Review
Ophthalmology
Leopold Schmetterer, Hendrik Scholl, Gerhard Garhoefer, Lucas Janeschitz-Kriegl, Federico Corvi, Srinivas R. Sadda, Felipe A. Medeiros
Summary: With the increasing number of interventional clinical trials in ophthalmology, novel targets and endpoints are being identified. Visual acuity, the gold standard endpoint for clinical trials, may not be sufficient for some indications, such as geographic atrophy and inherited retinal disease. Glaucoma drugs have been approved based on their ability to lower intraocular pressure (IOP), but recent findings suggest that not all drugs have the same effect on visual field progression at the same level of IOP reduction. Therefore, there is a need for novel surrogate endpoints in glaucoma trials. This article summarizes potential candidates for clinical endpoints in ophthalmology, with a focus on retinal disease and glaucoma, and evaluates their potential to serve as endpoints in pivotal trials.
PROGRESS IN RETINAL AND EYE RESEARCH
(2023)
Article
Urology & Nephrology
Hiddo J. L. Heerspink, Niels Jongs, Brendon L. Neuen, Patrick Schloemer, Muthiah Vaduganathan, Lesley A. Inker, Robert A. Fletcher, David C. Wheeler, George Bakris, Tom Greene, Glenn M. Chertow, Vlado Perkovic
Summary: The effects of newer kidney protective agents on smaller declines in eGFR have been assessed and found to be comparable to the effects on kidney failure or death due to kidney failure. This suggests that composite endpoints incorporating smaller declines in eGFR can reduce the required number of participants in clinical trials without compromising statistical power.
KIDNEY INTERNATIONAL
(2023)
Review
Clinical Neurology
Anna-Katharine Brem, Sajini Kuruppu, Casper de Boer, Marijn Muurling, Ana Diaz-Ponce, Dianne Gove, Jelena Curcic, Andrea Pilotto, Wan-Fai Ng, Nicholas Cummins, Kristina Malzbender, Vera J. M. Nies, Gul Erdemli, Johanna Graeber, Vaibhav A. Narayan, Lynn Rochester, Walter Maetzler, Dag Aarsland
Summary: Alzheimer's disease and other neurodegenerative diseases have significant impacts on daily activities and quality of life. Standard assessments lack sensitivity and digital technologies provide opportunities for reforming the evaluation of symptoms.
FRONTIERS IN NEUROLOGY
(2023)
Article
Medicine, General & Internal
Devan Mehrotra, Holly E. Janes, Thomas R. Fleming, Paula W. Annunziato, Kathleen M. Neuzil, Lindsay N. Carpp, David Benkeser, Elizabeth R. Brown, Marco Carone, Iksung Cho, Deborah Donnell, Michael P. Fay, Youyi Fong, Shu Han, Ian Hirsch, Ying Huang, Yunda Huang, Ollivier Hyrien, Michal Juraska, Alex Luedtke, Martha Nason, An Vandebosch, Honghong Zhou, Myron S. Cohen, Lawrence Corey, Jonathan Hartzel, Dean Follmann, Peter B. Gilbert
Summary: Several COVID-19 vaccine candidates are entering large-scale phase 3 clinical trials with proposed general clinical endpoint measures to facilitate evaluation and comparison. The potential shift towards more asymptomatic SARS-CoV-2 infections alongside vaccine protection against symptomatic COVID-19 is highlighted, along with its implications.
ANNALS OF INTERNAL MEDICINE
(2021)
Article
Mathematics, Interdisciplinary Applications
Michael R. Elliott
Summary: Surrogate markers are used in clinical trials for evaluating treatment effectiveness when obtaining final outcomes is time-consuming or costly. This review focuses on approaches using causal inference paradigm to define surrogate marker quality and efforts to evaluate the risk of surrogate paradox. Recent work in robust surrogate marker estimation is also discussed, with suggestions for future research.
ANNUAL REVIEW OF STATISTICS AND ITS APPLICATION
(2023)
Review
Geriatrics & Gerontology
James Mcdonald, Judith Sayers, Stefan D. Anker, Jann Arends, Trude Balstad, Vickie Baracos, Leo Brown, Asta Bye, Olav Dajani, Ross Dolan, Marie T. Fallon, Eilidh Fraser, Christine Griel, Aleksandra Grzyb, Marianne Hjermstad, Mariam Jamal-Hanjani, Gunnhild Jakobsen, Stein Kaasa, Donald Mcmillan, Matthew Maddocks, Iain Philips, Inger O. Ottestad, Kieran F. Reid, Mariana S. Sousa, Melanie R. Simpson, Ola Magne Vagnildhaug, Richard J. E. Skipworth, Tora S. Solheim, Barry J. A. Laird, Canc Cachexia Endpoints Working Grp
Summary: This systematic review assessed the frequency and diversity of physical function endpoints in cancer cachexia trials. The results showed that hand grip strength was the most commonly used physical function endpoint, while clinician assessments and patient-reported outcomes were also widely used. However, due to heterogeneity in study design, populations, intervention, and endpoint selection, there is currently no clear optimal endpoint and measurement method.
JOURNAL OF CACHEXIA SARCOPENIA AND MUSCLE
(2023)
Review
Gastroenterology & Hepatology
Benedicte Caron, Ferdinando D'Amico, Silvio Danese, Laurent Peyrin-Biroulet
Summary: This systematic review described the evolution of endpoints in randomized controlled trials of perianal Crohn's disease patients and observed significant changes in outcomes used in these trials, indicating the increasing use of radiological endpoints in studies of perianal fistulizing Crohn's disease.
JOURNAL OF CROHNS & COLITIS
(2021)
Review
Ophthalmology
Daniel Pauleikhoff, Laurenz Pauleikhoff, Emily Y. Chew
Summary: Macular Telangiectasia type 2 (MacTel) is a bilateral neurodegenerative disease associated with dysfunction in the serine and lipid metabolism, resulting in loss of Muller cells and photoreceptors. The analysis of the area of photoreceptor loss on en face OCT is the most reliable imaging endpoint for treatment trials in MacTel, showing a highly significant correlation with functional loss in microperimetry. This method is already being used in ongoing randomized trials to evaluate the efficacy of treatment.
Review
Oncology
James Isaacs, Aaron C. Tan, Brent A. Hanks, Xiaofei Wang, Kouros Owzar, James E. Herndon, Scott J. Antonia, Steven Piantadosi, Mustafa Khasraw
Summary: This article discusses the application of clinical trials in immuno-oncology, highlighting the importance of primary outcomes based on pharmacokinetic or pharmacodynamic immunologic mechanisms. It also explores the underutilization of these trials and showcases how new technologies and translational approaches can be effectively used in developing different types of immunotherapeutic agents.
CLINICAL CANCER RESEARCH
(2022)
Article
Mathematical & Computational Biology
H. M. James Hung, John Lawrence
Summary: Composite endpoints play an important role in cardiovascular and renal trials, but their use also brings challenges. For regulatory applications, defining proper estimands, handling intercurrent events, and interpreting trial results correctly are crucial. Key issues in component-specific analyses include dealing with dependent competing risk endpoints and conducting multiple endpoint testing. When developing treatments to relieve disease burden, considering all disease-related events is increasingly valued.
STATISTICS IN BIOPHARMACEUTICAL RESEARCH
(2023)
Review
Clinical Neurology
Mary M. Reilly, David N. Herrmann, Davide Pareyson, Steven S. Scherer, Richard S. Finkel, Stephan Zuechner, Joshua Burns, Michael E. Shy
Summary: Heritable neurological disorders provide insights into disease mechanisms, facilitating the development of novel therapeutic approaches. The challenges of measuring disease progression in rare and slowly progressive neurogenetic diseases are addressed through the development of clinical outcome assessments and disease biomarkers in inherited peripheral neuropathies. It is proposed that carefully developed biomarkers from imaging, plasma, or skin can predict meaningful progression in functional and patient-reported outcome assessments, enabling feasible clinical trials within a shorter duration for these rare and ultra-rare disorders.
ANNALS OF NEUROLOGY
(2023)
Article
Oncology
Alexander Fabian, Justus Domschikowski, Anne Letsch, Claudia Schmalz, Sandra Freitag-Wolf, Juergen Dunst, David Krug
Summary: The purpose of this study was to analyze the choice of primary endpoints in trials of palliative radiotherapy. The study found that patient-centered primary endpoints were relatively prevalent in published trials, but their use was still suboptimal. The use of patient-centered primary endpoints appeared to be lower in currently ongoing trials.
RADIOTHERAPY AND ONCOLOGY
(2022)
Article
Clinical Neurology
Alexandra Buehler, Marcel Wolbers, Fabian Model, Qing Wang, Shibeshih Belachew, Marianna Manfrini, Johannes Lorscheider, Ludwig Kappos, Jan Beyersmann
Summary: This study proposes a definition of recurrent disability progression events and compares the analysis of time-to-first-event and recurrent events. The results show that recurrent event analysis includes a larger number of progression events, leading to more accurate treatment effect estimates and increased statistical power.
MULTIPLE SCLEROSIS JOURNAL
(2023)
Review
Oncology
Ainhoa Madariaga, Rodrigo Sanchez-Bayona, Fernanda G. Herrera, Pedro T. Ramirez, Antonio Gonzalez Martin
Summary: Drug development plays a crucial role in improving outcomes for patients with gynecologic cancers. Clinical trials should measure whether new interventions result in clinically relevant improvements compared to standard care, using reproducible and appropriate endpoints. Overall survival and quality of life are the gold standards for measuring the benefits of new therapeutic strategies. Alternative endpoints, such as progression-free survival, provide early insights into the effects of new drugs but their correlation with overall survival or quality of life in gynecologic malignancies is unclear. Additionally, time-to-event endpoints like progression-free survival two and time to second subsequent treatment are valuable for assessing disease control in the longer term.
INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER
(2023)
Review
Neurosciences
Diane Stephenson, Reham Badawy, Soania Mathur, Maria Tome, Lynn Rochester
Summary: The burden of Parkinson's disease is increasing rapidly without objective biomarkers to measure disease progression; efforts to identify biomarkers have produced insights but robust disease progression biomarkers remain elusive; digital health technologies could complement traditional modalities in improving clinical research and therapeutic development.
JOURNAL OF PARKINSONS DISEASE
(2021)
Review
Gastroenterology & Hepatology
K. Gottlieb, V. Wacher, J. Sliman, M. Pimentel
ALIMENTARY PHARMACOLOGY & THERAPEUTICS
(2016)
Article
Gastroenterology & Hepatology
Michael A. Manfredi, Barham K. Abu Dayyeh, Yasser M. Bhat, Shailendra S. Chauhan, Klaus T. Gottlieb, Joo Ha Hwang, Sri Komanduri, Vani Konda, Simon K. Lo, John T. Maple, Faris M. Murad, Uzma D. Siddiqui, Michael B. Wallace, Subhas Banerjee
GASTROINTESTINAL ENDOSCOPY
(2015)
Review
Gastroenterology & Hepatology
Klaus Gottlieb, Simon Travis, Brian Feagan, Fez Hussain, William J. Sandborn, Paul Rutgeerts
INFLAMMATORY BOWEL DISEASES
(2015)
Article
Radiology, Nuclear Medicine & Medical Imaging
Klaus Gottlieb, Fez Hussain
BMC MEDICAL IMAGING
(2015)
Article
Medical Informatics
Klaus Gottlieb, J. Rick Turner, Barbara S. Gillespie, Fez Hussain
THERAPEUTIC INNOVATION & REGULATORY SCIENCE
(2015)
Article
Gastroenterology & Hepatology
Harris A. Ahmad, Klaus Gottlieb, Fez Hussain
GASTROENTEROLOGY REPORT
(2016)
Article
Gastroenterology & Hepatology
James D. Lewis, Lindsey Albenberg, Dale Lee, Mario Kratz, Klaus Gottlieb, Walter Reinisch
INFLAMMATORY BOWEL DISEASES
(2017)
Article
Gastroenterology & Hepatology
Klaus Gottlieb, Chenxiong Le, Vince Wacher, Joe Sliman, Christine Cruz, Tyler Porter, Stephen Carter
GASTROENTEROLOGY REPORT
(2017)
Article
Gastroenterology & Hepatology
Haihao Sun, Richard Vesely, Robert M. Nelson, Jan Taminiau, Peter Szitanyi, Maria Isaac, Agnes Klein, Shinobu Uzu, Donna Griebel, Andrew E. Mulberg
JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION
(2014)
Review
Gastroenterology & Hepatology
Walter Reinisch, Klaus Gottlieb, Jean-Frederic Colombel, Silvio Danese, Remo Panaccione, Julian Panes, Laurent Peyrin-Biroulet, David Rubin, Bruce E. Sands, Stefan Schreiber, Severine Vermeire, Andrew Mulberg, Bill Sandborn
CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
(2019)
Article
Medical Informatics
Russell Reeve, Klaus Gottlieb
THERAPEUTIC INNOVATION & REGULATORY SCIENCE
(2019)
Article
Medical Informatics
Russell Reeve, Klaus Gottlieb
THERAPEUTIC INNOVATION & REGULATORY SCIENCE
(2020)
Article
Gastroenterology & Hepatology
Klaus Gottlieb, Marco Daperno, Keith Usiskin, Bruce E. Sands, Harris Ahmad, Colin W. Howden, William Karnes, Young S. Oh, Irene Modesto, Colleen Marano, Ryan William Stidham, Walter Reinisch
Summary: Central reading is crucial in inflammatory bowel disease clinical trials, with room for improvements in various aspects. Experts propose a theoretical framework for enhancing statistical power, emphasizing the importance of factors like training, bowel preparation, and video quality.
Article
Gastroenterology & Hepatology
Klaus Gottlieb, James Requa, William Karnes, Ranga Chandra Gudivada, Jie Shen, Efren Rael, Vipin Arora, Tyler Dao, Andrew Ninh, James McGill
Summary: A deep learning algorithm was successfully trained to predict levels of UC severity from full-length endoscopy videos, with excellent agreement metrics compared to human central readers. Prospective data collection from a multinational clinical trial, use of videos instead of still images, and reporting of UCEIS and eMS all contributed to the success of the machine learning algorithm in predicting UC severity.