Type of submission Technical session(s) Keynotes session(s) Topic covered from the Call fo

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ASME会议投稿状态

ASME会议投稿状态

Author Status PageIn order to view your paper status, submit additional content, etc., you will need to log into your author account on the conference site. The page displayed after logging in, the Status page, is the platform where all paper information can be viewed or updated. The page is composed of two sections, Current Paper Status and Author Information, which are described below.Current Paper StatusThe Current Paper Status section displays paper information and status, and gives you, the contact author, the functionality to manage your technical submissions. Each paper number will be displayed on this page, along with the details of each paper.Paper numberPaper titleStatus/OptionsArea of interest (and topic if chosen)SessionConference organizer name (directly linked to their email address)Role of organizerSession schedule (when assigned)NOTE: The ability to show or hide area of interest, topic and session details can be controlled by choosing Show or Hide from the top portion of the page.The submission of your abstract initiates the process whereby your paper will flow through the online management system. The status of your paper will be listed in red under the Status/Options box. The various status statements are:●Abstract submitted: The abstract has been successfully submitted, and is awaitinginitial review from a conference organizer.●Abstract accepted: The abstract has been reviewed by the conference organizer andhas been accepted.●Abstract rejected: The abstract has been reviewed by the conference organizer andhas been rejected.●Draft paper received: The draft has been successfully submitted, and is awaitingreviewer assignment by a conference organizer.●Under review: The draft is under peer review.●Paper review completed: The peer review of the draft has been completed and thepaper is awaiting final determination of acceptance by a conference organizer.●Revision requested: After peer review, a revised version of your draft has beenrequested by a conference organizer.●Revised paper submitted: The revised draft has been successfully submitted and isawaiting final determination of acceptance by a conference organizer.●Draft paper accepted: The draft has been tentatively accepted for publication andpresentation, provided all publication requirements are submitted by the stated deadline. NOTE: Even if your draft is accepted without any required corrections you MUST still submit a final paper.●Draft paper rejected: The draft has been rejected for publication and presentation.●Paper withdrawn: The paper submitted has been withdrawn from the conference.●Final paper submitted: The final paper has been successfully submitted forpublication.As conference organizers manage your submissions through the tool, their decisions will enable the next function in the paper submittal process. The functions will be displayed under the Options box, as well as the top of the Status page. You will see the following links at different points during the conference cycle.●Update: Enables the author to update an abstract, paper type, paper title, presentingauthor biography and draft papers; final papers cannot be updated.●Submit Draft Paper: Enables the author to submit a draft paper.●Submit Final Paper: Enables the author to submit a final paper.●Submit Biography: Enables the author to submit a presenting author biography (fornon-published paper types).●Details: Enables the author to view paper details, including the technical area thepaper has been submitted to, organizer contact information, reviewer and organizer comments, and paper events.●Withdraw: Enables the author to withdraw the abstract/paper from the conference.●Re-instate: Enables the author to request their withdrawn abstract/paper to bere-instated.●Download Copyright Form: Enables the author download a copyright form in HTMLformat, pre-populated with paper and author information as entered from the author’s account.Author InformationThe Author Information section provides information on additional authors and the ability to manage them. Author information will be listed for each paper submitted. The following fields are shown.Paper NumberAuthor Name and RoleOptionsThe Options box will provide an author with the ability to manage their additional authors. The following functions are available.Update: Enables the author to update a co-author account.NOTE: If the co-author is a contact author for another paper or is an organizer you will not be able to update their information.Add: Enables the author to add an additional author.Delete: Enables the author to remove an author from the paper.Roles & Order: Enables the author to update author roles and order.。

SCI投稿过程经验分享-投稿状态

SCI投稿过程经验分享-投稿状态

SCI投稿过程经验分享-稿件状态投稿结束之后,要是文章格式没有问题且编辑觉得文章符合期刊范围,接下来就进入了漫长的等待。

急需文章的人不免会经常登录系统查看当前稿件状态,有些系统会把每一个状态更改都记录下来,非常详细,而有的期刊则长时间只显示一个“正在审稿”(under review)的状态。

下面放了一个期刊的审稿状态,并且翻译了一下。

Stage(状态)Start Date Manuscript Sent to Production(文章送去出版)21-Sep-2019 00:21:48 Manuscript Ready for Production(文章完成出版前的准备)20-Sep-2019 20:34:22 Decision Sent to Author(给作者发审稿结果)20-Sep-2019 20:34:22 Decision Letter Being Prepared(起草审稿结果)20-Sep-2019 17:37:50 Associate Editor Decision Completed(责任编辑完成审稿结果)20-Sep-2019 17:37:50 Associate Editor Decision Started(责任编辑起草审稿结果)17-Sep-2019 02:57:31 All Reviews Received(收到所有审稿结果)17-Sep-2019 02:57:31 Review Received(收到审稿结果)10-Sep-2019 06:02:53 All Reviewers Secured(所有审稿人都已确认)07-Sep-2019 02:38:33 Review Started(开始审稿)07-Sep-2019 02:38:33 First Reviewer Secured(确认第一个审稿人)07-Sep-2019 02:38:33 Potential Reviewer Agreed to Review(潜在的审稿人同意审稿)07-Sep-2019 02:38:33 Review Started(开始审稿)07-Sep-2019 01:58:08 Potential Reviewer Agreed to Review(潜在的审稿人同意审稿)07-Sep-2019 01:58:08 Potential Reviewer Invitation(s) Sent(给潜在的审稿人发送审稿邀07-Sep-2019 01:56:30请)Potential Reviewers Selected(确定潜在的审稿人)06-Sep-2019 22:56:42 Reviewer Assignment Started(开始寻找审稿人)02-Sep-2019 14:45:23 Securing Associate Editor(确认责任编辑)02-Sep-2019 14:45:23 Securing Editor(确认编辑)02-Sep-2019 14:45:23Submission Check by Editorial Office Completed(编辑完成检查稿02-Sep-2019 14:45:23件)Submission Check by Editorial Office Started(编辑开始检查稿件)02-Sep-2019 05:18:06 Securing Editor(确认编辑)02-Sep-2019 05:18:06 Manuscript Submitted to Editorial Office(编辑收到稿件)02-Sep-2019 05:18:05 Awaiting Author Adjustment/Approval of Converted Files01-Sep-2019 16:44:28(等待作者修正上次的文件)Submission Check by Editorial Office Failed(稿件发现有错误)01-Sep-2019 16:44:28 Submission Check by Editorial Office Started(编辑开始检查稿件)01-Sep-2019 08:08:51 Securing Editor(确认编辑)01-Sep-2019 08:08:51Manuscript Submitted to Editorial Office(编辑收到稿件)01-Sep-2019 08:08:50 Preliminary Manuscript Data Submitted (稿件完成提交)01-Sep-2019 06:17:55其他期刊的状态显示会有出入,但是大致都差不多。

去年英语四级作文submission

去年英语四级作文submission

去年英语四级作文submission全文共3篇示例,供读者参考篇1Submission for last year's English Cet-4 examLast year, I sat for the English Cet-4 exam, a standardized English proficiency test for college students in China. The exam consisted of four sections: listening, reading, writing, and translation. In this submission, I will reflect on my experience during the exam and share insights on how I prepared for each section.The listening section was challenging as it required a strong ability to understand spoken English at a fast pace. To prepare for this section, I practiced listening to various English-speaking podcasts and videos. I also took several mock exams to simulate the exam conditions. During the exam, I made sure to focus and concentrate on the audio materials to avoid missing any important information.The reading section tested my comprehension skills as well as my vocabulary and grammar knowledge. To prepare for this section, I read a variety of English texts such as newspaperarticles, academic journals, and literature. I also practiced skimming and scanning techniques to quickly extract information from the texts. During the exam, I carefully read each passage and paid attention to details to ensure accurate answers.The writing section required me to write an essay on a given topic within a limited time frame. To prepare for this section, I practiced writing essays on various topics and worked on improving my grammar and vocabulary. I also focused on structuring my essays properly with clear introduction, body, and conclusion. During the exam, I managed my time effectively and structured my essay logically to convey my ideas clearly.The translation section tested my ability to translate Chinese passages into English accurately. To prepare for this section, I practiced translating various types of texts such as news articles, essays, and literary works. I also focused on improving my vocabulary and understanding of idiomatic expressions in both languages. During the exam, I carefully read the passages and paid attention to nuances and context to provide accurate translations.Overall, the English Cet-4 exam was a challenging but rewarding experience. It helped me improve my Englishlanguage skills and test my proficiency in various areas. I learned the importance of practice, focus, and time management in achieving success in the exam. I will continue to work on improving my English skills and aim for better results in future exams.篇2Title: My Experience with Last Year's English CET-4 Writing SubmissionIntroduction:Last year, I took the English CET-4 exam, which is an important English proficiency test for college students in China. One of the key components of this exam is the writing section, where students are required to write an essay on a given topic. In this article, I will share my personal experience with last year's English CET-4 writing submission.My Preparation:In the weeks leading up to the exam, I devoted a significant amount of time to preparing for the writing section. I practiced writing essays on various topics, paying special attention to my grammar, vocabulary, and sentence structure. I also familiarized myself with common essay structures and techniques, such ashow to write a strong thesis statement and how to effectively support my arguments with examples and evidence.The Exam Day:On the day of the exam, I felt nervous but confident as I sat down to write my essay. The topic I was given was "The Impact of Social Media on Society", a topic that I had prepared for extensively. I quickly brainstormed my ideas and outlined my essay before diving into writing the actual essay.My Submission:I wrote a five-paragraph essay on the topic, starting with an introduction that provided an overview of the topic and my thesis statement. In the body paragraphs, I discussed the positive and negative impacts of social media on society, providing examples and evidence to support my arguments. Finally, I concluded the essay by summarizing my main points and restating my thesis statement.Reflection:Looking back on my writing submission, I feel proud of the essay that I wrote. I believe that I effectively articulated my ideas and supported my arguments with relevant examples and evidence. However, I also recognize areas where I can improve,such as expanding my vocabulary and refining my sentence structure.Conclusion:Overall, my experience with last year's English CET-4 writing submission was a valuable learning opportunity. It helped me to hone my writing skills and better understand how to effectively communicate my ideas in writing. I look forward to continuing to improve my English writing abilities and tackling future writing challenges with confidence.篇3Last year, I had the opportunity to take the English Proficiency Test for College Students, commonly known as the English 4th Level (CET-4) in China. This test is a mandatory requirement for all college students to graduate, as it demonstrates students' ability to communicate in English. The test consists of multiple-choice questions, cloze tests, reading comprehension, and a writing component, which requires candidates to write an essay on a given topic within a limited time frame.Preparing for the CET-4 exam was not an easy task. I spent months studying vocabulary, grammar, reading comprehensionskills, and writing strategies. I also practiced previous exam papers to familiarize myself with the test format and time constraints. Despite the challenges, the preparation process was rewarding as I could see my English skills improving with each practice session.On the day of the exam, I felt nervous but determined to do my best. The multiple-choice questions were tricky, but I managed to answer them by applying the strategies I had learned. The cloze tests and reading comprehension passages were challenging, but I focused on understanding the main ideas and key details to select the correct answers.The most daunting part of the exam was the writing section.I was given a topic about environmental protection and asked to write an essay in response. I brainstormed ideas, organized my thoughts, and wrote a coherent essay within the time limit. I felt relieved when I finished writing, knowing that I had put my best effort into it.After the exam, I felt a mix of emotions - relief that it was over, anxiety about the results, and pride in myself for completing the test. It was a long and challenging journey, but I was grateful for the experience as it had pushed me to improve my English skills and become a more confident English speaker.A few weeks later, the results were announced, and to my joy and relief, I had passed the CET-4 exam. It was a testament to my hard work and dedication to improving my English proficiency. I was proud of my achievement and grateful for the support and encouragement I had received from friends and teachers along the way.In conclusion, taking the CET-4 exam was a challenging but rewarding experience. It pushed me out of my comfort zone, improved my English skills, and boosted my confidence in using English as a second language. I am grateful for the opportunity to take the exam and prove to myself that with hard work and determination, I can achieve my goals.。

国际学术会议常用语(英语)

国际学术会议常用语(英语)

conference academic conference international conference symposiumannual meeting/symposium/conference forum, international forum workshopdates/important dates/key datestopic of interestslocation/venue conference location/venueissues/themes/(main)topics/scope of conferenceconference themes/topicstopic of interestscall for abstract/proposal/paper paper deadline deadline for abstract/full paper/proposal submissionsubmission deadlinedate for mortification of acceptanceinformed by…deadline for authors notificationdeadlinedeadline/closing date forregistration registration informationregistration fees and itemstelegraphic transfer onlydraft/checkdeadline extendedPaper acceptance/rejection will becamera ready version registration formofficial invitation letter bank transferpaymentbankconference schedule/program preliminary conference programfinal conference program opening ceremony/sessionkeynote session/parallel session/tutorial session keynote speechoral presentation poster presentation tea/coffee break(buffet) lunch/(buffet)supper (welcome)banquetopening introduction to speaker theme/paper presentationquestion and answer comment on speaker closing学术报告之后的问答讨论环节( Question and Answer Session )是同行之间交流的良好机会,双方可以针对报告中的具体问题进行探讨回答讨论环节可以让报告人通过互动及时地获得信息反馈并可以把在讨论中或得的建设性建议用于下一步的工作,因此对科研工作有很大的促进作用。

SCI期刊投稿各种状态显示对投稿...

SCI期刊投稿各种状态显示对投稿...

SCI期刊投稿各种状态显示对投稿...SCI 期刊投稿各种状态显示对投稿者来说是非常重要的,本文主要介绍了不同状态投稿者需要注意的事项。

1Submitted to Journal这是刚提交的状态。

一般的步骤是这样的:网上投稿Submit a manuscript:先到每个杂志的首页,打开submit paper 一栏,先以通讯作者的身份register 一个账号,然后以author login 身份登录,按照提示依次完成:Select Article Type、Enter Title、Add/Edit/Remove Authors、Submit Abstract、Enter Keywords、Select Classifications、Enter Comments、Request Editor、Attach Files,最后下载pdf,查看无误后,即可到投稿主页approve submission 或直接submit it。

总结:对于投稿之前和提交确认投稿过程,这里还需要对投稿新手强调以下几点。

因为这些小问题被编辑评个低印象分不划算,被打回也浪费了时间和精力。

一条条说来:大多数系统是要求word 投稿正文内容的,pdf 多不为接受格式。

但也有很少数要求用pdf 格式的,务必注意细看稿约。

文献格式是否按拟投杂志标准要求核准?有的投稿系统是可以直接检查的。

引用文献条数是否符合该杂志要求?有的杂志不特别要求,有的还是非常重视的。

如我之前投shock 杂志,编辑和一位审稿人都提到参考文献不要超过35 条。

如果你文章写完后,能够适当精简文献条数,那么,请删减几条吧。

?很多系统要求勾选同意一些如伦理道德的声明文件。

提交后可能会有一个小栏目提示对提交图片的质量做了初步审查(不合格的最好重新作图再上传)。

绝大多数投稿完成后需要view submission 和最后确认(approve submission)。

scs295-course-outline-semester-2-2015

scs295-course-outline-semester-2-2015

Course outlineCode: SCS295Title: Gender and CultureFaculty of Arts and BusinessSchool of Social SciencesTeaching Session: Semester 2Year: 2015Course Coordinator: Sonia TasconEmail: ***************.auTel: (07) 5456 52881. What is this course about?1.1 Course descriptionHow do we learn to become ‘proper’ women and ‘proper’ men? How does our understanding of sex, gender and sexuality impact on how we experience ourselves as men or women? This course introduces you to a sociological understanding of gender, by exploring the connections between gender, personal experience and social structures, and the changing social position of women and men in contemporary Australia. You are encouraged to examine issues related to gender such as stereotypes, media images of female and male bodies, health, sport and sexual ‘identity’ and sexual politics.1.2 Course content∙Defining gender and gender studies. Key terms and debates.∙Socio-historical context. History of gender issues. History of feminism.∙Understanding and theorising gender. Engaging with sociological perspectives and theories on gender. Engaging with multiple sociological perspectives.∙Exploring current global gender statistics and Australian based data.∙Gender across various life experiences, social arenas, and organisations (such as corporations and community organisations, states).∙Interaction of gender with other power hierarchies such as age and ethnicity.2. Unit value12 units4. Am I eligible to enrol in this course?Refer to the Coursework Programs and Awards - Academic Policy for definitions of “pre-requisites, co-requisites and anti-requisites”4.1 Enrolment restrictionsNil4.2 Pre-requisitesAny 2 courses or enrolled in AR505, AR605 or AR7074.3 Co-requisitesNil4.4 Anti-requisitesNil4.5 Specific assumed prior knowledge and skillsN/A5. How am I going to be assessed?5.1 Grading scaleStandard – High Distinction (HD), Distinction (DN), Credit (CR), Pass (PS), Fail (FL)Assessment Task 1: Take-home assignmentAssessment Task 2: In-class-group presentation analysing the impact of gender on men or women’s experiences in contemporary Australia and facilitated discussionAssessment Task 3: Major essay5.3 Additional assessment requirementsSafeAssignIn order to minimise incidents of plagiarism and collusion, this course may require that some of its assessment tasks are submitted electronically via SafeAssign. This software allows for text comparisons to be made between your submitted assessment item and all other work that SafeAssign has access to. If required, details of how to submit via SafeAssign will be provided on the Blackboard site of the course. Eligibility for Supplementary AssessmentYour eligibility for supplementary assessment in a course is dependent of the following conditions applying:a) The final mark is in the percentage range 47% to 49.4%b) The course is graded using the Standard Grading scalec) You have not failed an assessment task in the course due to academic misconduct5.4 Submission penaltiesLate submission of assessment tasks will be penalised at the following maximum rate: ∙5% (of the assessment task’s identified value) per day for the first two days from the date ident ified as the due date for the assessment task.∙10% (of the assessment task’s identified value) for the third day∙20% (of the assessment task’s identified value) for the fourth day and subsequent days up to and including seven days from the date identified as the due date for the assessment task.∙ A result of zero is awarded for an assessment task submitted after seven days from the date identified as the due date for the assessment task.Weekdays and weekends are included in the calculation of days late. To request an extension you must contact your course coordinator to negotiate an outcome.6. How is the course offered?6.1 Directed study hoursOn campus Lecture: 2 hours per weekOn campus Tutorial: 1 hour per week6.2 Teaching semester/session(s) offeredSemester 26.3 Course activities7. What resources do I need to undertake this course?7.1 Prescribed text(s)Building, Ground Floor, E Street.7.2 Required and recommended readingsLists of required and recommended readings may be found for this course on its Blackboard site. These materials/readings will assist you in preparing for tutorials and assignments, and will provide further information regarding particular aspects of your course.7.3 Specific requirementsN/A7.4 Risk managementThere is minimal health and safety risk in this course. It is your responsibility to familiarise yourself with the Health and Safety policies and procedures applicable within campus areas.8. How can I obtain help with my studies?In the first instance you should contact your tutor, then the Course Coordinator. Student Life and Learning provides additional assistance to all students through Peer Advisors and Academic Skills Advisors. You can drop in or book an appointment. To book: Tel: +61 7 5430 1226 or Email:******************************.au9. Links to relevant University policies and proceduresFor more information on Academic Learning & Teaching categories including:∙Assessment: Courses and Coursework Programs∙Review of Assessment and Final Grades∙Supplementary Assessment∙Administration of Central Examinations∙Deferred Examinations∙Student Academic Misconduct∙Students with a Disability.au/university/governance-and-executive/policies-and-procedures#academic-learning-and-teaching10. Faculty specific informationLocating Journal ArticlesIf you have been notified that the journal articles in this course are available on e-reserve, use the on-line library catalogue to find them. For journal articles not on e-reserve, click on the "Journals and Newspapers" link on the Library Homepage. Enter the journal title e.g. History Australia, then search for the volume and issue or keyword as needed.Assignment Cover SheetsThe Faculty of Arts and Business assignment cover sheet can be found on Blackboard or on the USC Portal at: Faculty of Arts and Business (Students) > Forms. It must be completed in full identifying student name, assignment topic, tutor and tutorial time. This must be attached securely to the front of each assessment item prior to submission. Claims of loss of assignments will not be considered unless supported by a receipt.Help: If you are experiencing problems with your studies or academic work, consult your tutor in the first instance or the Course Coordinator as quickly as possible.Difficulties: If you are experiencing difficulties relating to teaching and assessment you should approach your tutor in the first instance. If not satisfied after that you should approach in order your Course Coordinator, Program Coordinator then Head of School.General enquiries and student supportFaculty Student CentreTel: +61 7 5430 1259Fax: +61 7 5430 2859Email: ***************.au。

第2章 合同(Contract)【国际工程实务英语】

Chapterc2 合同Contract第一节建筑合同的种类Types of Construction Contract一、按计价机制分类的合同(Contracts according to Pricing Mechanism) (一)总价合同/ 包干合同/ 总包合同(Lump Sum Contract)承包商同意实施全部指定的工程,以获得一笔预先规定的总款项。

[kən'sent]The contractor consents to execute the entire specified work for a stated total sum.(二)成本补偿合同(Cost Reimbursement Contract)雇主承诺支付承包商主要成本/直接成本,也就是施工中使用到的实际人工费、设备费、材料费。

The client undertakes to pay the contractor the prime cost: that is, the actual cost of labor, plant and materials utilized in the execution of the works.除了直接成本外,承包商还被付有代替开办费和利润的一笔约定款额。

In addition to the prime cost, the contractor is paid an agreed sum to cover establishment charges and profit.(三)单价合同(Unit Price Contract)即使没有给出合同价,但由于双方就适用于该工程的费率达成一致,因此对于成本是有一定控制的。

There is some control over cost because the parties agree on the rates which will apply to the work even though there is no contract sum. (四)计量合同(Measurement Contract)在本合同协定下,工程的单价是可提前预算的,但总价只能到工程完工时估量、估价来确定。

班会流程记录英语作文(3篇)

第1篇Date: March 15, 2023Location: School AuditoriumTime: 2:00 PM - 4:00 PMAttendees: All students and faculty members of Class 10A---I. Introduction and Welcome (2:00 PM - 2:10 PM)- Speaker: The class president, Sarah Smith- Content:- Greetings to all attendees- Brief introduction of the agenda for the day- Reminder of the importance of class meetings and participationII. Approval of Minutes (2:10 PM - 2:15 PM)- Speaker: The class secretary, John Doe- Content:- Presentation of the minutes of the last class meeting held on February 15, 2023- Open floor for any corrections or additions- Approval of the minutes by majority voteIII. Reports from Class Representatives (2:15 PM - 2:45 PM)- Speaker: Sports Representative, Emily Johnson- Content:- Update on the upcoming school sports day- Details about the teams and training schedules- Invitation for interested students to join the teams- Speaker: Cultural Representative, Michael Lee- Content:- Announcement of the upcoming cultural week- Discussion of the events and activities planned- Call for volunteers to help organize and participate- Speaker: Academic Representative, Linda Chen- Content:- Report on the current academic performance of the class- Highlighting areas of improvement and challenges- Suggestions for study groups and additional resourcesIV. Open Forum (2:45 PM - 3:15 PM)- Moderator: The class teacher, Mr. William Brown- Content:- Open discussion for any student to raise concerns or suggestions- Topics covered included school facilities, extracurricular activities, and class policies- Students were encouraged to speak freely and respectfullyV. Special Guest Presentation (3:15 PM - 3:45 PM)- Speaker: Guest Speaker, Dr. Alice Wang- Content:- Talk on the importance of time management and stress relief- Interactive session on stress-busting techniques- Q&A session with the studentsVI. Group Activities (3:45 PM - 4:00 PM)- Activity: Group brainstorming session- Content:- Students were divided into small groups to discuss and propose ideas for a community service project- Each group presented their ideas to the class- Class vote to select the most feasible project---VII. Closing Remarks (4:00 PM - 4:05 PM)- Speaker: The class president, Sarah Smith- Content:- Summary of the key points discussed during the meeting- Appreciation for the participation and suggestions made- Reminder of the next class meeting date and timeVIII. Adjournment (4:05 PM - 4:10 PM)- The meeting was officially adjourned, and students were dismissed for the day.---This class meeting was a productive session that allowed for the exchange of ideas and the addressing of important issues within the class. The participation of all students was commendable, and the positive atmosphere contributed to a successful meeting.第2篇Date: [Date of the class meeting]Time: [Start time – End time]Location: [Location of the class meeting]Presided by: [Name of the class representative or teacher]Participants: [List of participants, including names and roles]I. Introduction and Opening RemarksThe class meeting was called to order at [start time] in the [location]. The class representative/teacher, [Name], welcomed all participants and briefly introduced the agenda for the meeting.II. Approval of Previous Meeting MinutesThe minutes of the previous class meeting were presented for approval. After a brief review, the class voted to approve the minutes as written.III. Reports from Sub-committeesA. Academic Committee ReportThe Academic Committee reported on the progress of ongoing projects and initiatives. [Name], the chair of the committee, highlighted thefollowing points:- Project Updates: The group is on track with the [specific project], which is expected to be completed by [deadline]. The committee isworking diligently to ensure that all tasks are completed on time.- Exam Schedule: The upcoming exams for the semester have been finalized. The dates and times will be posted on the class website and announced in the next class meeting.- Study Groups: The committee has organized study groups for students who are struggling with specific subjects. The schedules for thesegroups will be shared with the class.B. Social Committee ReportThe Social Committee reported on the upcoming events and activities. [Name], the chair of the committee, shared the following information:- Sports Day: The school will be hosting a Sports Day on [date].Students are encouraged to participate in various sports activities and showcase their talents.- Charity Drive: The committee is organizing a charity drive to supporta local community center. Students are invited to donate items such as clothing, toys, and food.- Movie Night: A movie night will be held on [date] in the school auditorium. The movie will be announced soon.C. Finance Committee ReportThe Finance Committee reported on the budget and expenses for the class. [Name], the chair of the committee, provided the following updates:- Budget Status: The current budget stands at [amount]. The committeehas allocated funds for various activities and initiatives.- Expenses: The committee has incurred expenses for [list of expenses]. The detailed expenses will be shared with the class.- Fundraising: The committee is exploring various fundraising opportunities to cover any shortfall in the budget.IV. Main Agenda ItemsA. Discussion on Upcoming Exam ScheduleThe class discussed the upcoming exam schedule and shared their concerns. The teacher provided guidance on how to prepare for the exams andoffered additional resources, such as tutoring sessions and review materials.B. Student Feedback on Class EnvironmentThe teacher invited students to share their feedback on the class environment. Several students expressed their concerns about noiselevels during breaks and suggested implementing a quiet hour during lunchtime.C. Announcement of Class ProjectsThe teacher announced the upcoming class projects and divided the students into groups. Each group was assigned a specific project and tasked with developing a plan to complete it.V. AdjournmentThe class meeting was adjourned at [end time]. The teacher thanked all participants for their contributions and encouraged them to stay engaged and supportive of each other throughout the semester.VI. Minutes ApprovalThe minutes of the class meeting were distributed to all participantsfor review and approval. The minutes will be finalized and shared with the class once any necessary revisions have been made.End of Minutes第3篇Date: [Insert Date]Time: [Insert Time]Location: [Insert Location]IntroductionThe class meeting was held on [Insert Date] at [Insert Time] in [Insert Location]. The purpose of the meeting was to discuss recent academic progress, upcoming events, and to address any concerns or questions that the students might have. The meeting was conducted in an orderly and constructive manner, ensuring that every voice was heard and every issue was addressed.Agenda1. Opening Remarks2. Academic Progress Report3. Upcoming Events4. Student Concerns and Questions5. Teacher’s Comments6. Conclusion and Announcements1. Opening RemarksThe class meeting commenced with a brief opening remarks by the class teacher, [Teacher’s Name]. He welcomed the student s and emphasized the importance of regular class meetings in fostering a sense of community and ensuring that everyone is on the same page regarding academic and extracurricular activities.2. Academic Progress Report[Teacher’s Name] then presented a comprehensive report on the academic progress of the class. He highlighted the strengths and weaknesses of each student and provided specific recommendations for improvement. The following points were covered:- Strengths: [List of students’ strengths]- W eaknesses: [List of students’ weaknesses]- Recommendations: [Detailed recommendations for improvement]The report was well-received by the students, and many expressed their gratitude for the personalized attention and guidance provided by the teacher.3. Upcoming EventsThe next item on the agenda was the announcement of upcoming events. [Teacher’s Name] discussed the following events:- Sports Day: [Date, Time, and Venue]- School Trip: [Date, Time, and Itinerary]- Science Fair: [Date, Time, and Venue]He encouraged students to participate actively in these events and reminded them of the importance of teamwork and collaboration.4. Student Concerns and QuestionsThis section of the meeting was dedicated to addressing the concerns and questions raised by the students. Several students came forward to share their concerns regarding:- Homework Assignments: [List of concerns]- Classroom Environment: [List of concerns]- Extracurricular Activities: [List of concerns][Teacher’s Name] and the class teacher [Co-Teacher’s Name] listened attentively to each student and provided appropriate responses and solutions. The following actions were decided upon:- Homework Assignments: [Detailed plan for addressing concerns]- Classroom Environment: [Detailed plan for addressing concerns]- Extracurricular Activities: [Detailed plan for addressing concerns]5. Teacher’s Comments[Teacher’s Name] then shared some general comments and feedback with the class. He commended the students for their hard work and dedication and encouraged them to continue striving for excellence. He also reminded the students of the importance of time management and self-discipline.6. Conclusion and AnnouncementsThe class meeting concluded with a summary of the key points discussed and the act ions that would be taken. [Teacher’s Name] reminded the students to stay focused and committed to their academic goals. He also announced the following:- Homework Assignment: [Details of the assignment]- Deadline for Submission: [Date and Time]- Next Class Meeting: [Date and Time]ConclusionThe class meeting was a productive and successful event that allowed students to voice their concerns, receive guidance, and be informed about upcoming events. The meeting fostered a sense of unity and collaboration among the students and reinforced the importance of academic and personal growth. The teachers were commended for their effective communication and commitment to the students’ well-being.。

FDA药物临床前指南-Guidance for Industry Unmarketed Investigational Drugs

Codevelopment of Two or More Unmarketed Investigational Drugs for Use in CombinationDRAFT GUIDANCEThis guidance document is being distributed for comment purposes only. Comments and suggestions regarding this draft document should be submitted within 60 days of publication in the Federal Register of the notice announcing the availability of the draft guidance. Submit comments to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All comments should be identified with the docket number listed in the notice of availability that publishes in the Federal Register.For questions regarding this draft document contact (CDER) Colleen Locicero 301-796-1114.U.S. Department of Health and Human ServicesFood and Drug AdministrationCenter for Drug Evaluation and Research (CDER)December 2010Clinical MedicalCodevelopment of Two or More Unmarketed Investigational Drugs for Use in CombinationAdditional copies are available from:Office of CommunicationsDivision of Drug Information, WO51, Room 220110903 New Hampshire Ave.Silver Spring, MD 20993Phone: 301-796-3400; Fax: 301-847-8714druginfo@/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htmU.S. Department of Health and Human ServicesFood and Drug AdministrationCenter for Drug Evaluation and Research (CDER)December 2010Clinical MedicalTable of Contents 1234 5 6 7 8 910111213141516171819202122 I.INTRODUCTION (1)II.BACKGROUND (2)III.DETERMINING WHETHER CODEVELOPMENT IS AN APPROPRIATEDEVELOPMENTOPTION (2)IV.NONCLINICAL CODEVELOPMENT (3)A.Demonstrating the Biological Rationale for the Combination (3)B.Nonclinical Safety Characterization (3)V.CLINICAL CODEVELOPMENT (4)A.Early Human Studies (Phase 1) (4)1.Safety of the Individual Components (4)2.Safety and Dosing of the Combination (5)B.Clinical Pharmacology (5)C.Proof of Concept Studies (Phase 2) (6)D. Confirmatory Studies (Phase 3) (8)VI.REGULATORY PROCESS ISSUES IN CODEVELOPMENT (8)A. Early Interaction with FDA (8)B. IND Submissions and Marketing Applications (9)beling Issues (9)D.Pharmacovigilance (9)232425262728Guidance for Industry1Codevelopment of Two or More Unmarketed Investigational Drugsfor Use in Combination2930 This draft guidance, when finalized, will represent the Food and Drug Administration’s (FDA’s) current31 thinking on this topic. It does not create or confer any rights for or on any person and does not operate to32 bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of33 the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA34 staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call35 the appropriate number listed on the title page of this guidance.36373839404142434445464748495051525354555657 I. INTRODUCTIONThis guidance is intended to assist sponsors in the codevelopment2 of two or more novel (not previously marketed) drugs to be used in combination to treat a disease or condition. The guidance provides recommendations and advice on how to address certain scientific and regulatory issues that will arise during codevelopment. It is not intended to apply to development of fixed-dose combinations of already marketed drugs or to development of a single new investigational drug to be used in combination with an approved drug or drugs. The guidance is also not intended to apply to vaccines, gene or cellular therapies, blood products, or medical devices.3FDA’s guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means that something is suggested or recommended, but not required.1 This guidance has been prepared by the Office of Medical Policy in the Center for Drug Evaluation and Research (CDER) at the Food and Drug Administration.2Codevelopment herein refers to the concurrent development of two or more drug products with the intent that the products be used in combination to treat a disease or condition.3 For purposes of this guidance, the term drug includes therapeutic biological products that are regulated by CDER. Consult the Therapeutic Biologics web page for further information on the types of biological products to which this guidance applies:/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/T herapeuticBiologicApplications/default.htmII. BACKGROUND585960616263646566676869707172737475767778798081828384858687888990919293949596979899 100 101 102 103 Combination therapy is an important treatment modality in many disease settings, including cancer, cardio-vascular disease, and infectious diseases. Recent scientific advances have increased our understanding of the pathophysiological processes that underlie these and other complex diseases. This increased understanding has provided further impetus for new therapeutic approaches using combinations of drugs directed at multiple therapeutic targets to improve treatment response or minimize development of resistance. In settings in which combination therapy provides significant therapeutic advantages, there is growing interest in the development of combinations of investigational drugs not previously developed for any purpose.Because the existing developmental and regulatory paradigm focuses primarily on assessment of the effectiveness and safety of a single new investigational drug acting alone, or in combination with an approved drug, FDA believes guidance is needed to assist sponsors in the codevelopment of two or more unmarketed drugs. Although interest in codevelopment has been most prominent in oncology and infectious disease settings, codevelopment also has potential application in other therapeutic settings. Therefore, this guidance is intended to describe a high-level, generally applicable approach to codevelopment of two or more unmarketed drugs. It describes the criteria for determining when codevelopment is an appropriate option, makes recommendations about nonclinical and clinical development strategies, and addresses certain regulatory process issues. III. DETERMININGWHETHERCODEVELOPMENT IS AN APPROPRIATE DEVELOPMENT OPTIONConcurrent development of two or more novel drugs for use in combination generally will provide less information about the safety and effectiveness of the individual drugs than would be obtained if the individual drugs were developed alone. How much less will vary depending on a variety of factors, including the stage of development at which the individual drug components cease to be studied independently. For example, in codevelopment scenarios in which rapid development of resistance to monotherapy is a major concern, it may not be possible or appropriate to obtain clinical data for the individual components of the combination beyond phase 1 testing. Because codevelopment will generally provide less information about the safety and effectiveness of the individual drugs, it will present greater risk compared to development of an individual drug. Therefore, FDA believes that codevelopment should ordinarily be reserved for situations that meet the following criteria:•The combination is intended to treat a serious disease or condition.•There is a compelling biological rationale for use of the combination (e.g., the agents inhibit distinct targets in the same molecular pathway, provide inhibition of both aprimary and compensatory pathway, or inhibit the same target at different binding sites to decrease resistance or allow use of lower doses to minimize toxicity).• A preclinical model (in vivo or in vitro) or short-term clinical study on an established biomarker suggests that the combination has substantial activity and provides greater thanadditive activity or a more durable response (e.g., delayed resistance) compared to the individual agents alone. 104105106107108109110111112113114115116117118119120121122123124125126127128129130131132133134135136137138139140141142143144145146 • There is a compelling reason for why the agents cannot be developed individually (e.g., monotherapy for the disease of interest leads to resistance and/or one or both of the agents would be expected to have very limited activity when used as monotherapy). FDA recommends that sponsors consult with FDA on the appropriateness of codevelopment before initiation of clinical development of the combination. IV. NONCLINICAL CODEVELOPMENT A. Demonstrating the Biological Rationale for the Combination The biology of the disease, pathogen, or tumor type should be sufficiently understood to provide a plausible biological rationale for the use of combination therapy to treat the disease or condition. For example, in an oncology setting the biological rationale may be to intervene at different steps in the cell proliferation pathway. The biological rationale for a combination anti-infective therapy may be to target different metabolic pathways or different steps in the replication cycle of the pathogen to reduce the chance of developing resistance to the therapy or increase efficacy in treating disease caused by resistant organisms (e.g., multidrug-resistant atypical tuberculosis). Sponsors should develop evidence to support the biological rationale for the combination in an in vivo (preferable) or in vitro model. The model should compare the activity of the combination to the activity of the individual components. Ordinarily, the model should demonstrate that, compared to the individual components, the combination has substantial activity and provides greater than additive activity or a more durable response in a pathophysiological process considered pertinent to the drug’s intended use in humans. An animal model of activity generally would not be necessary. However, if there is an animal model relevant to the human disease, valuable activity data, as well as information about the relative doses of the drugs, might be obtained from evaluating the combination in that model. B. Nonclinical Safety Characterization For detailed recommendations regarding nonclinical safety characterization for two or more investigational drugs to be used in combination, sponsors should consult the recently revised International Conference on Harmonisation (ICH) Guidance on Nonclinical Safety Studies.4 Section XVII of that guidance (Combination Drug Toxicity Testing) includes a discussion of nonclinical safety studies appropriate in a combination drug development setting involving two early stage entities. The ICH guidance defines early stage entities as compounds with limited clinical experience (i.e., phase 2 studies or less), so the discussion is specifically applicable to the4 Guidance for Industry: M3(R2) Nonclinical Safety Studies for the Conduct of Human Clinical Trials andMarketing Authorization, January 2010 (this guidance is a revision of 1997 ICH guidance M3: Nonclinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals).147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 type of development described in this guidance. In situations in which it is possible to obtain only limited clinical data for the individual drugs, additional nonclinical data for the individual drugs or combination may be needed before beginning human studies with the combination. (e.g., see section V.A.1).V. CLINICAL CODEVELOPMENTThis section provides a general roadmap and guiding principles for concurrent clinical development of two or more investigational drugs to be used in combination. It includes recommendations for characterizing the clinical safety and effectiveness of the combination and, to the extent needed or possible, the individual components of the combination.Note: The appropriate review division should always be consulted on the specifics of a given clinical development program.A. Early Human Studies (Phase 1)The main objectives of early studies in humans are to characterize the safety and pharmacokinetics of the individual components and then the combination and to provide data to support appropriate dosing for the combination in phase 2 testing.1. Safety of the Individual ComponentsWhenever possible, the safety profile of each individual drug should be characterized in phase 1 studies in healthy volunteers in the same manner as would be done fordevelopment of a single drug, including determination of the maximum tolerated dose(MTD), the nature of the dose limiting toxicity (DLT), and pharmacokinetic parameters.If there is a useful measure (e.g., biomarker) of pharmacologic activity, it will also beimportant to determine dose-response for that measure. If testing in healthy volunteers is not possible (e.g., if nonclinical data suggest a drug may be genotoxic or otherwiseunacceptable for studies in healthy volunteers), the safety profile of the individual drugs should be evaluated in patients with the disease of interest. These safety data will guide decisions in later studies about starting doses, dose escalation increments, and final dose selection.If it is not possible to characterize the safety of the individual drugs in humans (e.g.,where drug toxicity prevents use of healthy volunteers and monotherapy would beunethical in patients with the disease of interest), the sponsor should conduct nonclinical studies of the combination to support initial dosing of the combination in humans.The nonclinical data for the combination should include pharmacokinetic (absorption,distribution, metabolism, and excretion) and toxicokinetic data and appropriatebiomarker/target inhibition, if relevant.2. Safety and Dosing of the Combination 193194195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229 230 231 232 233 234 235 236 237For initial human effectiveness studies of the combination, the combination starting dose, dosing escalation intervals, and doses to be used in dose-response studies should bedetermined based on phase 1 safety data for the individual components, if available. Ifphase 1 safety data for the components are unavailable, nonclinical data for thecombination will be needed to determine the initial combination dose in humans (seeprevious paragraph). Phase 1 safety studies of the combination could also be conducted — for example, sequential testing in which subjects get drug A, then drug B, then AB — to support dosing in subsequent studies.B. ClinicalPharmacologyThe sponsor should conduct the same clinical pharmacology studies for each of the individual drugs in the combination as would be done if the drugs were being developed separately. In general, such studies include the assessment of bioavailability, characterization of pharmacokinetics, mass balance, the evaluation of effects of intrinsic (such as renal impairment and hepatic impairment) and extrinsic (such as food effect and drug interactions) factors on pharmacokinetics or pharmacodynamics, and exposure-response. Studies to address intrinsic and extrinsic factors could be conducted with the combination instead of the individual drugs.The evaluation of drug interaction potential follows the same sequence as in other development programs; results of in vitro drug metabolism and drug transporter studies inform the need for in vivo drug interaction studies. The role of pharmacogenomics should be investigated and incorporated into the combination drug development plan to identify potential sources of pharmacokinetic or pharmacodynamic variability.Dose-response should be evaluated for each drug of the combination. The results of such studies should be used to determine doses to further explore for the combination. If the drug products cannot be administered alone, various doses of each drug administered as the combination should be assessed.If one drug has no activity or minimal activity by itself, dose-response should be assessed when the drug products are administered in combination using a number of doses of the active drug and the inactive drug. The same approach should be used in evaluating dose-response for the combination of drugs where each drug has minimal activity when used alone.In addition to evaluating dose-response, response should be evaluated with respect to systemic drug concentration to provide insight into efficacy and safety as a function of drug exposure. Concentration-response assessments should be done in both phase 2 and phase 3 trials. To increase exposure ranges in phase 3 and to further assess dose-response, the incorporation of more than one dose of each of the drugs used in the combination in the phase 3 trials should be considered.C. Proof of Concept Studies (Phase 2) 238239240 241 242 243 244 245 246247 248 249 250 251 252 253 254 255 256 257 258 In general, phase 2 testing should accomplish the following to the extent needed for a given combination (e.g., to the extent not sufficiently established by existing data): •Demonstrate the contribution of each component of the combination to the extent possible and needed (given available nonclinical and pharmacologic data);•Provide evidence of the effectiveness of the combination; and•Optimize the dose or doses of the combination for phase 3 trials.The amount and types of clinical data needed and appropriate study designs will vary depending on the nature of the combination being developed, the disease, and other factors. For the types of combinations contemplated by this guidance, it will often be inappropriate to use monotherapy treatment arms in studies of the disease of interest, or it will be possible to administer the components of the combination as monotherapy only for short durations. In these circumstances, the study design typically employed to determine the contributions of the components to the combination — a four-arm factorial design comparing the combination to individual components and placebo or standard of care (SOC) therapy (AB v. A. v. B v. placebo or SOC) — will have limited utility. The following scenarios illustrate possible phase 2 study designs for combinations of two investigational drugs in different situations.Scenario 1: The components of the combination cannot be administered individually259 260261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278If in vivo or in vitro models, or phase 1 or other early clinical studies make clear that the components of the combination cannot be administered individually in clinical trials inthe disease of interest (e.g., because such testing would involve administering treatment known to be ineffective as monotherapy), or can’t be administered as monotherapy forthe duration needed to evaluate effectiveness (e.g., because of rapid development ofresistance), proof-of-concept evidence for the combination ordinarily should come froma study directly comparing the combination (AB) to SOC. Alternatively, if SOC isknown to be an effective therapy (not solely palliative), an add-on design could be used comparing the combination plus SOC to SOC alone.In some resistance scenarios, it may be possible to administer the individual drugs in acombination as monotherapy for a short duration, but long enough to establish proof ofconcept in humans. For example, direct-acting antivirals (DAAs) to treat chronichepatitis C virus infection can be administered as monotherapy for three days to establish antiviral activity and for initial dose exploration. For DAA studies of longer duration, the combination should be used or the individual components should be added to an activecontrol.55 See draft guidance for industry: Chronic Hepatitis C Virus Infection: Developing Direct-Acting Antiviral Agents for Treatment (section III. 4. b. – Phase 1b (proof-of-concept) trials) or consult the Division of Antiviral Drug Products in CDER for more specific recommendations.279 280 281 282 283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 298 299 Scenario 2: Each drug alone has activity and can be administered individuallyIf in vivo or in vitro models, or phase 1 or other early clinical studies indicate that each drug has some activity, but the combination appears to have greater than additive activity, and rapid development of resistance is not a concern, a four-arm, phase 2 trial comparing the combination to each drug alone and to placebo or SOC (AB v. A v. B v. SOC or placebo6) should be used to demonstrate the contribution of the components to the combination and proof of concept. As noted above, if SOC is a known effective therapy, a study design in which each of the arms is added to SOC could be used (AB + SOC v. A + SOC v. B + SOC v. placebo + SOC).An adaptive trial design with the same four treatment arms might also be used where appropriate, initially using the treatment arms described above. The single-drug arms could be terminated early if it became clear that they had much less activity than the combination. These designs could demonstrate the activity of each component of (i.e., the contribution of each component to the combination) without exposing the large numbers of patients typically required for phase 3 trials to therapeutic products with inadequate activity. For these trials, it may not be necessary to use a clinical endpoint as a primary efficacy measurement. A credible pharmacodynamic or other biomarker, such as tumor response, may be adequate.300 301 302 303 304 305 306 307 308 309 310 311 312 313 314 315 316 317 318 Scenario 3: One drug is active alone and one is inactiveIf in vivo or in vitro models, or phase 1 or other early clinical studies suggest that one of the drugs is inactive or minimally active and one drug is modestly active, but the combination has substantial activity, the more active drug generally will require greater scrutiny and should ordinarily be studied as a single drug in a phase 2 study. The minimally active drug generally would not require study as a single drug beyond initial phase 1 safety studies. In this scenario, proof of concept and the contribution of each component could be demonstrated using a three-arm comparison of the active drug alone, SOC, and the combination (AB v. A v. SOC), or the combination and the individual drug added to SOC where SOC is a known effective therapy (AB + SOC v. A + SOC v. SOC). If the inactive drug in a combination is a pharmacokinetic or metabolic enhancer that contributes to the activity of the combination only by increasing the therapeutic concentrations of the active drug, human pharmacokinetic data may provide adequate evidence to support the enhanced activity of the combination and demonstrate the contribution of the inactive drug. A confirmatory study of the combination would usually be needed to provide evidence of effectiveness for the combination (see section V.D). Dose Finding319 320321 322Dose-finding studies could be very important to refine the combination dose or doses and select doses for phase 3 trials. Depending on the role of each component, it may be6 Note that the placebo arm is intended to show the effect size compared to non-treatment, not to show the contribution of each component.323 324 325 326 327 328 329 330 331 332 333 334 335 336 337 338 339 340 341 342 343 344 345 346 347 348 349 350 351 352 353 354 355 356 357 358 359 360 361 362 363 364 365 366 367useful to test multiple doses of both components to establish a best dose in terms of risks and benefits. If one component in a two-drug combination is more active than the other, it may be more important to study multiple doses of the more active drug (as part of thecombination). For the same reason, it may be more important to study multiple doses ofa drug that is significantly more toxic than the other component of the combination.Other study designs and types of studies also may be appropriate.D. Confirmatory Studies (Phase 3)If findings from in vivo or in vitro models and/or phase 2 trials adequately demonstrate the contribution of each component to the combination, phase 3 trials comparing the combination to SOC or placebo generally will be sufficient to establish effectiveness. If the contribution of the individual components is not clear and it is ethically feasible to use a component or components of the combination as monotherapy in a study arm, it may be necessary to demonstrate the contribution of the components in phase 3 studies (e.g., by use of a factorial design). For example, if phase 2 data do not provide sufficient evidence of the contribution of each component of a two drug combination, but provide strong evidence that the combination is superior to one of the components, a phase 3 trial comparing the combination to the more active component alone and SOC may be needed to demonstrate that the less active component contributes to the activity of the combination. In this and other situations, it will often be useful to study more than one dose of the more active drug in phase 3 studies.Unexpected toxicity (e.g., serious adverse events observed at higher than expected rates) in phase 2 trials is a potential complication for development of a combination and progressing to phase 3 trials. If the toxicity can be attributed to one component of the combination, it may be possible to conduct phase 3 trials with the combination using a lower dose or doses of the more toxic component. If the toxicity cannot be attributed to an individual component of the combination, additional studies may be needed to identify the more toxic component and appropriate dosing for the combination before initiating phase 3 trials. The specifics of any phase 3 design should be discussed with the appropriate FDA review division at an End-of-Phase 2 meeting.VI. REGULATORY PROCESS ISSUES IN CODEVELOPMENTSponsors should consider a number of regulatory issues when planning the codevelopment of two or more novel drugs for use in combination. Key issues are outlined below.A. Early Interaction with FDASponsors are encouraged to communicate as early as possible (e.g., pre-IND meeting) with the appropriate FDA review division when considering codevelopment of innovative combination therapy. Sponsors also are encouraged to consult FDA frequently throughout the development process. We believe such communication will help facilitate development of the combination therapy.368 369 370 371 372 373 374 375 376 377 378 379 380 381 382 383 384 385 386 387 388 389 390 391 392 393 394 395 396 397 398B. IND Submissions and Marketing ApplicationsDecisions about the type of IND submission(s) and marketing application(s) needed (e.g., individual component submissions, combination submission) will depend on the sponsor's overall codevelopment and marketing strategy. Until FDA has more experience with codevelopment, FDA recommends that these decisions be made on a case-by-case basis in consultation with the appropriate review division.C. Labeling IssuesFDA also anticipates that the content of labeling for the combination and/or the components will be case specific, depending on the nature of the combination, the intended uses of the individual components, the marketing strategy, and other factors. Therefore, FDA does not believe it can provide generally applicable labeling guidance at this time. Again, we recommend consultation with the appropriate review division.D. PharmacovigilanceApplicants should develop a pharmacovigilance plan that takes into account the additional postmarket risks presented by initial marketing of two or more previously unapproved drugs for use in combination (compared to risks associated with marketing of a single drug). Risk will vary, depending on the nature of the combination and how the combination is marketed. The risk assessment should consider, among other things:•Potential for use of each drug individually;•Potential for use of any of the components of the combination in combinations with other drugs; and•Drugs likely to be co-administered with the combination.Applicants should discuss their pharmacovigilance plans with the appropriate review division and the Office of Surveillance and Epidemiology.。

11-07-0200-00-000u-tg-u-closing-report-2007

January 2007
doc.: IEEE 802.11-07/0200r0
TGu Closing Report
Date: 2007-01-18 Authors:
Name Stephen McCann Company Roke Manor Research Ltd (A Siemens Company) Address Roke Manor Research Ltd Old Salisbury Lane Romsey Hampshire SO51 0ZN UK Phone +44 1794 833341 email stephen.mccann@roke.co. uk
Patent Policy and Procedures: The contributor is familiar with the IEEE 802 Patent Policy and Procedures <http:// /guides/bylaws/sb-bylaws.pdf>, including the statement "IEEE standards may include the known use of patent(s), including patent applications, provided the IEEE receives assurance from the patent holder or applicant with respect to patents essential for compliance with both mandatory and optional portions of the standard." Early disclosure to the Working Group of patent information that might be relevant to the standard is essential to reduce the possibility for delays in the development process and increase the likelihood that the draft publication will be approved for publication. Please notify the Chair <stuart@> as early as possible, in written or electronic form, if patented technology (or technology under patent application) might be incorporated into a draft standard being developed within the IEEE 802.11 Working Group. If you have questions, contact the IEEE Patent Committee Administrator at <patcom@>.
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Next-Generation Embedded Java Operating System forSmart CardsLaurent LagosantoGemplus Software Research Labs,BP 100, 13881 Gemenos cedex, FrancePhone: +33 (0)4 4236 4196, Fax: +33 (0)4 4236 5555lago@Abstract. This paper deals with both the development and productionenvironments needed for future smart cards. Both are considered with asoftware-engineering standpoint. This approach results in an embedded Javaoperating system dedicated to support micro-server operations thanks topowerful Java and operating system features described in the first part of thispaper. The second part of this paper describes the Java embedded operatingsystem architecture and the production tools that enable a migration path from adevelopment platform up to a mass-produced and customized platform. IntroductionWhen the first Java Card specifications where issued, the card chips where roughly 8051-like derivatives (8-bits) with a few hundred of bytes of RAM and a few kilo bytes of EEPROM. These server constraints led the Java Card Forum and Sun to issue a specification [1] that had a lot of limitations compared to standard Java. This specification does not specify an operating system but an execution environment that every player in the smart card industry is able to implement on top of his own proprietary operating system.The silicon market evolution seems to indicate that next generation products will be based on much more powerful machines (32bit, RISC, Cache are becoming common in chip catalogs). The smart card industry, through the Java Card Forum, has clearly identified this evolution and has started initiatives like the Java Card 3.0 specification process that aim to define the next generation version of Java Card adapted to next generation hardware.Concurrently with this hardware evolution, Java has also evolved a lot. It is no more limited to the desktop environment and is now present in both the server market (with J2EE) and in the embedded market (with J2ME). This evolution brought interesting features to the Java platform: techniques for running long-lived applications are common on the server-side, and the minimal Java subset applicable to categories of devices has been defined with the J2ME configurations [2].The purpose of this paper is to have an overview of what can be considered now as the minimal Java features that can be integrated to modern smart card hardware and how these features can be turned into a card Operating System that cope with the smart card industry particular constraints like mass-production, personalization, post-issuance. The reason for targeting an operating system instead of an additional software layer like it’s done in the PC world with standard JDK is to use Java as the unique hardware abstraction for applications without intermediate levels, to reduce the footprint and maximize efficiency.2 Gemplus Developer Conference 2002The rest of this paper is organized as follows: the first section describes the desirable features for a Java OS and the second section explains how they are engineered in different platform configurations.Java Operating System FeaturesThe Java platform is defined in two separate specifications: the Java Virtual Machine Specification [3] and the Java Language Specification [4]. In the context of operating system these specifications are only relevant at the execution environment level, thus the selection of the Java OS features is guided by the classical needs of an operating system: code loading/linking, execution engine and memory management.The code delivery format: the Java Class fileThe class file is defined in the JVM spec [3], as the delivery format for the code of classes to load into a Java VM. This format is considered to be verbose and not compact, but it has some other properties that provide a maximal flexibility, both for development, deployment, and application code update. Other formats such as the Java Card 2.x CAP file or the JEFF file format [5] are focusing on file size reduction using techniques like linking information removal or file structure reorganization. These techniques have good result in size reduction but induce deployment/development constraints depending on the degree of size reduction. For example a CAP file can be 10% the size of the equivalent set of class files, but it requires an off-card conversion step for the developer and to maintain off-card a database of linking information to perform off-card pre-linking, which is a painful task for deployment and card management..We argue that on-card class file processing that provides the same reduction ratio as the JEFF conversion (50% reduction). The loading process can then be similar to the following figure:Figure 1: code loading/linking as a pipelined processNext-Generation Embedded Java Operating System for Smart Cards 3 Since the load/link operation occurs only once in the life-time on the class, we think that the development/deployment/interoperability benefits brought by loading standard class files are worth the effort of loading the class file in its entirety and applying an on-board conversion process that enables to store in card memory a structure equivalent to 50% of the original class file size.One of the main industrial advantage of choosing the class file and defining your own conversion process is that it provides freedom for differentiation: every card manufacturer can choose an internal format adapted to his own particular constraints. The Multithreaded Execution EngineThe Java platform has native support for multithreading and synchronization, and even in the lowest configurations defined for the embedded market like CLDC [6], this support is maintained. One may think that for embedded and resource constrained devices the support for multithreading may be too heavy to be reasonable. Actually, there are several reasons to keep multithreading support in the core of a very small Java operating system. The main reason is that it enables to write powerful application frameworks on top of the OS, in Java, without needing complex native modifications of the OS like it has happen when the SIMToolkit application model [7] has been introduced in Java Card. There are also obvious “classical” reasons to use threads that are extensively described in the literature [8]In such memory-limited devices as smart cards, the VM implementers must carefully choose an efficient and resource-saving implementation of the multithreading support. The existence of Java application only on top of a Java operating system, collaborating with native code and not with native applications like in a desktop PC seems to favors a green-thread like implementation rather than a native-thread implementation.Unified Memory Management: a Garbage Collector for Java and System Objects One very popular feature of the JVM is the automatically garbage-collected heap that is used to allocate Java objects when they are created, letting the burden of compacting, moving, freeing the memory to the system instead of the developer.This feature was missing in the Java Card specification and thus leads the developer of complex applications to develop their own memory management routines within the application code, written in Java. This is typically a failure of the Java Card to behave as an OS: the applications shouldn’t handle such sensitive task. There are several types of Garbage Collectors but the ones that seem the more appropriate to smart card-like environments are the generational collectors. This type of collector are well adapted to server-like long-lived applications which is typically the case of smart card applications.Traditionally, the memory management for object instances is separated from the memory management of system data like classes description, code, threads. This usually leads to complexity, bigger footprint of the memory management and static segmentation of the memory. We are experimenting an alternative to such a split organization that is to use a unified object-oriented memory manager that handles both applications and system objects. In this scheme, everything in the system is an object, including Java object instances, code, loaded classes, and every object in the system is subject to garbage collection.This unified memory management leads to a simpler management code, which is then probably smaller and more robust.4 Gemplus Developer Conference 2002Allowing Many Different Application ModelsAll the previous features of the JVM described above have a common objective: put in the OS the functionality that will make smaller and more efficient applications. One great strength of Java that was lost in Java Card and that we think must be reconsidered for next generation smart card OS is to be application model independent: the JVM doesn’t specify a particular application model, but provides all the core features that are necessary to build various successful frameworks such as Applets, Servlets or RMI Objects.Platform ConfigurationsThe smart card application and system designers and developers have considerations that are very similar to the people working in the mass-production embedded devices market: how to debug quickly/safely the OS and the applications, how to build quickly a product configuration, and how to decline an OS in a product range to leverage the investment. Furthermore, the smart card industry has his own particularities like for instance the need for personalization of every issued card with the holder information. Development IssuesThe use of Java is in itself the beginning of a solution for some of these problems, because of the wide range of products freely or commercially available to help designers and developers. But the high safety exigency on smart-card products implies that a maximum effort must be made on any tools that would allow the developers to operate in an environment as close as possible to the actual device. Debugging the code while it runsProduction IssuesOther tools are needed in the production and personalization phase of the cards. The ROMizer intervenes at the production step, to generate the code to mask into the chip’s ROM. It is complemented by the Memory Serializer which is used to build memory images stored in files, that will be sent to the card at initialization and personalization time to build the right memory structure that will put the card in the right state. Such tools are usually difficult to write and to maintain, but these tasks can be greatly simplified using the introspection capabilities provided by the unified object-oriented memory management introduced above.Next-Generation Embedded Java Operating System for Smart Cards 5A Configurable Integrated Operating SystemA solution to minimize the cost of these tools is to build an operating system that includes them from the beginning, in a configurable manner, and that can be declined from the same set of sources in different editions adapted to the targeted device. Such a configurable OS is illustrated in the following figure.C ode O ptimizer Perform ance featureF eature categories:Figure 2: A configurable operating systemFor example, a “developer edition” of the OS would include any developer features like an embedded debugging interface based on the JPDA standard [9], a shell-based console to administer the OS (load/remove classes, create threads,…). Such a complete edition would of course run on PC and on emulators only, not on real cards. Another declination would be the “post-issuance enabled edition” that would be the high-end embeddable version of the OS, targeted for high-end cards with post-issuance facilities (with a loader/linker). On the other extremity would be the “minimal edition”, targeted for low-end cards, without any post-issuance capabilities, that would have a much smaller footprint.ConclusionIn this paper we have highlighted some features of an embedded Java operating system suitable for next-generation smart cards considered as Java micro-server platforms. Three important Java operating system characteristics have been described (class file format acquisition, multithreading support, and a unified memory management). Their implementation has been shown feasible, and their usage and benefits has been described in the context of a configurable card platform architecture. Thanks to tools such as shell console, debugger, ROMizer and serializer, the migration path from a rich platform configuration up to a customized platform configuration has been explained.The overall benefit of this embedded Java operating system architecture is its adaptability for being used, on one hand as a full-fledge Java environment to rapidly develop and test applications, and on another hand as an engineering environment for mass-production of optimized embedded code hosted by limited devices. Though6 Gemplus Developer Conference 2002originally developed in the context of smart cards, such an architecture could be suitable in any embedded device in which the Java development platform can differ from the final Java deployment platform.References[1][2][3] Java Virtual Machine Specification,[4] Java Language Specification,[5][5][6][7] Concurrent Programming in Java. D. Lea. Sun Microsystems, 1999.ISBN 0-201-31009-0, Addison-Wesley[8]。

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