematic Review of Early Phase Pediatric Clinical Pharmacology Trials." Journal of Pediatric Pharmacology and Therapeutics 27, no. 7 (September 1, 2022): 609–17. http://dx.doi.org/10.5863/1551-6776-27.7.609.

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OBJECTIVE Children have generally been excluded from early-stage clinical trials owing to safety concerns based in social expectations and not data. However, the repositioning of adult therapeutics for pediatric use and the increase in the development of therapies for pediatric only conditions require the participation of children in phase 1–2 trials. Therefore, the aim of this article is to systematically review the history and current state of early phase pediatric clinical pharmacology trials in order to understand safety concerns, trends, and challenges in pediatric trials. METHODS This review analyzed the nature of early phase pediatric clinical trials conducted for nononcology conditions through a systematic search that was performed for pediatric non-oncologic phase 1 or phase 1–2 drug and vaccine studies in MEDLINE. RESULTS The data show that the number of early phase pediatric clinical trials is still small relative to adults but has been on the rise in the past decade with relatively few serious adverse effects observed. CONCLUSIONS The widespread concerns about children's safety when they participate in early phase clinical trials seem disproportionate, based on our findings. The data confirm that these studies can be conducted safely, and that their results can contribute significantly to pediatric pharmacotherapy.

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Ntsoane, T. P., M. Topic, and R. Bucher. "Near-surface in vitro studies of plasma sprayed hydroxyapatite coatings." Powder Diffraction 26, no. 2 (June 2011): 138–43. http://dx.doi.org/10.1154/1.3583181.

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Coatings of plasma sprayed hydroxyapatite (HAp), incubated in simulated body fluid for periods varying from 1 to 56 days, were characterized using conventional laboratory X rays. Quantitative phase analysis, employing TOPAS software, showed an opposite trend in the two main phases of the coating, viz., HAp and tetracalcium phosphate (TTCP). The former increased within the first 7 days of incubation whilst the latter decreased during the same period; both phases stabilized with further incubation. The crystallinity of the coatings exhibited a trend similar to that of HAp i.e., an increase in the early stages of incubation stabilization with further incubation. Results of residual stress determined with Bruker’s D8 Discover and analyzed with LEPTOS software, showed both the normal stress tensor components, σ11 and σ22, to be tensile, relaxing significantly in the early stages of incubation before stabilizing with further incubation.

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A. Rahman, Sri Kartika, Ampuan Hj Brahim Ampuan Hj Tengah, and Rozaiman Makmun. "The Role of Education in the Development of Jawi in Brunei Darussalam." Journal of Al-Tamaddun 17, no. 2 (December 21, 2022): 13–24. http://dx.doi.org/10.22452/jat.vol17no2.2.

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This literary research aims to discuss the role of education in the history and development of the usage of the Jawi script in Brunei. This discussion is divided into six phases. The first phase is the use of Jawi in education after the arrival of Islam. The second phase is its use during the early development of education between 1914 and 1941. The third phase is during the Japanese occupation era from 1942 until 1945. The fourth phase is in the pre-independence era between 1943 and 1983. The fifth phase is in the Bilingual Education policy from 1984 until 2007, and the last phase is during the National Education System for the 21st Century Policy, from 2008 until today. The researcher discovered that the role and importance of Jawi in the field of education remain relevant, especially in preserving it as the heritage and identity of the Malay race.

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Spinosa, Daniel, Elizabeth Howell, D'Erryl Williams, Catherine Watson, Tomi F. Akinyemiju, and Rebecca A. Previs. "Ovarian cancer clinical trials: Study the studies to terminate the terminations." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): 6069. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.6069.

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6069 Background: Clinical trials safely expand the arsenal of treatments available to future patients while providing hope to current patients, particularly ovarian cancer patients who often have poor prognoses. Trial termination for lack of efficacy or unacceptable toxicity are consistent with the aim of protecting patients in the pursuit of knowledge, but those are not the only reasons trials terminate early. Understanding why some clinical trials do not achieve their stated goals may aid in the design of future trials. Methods: Data were gathered from clinical trials registered to ClinicalTrials.gov. Included trials were interventional (as opposed to observational), were closed between 2004 and 2019, enrolled ovarian cancer patients, had submitted results, and were open at one or more domestic sites. For each trial, data were captured regarding study completion, reason for non-completion (if applicable), sites, phase, sponsor (defined as the study initiator, not necessarily the funder), and intervention type. Results: A total of 313 trials were examined, of which 262 met inclusion criteria. Of the 262 evaluable trials, 189 (72%) were completed and 72 (27%) terminated early. The most common reasons for early termination were low accrual (27 trials, 38%), lack of efficacy (15 trials, 21%), or insufficient funding (9 trials, 13%). Five trials (7%) were terminated early due to toxicity. Early phase trials are less likely to complete enrollment, with 11 out of 16 (65%) phase 1 trials, 135 out of 180 (75%) phase 2 trials, and 15 out of 16 (94%) phase 3 trials completed. Trials initiated by an academic center were twice as likely to be terminated early (41/103, 40%) as those initiated by industry (16/80, 20%), with remaining trials initiated by consortia, NCI, or non-academic oncology practices. Terminated trials were open at an average of 11 sites (range 1-317), while completed trials were open at an average of 27 sites (range 1-632). Trials that had multiple types of interventions, for instance a drug and a procedure, had a 34% early termination rate which was higher than the rate for trials with any single type of intervention. Conclusions: More than one in four ovarian cancer clinical trials are terminated early, rarely due to treatment efficacy or tolerability. Trials terminated for reasons other than patient outcomes represent a misallocation of resources or a missed opportunity for innovation. Further research is needed to understand the circumstances that allow for clinical trial completion such that available resources maximize patient benefit.

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Vissers, Maurits F. J. M., Jules A. A. C. Heuberger, and Geert Jan Groeneveld. "Targeting for Success: Demonstrating Proof-of-Concept with Mechanistic Early Phase Clinical Pharmacology Studies for Disease-Modification in Neurodegenerative Disorders." International Journal of Molecular Sciences 22, no. 4 (February 5, 2021): 1615. http://dx.doi.org/10.3390/ijms22041615.

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The clinical failure rate for disease-modifying treatments (DMTs) that slow or stop disease progression has been nearly 100% for the major neurodegenerative disorders (NDDs), with many compounds failing in expensive and time-consuming phase 2 and 3 trials for lack of efficacy. Here, we critically review the use of pharmacological and mechanistic biomarkers in early phase clinical trials of DMTs in NDDs, and propose a roadmap for providing early proof-of-concept to increase R&D productivity in this field of high unmet medical need. A literature search was performed on published early phase clinical trials aimed at the evaluation of NDD DMT compounds using MESH terms in PubMed. Publications were selected that reported an early phase clinical trial with NDD DMT compounds between 2010 and November 2020. Attention was given to the reported use of pharmacodynamic (mechanistic and physiological response) biomarkers. A total of 121 early phase clinical trials were identified, of which 89 trials (74%) incorporated one or multiple pharmacodynamic biomarkers. However, only 65 trials (54%) used mechanistic (target occupancy or activation) biomarkers to demonstrate target engagement in humans. The most important categories of early phase mechanistic and response biomarkers are discussed and a roadmap for incorporation of a robust biomarker strategy for early phase NDD DMT clinical trials is proposed. As our understanding of NDDs is improving, there is a rise in potentially disease-modifying treatments being brought to the clinic. Further increasing the rational use of mechanistic biomarkers in early phase trials for these (targeted) therapies can increase R&D productivity with a quick win/fast fail approach in an area that has seen a nearly 100% failure rate to date.

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Normolle, Daniel, Mack T. Ruffin, and Dean Brenner. "Design of Early Validation Trials of Biomarkers." Cancer Informatics 1 (January 2005): 117693510500100. http://dx.doi.org/10.1177/117693510500100111.

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The design of early-phase studies of putative screening markers in clinical populations is discussed. Biological, epidemiological, statistical and computational issues all affect the design of early-phase studies of these markers, but there are frequently little or no data in hand to facilitate the design. Early-phase studies must be designed as part of a development program, considering the final use of the marker, directly informing the decision to made at the study's conclusion. Therefore, they should test for sensitivity and specificity that would be minimally acceptable to proceed to the next stage of development. Designing such trials requires explicit assumptions about prevalence and false positive and negative costs in the ultimate target population. Early discussion of these issues strengthens the development process, since enthusiasm for developing technologies is balanced by realism about the requirements of a valid population screen. Receiver operating characteristic (ROC) curves, which are useful descriptive tools, may be misleading when evaluating tests in low-prevalence populations, because they emphasize the relationship between specificity and sensitivity in the range of specificity likely to be too low to be useful in mass screening applications.

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McNulty, Kelly Lee, Kirsty Jayne Elliott-Sale, Eimear Dolan, Paul Alan Swinton, Paul Ansdell, Stuart Goodall, Kevin Thomas, and Kirsty Marie Hicks. "The Effects of Menstrual Cycle Phase on Exercise Performance in Eumenorrheic Women: A Systematic Review and Meta-Analysis." Sports Medicine 50, no. 10 (July 13, 2020): 1813–27. http://dx.doi.org/10.1007/s40279-020-01319-3.

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Abstract Background Concentrations of endogenous sex hormones fluctuate across the menstrual cycle (MC), which could have implications for exercise performance in women. At present, data are conflicting, with no consensus on whether exercise performance is affected by MC phase. Objective To determine the effects of the MC on exercise performance and provide evidence-based, practical, performance recommendations to eumenorrheic women. Methods This review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Four databases were searched for published experimental studies that investigated the effects of the MC on exercise performance, which included at least one outcome measure taken in two or more defined MC phases. All data were meta-analysed using multilevel models grounded in Bayesian principles. The initial meta-analysis pooled pairwise effect sizes comparing exercise performance during the early follicular phase with all other phases (late follicular, ovulation, early luteal, mid-luteal and late luteal) amalgamated. A more comprehensive analysis was then conducted, comparing exercise performance between all phases with direct and indirect pairwise effect sizes through a network meta-analysis. Results from the network meta-analysis were summarised by calculating the Surface Under the Cumulative Ranking curve (SUCRA). Study quality was assessed using a modified Downs and Black checklist and a strategy based on the recommendations of the Grading of Recommendations Assessment Development and Evaluation (GRADE) working group. Results Of the 78 included studies, data from 51 studies were eligible for inclusion in the initial pairwise meta-analysis. The three-level hierarchical model indicated a trivial effect for both endurance- and strength-based outcomes, with reduced exercise performance observed in the early follicular phase of the MC, based on the median pooled effect size (ES0.5 = − 0.06 [95% credible interval (CrI): − 0.16 to 0.04]). Seventy-three studies had enough data to be included in the network meta-analysis. The largest effect was identified between the early follicular and the late follicular phases of the MC (ES0.5 = − 0.14 [95% CrI: − 0.26 to − 0.03]). The lowest SUCRA value, which represents the likelihood that exercise performance is poor, or among the poorest, relative to other MC phases, was obtained for the early follicular phase (30%), with values for all other phases ranging between 53 and 55%. The quality of evidence for this review was classified as “low” (42%). Conclusion The results from this systematic review and meta-analysis indicate that exercise performance might be trivially reduced during the early follicular phase of the MC, compared to all other phases. Due to the trivial effect size, the large between-study variation and the number of poor-quality studies included in this review, general guidelines on exercise performance across the MC cannot be formed; rather, it is recommended that a personalised approach should be taken based on each individual's response to exercise performance across the MC.

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Davidson, Karina W., Jazmin N. Mogavero, and Alexander J. Rothman. "Using early phase studies to advance intervention research: The science of behavior change." Health Psychology 39, no. 9 (September 2020): 731–35. http://dx.doi.org/10.1037/hea0000897.

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Rieder, Michael, and Daniel Hawcutt. "Design and conduct of early phase drug studies in children: challenges and opportunities." British Journal of Clinical Pharmacology 82, no. 5 (August 8, 2016): 1308–14. http://dx.doi.org/10.1111/bcp.13058.

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Wang, Hua, Kylyana S. Larriviere, Kristen E. Keller, Kathleen A. Ware, Ted M. Burns, Mark A. Conaway, David Lacomis, et al. "R(+) pramipexole as a mitochondrially focused neuroprotectant: Initial early phase studies in ALS." Amyotrophic Lateral Sclerosis 9, no. 1 (January 2008): 50–58. http://dx.doi.org/10.1080/17482960701791234.

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Røseth⁎, I. "Lived experience in early phase of postpartum depression. A review of qualitative studies." Journal of Affective Disorders 107 (March 2008): S119. http://dx.doi.org/10.1016/j.jad.2007.12.138.

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Wages, N. A., M. R. Conaway, C. L. Slingluff, M. E. Williams, C. A. Portell, P. Hwu, and G. R. Petroni. "Recent developments in the implementation of novel designs for early-phase combination studies." Annals of Oncology 26, no. 5 (May 2015): 1036–37. http://dx.doi.org/10.1093/annonc/mdv075.

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Byrne, M. M. "Meta-analysis of early phase I1 studies with paroxetine in hospitalized depressed patients." Acta Psychiatrica Scandinavica 80, S350 (June 1989): 138–39. http://dx.doi.org/10.1111/j.1600-0447.1989.tb07194.x.

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Delisle, Richard G. "Welcome to the Twilight Zone: a forgotten early phase of human evolutionary studies." Endeavour 36, no. 2 (June 2012): 55–64. http://dx.doi.org/10.1016/j.endeavour.2011.12.003.

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Al Hadidi, Samer, and Carlos A. Ramos. "Level of Evidence for FDA Drug Approvals in Pivotal Clinical Trials of Hematological Malignancies." Blood 136, Supplement 1 (November 5, 2020): 6. http://dx.doi.org/10.1182/blood-2020-136330.

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BACKGROUND Clinical trials are integral to improve treatment outcomes for patients with hematological malignancies. Although early phase (I/II) clinical trials may provide evidence of clinical efficacy, the main goal for early phase trials is to assess safety signal. Results of phase III clinical trials provide the strongest evidence to support the use of new cancer medications. The Food and Drug Administration (FDA) is responsible to ensure appropriate control and supervision of pharmaceutical drugs. METHODS On the basis of publicly available study protocols and FDA reviews, the authors reviewed the level of evidence in 52 clinical trials supporting 49 drug approvals from 2016 to 2020. Data cut point was May 2020. These trials resulted in approval of medications to treat leukemia, non-Hodgkin lymphoma, Hodgkin lymphoma, myelodysplastic syndrome, myeloproliferative neoplasms and multiple myeloma. RESULTS A total of 52 clinical trials were assessed in the 5 years period. Phase III trials supported 61.5% while earlier phase trials supported 36.5% of subsequent FDA hematological malignancies approvals. The level of evidence to support FDA approvals improved with time with 50% of approvals in 2016 and 2017 supported by phase III clinical trials compared to 69% in 2019. Approvals were based on early phase trials in mantle cell lymphoma (100%), chronic myeloid leukemia (100%), diffuse large B cell lymphoma (100%), classic Hodgkin's lymphoma (67%) and acute myeloid leukemia (56%). Phase III trials enrolled 87% of the patients (14238 from16429 patients). Eighteen drug approvals (37% of all approvals) were based on 13% of the total number of patients in the studied period. CONCLUSIONS Level of evidence to support drug approvals in hematological malignancies was based on early phase trials in more than a third of the times. Although early phase studies are appropriate for safety signals, further clinical activity assessment should be done to support the use of new drugs to treat hematological malignancies. Previous successful early phase studies failed to show clinical activity in phase III studies. Despite the fact that use of new approved drugs based on early phase studies evidence may be needed, patients and healthcare providers should be aware of such possibility when using newly approved medications. Figure Disclosures Ramos: Novartis: Membership on an entity's Board of Directors or advisory committees; Tessa Therapeutics: Research Funding; Kuur Therapeutics: Research Funding.

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Oosthuyse, Tanja, Andrew N. Bosch, and Susan Jackson. "Effect of Menstrual Phase on the Acetate Correction Factor Used in Metabolic Tracer Studies." Canadian Journal of Applied Physiology 28, no. 6 (December 1, 2003): 818–30. http://dx.doi.org/10.1139/h03-061.

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The acetate correction factor is used to account for retention of carbon label in exchange reactions of the tricarboxylic acid cycle in studies estimating free fatty acid oxidation with carbon-labeled tracers. Previous evidence indicates that substrate utilisation and metabolic rate vary across the menstrual cycle, which may alter the correction factor. We therefore derived the acetate correction factor for each of three menstrual phases (early follicular [EF], late follicular [LF], and midluteal [ML] phase) from the fractional recovery of 13CO2 from a constant infusion of sodium-[1-13C]acetate during 90 min of submaximal exercise (60%[Formula: see text]) in sedentary eumenorrhoeic women. There was no difference in the correction factor between the EF and LF or the LF and ML phases, but the correction factor derived in the ML phase was significantly lower than in the EF phase (p < 0.05). Neither energy expenditure nor whole body substrate utilisation during exercise varied significantly between menstrual phases and therefore cannot explain the observed difference in the correction factor. The lower correction factor in the ML phase, compared to the EF phase, would result in only a small increase of ∼6% in the calculated plasma free fatty acid oxidation rate. Key words: carbon isotopes, women, ovarian hormones, exercise, substrate oxidation

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Levy, Donna Elise, Srikanta Banerjee, and Fred K. Tabung. "The association of adaptive early phase study design and late phase study results in oncology using clinicaltrials.gov data." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e14078-e14078. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e14078.

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e14078 Background: Traditional methods such as the 3+3 design developed in the 1940s continue to be used in the majority of early phase oncology studies. Researchers have found that the traditional methods identify the appropriate dose level only 30% of the time. Patients are also exposed to sub-therapeutic doses due to the conservative methods. With these limitations on traditional design options, innovative methods need to be developed, adopted and assessed. Methods: This quantitative study assessed the association of the design methods (adaptive versus traditional) used for early phase oncology studies (adaptive versus traditional) and the outcome of late stage clinical trials. Differences by cancer type and by drug classification were also assessed. A sample of studies for this analysis was extracted from the National Institute of Health Clinical registry and results database. The data used for the analysis was extracted by the Clinical Trials Transformation Initiative (CTTI) Aggregate Analysis of ClinicalTrials.gov (AACT). Results: When assessing study design and outcome, there were lower odds of a positive outcome when adaptive methods were used though this association was not statistically significant (OR [95% highest posterior density (HPD)]:0.66 [0.20, 1.21]). Among the different drug types, using adaptive compared to traditional methods was associated with significantly higher odds of a positive outcome for taxanes, OR: 2.75, 95% HPD: 1.01, 5.16) and other, OR: 3.23, 95% HPD: 1.58, 5.46) but no association among studies of monoclonal antibodies or protein kinase inhibitors. There were no significant associations between early phase study design and outcome in late phase studies by cancer type (lung, breast, other). Conclusions: While results associated with the use of adaptive methods were not significant, further research should be conducted using all completed oncology clinical trials in the database to more precisely determine the relationship between adaptive study design in early phase oncology studies and outcomes in late stage studies. In addition, improvements in traditional versus adaptive design capture in the ClinicalTrials.gov database needs to be considered.

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Settlage, Calvin F., Sandra Bemesderfer, Judith Rosenthal, Joseph Afterman, and Philip M. Spielman. "The Appeal Cycle in Early Mother-Child Interaction: Nature and Implications of a Finding from Developmental Research." Journal of the American Psychoanalytic Association 39, no. 4 (December 1991): 987–1014. http://dx.doi.org/10.1177/000306519103900406.

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The appeal cycle was observed and delineated through research on mother-child interaction during the second year of life. As a repeated, circumscribed unit of developmental interaction, it is conceived to be an agent of developmental process and psychic structure formation. The appeal cycle has four phases: the adaptational phase, the distress phase, the appeal phase, and the interactional phase. The progression from the adaptational into the distress and appeal phases evidences the child's separation anxiety and failure of self-regulation in response to the experimentally induced attenuation of the mother-child relationship. A successful interactional phase reestablishes the relationship, regulates and restores the child's emotional equilibrium, and enables a return to self-regulation and adaptation. Because the interaction reinforces the functions and structures being developed through identification with the mother, the interactional phase is conceived to be an instrumental event in the mediation of psychic structure formation. The appeal cycle is discussed in comparison with similar phenomena in earlier phases of development and with other studies addressing development during the first two years of life. Directions for future research are noted.

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Saggese, Matilde, Divyanshu Dua, Emily Simmons, Charlotte Lemech, and Hendrik-Tobias Arkenau. "Research biopsies in the context of early phase oncology studies: clinical and ethical considerations." Oncology Reviews 7, no. 1 (August 30, 2013): 5. http://dx.doi.org/10.4081/oncol.2013.e5.

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The Personalized Medicine approach in oncology is a direct result of an improved understanding of complex tumor biology and advances in diagnostic technologies. In recent years, there has been an increased demand for archival and fresh tumor analysis in early clinical trials to foster proof-of-concept biomarker development, to understand resistance mechanisms, and ultimately to assess biological response. Although phase I studies are aimed at defining drug safety, pharmacokinetics, and to recommend a phase II dose for further testing, there is now increasing evidence of mandatory tumor biopsies even at the earliest dose-finding stages of drug development. The increasing demand for fresh tumor biopsies adds to the complexity of novel phase I studies and results in different challenges, ranging from logistical support to ethical concerns. This paper investigates key issues, including patients’ perceptions of research biopsies, the need for accurate informed consent, and alternative strategies that may guide the drug development process.

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McCarthy, Caroline, Stefano Fedele, Christian Ottensmeier, and Richard J. Shaw. "Early-Phase Interventional Trials in Oral Cancer Prevention." Cancers 13, no. 15 (July 30, 2021): 3845. http://dx.doi.org/10.3390/cancers13153845.

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The increasing breadth of molecular targets, promise of immune-targeted therapies and repurposed agents have heightened interest in cancer prevention. While, to date, testing of oral cancer chemoprevention strategies has failed to deliver therapeutic agents for routine clinical practice, there remains an urgent need for further clinical research to overcome this hurdle. Patients at the greatest risk of disease stand to benefit the most from inclusion in clinical trials; therefore, there is a need to carefully define this population using validated clinical and molecular markers. Safety, tolerability and the efficacy of interventions is assessed through carefully selected endpoints. These endpoints may include pharmacodynamic, clinical, histological and on-target molecular modifications as an individual or as a composite endpoint. Early-phase trials provide an area of opportunity to explore novel and repurposed agents in the setting of oral cancer chemoprevention, eventually leading to phase III trials with clinical endpoints such as transformation and clinical outcome; these studies are large, lengthy and expensive and should be reserved for the most promising of agents. This paper will explore current evidence in oral cancer chemoprevention, drug repurposing, selection of appropriate endpoints for early-phase trials and novel therapeutic angles in oral cancer chemoprevention.

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Metz, John T., Malcolm D. Cooper, Terry F. Brown, Leann H. Kinnunen, and Declan J. Cooper. "Neuroimaging in Drug Discovery and Development: Paradigms for Accelerating New Drug Availability." Journal of Pharmacy Practice 14, no. 5 (October 2001): 407–15. http://dx.doi.org/10.1106/bx9p-gcm4-gtef-jghn.

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The process of discovering and developing new drugs is complicated. Neuroimaging methods can facilitate this process. An analysis of the conceptual bases and practical limitations of different neuroimaging modalities reveals that each technique can best address different kinds of questions. Radioligand studies are well suited to preclinical and Phase II questions when a compound is known or suspected to affect well-understood mechanisms; they are also useful in Phase IV to characterize effective agents. Cerebral blood flow studies can be extremely useful in evaluating the effects of a drug on psychological tasks (mostly in Phase IV). Glucose metabolism studies can answer the simplest questions about whether a compound affects the brain, where, and how much. Such studies are most useful in confirming central effects (preclinical and early clinical phases), in determining effective dose ranges (Phase II), and in comparing different drugs (Phase IV).

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BARTLETT, A., M. BROWN, C. MARRIOTT, and P. J. WHITFIELD. "The infection of human skin by schistosome cercariae: studies using Franz cells." Parasitology 121, no. 1 (July 2000): 49–54. http://dx.doi.org/10.1017/s0031182099006034.

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Franz cells (2-chambered, air/fluid phase static diffusion devices, previously used for the study of drugs across viable human skin) are utilized for the first time to investigate the process of infection of human skin by Schistosoma mansoni cercariae. Skin obtained from cosmetic surgery sources was used in the Franz cells to describe the temporal dynamics of the early interaction of cercariae with skin. At 38 °C, about 50% of cercariae applied in water to the epidermal surface of the skin were irreversibly attached within 1 min and after 5 min about 85% were similarly irrecoverable. The technique also provides the means of following the early penetration path of cercariae by histological methods. Franz cell results on the dynamics of attachment/early penetration have been compared with those obtained using artificial skin equivalents and non-human mammalian skin models in the context of the physical and chemical differences between these systems and viable human skin. It is concluded that Franz cells provide a convenient system for directly investigating the early phases of S. mansoni cercariae interaction with human skin.

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Aykurt, Ayşegül, and Hayat Erkanal. "Archaeological Evidence for an Early Second Millennium BC Potter’s Kiln at Liman Tepe." Belleten 80, no. 287 (April 1, 2016): 1–22. http://dx.doi.org/10.37879/belleten.2016.1.

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This article will focus on a pottery kiln which is dated to the transition phase between the Early Bronze Age and the Middle Bronze Age in Liman Tepe. The kiln is not only important in terms of being one of the earliest examples on the Western Anatolian coast, but also for the local pottery sherds amongst its debris. They demonstrate the continuation of relationships with Central Anatolian cultures which began in the early periods. Very few centers in Western Anatolia have levels from the Early Bronze to Middle Bronze Age phase. This transition phase is being investigated in a comprehensive manner at Liman Tepe and this will provide an important contribution to understanding the region's chronology.

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Wajda, Justyna, Paulina Dumnicka, Małgorzata Maraj, Piotr Ceranowicz, Marek Kuźniewski, and Beata Kuśnierz-Cabala. "Potential Prognostic Markers of Acute Kidney Injury in the Early Phase of Acute Pancreatitis." International Journal of Molecular Sciences 20, no. 15 (July 30, 2019): 3714. http://dx.doi.org/10.3390/ijms20153714.

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Acute kidney injury (AKI) is a serious complication of acute pancreatitis (AP), which occurs in up to 70% of patients with severe AP and significantly increases the risk of mortality. At present, AKI is diagnosed based on dynamic increase in serum creatinine and decreased urine output; however, there is a need for earlier and more accurate biomarkers. The aim of the study was to review current evidence on the laboratory tests that were studied as the potential biomarkers of AKI in AP. We also briefly summarized the knowledge coming from the studies including sepsis or ICU patients since severe acute pancreatitis is associated with systemic inflammation and organ failure. Serum cystatin C and serum or urine NGAL have been shown to predict or diagnose AKI in AP; however, this evidence come from the single center studies of low number of patients. Other markers, such as urinary kidney injury molecule-1, cell cycle arrest biomarkers (tissue inhibitor metalloproteinase-2 and urine insulin-like growth factor-binding protein 7), interleukin-18, liver-type fatty acid-binding protein, or calprotectin have been studied in other populations suffering from systemic inflammatory states. In AP, the potential markers of AKI may be significantly influenced by either dehydration or inflammation, and the impact of these factors may be difficult to distinguish from kidney injury. The subject of AKI complicating AP is understudied. More studies are needed, for both exploratory (to choose the best markers) and clinical (to evaluate the diagnostic accuracy of the chosen markers in real clinical settings).

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Journal articles on the topic 'Early phase studies'

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