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"Protocol Design"
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HTTP/2 in action
\"HTTP--Hypertext transfer protocol--is the standard for exchanging messages between websites and browsers. And after 20 years, it's gotten a much-needed upgrade. With support for streams, server push, header compression, and prioritization, HTTP/2 delivers vast improvements in speed, security, and efficiency. 'HTTP/2 in action' teaches you everything you need to know to use HTTP/2 effectively. You'll learn how to optimize web performance with new features like frames, multiplexing, and push. You'll also explore real-world examples on advanced topics like flow control and dependencies. With ready-to-implement tips and best practices, this practical guide is sure to get you, and your websites, up to speed\"--Provided by publisher.
Book
New Benchmarks on Protocol Amendment Experience in Oncology Clinical Trials
Background
The drug development industry’s focus on cancer-related treatments continues to rise, with narrow patient populations and complex procedures increasing the complexity of oncology protocols at an accelerated rate compared to non-oncology drugs. Tufts Center for the Study of Drug Development utilized data from a study investigating the impact of protocol amendments to compare how oncology clinical trials differ from non-oncology and identify opportunities to optimize performance in oncology clinical trials.
Methods
Sixteen drug development industry companies contributed data from 950 protocols and 2,188 amendments to a study conducted in 2022 investigating protocol amendments. Analysis compared differences in amendment impact and causes between 249 oncology and 701 non-oncology protocols.
Results
Compared to non-oncology, oncology protocols had a significantly higher prevalence (72.1% and 91.1%, respectively) and number (3.0 and 4.0, respectively) of protocol amendments. Oncology protocols with amendments had significantly lower participant completion rates compared to oncology protocols
without
amendments, while no significant differences were found among non-oncology. During the COVID-19 pandemic, the study found an increased number of substantial amendments, lower completion rates, and higher dropout rates among oncology protocols compared to before the pandemic.
Conclusions
Efforts to prevent avoidable protocol amendments in the industry have not been effective in oncology, where increasingly complex designs are reflected in difficult to predict cycle times, barriers to recruitment and retention and an increase in protocol amendments.
Journal Article
The Impact of Protocol Amendments on Clinical Trial Performance and Cost
Background:
Tufts Center for the Study of Drug Development (Tufts CSDD), in collaboration with 15 pharmaceutical companies and contract research organizations, gathered data on substantial global protocol amendments to better understand how to manage and to reduce the significant unplanned expense and delays associated with major changes to finalized protocol designs.
Methods:
Data from 836 phase I-IIB/IV protocols were analyzed to understand amendment prevalence. Impact assessments were based on data from 136 randomly selected amendments. Data from 52 protocols were analyzed to derive estimates of the direct cost to implement amendments.
Results:
Tufts CSDD found that 57% of protocols had at least one substantial amendment, and nearly half (45%) of these amendments were deemed “avoidable.” Phase II and III protocols had a mean number of 2.2 and 2.3 global amendments, respectively. Protocols with one or more global amendments tended to be larger in scope, with longer patient recruitment durations and overall study durations compared with those without a global amendment. Protocols with at least one substantial amendment had fewer actual screened and enrolled patients relative to the original baseline plan than did those protocols without an amendment. The median direct cost to implement a substantial amendment was US$141,000 for a phase II protocol and $535,000 for a phase III protocol.
Conclusions:
The study findings provide insights into optimizing development planning, protocol design, and clinical trial management practices.
Journal Article
Measuring the Incidence, Causes, and Repercussions of Protocol Amendments
Drug development companies frequently amend finalized clinical trial protocols. Yet the incidence, causes, and impact of protocol amendments have never been quantified. Tufts Center for the Study of Drug Development (Tufts CSDD) conducted a study, in collaboration with 17 large and midsized pharmaceutical and biotechnology companies, examining more than 3,400 clinical trial protocols across development phases and therapeutic areas. Data on protocol characteristics, the number of amendments, the nature and incidence of changes per amendment, the causes of amendments, and the time and cost to implement amendments were among those analyzed. Tufts CSDD found that more than 40% of protocols were amended prior to the first subject/first visit, and one third of amendments were avoidable. Each amended protocol had an average of 2.3 amendments resulting in 4 months of incremental time to implement. Protocol amendments translate into significant unplanned expense and delays for research sponsors and unexpected burden for investigative sites. These findings underscore the substantial impact of protocol amendments on drug development efficiency and present an opportunity to realize substantial cycle time and cost savings.
Journal Article
Underwater sensor networks: applications, advances and challenges
This paper examines the main approaches and challenges in the design and implementation of underwater wireless sensor networks. We summarize key applications and the main phenomena related to acoustic propagation, and discuss how they affect the design and operation of communication systems and networking protocols at various layers. We also provide an overview of communications hardware, testbeds and simulation tools available to the research community.
Journal Article
Public key versus symmetric key cryptography in client–server authentication protocols
Every month, several new protocols are popping up, comparing themselves with a few others and claiming to outperform the whole state of the art. The most popular domain of protocols is the one for authentication in a client–server architecture for which both symmetric key- and public key-based protocols are being proposed. The usage of public key-based mechanisms has several consequences, not only with respect to an increased computational and communication cost, but also with respect to increased possibilities to strengthen the protocol by making it resistant against a semi-trusted third party. On the other hand, we also recall that symmetric key-based protocols can already offer a nice set of security features. We see a trend in the current generation of papers published on public key-based client–server authentication protocols, showing that only a very limited amount of them really exploit the power that public key cryptography can offer with respect to this privacy towards a semi-trusted third party, and most of them do not even satisfy the same security features able to be also realised by a much more efficient symmetric key-based protocol. This paper serves as a warm wake-up call to all protocol designers to rethink the usage of more heavyweight constructions compared to symmetric key-based mechanisms in order to ensure that if they are used, they also fully exploit their inherent strength.
Journal Article
New Benchmarks on Protocol Amendment Practices, Trends and their Impact on Clinical Trial Performance
The Tufts Center for the Study of Drug Development (Tufts CSDD) conducted a follow-up study in 2022 to assess trends in protocol amendment experiences and the impact amendments have had on clinical trial performance, particularly during the COVID-19 pandemic. Sixteen pharmaceutical companies and contract research organizations provided data on 950 protocols and 2188 amendments. The results show that, since 2015, the prevalence of protocols with at least one amendment in phases I–IV has increased substantially (from 57 to 76%) and the mean number of amendments per protocol has increased 60% to 3.3, up from 2.1. Phase I and III protocols saw the highest increases in the mean number of amendments implemented per protocol. A much higher percentage of amendments—77%—were deemed unavoidable with regulatory agency requests and changes to the study strategy as the top reasons cited for amending a protocol. The total average duration to implement an amendment has nearly tripled during the past decade. The time from identifying the need-to-amend to last oversight approval now takes an average of 260 days and the mean duration during which investigative sites operate with different versions of the clinical trial protocol spans 215 days. Protocols that implemented at least one amendment were more effective at increasing patient screening volume and reducing the actual number of patients enrolled relative to plan. Lastly, the prevalence of protocols with at least one amendment and mean number of amendments was significantly higher for protocols conducted during the pandemic.
Journal Article
Protocol Design and Performance Benchmarks by Phase and by Oncology and Rare Disease Subgroups
Background
Benchmark data characterizing protocol design practices and performance informs clinical trial design decisions and serves as important baseline measures for assessing protocol design behaviors and their impact during and post-pandemic.
Methods
Tufts CSDD, in collaboration with a working group of 20 major and mid-sized pharmaceutical companies and CROs, gathered phase I–III data from protocols completed just prior to the start of the global pandemic.
Results
Data for 187 protocols were analyzed to derive benchmarks overall and for two primary subgroups: oncology vs. non-oncology protocols and rare disease vs. non-rare disease protocols. The results show a continuing upward trend across all protocol design variables. Phase II and III protocols average more endpoints, eligibility criteria, protocol pages; investigative sites; countries and datapoints collected. Oncology and rare disease protocols’ enrolled-to-completion rates are much lower, involve a much higher average number of countries and investigative sites, require more planned patient visits and generate considerably more clinical research data. As such, oncology and rare disease clinical trial cycle times are longer—most notably at time periods occurring after study startup and prior to database lock—due to intense patient recruitment and retention challenges.
Conclusions
The results of this study present valuable design insights and comparative baseline measures. The implications of these results and the expected impact of decentralized clinical trials on protocol design practices and performance is discussed.
Journal Article
Assessing Participation Burden in Clinical Trials: Introducing the Patient Friction Coefficient
Protocol design complexity, and associated study volunteer burden, negatively impact patient recruitment and retention as well as overall research and development productivity. Complex protocols reduce the willingness of potential clinical trial participants to enroll and reduce retention rates. There have been few systematic assessments of protocol design characteristics to determine the burden placed on study volunteers, although such an assessment would offer a compelling opportunity to optimize trial designs and improve recruitment and retention performance. To be useful, an assessment would need to be patient-centric, and focused on the factors that influence participation throughout the clinical trial. Such an assessment would also need to accommodate the unique cost-value trade-off compared with current treatment patterns that each participant makes when choosing to participate and remain in a clinical trial. This article proposes a new methodology to quantify patient burden: the clinical trial patient friction coefficient (PFC). A case example is provided to illustrate the utility of the PFC. A number of applications for the PFC are envisioned: standardizing patient burden assessment to evaluate clinical trial design feasibility, shedding light on the impact of patient burden on clinical trial economics and performance, and conducting sensitivity analyses to identify factors that most reduce patient burden and improve the performance and efficiency of clinical trials.
Journal Article
Time-varying formation control for high-order linear swarm systems with switching interaction topologies
Time-varying formation control problems for high-order linear time-invariant swarm systems with switching interaction topologies are investigated. A general formation control protocol is proposed firstly. Then using a consensus based approach, necessary and sufficient conditions for swarm systems with switching interaction topologies to achieve a given time-varying formation are presented. An explicit expression of the time-varying formation reference function is given. It is revealed that the switching interaction topologies have no effect on the formation reference function and the motion modes of the formation reference can be specified. Furthermore, necessary and sufficient conditions for formation feasibility are presented. An approach to expand the feasible formation set is given and an algorithm to design the protocol for swarm systems with switching interaction topologies to achieve time-varying formations is provided. Finally, numerical simulations are presented to demonstrate theoretical results.
Journal Article