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International Journal of Radiation... Jan 2022Clinical trials are studies to test new treatments in humans. Typically, these treatments are evaluated over several phases to assess their safety and efficacy. Phase 1... (Review)
Review
Clinical trials are studies to test new treatments in humans. Typically, these treatments are evaluated over several phases to assess their safety and efficacy. Phase 1 trials are designed to evaluate the safety and tolerability of a new treatment, typically with a small number of patients (eg, 20-80), generally spread across several dose levels. Phase 2 trials are designed to determine whether the new treatment has sufficiently promising efficacy to warrant further investigation in a large-scale randomized phase 3 trial, as well as to further assess safety. These studies usually involve a few hundred patients. This article provides an overview of some of the most commonly used phase 2 designs for clinical trials and emphasizes their critical elements and considerations. Key references to some of the most commonly used phase 2 designs are given to allow the reader to explore in more detail the critical aspects when planning a phase 2 trial. A comparison of 3 potential designs in the context of the NRG-HN002 trial is presented to complement the discussion about phase 2 trials.
Topics: Clinical Trials, Phase II as Topic; Humans; Research Design
PubMed: 34363901
DOI: 10.1016/j.ijrobp.2021.07.1700 -
Postgraduate Medicine Sep 2011The recent focus of federal funding on comparative effectiveness research underscores the importance of clinical trials in the practice of evidence-based medicine and... (Review)
Review
The recent focus of federal funding on comparative effectiveness research underscores the importance of clinical trials in the practice of evidence-based medicine and health care reform. The impact of clinical trials not only extends to the individual patient by establishing a broader selection of effective therapies, but also to society as a whole by enhancing the value of health care provided. However, clinical trials also have the potential to pose unknown risks to their participants, and biased knowledge extracted from flawed clinical trials may lead to the inadvertent harm of patients. Although conducting a well-designed clinical trial may appear straightforward, it is founded on rigorous methodology and oversight governed by key ethical principles. In this review, we provide an overview of the ethical foundations of trial design, trial oversight, and the process of obtaining approval of a therapeutic, from its pre-clinical phase to post-marketing surveillance. This narrative review is based on a course in clinical trials developed by one of the authors (DJM), and is supplemented by a PubMed search predating January 2011 using the keywords "randomized controlled trial," "patient/clinical research," "ethics," "phase IV," "data and safety monitoring board," and "surrogate endpoint." With an understanding of the key principles in designing and implementing clinical trials, health care providers can partner with the pharmaceutical industry and regulatory bodies to effectively compare medical therapies and thereby meet one of the essential goals of health care reform.
Topics: Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Clinical Trials, Phase IV as Topic; Drug Evaluation; Humans; Randomized Controlled Trials as Topic; United States
PubMed: 21904102
DOI: 10.3810/pgm.2011.09.2475 -
Trends in Pharmacological Sciences Aug 2019Clinical trials consume the latter half of the 10 to 15 year, 1.5-2.0 billion USD, development cycle for bringing a single new drug to market. Hence, a failed trial... (Review)
Review
Clinical trials consume the latter half of the 10 to 15 year, 1.5-2.0 billion USD, development cycle for bringing a single new drug to market. Hence, a failed trial sinks not only the investment into the trial itself but also the preclinical development costs, rendering the loss per failed clinical trial at 800 million to 1.4 billion USD. Suboptimal patient cohort selection and recruiting techniques, paired with the inability to monitor patients effectively during trials, are two of the main causes for high trial failure rates: only one of 10 compounds entering a clinical trial reaches the market. We explain how recent advances in artificial intelligence (AI) can be used to reshape key steps of clinical trial design towards increasing trial success rates.
Topics: Artificial Intelligence; Clinical Protocols; Clinical Trials as Topic; Clinical Trials, Phase III as Topic; Drug Development; Humans; Patient Compliance; Patient Selection
PubMed: 31326235
DOI: 10.1016/j.tips.2019.05.005 -
Annals of Oncology : Official Journal... Jan 2023In 2021, the Food and Drug Administration Oncology Center of Excellence announced Project Optimus focusing on dose optimization for oncology drugs. The Methodology for... (Review)
Review
In 2021, the Food and Drug Administration Oncology Center of Excellence announced Project Optimus focusing on dose optimization for oncology drugs. The Methodology for the Development of Innovative Cancer Therapies (MDICT) Taskforce met to review and discuss the optimization of dosage for oncology trials and to develop a practical guide for oncology phase I trials. Defining a single recommended phase II dose based on toxicity may define doses that are neither the most effective nor the best tolerated. MDICT recommendations address the need for robust non-clinical data which are needed to inform trial design, as well as an expert team including statisticians and pharmacologists. The protocol must be flexible and adaptive, with clear definition of all endpoints. Health authorities should be consulted early and regularly. Strategies such as randomization, intrapatient dose escalation, and real-world eligibility criteria are encouraged whereas serial tumor sampling is discouraged in the absence of a strong rationale and appropriately validated assay. Endpoints should include consideration of all longitudinal toxicity. The phase I dose escalation trial should define the recommended dose range for later testing in randomized phase II trials, rather than a single recommended phase II dose, and consider scenarios where different populations may require different dosages. The adoption of these recommendations will improve dosage selection in early clinical trials of new anticancer treatments and ultimately, outcomes for patients.
Topics: Humans; Antineoplastic Agents; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Dose-Response Relationship, Drug; Medical Oncology; Neoplasms; Randomized Controlled Trials as Topic; Research Design; Therapies, Investigational
PubMed: 36182023
DOI: 10.1016/j.annonc.2022.09.158 -
Urologic Oncology May 2019Clinical trials organization can be daunting especially when orienting to a new system. The steps to a successful clinical trial are not concrete and vary based on the... (Review)
Review
BACKGROUND AND PURPOSE
Clinical trials organization can be daunting especially when orienting to a new system. The steps to a successful clinical trial are not concrete and vary based on the system.
METHODS
In this section the discussion centers on how to shape the question for the clinical trial which is rational and feasible to answer within the planned study design.
FINDINGS
Senior mentorship, collaboration and early involvement of stakeholders can help shape a successful clinical trial. Keeping in mind ethics and the processes within a system will make planning easier. Questions about key elements of the trial should be answered early to prevent delays of study initiation.
CONCLUSION
Clinical trial development and implementation can be very rewarding, but successful outcomes require careful planning and considerations.
Topics: Clinical Trials as Topic; Humans; Research Design
PubMed: 29395953
DOI: 10.1016/j.urolonc.2017.12.017 -
Journal of Parkinson's Disease 2022As the international community dealt with the ongoing COVID-19 pandemic, important progress continued to be made in the development of new drug-based therapies for the... (Review)
Review
BACKGROUND
As the international community dealt with the ongoing COVID-19 pandemic, important progress continued to be made in the development of new drug-based therapies for the neurodegenerative condition of Parkinson's disease (PD) in 2021. This progress included both "symptomatic treatments" (ST - improves/reduces symptoms of the condition) and "disease modifying treatments" (DMT - attempts to delay/slow progression by addressing the underlying biology of PD), which can be categorised further based on their mechanisms of action and class of drug.
OBJECTIVE
This report continues previous efforts to provide an overview of the pharmacological therapies - both ST and DMT - in clinical trials for PD during 2021- 2022, with the aim of creating greater awareness and involvement in the clinical trial process. We also hope to stimulate collaboration amongst all stakeholders, including industry, academia, advocacy organizations, and most importantly patient community.
METHODS
We conducted a review of clinical trials of drug therapies for PD using trial data obtained from the ClinicalTrials.gov and World Health Organisation (WHO) registries, and performed a breakdown analysis of studies that were active as of January 31st 2022. We also assessed active drug development projects that had completed one clinical phase but were yet to start the next.
RESULTS
There was a total of 147 clinical trials registered on the ClinicalTrials.gov website as active during the period of analysis. Of these trials, 91 (62%)were investigating STs, while 56 (38%)focused on DMTs. Approximately 1/3 of the studies (34.7%; 51 trials) were in Phase 1, while over half of the trials were in Phase 2 (50.3%; 74 trials). Only 15% (22 trials) of the studies were in Phase 3, of which only 3 trials were evaluating DMTs. Novel therapeutics (42%)were the most common type of agents being tested across all phases of testing, followed by repurposed agents (34%)and reformulations (20%).
CONCLUSION
Despite significant global health constraints, the development of new drug-based therapies for PD continued in 2021. Hopefully with a shift towards a post-pandemic world in which COVID-19 is better managed, we will see an increase in the number of clinical trials focused on drug development for PD. The need for more Phase 3 studies for DMTs remains acute.
Topics: COVID-19; Clinical Trials as Topic; Drug Development; Humans; Pandemics; Parkinson Disease
PubMed: 35527571
DOI: 10.3233/JPD-229002 -
Frontiers in Public Health 2022Decentralized clinical trials (DCTs) are studies in which the need for patients to physically access hospital-based trial sites is reduced or eliminated. The CoViD-19... (Review)
Review
Decentralized clinical trials (DCTs) are studies in which the need for patients to physically access hospital-based trial sites is reduced or eliminated. The CoViD-19 pandemic has caused a significant increase in DCT: a survey shows that 76% of pharmaceutical companies, device manufacturers, and Contract Research Organizations adopted decentralized techniques during the early phase of the pandemic. The implementation of DCTs relies on the use of digital tools such as e-consent, apps, wearable devices, Electronic Patient-Reported Outcomes (ePRO), telemedicine, as well as on moving trial activities to the patient's home (e.g., drug delivery) or to local healthcare settings (i.e., community-based diagnosis and care facilities). DCTs adapt to patients' routines, allow patients to participate regardless of where they live by removing logistical barriers, offer better access to the study and the investigational product, and permit the inclusion of more diverse and more representative populations. The feasibility and quality of DCTs depends on several requirements including dedicated infrastructures and staff, an adequate regulatory framework, and partnerships between research sites, patients and sponsors. The evaluation of Ethics Committees (ECs) is crucial to the process of innovating and digitalizing clinical trials: adequate assessment tools and a suitable regulatory framework are needed for evaluation by ECs. DCTs also raise issues, many of which are of considerable ethical significance. These include the implications for the relationship between patients and healthcare staff, for the social dimension of the patient, for data integrity (at the source, during transmission, in the analysis phase), for personal data protection, and for the possible risks to health and safety. Despite their considerable growth, DCTs have only received little attention from bioethicists. This paper offers a review on some ethical implications and requirements of DCTs in order to encourage further ethical reflection on this rapidly emerging field.
Topics: Humans; COVID-19; Delivery of Health Care; Pandemics; Telemedicine; Clinical Trials as Topic
PubMed: 36590004
DOI: 10.3389/fpubh.2022.1081150 -
Journal of the National Cancer Institute May 2009Phase I clinical trials are an essential step in the development of anticancer drugs. The main goal of these studies is to establish the recommended dose and/or schedule... (Review)
Review
Phase I clinical trials are an essential step in the development of anticancer drugs. The main goal of these studies is to establish the recommended dose and/or schedule of new drugs or drug combinations for phase II trials. The guiding principle for dose escalation in phase I trials is to avoid exposing too many patients to subtherapeutic doses while preserving safety and maintaining rapid accrual. Here we review dose escalation methods for phase I trials, including the rule-based and model-based dose escalation methods that have been developed to evaluate new anticancer agents. Toxicity has traditionally been the primary endpoint for phase I trials involving cytotoxic agents. However, with the emergence of molecularly targeted anticancer agents, potential alternative endpoints to delineate optimal biological activity, such as plasma drug concentration and target inhibition in tumor or surrogate tissues, have been proposed along with new trial designs. We also describe specific methods for drug combinations as well as methods that use a time-to-event endpoint or both toxicity and efficacy as endpoints. Finally, we present the advantages and drawbacks of the various dose escalation methods and discuss specific applications of the methods in developmental oncotherapeutics.
Topics: Antineoplastic Agents; Biomarkers, Tumor; Clinical Trials as Topic; Clinical Trials, Phase I as Topic; Combined Modality Therapy; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Approval; Drug Screening Assays, Antitumor; Humans; Medical Oncology; Neoplasms; Research Design; United States
PubMed: 19436029
DOI: 10.1093/jnci/djp079 -
The New England Journal of Medicine Jul 2016
Review
Topics: Biomarkers; Clinical Trials as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Government Regulation; Humans; Research Design; Sample Size
PubMed: 27406349
DOI: 10.1056/NEJMra1510061 -
Blood May 2011It is essential that there be consistency in the conduct, analysis, and reporting of clinical trial results in myeloma. The goal of the International Myeloma Workshop...
It is essential that there be consistency in the conduct, analysis, and reporting of clinical trial results in myeloma. The goal of the International Myeloma Workshop Consensus Panel 1 was to develop a set of guidelines for the uniform reporting of clinical trial results in myeloma. This paper provides a summary of the current response criteria in myeloma, detailed definitions for patient populations, lines of therapy, and specific endpoints. We propose that future clinical trials in myeloma follow the guidelines for reporting results proposed in this manuscript.
Topics: Clinical Trials as Topic; Clinical Trials, Phase III as Topic; Humans; Multiple Myeloma; Recurrence; Treatment Outcome
PubMed: 21292775
DOI: 10.1182/blood-2010-10-299487